INTRODUCTION: In Japan, evacuation at home is expected to increase in the future as a post-disaster evacuation type due to the pandemic, aging, and diverse disabilities of the population. However, more disaster-related indirect deaths occurred in homes than in evacuation centers after the 2011 Great East Japan Earthquake (GEJE). The health risks faced by evacuees at home have not been adequately discussed. STUDY OBJECTIVE: This study aimed to clarify the gap in disaster health management for evacuees at home compared to the evacuees at the evacuation centers in Minamisanriku Town, which lost all health care facilities after the 2011 GEJE. METHODS: This was a retrospective cross-sectional and quasi-experimental study based on the anonymized disaster medical records (DMRs) of patients from March 11 through April 10, 2011, that compared the evacuation-at-home and evacuation-center groups focusing on the day of the first medical intervention after the onset. Multivariable Cox regression analysis and propensity score (PS)-matching analysis were performed to identify the risk factors and causal relationship between the evacuation type and the delay of medical intervention. RESULTS: Of the 2,838 eligible patients, 460 and 2,378 were in the evacuation-at-home and evacuation-center groups, respectively. In the month after the onset, the evacuation-at-home group had significantly lower rates of respiratory and mental health diseases than the evacuation-center group. However, the mean time to the first medical intervention was significantly delayed in the evacuation-at-home group (19.3 [SD = 6.1] days) compared to that in the evacuation-center group (14.1 [SD = 6.3] days); P <.001). In the multivariable Cox regression analysis, the hazard ratio (HR) of delayed medical intervention for evacuation-at-home was 2.31 with a 95% confident interval of 2.07-2.59. The PS-matching analysis of the adjusted 459 patients in each group confirmed that evacuation at home was significantly associated with delays in the first medical intervention (P <.001). CONCLUSION: This study suggested, for the first time, the causal relationship between evacuation at home and delay in the first medical intervention by PS-matching analysis. Although evacuation at home had several advantages in reducing the frequencies of some diseases, the delay in medical intervention could exacerbate the symptoms and be a cause of indirect death. As more evacuees are likely to remain in their homes in the future, this study recommends earlier surveillance and health care provision to the home evacuees.

INTRODUCTION: Health workforce development is essential for achieving the goals of an effective health system, as well as establishing national Health Emergency and Disaster Risk Management (Health EDRM). STUDY OBJECTIVE: The objective of this Delphi consensus study was to identify strategic recommendations for strengthening the workforce for Health EDRM in low- and middle-income countries (LMIC) and high-income countries (HIC). METHODS: A total of 31 international experts were asked to rate the level of importance (one being strongly unimportant to seven being strongly important) for 46 statements that contain recommendations for strengthening the workforce for Health EDRM. The experts were divided into a LMIC group and an HIC group. There were three rounds of rating, and statements that did not reach consensus (SD ≥ 1.0) proceeded to the next round for further ranking. RESULTS: In total, 44 statements from the LMIC group and 34 statements from the HIC group attained consensus and achieved high mean scores for importance (higher than five out of seven). The components of the World Health Organization (WHO) Health EDRM Framework with the highest number of recommendations were "Human Resources" (n = 15), "Planning and Coordination" (n = 7), and "Community Capacities for Health EDRM" (n = 6) in the LMIC group. "Policies, Strategies, and Legislation" (n = 7) and "Human Resources" (n = 7) were the components with the most recommendations for the HIC group. CONCLUSION: The expert panel provided a comprehensive list of important and actionable strategic recommendations on workforce development for Health EDRM.

Disaster endangers the nutritional health of children with resulting effects on their mental, physical, and social well-being. Adequate infant and young child feeding (IYCF) in disaster prevents malnutrition and save lives. Although much progress has been made in nutritional support in disaster, malnutrition among children is still evident. This scoping review study was conducted to identify gaps in child nutrition in disaster. Published articles (1946-2020) in PubMed were sought primarily and were assessed with some additional relevant articles. Overall, 103 articles were included in the scope of this review. Increased morbidity and mortality from malnutrition (macro- and micro-nutrient deficiencies), communicable diseases and mental health issues are nutritional effects of disaster. Pre-disaster malnutrition, food insecurity, living environments in shelters, poor breast-feeding practices, sociocultural factors, and organizational and administrative challenges strongly affect child nutrition in disaster. The efforts and collaboration of relief agencies resulted in the development of standardized guidelines and codes represented as the Sphere Project and Operational Guideline for IYCF in Emergency. This study recommends a well-coordinated and explicit approach that includes preparedness, advocacy, development/updating of policies, and education of children, family and relief aid workers on nutrition. Periodic nutritional assessment of children and nutritional support in disaster by designated IYCF authority are necessary. Education and participation of the general population are also important. Future assessments must examine food allergies in children and nutrition effects on child mental health in disaster.

膵癌登録は日本膵臓学会が行っている膵腫瘍症例の全国登録事業であり、1981年に開始され今年で40年を迎える。2012年にはNational Clinical Database(NCD)に実装され現在はNCDを用いて症例登録がなされている。NCD膵癌登録ではそれ以前の旧登録データと比較し、内科系施設からの登録が少ないという大きな課題を有している。近年発足した日本膵臓学会認定指導医制度の施設認定の条件に膵癌登録の登録件数が盛り込まれ、最近5年間のNCD膵癌登録症例数が年間平均ほぼ20例以上であることが求められている。今後ゲノム医療の発展に伴い、遺伝子異常に関連した診療情報を登録項目に含めることについて近い将来議論が必要になると考えられる。遺伝子変異に関する診療情報を登録するにはオプトアウト方式からオプトイン方式による登録変更が必要になると考えられ、最高レベルの情報漏洩対策が要求される。(著者抄録)

The Sendai Framework for Disaster Risk Reduction 2015-2030 placed human health at the centre of disaster risk reduction, calling for the global community to enhance local and national health emergency and disaster risk management (Health EDRM). The Health EDRM Framework, published in 2019, describes the functions required for comprehensive disaster risk management across prevention, preparedness, readiness, response, and recovery to improve the resilience and health security of communities, countries, and health systems. Evidence-based Health EDRM workforce development is vital. However, there are still significant gaps in the evidence identifying common competencies for training and education programmes, and the clarification of strategies for workforce retention, motivation, deployment, and coordination. Initiated in June 2020, this project includes literature reviews, case studies, and an expert consensus (modified Delphi) study. Literature reviews in English, Japanese, and Chinese aim to identify research gaps and explore core competencies for Health EDRM workforce training. Thirteen Health EDRM related case studies from six WHO regions will illustrate best practices (and pitfalls) and inform the consensus study. Consensus will be sought from global experts in emergency and disaster medicine, nursing, public health and related disciplines. Recommendations for developing effective health workforce strategies for low- and middle-income countries and high-income countries will then be disseminated.

背景:慢性膵炎は内科治療が困難な際に手術適応があるが、その至適時期については、明らかにされていない。目的:慢性膵炎手術症例において術前の有病期間と術後成績を解析し、手術の至適時期を検討する。方法:2005年1月〜2016年4月に当科で慢性膵炎に対し、膵管ドレナージ術を施行した50症例を、発症から手術までの期間が5年未満の早期群と5年以上の晩期群に分け、その成績を検討した。結果:患者背景、手術成績、周術期成績は両群間で有意差は認めなかった。疼痛は両群ともに有意に改善した。手術前後で栄養状態は両群ともに改善を認め、両群間で有意差は認めなかった。新規の糖尿病や膵癌発症は認めなかった。結論:膵管ドレナージ術は罹患期間に関わらず有用であった。手術成績に差がないことから、内科的治療に抵抗性となった場合、早期手術は有病期間を減じ、QOLを改善することが可能と思われる。(著者抄録)

背景:慢性膵炎は内科治療が困難な際に手術適応があるが、その至適時期については、明らかにされていない。目的:慢性膵炎手術症例において術前の有病期間と術後成績を解析し、手術の至適時期を検討する。方法:2005年1月〜2016年4月に当科で慢性膵炎に対し、膵管ドレナージ術を施行した50症例を、発症から手術までの期間が5年未満の早期群と5年以上の晩期群に分け、その成績を検討した。結果:患者背景、手術成績、周術期成績は両群間で有意差は認めなかった。疼痛は両群ともに有意に改善した。手術前後で栄養状態は両群ともに改善を認め、両群間で有意差は認めなかった。新規の糖尿病や膵癌発症は認めなかった。結論:膵管ドレナージ術は罹患期間に関わらず有用であった。手術成績に差がないことから、内科的治療に抵抗性となった場合、早期手術は有病期間を減じ、QOLを改善することが可能と思われる。(著者抄録)

During a disaster, all hospitals are expected to function as "social critical institutions" that protect the lives and health of people. In recent disasters, numerous hospitals were damaged, and this hampered the recovery of the affected communities. Had these hospitals business continuity plans (BCPs) to recover quickly after the disaster, most of the damage could have been avoided. This study conducted a scoping review of the historical trend and regional differences in hospital BCPs to validate the improvement of the BCP concept based on our own experience at Tohoku University Hospital, which was affected by the 2011 Great East Japan Earthquake and Tsunami (GEJET). We searched PubMed by using keywords related to BCP and adapted 97 articles for our analysis. The number of articles on hospital BCPs has increased in the 2000s, especially after Hurricane Katrina in 2005. While there are regional specificity of hazards, there were many common topics and visions for BCP implementation, education, and drills. From our 2011 GEJET experience, we found that BCPs assuming region-specific disasters are applicable in various types of disasters. Thus, we suggest the following integral and universal components for hospital BCPs: (1) alternative methods and resources, (2) priority of operation, and (3) resource management. Even if the type and extent of disasters vary, the development of BCPs and business continuity management strategies that utilize the abovementioned integral components can help a hospital survive disasters in the future.

In 2011, Minamisanriku Town lost all of its medical facilities during the Great East Japan Earthquake. Using 10,459 anonymized disaster medical records of affected people in Minamisanriku Town, we assessed the prevalence and risk factors of sleep disturbance, which is known to exacerbate non-communicable diseases (NCDs) and anxiety disorder. Because sleep disturbance is a part of mental health issues, we divided the patients into two groups: patients (n = 492) with mental health issues other than sleep disturbance and the remaining (n = 9,967) with other comorbidities. Out of 492 patients with mental health issues, 295 patients (60.0%, 114 male, 158 female and 23 unknown) had sleep disturbance who might have required specific treatments. Out of the remaining 9,967 patients, 1,203 patients (12.1%, 361 male and 769 female and 73 unknown) had sleep disturbance. Univariate and multivariate analyses of the 9,967 patients revealed that the odds ratio (OR) of sleep disturbance was higher for female (OR 1.95), elderly persons over 60 (OR 16.15) and residing in evacuation centers (OR 1.36). Patients with two or more NCD had higher risk (OR 1.42). Importantly, sleep disturbance affects younger patients without NCD residing in evacuation center. Emergency medical teams most frequently prescribed benzodiazepines both for sleep induction and anxiolysis. In addition to high risk groups (female, older, with other mental health issues, residing in evacuation center), it is important to survey sleep disturbance in younger and healthier populations especially in evacuation centers and to provide psychosocial and medical support for them.

: Leptospirosis becomes severe, with a fatality rate of &gt;10%, and manifests as severe lung injury accompanied by acute kidney injury. Using urine and blood samples of 112 patients with leptospirosis, osteopontin (OPN), galectin-9 (Gal-9) and other kidney-related biomarkers were measured to understand the pathological and diagnostic roles of OPN and Gal-9 in leptospirosis. Plasma levels of full-length (FL)-OPN (pFL-OPN) (p &lt; 0.0001), pFL-Gal-9(p &lt; 0.0001) and thrombin-cleaved OPN (p &lt; 0.01) were significantly higher in patients with leptospirosis than in healthy controls (n = 30), as were levels of several indicators of renal toxicity: serum cystatin C (p &lt; 0.0001), urine N-acetyl-β-glucosaminidase (NAG)/creatinine (p &lt; 0.05), and urine clusterin/creatinine (p &lt; 0.05). pFL-Gal-9 levels were negatively correlated with pFL-OPN levels (r = −0.24, p &lt; 0.05). pFL-OPN levels were positively correlated with serum cystatin C (r = 0.41, p &lt; 0.0001), urine NAG/creatinine (r = 0.35, p &lt; 0.001), urine clusterin/creatinine (r = 0.33, p &lt; 0.01), and urine cystatin C/creatinine (r = 0.33, p &lt; 0.05) levels. In a group of patients with abnormally high creatinine levels, significantly higher levels of serum cystatin C (p &lt; 0.0001) and pFL-OPN (p &lt; 0.001) were observed. Our results demonstrate that pFL-OPN reflect kidney injury among patients with leptospirosis.

BACKGROUND: Total pancreatectomy is required to completely clear tumours that are locally advanced or located in the centre of the pancreas. However, reports describing clinical outcomes after total pancreatectomy are rare. The aim of this retrospective observational study was to assess clinical outcomes following total pancreatectomy using a nationwide registry and to create a risk model for severe postoperative complications. METHODS: Patients who underwent total pancreatectomy from 2013 to 2017, and who were recorded in the Japan Society of Gastroenterological Surgery and Japanese Society of Hepato-Biliary-Pancreatic Surgery database, were included. Severe complications at 30 days were defined as those with a Clavien-Dindo grade III needing reoperation, or grade IV-V. Occurrence of severe complications was modelled using data from patients treated from 2013 to 2016, and the accuracy of the model tested among patients from 2017 using c-statistics and a calibration plot. RESULTS: A total of 2167 patients undergoing total pancreatectomy were included. Postoperative 30-day and in-hospital mortality rates were 1·0 per cent (22 of 2167 patients) and 2·7 per cent (58 of 167) respectively, and severe complications developed in 6·0 per cent (131 of 2167). Factors showing a strong positive association with outcome in this risk model were the ASA performance status grade and combined arterial resection. In the test cohort, the c-statistic of the model was 0·70 (95 per cent c.i. 0·59 to 0·81). CONCLUSION: The risk model may be used to predict severe complications after total pancreatectomy.

BackgroundWe established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environmental interactions on the incidence of major diseases such as cancer and cardiovascular diseases.MethodsWe asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria was aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), for example, carotid echography, calcaneal ultrasound bone mineral density, and so on. All participants agreed to measure genome information and to distribute their information widely.ResultsAs a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants with Type 1 survey were more likely to have psychological distress than those of Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents regardless of sex.ConclusionThis cohort comprised large sample size and it contains information on disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.

BACKGROUND: The importance of peritoneal washing cytology status both as a sign of irresectability and as a prognostic factor for pancreatic ductal adenocarcinoma remains controversial. The purpose of this nationwide, cancer registry-based study was to clarify the clinical implications of operative resection in patients who had positive cytology status. METHODS: Clinical data from 1,970 patients who underwent tumor resection were collected from the Pancreatic Cancer Registry in Japan. Clinicopathologic factors and overall survival curves were analyzed, and multivariate Cox proportional hazard models were evaluated. RESULTS: Among the 1,970 patients analyzed, positive cytology status was found in 106 patients and negative cytology status was found in 1,864 patients. The positive cytology status group had a greater frequency of pancreatic body and tail cancer and greater preoperative serum carbohydrate antigen 19-9 levels than the negative cytology status group (P < .001 each). The ratio of peritoneal recurrence tended to be greater in the positive cytology status group (14% vs 43%; P < .001). Overall median survival times were less in the positive cytology status group (17.5 months vs 29.4 months; P < .001). The 5-year survival rates were 13.7% and 31.1% in the positive cytology status and negative cytology status groups, respectively. Multivariate analysis of positive cytology status patients revealed that adjuvant chemotherapy was an independent prognostic factor. CONCLUSION: Positive cytology status was an adverse prognostic factor in patients who underwent resection for pancreatic ductal adenocarcinoma but did not preclude attempted curative resection. Curative resection followed by adjuvant chemotherapy may contribute to long-term prognosis in patients with positive cytology status.

The medical records of service in disaster provided at a place other than a medical facility are defined as disaster medical records (DMRs). In this epidemiological study, to clarify medical need characteristics and trends after disaster, we analyzed the all anonymized DMRs of Minamisanriku Town that lost medical facilities in 2011 Great East Japan Earthquake and its consequent tsunami. After screening of duplicated or irrelevant documents, there were 10,464 DMRs with 18,532 diagnoses from March 11 through May 13. From 34 diagnostic groups according to International Classification of Diseases (ICD)-10, we integrated diagnostic groups into five modules that might require treatment concepts of different types: non-communicable disease (NCD), infectious disease, mental health issue, trauma, and maternal and child health (MCH). Age and sex distributions of the patients were similar to those of population before the disaster. The largest diagnostic module was NCD (68%), followed by infectious disease (21%), mental health issues (6%), trauma (4%), and MCH (0.2%). The age-specific rate of NCD exhibited a similar or suppressed level from that of nationwide survey, with higher rate of pollinosis among young population. Infectious disease increased in most age groups but there was no apparent outbreak because of early interventions. Sleep deprivation was twice as frequent in middle-aged women, compared with men. Trauma and MCH were less frequent, but each exhibited a unique time trend. Trauma onset was continuously recorded, while MCH visits were concentrated on a specific day. The medical need after disaster dynamically changes, and appropriate anticipatory countermeasures are necessary.

OBJECTIVE: Pneumonia remains the leading cause of hospitalisations and deaths among children aged <5 years. Diverse respiratory pathogens cause acute respiratory infections, including pneumonia. Here, we analysed viral and bacterial pathogens and risk factors associated with death of hospitalised children. DESIGN: A 9-year case series study. SETTING: Two secondary-care hospitals, one tertiary-care hospital and one research centre in the Philippines. PARTICIPANTS: 5054 children aged <5 years hospitalised with severe pneumonia. METHODS: Nasopharyngeal swabs for virus identification, and venous blood samples for bacterial culture were collected. Demographic, clinical data and laboratory findings were collected at admission time. Logistic regression analyses were performed to identify the factors associated with death. RESULTS: Of the enrolled patients, 57% (2876/5054) were males. The case fatality rate was 4.7% (238/5054), showing a decreasing trend during the study period (p<0.001). 55.0% of the patients who died were either moderately or severely underweight. Viruses were detected in 61.0% of the patients, with respiratory syncytial virus (27.0%) and rhinovirus (23.0%) being the most commonly detected viruses. In children aged 2-59 months, the risk factors significantly associated with death included age of 2-5 months, sensorial changes, severe malnutrition, grunting, central cyanosis, decreased breath sounds, tachypnoea, fever (≥38.5°C), saturation of peripheral oxygen <90%, infiltration, consolidation and pleural effusion on chest radiograph.Among the pathogens, adenovirus type 7, seasonal influenza A (H1N1) and positive blood culture for bacteria were significantly associated with death. Similar patterns were observed between the death cases and the aforementioned factors in children aged <2 months. CONCLUSION: Malnutrition was the most common factor associated with death and addressing this issue may decrease the case fatality rate. In addition, chest radiographic examination and oxygen saturation measurement should be promoted in all hospitalised patients with pneumonia as well as bacteria detection to identify patients who are at risk of death.

PURPOSE: The Frey procedure is an effective surgery for chronic pancreatitis (CP) patients who have pancreatic head lesions with dilation of the main pancreatic duct. However, pancreatic tail lesions can cause relapsing pancreatitis after the procedure. Therefore, additional distal pancreatectomy (DP) might complement the therapeutic effect of the Frey procedure in controlling inflammation of the pancreatic tail. The Frey procedure with DP (Frey + DP) is indicated for inflammatory lesions in the pancreatic head and tail. In this study, we assessed the usefulness of Frey + DP using the retrospective clinical data of our cases. METHODS: The clinical outcomes were compared between CP patients who underwent the Frey procedure (N = 44) and Frey + DP (N = 13) from January 2005 to April 2016. RESULTS: Frey + DP showed similarly good therapeutic effects to the Frey procedure with regard to the postoperative stay, morbidity, mortality, pain relief and nutrition, although the Frey + DP had a longer operative time, more bleeding and higher incidence of diabetes mellitus than the Frey procedure because of the additional DP. One patient in the Frey group received additional DP because of recurrent pain due to the tail lesion. CONCLUSION: Frey + DP can be a promising treatment for CP patients with pancreatic head and tail lesions.

© 2018, Fuji Technology Press. All rights reserved. A healthy community is a community resilient to disaster. The Sendai Framework for Disaster Risk Reduction considers disaster impacts on health and encourages the implementation of disaster medicine and access to mental health services. Life expectancy (LE) is a basic statistic that indicates public health achievements and social development, including the health system, infrastructure, and accurate vital statistics. Thus, we hypothesized that LE corelates with disaster risk and strategies to achieve long LE can help achieving disaster risk reduction. We compared the disaster risk obtained from Index for Risk Management (IN-FORM) with the LE of both genders at birth to identify which component of INFORM risk correlates with LE. A correlation analysis revealed that overall INFORM risk negatively correlated with LE. The natural hazard category did not correlate with LE, but the human hazard category, vulnerability, and lack of coping capacity negatively correlated with LE. In the vulnerability dimension, indicators of socioeconomic vulnerability, health conditions, and children U5 negatively correlated with LE. In the lack of coping capacity dimension, indicators of communication, physical infrastructure, and access to health care negatively correlated with LE. Japan has achieved the longest LE and a low INFORM risk because of its lower vulnerability and reduced lack of coping capacity, including healthrelated indicators. In a cluster analysis of LE and INFORM categories of risk, we divided countries into four clusters and found categories that could be improved. Compared with another global disaster risk index, the Word Risk Index (WRI), the INFORM risk index seems to represent the overall disaster risk better, though they have different aspects of risk evaluation. The WRI is also negatively correlated with LE, supporting our hypothesis. In conclusion, LE is an important indicator of disaster risk and strategies to achieve long LE can be effective and important strategies in disaster risk reduction.

【目的】日本膵臓学会膵癌登録におけるT1膵癌について解析したので報告する。【対象と方法】2001年から2013年までに登録された通常型膵癌20,226例のうち、膵癌取扱い規約第7版に基づきT1症例777例を解析対象とした。T1a(≦5mm)、T1b(5mm<、≦10mm)、T1c(10mm<、≦20mm)に分けて臨床病理学的因子や予後について検討した。【結果】T1aは16例(2.1%)、T1bは126例(16.2%)、T1cは635例(81.7%)であった。T1aとT1bの5年生存率はそれぞれ73.8%、62.4%で両者に有意差はなかった。T1cの5年生存率は47.9%でT1bと比較して有意に不良であった(P=0.0255)。T1aとT1bを合わせた10mm以下T1の5年生存率は63.1%で、それ自体の予後は良好とはいえないが、T1cと比較すると有意に良好であった(P=0.0196)。【結語】10mm以下の膵癌であっても予後は満足すべきものではなく、治療成績をさらに向上させていく必要がある。(著者抄録)

Along with large-scale loss of life, infrastructural damage, and material losses, health issues have become a crucially important problem after natural disasters. Survivors must confront the threat of health risks, especially infectious diseases, as a result of limited health supplies, services, and facilities. Limited knowledge about health risks following disasters, in addition to lack of awareness, contributes to the occurrence of infectious diseases that are fundamentally preventable. This study was conducted to review eight major natural disasters in Indonesia that were followed by outbreaks of infectious disease. Results emphasize the importance of integrated health education in schools and community-based disaster risk reduction (DRR) plans, including information dissemination, to create resilient communities. Water-borne and air-borne infectious diseases were the most common illnesses following the eight major natural disasters as a result of aftereffects. Facing the challenges, schools and community centers can be agents to disseminate health promotion information so that people become more aware of health risks and conduct good practices related to prevention, response, and recovery. Health education and promotion can be integrated into curriculum-based or training-based DRR programs as modules, short courses, drills, and printed and visual media.

Healthcare workers (HCWs) are often exposed to nosocomial infection when caring for patients with Ebola Virus Disease (EVD). During the 2014-2016 EVD outbreak in West Africa, more than 200 HCWs died of EVD in Sierra Leone. To determine the factors that are important for preventing infection among HCWs during EVD outbreak, we used agent-based modeling and simulation (ABMS) by focusing on education, training and performance of HCWs. Here, we assumed 1, 000 HCWs as "agents" to analyze their behavior within a given condition and selected four parameters (P1-P4) that are important in the prevention of infection: "initially educated HCWs (P1)", "initially educated trained (P2)", "probability of seeking training (P3)" and "probability of appropriate care procedure (P4)." After varying each parameter from 0% to 100%, P3 and P4 showed a greater effect on reducing the number of HCWs infected during EVD outbreak, compared with the other two parameters. The numbers of infected HCWs were decreased from 897 to 26 and from 1,000 to 59, respectively, when P3 or P4 was increased from 0% to 100%. When P2 was increased from 0% to 100%, the number of HCWs infected was decreased from 166 to 44. Paradoxically, the number of HCWs infected was increased from 56 to 109, when P1 was increased, indicating that initial education alone cannot prevent nosocomial infection. Our results indicate that effective training and appropriate care procedure play an important role in preventing infection. The present model is useful to manage nosocomial infection among HCWs during EVD outbreak.

OBJECTIVE: Noncommunicable diseases (NCDs), including mental disorders, have become major threats to human health worldwide. People with NCDs are particularly vulnerable to disasters. We systematically reviewed reports describing studies of NCDs at the time of the Great East Japan Earthquake (GEJE) to clarify the circumstances of people with NCDs and to build strong measures to support them. METHODS: Relevant articles published from March 2011 through December 2016 were collected by searching the PubMed database (National Library of Medicine). We specifically examined reports describing NCDs and including the key words "East Japan Earthquake." NCDs included every disease type aside from injury and infectious disease. RESULTS: We collected 160 relevant articles, 41 of which described NCDs that existed in residents before the GEJE. Articles describing respiratory diseases and mental illnesses were found most frequently. Interruption of regular treatment was the most frequent problem, followed by lack of surveillance capacity. We found 101 reports describing NCDs that had developed after the GEJE, of which 60% were related to mental health issues. CONCLUSIONS: NCDs pose major health issues after large-scale disasters. Establishment of strong countermeasures against interruption of treatment and surveillance systems to ascertain medical needs for NCDs are necessary to prepare for future disasters. (Disaster Med Public Health Preparedness. 2018; 12: 396-407).

慢性膵炎に対するFrey手術(膵頭部芯抜きを伴う膵管空腸側々吻合術)は、主膵管径が5mm以上あるときに適応となり、手術侵襲も少なく疼痛除去効果に優れた術式である。Frey手術後の再燃は、十分にドレナージされない膵管が残存することが理由で、アルコール性や特発性など成因の除去が困難な場合に起きる。膵尾部での再燃がもっとも多く、膵尾部切除を再手術時あるいは初回手術時に併施するのが治療あるいは再燃予防になる。Frey手術によって炎症が沈静化することは残膵の膵癌発生予防に寄与するので、内科的治療で慢性膵炎がコントロールできない揚合は、漫然と治療を継続せずすみやかに外科治療に移行すべきである。Frey手術後は、膵内外分泌機能の補充により、膵性糖尿病、低栄養の発生を予防しながら、残膵病変の有無を定期的に長期間フォローアップすることが肝要である。(著者抄録)

We investigated the efficacy of a Wilms' tumor gene 1 (WT1) vaccine combined with gemcitabine (GEMWT1) and compared it with gemcitabine (GEM) monotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) in a randomized phase II study. We randomly assigned HLA-A*02:01- or HLA-A*24:02-positive patients with advanced PDAC to receive GEMWT1 or GEM. We assessed WT1-specific immune responses via delayed-type hypersensitivity (DTH) to the WT1 peptide and a tetramer assay to detect WT1-specific cytotoxic T lymphocytes (WT1-CTL). Of 91 patients enrolled, 85 were evaluable (GEMWT1: n = 42; GEM: n = 43). GEMWT1 prolonged progression-free survival [PFS; hazard ratio (HR), 0.66; P = 0.084] and improved overall survival rate at 1 year (1-year OS%; GEMWT1: 35.7%; GEM: 20.9%). However, the difference in OS was not significant (HR: 0.82; P = 0.363). These effects were particularly evident in metastatic PDAC (PFS: HR 0.51, P = 0.0017; 1-year OS%: GEMWT1 27.3%; GEM 11.8%). The combination was well tolerated, with no unexpected serious adverse events. In patients with metastatic PDAC, PFS in the DTH-positive GEMWT1 group was significantly prolonged, with a better HR of 0.27 compared with the GEM group, whereas PFS in the DTH-negative GEMWT1 group was similar to that in the GEM group (HR 0.86; P = 0.001). DTH positivity was associated with an increase in WT1-CTLs induced by the WT1 vaccine. GEM plus the WT1 vaccine prolonged PFS and may improve 1-year OS% in advanced PDAC. These clinical effects were associated with the induction of WT1-specific immune responses. Cancer Immunol Res; 6(3); 320-31. ©2018 AACR.

切除を企図して治療を開始したBorderline resectable(BR)膵癌163例を対象とし、術前治療(N群)86例(男性49例、女性37例、中央値66歳)、手術先行(S群)77例(男性39例、女性38例、中央値69歳)であった。術前治療は86例に施行され、Gemcitabine+S1併用(GS)療法による化学療法63例、S1併用化学放射線療法(CRT)15例、両者の逐次併用が7例であった。ITT解析でN群の5年生存率は26%で、S群の12%に比べ有意に良好であった。S群の全生存期間中央値は14.7ヵ月で、切除50例の無再発生存期間中央値は11.7ヵ月であった。単変量解析で、治療開始前因子から予後予測因子を抽出すると、腫瘍径、SUVmaxが有意な因子として抽出された。多変量解析を行うと、SUVmaxのみが独立した予後因子として抽出された。

© 2017, Springer Japan KK. Purpose: The aim of surgical intervention for chronic pancreatitis (CP) is to relieve symptoms and improve quality of life. However, the precise effect of surgery on the nutritional status of CP patients, which is often impaired by exocrine and endocrine pancreatic dysfunction, has not been elucidated. We conducted this study to evaluate whether Frey’s procedure improves the nutritional status of CP patients. Methods: The nutritional status of 35 patients who underwent Frey’s procedure for CP at our institute between April 2005 and December 2014, was assessed by the controlling nutritional status (CONUT) scoring before and 1 year after the surgery, and compared with that of seven CP patients who underwent pancreatoduodenectomy. The occurrence of postoperative hepatic steatosis was also monitored. Results: The nutritional status improved after Frey’s procedure, but not after pancreatoduodenectomy. The median postoperative CONUT score after Frey’s procedure was significantly lower than the preoperative score (1.0 ± 0.5 vs. 4.0 ± 2.5; p &lt; 0.001). Conclusion: Frey’s procedure is superior to pancreatoduodenectomy for improving the nutritional status of CP patients.

© 2018, Springer International Publishing AG. After the Great East Japan Earthquake (GEJE) and Tsunami in 2011, the physical and mental health of the affected people showed completely different characteristics from those of earlier disasters. Despite the lower number of injured people compared to those affected by the Great Hanshin Awaji Earthquake (GHAE) in 1995, the health needs were mainly non-communicable diseases and mental health issues. Those needs far exceeded the damaged state of local health care facilities. The nationwide disaster medical system established after GHAE worked fully for the first time, but further improvements of the response system, such as implementation of a disaster medical and public health coordinator, more efficient emergency medical information systems, and the establishment of specialized health care assistance teams including psychiatry, rehabilitation, reproductive health, public health, and oral care, were found to be necessary after GEJE. Reconstruction of the damaged hospitals should be based on the safe hospital concept and the prioritized parts of community reconstruction during this era of aging and urbanization of populations. Disaster risk reduction (DRR) is achieved by decreasing hazard exposure and vulnerability while increasing the capacity for adaptation. The Sendai Framework for DRR 2015–2030 adopted by 185 member states at the Third World Conference 2015 in Sendai, emphasizes the effects of disasters on physical and mental health. The Bangkok Principle was adopted to implement its health aspects. Now it is necessary to accumulate scientific evidence clarifying the relation between health and DRR such as the correlation between life expectancy and the disaster risk index. By incorporating health as a central target of DRR, our community can be made sustainable, healthy, and resilient against disasters.

BACKGROUND: The prognosis for pancreatic cancer remains dismal because many patients are diagnosed with unresectable cancer at the initial diagnosis. Recently, conversion surgery was reported as an effective treatment for initially unresectable pancreatic cancer with a favorable response to non-surgical treatment lasting over 240 days. Here, we describe a case of locally advanced pancreatic cancer (LAPC) successfully resected after treatment with S-1 and radiation followed by gemcitabine/nab-paclitaxel therapy. CASE PRESENTATION: A 73-year-old man with LAPC was referred to our hospital. Computed tomography findings revealed a 2.5-cm mass in the pancreatic body that had invaded the celiac artery, common hepatic artery, and splenic artery. Superior mesenteric artery (SMA) encasement was not observed, but tumor abutment over 180° with the main tumor was detected. Staging laparoscopy showed no findings of distant metastasis, and washing cytology revealed no malignancy. He was diagnosed with unresectable pancreatic cancer. Treatment with S-1 with radiation therapy followed by gemcitabine with nab-paclitaxel was performed. Six months after the initial treatment, the tumor size had decreased to 1.2 cm, and encasement of the main artery was diminished. Though abutment to the main artery, including the SMA, was still detected, distal pancreatectomy with celiac artery resection was performed. The histopathological findings around the celiac artery revealed fibrous changes with an Evans classification of grade IIb. There was no residual cancer at the periphery; thus, R0 resection was achieved. The patient has been healthy and without recurrence for more than 12 months since the initial treatment. CONCLUSIONS: Gemcitabine/nab-paclitaxel therapy revealed high response rate for metastasic pancreatic cancer (PC), but the effect for LAPC proposing conversion surgery was not well discussed. In this case, we achieve R0 resection combined with chemoradiation therapy and gemcitabine/nab-paclitaxel therapy. This regimen was also effective for LAPC and may be used to increase the population of conversion surgery by its high response rate.

PURPOSE: To evaluate the risk factors for peritoneal recurrence (PR) of pancreatic adenocarcinoma and to discuss the appropriate management strategies. METHODS: We reviewed the medical records of 236 patients who underwent pancreatectomy for pancreatic adenocarcinoma. We then compared the clinicopathological characteristics of patients with vs. those without PR. The independent risk factors for PR were defined using the Cox proportional hazards regression model. RESULTS: The median survival of patients with PR was 13.3 months after surgical treatment. The PR group had a significantly higher incidence of portal vein resection, longer operative time (≥648 min), greater blood loss (≥2179 mL), blood transfusion, tumor size, portal vein invasion, artery invasion, pancreatic nerve plexus invasion, and histological grade. Multivariate analysis revealed that excessive blood loss (≥2179 mL; P = 0.010), artery invasion (P = 0.025), pancreatic nerve plexus invasion (P = 0.001), and histological grade 3 (P = 0.011) were independent risk factors for PR. Excessive blood loss was also strongly related to tumor size (P = 0.018). CONCLUSIONS: Local invasion and tumor size-related factors suggested the possibility of intraoperative dissemination at the time of tumor resection. Preoperative treatment and an operative procedure to prevent tumor exposure may help prevent PR.

The rare and deadly Ebola virus disease (EVD) is caused by Ebola virus (EBOV) infection. The 2014-2015 EVD outbreak in West Africa was unprecedented. Person-to-person transmission of EBOV by direct contact with the body or bodily fluids of an infected person through broken skin or unprotected mucous membrane caused rapid outbreak in communities. Nosocomial infection was the cause of death of many health care workers (HCWs). This paper aims to reveal the importance and effect of intensive education of HCWs when combating an outbreak such as EVD. We compared the curricula of two educational programs and analyzed their effects by the trend of weekly new patients. In September 2014, a three-day training program on infection, prevention and control (IPC) was organized for nurses, but it was not sufficient to achieve good outcome. In December 2014, a newly established National Ebola Training Academy was set up to offer a platform of clinical training modules for frontline Ebola response workers. This academy addressed the training needs of clinicians and hygienists who were working or will work at Ebola treatment centers that were established after the onset of the 2014 outbreak. Increased intensive contents and simulated training at the academy improved HCWs' understanding of EVD, IPC and patient care, which subsequently contributed to the survival of patients. The rapid settlement of the outbreak after introducing the Academy indicates that appropriate intensive education of HCWs is the key activity carried out to control the outbreak of EVD in Sierra Leone.

In the 2011 Great East Japan Earthquake (GEJE), successful medical and public health coordination by pre-assigned disaster medical coordinators saved many affected people, though the coordination itself had difficulties. This study aims to clarify the implementation and the challenges of disaster medical coordinators in Japan. We performed questionnaire surveillance in 2012 and 2014 to all prefectural government on assignment of disaster medical coordinators, their expected roles and supporting system. Out of all 47 prefectures, assignment or planning of disaster medical coordinators jumped up from four (8.5%) to 43 (91.5%) by the end of 2015. The most expected role is the coordination with Japan Disaster Medical Assistant Team (DMAT) and with other early responders. The evacuation center management, public health coordination and preparedness before disaster are less frequently expected. The supporting materials, human resource, and tools for communication vary according to the prefecture. Successful implementation requires the effort of health and governmental stakeholders. The coordination between prefectural and local coordinators and the coordination between medical and public health authorities still need to be improved. The roles of disaster medical coordinators depend on the local context and types of hazards. Education and training to build fundamental capacity is necessary. In conclusion, Japanese disaster medical system rapidly implemented disaster medical coordinator after GEJE. Their roles and standardization are challenging, but education, training and systematic support by the local government will enhance the effective preparedness and response of the health sector in disasters.

Damage-associated molecular patterns (DAMPs) are endogenous cellular molecules released to the extracellular environment in response to stress conditions such as virus infection. Galectins are β-galactoside-binding proteins that are widely expressed in cells and tissues of the immune system, are localized in the cell cytoplasm, and have roles in inflammatory responses and immune responses against infection. Elevated levels of galectin-9 (Gal-9) in natural human infections have been documented in numerous reports. To investigate the effect of dengue virus (DENV) infection on expression of endogenous Gal-9, monocytic THP-1 cells were infected with varying doses of DENV-3 (multiplicity of infection (MOI) 0.01, 0.03 and 0.1) and incubated at varying time points (Day 1, Day 2, Day 3). Results showed augmentation of Gal-9 levels in the supernatant, reduction of Gal-9 levels in the cells and decreased expression of LGALS9 mRNA, while DENV-3 mRNA copies for all three doses remained stable through time. Dengue virus induced the secretion of Gal-9 as a danger response; in turn, Gal-9 and other inflammatory factors, and stimulated effector responses may have limited further viral replication. The results in this pilot experiment add to the evidence of Gal-9 as a potential DAMP.

The GEST study showed non-inferiority of S-1 but not superiority of gemcitabine plus S-1 (GS) to gemcitabine alone for overall survival with the data by the cut-off date of 31st July in 2010 for chemo-na &lt; ve patients with advanced pancreatic cancer. We considered it important to determine whether S-1 maintains non-inferiority after a long-term follow-up in the GEST study and to obtain a firm positive conclusion. In addition, it may be an interesting challenge to explore the efficacious profile of GS in the long-term follow-up study. Using the data from the follow-up period, background and efficacy in patients from Taiwan and Japan, as well as the rates of tumor shrinkage in locally advanced and metastatic patients (Waterfall plot) were also analyzed. The results of the primary analysis were reconfirmed, and subset analysis of overall survival and progression-free survival was performed based on the overall survival data updated by the cut-off date of 31st July in 2011. The median follow-up period was 29.8 months, and 795 deaths occurred (95.6%). The median overall survival was 8.8 months for gemcitabine, 9.7 months for S-1 (hazard ratio [HR], 0.96; 97.5% confidence interval [CI], 0.79-1.17), and 9.9 months for GS (HR 0.91; 97.5% CI 0.75-1.11). In patients with performance status (PS) 0, the median overall survival was 9.8 months for gemcitabine, 10.9 months for S-1, and 10.5 months for GS. In patients with PS 1, the median overall survival was 6.2 months for gemcitabine, 6.3 months for S-1, and 9.6 months for GS. Our survey reconfirmed the non-inferiority of S-1 to gemcitabine and showed S-1 can be used as one of the standard treatment options for advanced pancreatic cancer. ClinicalTrials.gov: NCT00498225.

Objectives: Platelet-derived growth factor receptor beta (PDGFR beta) and hepatocyte growth factor receptor (MET) expressed on pancreatic stellate cells (PSCs) are suggested as important components modulating the interactions between pancreatic cancer cells (PCCs) and PSCs. The objective of this study is to clarify the effect of MK2461, a multikinase inhibitor targeting MET and PDGFR beta, on the interaction between PCCs and PSCs. Methods: In this study, we profiled the expression of receptor tyrosine kinases (including PDGFR beta and MET) in pancreatic cancer with quantitative targeted absolute proteomics using liquid chromatography tandem mass spectrometry. In addition, the effect of MK2461 on PCC-PSC interaction was investigated using PSCs prepared from pancreatic cancer tissues. Results: In PSCs, PDGFR beta and MET were upregulated compared with other receptor tyrosine kinases. Conditioned medium from PSCs promoted the proliferation of PCCs, and vice versa. Moreover, MK2461 suppressed the effects of conditioned medium on PCCs and PSCs. Finally, MK2461 significantly inhibited tumor growth in mice coinjected with PCCs and PSCs. Conclusions: The PDGFR beta and MET may play a critical role in the interaction between PCCs and PSCs, which was modulated by MK2461. Therefore, MK2461 may have therapeutic potential in the treatment of pancreatic cancer.

Background This multi-institutional study aimed to assess the benefits of anterior approach for right hepatectomy with hanging maneuver (ARH-HM) for hepatocellular carcinoma (HCC) compared with conventional right hepatectomy (CRH). Methods From January 2000 to December 2012, 306 patients with HCC &gt;= 5 cm were divided into two groups: ARH-HM (n = 104) and CRH (n = 202). Results After one-to-one propensity score-matched analysis, 72 ARH-HM and 72 CRH patients presented comparable background factors. Patients in the ARH-HM group demonstrated significantly less intraoperative blood loss (480 vs. 1,242 g, P &lt; 0.001) and a lower frequency of red cell concentrate transfusion (21.1% vs. 50.7%, P &lt; 0.001) compared with patients in the CRH group. The 5-year overall survival rate was significantly better in the ARH-HM group compared with the CRH group (50.2% vs. 31.4%, P = 0.021). Limited to patients with HCC &gt;= 10 cm, recurrence-free and overall survival of the ARH-HM group was significantly greater than those of the CRH group. Conclusion In comparison with CRH, ARH-HM for large HCC can provide better overall survival rates with a decrease in intraoperative blood loss and transfusion rates. Survival impact was evident especially in patients with HCC &gt;= 10 cm.

© 2017 The Japanese Society of Gastroenterological Surgery. The patient was an 85-year-old woman with poor appetite and fatigue. She was referred to us after a giant cystic tumor was observed on abdominal US. CT revealed a 15-cm cystic lesion that extended to the pelvis and scattered nodular lesions with contrast enhancement, which suggested a malignant tumor. ERCP showed communication with the pancreatic duct at the pancreatic head, indicating an intraductal papillary mucinous neoplasm (IPMN). The cyst protruding outside the pancreas was resected, and the surgery was finished after no tumor progression into the pancreatic duct stump was observed. Histopathological examination indicated an IPMN with low-to-intermediategrade dysplasia. Genetic analysis of a nodular lesion showed a GNAS mutation, confirming the diagnosis of IPMN. The rarity of the morphology in this case provides many suggestions for preoperative and postoperative diagnoses, selecting operative procedures, and other related matters.

Osteopontin (OPN) is a multifunctional matricellular protein produced by a broad range of cells including osteoclasts, macrophages, T cells, endothelial cells, and vascular smooth muscle cells. OPN modulates various physiological and pathological events such as inflammation, wound healing, and bone formation and remodeling. Dengue virus (DENV) infection causes an increase in plasma OPN levels, which is correlated with the severity of symptoms and coagulation abnormalities. DENV infection also induces OPN gene expression in human macrophages. This study investigated the inhibitory effects of brefelamide and its methyl ether derivative on DENV-3 by measuring changes in OPN levels in human THP-1 and 293T cell lines infected at different multiplicities of infection and post-infection time points. OPN mRNA expression and viral RNA were detected by reverse transcriptase quantitative real-time PCR, whereas protein level was determined by enzyme-linked immunosorbent assay. We found that viral copy number was higher in 293T than in THP-1 cells. However, THP-1 constitutively expressed higher levels of OPN mRNA and protein, which were enhanced by DENV-3 infection. Brefelamide and its derivative suppressed OPN production in DENV-3 infected THP-1 cells; the effective doses of these compounds had no effect on uninfected cells, indicating low cytotoxicity. These results suggest that brefelamide and its methyl ether derivative have therapeutic effects in preventing inflammation, coagulopathy, and fibrinolysis caused by OPN upregulation induced by DENV-3 infection.

OBJECTIVE: This study was performed to compare health-related quality of life (HRQOL) of gemcitabine plus S-1 (GS), S-1 alone and gemcitabine alone as first-line chemotherapy for locally advanced or metastatic pancreatic cancer in the GEST (Gemcitabine and TS-1 Trial) study and to assess the impacts of adverse events and tumour response on HRQOL. METHODS: Patients were randomly assigned to receive gemcitabine alone (1000 mg/m2 weekly for 3 of 4 weeks), S-1 alone (80, 100 or 120 mg/day twice daily for 4 of 6 weeks) or GS (gemcitabine at 1000 mg/m2 weekly plus S-1 at 60, 80 or 100 mg/day twice daily for 2 of 3 weeks). HRQOL was assessed using the EuroQoL-5D (EQ-5D) questionnaire at baseline and weeks 6, 12, 24, 48 and 72. EQ-5D scores, quality-adjusted life months (QALMs), quality-adjusted progression-free months (QAPFMs) and time until definitive HRQOL deterioration (TUDD) were compared among the three groups. The impacts of adverse events and tumour response on EQ-5D scores were analysed. RESULTS: Including EQ-5D scores after death as 0, the mean profile was significantly better in the GS than gemcitabine group (difference, 0.069; p=0.003), but not the S-1 group (difference, -0.011; p=0.613). The mean profiles until death were similar in the three groups. QALMs, QAPFMs and TUDD were significantly longer in the GS than gemcitabine group (p<0.001, p<0.001 and p=0.004, respectively), but not the S-1 group (p=0.563, p=0.741 and p=0.701, respectively). Fatigue, anorexia and tumour response were significantly associated with changes in EQ-5D scores. CONCLUSIONS: GS achieved better HRQOL than gemcitabine alone, resulting a good balance between overall survival and HRQOL benefits. S-1 alone provides HRQOL similar to that provided by gemcitabine alone. Preventing fatigue and anorexia and maintaining better response would improve HRQOL.

OBJECTIVES: The aim of this study was to determine the characteristics of patients with pancreatic ductal adenocarcinoma younger than 40 years. METHODS: Data from the Japan Pancreas Society's nationwide Pancreatic Cancer Registry were analyzed retrospectively. Clinicopathological characteristics were compared in patients who were grouped according to age, namely, younger than 40 years versus 40 years and older. RESULTS: Of the 36 145 patients in the database, the younger group included 526 (1.5%) patients. A family history of pancreatic cancer was not more frequent in the younger group. The frequency of Union Internationale Contre le Cancer T4 and M1 were both significantly higher in younger patients, resulting in a higher percentage of patients with Union Internationale Contre le Cancer stage IV. Pancreatectomy was performed less frequently in the younger group, and R0 resection was also less frequent. The overall survival rate was significantly better in the older group, whereas in surgically resected patients, the overall survival and recurrence-free survival rates were not different between the 2 groups. CONCLUSIONS: Younger patients with pancreatic adenocarcinoma were more often diagnosed at advanced stages, and the overall survival rate was worse than that in older patients. Family genetic background and the prognoses of patients who underwent surgery were similar between the 2 groups.

The Great East Japan Earthquake (GEJE) and resulting tsunami of March 11, 2011 gave rise to devastating damage on the Pacific coast of the Tohoku region. The Tohoku Medical Megabank Project (TMM), which is being conducted by Tohoku University Tohoku Medical Megabank Organization (ToMMo) and Iwate Medical University Iwate Tohoku Medical Megabank Organization (IMM), has been launched to realize creative reconstruction and to solve medical problems in the aftermath of this disaster. We started two prospective cohort studies in Miyagi and Iwate Prefectures: a population-based adult cohort study, the TMM Community-Based Cohort Study (TMM CommCohort Study), which will recruit 80 000 participants, and a birth and three-generation cohort study, the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study), which will recruit 70 000 participants, including fetuses and their parents, siblings, grandparents, and extended family members. The TMM CommCohort Study will recruit participants from 2013 to 2016 and follow them for at least 5 years. The TMM BirThree Cohort Study will recruit participants from 2013 to 2017 and follow them for at least 4 years. For children, the ToMMo Child Health Study, which adopted a cross-sectional design, was also started in November 2012 in Miyagi Prefecture. An integrated biobank will be constructed based on the two prospective cohort studies, and ToMMo and IMM will investigate the chronic medical impacts of the GEJE. The integrated biobank of TMM consists of health and clinical information, biospecimens, and genome and omics data. The biobank aims to establish a firm basis for personalized healthcare and medicine, mainly for diseases aggravated by the GEJE in the two prefectures. Biospecimens and related information in the biobank will be distributed to the research community. TMM itself will also undertake genomic and omics research. The aims of the genomic studies are: 1) to construct an integrated biobank; 2) to return genomic research results to the participants of the cohort studies, which will lead to the implementation of personalized healthcare and medicine in the affected areas in the near future; and 3) to contribute the development of personalized healthcare and medicine worldwide. Through the activities of TMM, we will clarify how to approach prolonged healthcare problems in areas damaged by large-scale disasters and how useful genomic information is for disease prevention.

Background: Galectin-9 (Gal-9) is a beta-galactoside-binding lectin that interacts with sugar moieties on glycoproteins and glycolipids of cells and pathogens. Gal-9 is known as an immune modulator that induces cell death via interaction with T cell immunoglobulin and mucin domain-3 (Tim3), a co-inhibitory receptor, and it inhibits production of several pro-inflammatory cytokines (TNF, IL-6 and IL-1 alpha) and enhances production of IL-10. To understand the immune pathology of malaria, the Gal-9 in plasma was measured. Methods: Plasma samples and clinical parameters were obtained from 50 acute malaria cases (nine severe and 41 uncomplicated cases) from Thailand at three time points: day 0, day 7 and day 28. Gal-9 levels were determined by ELISA. A total of 38 species of cytokines and chemokines were measured using a BioPlex assay. Results: Gal-9 levels were higher at day 0 compared to day 7 and day 28 (P &lt; 0.0001). Gal-9 levels were also higher in severe malaria (SM) cases compared to uncomplicated (UM) cases at day 0 and day 7 (923 vs 617 pg/mL; P = 0.03, and 659 vs 348 pg/mL; P = 0.02 respectively). Median Gal-9 levels were higher in patients with blood urea nitrogen to creatinine ratio (BUN/creatinine) = 20 (mg/dL) than in patients with BUN/creatinine &lt; 20 (mg/dL) at day 0 (817.3 vs 576.2 pg/mL, P = 0.007). Gal-9 was inversely significantly correlated with chloride levels in both SM and UM cases (rs = -0.73 and rs = -0.46, respectively). In both UM and SM cases, Gal-9 was significantly associated with pro-and anti-inflammatory cytokines and chemokines such as TNF, IL-6, IFN-alpha 2, IFN-gamma, IL-1R alpha and IL-10. These correlations were observed at day 0 but disappeared at day 28. Conclusions: Gal-9 is released during acute malaria, and reflects its severity. This elevation of Gal-9 in acute malaria infection raises the possibility of its role in termination of the immune response by binding to Tim-3, a receptor of Gal-9.

BACKGROUND: Lymph node dissection in Rouviere's sulcus (RS) is essential during left-sided hepatectomy and caudate lobectomy for hilar cholangiocarcinoma. However, the small segmental or subsegmental arteries (SA/SSA) are often encountered in RS and must be preserved to prevent critical complications, such as liver infarction or liver failure. The aim of this study is to elucidate the anatomy of SA/SSA around RS, which should be understood preoperatively. METHODS: Between January 2008 and April 2013 from a total of 124 consecutive patients with hilar cholangiocarcinoma, preoperative multidetector-row computed tomography (MDCT) images were obtained at our institution and evaluated. The bifurcation patterns of the SA/SSA, the courses of the posterior SA/SSA and the bifurcation site of the SA/SSA were investigated using MDCT images. RESULTS: The typical form, in which right hepatic artery (RHA) bifurcated into the anterior (Aant) and posterior (Apost) hepatic artery and thereafter, Aant/Apost bifurcated into the SA and SSA, was observed in 75 patients (60.5 %). On the other hand, the atypical forms, in which the SA/SSA were independently branched off from RHA before the main bifurcation of the Aant and Apost, were observed in 43 patients (34.7 %). The prior branched arteries supplied the whole or ventral area of segment VI (A6 or A6a) in 11 patients (8.9 %), which was most commonly observed in the atypical form. 15 patients (34.9 %) of the 43 patients with atypical form had partially supraportal posterior branches, that showed early-bifurcated posterior SA/SAA following supraportal course, while the other posterior SA/SSA followed infraportal course. The SA/SSA were extrahepatically bifurcated in 82 patients (66.1 %), comprised of all 43 atypical form and 39 of typical form, while the SA/SSA were intrahepatically bifurcated in remaining 36 patients of typical forms (29.0 %). CONCLUSION: The extrahepatic bifurcation of the SA/SSA from RHA was relatively common. The early-bifurcated SA/SSA was often observed (34.7 % of total cohort) and, in 34.8 % of those atypical forms, posterior SA/SSA from RHA followed a supraportal course. The detailed preoperative knowledge of the anatomy, including SA/SSA, is crucial for left-sided hepatectomy for hilar cholangiocarcinoma.

Background/objective: To evaluate the usefulness of genetic markers in pancreatic juice (9), and the combination of these markers with telomerase activity in the differential diagnosis of pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis. Methods: We conducted a meta-analysis for the diagnostic utility of the four major altered genes in PDAC (KRAS, CDKN2A/p16, TP53, and SMAD4/DPC4), telomerase activity, and a combination assay using PJ samples. A literature search was conducted in MEDLINE, Cochrane Library, and Web of Science. Data were pooled and presented as diagnostic sensitivity and specificity with 95% confidence intervals (CIs). Results: Thirty-nine studies fulfilled the inclusion criteria. Pooled estimates of KRAS analysis were as follows: sensitivity was 0.67 (95% CI, 0.63-0.71) and specificity, 0.82 (95% CI, 0.79-0.85). For telomerase activity analysis, sensitivity was 0.82 (95% CI, 0.76-0.87) and specificity, 0.96 (95% CI, 0.90-0.99). The other three tumor suppressors demonstrated low sensitivity. The data did not suggest any publication bias. A combined analysis of KRAS and telomerase activity showed a higher diagnostic sensitivity (0.94; 95% CI, 0.83-0.99) than KRAS alone. A combined analysis of telomerase activity and cytology revealed more reliable diagnostic accuracy than telomerase activity alone, with high sensitivity (0.88; 95% CI, 0.74-0.96) and specificity (1.00; 95% CI, 0.91-1.00). Conclusions: The most reliable marker in PJ samples for diagnosis of PDAC was telomerase activity. Telomerase activity can play a central role in diagnostic analysis using PJ samples, and can increase diagnostic accuracy when combined with KRAS mutations or cytological examination. (C) 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Objective:The aim of the study was to evaluate the relationship between hospital volume and outcome after pancreaticoduodenectomy (PD).Summary Background Data:Previous reviews for the hospital volume-outcome relationship after pancreatic resection were limited owing to clinical or methodological heterogeneity, resulting from differences in surgical procedures and high-volume hospital (HVH) definitions across studies.Methods:We conducted a rigorous meta-analysis on the influence of hospital volume on various outcomes after PD using strict inclusion criteria and single cutoff values for HVHs.Results:Thirteen studies based on nationwide databases from 11 countries, and including 58,023 patients in total, were included in this study. The overall pooled odds ratio (OR) for mortality favoring the HVH group was 2.37 [95% confidence interval (CI): 1.95-2.88] with high heterogeneity (I-2 = 63%). We therefore classified all included studies into categories according to the cutoff values for HVH as defined in each individual study. The pooled OR for each category of 1 to 19, 20 to 29, and 30 PDs per year was 1.94, 2.34, and 4.05, respectively. There were significant differences among these categories (I-2 = 58.9%, P = 0.09). The 2 former categories showed no statistical interstudy heterogeneities. The data did not suggest publication bias. These trends persisted in all subgroup analyses. Postoperative length of stay in the HVH group was significantly shorter with mild interstudy heterogeneity.Conclusions:This meta-analysis included studies from different countries with disparate health care systems and provided strong evidence for an inverse association between higher hospital volume and lower mortality after PD. Variations in HVH cutoff values across studies majorly influenced the overall heterogeneity.

After disaster, the victims lose their safe lives and are even exposed to nature where they could suffer from animal bites and vectors followed by suffering from zoonosis or vector-born diseases. Because of the urgent need for rapid and cheap diagnosis for infectious diseases after disaster, anonymous questionnaire clarified that leptospirosis, dengue, diarrhea, and cholera were recognized as common disaster-related infections in the Philippines, while diarrhea and pneumonia were more common in Indonesia. It should also be noted that infectious disease itself such as tuberculosis associated with acquired immune deficiency syndrome in South Africa is a disaster. Thus, the possible occurrence of similar situation in Asia should be prevented. We have conducted an international collaborative research in the Philippines and Indonesia on dengue virus, leptospira and mycobacterium tuberculosis (MTB) infectious diseases. Development of point-of-care testing for molecular diagnosis and disease severity was the principal purpose of the research. Loop-mediated isothermal amplification assay, which does not require a source of electricity, was developed for leptospirosis, dengue and MTB and has been proved to be useful where resource is limited. The plasma levels of matricellular proteins, including galectin-9 and osteopontin, were found to reflect the disease seventies in dengue virus and MTB infection, probably because matricellular proteins are one of the most functional extracellular proteins that are associated with inflammatory edema. The study on disaster-related infectious disease facilitates the international cooperation for development of point-of-care testing for tropical infectious diseases.

Objectives The occurrence of hepatic steatosis after pancreatectomy is known to be associated with the remnant pancreatic function. However, other risk factors for hepatic steatosis after pancreatectomy remain unknown. The aims of this study were to identify other risk factors in addition to the remnant pancreatic function and elucidate the relationship between postoperative hepatic steatosis and pancreatic exocrine insufficiency in totally pancreatomized patients. Methods Forty-three patients who underwent total pancreatectomy were analyzed. Hepatic steatosis was defined as the attenuation of unenhanced computed tomography values. Clinical findings and laboratory data were compared between patients with and without hepatic steatosis. Results Sixteen (37.2%) patients developed hepatic steatosis after total pancreatectomy, with marked declines in the Controlling Nutritional Status score and body mass index. Multiple linear regression analysis revealed that the attenuation of computed tomography values was correlated with female sex (P = 0.002), early postoperative serum albumin levels (P = 0.003), and pancreatic enzyme replacement therapy with high-dose pancrelipase (P = 0.032). Conclusions Postoperative hepatic steatosis after pancreatectomy is associated with sex, malnutrition, and pancreatic exocrine insufficiency. High-dose pancreatic enzyme replacement therapy may have preventive effects on hepatic steatosis occurring after pancreatectomy.

In Indonesia, the Aceh earthquake and tsunami in 2004 killed 127,000 people and caused half a million injuries, while the Yogyakarta earthquake in 2006 caused 5,700 deaths and 37,000 injuries. Because disaster-affected areas are vulnerable to epidemic-prone diseases and tetanus is one such disease that is preventable, we systematically reviewed the literature related to tetanus outbreaks following previous two natural disasters in Indonesia. Based on our findings, recommendations for proper vaccination and education can be made for future countermeasures. Using specified keywords related to tetanus and disasters, relevant documents were screened from PubMed, the WHO website, and books. Reports offering limited data and those released before 2004 were excluded. In all, 16 publications were reviewed systematically. Results show that 106 cases of tetanus occurred in Aceh, with a case fatality ratio (CFR) of 18.9%; 71 cases occurred in Yogyakarta, with CFR of 36.6%. For both outbreaks, most patients had been wounded during scavenging or evacuation after the disaster occurred. Poor access to health care because of limited transportation or hospital facilities, and low vaccination coverage and lack of awareness of tetanus risk contributed to delayed treatment and case severity. Tetanus outbreaks after disasters are preventable by increasing vaccination coverage, improving wound care treatment, and establishing a regular surveillance system, in addition to good practices of disaster management and supportive care following national guidelines. Furthermore, health education for communities should be provided to raise awareness of tetanus risk reduction.

Background: In the GEST study of unresectable pancreatic cancer, S-1 demonstrated non-inferiority compared to gemcitabine, but gemcitabine plus S-1 (GS) did not show superiority over gemcitabine for overall survival (OS). We performed subgroup analysis of these data focused on the efficacy and safety of these regimens as a first-line treatment for elderly patients. Methods: Elderly patients (&gt;= 70 years, n = 261) treated for unresectable pancreatic cancer (GS: n = 90, S-1: n = 85 and gemcitabine: n = 86) were analysed. Results: No significant differences between the GS, S-1, or gemcitabine groups in OS (median: 10.2, 8.0 and 8.5 months, respectively) or objective response rates (27.6%, 25.3% and 14.3%, respectively) were noted. Grade &gt;= III adverse haematological events were observed more frequently in GS-treated than in S-1- or gemcitabine-treated elderly patients (p &lt; 0.001 and p=0.016, respectively). Four of 8 patients aged &gt;= 80 years experienced serious adverse events. Conclusions: S-1 and gemcitabine are both efficacious options for treatment of elderly patients with unresectable pancreatic cancer. Conversely, first-line treatment of elderly patients with GS should only be used after careful consideration. (C) 2015 Elsevier Ltd. All rights reserved.

Objective The aim of the study was to clarify clinicopathological features of type 2 autoimmune pancreatitis (AIP) in Japan; a multicenter survey was carried out. Methods The first screening collected patients with pancreatitis whose pancreatic tissue samples were available and who fulfilled at least 1 of the following 3 criteria as possible type 2 AIP: (1) histological presence of granulocytic epithelial lesion, (2) age of 50 years or younger, and (3) association of ulcerative colitis, Sjogren syndrome, and/or primary biliary cirrhosis. Patients with histologically confirmed type 1 AIP were also collected as a control. Clinical information was gathered by questionnaire. Results A histological re-evaluation identified 8 patients with type 2 AIP and 20 with type 1 AIP. Three of the latter had intralobular neutrophilic infiltration. Factors more frequent in type 2 included age younger than 40 years, abdominal pain, and elevation of serum amylase and lipase, whereas patients with type 1 more frequently showed jaundice, elevated serum IgG and IgG4, presence of autoantibodies, association of IgG4-related disease, sclerosing cholangitis and diabetes mellitus, and imaging findings of intrapancreatic biliary stenosis and extrapancreatic biliary dilatation. Conclusions The clinical features of type 2 AIP in Japan were similar to those of western countries. Intralobular neutrophilic infiltration in type 1 is a potential pitfall, especially in the biopsy-based diagnosis.

Background The efficacy of intramuscular islet transplantation is poor despite being technically simple, safe, and associated with reduced rates of severe complications. We evaluated the efficacy of combined treatment with extracellular matrix (ECM) and growth factors in intramuscular islet transplantation. Methods Male BALB/C mice were used for the in vitro and transplantation studies. The following three groups were evaluated: islets without treatment (islets-only group), islets embedded in ECM with growth factors (Matrigel group), and islets embedded in ECM without growth factors [growth factor-reduced (GFR) Matrigel group]. The viability and insulin-releasing function of islets cultured for 96 h were significantly improved in Matrigel and GFR Matrigel groups compared with the islets-only group. Results Blood glucose and serum insulin levels immediately following transplantation were significantly improved in the Matrigel and GFR Matrigel groups and remained significantly improved in the Matrigel group at postoperative day (POD) 28. On histological examination, significantly decreased numbers of TdT-mediated deoxyuridine triphosphate-biotin nick end labeling-positive islet cells and significantly increased numbers of Ki67-positive cells were observed in the Matrigel and GFR Matrigel groups at POD 3. Peri-islet revascularization was most prominent in the Matrigel group at POD 14. Conclusions The efficacy of intramuscular islet transplantation was improved by combination treatment with ECM and growth factors through the inhibition of apoptosis, increased proliferation of islet cells, and promotion of revascularization.

Islet autotransplantation following total pancreatectomy differs from allograft transplantation with respect to the requirement of biliary reconstruction. Although it is known that careful consideration should be given to postoperative cholestatic liver injury after biliary reconstruction, its direct effects on transplanted islets have not been completely elucidated. In this study, we developed a murine model of postoperative cholestatic liver injury after biliary reconstruction with islet autotransplantation that involved syngeneic intraportal islet transplantation into chemically induced diabetic mice and common bile duct ligation. We assessed the viability and function of the transplanted islets. The impaired viability of transplanted islets and increased blood glucose levels indicated restoration of the diabetic state after common bile duct ligation in this murine model. Furthermore, impaired islet viability and function occurred earlier in the transplanted islets than in the surrounding liver tissues, which was consistent with the faster and higher expression of oxidative stress markers in the transplanted islets. Transplanted islets may be more vulnerable to oxidative stress caused by cholestatic liver injury than the surrounding liver tissue. Therefore, patients should be intensively managed after total pancreatectomy with islet autotransplantation to preserve viability and function of the transplanted islets.

© 2015, The Author(s). The Sendai Framework for Disaster Risk Reduction 2015–2030 (SFDRR) is the first global policy framework of the United Nations’ post-2015 agenda. It represents a step in the direction of global policy coherence with explicit reference to health, development, and climate change. To develop SFDRR, the United Nations Office for Disaster Risk Reduction (UNISDR) organized and facilitated several global, regional, national, and intergovernmental negotiations and technical meetings in the period preceding the World Conference on Disaster Risk Reduction (WCDRR) 2015 where SFDRR was adopted. UNISDR also worked with representatives of governments, UN agencies, and scientists to develop targets and indicators for SFDRR and proposed them to member states for negotiation and adoption as measures of progress and achievement in protecting lives and livelihoods. The multiple efforts of the health community in the policy development process, including campaigning for safe schools and hospitals, helped to put people’s mental and physical health, resilience, and well-being higher up the disaster risk reduction (DRR) agenda compared with the Hyogo Framework for Action 2005–2015. This article reviews the historical and contemporary policy development process that led to the SFDRR with particular reference to the development of the health theme.

Recent basic and clinical studies have assessed the use of highly sensitive imaging modalities for visualizing transplanted islets. We investigated the utility of enhanced ultrasonography, combined with fluorescent acoustic liposome nano/microbubbles (FALs), for evaluating angiogenesis and the endocrine function of transplanted islets. BALB/c mice were classified into three groups: Diabetic mice that underwent syngeneic islet transplantation into the subrenal capsule and achieved normoglycemia (Tx group); those that failed to achieve normoglycemia (Tx-DM group); and those not receiving any treatment (DM group). Mice were examined by FAL-enhanced high frequency ultrasonography. The echogenicity of the islets increased rapidly within the first minute after injection of FALs and remained at a higher level in the Tx group, while small increases were observed in the other two groups. In histological assessments, fluorescently stained erythrocytes could be seen in and around the transplanted islets, indicating that the transplanted islets were enhanced by infusion of FALs via vessel networks between the engrafted islets and tissue. Furthermore, the echogenicity correlated significantly with endocrine parameters, including blood glucose (BG), serum insulin, and the BG change in the glucose tolerance test. In conclusion, the echogenicity of the islets under FAS-enhanced ultrasonosonography correlated with the endocrine status of transplanted islets.

Introduction: The aim of this study was to shed light on damage to water supply facilities and the state of water resource operation at disaster base hospitals in Miyagi Prefecture (Japan) in the wake of the Great East Japan Earthquake (2011), in order to identify issues concerning the operational continuity of hospitals in the event of a disaster. Methods: In addition to interview and written questionnaire surveys to 14 disaster base hospitals in Miyagi Prefecture, a number of key elements relating to the damage done to water supply facilities and the operation of water resources were identified from the chronological record of events following the Great East Japan Earthquake. Results: Nine of the 14 hospitals experienced cuts to their water supplies, with a median value of three days (range=one to 20 days) for service recovery time. The hospitals that could utilize well water during the time that water supply was interrupted were able to obtain water in quantities similar to their normal volumes. Hospitals that could not use well water during the period of interruption, and hospitals whose water supply facilities were damaged, experienced significant disruption to dialysis, sterilization equipment, meal services, sanitation, and outpatient care services, though the extent of disruption varied considerably among hospitals. None of the hospitals had determined the amount of water used for different purposes during normal service or formulated a plan for allocation of limited water in the event of a disaster. Conclusion: The present survey showed that it is possible to minimize the disruption and reduction of hospital functions in the event of a disaster by proper maintenance of water supply facilities and by ensuring alternative water resources, such as well water. It is also clear that it is desirable to conclude water supply agreements and formulate strategic water allocation plans in preparation for the eventuality of a long-term interruption to water services.

Purpose Adenosquamous carcinoma of the pancreas is a rare subtype of pancreatic cancer. We herein describe the clinicopathological features of surgically resected cases of adenosquamous carcinoma of the pancreas. Methods From 2001 to 2011, 132 patients underwent R0 resection for Stage IIA or IIB pancreatic cancer. The survival rate, pathological features and recurrence status were reviewed. Results Out of 132 patients, 121 patients had tubular adenocarcinoma, and only seven had adenosquamous carcinoma (ASC). The incidence of ASC increased with the tumor size. The overall survival and disease-free survival periods of the patients with ASC were significantly shorter than those of patients with tubular adenocarcinoma (p = 0.0153 and p = 0.0045). The histological findings revealed more marked venous invasion in ASC compared to tubular adenocarcinoma (G1, G2 and G3). The proportion of v3 cases, which denotes the most severe venous invasion, was 31.3 % in G1, 47.3 % in G2, 60.0 % in G3 and 71.4 % in ASC cases, respectively. Other factors, including lymphatic and nerve invasion, were not correlated with the histological subtypes. The incidence of ASC was 11.1 % in the tumors more than 6 cm in diameter, and 0 % in those less than 2 cm in diameter. Conclusions We revealed that adenosquamous carcinoma of the pancreas is associated with a poor outcome, and also clarified its clinicopathological features.

Background/Aims: This multicenter and single arm phase II clinical trial was performed to examine the safety and efficacy of modified FOLFOX6 (mFOLFOX6) as adjuvant treatment after resection of liver metastases from colorectal cancer. Methodology: Patients who had undergone R0-1, resection of liver metastases were assigned to 12 cycles of mFOLFOX6. The primary end point was disease-free survival (DFS). Results: We enrolled 49 cases and analyzed adverse events in 48 cases, since in one patient cancer recurred before starting treatment. As to the relative dose intensity, 5-FU was 78.8%, and oxaliplatin was 75.9%. Adverse events of Grade 3 and above included 18 cases of neutropenia (37.5%), 4 cases of sensory neuropathy (8.3%), 4 cases of thrombocytopenia (8.3%) and 4 cases of allergy (8.3%), and there were no cases of fatality caused by adverse events. The most difference of adverse event compared with MOSAIC trial (Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer) was thrombocytopenia. The 2-year DFS was 59.2% (95% CI: 36.7-78.4) in the 49 enrolled cases. Conclusion: mFOLFOX6 after hepatectomy was tolerable. And mFOLFOX6 also seemed to improve DFS. mFOLFOX is one of the options for such patients and appears promising as an adjuvant treatment.

The current outbreak of Ebola virus disease (EVD) is due to a lack of resources, untrained medical personnel, and the specific contact-mediated type of infection of this virus. In Japan's history, education and mass vaccination of the native Ainu people successfully eradicated epidemics of smallpox. Even though a zoonotic virus is hard to control, appropriate precautions and personal protection, as well as anti-symptomatic treatment, will control the outbreak of EVD. Ebola virus utilizes the antibody-dependent enhancement of infection to seed the cells of various organs. The pathogenesis of EVD is due to the cytokine storm of pro-inflammatory cytokines and the lack of antiviral interferon-2. Matricellular proteins of galectin-9 and osteopontin might also be involved in the edema and abnormality of the coagulation system in EVD. Anti-fibrinolytic treatment will be effective. In the era of globalization, interviews of travelers with fever within 3 weeks of departure from the affected areas will be necessary. Not only the hospitals designated for specific biohazards but every hospital should be aware of the biology of biohazards and establish measures to protect both patients and the community. (Disaster Med Public Health Preparedness. 2014;0:1-5)

Aims/Hypothesis Although the muscle is one of the preferable transplant sites in islet transplantation, its transplant efficacy is poor. Here we attempted to determine whether an intramuscular co-transplantation of mesenchymal stem cells (MSCs) could improve the outcome. Methods We co-cultured murine islets with MSCs and then analyzed the morphological changes, viability, insulin-releasing function (represented by the stimulation index), and gene expression of the islets. We also transplanted 500 islets intramuscularly with or without 5 x 10(5) MSCs to diabetic mice and measured their blood glucose level, the glucose changes in an intraperitoneal glucose tolerance test, and the plasma IL-6 level. Inflammation, apoptosis, and neovascularization in the transplantation site were evaluated histologically. Results The destruction of islets tended to be prevented by co-culture with MSCs. The stimulation index was significantly higher in islets co-cultured with MSCs (1.78 +/- 0.59 vs. 7.08 +/- 2.53; p = 0.0025). In terms of gene expression, Sult1c2, Gstm1, and Rab37 were significantly upregulated in islets co-cultured with MSCs. Although MSCs were effective in the in vitro assays, they were only partially effective in facilitating intramuscular islet transplantation. Co-transplanted MSCs prevented an early inflammatory reaction from the islets (plasma IL-6; p = 0.0002, neutrophil infiltration; p = 0.016 inflammatory area; p = 0.021), but could not promote neovascularization in the muscle, resulting in the failure of many intramuscular transplanted islets to engraft. Conclusions In conclusion, co-culturing and co-transplanting MSCs is potentially useful in islet transplantation, especially in terms of anti-inflammation, but further augmentation for an anti-apoptosis effect and neovascularization is necessary.

Objective: This study aimed to clarify the management of emergency electric power and the operation of radiology diagnostic devices after the Great East Japan Earthquake. Methods: Timing of electricity restoration, actual emergency electric power generation, and whether radiology diagnostic devices were operational and the reason if not were investigated through a questionnaire submitted to all 14 disaster base hospitals in Miyagi Prefecture in February and March 2013. Results: Commercial electricity supply resumed within 3 days after the earthquake at 13 of 14 hospitals. Actual emergency electric power generation was lower than pre-disaster estimates at most of the hospitals. Only 4 of 11 hospitals were able to generate 60% of the power normally consumed. Under emergency electric power, conventional X-ray and computed tomography (CT) scanners worked in 9 of 14 (64%) and 8 of 14 (57%) hospitals, respectively. The main reason conventional X-ray and CT scanners did not operate was that hospitals had not planned to use these devices under emergency electric power. Only 2 of the 14 hospitals had a pre-disaster plan to allocate emergency electric power, and all devices operated at these 2 hospitals. Conclusions: Pre-disaster plans to allocate emergency electric power are required for disaster base hospitals to effectively operate radiology diagnostic devices after a disaster.

Here we report a rare case of late recurrence of pancreatic cancer 8 years after surgery. A woman in her mid-fifties was hopitalized for examination of epigastralgia. Computed tomography (CT) revealed a 4 cm nodule at the pancreatic head with suspected invasion of the superior mesenteric vein. She underwent pancreaticoduodenectomy with wedge resection of superior mesenteric vein and intraoperative radiation therapy. Pathological findings showed moderately differentiated tubular adenocarcinoma and T3N1 MO, Stage II B according to The Union for International Cancer Control (UICC) TNM classification. As adjuvant chemotherapy, 56 courses of gemcitabine (GEM) were administered in 3.5 years. Because of long-term use of GEM, common terminology criteria for adverse events (CTCAE) Grade 3 anemia occurred, and chemotherapy was discontinued. Tumor markers were evaluated every month and CT scans were taken every 6 months for 5 years. Subsequently, CT was performed annually. The patient was hospitalized for high-grade fever, 8.5 years after surgery. CT, magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT) detected local recurrence with liver metastases. GEM was administered again, but was ineffective. The patient died 9 years after surgery. In conclusion, even if long-term survival is achieved in pancreatic cancer, follow-ups should not be stopped.

Objectives: Although the somatostatin analog octreotide (OCT) has been used for uncontrollable insulinoma, the mechanism involved is still unknown. The aim of this study was to elucidate the therapeutic effect of OCT for insulinoma. Methods: Mouse insulinoma cell line MIN6 cells were cultured with OCT to clarify its antiproliferative effects, the expression of somatostatin receptor subtypes, cell cycle, p27 expression, and cdc2 kinase activity. The changes of the messenger RNA expression profiles were examined by microarray analysis. Intraperitoneal OCT treatment was given to insulinoma model IT6 mice for 4 weeks. Results: MIN6 cells expressed somatostatin receptor 2A, 3, and 5 under the OCT treatment. Octreotide showed a dose-dependent antiproliferative effect on MIN6 cells but not on the other cell lines. p27 expression and cdc2 kinase activity in MIN6 cells became prominent with OCT treatment. At the messenger RNA level, several molecules in the mitogen-activated protein kinase signaling pathway were down-regulated. The sizes of the individual tumors tended to be smaller in the OCT-treated group. p27 expression was seen in the tumor tissue, but no apoptotic marker was detected. Conclusion: Octreotide acted through a cytostatic mechanism and could be an effective therapy for insulinoma.

As the impacts of natural disasters have grown more severe, the importance of education for disaster medicine gains greater recognition. We launched a project to establish an international educational program for disaster medicine. In the present study, we surveyed medical personnel and medical/public health students in the Philippines (n = 45) and Indonesia (n = 67) for their awareness of the international frameworks related to disaster medicine: the Human Security (securing individual life and health), the Sphere Project (international humanitarian response), and the Hyogo Framework for Action 2005-2015 (international strategy for disaster reduction). In both countries, more than 50% responders were aware of human security, but only 2 to 12% were aware of the latter two. The survey also contained questions about the preferred subjects in prospective educational program, and risk perception on disaster and disaster-related infections. In the Philippines, significant disasters were geophysical (31.0%), hydrological (33.3%), or meteorological (24.8%), whereas in Indonesia, geophysical (63.0%) and hydrological (25.3%) were significant. Moreover, in the Philippines, leptospirosis (27.1%), dengue (18.6%), diarrhea (15.3%), and cholera (10.2%) were recognized common disaster-related infections. In Indonesia, diarrhea (22.0%) and respiratory infection (20.3%) are major disaster-related infections. Water-related infections were the major ones in both countries, but the profiles of risk perception were different (Pearson's chi-square test, p = 1.469e-05). The responders tended to overestimate the risk of low probability and high consequence such as geophysical disaster. These results are helpful for the development of a postgraduate course for disaster medicine in Asia Pacific countries.

GNAS, a gene encoding G protein stimulating a subunit, is frequently mutated in intraductal papillary mucinous neoplasms (IPMNs), which are indolent and slow-growing pancreatic tumors that secrete abundant mucin. The GNAS mutation is not observed in conventional ductal adenocarcinomas of the pancreas. To determine the functional significance of the GNAS mutation in pancreatic ductal lineage cells, we examined in vitro phenotypes of cells of pancreatic ductal lineage, HPDE, PK-8, PCI-35, and MIA PaCa-2, with exogenous expression of either wild-type or mutated (R201H) GNAS. We found that exogenous GNAS upregulated intracellular cyclic adenine monophosphate (cAMP), particularly in mutated GNAS transfectants, and upregulated expression of MUC2 and MUC5AC in HPDE and PK-8 cells. By contrast, exogenous GNAS inhibited expression of mucin genes in PCI-35 and MIA PaCa-2 cells, despite upregulation of cAMP. We examined global gene expression profiles of some of the cells transfected with exogenous mutated GNAS (PK-8, PCI-35, and MIA PaCa-2), and found that PK-8 cells exhibited drastic alterations of the gene expression profile, which contrasted with modest alterations in PCI-35 and MIA PaCa-2 cells. To identify a cause of these different effects of exogenous mutated GNAS on phenotypes of the cells, we examined effects of interactions of the signaling pathways of G protein-coupled receptor (GPCR), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) on expression of mucin genes. The MAPK and PI3K pathways significantly influenced the expression of mucin genes. Exogenous GNAS did not promote cell growth but suppressed it in some of the cells. In conclusion, mutated GNAS found in IPMNs may extensively alter gene expression profiles, including expression of mucin genes, through the interaction with MAPK and PI3K pathways in pancreatic ductal cells; these changes may determine the characteristic phenotype of IPMN. PK-8 cells expressing exogenous mutated GNAS may be an ideal in vitro model of IPMN.

Summary: Intraportal islet transplantation has a long history as a procedure for clinical islet transplantation. However, many recent studies revealed that the intraportal procedure has some disadvantages in transplant efficiency and safety. Many candidates as an optimal transplant site for islets have been assessed, but further studies and clinical trials are still necessary. Intramuscular and subcutaneous spaces are important candidates, because the transplant and biopsy procedures are simple approaches with minimal invasion and few complications. Although they are sites with hypovascularity and hypoxia, which contribute to the poor transplant efficiency, many experimental trials for improving the outcome in intramuscular and subcutaneous islet transplantations have been performed, focusing on early angiogenesis and scaffolds for engrafting transplanted islets. We review current progress in intramuscular and subcutaneous islet transplantations and discuss ways to develop them as optimal transplant sites for islets. © 2013 John Wiley &amp Sons, Ltd.

Based on the results of first-line chemotherapy for advanced pancreatic cancer, S-1 was confirmed to be non-inferior to gemcitabine. However, the recommended regimen of 4 weeks of administration followed by 2 weeks of drug withdrawal frequently causes adverse effects. On the other hand, we experienced in clinical practice that alternate-day administration of S-1 reduced adverse effects and were tolerable for advanced pancreatic cancer patients unwilling to continue the standard daily administration. We therefore conducted a multicenter cooperative prospective study to compare daily with alternate-day administration of S-1 for advanced pancreatic cancer. Patients with advanced pancreatic cancer were eligible for enrollment in this trial. S-1 was administered at a dose of 40-60 mg twice daily, calculated according to body surface area, on Monday, Wednesday, Friday, and Sunday. Each treatment cycle was 42 days. The primary end point was overall survival (OS). Secondary end points were safety, response rate (RR), progression-free survival (PFS), and time to treatment failure (TTF). Forty-eight patients were evaluable for response. OS as the primary end point was 8.4 months (95 % CI 5.4-10.8), and the 1-year survival rate was 29.2 %. PFS was 5.5 months, and TTF was 3.9 months. RR was 10.4 %, and the disease control rate was 79.2 %. Grade 3/4 hematological and non-hematological toxicities were minor. All of these adverse reactions were tolerable and reversible. The current data demonstrate the mitigation of adverse effects with alternate-day administration of S-1, and this appears to be a more sustainable option for advanced pancreatic cancer.

Pancreatic cancer is a highly lethal disease with a poor prognosis the molecular mechanisms of the development of this disease have not yet been fully elucidated. N-myc downstream regulated gene 2 (NDRG2), one of the candidate tumor suppressor genes, is frequently downregulated in pancreatic cancer, but there has been little information regarding its expression in surgically resected pancreatic cancer specimens. We investigated an association between NDRG2 expression and prognosis in 69 primary resected pancreatic cancer specimens by immunohistochemistry and observed a significant association between poor prognosis and NDRG2-negative staining (P = 0.038). Treatment with trichostatin A, a histone deacetylase inhibitor, predominantly up-regulated NDRG2 expression in the NDRG2 low-expressing cell lines (PANC-1, PCI-35, PK-45P, and AsPC-1). In contrast, no increased NDRG2 expression was observed after treatment with 5-aza-2′ deoxycytidine, a DNA demethylating agent, and no hypermethylation was detected in either pancreatic cancer cell lines or surgically resected specimens by methylation specific PCR. Our present results suggest that (1) NDRG2 is functioning as one of the candidate tumor-suppressor genes in pancreatic carcinogenesis, (2) epigenetic mechanisms such as histone modifications play an essential role in NDRG2 silencing, and (3) the expression of NDRG2 is an independent prognostic factor in pancreatic cancer. © 2013 Elsevier Inc. All rights reserved.

Introduction: The glucagon provocative test is useful for the diagnosis of gastrinoma. The aim of this study was to determine the criteria for the glucagon provocative test. Methods: This study reviewed 8 patients that underwent the glucagon provocative test preoperatively and in whom the diagnosis was confirmed as gastrinoma histologically. The glucagon provocative test was performed by administering glucagon (20 μg/kg) intravenously, followed by 20 μg/kg h for the next 30 min, and plasma gastrin levels were measured 3 and 1 min before and 3, 5, 7, 10, 15, 20, and 30 min after the administration of glucagon. This study evaluated the peak value of plasma gastrin and the time required to reach the peak. Results: Two of the 8 patients had multiple endocrine neoplasm type 1. The basal plasma gastrin levels ranged from 524 to 10,300 pg/ml. The time required to reach the peak was 3-10 min for all patients. The increase in the peak from the basal value was 235-8,920 pg/ml, and the percentage of increase was 38-337 %. Conclusions: These results suggest that a diagnosis of gastrinoma should thus be made when plasma gastrin levels peak within 10 min after glucagon administration, with an increase of greater than 200 pg/ml and greater than 35 % of the basal value. © 2012 Springer.

Surgical resection is the only curative strategy for pancreatic ductal adenocarcinoma (PDAC), but recurrence rates are high even after purported curative resection. First-line treatment with gemcitabine and S-1 (GS) is associated with promising antitumor activity with a high response rate. The aim of this study was to assess the feasibility and efficacy of GS in the neoadjuvant setting. In a multi-institutional single-arm phase 2 study, neoadjuvant chemotherapy (NAC) with gemcitabine and S-1, repeated every 21 days, was administered for two cycles (NAC-GS) to patients with resectable and borderline PDAC. The primary end point was the 2-year survival rate. Secondary end points were feasibility, resection rate, pathological effect, recurrence-free survival, and tumor marker status. Of 36 patients enrolled, 35 were eligible for this clinical trial conducted between 2008 and 2010. The most common toxicity was neutropenia in response to 90 % of the relative dose intensity. Responses to NAC included radiological tumor shrinkage (69 %) and decreases in CA19-9 levels (89 %). R0 resection was performed for 87 % in resection, and the morbidity rate (40 %) was acceptable. The 2-year survival rate of the total cohort was 45.7 %. Patients who underwent resection without metastases after NAC-GS (n = 27) had an increased median overall survival (34.7 months) compared with those who did not undergo resection (P = 0.0017). NAC-GS was well tolerated and safe when used in a multi-institutional setting. The R0 resection rate and the 2-year survival rate analysis are encouraging for patients with resectable and borderline PDAC.

症例は68歳男性。早期胃癌に対する加療時に施行したスクリーニング目的のCTにて、膵尾部に遅延濃染を呈する30mm大の腫瘤を認めた。血清IgG4値が258mg/dlと高値であり自己免疫性膵炎(AIP)も疑われたが、EUS-FNAにて腺癌の組織像を認め、膵尾部癌の診断で膵体尾部切除術を施行した。病理組織学的所見では、膵癌組織に加えて周囲に著明な線維化とリンパ球形質細胞浸潤を認めた。あわせて閉塞性静脈炎と著明なIgG4陽性形質細胞浸潤というAIPに類似した組織像も認めた。術後、血清IgG4値は144mg/dlに低下した。近年、AIPに膵癌を合併した症例や、AIPに類似した間質所見を呈する膵癌症例の報告がある。膵腫瘍の鑑別には、臨床像とあわせてEUS-FNAを用いた病理組織学的診断が有用と考えられた。(著者抄録)

While islet transplantation is considered a useful therapeutic option for severe diabetes mellitus (DM), the outcome of this treatment remains unsatisfactory. This is largely due to the damage and loss of islets in the early transplant stage. Thus, it is important to monitor the condition of the transplanted islets, so that a treatment can be selected to rescue the islets from damage if needed. Recently, numerous trials have been performed to investigate the efficacy of different imaging modalities for visualizing transplanted islets. Positron emission tomography (PET) and magnetic resonance imaging (MRI) are the most commonly used imaging modalities for this purpose. Some groups, including ours, have also tried to visualize transplanted islets by ultrasonography (US). In this review article, we discuss the recent progress in islet imaging. © 2013 Landes Bioscience.

While islet transplantation is considered a useful therapeutic option for severe diabetes mellitus (DM), the outcome of this treatment remains unsatisfactory. This is largely due to the damage and loss of islets in the early transplant stage. Thus, it is important to monitor the condition of the transplanted islets, so that a treatment can be selected to rescue the islets from damage if needed. Recently, numerous trials have been performed to investigate the efficacy of different imaging modalities for visualizing transplanted islets. Positron emission tomography (PET) and magnetic resonance imaging (MRI) are the most commonly used imaging modalities for this purpose. Some groups, including ours, have also tried to visualize transplanted islets by ultrasonography (US). In this review article, we discuss the recent progress in islet imaging. © 2013 Landes Bioscience.

Objectives: Pancreatic cancer is one of the most lethal malignancies; its poor prognosis is strongly associated with invasion and metastasis. Expression of S100A4 has been reported to correlate with poor prognosis in various cancers. We have investigated the role of S100A4 in pancreatic cancer tumorigenesis and its clinicopathologic significance. Methods: Protein expression of S100A4 was examined by Western blot in pancreatic cancer cell lines and a human pancreatic ductal epithelium cell line, HPDE-6. Then the expressions of S100A4, TP53, and CD133 were examined immunohistochemically in resected specimens from 83 patients with pancreatic cancer to clarify their clinicopathologic significance. Survival analyses were performed using the Kaplan-Meier method and the Mantel-Cox method. Results: Forty-eight (58%) of 83 patients with pancreatic cancer positively expressed S100A4, and 50 (60%) and 29 (36%) patients positively expressed TP53 and CD133, respectively. S100A4 expression was significantly correlated with perineural invasion (P = 0.029) and invasion pattern (P = 0.001). Neither TP53 nor CD133 expression showed significant correlations with any other parameters. Conclusions: Our present results suggest that S100A4 plays an important role in the invasiveness, particularly with perineural invasion and invasion pattern, of pancreatic cancer. Development of new strategies targeting S100A4 or its downstream effectors is warranted.

Invasive ductal adenocarcinoma (IDA) of the pancreas manifests poor prognosis due to the early invasion and distant metastasis. In contrast, intraductal papillary mucinous adenoma or carcinoma (IPMA or IPMC) reveals better clinical outcomes. Various molecular mechanisms contribute to these differences but entire picture is still unclear. Recent researches emphasized the important role of miRNA in biological processes including cancer invasion and metastasis. We previously described that miR-126 is down-regulated in IDA compared with IPMA or IPMC, and miR-126 regulates the expression of invasion related molecule disintegrin and metalloproteinase domain-containing protein 9 (ADAM9). Assessing the difference of miRNA expression profiles of IDA, IPMA, and IPMC, we newly identified miR-197 as an up-regulated miRNA specifically in IDA. Expression of miR-197 in pancreatic cancer cells resulted in the induction of epithelial-mesenchymal transition (EMT) along with the down-regulation of p120 catenin which is a putative target of miR-197. Direct interaction between miR-197 and p120 catenin mRNA sequence was confirmed by 3′UTR assay, and knockdown of p120 catenin recapitulated EMT induction in pancreatic cancer cells. In situ hybridization of miR-197 and immunohistochemistry of p120 catenin showed mutually exclusive patterns suggesting pivotal role of miR-197 in the regulation of p120 catenin. This miR-197/p120 catenin axis could be a novel therapeutic target. © 2012 Wiley Periodicals, Inc.

To improve the function of the polyvinyl alcohol (PVA) bioartificial pancreas, we focused on bone marrow derived mesenchymal stem cells (MSCs). We examined whether the function of PVA-encapsulated rat islets could be improved by coencapsulation with syngeneic MSCs. We macroencapsulated 1,500 rat islet equivalents (IEQ) with or without 1 x 10(6) MSCs with the use of 3% PVA solution before implantation intraperitoneally into diabetic BALB/c mice. We evaluated the function of the device in vitro (the residual rate, viability, and insulin-releasing function of the islets) and in vivo assessments (blood glucose and serum C-peptide changes after transplantation and glucose tolerance test). Although cultured islets also were destroyed, the shapes of the islets cocultured with MSCs were preserved but not different from encapsulated islets without MSCs. At 96 hours after culture the residual rates of islet recovery among those cocultured with versus without MSCs were 66% versus 39.5%, respectively, (P = .03). On the other hand, there was no significant difference between encapsulated islets with versus without MSCs. Furthermore, the stimulation index of the islets was improved by coculture with MSCs (2.6 +/- 0.6 vs 1.4 +/- 0.1; P = .03), but no beneficial effects were observed between islets encapsulated with versus without MSCs. The viability of islets cocultured with MSCs was significantly better than that without MSCs (84.2 +/- 2.5 vs 73.3 +/- 0.9; P = .037), but MSCs did not improve the viability of encapsulated islets. There were no significant differences in blood glucose or serum C-peptide between islets encapsulated with versus without MSCs. The histologic findings showed many degenerative islets and MSCs soon after transplantation. In conclusion, further studies are necessary to develop a novel PVA bioartificial pancreas that can be used with MSCs.

Purpose The present phase III study was designed to investigate the noninferiority of S-1 alone and superiority of gemcitabine plus S-1 compared with gemcitabine alone with respect to overall survival. Patients and Methods The participants were chemotherapy-naive patients with locally advanced or metastatic pancreatic cancer. Patients were randomly assigned to receive only gemcitabine (1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle), only S-1 (80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle), or gemcitabine plus S-1 (gemcitabine 1,000 mg/m2 on days 1 and 8 plus S-1 60, 80, or 100 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle). Results In the total of 834 enrolled patients, median overall survival was 8.8 months in the gemcitabine group, 9.7 months in the S-1 group, and 10.1 months in the gemcitabine plus S-1 group. The noninferiority of S-1 to gemcitabine was demonstrated (hazard ratio, 0.96; 97.5% CI, 0.78 to 1.18; P &lt; .001 for noninferiority), whereas the superiority of gemcitabine plus S-1 was not (hazard ratio, 0.88; 97.5% CI, 0.71 to 1.08; P = .15). All treatments were generally well tolerated, although hematologic and GI toxicities were more severe in the gemcitabine plus S-1 group than in the gemcitabine group. Conclusion Monotherapy with S-1 demonstrated noninferiority to gemcitabine in overall survival with good tolerability and presents a convenient oral alternative for locally advanced and metastatic pancreatic cancer. J Clin Oncol 31: 1640-1648. (C) 2013 by American Society of Clinical Oncology

Objectives: Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis associated with chronic pancreatitis and pancreatic cancer. Connexins (Cxs) allow direct intercellular communications as components of gap junction but also play important roles in the regulation of cell proliferation, cell differentiation, and tissue development. We here examined the expression of Cxs and Cx-mediated regulation of cell functions in PSCs. Methods: Human PSCs were isolated from patients undergoing operation for chronic pancreatitis or pancreatic cancer. The expression of Cxs was examined by reverse transcription polymerase chain reaction, Western blotting, and immunofluorescent staining. The roles of Cxs in PSC functions were examined by using carbenoxolone, a broad-spectrum Cx inhibitor, and small interfering RNA for Cx43. Results: Human activated PSCs expressed a variety of Cxs including Cx43 both in vitro and in vivo. Carbenoxolone inhibited platelet-derived growth factor-BB-induced proliferation and migration, and type I collagen expression in PSCs. In addition, carbenoxolone inhibited the activation of quiescent PSCs to a myofibroblastlike phenotype. Decreased Cx43 expression by small interfering RNA resulted in decreased proliferation and type I collagen expression. Conclusions: Pancreatic stellate cells expressed a variety of Cxs. Connexins, especially Cx43, might regulate the cell functions and activation of PSCs.

Pancreatic cancer is among the most lethal malignancies worldwide. We aimed to identify novel prognostic markers by applying mass spectrometry (MS)-based proteomic analysis to formalin-fixed paraffin-embedded (FFPE) tissues. Resectable, node positive pancreatic ductal adenocarcinoma (PDAC) with poor (n = 4) and better (n = 4) outcomes, based on survival duration, with essentially the same clinicopathological backgrounds, and noncancerous pancreatic ducts (n = 5) were analyzed. Cancerous and noncancerous cells collected from FFPE tissue sections by laser microdissection (LMD) were processed for liquid chromatography (LC)-tandem MS (MS/MS). Candidate proteins were identified by semiquantitative comparison and then analyzed quantitatively using selected reaction monitoring (SRM)-based MS. To confirm the associations between candidate proteins and outcomes, we immunohistochemically analyzed a cohort of 87 cases. In result, totally 1,229 proteins were identified and 170 were selected as candidate proteins for SRM-based targeted proteomics. Fourteen proteins overexpressed in cancerous as compared to noncancerous tissue showed different expressions in the poor and better outcome groups. Among these proteins, we found that three novel proteins ECH1, OLFM4 and STML2 were overexpressed in poor group than in better group, and that one known protein GTR1 was expressed reciprocally. KaplanMeier analysis showed high expressions of all four proteins to correlate with significantly worse overall survival (p &lt; 0.05). In conclusion, we identified four proteins as candidates of prognostic marker of PDAC. The combination of shotgun proteomics verified by SRM and validated by immunohistochemistry resulted in the prognostic marker discovery that will contribute the understanding of PDAC biology and therapeutic development.

This study investigated the clinicopathological features and surgical management of solid pseudopapillary neoplasms at a single institution in Japan. Seventeen patients (the largest series in Japan) those underwent surgery for pathologically confirmed solid pseudopapillary neoplasms were retrospectively reviewed. Sixteen patients were women and their mean age was 34.1 years. Most patients were asymptomatic (n = 11), and the average tumor diameter was 51.8 mm. The most common imaging characteristic was tumors of solid and cystic type (n = 10), which were most commonly located in the pancreatic body (n = 7). All patients underwent surgical exploration, i.e., distal pancreatectomies in 7 patients (laparoscopically performed in 2); middle pancreatectomies, 4; pancreaticoduodenectomies, 4; enucleation, 1; and liver resection, 1. No surgical mortalities occurred, and postsurgical complications occurred in 9 patients. Four patients had malignant tumors. One patient with liver metastases experienced recurrence, which was well controlled by paclitaxel. The remaining patients were disease free at a median follow-up of 51 months. Solid pseudopapillary neoplasms can be treated by complete tumor resection with limited resection or a minimally invasive approach when applicable. The combination of surgical resection and chemotherapy may therefore prolong survival, even in malignant cases.

Background/Aims: Recently the role of tumor-associated macrophages (TAMs) on immunity has been variously discussed. We studied a series of cell surface antigens in TAMs in colorectal cancer tissues and their corresponding normal tissues using flow cytometry to find out prognostic indicators of these patients. Methodology: We assessed the numbers of CD14+ macrophages positive for each of the cell surface antigens (CD80, CD86, HLA-DR, CD1a, CD40 and CD83) in cancer tissues and corresponding normal tissues among 31 patients with colorectal cancer, and performed the univariate and multivariate analysis to find out prognostic indicators for overall survival among the patients. Results: The numbers of CD80+, CD86+ and HLADR+ TAMs in the cancer tissues were higher than those in corresponding normal tissues. Inversely CD40+ and CD83+ macrophages in cancer tissues were less than those in normal tissues. With the multivariate analysis, the number of CD40+ TAMs, as well as lymph node metastasis and distant metastasis, was shown to be an independent prognostic factor of colorectal cancer patients. Conclusions: The dense infiltration of CD40+ TAM in colorectal cancer tissues indicates a favorable prognosis, which suggests that CD40 plays an important role in the tumor immunity of colorectal cancer.

The paper reports on a discovery field exercise used to examine how disaster responders can use an audio and video equipped robot to interact with a trapped victim. In the exercise, a small robot with two-way video and audio communication was inserted into a physically simulated building collapse next to a trapped victim, and was provided to a team of trained responders as a means for performing remote triage and victim monitoring. The interaction between the responders and the victim was examined, with emphasis on how the responders adapted to different video and audio capabilities, and how they might have responded to different populations and injuries that may limit communication. The ad hoc interaction protocols used by the responders were observed in the field exercise, and four interaction schemes were identified: Two-way Video with Two-way Audio, One-way Video (from Robot to Responders) with Two-way Audio, Two-way Video with no Audio, and One-way Video (from Robot to Responders) with no audio. The interaction schemes are defined according to the minimum capabilities of the robot and victim, the requirements of the responders, and preliminary protocols required for each interaction scheme. From observations made about the exercise, the paper identifies minimalistic interfaces and transparency of robot state as key areas for improving a robotmediated interaction between responders and victims. © 2013 IEEE.

Pancreatic intraepithelial neoplasia (PanIN) is one of the most important issues for the early detection of pancreatic ductal adenocarcinoma. In particular, PanIN-3 is recognized as a precancerous lesion, e.g., carcinoma in situ, high-grade dysplasia, and severe dysplasia. We report a rare, completely resected case of PanIN-3 in the main pancreatic duct (MPD) detected from localized pancreatitis. A 63-year-old man developed upper abdominal pain with hyperamylasemia. He underwent distal pancreatectomy soon after recovery because an abnormal narrow segment, suggesting PanIN, was identified in the pancreatic body by endoscopic retrograde cholangiopancreatography. Histopathological findings revealed a PanIN-3 located in the MPD that could be resected completely. This finding suggests that if unidentified localized pancreatitis develops, we should carefully examine the fine structural changes in the MPD. © Springer 2013.

Background/objectives: As intraductal papillary mucinous neoplasm (IPMN) of the pancreas is associated with acute pancreatitis (AP) in some cases, predicting the risk of pancreatitis is as important as predicting the risk of malignancy in IPMN cases. In this study, we attempted to clarify the characteristics of IPMN associated with AP, compared to those of IPMN not associated with AP. Methods: From January 2006 to March 2013, data from 88 patients who underwent surgery for IPMN were retrospectively investigated and analyzed. We evaluated clinical and pathological variables of each patient and compared patients with IPMN with AP to those without AP. Furthermore, we presented representative cases of mild and severe pancreatitis caused by IPMN. Results: Overall, 12 of 88 patients with IPMN (13.6%) had AP. Seven of the 12 patients had a single episode of AP, whereas the remaining 5 patients were diagnosed with IPMN with repeated AP. Ten of 12 patients with AP were diagnosed with mild AP and the remaining 2 with severe AP. Regarding clinical findings, the proportion of dilated papilla with mucin extrusion was significantly higher in patients with IPMN with AP than in those without AP (p = 0.035). Histological findings indicated that the proportion of intestinal-subtype IPMN was significantly higher in patients with IPMN with AP (p = 0.013). Conclusions: AP caused by IPMN derives mostly from intestinal IPMN. Dilated papilla with mucin extrusion can be a potential predictor of AP. Copyright © 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

The precise relationship between GCF2 expression and carcinogenesis has not yet been established. To clarify the metastatic potential of GCF2 in colorectal cancer, HT-29 cells stably suppressing GCF2 expression were injected into the spleens of severe combined immunodeficient (SCID) mice. GCF2 suppression reduced the number of metastatic foci in the liver and reduced fibronectin-induced cell adhesion, migration, and invasion. Downstream from the integrin signaling pathways. GCF2 regulates RhoA interaction with the RGS domain of Leukemia associated RhoGEF (LARG). Altogether, our results suggest that GCF2 plays an important role in colorectal cancer metastasis by regulating RhoA-induced cell adhesion, migration, and invasion. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Objectives: Since 1981, the Japan Pancreas Society has been hosting a nationwide pancreatic cancer registry. To commemorate its 30th anniversary, we review its history and latest achievement. Methods: During 3 decades, more than 350 leading institutions in Japan contributed voluntarily to register and periodic follow-up. The registry was modified to protect privacy by encrypting and hash algorithm. Results: From 1981 to 2007, 32,619 cumulative records were analyzed. The overall survival of invasive cancer was improved significantly. More patients with earlier stage or with intraductal and cystic neoplasms underwent resection. The strongest prognostic factor of Union for International Cancer Control (UICC) stage IIA and IIB tubular adenocarcinoma in the pancreatic head was histological grade, followed by tumor size, extent of lymph node dissection, and postoperative chemotherapy. The 5-year survival rate of Union for International Cancer Control stage 0 reached 85%. The improvement of survival of patients with invasive cancer in Japan can be attributed to the introduction of effective chemotherapies, regionalization, and the earlier diagnosis and treatment. Simple definition of "early pancreatic cancer" is needed. Conclusions: At the 30th year anniversary, the Japan Pancreas Society nationwide pancreatic cancer registry is more shining than ever for current perspectives and for future diagnostic and treatment tactics.

Background/Aims: The rate and site of bone metastasis from cholangiocarcinoma as well as the prognosis are unclear. Therefore, we intend to make a comparative review of the background to bone metastasis, examine a high-risk group for bone metastasis and use the data towards the improvement in quality of life. Methodology: We studied 200 cases of cholangiocarcinoma resected in our division from January 2003 to April 2010. Results: Bone metastasis was confirmed in four cases (2.0%). The survival period after the diagnosis of bone metastasis ranged from 2.9 months to 21.6 months and the average was 6.7 months. We studied histopathological findings of bone metastasis, lymph node metastasis, lymphatic invasion, blood vessel invasion and perineural invasion (ly, v and pn) and found that all of four bone metastasis cases were positive for lymph node metastasis which was a statistically significant factor affecting bone metastasis. Conclusions: Since the number of cases we studied is small, it is difficult to determine whether lymph node metastasis is a risk factor for bone metastasis; however, we think it is necessary to take the probability of bone metastasis into consideration when we provide medical care to patients positive for lymph node metastasis.

Aromatase is one of the key estrogen-producing enzymes and is regarded as one of the therapeutic targets in estrogen receptor-positive breast cancer patients. Human colon carcinoma has also been recently proposed as being an estrogen-responsive malignancy, but the detailed status of aromatase has not yet been reported. Therefore, in this study, we evaluated the aromatase expression in colon carcinoma using immunohistochemistry and real-time polymerase chain reaction. Aromatase mRNA was significantly higher (p=0.03) in colon carcinoma than in the corresponding non-neoplastic mucosa (n=31). Aromatase immunoreactivity tended to be positively associated with the intratumoral concentration of estrogens (n=53), and in particular, the concentration of estradiol was significantly higher (p=0.02) in aromatase-positive cases in men. Aromatase immunoreactivity was detected in the cytoplasm of the carcinoma cells in 217/328 (65%) examined colon carcinoma cases. Aromatase immunoreactivity was significantly positively correlated with tubular differentiation, and inversely correlated with Ki-67 labeling index, although not necessarily correlated with the clinical outcome of the patients. All these results demonstrate that colon carcinoma expresses functional aromatase, and that estrogens are locally synthesized in the tumor tissues. The findings reported here could contribute to a better understanding of the actions of estrogen in colon carcinoma.

Multiple proteins are involved in activation and inactivation of 2',2'-difluorodeoxycytidine (gemcitabine, dFdC). We aimed to clarify the mechanism of dFdC resistance in a pancreatic cancer cell line by applying a combination of targeted proteomic and metabolomic analyses. Twenty-five enzyme and transporter proteins and 6 metabolites were quantified in sensitive and resistant pancreatic cancer cell lines, PK9 and RPK9, respectively. The protein concentration of deoxycytidine kinase (dCK) in RPK9 cells was less than 0.02-fold (2 %) compared with that in PK9 cells, whereas the differences (fold) were within a factor of 3 for other proteins. Targeted metabolomic analysis revealed that phosphorylated forms of dFdC were reduced to less than 0.2 % in RPK9 cells. The extracellular concentration of 2',2'-difluorodeoxyuridine (dFdU), an inactive metabolite of dFdC, reached the same level as the initial dFdC concentration in RPK9 cells. However, tetrahydrouridine treatment did not increase phosphorylated forms of dFdC and did not reverse dFdC resistance in RPK9 cells, though this treatment inhibits production of dFdU. Combining targeted proteomics and metabolomics suggests that acquisition of resistance in RPK9 cells is due to attenuation of dFdC phosphorylation via suppression of dCK.

Purpose: It is still technically difficult to collect high purity cancer cells from tumor tissues, which contain noncancerous cells. We hypothesized that xenograft models of NOG mice expressing enhanced green fluorescent protein (eGFP), referred to as NOG-EGFP mice, may be useful for obtaining such high purity cancer cells for detailed molecular and cellular analyses. Methods: Pancreato-biliary cancer cell lines were implanted subcutaneously to compare the tumorigenicity between NOG-EGFP mice and nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. To obtain high purity cancer cells, the subcutaneous tumors were harvested from the mice and enzymatically dissociated into single-cell suspensions. Then, the cells were sorted by fluorescence-activated cell sorting (FACS) for separation of the host cells and the cancer cells. Thereafter, the contamination rate of host cells in collected cancer cells was quantified by using FACS analysis. The viability of cancer cells after FACS sorting was evaluated by cell culture and subsequent subcutaneous reimplantation in NOG-EGFP mice. Results: The tumorigenicity of NOG-EGFP mice was significantly better than that of NOD/SCID mice in all of the analyzed cell lines (p &lt; 0.01). Sorting procedures enabled an almost pure collection of cancer cells with only slight contamination by host cells. Reimplantation of the sorted cancer cells formed tumors again, which demonstrated that cell viability after sorting was well maintained. Conclusions: This method provides a novel cancer sampling system for molecular and cellular analysis with high accuracy and should contribute to the development of personalized medicine.

局所進行膵頭部癌に対しての術前化学療法は現在広く行われている治療法であり、画像上腫瘍縮小を認めない場合でも局所浸潤部への効果が期待される。今回われわれは術前治療を施行し切除し得た2症例を経験したので報告する。症例1:50歳代男性。前医で上腸間膜動脈(SMA)/上腸間膜静脈(SMV)への浸潤を疑う切除不能局所進行膵頭部癌と診断。当科紹介受診後術前放射線化学療法施行したがSDであった。亜全胃温存膵頭十二指腸切除術(SSPPD)を施行。SMV切離非再建で切除しR0を得た。症例2:70歳代男性。前医で直径4cm大の膵頭部腫瘤、SMVのencasementが存在した。当科にて術前化学療法施行、画像上効果判定はSD。SSPPD・左腎静脈をグラフトとして用いてSMV再建しR0であった。(著者抄録)

Background/Aims: Gemcitabine is widely used as a first-line therapy for biliary tract cancer (BTC). However, few studies have been conducted to analyze second-line therapies. Methodology: From 33 patients who had been administered gemcitabine following resection between May 2005 and August 2007, we retrospectively analyzed the safety and efficacy of S-1 in 11 cases who received S-1 as second-line therapy due to recurrence or relapse of the primary disease. Results: Among the adverse events (AEs) observed during S-1 administration, the most common was a decrease in the concentration of hemoglobin, followed by thrombocytopenia. No Grade 4 AEs or worse were detected. In addition, the AEs and their respective severity strongly resembled those of gemcitabine used as a first-line therapy. There were 7 cases that could be evaluated according to RECIST criteria, of which 1 was considered in the partial response and 3 as stable disease. The medians of time to progression after S-1 administration and survival after S-1 administration were 5.6 months and 31 months, respectively. Conclusions: S-1 could be taken safely as a second-line therapy without provoking severe AEs. By preventing the cessation of S-1 administration due to its AEs, more continued S-1 administration could lead to a better prognosis for BTC.

Background: Postoperative pancreatic fistula (POPF) remains one of the most common causes of morbidity following pancreaticoduodenectomy (PD). This randomized trial examined whether external stent drainage of the pancreatic duct decreases the rate of POPF after PD and subsequent pancreaticojejunostomy (PJ). Methods: Consecutive patients who underwent PD with subsequent construction of a duct-to-mucosa PJ were randomized into a stented and a non-stented group. The primary outcome was the incidence of clinically relevant POPF. Secondary outcomes were morbidity and mortality rates, and hospital stay. Results: Of 114 PD procedures, 93 were suitable for inclusion in the study after informed consent. The rate of clinically relevant POPF was significantly lower in the stented group than in the non-stented group: three of 47 (6 per cent) versus ten of 46 (22 per cent) (P = 0.040). Among patients with a dilated duct, rates of POPF were similar in both groups. Among patients with a non-dilated duct, clinically relevant POPF was significantly less common in the stented group than in the non-stented group: two of 21 (10 per cent) versus eight of 20 (40 per cent) (P = 0.033). No significant differences in morbidity or mortality were observed. Univariable analysis identified body mass index (BMI), pancreatic cancer, pancreatic texture, pancreatic duct size and duct stenting as risk factors related to clinically relevant POPF. Multivariable analysis taking these five factors into account identified high BMI (risk ratio (RR) 11.45; P = 0.008), non-dilated duct (RR 5.33; P = 0.046) and no stent (RR 10.38; P = 0.004) as significant risk factors. Conclusion: External duct stenting reduced the risk of clinically relevant POPF after PD and subsequent duct-to-mucosa PJ. Registration number: UMIN000000952 (http://www.umin.ac.jp/ctr/index-j.htm).

Although gemcitabine is the most effective chemotherapeutic agent against pancreatic cancer, a growing concern is that a substantial number of patients acquire gemcitabine chemoresistance. To elucidate the mechanisms of acquisition of gemcitabine resistance, we developed gemcitabine-resistant cell lines from six human cancer cell lines; three pancreatic, one gastric, one colon, and one bile duct cancer. We first analyzed gemcitabine uptake using three paired parental and gemcitabine resistant pancreatic cancer cell lines (PK-1 and RPK-1, PK-9 and RPK-9. PK-59 and RPK-59) and found that uptake of gemcitabine was rapid. However, no DNA damage was induced in resistant cells. We further examined the microarray-based expression profiles of the cells to identify genes associated with gemcitabine resistance and found a remarkable reduction in the expression of deoxycytidine kinase (DCK). DCK is a key enzyme that activates gemcitabine by phosphorylation. Genetic alterations and expression of DCK were studied in these paired parental and derived gemcitabine-resistant cell lines, and inactivating mutations were found only in gemcitabine-resistant cell lines. Furthermore, siRNA-mediated knockdown of DCK in the parental cell lines yielded gemcitabine resistance, and introduction of DCK into gemcitabine-resistant cell lines invariably restored gemcitabine sensitivities. Mutation analyses were expanded to three other different paired cell lines, DLD-1 and RDLD-1 (colon cancer cell line), MKN-28 and RMKN-28 (gastric cancer cell line), and TFK-1 and RTFK -1 (cholangiocarcinoma cell line). We found inactivating mutations in RDLD-1 and RTFK-1 and decreased expression of DCK in RMKN-28. These results indicate that the inactivation of DCK is one of the crucial mechanisms in acquisition of gemcitabine resistance. (C) 2012 Elsevier Inc. All rights reserved.

Distal pancreatectomy is indicated for lesions in the pancreatic body and tail. Understanding of the anatomical structure of the pancreas and its surroundings is required in various situations in left upper abdominal surgery including the laparoscopic approach. Spleen-preserving distal pancreatectomy is indicated for lesions confined to the pancreas. Two major spleen-preserving procedures reported are the Warshaw procedure that conserves the spleen by blood flow from the short gastric vessels and the Kimura procedure that preserves the spleen with splenic vessels. Considering the laparoscopic approach, the surgeon may preserve splenic vessels from the median toward the splenic hilum without mobilization of the spleen. A standard distal pancreatectomy using the medial approach is presented on video. The intraoperative complications of distal pancreatectomy can be minimized by avoiding splenic capsule injury, by careful differentiation of the splenic artery from the common hepatic artery, and by secure closure of the splenic vein stump. The incidence of postoperative pancreatic fistula following distal pancreatectomy is reported to be 13% in a nationwide pancreatic cancer registry. Based on the results of an international randomized trial of hand-sewn and staple closure of the pancreatic stump, the closure method of the pancreatic stump can be the surgeon's choice.

Middle pancreatectomy is parenchyma- and adjacent organ-sparing pancreatectomy indicated for small tumors located in the body, but deeply located in the gland, and therefore hard to enucleate. Others lesions including pancreatic trauma or arteriovenous malformation are also candidate targets. Invasive ductal carcinoma, even when the tumor is small enough, is not eligible because the most of these tumors show extrapancreatic invasion. After exposure of neck to body of the pancreas, middle pancreatectomy was performed by proximal and distal transection, reconstruction after Roux-Y pancreaticojejunostomy, which is the most common. This procedure is low-invasive and allow the preservation of exocrine and endocrine pancreatic function without loss of duodenal passage, however, it also has a high morbidity associated with pancreatic fistula. This article provides indications and surgical techniques with special focus on the procedure of middle pancreatectomy.

Background. Wrapping is thought to prevent pancreatic fistula and postoperative hemorrhage for pancreaticoduodenectomy (PD), and we analyzed whether oinentum/falcifonn ligament wrapping decreases postoperative complications after PD. Methods. This is a retrospective study of wrapping using the omentum/falciform ligament in patients that underwent PD between January 2006 and June 2008 in 139 institutions that were members of the Japanese Society of Pancreatic Surgery. Results. Ninety-one institutions responded to the questionnaires, and data were accumulated from 3,288 patients. The data from 2,597 patients were acceptable for analysis; 918 (35.3%) patients underwent wrapping and 1,679 patients did not. A pancreatic fistula occurred in 623 patients (37.3%) in the nonwrapping group, in comparison to 393 patients (42.8%) in the wrapping group (P = .006). The incidence of a grade B/C pancreatic fistula was lower in the nonwrapping group than the wrapping group (16.7% vs 21.5%; P =.002). An intra-abdominal hemorrhage occurred in 54 patients (3.2%) in the nonzorapping group, which was similar to the incidence in the wrapping group (32 patients; 3.5 %). The mortality was 1.3% and 1.0% in nonwrapping and wrapping groups, respectively. A multivariate analysis revealed 7 independent risk factors for pancreatic fistula; male, hypoalbuminemia, soft pancreas, long operation time, extended resection, pylorus preservation, and omentum wrapping. There were 4 independent risk factors for early intra-abdominal hemorrhage and 2 independent risk factors for late intra-abdominal hemorrhage. Conclusion. This retrospective study revealed that mention wrapping did not decrease the incidence of pancreatic fistula. An additional validation study is necessary to evaluate the efficacy of wrapping for PD. (Surgery 2012;151:183-91.)

Objective: To examine the clinicopathologic features and clonal relationship of multifocal intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Background: Intraductal papillary mucinous neoplasms are increasingly diagnosed cystic precursor lesions of pancreatic cancer. Intraductal papillary mucinous neoplasms can be multifocal and a potential cause of recurrence after partial pancreatectomy. Methods: Thirty four patients with histologically documented multifocal IPMNs were collected and their clinicopathologic features catalogued. In addition, thirty multifocal IPMNs arising in 13 patients from 3 hospitals were subjected to laser microdissection followed by KRAS pyrosequencing and loss of heterozygosity (LOH) analysis on chromosomes 6q and 17p. Finally, we sought to assess the clonal relationships among multifocal IPMNs. Results: We identified 34 patients with histologically documented multifocal IPMNs. Synchronous IPMNs were present in 29 patients (85%), whereas 5 (15%) developed clinically significant metachronous IPMNs. Six patients (18%) had a history of familial pancreatic cancer. A majority of multifocal IPMNs (86% synchronous, 100% metachronous) were composed of branch duct lesions, and typically demonstrated a gastric-foveolar subtype epithelium with low or intermediate grades of dysplasia. Three synchronous IPMNs (10%) had an associated invasive cancer. Molecular analysis of multiple IPMNs from 13 patients demonstrated nonoverlapping KRAS gene mutations in 8 patients (62%) and discordant LOH profiles in 7 patients (54%); independent genetic alterations were established in 9 of the 13 patients (69%). Conclusions: The majority of multifocal IPMNs arise independently and exhibit a gastric-foveolar subtype, with low to intermediate dysplasia. These findings underscore the importance of life-long follow-up after resection for an IPMN.

Due to current improvements in techniques for islet isolation and transplantation and protocols for immunosuppressants, islet transplantation has become an effective treatment for severe diabetes patients. Many diabetic animal models have contributed to such improvements. In this paper, we focus on 3 types of models with different mechanisms for inducing diabetes mellitus (DM): models induced by drugs including streptozotocin (STZ), pancreatomized models, and spontaneous models due to autoimmunity. STZ-induced diabetes is one of the most commonly used experimental diabetic models and is employed using many specimens including rodents, pigs or monkeys. The management of STZ models is well established for islet studies. Pancreatomized models reveal different aspects compared to STZ-induced models in terms of loss of function in the increase and decrease of blood glucose and therefore are useful for evaluating the condition in total pancreatomized patients. Spontaneous models are useful for preclinical studies including the assessment of immunosuppressants because such models involve the same mechanisms as type 1 DM in the clinical setting. In conclusion, islet researchers should select suitable diabetic animal models according to the aim of the study.

Segmentectomy is anatomical resection of segments based on the classification of Couinaud. This procedure is performed mainly for hepatocellular carcinoma. Invasion of portal vein and intrahepatic metastases often occur with hepatocellular carcinoma. Thus, it is desirable to perform anatomical resection of the cancer-bearing areas for curative purpose. However, segmentectomy is selected when extensive resection must be avoided to preserve liver function. There are major differences between segmentectomy of the left hemiliver (Sg 2-4) and right hemiliver (Sg 5-8). In the former, the branches (third-order branches) arising from the umbilical portion of the portal vein can be ligated prior to liver resection. In the latter, manipulation is difficult. Therefore, ultrasonically guided segmental staining is performed by puncturing the portal branch and injecting a dye. This report described techniques for segmentectomy.

膵癌の切除術後生存率は過去30年で有意に上昇している．その理由は，有効な抗癌剤のわが国への導入と補助療法の標準化，high volume centerでの治療成績の向上，そしてより早期での外科切除がなされていることである．拡大切除により「癌をとりきる」考え方から「標準切除」へと変化し，有効な補助療法の探索が臨床研究で積極的に行われている．より早期の病変を切除する外科治療の役割は今後もきわめて重要である．<br>

Background: Pancreatic cancer is among the most lethal malignancies worldwide. This study aimed to identify a novel prognostic biomarker, facilitating treatment selection, using mass spectrometry (MS)-based proteomic analysis with formalin-fixed paraffin-embedded (FFPE) tissue. Results: The two groups with poor prognosis (n = 4) and with better prognosis (n = 4) had been carefully chosen among 96 resected cases of pancreatic cancer during 1998 to 2007 in Tohoku University Hospital. Although those 2 groups had adjusted background (UICC-Stage IIB, Grade2, R0, gemcitabine adjuvant), there was a significant difference in postoperative mean survival time (poor 21.0 months, better 58.1 months, P = 0.0067). Cancerous epithelial cells collected from FFPE tissue sections by laser micro-dissection (LMD) were processed for liquid chromatography-tandem mass spectrometry (LC-MS/MS). In total, 1099 unique proteins were identified and 6 proteins showed different expressions in the 2 groups by semi-quantitative comparison. Among these 6 proteins, we focused on Nm23/Nucleoside Diphosphate Kinase A (NDPK-A) and immunohistochemically confirmed its expression in the cohort of 96 cases. Kaplan-Meier analysis showed high Nm23/NDPK-A expression to correlate with significantly worse overall survival (ρ = 0.0103). Moreover, in the multivariate Cox regression model, Nm23/NDPK-A over-expression remained an independent predictor of poor survival with a hazard ratio of 1.97 (95% CI 1.16-3.56, ρ = 0.0110). Conclusions: We identified 6 candidate prognostic markers for postoperative pancreatic cancer using FFPE tissues and immunohistochemically demonstrated high Nm23/NDPK-A expression to be a useful prognostic marker for pancreatic cancer. © 2012 Takadate et al. licensee BioMed Central Ltd.

As chemotherapy advances, patients who had liver metastases often come to receive liver resection after their chemotherapy, including oxaliplatin-based chemotherapy. We experienced a case of an acute hypersensitivity reaction to reintroduced-oxaliplatin at the second course of oxaliplatin-based adjuvant chemotherapy, after neoadjuvant chemotherapy for liver metastases originating from colon cancer. There is a report that hypersensitivity reactions are frequent in the second course of the reintroduced-oxaliplatin-based regimen. It is thought that the prevention is necessary at the second course even if there is no significant symptom at the first course. Similar cases will increase as neoadjuvant therapies spread in the future therefore, prescriptions for preventing hypersensitivity are necessary when administering reintroduced-oxaliplatin base chemotherapy.

We report a case of severe hepatic failure caused by gemcitabine hydrochloride (GEM) monotherapy after pancreaticoduodenectomy for advanced pancreatic cancer. A 73-year-old woman received GEM as an adjuvant chemotherapy. She suffered from progressive edema, fatigue, and jaundice after the third GEM administration. Severe liver dysfunction and elevation of bilirubin was observed. A computed tomography scan and magnetic resonance imaging showed diffuse liver swelling suggesting severe hepatic edema with fat accumulation. Needle biopsy of the liver revealed remarkable cholestasis and fat deposition with mild damage of hepatocytes. Drug-induced liver failure was suspected. GEM-stimulated lymphocyte test was negative, but antinuclear antibody was elevated with a marked inflammatory response. She improved to an almost normal condition by steroid and liver protective therapies within a week. Although the frequency of liver failure induced by GEM monotherapy is very rare, it could be fatal. It is important to distinguish it from other causes of liver dysfunction following pancreaticoduodenectomy. Early detection and appropriate drug therapy can improve the prognosis. © 2011 Springer.

Islet transplantation is characterized by the transplantation of isolated islets from donor pancreata into a diabetic recipient. Although it is a viable choice in the treatment of insulin dependent diabetes mellitus, most patients (approximately 90%) require insulin five years after transplantation. Recently, the co-transplantation of mesenchymal stem cells (MSCs) and islets in animal studies has revealed the effectiveness of MSCs co-transplantation for improving islet function. The mechanisms underlying the beneficial impact of MSCs include immunomodulation and the promotion of angiogenesis. In this review, we discuss MSCs and how they support improved graft survival and function. (C) 2011 Baishideng. All rights reserved.

Background/Aims: The feasibility of neoadjuvant chemoradiation therapy for cholangiocarcinoma, followed by conventional resection, has not been determined yet. Here, a phase I study of neoadjuvant chemoradiation therapy, named NACRAC, was performed to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of gemcitabine when combined with external beam radiation therapy for resectable cholangiocarcinoma. Methodology: From August 2007 to June 2008, 12 patients provided informed consent. Preoperative radiation was administered in 1.8Gy daily fractions up to a total dose of 45Gy. Gemcitabine was administered at day land 8 every three weeks. The initial dose of gemcitabine was started from 400mg/m2(.) Results: One patient was not able to start treatment because of bleeding caused by a duodenal ulcer and cholangitis. At 800mg/m(2) of gemcitabine, one patient out of three failed to complete the treatment because of Grade 3 hematological toxicity. In another three cases of 800mg/m(2), the second case could not complete the treatment because of cholangitis. Then, 600mg/m(2) was determined to be the MTD, and the RD dose decided as 600mg/m(2). Conclusions: The RD of gemcitabine in NACRAC study was determined to be 600mg/m(2). NACRAC study should proceed to a phase II trial to evaluate the effectiveness.

Background We evaluated the efficacy and feasibility of paclitaxel in patients with gemcitabine-refractory pancreatic cancer. We also evaluated the correlation between tumor marker decline and response rate. Methods Thirty patients histologically diagnosed with pancreatic cancer who had undergone paclitaxel treatment as salvage chemotherapy were retrospectively analyzed. Paclitaxel treatment was performed with 80 mg/(m(2) week) for 3 weeks followed by 1 week rest, and this was continued until failure. Tumor marker response was evaluated by measuring levels of carbohydrate antigen 19-9, carcinoembryonic antigen, and DUPAN-2 monthly. Results In total, 272 weekly paclitaxel treatments were performed. The median number of treatments per patient was 8 (range 1-22). The median overall survival from the start of paclitaxel treatment was 6.7 months (range 1.2-18.8). The response rate was 10% (3/30 patients) and the disease control rate was 46.7% (14/30 patients). Although grade 3 and 4 hematological and non-hematological toxicities were seen in 7 and 6 patients, respectively, adverse events were managed by conservative treatment. We found a significant correlation between the disease control rate and tumor marker decline within 2 months of paclitaxel treatment (P = 0.01). Patients with tumor marker decline tended to survive longer. Conclusion Weekly administration of paclitaxel in patients with gemcitabine-refractory pancreatic cancer seems to be well tolerated and can be effective. Paclitaxel treatment should be considered as salvage chemotherapy after gemcitabine failure in patients with good performance status.

切除可能膵癌に対する標準治療は，切除+術後補助化学療法であるが，その成績は十分とはいえない．術前治療は，全身状態の良い術前に行われることで，根治切除率を高め，また治療反応性を確認できる利点がある．食道癌や乳癌では既に標準治療として行われているが，膵癌では少数例での検討のみであり，さらなる検討が必要である．治療の有効性指標として，R0切除率などとともに，血清腫瘍マーカーの推移（治療前後・切除後）は重要である．これまでの検討では，全身化学療法による術前治療は，安全に施行可能で，切除機会の喪失もほとんどなく，今後他施設で前向きに症例を集積していくべきである．<br>

We performed in vitro and in vivo experiments of the anti-epidermal growth factor receptor (EGFR) x anti-CD3 bispecific diabody (hEx3-Db) with the IgG-like bispecific antibodies (BsAbs) (hEx3-scFv-Fc and hEx3-scDb-Fc) and the anti-EGFR therapeutic antibody cetuximab to assess the effect of BsAbs on cancer growth inhibition. In vitro, efficacy of the BsAbs and cetuximab were compared by growth inhibition assays of human cell lines of bile duct (TFK-1, HuCC-T1, OCUCh-LM1), epidermoid (A431), gastric (Kato-III), colon (DLD-1, SW480), and breast (SK-BR-3, MCF-7) cancer. In vivo, in three mouse models, we evaluated the anti-tumor activity of hEx3-Db and cetuximab, assessed the effect of hEx3-Db alone, and compared the antitumor activity of hEx3-Db with the IgG-like BsAbs. In vitro, hEx3-scFv-Fc showed nearly 100% killing activity for all cell lines. Both in vitro and in vivo, hEx3-Db needed CD3-positive phenotypes to induce a growth inhibitory effect. In contrast, IgG-like BsAbs showed monotherapeutic effects in vivo by inducing antibody-dependent cellular cytotoxicity (ADCC) similar to cetuximab. However, enhancement was not observed when lymphokine-activated killer cells with the T-cell phenotype were co-injected. Results suggest that IgG-like BsAbs could not efficiently direct T lymphocytes toward tumor cells to induce ADCC due to steric hindrance on binding to CD3- and Fc-receptor-positive phenotypes. Although hEx3-scFv-Fc showed high cytotoxicity in vitro, its high molecular weight limits its usefulness. With an in vivo effect comparable to hEx3-scFv-Fc and its realistic molecular weight, hEx3-scDb-Fc shows promise as a novel recombinant therapeutic antibody and may be modified to enhance its potency by prevention of steric hindrance.

Islet transplantation is a cell replacement therapy to improve glycometabolic control in type 1 diabetic patients. Establishing methods to monitor engrafted islets, as well as the islet preparation, is important when performing islet transplantation. Since current imaging techniques are still not available to directly detect transplanted islets, we propose a novel method to visualize transplanted islets using high-frequency ultrasound (HF-US), and to evaluate the correlation between these US findings and metabolic parameters. We transplanted syngeneic (BALB/c mice) and xenogeneic (SD rats) islets into the renal subcapsular space of diabetic mice. The recipient mice were examined by HF-US until post-operative day (POD) 28 and, while syngeneic islets could be detected by HF-US throughout the observational period, the xenogeneic islets had vanished by POD 28. The islet volume calculated by HF-US was correlated with the number of transplanted islets (R-2 = 0.31, p = 0.0003) and the metabolic function of islets (blood glucose: R-2 = 0.15, p &lt; 0.0001, serum insulin: R-2 = 0.22, p &lt; 0.0001). In conclusion, HF-US may be a useful imaging modality for visualizing the islet mass in renal subcapsular transplantation models. It may also be an available modality for clinical settings in the future.

Islet transplantation is a cell replacement therapy to improve glycometabolic control in type 1 diabetic patients. Establishing methods to monitor engrafted islets, as well as the islet preparation, is important when performing islet transplantation. Since current imaging techniques are still not available to directly detect transplanted islets, we propose a novel method to visualize transplanted islets using high-frequency ultrasound (HF-US), and to evaluate the correlation between these US findings and metabolic parameters. We transplanted syngeneic (BALB/c mice) and xenogeneic (SD rats) islets into the renal subcapsular space of diabetic mice. The recipient mice were examined by HF-US until post-operative day (POD) 28 and, while syngeneic islets could be detected by HF-US throughout the observational period, the xenogeneic islets had vanished by POD 28. The islet volume calculated by HF-US was correlated with the number of transplanted islets (R-2 = 0.31, p = 0.0003) and the metabolic function of islets (blood glucose: R-2 = 0.15, p &lt; 0.0001, serum insulin: R-2 = 0.22, p &lt; 0.0001). In conclusion, HF-US may be a useful imaging modality for visualizing the islet mass in renal subcapsular transplantation models. It may also be an available modality for clinical settings in the future.

Objectives: The aim of this study was to compare the benefits between endoscopic drainage and surgical drainage of the pancreatic duct for patients with chronic calcified pancreatitis. Methods: A total of 68 patients were classified into endoscopic (n = 34) or surgical (n = 34) treatment groups. Patients receiving endoscopic treatment were further divided into 2 subgroups: a short-period group, patients who could discontinue serial pancreatic stenting within 1 year (n = 19); and a long-period group, patients who needed pancreatic drainage by serial endoscopic stenting for more than 1 year (n = 15). The medical records of these patients were retrospectively analyzed. Results: Hospital stays, frequency of hospitalizations, and medical expense were similar between the short-period endoscopic treatment group and surgery group. On the other hand, patients in the long-period endoscopic treatment group required significantly longer hospital stays, more frequent hospitalizations, and had higher medical expenses than the short-period endoscopic treatment group as well as than the surgery group. Conclusions: Patients who underwent serial endoscopic stenting for more than 1 year showed no benefit compared with surgical treatment in terms of the frequency of hospital stays and medical costs.

Emphysematous pancreatitis (air in the parenchyma) was previously considered an indication for surgery, but some recent studies have reported good clinical outcomes with non-operative management. As a step toward establishing a better treatment strategy, we report a case of fulminant pancreatitis with massive hemorrhage into the emphysematous space. A 75-year-old man was admitted with worsening abdominal pain with obstructive jaundice and renal failure 28 h after the onset. He was diagnosed as having emphysematous pancreatitis with slight pancreatic necrosis. Despite conservative treatment with intensive care, sudden cardiac and respiratory failure occurred, and he died 53 h after onset. The autopsy findings revealed biliary sludge and massive bleeding in the retroperitoneal space around the pancreas, suggesting that temporary obstruction of the bile duct with sludge induced emphysema and the hemorrhage rapidly spread into the broadened emphysematous space. Whereas conservative management has been thought to be appropriate in selected cases of emphysematous pancreatitis, when there is pancreatic emphysema in the early phase, a fulminant course tends to develop. Since there is a risk of massive bleeding into the emphysematous space, endoscopic or invasive drainage performed to collapse the emphysematous space could benefit the outcome. © Springer 2011.

Identification and characterization of epigenetically silenced genes is important for cancer research, because information from hypermethylated genes provides clues to understand roles of epigenetics in tumorigeneses and genes frequently methylated in a tumor-specific manner can be used as tumor markers. Here, we describe the identification of transcriptionally silenced hypermethylated genes in pancreatic cancer cells by using a novel method called "microarray coupled with methyl-CpG targeted transcriptional activation" (MeTA-array for short), which can effectively reactivate genes containing the stringent criteria of CpG islands at promoter regions. Three representative pancreatic cancer cell lines, AsPC-1, MIA PaCa-2 and PANC-1, with a normal pancreatic ductal epithelial cell line HPDE as a control, were examined with this method, and 19 genes were upregulated twofold or more in all the three cancer cell lines after MeTA; 16 of these 19 genes have not been detected previously when using a conventional DNA demethylating agent, 5-aza-2'-deoxycytidine. Among these 16 genes, CSMD2, SLC32A1, TMEM204 and TRH were further analyzed by methylation-specific PCR, and we found that 90% (19/21) of CSMD2, 100% (21/21) of SLC32A1, 95% (20/21) of TMEM204 and 100% (21/21) of TRH were methylated in our series of pancreatic cancer cell lines. Furthermore, CSMD2, SLC32A1 and TRH were also hypermethylated in primary pancreatic cancers in a tumor-specific manner. These results suggest that MeTA-array is a highly efficient method for identifying methylation-mediated transcriptionally silenced genes in human pancreatic cancer and that this method can be applied to other types of human cancer. (C) 2011 Elsevier Inc. All rights reserved.

Lymphangioma is a benign and congenital malformation of the lymphatic system. Most lymphangiomas are preferentially located in the head and neck region. The abdominal organs are uncommon sites of origin. Several cases of lymphangioma in abdominal organs were reported, however, the pancreas is one of the rarest origins. Generally, intra-abdominal lymphangioma is asymptomatic and found incidentally, but in some cases, the patient complains of abdominal distension or a palpable mass. We describe the case of a 38-year-old male who presented with sudden-onset upper abdominal pain. Rupture of a cystic tumor of the pancreatic head was suspected, based on the findings of computed tomography, magnetic resonance imaging and endoscopic ultrasonography. Subtotal stomach-preserving pancreaticoduodenectomy was undertaken. The tumor, which was 4 × 4.5 × 8 cm in size, was pathologically diagnosed as a cystic lymphangioma. In conclusion, pancreatic lymphangioma is mostly asymptomatic, a ruptured case causing 'acute abdomen' has never been reported. Since lymphangioma is benign, it could be observed with accurate diagnosis. The surgical indication would be limited to cases of symptomatic lymphangiomas. Copyright © 2011 S. Karger AG, Basel.

Objective The clinicopathological significance of four morphological types of intraductal papillary mucinous neoplasms of the pancreas (IPMNs; gastric, intestinal, pancreatobiliary and oncocytic) was assessed. Design Retrospective multicentre analysis of 283 surgically resected IPMNs. Results Of the 283 IPMNs, 139 were of the gastric type, 101 were intestinal, 19 were pancreatobiliary and 24 were oncocytic. These types were significantly associated with clinicopathological factors including sex (p=0.0032), age (p=0.00924), ectatic duct size (p=0.0245), detection of mural nodules (p=4.09x10(-6)), histological grade (p &lt; 2.20x10(-16)), macroscopic types with differential involvement of the pancreatic duct system (p=3.91x10(-5)), invasive phenotypes (p=3.34x10(-12)), stage (p &lt; 2.20x10(-16)) and recurrence (p=0.00574). Kaplan-Meier analysis showed significant differences in patient survival by morphological type (p=5.24x10(-6)). Survival rates at 5 and 10 years, respectively, were 0.937 (95% CI 0.892 to 0.984) for patients with gastric-type IPMNs; 0.886 (95% CI 0.813 to 0.965) and 0.685 (95% CI 0.553 to 0.849) for those with intestinal-type IPMNs; 0.839 (95% CI 0.684 to 1.000) and 0.734 (95% CI 0.526 to 1.000) for those with oncocytic-type IPMNs; and 0.520 (95% CI 0.298 to 0.909) and undetermined for those with pancreatobiliary-type IPMNs. Analysis by the Cox proportional hazards model comparing prognostic risks determined by stage and the morphological and macroscopic types indicated that staging was the most significant predictor of survival (p=3.68x10(-8)) followed by the morphological type (p=0.0435). Furthermore, the morphological type remained a significant predictor in a subcohort of invasive cases (p=0.0089). Conclusion In this multicentre retrospective analysis, the morphological type of IPMN appears to be an independent predictor of patient prognosis.

Backgrouns/Aims There are few studies about the assessment of pancreatic function using computed tomography (CT) volumetry. In this study, we examined the correlation between CT volumetry and endocrine parameters (blood glucose and HbA1c) of the pancreas. Methods A total of 68 patients underwent enhanced CT for pancreatic disease from January to December in 2008. In particular, we analyzed the correlation of diabetic status and pancreatic CT parameters at 1 year after pancreatoduodenectomy in 32 patients. CT parameters including volume, volume/body weight, arterial phase density, the arterial phase to portal phase density ratio (A/P ratio) of the pancreas, and size of pancreatic duct were also analyzed. Correlation between CT parameters and diabetic status was analyzed preoperatively and postoperatively by ANOVA test. Results The preoperative diabetic status and parameters correlated well with arterial phase density (p=0.004), A/P ratio, and pancreatic duct size (p &lt; 0.0001). In the patients who underwent pancreatectomy, two out of 25 patients without preoperative diabetes mellitus (DM) had DM, and two out of seven patients with preoperative DM recovered from DM. Postoperative CT parameters correlated with the DM status 1 year after pancreatectomy. Conclusion CT is a useful modality for evaluation of the pancreatic endocrine function and could be used for the prediction of postoperative diabetic outcome.

Purpose: To assess retrospectively the cause cif hepatic failure related to hepatic arterial embolization (HAE) for hemostasis after pancreaticoduodenectomy or hepatic lobectomy. Materials and Methods: Between June 1993 and March 2006, Twenty HAEs in 17 patients (15 men, two women: mean age, 64 years) were performed. Angiographic findings, including portal vein stenosis, collateral arterial pathways after HAE, and the difference of embolic materials, were recorded. The morbidity (hepatic failure and abscess) and mortality were detailed according to collateral arterial pathways, portal vein stenosis, and embolic material used. Results: Bleeding was controlled in all patients, although two patients required repeat embolization. Hepatic failure (n = 8) and abscess (n = 2) arose in nine of 20 HAEs. Death occurred after six of eight HAEs complicated by hepatic failure. The morbidity and mortality rates of HAE were 45% and 30%, respectively. Hepatic complication was eight times more likely to occur (P = .005) in cases with no hepatic collaterals involving hepatic, replaced, or accessory hepatic arteries. Death was observed only in the cases without hepatic collaterals (P = .011). The correlation between the embolization outcome and the presence of portal vein stenosis or the difference of embolic materials was not significant (P &gt; .61). Conclusions: HAE can be used to successfully control bleeding secondary to hepatic arterial rupture. In the absence of hepatic collaterals, collateral circulation distal to the occlusion from nonhepatic sources may be inadequate and lead to hepatic failure after HAE.

The purpose of this study was to obtain a comprehensive understanding of the impact of postoperative tumor marker (TM) normalization on survival after pancreatectomy for pancreatic carcinoma. We propose the concept of surgical RECIST based on residual tumor and TM status. A total of consecutive patients with pancreatic carcinoma underwent pancreatectomy between August 1, 1989, and August 1, 2008. Pre- and postoperative TM values were available for 194 patients. The relationship between TM status, survival, and other clinical and demographic data was determined with univariate log-rank tests and Cox proportional hazards analysis. Postoperative TM levels remained elevated in 92 patients (47.4%; partial responders). TM levels normalized in 102 patients (52.6%; complete responders). Lymph node metastases, portal vein resection, absence of retroperitoneal clearance, residual tumor, preoperative high CA19-9, and surgical partial response were associated with decreased survival. Nodal stage (P = 0.0227) and surgical RECIST (P = 0.025) were significant predictors of survival. Partial responders had a significantly lower median survival time (P = 0.0008) and significantly higher frequency of hepatic metastasis (P = 0.0299). Postresection TM normalization is a strong prognostic factor for pancreatic cancer. The efficacy of pancreatic cancer surgery should be evaluated in the context of both local clearance and serum TM kinetics.

We describe here a case of von Hippel-Lindau (VHL) disease with a serous cystic neoplasm of the whole pancreas. The patient was a 35-year-old woman suffering from a palpable abdominal tumor. She had a history of hemangioblastomas of the cerebellum. CT revealed large solid tumors in the pancreatic head and body, and multiple cystic lesions in the whole pancreas as well as a right renal tumor. When endoscopic retrograde cholangiopancreatography (ERCP) was performed, bleeding from the duodenal papilla was detected. Since she had some distinguishing clinical features, the diagnosis of VHL disease was made. The preoperative diagnosis of the pancreatic lesion was serous cystic neoplasms with hemosuccus pancreaticus and total pancreatectomy was performed. Histological examination of the specimen revealed serous cystic neoplasms which occupied the entire pancreas. VHL cases operated on for serous cystic neoplasms of the entire pancreas are very rare.

It is difficult to distinguish pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) when stricture is present in the pancreatic duct. Endoscopic brushing cytology is a convenient method for investigating strictures in the pancreatic duct, however, the diagnostic sensitivity of this method for PDAC is reported to be low (40-70%). Recently, we revealed that MSX2 is frequently expressed in PDAC cells but not in normal cultured pancreatic duct or stellate cells. Thus, we analyzed MSX2 expression levels in brushing samples to examine whether this would differentiate PDAC from CP. Cytologic brushing specimens were obtained from pancreatic duct strictures during endoscopic retrograde cholangiopancreaticography in 82 patients. The brushing fluid was subjected to cytological diagnosis and RNA extraction. The expression level of MSX2 was evaluated by one-step real-time RT-PCR. MSX2 expression levels were significantly higher in PDAC than in CP (P = 0.0000007), and the expression level was associated with positive cytology (P = 0.013). The sensitivity, specificity, and diagnostic accuracy for PDAC of cytology and MSX2 expression in ductal strictures were: 47.4%, 100%, and 63.4%, and 73.7%, 84.0%, and 79.3%, respectively. The sensitivity and accuracy of MSX2 expression levels for diagnosis were much higher than those of cytology. This suggests that the evaluation of MSX2 levels in endoscopic retrograde cholangiopancreaticography brushing samples would be useful for distinguishing PDAC from CP. (Cancer Sci 2011; 102: 157-161).

The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs promote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Because epithelial-mesenchymal transition (EMT) plays a critical role in the progression of pancreatic cancer, we hypothesized that PSCs promote EMT in pancreatic cancer cells. Panc-1 and SUIT-2 pancreatic cancer cells were indirectly co-cultured with human PSCs isolated from patients undergoing operation for pancreatic cancer. The expression of epithelial and mesenchymal markers was examined by real-time PCR and immunofluorescent staining. The migration of pancreatic cancer cells was examined by scratch and two-chamber assays. Pancreatic cancer cells co-cultured with PSCs showed loose cell contacts and a scattered, fibroblast-like appearance. The expression of E-cadherin, cytokeratin 19, and membrane-associated beta-catenin was decreased, whereas vimentin and Snail (Snai-1) expression was increased more in cancer cells co-cultured with PSCs than in mono-cultured cells. The migration of pancreatic cancer cells was increased by co-culture with PSCs. The PSC-induced decrease of E-cadherin expression was not altered by treatment with anti-TGF-beta-neutralizing antibody, excluding a central role of TGF-beta in this process. In conclusion, PSCs promoted EMT in pancreatic cancer cells suggesting a novel mechanism by which PSCs contribute to the aggressive behavior of pancreatic cancer cells. (C) 2010 Elsevier Inc. All rights reserved.

The Frey procedure, the coring out of the pancreatic head and longitudinal pancreaticojejunostomy, is a safe, easy, and reliable method to solve most of the problems associated with chronic pancreatitis. During long-term follow up, unexpected relapse in the pancreatic tail was encountered. The pattern of failure and the rationale for a new procedure to treat or prevent such relapse were investigated. From 1992 to 2008, 71 patients with chronic pancreatitis underwent the Frey procedure at Tohoku University Hospital. The etiology was alcoholic in 92.6% of them, followed in incidence by idiopathic and hereditary chronic pancreatitis. In the primary operation, besides the Frey procedure, combined resection of the pancreatic tail was performed in three patients, and choledochoduodenostomy was performed in one patient. The follow-up rate was 92.9%, with a median period of 46 months. The incidence of early postoperative complications was 18.4%, with one reoperation for gastrointestinal bleeding from the splenic artery. Pain control was achieved in all patients and there was no operative mortality. During the long-term follow up of 62 patients with the Frey procedure, eight patients had relapse of inflammation and required reoperation. Five of these eight patients had a pseudocyst in the pancreatic tail and underwent distal pancreatectomy (DP). Relapse occurred in alcoholic middle-aged male patients, and in the patients with hereditary and idiopathic pancreatitis. Frey-DP and Frey-spleen-preserving DP (SPDP) procedures can be performed safely and effectively to treat the relapse and to prevent relapse in the pancreatic tail.

50歳男性、乳頭部癌に対し幽門輪温存膵頭十二指腸切除術(膵胃吻合)を施行され、6年後膵胃吻合部狭窄にともなう慢性膵炎、膵石症を併発した。超音波内視鏡下に膵管ステントを留置し症状が改善するも、9ヵ月後膵炎が頻回に再燃したため当科にて膵管空腸側々吻合(膵管ドレナージ術)を施行した。膵管空腸側々吻合術は膵頭切除後の慢性膵炎に対して有効で安全に施行し得、残膵機能温存の観点からも推奨される術式だと考えられた。(著者抄録)

A 50-year-old man with a cancer of the papilla of Vater underwent pylorus-preserving pancreatoduodenectomy reconstructed with pancreatogastrostomy in 2002. He began to complain of upper abdominal and back pain in April 2008. Abdominal CT scan revealed pancreatolithiasis with dilatation of the remnant main pancreatic duct. An upper intestinal endoscopy could not discern the orifice of the pancreatic duct. He was treated by transgastric EUS-guided drainage of the pancreatic duct several times, and ESWL for pancreatolithiasis. However, he had repeated pancreatitis. Surgical intervention was carried out to treat the obstructive pancreatitis in April 2009. Longitudinal pancreaticojejunostomy was performed without resection of the obstructive pancreatogastrostomy. The postoperative recovery was uneventful, and the patient remains asymptomatic after the second operation. We concluded that the longitudinal pancreaticojejunostomy is a safe and effective alternative for chronic pancreatitis after stenotic pancreatico-digestive tract anastomosis following pancreatoduodenectomy, especially for cases in which endoscopic stenting is ineffective.

Objectives: The Notch signaling pathway is evolutionarily conserved and regulates cell-fate decisions in a variety of organ development. Previous studies have shown that delta-like ligand 4 (DLL4), one of trans-membranous Notch ligands, is up-regulated at the site of tumor growth, especially of tumor angiogenesis. In this study, we examined the effects of the DLL4-Notch signaling on tumor angiogenesis using the neutralizing monoclonal antibodies against DLL4. Methods: The neutralizing monoclonal antibodies against murine DLL4 (HMD4-2) were newly established, and their effects on tumor growth and angiogenesis were evaluated using the mice subcutaneously implanted human pancreatic cancer cells (PK-1) in the dorsal flank area. To further assess the effects on tumor angiogenesis, PK-1 cells were implanted in skinfold chambers inserted on the dorsal area of the mice. Results: Treatment (intraperitoneally) with HMD4-2 suppressed the in vivo tumor growth with marked decrease of tumor vasculature and had no direct inhibitory effect on PK-1 cells in vitro. Real-time sequential analysis using the skinfold chamber model revealed the antiangiogenic effect of HMD4-2. Conclusions: These results suggests that cell-to-cell interaction via DLL4-Notch signaling pathway has been implicated in tumor angiogenesis, and control of this pathway can be a new therapeutic approach to solid tumor.

To distinguish malignant from benign branch duct (BD)-intraductal papillary mucinous neoplasm (IPMN) still remains difficult. Recently, we revealed that MSX2 was frequently expressed in pancreatic cancer and its expression was correlated with aggressive behavior of the cancer. The aim of this study was to assess the involvement of MSX2 in IPMN development and whether its expression would differentiate malignant from benign IPMN. Seventeen microdissected lesions and 45 IPMN tissues were used for quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. The role of MSX2 in the pancreatic duct cell was assessed by the induced expression of MSX2 in a normal human pancreatic duct epithelial cell line (HPDE). Malignant IPMN expressed significantly higher levels of MSX2 mRNA than benign IPMN lesions. MSX2 protein expression was frequently found in borderline and malignant lesions (20/29, 68.9%), while its expression was seen in only one of 16 benign IPMN tissues. Univariate analysis showed that nodules of 6 mm or more and MSX2 expression were significantly correlated with the malignancy of BD-IPMN (P = 0.022 and 0.0026, respectively), and multivariate analysis revealed that only MSX2 expression was identified as an independent factor to predict malignant BD-IPMN. HPDE cells expressing MSX2 showed increased cellular proliferation compared to control cells. Based on our results, MSX2 plays a pivotal role in the development of IPMN through growth stimulation of tumor cells, and its expression was identified as an independent predictive factor for malignancy of BD-IPMN.

Hilar cholangiocarcinoma and intrahepatic cholangiocarcinoma involving the hepatic hilus are defined as "perihilar cholangiocarcinoma". The principle of surgical treatment is hemi-hepatectomy or trisectionectomy of the liver, caudate lobectomy, and resection of the extrahepatic bile duct for complete resection of the tumor. The aim of this study was to review the outcomes of major hepatectomy for perihilar cholangiocarcinoma. Using the Kaplan-Meier method and the Cox proportional hazards model, we analyzed the results in 125 patients with perihilar cholangiocarcinoma who had undergone major hepatectomy. Right hepatectomy, right trisectionectomy, left hepatectomy, and left trisectionectomy were performed in 66, 8, 49, and 2 patients, respectively. Curative resection was achieved in 79 patients (63.2%). Mortality and morbidity rates were 8.0 and 48.7%, respectively. The overall 1-, 3-, and 5-year survival rates of all patients were 73.2, 36.7, and 34.7%, respectively. The median survival was 26.8 months. Multivariate analysis showed that the independent prognostic factors for overall survival were gender, histopathological grading, curative resection, and American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) pT. Major hepatectomy for perihilar cholangiocarcinoma was acceptable and showed satisfactory outcomes. For long-term survival in these patients, the surgeon should aim for complete resection of the tumor with negative margins.

<b>要旨：</b>症例は78歳，男性．2003年4月肝後区域に径26 mm大の肝腫瘍を認め当科紹介された．本人希望により他院を紹介したが，自己判断で治療は受けなかった．2005年前医にて同部位に腫瘍を指摘され，同年12月再度当科を紹介された．CTでは肝後区域を中心に肝門部，尾状葉へ及ぶ不整形で境界不明瞭な低吸収域を認め，門脈右枝は腫瘤により狭窄し肝右葉は著明に萎縮していた．肝内胆管癌の術前診断にて2006年2月肝拡大右葉切除術を施行した．病理検査では，拡張胆管内に異型細胞の乳頭状増生を認め乳頭腺癌と診断されたが，末梢胆管にまで上皮内進展がみられ，胆管内乳頭状腫瘍の範疇に含まれるものと考えられた．患者は術後3年を経過し再発を認めず外来通院中である．胆管内乳頭状腫瘍は比較的新しい概念であり予後良好と考えられるが，無治療にて長期間経過後に治癒切除しえた報告は稀である．同疾患概念確立の一助となると考え今回報告する．<br>

Granular cell tumors, also called Abrikossof's tumors, were originally described by Abrikossof A in 1926. The first case of a pancreatic granular cell tumor was described in 1975 and only 6 cases have been reported. We describe a case of granular cell tumor in the pancreas showing pancreatic duct obstruction. Because imaging studies showed findings compatible with those of pancreatic carcinoma, the patient underwent distal pancreatectomy. Histological examination showed that the tumor consisted of a nested growth of large tumor cells with ample granular cytoplasm and small round nuclei. The tumor cells expressed S-100 protein and were stained with neuron-specific enolase and periodic acid-Schiff, but were negative for desmin, vimentin, and cytokeratin. The resected tumor was diagnosed as a granular cell tumor. To our knowledge, this is the seventh case of Granular cell tumor of the pancreas to be reported. (C) 2010 Baishideng. All rights reserved.

Approximately 35-60% of patients with colorectal cancers will develop liver lesions during their life span. Previously colorectal liver metastases have traditionally been categorized as incurable systemic disease. However, the introduction of new chemotherapeutic regimens (e. g. FOLFOX or FOLFIRI) and recent technical innovations (e. g. staged hepatic resection and percutaneous transhepatic portal embolization) has allowed us to perform hepatic resection with curative intent. Additionally, a neoadjuvant strategy has expanded the criteria for liver resection, and more active molecular therapeutic agents are now available. As a result, a recent advancement has enhanced the overall 5-year survival from 30% to 58% for colorectal liver metastases. Despite these facts, many patients still experience a recurrence after hepatic resection. Modern treatment of colorectal liver metastases requires a multimodal approach to increase the number of patients who may benefit from surgical treatment of colorectal liver metastases.

A 45-year-old man underwent a low anterior resection for rectal cancer [T3, N1, MO, Stage Ha: UICCJ. He received a postoperative systemic chemotherapy with 5-FU and LV. Five months after the operation, multiple liver metastases were detected in the right hepatic lobe (S5, 6, 8). Right hepatectomy was performed. Seventeen courses of postoperative hepatic arterial infusion (HAI) chemotherapy (weekly high-dose 5-FU regimen) were performed without severe adverse events. He was still alive with no sign of recurrence for 69 months after hepatectomy. After liver resection for metastases of colorectal cancer, although a systemic chemotherapy has been mainly performed, HAI chemotherapy is one of the important options for prevention of local recurrence.

症例は77歳，男性．十二指腸乳頭部癌で，膵頭十二指腸切除術を施行．術後ICU入室時より頻脈を認め，44時間後には呼吸不全を併発したため，人工呼吸管理を開始した．次第に腹部の膨瘤が増大するとともに，腹腔内に留置されたドレーンより異臭を伴う排液を認めたため，再開腹術施行．腹腔内には中等量の腹水貯留以外に異常を認めなかった．再手術後も全身状態の改善は得られず，初回手術後83時間後に急性循環不全にて死亡した．腹水および動脈血培養から<I>Aeromonas hydrophila</I>が検出されたため，同菌による敗血症と診断した．<BR>本菌による敗血症は極めてまれであり，特に術後の早期診断は困難である．その一方で病態の進行は電撃的であるため，診断時すでに救命困難な場合も多い．本菌に対する認知度を高めるとともに，術前に予防的対策をとることが，本疾患に対する最も有効な治療手段であろうと考えられた．

S100A4 protein belongs to the S100 subfamily, which has grown to be one of the large Subfamilies of the EF-hand Ca(2+)-binding proteins, and overexpression of S100A4 is suggested to associate with cell proliferation, invasion, and metastasis. We observed frequent overexpression of S100A4 in pancreatic cancer cell lines and further analyzed RNAi-mediated knockdown to address the possibility of its use as a therapeutic target for pancreatic cancer. The specific knockdown of S100A4 strongly suppressed cell growth, induced G2 arrest and eventual apoptosis, and decreased cell migration. Furthermore, microarray analyses revealed that knockdown of S100A4 induced expression of the tumor suppressor genes PRDM2 and VASH1. Our present results suggest the possibility that the inhibition of S100A4 can be utilized in antitumor applications for patients with pancreatic cancer. (C) 2009 Elsevier Inc. All rights reserved.

S100A4 protein belongs to the S100 subfamily, which has grown to be one of the large Subfamilies of the EF-hand Ca(2+)-binding proteins, and overexpression of S100A4 is suggested to associate with cell proliferation, invasion, and metastasis. We observed frequent overexpression of S100A4 in pancreatic cancer cell lines and further analyzed RNAi-mediated knockdown to address the possibility of its use as a therapeutic target for pancreatic cancer. The specific knockdown of S100A4 strongly suppressed cell growth, induced G2 arrest and eventual apoptosis, and decreased cell migration. Furthermore, microarray analyses revealed that knockdown of S100A4 induced expression of the tumor suppressor genes PRDM2 and VASH1. Our present results suggest the possibility that the inhibition of S100A4 can be utilized in antitumor applications for patients with pancreatic cancer. (C) 2009 Elsevier Inc. All rights reserved.

LIV-1 is a downstream target of STAT3 and is essential for the nuclear localization of Snail, a master regulator of epithelial to mesenchymal transition (EMT). Little is known about the association of LIV-1 with pancreatic carcinoma development, therefore, expression of LIV-1 mRNA was analyzed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in 9 cultured cell lines (8 carcinoma and I normal duct cell lines) and 24 pancreatic tissues (12 carcinoma and 12 normal tissues). Localization of this gene product was investigated by immunohistochemistry in 72 pancreatic carcinoma and the relation between its expression and clinicopathological findings was examined. To assess the function of LIV-1 in pancreatic carcinoma cells, stable siRNA expressing Panc-1 cells were generated. Higher expression of LIV-1 mRNA was found in both pancreatic carcinoma cell lines and pancreatic carcinoma tissues compared to normal duct cell line and histologically normal tissues, respectively. Immunohistochemical analysis revealed that LIV-1 expression was frequently found in 76.4% of pancreatic carcinoma tissues and its expression level was associated with tumor size and lymphatic infiltration. Down-regulated LIV-1 cells showed significant inhibition of anchorage-dependent or -independent proliferation and cell motility in vitro and reduction of tumor growth and metastasis in vivo. Furthermore, nuclear expression of Snail was decreased and E-cadherin expression was restored in LIV-1 siRNA expressing pancreatic carcinoma cells. These findings indicate that LIV-1 may be involved in acquisition of the aggressive phenotype of human pancreatic carcinoma cells through the induction of epithelial to mesenchymal transition.

BACKGROUND: This multicentre randomised phase III trial was designed to determine whether adjuvant chemotherapy with gemcitabine improves the outcomes of patients with resected pancreatic cancer. METHODS: Eligibility criteria included macroscopically curative resection of invasive ductal carcinoma of the pancreas and no earlier radiation or chemotherapy. Patients were randomly assigned at a 1 : 1 ratio to either the gemcitabine group or the surgery-only group. Patients assigned to the gemcitabine group received gemcitabine at a dose of 1000 mgm(-2) over 30 min on days 1, 8 and 15, every 4 weeks for 3 cycles. RESULTS: Between April 2002 and March 2005, 119 patients were enrolled in this study. Among them, 118 were eligible and analysable (58 in the gemcitabine group and 60 in the surgery-only group). Both groups were well balanced in terms of baseline characteristics. Although heamatological toxicity was frequently observed in the gemcitabine group, most toxicities were transient, and grade 3 or 4 non-heamatological toxicity was rare. Patients in the gemcitabine group showed significantly longer disease-free survival (DFS) than those in the surgery-only group (median DFS, 11.4versus 5.0 months; hazard ratio = 0.60 (95% confidence interval (CI): 0.40-0.89); P = 0.01), although overall survival did not differ significantly between the gemcitabine and surgery-only groups (median overall survival, 22.3 versus 18.4 months; hazard ratio = 0.77 (95% CI: 0.51-1.14); P = 0.19). CONCLUSION: The current results suggest that adjuvant gemcitabine contributes to prolonged DFS in patients undergoing macroscopically curative resection of pancreatic cancer. British Journal of Cancer (2009) 101, 908-915. doi:10.1038/sj.bjc.6605256 www.bjcancer.com Published online 18 August 2009 (C) 2009 Cancer Research UK

The cyclin-dependent kinase inhibitor (CDK1) p27(kip1) is a negative regulator of cell cycling and has antitumor effects. In our previous study, the recombinant adenovirus expressing wild-type p27(kip1) (Adp27-wt) induced cell cycle arrest and apoptosis, and proved that p27 is a tumor suppressor gene like p53. Another adenovirus vector expressing mutant p27(kip1) (Adp27-mt), which inhibited degradation by the ubiquitin-proteasome system, showed increased protein stability and caused a stronger induction of apoptosis. Recently, the p27(kip1) protein binding with Jab1 (Jun activating binding protein 1) was found to translocate from the nucleus into the cytosol, and then become degraded by the 26S proteasome system. The inhibition of nuclear-cytoplasmic translocation increases the protein stability of p27(kip1) and p27(kip1) with a deletion of the Jab1-binding region (p27-jab-d) is not translocated and not degraded. Therefore, a new recombinant adenovirus (Adp27-jab-d) expressing p27-jab-d was made which was able to induce greater cytotoxicity. Adp27-jab-d inhibited the growth of human cholangiocarcinoma cell line (TFK-1) cells in vitro at 3.3 times (IC50) lower concentration than Adp27-wt. Moreover, in a xenografted severe combined immuno-deficient (SCID) mouse model injected with TFK-1 cells in the subcutaneous tissue, treatment by intratumor injection of Adp27-jab-d once a day for 3 days after the tumor was established, inhibited tumor growth more strongly than Adp27-wt or Adp27-mt and even induced tumor regression. However, the flow cytometric TUNEL assay showed little enhancement of apoptosis. Adp27-jab-d was thought to induce not only apoptosis but also necrosis, which was due to a specific effect of the Adp27-jab-d. Thus, by enhancing the cytotoxicity through inhibiting the translocaton of p27(kip1), p27(kip1) lacking the Jab1-binding region might be useful for cancer therapy. The control protein localization might also be a new target not only for cancer treatment, but also other diseases.

Circadian rhythms are the daily oscillations of multiple biological processes regulated by an endogenous clock. The Period2 gene is essential in controlling the circadian rhythm and plays an important role in tumor suppression. We examined whether the overexpression of the mouse Period2 gene (mPer2) in cultured tumor cells from human tissues inhibits cell growth, using the recombinant adenovirus vector AdmPer2. The overexpression of mPer2 in human pancreatic cancer cells (Panc1, Aspc1) reduced cellular proliferation and induced apoptotic cell death. Infection with AdmPer2 also inhibited cell-cycle progression, inducing arrest at the G(2)-M phase. Western blotting analyses confirmed that infection with AdmPer2 reduced Bcl-X(L), Cdc2 and cyclin B1 protein, whereas it increased Bax protein in Aspc1 cells. The overexpression of mPer2 suppressed Cdc2 kinase activity. Moreover, infection with AdmPer2 resulted in dose-dependent synergic cell killing effects with the anticancer agent cisplatin (CDDP) in human pancreatic cancer cells. This synergic effect might be related to the reduction of Bcl-X(L) induced by infection with AdmPer2. Our results suggest that the circadian gene Period2 may play an important role in suppression of cell proliferation in human cancer, and additionally Period2 gene expression level may influence the sensitivity, to cisplatin depending on Bcl-X(L) expression level.

The prognosis of cholangiocarcinoma patients is extremely poor despite the aggressive multidisciplinary cancer therapies that have been used clinically (1). Recently, molecular target therapy has attracted attention. Epidermal growth factor receptor (EGFR) tyrosine kinase (TK) is a promising target for anticancer therapy. ZD1839 (IRESSA (R)) is an orally active, selective inhibitor of EGFR-TK. This study examined the effects of ZD1839 in TFK-1 and HuCCT1, the human cholangiocarcinoma cell lines that express EGFR. Somatic mutations in the TK domain of the EGFR gene are associated with the sensitivity of lung cancers to ZD1839 (2). In the analysis of the EGFR sequence, no mutations were found in TFK-1 and HuCCT1. The TFK-1 and HuCCT1 cells showed almost the same sensitivity to ZD1839. It is shown that ZD1839 induced apoptotic cell death of TFK-1 cells as indicated by apoptotic morphological changes and an enhancement of TUNEL-positive cells. ZD1839 produced a dose-dependent inhibition of cellular proliferation in TFK-1. Cell cycle analysis demonstrated that ZD1839 induces G1 arrest. Moreover, concurrent evaluation of the expression of p27(KiP1) protein and Jun activating domain-binding protein 1 (Jab1) with ZD1839 by Western blotting analysis was performed. It was found that ZD1839 activity causes an increase of p27(Kip1) stability that correlates with Jab1 down-regulation. Thus, ZD1839 affects key cellular pathways, controlling cell proliferation and apoptosis. Furthermore, the treatment of TFK-1 with ZD1839 reduced the cell survival after radiation exposure. ZD1839 in combination with radiation produced a dose-dependent and synergic inhibitory effect on cellular proliferation. In conclusion, these results suggest that ZD1839 may have clinical activity against cholangiocarcinoma.

Previous epidemiologic and in vitro studies have indicated a potential involvement of estrogens in the pathogenesis of human colon carcinoma, but the precise roles of estrogens have remained largely unknown. Therefore, in this study, we first measured intratumoral concentrations of estrogens in 53 colon carcinomas using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS). Tissue concentrations of total estrogen [estrone (E-1) + estradiol] and E, were significantly (2.0- and 2.4-fold, respectively) higher in colon carcinoma tissues than in nonneoplastic colonic mucosa (n = 31), and higher intratumoral concentrations of total estrogen and EC were significantly associated with adverse clinical outcome. Intratumoral concentration of total estrogen was significantly associated with the combined status of steroid sulfatase (STS) and estrogen sulfotransferase (EST), but not with that of aromatase. Thus, we subsequently examined the STS/EST status in 328 colon carcinomas using immunohistochemistry. Immunoreactivities for STS and EST were detected in 61% and 44% of the cases, respectively. The -/+ group of the STS/EST status was inversely associated with Dukes' stage, depth of invasion, lymph node metastasis, and distant metastasis and positively correlated with Ki-67 labeling index of the carcinomas. In addition, this -/+ group had significantly longer survival, and a multivariate analysis revealed the STS/EST status as an independent prognostic factor. Results from our present study showed that the STS/EST status of carcinoma tissue determined intratumoral estrogen levels and could be a significant prognostic factor in colon carcinoma, suggesting that estrogens are locally produced mainly through the sulfatase pathway and play important roles in the progression of the disease. [Cancer Res 2009;69(3):914-22]

Frey&apos;s procedure for chronic pancreatitis (CP) has been minimized gradually in our institution in recent years. We compared the functional outcome of minimized Frey&apos;s procedure with that of modified Frey&apos;s procedure to establish how deeply and widely we should cut into the head of the pancreas. Between January 1992 and December 2006, we performed Frey&apos;s procedure on 57 patients; as modi-fied Frey&apos;s procedure from 1992 to 2001, then as minimized Frey&apos;s procedure from 2002 to 2006. The patients&apos; pre- and postoperative pain scores (PS), rates of readmission, body mass indexes (BMI), plasma glucose levels (PG), hemoglobin A1c, daily insulin use (DIU), and pancreatic function diagnostant were systematically reviewed and compared between the two groups. Frey&apos;s procedure resulted in a significant decrease in PS (P &lt; 0.001) and a significant increase in BMI (P = 0.01). There were no significant differences in the pre- and postoperative PG or DIU. The outcome of the late group was similar to that of the early group in terms of pain relief and preservation of endocrine function. There was no early postoperative mortality. These findings suggest that minimum Frey&apos;s procedure is sufficient for resolving intractable pain and improving nutritional status in most patients with CP.

Previous epidemiologic and in vitro studies have indicated a potential involvement of estrogens in the pathogenesis of human colon carcinoma, but the precise roles of estrogens have remained largely unknown. Therefore, in this study, we first measured intratumoral concentrations of estrogens in 53 colon carcinomas using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS). Tissue concentrations of total estrogen [estrone (E-1) + estradiol] and E, were significantly (2.0- and 2.4-fold, respectively) higher in colon carcinoma tissues than in nonneoplastic colonic mucosa (n = 31), and higher intratumoral concentrations of total estrogen and EC were significantly associated with adverse clinical outcome. Intratumoral concentration of total estrogen was significantly associated with the combined status of steroid sulfatase (STS) and estrogen sulfotransferase (EST), but not with that of aromatase. Thus, we subsequently examined the STS/EST status in 328 colon carcinomas using immunohistochemistry. Immunoreactivities for STS and EST were detected in 61% and 44% of the cases, respectively. The -/+ group of the STS/EST status was inversely associated with Dukes' stage, depth of invasion, lymph node metastasis, and distant metastasis and positively correlated with Ki-67 labeling index of the carcinomas. In addition, this -/+ group had significantly longer survival, and a multivariate analysis revealed the STS/EST status as an independent prognostic factor. Results from our present study showed that the STS/EST status of carcinoma tissue determined intratumoral estrogen levels and could be a significant prognostic factor in colon carcinoma, suggesting that estrogens are locally produced mainly through the sulfatase pathway and play important roles in the progression of the disease. [Cancer Res 2009;69(3):914-22]

We report a case of advanced bile duct carcinoma arising in a 15-year-old female with pancreaticobiliary maljunction and congenital biliary cystic disease. Pancreaticoduodenectomy and partial resection of the liver was performed. Surgical and histopathological findings indicated advanced tubular adenocarcinoma, classified as final stage IVb according to the General rules for surgical and pathological studies on cancer of the biliary tract proposed by the Japanese Society of Biliary Surgery, 5th edition, and stage IV according to the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC), 6th edition. She underwent chemotherapy with gemcitabine HCl after discharge. She died of cachexia 14 months after the surgery. Although it is well known that biliary malignancies arise frequently in patients with pancreaticobiliary maljunction, it is uncommon for advanced bile duct carcinoma to occur in a 15-year-old female. We should pay attention to the possibility of biliary malignancy in patients with pancreaticobiliary maljunction and congenital biliary cystic disease, even when the patients are juveniles.

Background/Purpose. This study was designed to establish institutional indications for pancreatic islet transplantation by examining patients with total pancreatectomy as candidates for islet allotransplantation. Methods. In 12 patients who underwent total pancreatectomy, we compared pre-and postoperative plasma glucose level, body mass index, HbA1c, and daily insulin use; we examined candidacy for islet allotransplantation based on the guidelines of Japan's islet transplantation registry. Results. Eight of the 12 patients with total pancreatectomy were operated for intraductal papillary mucinous neoplasm. At our institution, the 5-year survival of patients with intraductal papillary mucinous neoplasm was far better (76.3%) than that of patients with pancreatic cancer. Postoperatively, plasma glucose level, HbA1c, and daily insulin use were increased in all patients with total pancreatectomy. Of the 12 patients treated with total pancreatectomy, 4 (intraductal papillary mucinous neoplasm, n = 2; islet cell tumor, n = 1; and acute pancreatitis due to arteriovenous malformation, n = 1) showed deteriorated diabetic control and therefore were considered to be candidates for islet allotransplantation according to the guidelines. Conclusions. Islet allotransplantation could be indicated for patients with favorable postoperative survival who have had a total pancreatectomy for either benign or neoplastic disease.

Background: p27(Kip1) is a cyclin-dependent kinase inhibitor which has been reported to be associated with invasion, metastasis and angiogenesis in malignant tumors, but its mechanism of action remains unknown. Here, it was examined whether p27(Kip1) has an inhibitory effect on cancer cell invasion and correlates with matrix metalloproteinase expression (MMPs). Material and methods: The human breast cancer cell line MDA-MB-231 and MDA-MB-231 transfected p27(Kip1) MDA-MB-p27 were used for the invasion assay, Western blotting and real-time quantitative RT-PCR. Results: In the invasion assay, the invasion of MDA-MB-p27 was significantly less than that of the parent cell line. In Western blotting analyses, the protein level of MMP-9 was also reduced in MDA-MB-p27. Furthermore, the activity of MMP-9 in cell culture supernatants was lower in MDA-MB-p27 as compared with enzyme-linked immunosorbent assays. In real-time quantitative RT-PCR, the mRNA level of MMP9 was lower in MDA-MB-p27 cells. Conclusion: Upregulation of p27(Kip1) remarkably inhibited the invasion of the breast cancer cells, in part due to the reduced expression of MMP-9. This is the first report of p27(Kip1) modulating MMP9 and indicating that p27(Kip1) might play a key role in tumor cell invasion.

Although some kinds of bile acids have been implicated in colorectal cancer development, the mechanism of cancer progression remains unexplored in hepatobiliary cancer. From our personal results using complementary DNA microarray, we found that chenodeoxycholic acid (CDCA) induced Snail expression in human carcinoma cell lines derived from hepatocellular carcinoma and cholangiocarcinoma. Snail expression plays an important role in the regulation of E-cadherin and in the acquisition of invasive potential in many types of human cancers including hepatocellular carcinoma. We found that CDCA and lithocholic acid (LCA) induced Snail expression in a concentration-dependent manner and down-regulated E-cadherin expression in hepatocellular carcinoma and cholangiocarcinoma cell lines. Moreover, Snail short interference RNA (siRNA) treatment reduced the down-regulation of E-cadherin by CDCA or LCA. Luciferase analysis demonstrated that the promoter region from -111 to -24 relative to the transcriptional start site was necessary for this induction and, at least in part, nuclear factor Y (NF-Y) and stimulating protein 1 (Sp1) might be an inducer of Snail expression in response to bile acids. In addition, using an in vitro wound healing assay and invasion assay, we observed that CDCA and LCA induced cell migration and invasion. These results suggest that bile acids repress E-cadherin through the induction of transcription factor Snail and increase cancer invasiveness in human hepatocellular carcinoma and cholangiocarcinoma. Inhibition of this bile acid-stimulated pathway may prove useful as an adjuvant in the therapy of hepatocellular carcinoma.

Frequent loss of heterozygosity on the long arm of chromosome 18 is observed in pancreatic cancer. Previous studies suggested the existence of one or more tumor-suppressor genes other than SMAD4 on chromosome 18. To identify the candidate tumor-suppressor gene(s), we compared gene expression by cDNA microarray analyses using a pancreatic cancer cell line Panc-1 and its hybrid cell lines showing suppressed cell growth after introduction of one normal copy of chromosome 18. The microarray analyses identified 38 genes on chromosome 18 that showed differential expressional levels. Among these genes, phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1/APR/NOXA) was identified as one of the candidates for tumor suppressor. Expression vector-mediated introduction of PMAIP1 suppressed cell proliferation, and RNAi-mediated knockdown of PMAIP1 induced recovery of cell growth. These results suggest that PMAIP1 may play an important role in the progression of pancreatic cancer.

Background. Evidence is accumulating that bile acids are involved in colon cancer development, but their molecular mechanisms remain unexplored. Bile acid has been reported to be associated with induction of the cyclooxygenase-2 (COX-2) gene. Because the human liver-specific organic anion transporter-2 (LST2/OATP8/OATP1B3) is expressed in gastrointestinal cancers and might transport bile acids to the intracellular space, we studied the molecular mechanisms by which bile acids induce the transcription of COX-2, and the role of LST-2 in colonic cell lines. Methods. Transcriptional activity of COX-2 was measured using a human COX-2 promoter-luciferase assay under various concentrations of bile acids. Electrophoresis mobility shift assays (EMSAs) for peroxisome proliferator-activated receptor (PPAR) alpha and cyclic AMP responsive element (CRE) were performed. Results. The COX-2 promoter was induced by lithocholic acid (LCA), deoxycholic acid (DCA), and chenodeoxycholic acid (CDCA). Deletion and site-directed mutation analyses showed that CRE is the responsive element for LCA. An adenovirus expression system revealed that LST-2 is responsible for induction of COX-2. By EMSA using oligonucleotides of CRE, we observed formation of a specific protein-DNA complex, which was inhibited by a specific antibody against PPARa and CRE. A PPAR alpha-specific agonist induced transcription of COX2. Conclusion. These results indicate that COX-2 is transcriptionally activated by the addition of LCA, CDCA, and DCA and that LST-2 plays an important role by transporting bile acid to the intracellular space. Moreover, LCA-dependent COX-2 gene activation consists of a transcriptional complex including PPARa and CRE-binding protein. Thus, this induction of COX-2 may participate in carcinogenesis and progression of colorectal cancer cells.

Periostin is a secretory protein that has been suggested to function as a cell adhesion molecule and promote the invasiveness or growth rate of tumors. However, little is known about the association of its expression and epithelial to mesenchymal transition (EMT), which is considered to play a crucial role in cancer cell metastasis. Thus, the authors investigated whether periostin could be involved in the process of EMT and the role of this gene in pancreatic cancer development. The expression of periostin was observed mainly in stromal cells but very little in cancer cells by immunohistochemistry and real-time RT-PCR. In vitro, pancreatic stellate cells (PSCs) exhibited a much higher basal expression of periostin compared with cancer cells. Periostin secreted in the supernatant from 293T cells that expressed periostin (approximately 150 ng/ml) inhibited the migration of pancreatic cancer cells. Coculture assay revealed that periostin expression in PSC was induced by pancreatic cancer cells. To assess the direct role of periostin in pancreatic cancer cells, the authors generated pancreatic cancer cell lines that stably express periostin. The induced expression of periostin (to 150 ng/ml) altered the morphology of cancer cells, changing them from mesenchymal to epithelial phenotypes with the induction of epithelial markers and a reduction of mesenchymal markers, and showed reduced cell migration in vitro and formed smaller tumors as well as suppressed metastasis in vivo. On the other hand, high concentration of recombinant periostin (1 mu g/ml) promoted cell migration with AKT activation. The findings suggest that periostin has biphasic effect on the development of pancreatic cancer. (C) 2008 Wiley-Liss, Inc.

Periostin is a secretory protein that has been suggested to function as a cell adhesion molecule and promote the invasiveness or growth rate of tumors. However, little is known about the association of its expression and epithelial to mesenchymal transition (EMT), which is considered to play a crucial role in cancer cell metastasis. Thus, the authors investigated whether periostin could be involved in the process of EMT and the role of this gene in pancreatic cancer development. The expression of periostin was observed mainly in stromal cells but very little in cancer cells by immunohistochemistry and real-time RT-PCR. In vitro, pancreatic stellate cells (PSCs) exhibited a much higher basal expression of periostin compared with cancer cells. Periostin secreted in the supernatant from 293T cells that expressed periostin (approximately 150 ng/ml) inhibited the migration of pancreatic cancer cells. Coculture assay revealed that periostin expression in PSC was induced by pancreatic cancer cells. To assess the direct role of periostin in pancreatic cancer cells, the authors generated pancreatic cancer cell lines that stably express periostin. The induced expression of periostin (to 150 ng/ml) altered the morphology of cancer cells, changing them from mesenchymal to epithelial phenotypes with the induction of epithelial markers and a reduction of mesenchymal markers, and showed reduced cell migration in vitro and formed smaller tumors as well as suppressed metastasis in vivo. On the other hand, high concentration of recombinant periostin (1 mu g/ml) promoted cell migration with AKT activation. The findings suggest that periostin has biphasic effect on the development of pancreatic cancer. (C) 2008 Wiley-Liss, Inc.

A 74-year-old man was hospitalized for the investigation of fever and severe general fatigue. Laboratory examinations revealed severe leukocytosis, with a leukocyte count of 29 500/mm(3). Computed tomography, ultrasonography, and endoscopic retrograde cholangiopancreatography showed a pancreatic tumor with a diameter of 70 mm. We performed distal pancreatectomy with splenectomy and gastrectomy because there was invasion of the posterior wall of the stomach. The leukocyte count decreased to 16900/mm(3) immediately following the operation, but it began to increase again a week later, ultimately reaching 213000/mm(3). We measured the serum granulocyte-colony stimulating factor (G-CSF) concentration and the G-CSF expressions in the resected specimens with immunohistochemistry, the findings of which confirmed the diagnosis of G-CSF-producing pancreatic cancer. G-CSF-producing tumors are considered to be in a category of rare malignant diseases originating in various organs, which carry a poor prognosis. However, G-CSF-producing pancreatic cancer is extremely rare. On postoperative day (POD) 35, an intraabdominal recurrence was detected with marked leukocytosis, and on POD 42 the patient died without receiving postoperative cancer therapy.

Sonic hedgehog (SHH) is frequently expressed in pre-cancerous lesions and carcinoma of the pancreas. A recent study revealed that its expression was higher in the intraductal papillary mucinous neoplasm (IPMN) of the pancreas than in the pancreatic carcinoma. However, the correlation between its signaling pathway and turnorigenesis of IPMN has not yet been well documented. We investigated the expression of mRNA and protein of SHH as well as its downstream transcription factor Gli1 in 19 microdissected lesions from 15 cases and in 75 lesions from 33 cases of the IPMN by one-step quantitative real-time reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. SHH and Gli1 mRNAs were detected in all the examined lesions and 8 out of 19 lesions in IPMNs, respectively. SHH and Gli1 mRNAs were likely to be up-regulated from the adenoma and from borderline to carcinoma cells, respectively. Immunohistochemical analysis also reported that SHH and Gli1 expression was correlated with the grade of cell atypia. These findings suggested that HH signaling was activated in IPMNs and contributed to tumorigenesis in these types of neoplasms.

Objectives: Although the stimulation index (SI) is widely used as a parameter that reflects the insulin releasing function of isolated islets, comparison between the outcomes of different institutions is problematic. This basic study was conducted for 2 objectives as we aimed to determine the optimal high glucose level for rat islets and clarify the available evidence in this field. Methods: We isolated islets of 3 rat strains (Lewis, Sprague-Dawley, and Wistar-n = 5 per strain) and measured the viability of the islets. We measured the amount of insulin released after high and low glucose stimulation. The SI was calculated as a ratio of the insulin value after high glucose stimulation divided by insulin value after low glucose stimulation. We examined the correlation between SI and viability at the high glucose levels. Results: Isolated islets released insulin corresponding to the changes of high glucose level. The highest correlation coefficient between SI and viability was seen at a glucose level of 16.5 mmol/L (R-2 = 0.546, correlation coefficient = 0.154) followed by 19.3 mmol/L (R-2 = 0.541, correlation coefficient = 0.169). Conclusions: We could optimize the high glucose level at 16.5 to 19.3 mmol/L (300-350 mg/dL) for isolated rat islets, with evidence acquired from correlation studies between SI and viability.

MSX2 is thought to be a regulator of organ development and a downstream target of the ras signaling pathway; however, little is known about the role of MSX2 in the development of pancreatic cancers, most of which harbor a K-ras gene mutation. Therefore, we examined whether the presence of MSX2 correlates with the malignant behavior of pancreatic cancer cells. BxPC3 pancreatic cancer cells that stably overexpress MSX2 showed a flattened and scattered morphology accompanied by a change in localization of E-cadherin and beta-catenin from membrane to cytoplasm. Cell proliferation rate, cell migration, and anchorage-independent cell growth were enhanced in MSX2-expressing cells. Injection of MSX2-expressing cells into the pancreas of nude mice resulted in a significant increase in liver metastases and peritoneal disseminations compared with injection of control cells. Microarray analysis revealed a significant induction of Twist 1 expression in cells that express MSX2. When MSX2 was inactivated in pancreatic cancer cells following transfection with an MSX2-specific small interfering RNA, Twist 1 was down-regulated. Immunohistochemistry of human pancreatic carcinoma tissue revealed that MSX2 was frequently expressed in cancer cells, and that increased expression of MSX2 significantly correlated with higher tumor grade, vascular invasion, and Twist I expression. These data indicate that MSX2 plays a crucial role in pancreatic cancer development by inducing changes consistent with epithelial to mesenchymal transition through enhanced expression of Twist 1.

目的：日本膵臓学会膵癌登録委員会の公表した膵癌登録報告2007のダイジェストとしてすでに公表された28655例のデータに基く解析を加え，主要な図と，新たな図，正誤表をつけて報告する．<br> 方法：構成を膵癌登録報告と同じくし，ページ数により示したデータから得られる解釈をなるべく客観的に解説した．統計解析は新たに加えた図も膵癌登録報告と同様に生命保険数理法とWilcoxon Gehan testを用い，既存のデータの統計結果はそのまま利用した．膵癌取り扱い（JPS）規約とUICC規約による生存率を主に比較した．<br> 結果：1980年代，1990年代と比較し，観察期間は短いが2001-2004年登録の膵癌の生存率は有意に改善した．膵管内腫瘍，粘液性嚢胞腫瘍，膵内分泌腫瘍の進展度分類でJPS規約のほうが良好な生存率予測を示した．膵管内腫瘍の深達度別生存率がはじめて示され，世界に類をみないデータである．<br>

An 84-year-old woman was admitted to the hospital because of pyloric stenosis caused by gastric cancer. Abdominal computed tomography and magnetic resonance imaging failed to demonstrate the gallbladder, but showed a gallstone in a ductlike structure parallel to the common bile duct. When laparotomy was performed, the gallbladder and the fossa were not observed, and a blind-end duct, similar to a cystic duct, was found beside the common bile duct. Incisional exploration of the common bile duct was done after distal gastrectomy; the gallstone was not found in the common bile duct, but in the duct parallel to it. By observing the duct beneath the common bile duct with a cholangioscope, we considered it to be a hypoplastic cystic duct. After the gallstone was removed, a T-tube was placed into the common bile duct. Agenesis of the gallbladder is a rare congenital anomaly and is often asymptomatic. As far as we know, this is the first report of gallbladder agenesis with a hypoplastic cystic duct impacted with a stone. Careful intraoperative examination using a cholangioscope is useful to confirm the structure of the common bile duct.

Background/Aims: Patients with intraductal papillary-mucinous neoplasm (IPMN) of the pancreas are likely to have a better prognosis than those with conventional pancreatic ductal adenocarcinoma. Recently there have been some reports on extrapancreatic malignant neoplasms (EPM) occurring in patients with IPMN. The purpose of this study was to discover the characteristic features of IPMN with EPM compared with IPMN without EPM. Methods: 61 patients with IPMN who underwent surgery at Tohoku University Hospital between 1988 and 2006 were retrospectively analyzed. Results: The 61 patients with IPMN in this study comprised 25 with intraductal papillary-mucinous adenomas (IPMA) and 36 with intraductal papillary-mucinous carcinomas (IPMC) including 6 with invasive carcinomas. Synchronous and metachronous EPM were observed in 15 out of the 61 patients (24.6%). Three of these patients, including 2 with IPMA and 1 with invasive carcinoma associated with IPMC, died of the EPM. None of the features, including sex, age, smoking, family history, macroscopic types (main duct type or branch duct type), histological types (gastric, intestinal, pancreatobiliary or oncocytic), and aberrant expression of molecules including CDKN2A, TP53, SMAD4 and DUSP6, except for the histological diagnoses were associated with the occurrence of EPM, i.e., the EPM occurred more often in patients with IPMA (10 out of 25) than in those with IPMC (5 out of 36) in our series (p = 0.0199 by the chi(2) test, p = 0.0330 by Fisher's exact probability test, p = 0.0422 by Yates' correction). Conclusion: Patients with IPMA were more likely to have EPM than those with IPMC. Patients with IPMA are usually expected to have a fair prognosis but EPM could be fatal in some of them, so it must be noted during follow-up. Copyright (C) 2008 S. Karger AG, Basel and IAP

Objectives: Intraductal papillary-mucinous neoplasm (IPMN) of the pancreas encompasses a spectrum of neoplasms with both morphological and immunohistochemical variations of mucin glycoproteins. Recently, a consensus nomenclature and criteria were histologically defined for classifying these variants of IPMNs into gastric, intestinal, pancreatobiliary, and oncocytic types. The purpose of this study was to determine associations between the histological types and clinicopathological features in patients with IPMN. Methods: Sixty- one patients with IPMN operated upon at Tohoku University Hospital between 1988 and 2006 were retrospectively analyzed. Results: Our series included 27 gastric-, 29 intestinal-, 4 pancreatobiliary-, and 1 oncocytic-type IPMNs. Statistically, the types of IPMN were significantly associated with the histological diagnoses, macroscopic types, and survival of the patients. Characteristically, the gastric- type IPMNs were likely to be diagnosed as benign, to be confined to branch ducts, and to have fair prognoses. On the other hand, the intestinal- type IPMNs were likely to be diagnosed as malignant, occupy the main duct, and have poor prognoses. Because of the small number of pancreatobiliary-type IPMNs and only 1 case of oncocytic-type IPMN, we were unable to determine any of their clinicopathological characteristics in our series. Conclusions: Evaluation of the histological types of IPMN may help to predict the clinical course of patients with IPMN and to design improved clinical management for these patients.

Since 198 1, the Japan Pancreas Society (JPS) and National Cancer Center have jointly maintained the nationwide pancreatic cancer registry. Currently, there are 28,655 cases registered, with 12,608 cases of histologically confirmed invasive pancreatic cancer. Since the last revision of the International Union Against Cancer (UICC) classification in 2002, the survival analysis of the patients registered from 2001 to 2004 became possible for the first time. Using this detailed database, the rational of R0 resection was investigated. From 2001 to 2004, 2617 cases of histologically confirmed invasive ductal carcinoma of the pancreas were registered. According to the UICC classification, R0 resection becomes problematic mostly in UICC stage IIa and IIb. Of 1039 patients who underwent pancreatectorny for the tumor in the head of the pancreas, 160 had UICC stage IIa disease, and 468 had UICC stage IIb disease. The relationship between the survival and the extent of disease, together with portal vein (PV) resection, plexus (PL) resection, were analyzed. PV, retroperitoneal, and PL infiltration had a significant impact on the accomplishment of R0 resection in univariate and multivariate analyses: There was no advantage of PV resection for both PV (-) and PV (+) disease among UICC stage IIa or IIb patients, suggesting no benefit of prophylactic PV resection. Similarly, survival depends on PL invasion but not on combined resection of PL. There was no survival benefit associated with the extent of lymph node dissection. Survival among patients treated in the 2000s, after the introduction of gemcitabine in Japan, is significantly better than that of patients treated in the 1980s and 1990s. Although survival after pancreatectomy depends on the extent of disease rather than the surgical procedures, the chronologic improvement in survival indicates that chemotherapy had a significant impact on survival; development of new treatment modalities is awaited. (C) 2007 Excerpta Medica Inc. All rights reserved.

A 72-year-old woman, who had undergone pylorus-preserving pancreatoduodenectomy 3 years before for cancer of Vater's papilla associated with a branch-type intraductal papillary-mucinous adenoma (IPMA), developed dilatation of the main duct and a nodular lesion in the remnant pancreas. Total pancreatectomy was performed, which revealed that the lesion was intraductal papillary-mucinous adenocarcinoma (IPMC) with minimal invasion, suggesting the metachronous multicentric occurrence of this intraductal papillary-mucinous neoplasm (IPMN). Because there were no malignant cells at the pancreaticojejunostomy, and because the histological appearance of the main-duct IPMC was different from that of the IPMA in the primary specimen, the main-duct IPMC was thought to be of different origin from the IPMA. These findings suggest that careful surveillance of the gastrointestinal tract and careful follow up are necessary for IPMN, because an IPMN could be associated with other gastrointestinal tract malignancies.

Backgroun/Purpose: Hilar cholangiocarcinoma is the one of the most difficult carcinomas to diagnose because of the localization of the main tumor at the hepatic hilus, and because of the complex anatomy of the biliary, artery, and portal systems. To perform a curative operation, it is important to evaluate the extent of carcinoma and the resectability. Hilar cholangiocarcinoma often extends along the axis of the bile duct. Percutaneous transhepatic cholangiogaraphy (PTC) and/or endoscopic retrograde cholangiography (ERC) are usually performed to diagnose the extent of the hilar cholangiocarcinoma. However, computed tomography (CT) was thought not to be useful because its resolution is poor. Now that multidetector row CT (MDCT) and high-performance imaging systems are available, the diagnostic strategy for hilar cholangiocarcinoma has changed. Methods: In this study, we analyzed the preoperative diagnostic imaging of 24 consecutive patients whose hilar cholangiocarcinoma was confirmed by histopathological examination. All patients were submitted to 16-channel MDCT, except for those with an allergy to iodine contrast medium. The data obtained from MDCT were analyzed and checked by both radiologists and surgeons, using multiplanar reconstruction (MPR) images. Results: The accuracy of diagnosis of horizontal spreading was 80.9% and that of vertical spreading was 100%. However, the sensitivity for lymph node metastasis was insufficient. Based on the data from MDCT and other examinations, all patients underwent surgery. Curative operation was performed in 15 patients (62.5%). Conclusions: Our results indicate that 16-channel MDCT is reliable for the diagnosis of hilar cholangiocarcinoma, especially prior to bile duct drainage. Thus, it is important to perform MDCT when patients with obstructive jaundice are encountered.

AIM: To evaluate the significance of BNIP3 in the pathogenesis of pancreatic cancer, we analyzed the relationship between the expression of BNIP3 and survival rate of the patients with pancreatic cancer, or chemosensitivities in pancreatic cancer cell lines, particularly for gemcitabine, the first-line anti-tumor drug for pancreatic cancer. METHODS: To compare the expression level of BNIP3 with the resistance to gemcitabine, eight pancreatic cancer cell lines were subjected to gemcitabine treatment and the quantitative real-time RT-PCR method was used to evaluate BNIP3 expression. Immunohistochemical analysis was also performed using 22 pancreatic cancer specimens to study relationship between BNIP3 expression and survival rate. RESULTS: Although no significantly positive association between BNIP3 mRNA level and gemcitabine chemosensitivity was observed, pancreatic canter cell lines that were sensitive to gemcitabine treatment tended to show high levels of BNIP3 expression. The converse, an absence of BNIP3 expression, was not correlated with gemcitabine resistance. We further compared the BNIP3 expression profiles of resected primary pancreatic cancer specimens with the prognosis of the patients, and found a tendency of favorable prognosis and low BNIP3 expression. CONCLUSION: High levels of BNIP3 expression cannot be used as one of the predicting factors for gemcitabine chemosensitivity, and some yet to be known factors will have to fill the gap for the accurate prediction of pancreatic cancer chemosensitivity to gemcitabine. However, BNIP3 expression may have an impact on prediction of prognosis of patients with pancreatic cancer. (c) 2007 WJG. All rights reserved.

AIM: To evaluate the significance of BNIP3 in the pathogenesis of pancreatic cancer, we analyzed the relationship between the expression of BNIP3 and survival rate of the patients with pancreatic cancer, or chemosensitivities in pancreatic cancer cell lines, particularly for gemcitabine, the first-line anti-tumor drug for pancreatic cancer. METHODS: To compare the expression level of BNIP3 with the resistance to gemcitabine, eight pancreatic cancer cell lines were subjected to gemcitabine treatment and the quantitative real-time RT-PCR method was used to evaluate BNIP3 expression. Immunohistochemical analysis was also performed using 22 pancreatic cancer specimens to study relationship between BNIP3 expression and survival rate. RESULTS: Although no significantly positive association between BNIP3 mRNA level and gemcitabine chemosensitivity was observed, pancreatic canter cell lines that were sensitive to gemcitabine treatment tended to show high levels of BNIP3 expression. The converse, an absence of BNIP3 expression, was not correlated with gemcitabine resistance. We further compared the BNIP3 expression profiles of resected primary pancreatic cancer specimens with the prognosis of the patients, and found a tendency of favorable prognosis and low BNIP3 expression. CONCLUSION: High levels of BNIP3 expression cannot be used as one of the predicting factors for gemcitabine chemosensitivity, and some yet to be known factors will have to fill the gap for the accurate prediction of pancreatic cancer chemosensitivity to gemcitabine. However, BNIP3 expression may have an impact on prediction of prognosis of patients with pancreatic cancer. (c) 2007 WJG. All rights reserved.

Objectives: Acinar cell carcinoma (ACC) of the pancreas is a rare tumor, and many aspects remain unclear because no large-scale clinical studies have been conducted. Methods: The present study investigated the clinical characteristics, treatment, and therapeutic outcomes of 115 patients registered in the Pancreatic Cancer Registry of the Japan Pancreas Society, and therapeutic plans were reviewed. Results: Although ACC has been associated with advanced stage and poor prognosis, this tumor was resectable in 76.5% of the patients, and the 5-year survival rate after resection was favorable, being 43.9%. Conclusions: Confirming the diagnosis of ACC preoperatively is difficult, but this diagnosis should be kept in mind while planning surgery for ordinary pancreatic cancer. Once the diagnosis has been confirmed, a possibility of surgical resection should be pursued to achieve better prognosis. If ACC is unresectable or recurrent, chemotherapy is likely to prove useful. Multidisciplinary therapy centering on the role of surgery will need to be established.

Objectives: We have developed a bioartificial pancreas transplantation method using polyvinyl alcohol. Using this model, the relationship between hyperglycemia and parameters that represent renal function was investigated. Methods: Plasma glucose, 1,5-anhydro-D-glucitol (1,5-AG), and renal factors including plasma urea nitrogen and creatinine levels, urine volume, glucose, and albumin were examined once a week for 9 weeks in diabetic mice with or without transplantation of encapsulated rat islets, and in normal C57BL/6 mice. The mesangial matrix fraction of the glomerulus was measured histologically. The mice were classified into 3 groups according to their mean plasma glucose levels as either severe (n = 17) or mild (n = 23) hyperglycemia or normoglycemia (n = 11). The plasma glucose, renal factors, and mesangial matrix fraction were tested by single and multiple regression analyses. Results: Almost all the renal factors correlated significantly with mean plasma glucose and 1,5-AG levels. The level and duration of hyperglycemia estimated by the area under the curve above basal correlated most significantly with mesangial matrix fraction. Conclusions: Bioartificial pancreas transplantation significantly reduced the deterioration of renal factors. The 1,5-AG was useful to predict urine albumin loss. The level and duration of hyperglycemia determined the degree of renal damage, which were reduced by bioartificial pancreas transplantation.

Enteric anisakiasis is relatively rare, and the preoperative diagnosis is difficult. We report 3 cases of enteric anisakiasis: 1 was confirmed by operation, and the other 2 cases were suspected by the patient history. The 1st patient was a 48-year-old female presenting with abdominal pain. An abdominal computed tomography scan showed a dilated small intestine and accumulation of ascites. We performed partial resection of the small intestine, and an Anisakis nematode was found on the wall of the resected bowel. After surgery, the detailed history revealed that the patient consumed a raw sardine with vinegar and miso, fermented soybean paste. Three days after her operation, 2 men presenting with abdominal pain visited the hospital, and computed tomography scans of the patients showed dilated small intestines and accumulation of ascites. By taking patient histories, we found that both of them consumed sardines with vinegar and miso, and both were given conservative treatment with fasting and transfusion. By the experience of the 1st case, we could diagnose the following 2 cases as having enteric anisakiasis. In conclusion, the possibility of anisakiasis should be considered in patients with abdominal pain after ingesting raw fish, especially when intestinal obstruction is suspected. Copyright (c) 2007 S. Karger AG, Basel

Background: In Japan the annual incidence of pancreatic cancer has increased over the last decade, but no advancement has been made in the long-term prognosis after resection. The significant differences in the surgical procedures between Western countries and Japan have been discussed. Therefore, an adequate comparison and analysis of the data from Japan, Europe and the USA is required. This review evaluates many important published reports from Japan which influence surgical procedure. Methods: Several important highlights and controversies regarding the concept of surgical treatment and surgical procedure are discussed comparing the results in Japan with those in Western countries. Results: No significant difference in diagnostic strategy using various imaging methods was observed between Japan and Europe. The stage classification for pancreatic cancer by the Japanese Pancreatic Society ( JPS) seems to be superior to others, because the results on long-term prognosis after pancreatectomy of cases with pancreatic head cancer, diagnosed as tubular adenocarcinoma, has been arranged logically. Pancreatectomy with extended radical dissection is recommended in Japan, but several clinical studies from Europe and the USA suggest that this is ineffective. The basic concepts of this controversy have recently come closer altogether. Scientific clinical trials for instance on the necessity of adjuvant treatment, etc., are now on-going. Conclusion: The characteristics on diagnosis and treatment of pancreatic cancer in Japan are described. The JPS registration system for pancreatic cancer can provide much more information, i.e. dependency on diagnostic methods, highly frequent sites of lymph node and of distant metastases, the prognosis of small pancreatic cancers, etc. The indication for any surgical treatments should be limited to cases with the possibility of cancer free margins. Copyright (C) 2007 S. Karger AG, Basel.

Purpose. We investigated the potentiation of combination therapy using tumor necrosis factor (TNF) with TNP-470, a potent angiogenesis inhibitor. Methods. We evaluated the antitumor effect in vivo against subcutaneous (s.c.) MC38 mouse colon adenocarcinoma tumors in C57BL/6 mice. The mice were treated with a single bolus injection via the tail vein of 3 or 8 mu g rhTNF in 0.5% bovine serum albumin/normal saline (BSA/NS), or with 0.5% BSA/NS alone as a control, with or without TNP-470 pretreatment, given as 30 or 60mg/kg x 2 days, s.c. DNA synthesis in human umbilical endothelial cells (HUVEC) was assessed by [H-3]thymidine uptake after incubation with TNF, with or without TNP-470. Results. The antitumor effect of TNP-470 pretreatment combined with 3 mu g recombinant human (rh) TNF injection resulted in an 80% reduction of tumor volume compared with the control. This was significantly better than that induced by 3 mu g rhTNF alone (P &lt; 0.005). DNA synthesis in HUVEC was inhibited by TNF with TNP-470 in a dose-dependent manner, but there was no enhanced effect against MC38 in vitro. Conclusions. These results suggest that the combination of the angiogenesis inhibitor TNP-470 and TNF might have a synergistic antitumor effect on solid tumors in vivo.

Objective: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas show heterogeneous proliferations with latent malignancy. Mucins (MUC) are high-molecular-weight glycoproteins, with an aberrant expression profile in various malignancies. Recently, MUC4 and MUC5AC expressions have been demonstrated to correlate with the unfavorable and the favorable prognosis of pancreatic duct cell carcinoma, respectively. However, little is known about these mucin expressions in IPMNs. Methods: To clarify the role of MUC4 and MUC5AC expressions in IPMNs, the expression profiles of MUC4 and MUC5AC were investigated in 50 lesions from 17 specimens with 16 IPMNs by immunohistochemistry, using each of their specific antibodies. Results: The expression of MUC4 was found in the lesions ranging from adenoma to cancer lesions of IPMNs, whereas it was undetectable in normal and hyperplastic lesions. Frequent expression of MUC4 is found in the higher grade of IPMNs (borderline and cancer lesions; 16/18 lesions, 94%). The differences were independently significant (P &lt; 0.001) when the cutoff point was set between adenoma and borderline IPMNs. Similarly, frequent expression of MUC5AC was detected in the lesions from adenoma to cancer of IPMNs (32/34, 94%), whereas no intense expression was detected in normal or hyperplastic lesions. The significant difference was found when the cutoff point was set between hyperplasia and adenoma of IPMNs (P &lt; 0.001). Conclusions: These results indicated that the expressions of MUC4 and MUC5AC are potential markers to distinguish adenoma or above malignant lesions of IPMNs from lesser malignant ones, respectively.

Pancreatic arteriovenous malformation (AVM) is a relatively rare disease. Based on our literature search, 51 cases of pancreatic AVM have been reported since 1968. The gastrointestinal bleeding is the most common presenting symptom (24/51 cases [47%]). There were only 6 cases of pancreatitis in these cases. We describe 2 cases of acute pancretitis with pancreatic AVM. The patients who were diagnosed with acute pancreatitis were admitted to our hospital. Pancreatitis was considered to be caused by pancreatic AVM by some modalities of diagnostic imaging. The respective pancreatic AVM lesions of patients were resected to prevent the recurrence of pancreatitis. They are asymptomatic after the surgery. Pancreatic AVM is thought to be the one of the reasons for acute pancreatitis.

An adenovirus (Adv) retaining normal E1A but lacking the 55 kDa E1B protein replicates preferentially in TP53-deficient cancer cells including pancreatic cancer cell lines, resulting in the oncolysis of the tumor. When tumor cells are exposed to hypoxia, hypoxia-inducible factor-1 alpha (HIF-1 alpha) is stabilized and activated to promote the transcription of several genes such as vascular endothelial growth factor (VEGF), but in the presence of E1A hypoxia-induced VEGF m-RNA synthesis is inhibited by E1A binding to p300. In this study, we demonstrated that the cancer cells infected with a mutant Adv in which the p300 binding site in E1A was partially deleted induced a higher expression level of VEGF as compared to those of Adv with normal E1A. An immunoprecipitation study for E1A confirmed that mutant E1A had a reduced binding capacity for p300. Although the expressions of HIF-1 alpha m-RNA were almost the same in both cancer cells infected with the mutant Adv and those with the wild Adv, the amount of HIF-1 alpha protein in cancer cells infected with the wild E1A Adv was lower than in those infected with the mutant E1A type Adv. In vivo, in contrast to the angiogenesis treated with mutant E1A, wild-E1A inhibited tumor angiogenesis significantly. These results suggested that E1A suppressed the production of VEGF and inhibited tumor angiogenesis by binding with p300, resulting in the inhibition of the HIF-1 alpha-mediated transcription of genes through binding to HRE. This study demonstrates, for the first time, the effect of an oncolytic replication-competent Adv in inhibiting tumor angiogenesis.

膵動静脈奇形(AVM)に膵炎を伴った症例を経験したので報告する.症例は49歳男性,繰り返す側腹部痛を主訴に受診し,画像上膵炎および膵AVMが疑われ,膵頭十二指腸切除が施行された.組織学的に,膵頭部にAVMに相当する血管病変が認められ,部分的に慢性膵炎およびその急性増悪の所見が観察された.慢性あるいは急性の膵炎と思われる症例でも,背景にAVMが存在する場合があるため,疑わしい場合には弾性線維染色を行って確認することが重要と思われる(著者抄録)

It has recently been recognized that anandamide (arachidonylethanolamide), which is an endogeneous-cannabinoid (endocannabinoid), mediates septic shock. Cannabinoid means a mind-active material in cannabis (marijuana).. Anandamide is mainly produced by macrophages. Cannabinoid I (CB 1) receptor, which is one of the cannabiniod receptors, is also known to mediate hypotensive shock. The role of endocannabinoids in the progression of acute pancreatitis is unclear. The aims of this study are to clarify their relationship and to find a new therapeutic strategy by regulating the endocannabinoid signaling in acute pancreatitis. Male Wistar rats were injected with caerulein intravenously to induce mild edematous pancreatitis or injected with 5% sodium taurocholate to the bilio-pancreatic duct to induce severe necrotizing pancreatitis. The animals in the latter group were also injected with a CB I receptor antagonist, AM251, or vehicle solution to see if the inhibition of endocannabinoids improves their survival. Plasma anandamide level was measured by the liquid chromatography/tandem mass spectrometry method. In both models of acute pancreatitis, the plasma anandamide levels were increased, and the levels were significantly higher in rats with severe necrotizing pancreatitis than those in rats with mild edematous pancreatitis. The mean arterial pressure and survival rate were significantly improved by the treatment with AM251, despite that the local inflammatory changes in the pancreas and various parameters (white blood cells, hematocrit, serum amylase, and serum interleukin-6) were similar. This is the first report to show that endocannabinoids are involved in the deterioration of acute pancreatitis and that the down-regulation of endocannabinoid signaling may be a new therapeutic strategy for severe acute pancreatitis. (c) 2005 Tohoku University Medical Press

Objectives: The rat experimental model of continuous regional arterial infusion of protease inhibitor (CRAI) on acute pancreatitis has yet to be established. Therefore, the aims of this study were ( 1) to establish the rat experimental model of CRAI and ( 2) to evaluate the effects of nafamostat on rat severe acute pancreatitis via different routes of administration. Methods: The rat internal jugular vein or the celiac artery was infused with nafamostat, and the concentration of nafamostat in the lung and pancreas was measured. After the induction of severe acute pancreatitis, rats received intravenous or regional intraarterial infusion of nafamostat and then concentrations of trypsinogen activated peptide ( TAP) and serum interleukin (IL-6), and histologic sections of the pancreas were examined and the 96-hour survival rate was evaluated. Results: CRAI rats had higher concentrations of nafamostat in the pancreas than those infused intravenously. However, CRAI rats had lower concentrations of nafamostat in the lung that those infused intravenously. CRAI significantly reduced the levels of TAP and pancreatic necrosis. Moreover, the levels of serum IL-6 and the mortality rate were significantly reduced after CRAI compared with the intravenous infusion of nafamostat. Conclusion: The effectiveness of the rat experimental model of CRAI on acute pancreatitis was clearly demonstrated. The concentration of nafamostat in the lung and pancreas and the effects of nafamostat differ according to the route of administration.

AURKA/STK15/BTAK, the gene encoding Aurora A kinase that is involved in the regulation of centrosomes and segregation of chromosomes, is frequently amplified and overexpressed in various kinds of human cancers, including pancreatic cancer. To address its possibility as a therapeutic target for pancreatic cancer, we employed the RNA interference technique to knockdown AURKA expression and analyzed its phenotypes. We found that the specific knockdown of AURKA in cultured pancreatic cancer cells strongly suppressed in vitro cell growth and in vivo tumorigenicity. The knockdown induced the accumulation of cells in the G(2)-M phase and eventual apoptosis. Furthermore, we observed a synergistic enhancement of the cytotoxicity of taxanes, a group of chemotherapeutic agents impairing G2-M transition, by the RNA interference-mediated knockdown of AURKA. These results indicate that inhibition of AURKA expression can result in potent antitumor activity and chemosensitizing activity to taxanes in human pancreatic cancer.

AURKA/STK15/BTAK, the gene encoding Aurora A kinase that is involved in the regulation of centrosomes and segregation of chromosomes, is frequently amplified and overexpressed in various kinds of human cancers, including pancreatic cancer. To address its possibility as a therapeutic target for pancreatic cancer, we employed the RNA interference technique to knockdown AURKA expression and analyzed its phenotypes. We found that the specific knockdown of AURKA in cultured pancreatic cancer cells strongly suppressed in vitro cell growth and in vivo tumorigenicity. The knockdown induced the accumulation of cells in the G(2)-M phase and eventual apoptosis. Furthermore, we observed a synergistic enhancement of the cytotoxicity of taxanes, a group of chemotherapeutic agents impairing G2-M transition, by the RNA interference-mediated knockdown of AURKA. These results indicate that inhibition of AURKA expression can result in potent antitumor activity and chemosensitizing activity to taxanes in human pancreatic cancer.

Objectives: The angiographic appearance of acute necrotizing pancreatitis (ANP) demonstrates ischemic change with vasospasm in and around the pancreas. We investigated the role of vasospasm in pancreatic ischemia and necrosis in the early phase of human ANP. Methods: The relationship between the angiographic abnormalities and the perfusion status of the pancreas documented by contrast-enhanced computed tomography (CE-CT) was examined in 102 patients with ANP who were admitted during the early phase of the disease. Results: Ischemic change with vasospasm on angiography of the intrapancreatic and extrapancreatic arteries was observed and corresponded with the poorly perfused area of the pancreas detected by CE-CT done at admission. Resultant pancreatic necrosis was confirmed on follow-up CE-CT examination consistent with the location where angiography demonstrated ischemic change with vasospasm. Severe ischemic change on angiography was primarily observed in patients in whom more than 50% of the pancreas was poorly perfused. The extent of the ischemic change was correlated with the extent of the poorly perfused area of the pancreas and the mortality rate. Conclusion: These results suggest that vasospasm is involved in the development of pancreatic ischemia and necrosis in the early phase of ANP.

The interaction of immature dendritic cells ( DC) with irradiated pancreatic cancer cells was examined. Flow cytometric analysis using annexin V and propidium iodide revealed that ionizing radiation (25-35 Gy X-ray) induced both apoptosis and necrosis in pancreatic cancer cell lines. After irradiation, PK-1 and Panc-1 cells were likely to undergo necrosis, whereas MIAPaCa-2 cells underwent apoptosis. When DiO-stained immature DCs were co-incubated with DiI-stained irradiated MIAPaCa-2, it was observed under fluorescent microscopy that DCs phagocytized dead tumor cells as early as 4 h after co-incubation. The DCs' phagocytosis of irradiated tumor cells was also confirmed by flow cytometry. These results suggest that irradiated pancreatic cancer cells, which undergo both apoptosis and necrosis, could be a good source of tumor-associated antigens for cross-presentation by DCs. Copyright (C) 2005 S. Karger AG, Basel.

To date, the events that mediate tumor progression in pancreatic cancer are still poorly understood. Cytogenetic, allelotype, and somatic cell hybrid studies in human pancreatic adenocarcinoma have suggested that chromosome 18 may carry tumor suppressor genes (TSGs), including SMAD4. We previously identified that LOH of 18q at the SMAD4 locus, along with LOHs on 17p and 12q, positively associated with poor prognoses of pancreatic cancer patients. However, restoration of the SMAD4 gene did not suppress in vitro proliferation of pancreatic cancer cells that harbored homozygous deletion of this gene. An intraductal papillary mucinous neoplasm (IPMN) is thought to be one of the premalignant lesions of the pancreas that progresses to carcinoma. Although there were frequent LOH (7/14, 50%) at the SMAD4 locus in IPMN samples, SMAD4 protein was observed immunohistochemically in tumor cells, and no mutations of the SMAD4 gene were observed, suggesting that it is the existence of a TSG in 18q, other than SMAD4, that suppresses cell growth. To functionally assess the activity of chromosome 18 in pancreatic cancer, we transferred a normal copy of the chromosome into pancreatic ductal carcinoma cells with and without completely inactivated SMAD4. In this study, in vitro growth of the hybrid cells was significantly suppressed compared with the parental cells, regardless of the initial SMAD4 status. To estimate the metastatic ability of the hybrids, we used a lung colonization model. At the end of the experiment, there was significant suppression of the number of surface metastases developing in mice injected with hybrids in comparison with those injected with parental cells. To identify and characterize genes that are involved in the progression of pancreatic cancer, we used microarray expression analysis employing a 20k oligo-array system. It was revealed that there was increased expression of 4 genes relating to apoptosis in the 18 chromosome hybrids cells compared with the parental cells. We are now analyzing the function of these genes.

Small pancreatic cancers, intractable diseases, offer the possibility of cure. Can this be true? Through the National Pancreatic Cancer Registry, the Japan Pancreas Society (JPS) has collected 822 cases of invasive cancer with tumors &lt; 2 cm in diameter (TS1 pancreatic cancer). Papillary adenocarcinoma and the well-differentiated type of tubular adenocarcinoma are more frequent in TS1 pancreatic cancer than the larger tumors, suggesting that further genetic and phenotypic changes occur during their progression. Patients with TS1 pancreatic cancer presented with abdominal pain, jaundice, and exacerbation of diabetes, while 17.3% of them had no symptoms. Further imaging diagnosis should be employed to detect TS1 pancreatic cancer, but conventional US and ERCP play an important role in the diagnostic process. In this study, of 822 patients with TS1 pancreatic cancer, only 216 patients (26.3%) had T1 tumors because of invasion to adjacent tissue. There were 306 patients (37.2%) with lymph node metastasis, of whom 63 (7.7%) had N3 metastasis that is counted as a distant metastasis. As a result, only 136 patients (16.5%) had stage I disease with a median survival time of 78.2 months and a 5-year survival rate of 58.1%. Small pancreatic cancer does not necessarily mean early pancreatic cancer, and surgery alone is not sufficient to cure this disease.

The prognosis of pancreatic cancer is defined by the histology and extent of disease. Preoperative histologic diagnosis and diagnostic imaging are fundamentals in managing the disease, but it is not rare to find unexpected peritoneal dissemination or liver metastasis at the time of operation. The overall resectability rate of pancreatic cancer is 40% in Japan. Resecting the portal vein and peripancreatic plexus were performed on 40% of the patients who underwent pancreatectomy for invasive cancer in the head of the pancreas. Longterm survival was only found in patients who underwent pancreatectomy. Radical lymph node dissection, or combined resection of the large vessels, did not seem to improve survival further than the standard resection. Multidisciplinary treatments combined with surgery were performed, and various effects of postoperative chemotherapy after pancreatectomy, intraoperative- and postoperative-radiation therapy, or postoperative chemotherapy for unresectable tumor, were shown. Development of unconventional therapies and refinement of the conventional therapy should be promoted on a randomized prospective trial basis. To promote this effort, which requires the international comparisons and cooperation, JPS developed a computerized JPS registration system downloadable from the JPS website (http://www.kojin.or.jp/suizou/index.html).

BACKGROUND: In a previous work, we demonstrated that loss of heterozygosity of 18q is a frequent event significantly associated with poor prognosis in pancreatic cancer. We hypothesized that restoration of heterozygosity of chromosome 18 in pancreatic cancer cells would reduce their tumorigenicity. This study was intended to provide functional evidence for the existence of new tumour suppressor gene(s) located on chromosome 18. METHOD: Restoration of heterozygosity was achieved by introducing a normal copy of chromosome 18 into pancreatic ductal carcinoma using a microcell-mediated chromosome transfer technique. The tumorigenicity and metastatic ability of both the parental cells and resulting hybrids were assessed in vitro and in vivo. RESULTS: In vitro growth of hybrid clones was significantly delayed compared to parental cells. This was paralleled by a significantly lower rate of promoting invasive carcinoma in nude mice and a longer latency with hybrid cells compared with parental tumour cells. Hybrid clones showed significant suppression in the number of surface lung metastases when compared with parental cells. CONCLUSION: These data represent strong functional evidence that chromosome 18q encodes strong tumour and metastasis suppressor activity that is able to switch human pancreatic cancer cells to a dormant phenotype.

Introduction: Macrophages are considered to play an essential role in the events leading to systemic inflammatory response. Some are known to reside in the peritoneal cavity but there are no reports defining the participation of peritoneal macrophages (PMs) in the progression of acute pancreatitis. Aim: To clarify the role of PMs in the progression of acute pancreatitis. Methodology: Acute pancreatitis was induced in rats from which macrophages other than PMs were greatly depleted, and in rats greatly depleted of macrophages including PMs. Macrophages were depleted by the injection of liposome encapsulated dichloromethylene bisphosphonate. After the induction of acute pancreatitis, local pancreatic inflammation, intraperitoneal inflammation and lung injury were compared between the 2 groups. Results: Local pancreatic inflammation did not differ between the 2 groups. However, intraperitoneal inflammation was clearly improved by the depletion of PMs. Serum cytokine level and lung injury were also improved by the depletion of PMs. Conclusion: Peritoneal macrophages extend inflammation from the pancreas to the peritoneal cavity and subsequently induce lung injury in acute pancreatitis. Peritoneal macrophages play an essential role in the systemic inflammatory response and the progression of acute pancreatitis in the rat.

Although patients with unresectable pancreatic tumors have been treated with 5-fluorouracil (5FU)-based combination chemotherapy, the drug resistance of cancer cells presents a crucial therapeutic problem. It was reported that UPRT overcomes 5FU resistance. UPRT catalyzes the synthesis of 5-fluorouridine monophosphate (FUMP) from Uracil and phosphoribosylpyrophosphate (PRPP). The antitumor effect of 5FU is enhanced by augmenting S-fluorodeoxyuridine monophosphate (FdUMP) converted from FUMP, which inhibits thymidylate synthetase (TS). We first demonstrated that injecting an E1-deficient adenoviral vector (Adv) expressing UPRT (AxCAUPRT) followed by 5-FU treatment resulted in a volume reduction of xenotransplanted human tumors. In examining the therapeutic effect of AxCAUPRT/ 5-FU against peritoneal dissemination, we found that nonselective gene transduction of AxCAUPRT caused severe adverse effects arising from the increase of F-dUMP in normal intestine. Because the therapeutic gene delivered by a restricted replication-competent Adv lacking 55 kDa E1B protein (AxE1AdB) is speculated to be expressed selectively in tumors, mice with established tumors were injected with AxE1AdB and E1-deleted Adv expressing the lacZ reporter gene (AxCA1acZ). The expression of the reporter gene (lacZ) was selectively enhanced in disseminated tumors. The therapeutic advantage of restricted replication competent Adv that expresses UPRT (AxE1AdB-UPRT) was evaluated in an intraperitoneal disseminated tumor model. To study the anti-tumor effect of AxE1AdB-UPRT/5FU, mice with disseminated AsPC-1 tumors were administered the Adv, followed by the 5FU treatment. It was shown that the treatment with AxE1AdB-UPRT/5FU caused a dramatic reduction of the disseminated tumor burden without toxicity in normal tissues. Our results showed that the AxE1AdB-UPRT/5FU system is a promising tool for intraperitoneal disseminated pancreatic cancer. (C) 2002 Wiley-Liss, Inc.

Introduction: Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis. The soluble form of flt-1 VEGF receptor inhibits VEGF activity in a dominant-negative manner. Aim: This study demonstrated the regional tumor suppression effect of adenovirus-mediated soluble flt-1 in human pancreatic cancer cells. Methodology: The VEGF expression level was examined in nine cell lines. Panc-1 and PK-8 were used as lower- and higher-VEGF-producing cell lines, respectively. The in vitro proliferation of cancer cells infected with adenovirus vectors encoding soluble flt-1 (Adsflt) and control vectors (AdLacZ) was not different. To assess the in vivo tumor growth suppression, cancer cells were inoculated subcutaneously in SCID mice. Adsflt, AdLacZ, or vehicle was injected directly into the tumors. The early process of tumor angiogenesis in a dorsal skinfold chamber was monitored by intravital microscopy. Results: In both Panc-1 cells and PK-8 cells, the tumor growth of the Adsflt-treated group was significantly suppressed. The microvessel density, revealed by CD31 immunostaining, was also significantly lower in the Adsflt-treated group. Apoptosis index was higher in the Adsflt group. Immunofluorescence staining revealed the expression of VEGF not only in cancer cells but also in tumor stromal cells. Wild-type cells and AdLacZ-infected cells prompted strong tumor angiogenesis, whereas Adsflt-infected cells failed to exert such an effect. Conclusion: These results indicate that antiangiogenic gene therapy using soluble flt-1 might be an effective approach for pancreatic cancer treatment.

Background. The purpose of this study was to clarify the still poorly understood dynamics of peritoneal inflammatory cells (PICs) in acute pancreatitis. Methods. Acute pancreatitis of 3 different degrees of severity was induced in mate Wistar rats. Peritoneal lavage was performed at 1, 6, 12, and 24 hours after the induction, and the fluids collected were analyzed for the number and subpopulation of PICs. The levels of apoptosis and necrosis, cytokines, and bacterial infection were also investigated. Results. The number of PICs was increased in mild and moderate pancreatitis, and the infiltration of inflammatory cells had occurred. In severe pancreatitis, the number of PICs increased until 6 hours after the induction, but thereafter the number decreased. Infiltration of neutrophils occurred 6 hours after the induction, but it was not sustained thereafter and infiltration of peritoneal macrophages did not occur. Cytokines' in the lavage fluid increased in all 3 models during the first 6 hours after the induction. Subsequently, cytokines were reduced in mild and moderate pancreatitis but significantly increased in severe pancreatitis. The level of bacterial infection increased according to the severity. Conclusions. The relationship between the PIC dynamics and cytokine levels in severe pancreatitis is very different from that observed in mild or moderate pancreatitis. (Surgery 2002;132:86-92.).

Background. The number of dendritic cells (DC) in the local tu nor environment correlates with patient survival in numerous tumors. The relationship of DC infiltration in the tumor microenvironment and prognosis was examined in patients with pancreatic adenocarcinoma. Methods. Forty-seven pancreatectomy specimens with a diagnosis of pancreatic adenocarcinoma were identified retrospectively and analyzed with the dendritic cell markers S-100 and CD1a. Patient survival was correlated with these markers and with p53, CD3, CD20, CD68, Ki-67. Results. Significant numbers (&gt;3 per high-powered field) of tumor-associated S100(+) or GD1a(+) cells were found in only 2/47-patients (4%). 117 en present, dendritic cells were located outside the margin of the tumor CD3, CD68, and CD20 positive cells were rare or absent in 96%, 92%, and 93% of the specimens. A correlation with survival and numbers of immune cells could not be made secondary to their rarity. The median survival was 18.9 months. No other indices measured correlated with survival. Conclusions. In patients with pancreatic adenocarcinoma, there is a paucity of immune cells within the tumor.

Dendritic cells (DCs) activated by CD40L-expressing CD4(+) T cells act as mediators of "T helper (Th)" signals for CD8(+) T lymphocytes, inducing their cytotoxic function and supporting their long-term activity. Here, we show that the optimal activation of DCs, their ability to produce high levels of bioactive interleukin (IL)-12p70 and to induce Th1-type CD4(+) T cells, is supported by the complementary DC-activating signals from both CD4(+) and CD8(+) T cells. Cord blood- or peripheral blood-isolated naive CD8(+) T cells do not express CD40L, but, in contrast to naive CD4(+) T cells, they are efficient producers of IFN-gamma at the earliest stages of the interaction with DCs. Naive CD8(+) T cells cooperate with CD40L-expressing naive CD4(+) T cells in the induction of IL-12p70 in DCs, promoting the development of primary Th1-type CD4(+) T cell responses. Moreover, the recognition of major histocompatibility complex class I-presented epitopes by antigen-specific CD8(+) T cells results in the TNF-alpha- and IFN-gamma-dependent increase in the activation level of DO and in the induction of type-1 polarized mature DCs capable of producing high levels of IL-12p70 upon a subsequent CD40 ligation. The ability of class I-restricted CD8(+) T cells to coactivate and polarize DCs may support the induction of Th1-type responses against class I-presented epitopes of intracellular pathogens and contact allergens, and may have therapeutical implications in cancer and chronic infections.

Dendritic cells (DCs) activated by CD40L-expressing CD4(+) T cells act as mediators of "T helper (Th)" signals for CD8(+) T lymphocytes, inducing their cytotoxic function and supporting their long-term activity. Here, we show that the optimal activation of DCs, their ability to produce high levels of bioactive interleukin (IL)-12p70 and to induce Th1-type CD4(+) T cells, is supported by the complementary DC-activating signals from both CD4(+) and CD8(+) T cells. Cord blood- or peripheral blood-isolated naive CD8(+) T cells do not express CD40L, but, in contrast to naive CD4(+) T cells, they are efficient producers of IFN-gamma at the earliest stages of the interaction with DCs. Naive CD8(+) T cells cooperate with CD40L-expressing naive CD4(+) T cells in the induction of IL-12p70 in DCs, promoting the development of primary Th1-type CD4(+) T cell responses. Moreover, the recognition of major histocompatibility complex class I-presented epitopes by antigen-specific CD8(+) T cells results in the TNF-alpha- and IFN-gamma-dependent increase in the activation level of DO and in the induction of type-1 polarized mature DCs capable of producing high levels of IL-12p70 upon a subsequent CD40 ligation. The ability of class I-restricted CD8(+) T cells to coactivate and polarize DCs may support the induction of Th1-type responses against class I-presented epitopes of intracellular pathogens and contact allergens, and may have therapeutical implications in cancer and chronic infections.

We investigated the in vitro effects of combining interleukin-18 (IL-18) and IL-2 on human lymphocytes. The combined use of these two cytokines synergistically enhanced the proliferation, cytolytic. activity, and interferon-gamma production of peripheral blood mononuclear cells. Phenotypic analysis revealed a preferential expansion of CD56(+)CD3(-) cells and an upregulation of IL-2 receptor-cu expression on natural killer cells. Isolated natural killer cells showed a substantial increase in proliferation and cytotoxicity compared with CD4(+) and CD8(+) T cells. The combined use of IL-18 and IL-2 should be considered a viable strategy to induce an antitumor response in vivo.

Although surgical resection is considered to be the only approach that offers a possibility of cure to patients with pancreatic cancer, the prognosis of the disease has not been improved markedly by any surgical procedures in the past 20 years. Large-scale randomized prospective clinical trials are being conducted in the United States and Italy, comparing standard lymph node dissection with extended lymph node dissection. Although preoperative chemoradiation has various advantages in the treatment of pancreatic cancer, it does not contribute to its downstaging and eventual cure. The combination of leucovorin, 5-fluorouracil (5-FU), and extracorporeal irradiation, however, has been proven to improve the patient's quality of life (QOL). Palliative surgery still requires further research in areas such as the examination of morbidity rates and the duration of bypass effects, now that laparoscopic and endoscopic surgery have both been well developed. Recent biological research has revealed the mechanisms of the carcinogenesis and the progression of pancreatic cancer, and, against this background, we assume that more effective trials will be conducted soon. Immunotherapy with dendritic cells, as well as gene therapy with mutant adenovirus, has already been employed clinically. Pancreatic cancer therapy is now facing new prospects.

As an antitumor agent, interleukin-12 (IL-12) has been revealed to be a key regulator of the immune response, particularly that involving CTL and natural killer (NK) cells. We report herein the antiangiogenesis effect of IL-12 on human as well as murine tumors in NK-depleted severe-combined immunodeficient mice using fibroblasts genetically engineered to secrete this cytokine. Although the in vitro growth of tumor cells was not affected by the presence of IL-12, coinoculation of IL-12-secreting fibroblasts strongly inhibited tumor growth in immunodeficient mice. The neovascularization surrounding the tumor was remarkably inhibited in the area in which the IL-12-secreting fibroblasts were implanted, resulting in the suppression of tumor growth. Lectin staining in tumor sample sections also showed a significant reduction in the number of vessels. The RNA expression of IFN-gamma and its inducible antiangiogenic chemokine IFN gamma-inducible protein 10 was stimulated in endothelial cells cultured with IL-12. It was also found that IL-12 down-regulated the expression of the endothelial cell mitogens vascular endothelial growth factor and basic fibroblast growth factor. The antitumor effects of IL-12 were accompanied by interesting histological changes consisting of a high degree of keratinization and apoptosis and a decrease in the proliferation rate of human tumors and extensive necrosis in the murine ones.

Background: The prognosis of patients with resected pancreatic cancer remains poor. This study evaluated the effect of adoptive immunotherapy (AIT) using intraportal infusion of lymphokine-activated killer (LAK) cells after curative resection and intraoperative radiation therapy (IORT) on advanced pancreatic cancer. Methods: Twenty-nine consecutive patients with advanced pancreatic cancer (Japan Pancreas Society stage III or IV) were divided into two groups. The control group (n = 17) underwent tumour resection and IORT. The treatment group (n = 12) underwent resection, IORT and intraportal infusion of LAK cells combined with recombinant interleukin 2 (rIL-2). The incidence of liver metastasis and the survival rate of these two groups were compared. Results: Although the overall survival between groups was not statistically different (P = 0.082), there were more patients (four) alive 3 years after operation in the test group (36 per cent versus zero), and the incidence of liver metastases in the treatment group was significantly lower (three of 12 versus ten of 15; P &lt; 0.05). LAK therapy influenced survival positively in multivariate analysis. Conclusion: These preliminary observations suggest that AIT warrants further study as a possible adjuvant for patients undergoing curative resection and IORT for pancreatic cancer.

Hypothesis: Intraductal papillary mucinous tumors (IPMTs) of the pancreas may be meaningfully construed as representing 2 clinically distinct subtypes: main duct tumors (MDT) and branch duct tumors (BDT). Design: Retrospective study. Setting: University hospital from January 1988 through December 1994. Patients and Intervention: We reviewed diagnostic findings and late results of surgical treatment in 30 patients with IPMT. Results: The tumor was located in the head of the pancreas more often in BDT than in MDT (65% [11/17] and 23% [3/13 ], respectively). Of the 13 patients with MDTs, 12 (92%) had intraductal papillary adenocarcinoma (noninvasive and minimally invasive types) and/or carcinoma in situ (carcinoma in situ: low papillary and/or flat tumor cells), and 3 (23%) had stromal invasion. Of the 17 patients with BDTs, 5 (29%) had intraductal papillary adenocarcinoma and/or carcinoma in situ. Two pancreatoduodenectomies and 8 pylorus-preserving pancreatoduodenectomies were performed in 10 of the 17 patients with BDTs, distal pancreatectomy in 7 patients with MDTs, and total pancreatectomy in 4 patients with MDTs. The 5-year survival rates were 47% for MDT and 90% for BDT. Four of 6 patients with MDTs who died had local recurrence. One patient died of liver metastasis and 1 of esophageal cancer. Only 1 patient with BDT of the 2 who died had recurrent disease. Conclusion: Intraductal papillary mucinous tumors may be composed of 2 clinically distinct subtypes: MDTs and BDTs. Initially, although distal pancreatectomy can be recommended for most MDTs, the need for cancer-free margins in this more aggressive type may necessitate total pancreatectomy. Pylorus-perserving pancreatoduodenectomies is recommended for most BDTs, but, because these tumors are more often adenomas, a good prognosis can be expected.

Experimental evidence has directly implicated matrix metalloproteinases (MMPs) in the remodeling of the stromal tissue surrounding tumors. Thus, MMP inhibitors could limit the expansion of both neoplastic cell compartment and endothelial cell compartment of a tumor. Much of the work on the role of MMP inhibitors has concentrated on their inhibitory effects on tumor cell invasion. We have examined the effects of a new MMP inhibitor, KB-R7785 (acting an MMP-1, MMP-3, and MMP-9), on tumor angiogenesis and metastasis of murine colon adenocarcinoma (C-26) in two tumor models in BALB/c mice (transparent chamber model and lung: colonization model). KB-R7785 has not shown inhibitory effects on in vitro growth of either C-26 or KOP2.16 murine endothelial cells. In vivo, KB-R7785 administrated twice daily for 15 days (100 mg/kg, i.p.), starting the day of tumor inoculation (5 x 10(5) C26 cells) in transparent chamber, has resulted in 88.2% suppression of tumor growth, compared with that in vehicle-administered mice (controls). Tumors grown in controls have doubled their area in 3.3 days, whereas those treated by KB-R7785 progressed almost four times slower (tumor area doubling time, 12 days). KB-R7785 rendered centrally avascular tumors with only a rim of peripheral neovasculature, which had significant lower functional vascular density and vascular area than the corresponding parameters in control tumors 10 days after inoculation [79.9 +/- 6.7 cm/cm(2) versus 164.1 +/- 10.1 cm/cm(2) (P &lt; 0.01) and 19.8 +/- 1.5% versus 42.6 +/- 2.7% (P &lt; 0.01), respectively]. In the lung colonization model (tail vein inoculation of 5 x 10(5) C-26 cells), administration of KB-R7785 (100 mg/kg, i.p.) twice daily for 20 days has reduced the number of surface metastasis by 85.8% and abolished the tumor burden, as compared with controls. The few metastatic colonies found in the lungs of KB-R7785 treated mice appeared to be dormant (i.e, staining with von Willebrand factor antibody revealed few, if any, positive cells within the metastatic foci from MMP inhibitor-treated lungs, whereas terminal deoxynucleotidyl transferase-mediated nick end labeling showed a 4-fold increase in the rate of tumor cell apoptosis compared with controls, The fact that KB-R7785 interferes with early steps of angiogenesis and cancer spread suggests that MMP inhibitors may control both primary and secondary tumor growths by limiting the expansion of endothelial cells, as well as cancer cells, composing the tumors.

Background: Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma. and hyperparathyroidism. MEN 2 is caused predominantly by germ-line mutations of the RET proto-oncogene. This study aimed to clarify the genotype-phenotype correlation in MEN 2 patients in Japan in order to modify the clinical management according to the genotype. Methods: Constitutive DNA of 64 MEN 2 patients (48 kindreds) were searched for mutations at exons 10, 11, 13, 14 and 16 of the RET proto-oncogene using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), direct sequencing and restriction enzyme digestion. The clinical characteristics of the patients were obtained from a previous nationwide questionnaire survey Results: Overall, 62 (96.9%) out of 64 patients had a germ-line point mutation at the hot spots. MTC and pheochromocytoma occurred equally in every genotype except C630S. Specific genotype had a correlation between tumor size and age at the operation for MTC or extent of MTC, i.e. C618S developed late onset type of MTC as compared with that of C634R, C634Y and M918T. Small MTC in C634R may be less aggressive than those in C634Y and M918T. Conclusions: DNA testing has good clinical implications for the management of patients with MEN 2 and the timing and operative procedures of thyroidectomy can be modified according to the genotype.

Intraoperative radiotherapy (IORT) is an innovative treatment approach for cancer of the pancreas. The common causes of treatment failure in pancreatic cancer are regional recurrence and distant metastasis. While at present the benefit of IORT in unresectable pancreatic cancer is still controversial and awaits further prospective trials for its clarification, the experience gathered over a period of 30 years with IORT for pancreatic cancer does suggest that IORT should be part of the adjuvant therapy of surgical resection. A combination with pre- or postoperative external beam radiotherapy and chemotherapy may be beneficial for both resectable and unresectable patients. IORT was shown to be a relatively safe intervention and it notably improved the quality of life of patients with locally advanced pancreatic carcinomas by alleviating their pain. Here, we summarize and discuss the experience reported to date and present our historical analysis of IORT for pancreatic cancer. © Springer-Verlag 1998.

In individuals who carry germline mutations in tumor suppressor genes predisposing them to inherited cancer syndromes, occurrence of somatic mutations in the same genes contributes to tumorigenesis. Germline mutations in the RET proto-oncogene predispose individuals to multiple endocrine neoplasia (MEN) type 2 syndromes, Since these mutations are oncogenic by themselves, somatic mutations in the same gene had been thought unnecessary, Recently, a somatic mutation at codon 918 of RET was reported in medullary thyroid carcinoma (MTC) and C-cell hyperplasia in patients with MEN 2A or familial MTC (FMTC), suggesting its possible contribution to tumorigenesis. We describe here a novel somatic mutation at codon 919 in a patient with FMTC carrying a germline mutation at codon 768 that may also be related to tumor progression.

MEN (multiple endocrine neoplasia) type 2 syndrome is an inherited disease characterized by medullary thyroid carcinoma, pheochromocytoma, hyperparathyroidism and/or developmental anomalies. Germ-line mutations of the RET proto-oncogene have recently been identified as the underlying cause of the syndrome. Accordingly, several investigators have advocated prophylactic total thyroidectomy for medullary thyroid carcinoma at an early age in MEN 2 gene carriers identified by DNA analysis. Before applying this strategy in Japan, the biological behavior of each category of tumor in MEN 2 syndrome, and medullary thyroid carcinoma in particular, should be well understood. We conducted a nationwide questionnaire survey to clarify the clinicopathological features of MEN 2 in Japan, obtaining data for 230 patients diagnosed as having MEN 2, They included 84 males and 146 females, with a median age of 37.5 years (range 5-83), Patients were categorized as 179 with MEN 2A, 17 with MEN 2B, 12 with familial medullary thyroid carcinoma and 22 'other', Medullary thyroid carcinoma, pheochromocytoma and parathyroid lesions occurred in 224 (97%), 132(57%) and 25(11%) patients respectively. Twelve patients (5.2%) died of medullary thyroid carcinoma and 11 patients died of other or unknown causes, Of 163 patients for whom follow-up data were obtained, 82(50%) experienced recurrences of medullary thyroid carcinoma, including symptomatic recurrent tumors in 24 patients and elevated calcitonin levels alone in 54. In the era of BET mutational analysis for screening relatives of patients with MEN 2, these data provide useful information about surgical management for patients with MEN 2 in Japan.

Multiple endocrine neoplasia (MEN) 2A is an inherited disease characterized by the development of medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. It has recently been shown to be associated with germ-line mutations in the RET proto-oncogene. We describe a 21-year-old man from a MEN 2A family who was found by DNA analysis to be a gene carrier of MEN 2A and then was diagnosed, using a stimulated calcitonin test, as having presymptomatic medullary thyroid carcinoma, His morbidity seems to have been cured by total thyroidectomy as postoperative calcitonin levels after stimulation are normal, It is concluded that direct genetic analysis for mutations in the RET proto-oncogene should be the diagnostic test of choice for identifying family members at risk for MEN 2A.

In the human pancreatic cancer cell line PANC1, we detected several DNA fragments with abnormally intensified signals by restriction landmark genomic scanning. Major five of these fragments were cloned. All of the cloned fragments were mapped at the 19q13.1-13.2 region where the AKT2 oncogene was located. Southern blotting using the cloned DNA fragments and a fragment of AKT2 cDNA as probes revealed that the AKT2 gene was amplified in 3 of 12 pancreatic cancer cell Lines analyzed including PANC1 and in 3 of 20 primary pancreatic cancers. The AKR gene was overexpressed in the 3 cell lines with the amplified gene. The results suggest that the AKT2 gene is a candidate oncogene activated by amplification in some human pancreatic cancers. (C) 1996 Academic Press, Inc.

We examined whether lymphatic metastasis was inhibited by the potent angiogenesis inhibitor AGM-1470 [O-(chloroacetyl-carbamoyl)fumagillol, TNP-470] using a rat lymphatic metastasis model. Clone A of the rat fibrosarcoma AS653HM, when inoculated into the footpads of syngeneic rats, highly and preferentially metastasized to lymph nodes. In contrast, when AGM-1470 was administered subcutaneously to rats bearing the tumor cells, the tumor growth and incidence of metastasis in the lymph nodes were reduced in a dose- and schedule-dependent manner. Similar inhibition of lymphatic metastasis was also observed in the rats in which treatment with AGM-1470 was initiated following resection of the primary tumor in the foot, indicating that the treatment with AGM-1470 inhibited the progression of lymphatic metastasis at the metastatic sites of the lymph nodes. These results suggest that AGM-1470 can be a potential agent to prevent lymphatic metastasis.

We examined whether the novel point mutation from GCC (Ala) to GAC (Asp) at codon 664 in exon 11 of RET proto-oncogene, which we had found in two small cell lung carcinoma (SCLC) cell lines, existed in genomic DNA of tumor tissues of the two SCLC patients from whom these SCLC cell lines were derived. Sequence analysis revealed that point mutation identical to that of the SCLC cell lines was present in amplified alleles of single-strand conformational variants in genomic DNA of the tumor tissues, whereas it was not detected in genomic DNA of non-tumor tissues of the patients, These results indicate that this mutation had initially occurred in the SCLC patients and was of somatic origin.

Background/Aims: New therapeutic approach is required for pancreatic cancer, one of the most intractable malignancies. The role of angiogenesis in the tumor growth of a Syrian hamster pancreatic cancer cell line HPD-NR, which closely resembles its human counterpart, was investigated. Methods: Angiogenic activity was measured as stimulation of growth of human umbilical vein endothelial cells (HUVEC), and angiogenic factors produced by HPD-NR cells were identified by reverse-transcription polymerase chain reaction and Northern blot analysis. Then in vitro and in vivo antitumor effects of a potent angiogenesis inhibitor, O-(chloroacetylcarbamoyl)fumagillol (AGM-1470), were examined. Results: The conditioned medium of HPD-NR cells stimulated the growth of HUVEC, and four hamster angiogenic factors were detected with an overexpression of transforming growth factor alpha and vascular endothelial growth factor messenger RNAs. AGM-1470 specifically inhibited the growth of HUVEC and that of HPD-NR tumors in vivo with decreased vascularity of the tumors but not the growth of HPD-NR cells in vitro. Conclusions: The results suggest that angiogenesis plays an important role in tumor growth of HPD-NR cells and can be a new target of medical therapy for pancreatic cancer.