PURPOSE: Nutritional scores have been reported to be useful prognostic factors for various cancers. This study evaluated the usefulness of the preoperative controlling nutritional status (CONUT) score as a predictor of recurrence of non-small cell lung cancer (NSCLC). METHODS: The present study included 422 patients with stage I-IIIA NSCLC who underwent complete resection at Tohoku University Hospital between January 2010 and December 2016. The patients were divided into the low-CONUT and high-CONUT groups based on their CONUT scores. Overall survival (OS), recurrence-free survival (RFS), and cumulative recurrence rates in the low- and high-CONUT groups were evaluated retrospectively. RESULTS: One hundred forty-seven patients (34.8%) were assigned to the high-CONUT group. The high-CONUT group had a significantly worse performance status, pleural invasion, vascular invasion, and lung metastasis. In the whole cohort, the low-CONUT group showed better overall survival, recurrence-free survival, and a low cumulative recurrence rate in comparison to the high-CONUT group. There was no significant difference in prognosis or recurrence between the low- and high-CONUT groups after propensity score matching. CONCLUSION: Patients with a high CONUT score may be at high risk of recurrence because of the high frequency of pleural invasion, vascular invasion, and lung metastasis.

PURPOSE: This single-institution retrospective cohort study was conducted to assess the prognostic significance of perioperative changes in the prognostic nutritional index (PNI) in patients who underwent surgery for non-small cell lung cancer (NSCLC). METHODS: Clinicopathological data were collected from 441 patients who underwent lobectomy for NSCLC between 2010 and 2016.The PNI ratio (postoperative PNI/preoperative PNI) was used as an indicator of perioperative PNI changes. Prognostic differences were investigated based on PNI ratios. RESULTS: The optimal cut-off value of the PNI ratio for overall survival (OS) was set at 0.88 using a receiver operating characteristic curve. The PNI ratio was inversely related to a high smoking index, interstitial lung disease, and postoperative pulmonary complications. The 5-year OS rates for the high vs. low PNI ratio groups were 88.2% vs. 68.5%, respectively (hazard ratio [HR]: 3.04, 95% confidence interval [CI]: 1.90-4.86). Multivariable analysis revealed that a low PNI ratio was significantly associated with poor prognosis (HR: 2.94, 95% CI: 1.77-4.87). The PNI ratio was a more sensitive indicator than postoperative PNI status alone for identifying patients at high risk of mortality, particularly those with non-lung cancer causes. CONCLUSION: The perioperative PNI change is a significant prognostic factor for patients with NSCLC.

Abstract Background Interstitial lung disease (ILD) represents a heterogeneous group of lung disorders characterized by fibrotic lung tissue changes. In regions with severe donor shortages, single-lung transplantation (SLTx) is often preferred over bilateral lung transplantation for advanced ILD. However, temporal changes and complications in the retained native lung remain poorly understood. Methods A retrospective analysis of 149 recipients who had undergone SLTx was conducted, including 34 ILD SLTx recipients. Native-lung volume, radiological alterations, and perfusion were assessed at distinct post-SLTx time points. Statistical analyses compared ILD and non-ILD SLTx groups. Results Our study revealed a progressive reduction in native-lung volume over time, accompanied by radiographic deterioration and declining perfusion. Complications in the retained native lung were observed, such as pneumothorax (29.4%), pulmonary aspergillosis (11.8%), and acute exacerbation (8.9%). Long-term survival rates were similar between ILD and non-ILD SLTx recipients. Conclusions This study illuminates the unique challenges and complications with respect to the native lung following SLTx for ILD. Ongoing monitoring and tailored management are essential. Despite limitations, this research contributes to our understanding of the temporal progression of native-lung complications post-SLTx for ILD, underscoring the need for further investigation.

Abstract Letermovir, initially approved for cytomegalovirus (CMV) prophylaxis in hematopoietic stem-cell transplantation, has gained attention for off-label use in lung-transplant (LTx) recipients. Given the high susceptibility of LTx recipients to CMV infection, this study explores the effectiveness and safety of letermovir prophylaxis. A retrospective analysis of using letermovir for LTx recipients at Tohoku University Hospital (January 2000 to November 2023) was conducted. Case summaries from other Japanese transplant centers and a literature review were included. Six cases at Tohoku University Hospital and one at Kyoto University Hospital were identified. Prophylactic letermovir use showed positive outcomes in managing myelosuppression and preventing CMV replication. The literature review supported the safety of letermovir in high-risk LTx recipients. Despite limited reports, our findings suggest letermovir’s potential as prophylaxis for LTx recipients intolerant to valganciclovir. Safety, especially in managing myelosuppression, positions letermovir as a promising option. However, careful consideration is important in judiciously integrating letermovir into the treatment protocol.

Whole lung engineering and the transplantation of its products is an ambitious goal and ultimately a viable solution for alleviating the donor-shortage crisis for lung transplants. There are several limitations currently impeding progress in the field with a major obstacle being efficient revascularization of decellularized scaffolds, which requires an extremely large number of cells when using larger pre-clinical animal models. Here, we developed a simple but effective experimental pulmonary bioengineering platform by utilizing the lung as a scaffold. Revascularization of pulmonary vasculature using human umbilical cord vein endothelial cells was feasible using a novel in-house developed perfusion-based bioreactor. The endothelial lumens formed in the peripheral alveolar area were confirmed using a transmission electron microscope. The quality of engineered lung vasculature was evaluated using box-counting analysis of histological images. The engineered mouse lungs were successfully transplanted into the orthotopic thoracic cavity. The engineered vasculature in the lung scaffold showed blood perfusion after transplantation without significant hemorrhage. The mouse-based lung bioengineering system can be utilized as an efficient ex-vivo screening platform for lung tissue engineering.

PURPOSES: Delayed chest closure (DCC) is a widely accepted procedure in the context of lung transplantation (LTx); yet there are few reports detailing its long-term survival and clinical outcomes. METHODS: We reviewed the medical records of recipients who underwent deceased-donor lung transplantation (LTx) at Tohoku University Hospital. Long-term survival, including overall survival, freedom from chronic lung allograft dysfunction (CLAD), and CLAD-free survival and the clinical outcomes of graft function and physical performance and constitution were reviewed in recipients with DCC. RESULTS: Between 2009 and 2022, 116 patients underwent LTx, 33 of whom (28.4%) required DCC. The intra-and post-operative courses of the recipients who required DCC were more complicated than those of the recipients who underwent primary chest closure (PCC), with frequent volume reduction surgery and longer periods of invasive mechanical ventilation. Pulmonary vascular disease was considered a risk factor for these complications and DCC. Nonetheless, long-term survival and graft functions were comparable between the DCC and PCC groups. The physical performance and constitution of recipients who required DCC continued to improve, and by 2 years after transplantation, exhibited almost no difference from those who underwent PCC. CONCLUSIONS: In view of the profoundly complicated intra- and post-operative courses, DCC should be performed cautiously and only when clinically indicated, despite which it can result in equivalent long-term survival and acceptable outcomes to PCC.

BACKGROUND: Analyzing HLA polymorphism in lung transplantation (LTx) is important, given its impact on LTx recipient survival and graft function. Accordingly, we conducted a retrospective study to examine the influence of HLA mismatch and donor-specific antibodies (DSA) on short-term outcomes and early-phase post-LTx complications. METHOD: HLA antigen or eplet mismatch in LTx patients at Tohoku University Hospital from 2018 to 2023 was determined, and DSA was measured on admission for surgery to identify preformed DSA and at weeks 4 to 12 post-LTx for de novo DSA, respectively. RESULTS: The participants were 45 LTx recipients, HLA-A/B/DR antigen mismatch (5-6 of 6) being identified in 57%, HLA-A/B/Cw/DR/DQ mismatch (8-10 of 10) in 57%, and HLA eplet mismatch (>61) in 46%. The prevalence of preformed DSA was 24%, and persistence (uncleared) was 16%. The incidence of de novo DSA was 16% after LTx. During the study,16 recipients experienced grade 3 primary graft dysfunction (PGD), 8 developed acute rejection, and 5 died. No HLA-related variables were significantly associated with post-LTx mortality and were not risk factors for high-grade PGD or acute rejection. CONCLUSION: Despite limitations in sample size, resulting in tentative findings, the study serves as a crucial pilot study for an ongoing multicenter prospective trial in Japan.

OBJECTIVE: This study aims to compare the post-transplant survival of untwinned single lung transplantation (SLT) to twinned SLT. In untwinned SLT, the contralateral lung is judged unsuitable for transplantation and might affect the lung graft within the donor body and recipient survival after SLT. METHODS: A retrospective analysis was conducted on 84 SLT recipients at our center, divided into untwinned SLT and twinned SLT groups. The demographics of donors and recipients, surgical characteristics, complications, mortality, and survival rates were compared. RESULTS: There were no significant differences in recipient and donor demographics between the two groups. Surgical characteristics showed no significant differences. Microbiological findings of the transplanted lungs indicated a low incidence of positive cultures in both groups. 3-month to 1-year mortality and overall survival rates were comparable between the two groups. CONCLUSION: At our institution, both untwinned and twinned SLT procedures exhibited excellent survival rates without significant differences between the two procedures. The favorable outcomes observed may be associated with the strategic advantages of Japan's MC system and the diligent management of marginal donor lungs although this requires further investigation to elucidate the specific contributory factors.

With the rising demand for lung transplants, especially for adults with smaller chest cavities and children, a significant donor-recipient size mismatch challenge exists. A solution is lobar lung transplants from deceased donors with otherwise unsuitable lungs due to local damage. Despite its promise, early post-transplant mortality rates are comparatively high, emphasizing the need for meticulous donor selection and graft evaluation. This video tutorial introduces a detailed methodology for a porcine left upper lobar lung transplant model, from preoperative measures to reperfusion. Steps encompass preoperative measures, donor and recipient preparations, graft procurement and specific anastomosis procedures for the bronchus, pulmonary artery and left atrium. This guidance, derived from rigorous translational research, not only contributes to the knowledge of safe lobar lung transplants in animals but also promises potential implications for clinical practice.

BACKGROUND AND OBJECTIVE: Lung transplantation (LTx) in Japan has taken steps toward increasing the number of donors and recipients and is at the maturity stage of development, at which point pulmonologists (hereinafter referred to as "respirologists") become involved in transplant practice. Because of severe donor shortage and limited number of LTx surgeries, most of transplant process from candidacy evaluation to post-operative management has been handled only by thoracic surgeons, which takes away opportunities from respirologists to manage LTx recipients. Given the growth of both LTx and the number of patients with complex problems, cooperation with respirologists in transplant practice is urgently needed to achieve transplant success in Japan. METHODS: Authors summarized current transplant circumstance in Japan from the transplant physician's standpoint. A systematic search through PubMed database and Google Scholar was performed by terms of "respirologists", "pulmonologist", "lung transplant" or "Japan" from 2000 and 2022. Thoracic surgeons working at each transplant center were asked to complete a questionnaire on physicians' intervention to LTx. KEY CONTENT AND FINDINGS: The roles of respirologists in LTx differ with facility size and function, depending on whether they are working at a non-transplant center with other respirologists or at a transplant center with transplant physicians. LTx centers are currently devoted to educating respirologists who work at non-transplant or low-volume transplant centers in order for them to deal with patients before and after transplantation. CONCLUSIONS: Joint efforts and training of outstanding personnel who can take care of recipients are required, this being the greatest issue for the success of transplantation in Japan.

BACKGROUND: von Willebrand factors (vWFs), hemostatic factors, are produced as large multimers and are shear stress-dependently cleaved to become the appropriate size. A reduction in vWF large multimers develops in various conditions including the use of extracorporeal life support, which can cause excessive-high shear stress in the blood flow and result in hemostatic disorders. The objective of this prospective study was to investigate the impact of venovenous extracorporeal membrane oxygenation (VV ECMO) use on the status of vWF large multimers and hemostatic disorders during single lung transplantation (SLT). METHODS: We prospectively enrolled 12 patients who underwent SLT at our center. Among them, seven patients were supported by VV ECMO intraoperatively (ECMO group) and the remaining five patients underwent SLT without ECMO support (control group). The vWF large multimer index (%) was defined as the ratio of the large multimer proportion in total vWF (vWF large multimer ratio) derived from a patient's plasma to that from standard human plasma. RESULTS: The vWF large multimer index at the end of the surgery was significantly lower in the ECMO group than in the control group (112.6% vs. 75.8%, respectively; P<0.05). The intraoperative blood loss and the amounts of intraoperative transfusion products in the ECMO group tended to be greater than those in the control group; however, the differences were not significant. CONCLUSIONS: During SLT, the use of VV ECMO caused a decrease in the vWF large multimer index. The short duration of time of VV ECMO use in our study did not significantly affect the intra- and postoperative outcomes including blood loss, blood transfusion, and re-exploration thoracotomy for bleeding. Nevertheless, to comprehensively evaluate the actual influence of this decrease in the vWF large multimer index on intra- and postoperative outcomes, a multicenter larger-scale study is warranted.

BACKGROUND: Lung transplant (LTx) recipients are at higher risk of infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). There is an increasing demand for additional analysis regarding the efficacy and safety of after the initial series of mRNA SARS-CoV-2 vaccines in Japanese transplant recipients. METHOD: In this open-label, nonrandomized prospective study carried out at Tohoku University Hospital, Sendai, Japan, LTx recipients and controls received third doses of either the BNT162b2 or the mRNA-1273 vaccine, and the cellular and humoral immune responses were analyzed. RESULTS: A cohort of 39 LTx recipients and 38 controls participated in the study. The third dose of SARS-CoV-2 vaccine promoted much greater humoral responses at 53.9 % of LTx recipients than after the initial series at 28.2 % of patients without increasing the risk of adverse events. However, still fewer LTx recipients responded to the SARS-CoV-2 spike protein with the median IgG titer of 129.8 AU/mL and with the median IFN-γ level of 0.01 IU/mL when compared to controls with those of 7394 AU/mL and 0.70 IU/mL, respectively. CONCLUSION: Although the third dose of mRNA vaccine in LTx recipients was effective and safe, impaired cellular and humoral responses to SARS-CoV-2 spike protein were noted. Given lower antibody production and establishing vaccine safety, repeating the administration of mRNA vaccine will lead to robust protection in such a high-risk population (jRCT1021210009).

OBJECTIVES: Standard bilateral lung transplantation (BLT) is not feasible for patients with pulmonary arterial hypertension (PAH) complicated with a giant pulmonary arterial aneurysm (PAA). This study aimed to describe the outcomes of BLT with pulmonary artery reconstruction (PAR) using donor aorta for such patients. METHODS: This is a retrospective single-centre study reviewing PAH patients with a PAA who received BLT with PAR using donor aorta from January 2010 through December 2020. We compared the characteristics and short- and long-term outcomes of recipients receiving PAR (PAR group) with those who had no PAA and received standard BLT (non-PAR group). RESULTS: Nineteen adult PAH patients underwent cadaveric lung transplantation during the study period. Among them, 5 patients with a giant PAA (median pulmonary artery trunk diameter, 69.9 mm) underwent BLT with PAR using donor aorta and the others received standard BLT. Although the operation time tended to be longer in the PAR group compared with the non-PAR group (1239 vs 958 mins, P = 0.087), 90-day mortality (PAR group: 0% vs non-PAR group: 14.3%, P > 0.99), and 5-year survival rate (PAR group: 100% vs non-PAR group: 85.7%, P = 0.74) was comparable between the groups. No dilatation, constriction or infection of the aortic grafts were recorded during the study period with a median follow-up time of 94 months in the PAR group. CONCLUSIONS: Lung transplantation with PAR using donor aorta is a valid surgical option for PAH patients complicated with a giant PAA.

Patients with lymphangioleiomyomatosis (LAM) and lung transplantations are treated with multiple drugs, such as tacrolimus, mycophenolate mofetil, prednisolone, and itraconazole, for long-term suppression of rejection response and prevention of infection. Additional drugs are required when lung transplant recipients develop graft complications. Therefore, managing polypharmacy is critical because of drug-drug interactions caused by various factors, including drug-metabolizing enzymes such as cytochrome P450 3A (CYP3A). The patient was a 48-year-old woman (height 144.9 cm and weight 38.4 kg) who underwent lung transplantation for LAM. Mycophenolate mofetil, tacrolimus (target blood concentration, 4.0-8.0 ng/mL), and prednisolone were administered for immunosuppression, and itraconazole and clarithromycin were administered to manage graft infection. The patient developed unilateral lymphedema, predominantly in the left leg; therefore, sirolimus was initiated with a target blood concentration of 3.0-5.0 ng/mL. In addition to 1.0 mg/day of sirolimus, tacrolimus (0.3 mg/day), itraconazole (100 mg/day), and clarithromycin (800 mg/day) were added. Blood sirolimus concentrations ranged from 18.8 to 36.9 ng/mL on days 6 to 9; thus, treatment with sirolimus was stopped because of over-target blood concentrations. Blood concentrations of sirolimus and tacrolimus were successfully managed without adverse events using therapeutic drug monitoring (TDM) and azole anti-fungal substitution of azithromycin instead of clarithromycin although sirolimus concentration was relatively lower compared to the target range. Thereby, frequent TDM, management of polypharmacy that influences CYP3A activity, and possibly CYP3A genotyping should be appropriately conducted for personalized medicine.

RATIONALE: Nontuberculous mycobacterial (NTM) diseases are difficult-to-treat infections, especially in lung transplant (LTx) candidates. Currently, there is a paucity of recommendations on the management of NTM infections in LTx, focusing on Mycobacterium avium complex (MAC), M. abscessus and M. kansasii. METHODS: Pulmonologists, infectious disease specialists, LTx surgeons and Delphi experts with expertise in NTM were recruited. A patient representative was also invited. Three questionnaires comprising questions with multiple response statements were distributed to panellists. Delphi methodology with a Likert scale of 11 points (5 to -5) was applied to define the agreement between experts. Responses from the first two questionnaires were collated to develop a final questionnaire. The consensus was described as a median rating >4 or <-4 indicating for or against the given statement. After the last round of questionnaires, a cumulative report was generated. RESULTS: Panellists recommend performing sputum cultures and a chest computed tomography scan for NTM screening in LTx candidates. Panellists recommend against absolute contraindication to LTx even with multiple positive sputum cultures for MAC, M. abscessus or M. kansasii. Panellists recommend MAC patients on antimicrobial treatment and culture negative can be listed for LTx without further delay. Panellists recommend 6 months of culture-negative for M. kansasii, but 12 months of further treatment from the time of culture-negative for M. abscessus before listing for LTx. CONCLUSION: This NTM LTx study consensus statement provides essential recommendations for NTM management in LTx and can be utilised as an expert opinion while awaiting evidence-based contributions.

BACKGROUND: Indium lung is characterized by interstitial pneumonia and/or emphysema which occurs in indium-tin oxide (ITO) workers. Indium lung is now known to progress after stopping exposure to ITO, but the long-term influences of ITO remain unclear. CASE PRESENTATION: Forty seven years old, a never-smoker, who had been engaged in an ITO manufacturing process for 8 years. Emphysema was indicated by the medical check-up for ex-ITO workers, and he was diagnosed with indium lung. He underwent partial lung resections for pneumothorax two times, and obstructive pulmonary dysfunction had progressed through the years. He underwent right single lung transplant 20 years after ITO exposure. Pathologically, his lung showed severe distal acinar emphysema and honeycomb change. Fibrosis and destruction of the lung tissue significantly progressed compared to the previous partial resections. Scanning electron microscopy combined with energy dispersive spectroscopy revealed that the deposited particles contained indium and tin. After the transplantation, his respiratory function was improved. CONCLUSIONS: In this case, ITO resided in the lung tissue for 20 years, and lung tissue destruction kept progressing. Careful medical follow-up is recommended for ITO-workers even if they are asymptomatic.

BACKGROUND: To date, reports addressing the antibody response following mRNA SARS-CoV-2 vaccination in lung transplant (LTX) recipients are limited. Thus, the aim of this clinical study was to investigate the efficacy and safety of the vaccines in LTX recipients compared to controls. METHODS: An open-label, nonrandomized prospective study was conducted at Tohoku University Hospital. LTX recipients and controls who received either the BNT162b2 vaccine or the mRNA-1273 vaccine were recruited, and SARS-CoV-2 IgG was measured before and after vaccination. The adverse events were reviewed. Predictors of negative serology after vaccination were evaluated with logistic regression. RESULTS: Forty-one LTX recipients and 24 controls were analyzed. Although all controls had a positive antibody response to a SARS-CoV-2 mRNA vaccine, antibody response was found in 24.4% of LTX recipients (p < .0001). The amount of SARS-CoV-2 IgG following the 2nd dose significantly climbed to 6557 AU/mL in controls, whereas the increase in IgG in LTX recipients was 8.3 AU/mL (p < .0001). Fewer LTX recipients developed systemic fever than controls (p < .0001) despite equivalent overall adverse event percentages in both groups. A higher plasma concentration of mycophenolate was a significant predictor of negative serology (p = .032). CONCLUSIONS: An impaired antibody response to mRNA vaccines was significantly found in LTX recipients compared to controls and was associated with the plasma concentration of mycophenolate. While repeating mRNA vaccination may be one of the strategies to improve antibody response given the safety of the vaccines, emerging data on humoral immune responses based on immunosuppression regimens in LTX recipients should be studied (jRCT1021210009).

OBJECTIVES: The objective of the present study was to examine the effect of venovenous extracorporeal membrane oxygenation (VV ECMO) use on the hemodynamics during single lung transplantation (SLT) and post-operative course. METHODS: Forty-seven patients who underwent SLT for end-stage lung diseases in our lung transplant center between January 2010 and December 2019 were included in this study. The recipients were divided into 3 groups according to the type of intra-operative ECMO. No type of ECMO was intra-operatively used in the patients of the NO ECMO group. The patients in the venoarterial (VA) and VV ECMO groups were put on VA and VV ECMO during the surgery, respectively. The data were compared among the three groups. RESULTS: There were 13 SLT cases in the NO ECMO group, 23 SLT cases in the VA ECMO group and 11 SLT cases in the VV ECMO group. Re-exploration for bleeding was performed in 3 (13.0%) recipients in the VA ECMO group. No recipients required re-exploration in the other groups. In the NO ECMO group, systolic pulmonary arterial pressure (sPAP) was significantly elevated during the main pulmonary artery clamp on the SLT side and it was decreased in the VA ECMO group because of the bypass flow. Interestingly, sPAP was significantly decreased in the VV ECMO group as well. CONCLUSIONS: VV ECMO decreases the PAP during SLT which could be a choice for extracorporeal life support during lung transplant surgery for patients, even those with pulmonary hypertension.

The patient was a 41-year-old man. He was diagnosed with pleurisy and came to our hospital. The pleural effusion and pleurisy remained even after administration of sufficient doses of antibiotics. A thorough examination revealed an anterior mediastinal tumor. Six months later, pericarditis also developed. Autoimmune diseases, infections, and malignant diseases were suspected, but a definitive diagnosis could not be made. In order to confirm the diagnosis, anterior mediastinal tumor resection and pleural biopsy were performed. The anterior mediastinal tumor was diagnosed as cholesterin granuloma pathollogically. Cholesterin granuloma is a granuloma formed by deposition of cholesterin crystals and cholesterin granuloma occurring in the mediastinum is extremely rare.

BACKGROUND: As lung transplantation (LTX) is a valuable treatment procedure for end-stage pulmonary disease, delayed referral to a transplant center should be avoided. We aimed to conduct a single-center analysis of the survival time after listing for LTX and waitlist mortality in each disease category in a Japanese population. METHODS: We included patients listed for LTX at Tohoku University Hospital from January 2007 to December 2020 who were followed up until March 2021. Pulmonary disease was categorized into the Obstructive, Vascular, Suppurative, Fibrosis, and Allogeneic groups. Risk factors for waitlist mortality were assessed using a Cox proportional hazards model. The Kaplan-Meier method was used to model time to death. RESULTS: We included 269 LTX candidates. Of those, 100, 72, and 97 patients were transplanted, waiting, and dead, respectively. The median time to LTX and time to death were 796 days (interquartile range [IQR] 579-1056) and 323 days (IQR 129-528), respectively. The Fibrosis group showed the highest mortality (50.9%; p < .001), followed by the Allogeneic (35.0%), Suppurative (33.3%), Vascular (32.1%), and Obstructive (13.1%) groups. The Fibrosis group showed a remarkable risk for waitlist mortality (hazard ratio 3.32, 95% CI 2.11-4.85). CONCLUSIONS: In Japan, the waiting time is extremely long and candidates with Fibrosis have high mortality. There is a need to document outcomes based on the underlying disease for listed LTX candidates to help determine the optimal timing for listing patients based on the estimated local waiting time.

BACKGROUND: While lung transplant (LTX) can be an effective therapy to provide the survival benefit in selected populations, post-transplant outcome in LTX recipients with bronchiectasis other than cystic fibrosis (CF) has been less studied. Pseudomonas aeruginosa, often associated with exacerbations in bronchiectasis, is the most common micro-organism isolated from LTX recipients. We aimed to see the outcomes of patients with bronchiectasis other than CF after LTX and seek the risk factors associated with pre- and post-transplant Pseudomonas status. METHODS: Patients who underwent LTX at Tohoku University Hospital between January 2000 and December 2020 were consecutively included into the retrospective cohort study. Pre- and post-transplant prevalence of Pseudomonas colonization between bronchiectasis and other diseases was reviewed. Post-transplant outcomes (mortality and the development of chronic lung allograft dysfunction (CLAD)) were assessed using a Cox proportional hazards and time-to-event outcomes were estimated using the Kaplan-Meier method. RESULTS: LTX recipients with bronchiectasis experienced a high rate of pre- and post-transplant Pseudomonas colonization compared to other diseases with statistical significance (p < 0.001 and p < 0.001, respectively). Nevertheless, long-term survival in bronchiectasis was as great as non-bronchiectasis (Log-rank p = 0.522), and the bronchiectasis was not a trigger for death (HR 1.62, 95% CI 0.63-4.19). On the other hand, the chance of CLAD onset in bronchiectasis was comparable to non-bronchiectasis (Log-rank p = 0.221), and bronchiectasis was not a predictor of the development of CLAD (HR 1.88, 95% CI 0.65-5.40). CONCLUSIONS: Despite high prevalence of pre- and post-transplant Pseudomonas colonization, the outcome in LTX recipients with bronchiectasis other than CF was comparable to those without bronchiectasis.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease that occurs in premature infants and the prognosis is variable depending on the comorbidities including fibrosis, emphysema, or pulmonary hypertension (PH). We present a case of a 9-year-old girl who developed PH associated with severe BPD (BPD-PH) and underwent bilateral lung transplantation (BLTx). Case description A 9-year-old girl was admitted to our department to undergo BLTx. She was born at 23 weeks and 4 days gestation with a weight of 507 g. She received ventilation for the first 2 months and required further respiratory care due to repetitive, severe respiratory infections. She was diagnosed with BPD-PH at 6 months of age and oral administration of pulmonary vasodilators were initiated. She was registered as a lung transplant candidate at 4 years of age after the life-threatening exacerbation. Chest computed tomography (CT) revealed severe lung conditions with ground-glass opacities and emphysematous low-density areas in the upper and lower lobes. BLTx from a brain-dead male donor was performed. The pathological findings of her resected lung revealed saccular, hypoplastic lung with alveolar repair/regeneration, and medial hypertrophy and muscularization of peripheral arteries. The postoperative course was mostly uneventful. She was free from oxygen administration and showed no signs of PH after 6 months of the surgery. CONCLUSION: This is the first case report of BLTx in a pediatric, irreversible BPD-PH patient with detailed pathohistological findings and clinical examination. Lung transplantation is one of the treatment options for severe BPD-PH.

In recent years, with the improvement of diagnostic techniques and treatment outcomes, the number of lung cancer cases after esophageal cancer treatment has been increasing. In general, severe adhesions are expected in the right lung, during lung resection after esophageal cancer surgery. In this study, we reviewed intraoperative findings of lung resection with respect to the influence of different treatment methods for esophageal cancer, the site of adhesion formation for each lobe, and the techniques and precautions for lung resection. There were no difficulty in the left upper major segmentectomy. During the left lower lobectomy, the inflammation around the inferior pulmonary vein was noted. The adhesions between the reconstructed gastric tube and the inferior pulmonary vein were found during the right lower lobectomy. During the right upper lobectomy, severe adhesions between the lung and the superior vena cava as well as the gastric tube in the posterior mediastinum were observed, which should be paid much attention.

Although single-lung transplant on the side with better lung function is challenging in patients with significantly asymmetrical lung function between the right and left sides, it sometimes can be a realistic option because of the recipient's condition and from the viewpoint of organ sharing. We report our experience with a successful case of single-lung transplant on the side with a pulmonary perfusion ratio of 89%. The transplant was performed with the patient under central venoarterial extracorporeal membrane oxygenation through a clamshell incision, and the patient had an acceptable short- and long-term outcome with a remarkable improvement of lung function.

<title>Abstract</title><sec> <title>Background</title> Lung transplant (LTX) can provide a survival benefit and improve physical function for selected patients with advanced pulmonary disease. Sarcopenia is a systemic muscle-failure that can be found in a variety of life stages and disabilities. In this study, we follow the evolution of each variable defined in sarcopenia and the outcomes in LTX recipients with post-transplant sarcopenia. </sec><sec> <title>Methods</title> Patients who underwent LTX at Tohoku University Hospital between 2013 and 2018 were consecutively included in the retrospective cohort study, with follow-up to 2019. Sarcopenia was defined by low muscle mass (the cross-sectional area (CSA) of erector spinae muscle (ESM) in thoracic CT with a threshold &lt; 17.24 cm²/m²) and either low muscle strength (hand-grip with a threshold of &lt; 26 kg in males and of &lt; 18 kg in females) or physical performance (6-min walk distance with a threshold &lt; 46.5% of predicted distance). </sec><sec> <title>Results</title> Fifty-five recipients were included into the study, of whom 19 patients were defined as sarcopenic and 36 as non-sarcopenic. The muscle mass improved after transplant in both sarcopenic and non-sarcopenic individuals: the median ESM-CSA enlarged from 17.25 cm²/m² in 2 months post-LTX to 18.55 cm²/m² in 12 months (<italic>p</italic> &lt; 0.001) and 17.63 cm²/m² in 36 months (<italic>p</italic> &lt; 0.001) in non-sarcopenic individuals, while in sarcopenic patients it improved from 13.36 cm²/m² in 2 months to 16.31 cm²/m² in 12 months (<italic>p</italic> &lt; 0.005) and 18.01 cm²/m² in 36 months (<italic>p</italic> &lt; 0.001). The muscle mass in sarcopenia substantially recovered to close to non-sarcopenic conditions within 36-months (<italic>p</italic> &lt; 0.001 in 2 months and <italic>p</italic> = 0.951 in 36 months). Accordingly, muscle strength and physical performance in both groups improved over time. No difference in survival was seen in both groups (Log-rank <italic>p</italic> = 0.096), and sarcopenia was not associated with an overall hazard of death (<italic>p</italic> = 0.147). There was no difference in the cumulative incidence of chronic lung allograft dysfunction between patients with or without sarcopenia (Log-rank <italic>p</italic> = 0.529). </sec><sec> <title>Conclusions</title> Even patients with post-transplant sarcopenia have a chance to recover physical function to levels close to those without sarcopenia several years post LTX. </sec>

The incidence of postoperative pulmonary torsion is not frequent but it has a high mortality rate once it occurs, and prompt diagnosis and treatment are required. From past reports, it is considered effective to point out disruption of pulmonary blood flow by contrast-enhanced computed tomography (CT) examination for diagnosis. However, the comparison of pre- and post-operative plain CT images is considered to be useful in diagnosing lung torsion, and postoperative CT lung window setting sagittal images were examined in three cases of postoperative lung torsion. Results indicate that pulmonary torsion of the middle lobe after right lower lobectomy and the middle lobe after right upper lobectomy can be diagnosed by the present method.

OBJECTIVES: One of the serious problems after lung transplantation is chronic lung allograft dysfunction (CLAD). Most CLAD patients pathologically characterized by obliterative bronchiolitis (OB). Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)-Ig is a combination protein of the Fc fragment of human IgG1 linked to the extracellular domain of CTLA4. The aim of the study was to examine the effect of CTLA4-Ig therapy on OB using a mouse intrapulmonary tracheal transplantation (IPTT) model. METHODS: IPTT was performed between BALB/c (donor) and C57BL/6 (recipient) mice. Abatacept, which is a commercially available form of CTLA4-Ig, was intraperitoneally injected in recipient mice immediately after surgery, on days 7, 14, and 21. The mice in the control group received human IgG. RESULTS: We performed semi-quantitative analysis of graft luminal obliteration at post-transplant day 28. We calculated the obliteration ratio of the lumen of the transplanted trachea in each case. The obliteration ratio was significantly lower in the CTLA4-Ig group than that in the control group (91.2 ± 2.1% vs. 47.8 ± 7.9%, p = 0.0008). Immunofluorescent staining revealed significantly decreased lymphoid neogenesis in the lung. CONCLUSIONS: CTLA4-Ig therapy attenuated tracheal obliteration with fibrous tissue in the mouse IPTT model. The attenuation of fibrous obliteration was correlated with the inhibition of lymphoid neogenesis.

<title>Abstract</title> <sec> <title>Background</title> Anti-human leukocyte antigen (HLA) antibody testing was approved by the Japanese government in 2018. As such, there was no longitudinal data regarding the HLA-sensitization of lung transplant (LTX) patients in Japan. We therefore set out to measure anti-HLA antibodies from all our LTX patients during their annual follow-up to characterize the sensitization status in the Japanese population. </sec> <sec> <title>Methods</title> The cross-sectional study was conducted for consecutive LTX recipients who underwent transplantation from January 2000 to January 2020 at Tohoku University Hospital (TUH). The serum from the recipients was screened for anti-HLA antibody with the panel-reactive assay (PRA) and the donor-specific antibodies (DSA). </sec> <sec> <title>Results</title> Sensitization was reviewed in 93 LTX recipients, showing 23 positive (24.7%) and 70 negative (75.3%) PRA. More sensitized recipients were found in recent transplantations (60.9% (14/23), ≤5 years post LTX) than in older transplantations (17.4% (4/23), 5–10 years or 21.7% (5/23), ≥10 years post LTX) (<italic>p</italic> = 0.04). Even fewer recipients had DSA (5.4%, 5/93), among whom 4/5 (80%) were recently transplanted. </sec> <sec> <title>Conclusion</title> The rate of PRA positive LTX recipients in our population was lower compared with those in previous reports from US and Europe. More sensitized LTRs were found in recent transplantations than the older cohort, and DSA was identified primarily in the recent recipients. Due to several limitations, it is still unclear whether the sensitization would be related the development of CLAD or survival, yet this study would be fundamental to the future anti-HLA body study in Japanese population. </sec>

BACKGROUND: The therapeutic drug monitoring of mycophenolic acid (MPA) has been investigated for renal and heart transplantations; however, its usefulness in lung transplantation is unclear. METHODS: The MPA area under the plasma concentration-time curve (AUC) was calculated in 59 adult lung transplant recipients. The MPA AUC0-12 s were compared among the three groups determined by the presence of adverse events (no events, infection, and chronic lung allograft dysfunction [CLAD]). Next, MPA AUC0-12 thresholds for the adverse events were identified by receiver operating characteristic analysis. Cumulative occurrence rate of the adverse events was compared between two groups (adequate and inadequate groups) according to the thresholds. RESULTS: The MPA AUC0-12 s in the no event, infection, and CLAD groups were 30.3 ± 6.5, 36.8 ± 10.7, and 20.6 ± 9.6 µg·h/mL, respectively (P = .0027), while the tacrolimus trough levels were similarly controlled in the groups. The thresholds of MPA AUC0-12 for the occurrence of infection and CLAD were 40.5 and 22.8 µg·h/mL, respectively. The cumulative occurrence rate of adverse events of adequate group (15.3%) was significantly lower than that of inadequate group (56.0%) (P = .0050). CONCLUSIONS: The MPA AUC0-12 may affect the occurrence of adverse events in lung transplant recipients.

Acute kidney injury (AKI) is a common complication after lung transplant (LTx), and continuous renal replacement therapy (CRRT) is increasingly of use to critically ill patients who have developed AKI. However, the optimal timing or threshold of kidney impairment for which to commence CRRT after LTx has been uncertain. There has also been limited information on the impact of CRRT among LTx recipients (LTRs) introduced in the early posttransplant period on survival, graft function, and renal function. We aimed to review LTRs who developed AKI requiring CRRT postoperatively and followed their long-term outcomes at Tohoku University Hospital (TUH). Methods: Medical records of consecutive patients who underwent LTx at TUH between 2000 and 2018 were reviewed, with follow-up to 2019 inclusive. Results: Although mortality in those who required CRRT (n = 21) was increased versus those who did not require CRRT (n = 85)(P = 0.024), conditional survival beyond 3-month posttransplant was not affected (P = 0.131). Additionally, the cumulative incidence of chronic lung allograft rejection (P = 0.160) and the development of chronic kidney disease (P = 0.757) were not significant between groups. Conclusions: The initiation of CRRT posttransplant may be a useful strategy to preserve cardiac and optimize volume management among critically ill patients.

Mycobacterium xenopi is associated with the highest mortality among pulmonary nontuberculous mycobacterial (NTM) infections, but whether this is due to the infection or other factors is unclear. There is little information regarding outcomes among patients infected with M. xenopi versus other NTM species. We conducted a retrospective matched cohort study comparing M. xenopi pulmonary disease (Mx-PD) to M. avium complex (MAC)-PD. Patients were matched by sex, age, radiologic subtype, and presence of cavitation. Baseline clinical characteristics, treatment, and outcomes were compared using matched analyses. We identified 70 Mx-PD cases: 29 fibrocavitary-type, 28 nodular-bronchiectatic-type, and 13 unclassifiable-type CT patterns, mean (SD) age 63 (13) years, and 54.3% (n = 38) female. Median follow-up duration was longer in the Mx-PD cohort (1552 days versus 1035 days, p = 0.01). Symptoms, radiologic phenotype, and pulmonary function were similar between groups although the Charlson Comorbidity Index was numerically higher in Mx-PD patients (3.6 versus 3.2, p = 0.08). Rifamycins were used less frequently in Mx-PD (59.5% versus 85.7%, p = 0.02). Although combined clinical and radiologic improvement was similar between the groups, successful treatment was more common with Mx-PD (40.5% versus 16.7%, p = 0.02) owing to superior culture conversion (70.8% versus 33.3%, p = 0.0001). Mortality 24 months after initiation of treatment was numerically but not statistically greater in the Mx-PD cohort (20.4% versus 10.3%, p = 0.32). Among matched Mx-PD and MAC-PD patients, standard anti-mycobacterial treatment was significantly more likely to achieve culture conversion and successful treatment for Mx-PD patients. Mortality among Mx-PD patients was numerically, but not statistically higher, possibly explained by increased comorbidity burden.

Owing to advanced respiratory disease among lung transplant (LTX) candidates, some could develop nontuberculous mycobacteria-pulmonary disease (NTM-PD). However, the appropriate management of NTM-PD found at the time of LTX is not clear. We, therefore, established a management protocol for peri-transplant NTM-PD, defined by the presence of granulomas and mycobacteriologic evidence of NTM in the explant. Between 2013 and 2014, 230 LTX recipients (LTRs) who survived >30 days post LTX were followed up to 2017. Of these, 7.8% (18/230) LTRs were diagnosed with peri-transplant NTM-PD and treated with Azithromycin 250mg/day, Ethambutol 15mg/kg/day and Moxifloxacin 400mg/day for 12 months according to the protocol. There was no significant difference in the incidence of post-transplant NTM-PD (p=0.362), chronic lung allograft dysfunction (p=0.530) and mortality (p=0.152) between LTRs with/without peri-transplant NTM-PD as long as being managed with anti-mycobacterial drugs during the early phase of post-transplantation. Patients with NTM-PD other than Mycobacterium abscessus diagnosed at the time of LTX were safely managed and did not experience significantly higher rates of post-transplant NTM-PD.

Background:Drug-resistant tuberculosis (TB) poses a major public health concern worldwide. However, no studies have addressed risk factors for drug resistance in Ontario, which has its own unique profile of immigrants. We evaluated demographic and clinical risk factors for drug-resistant TB among patients treated at West Park Healthcare Centre, located in Toronto, Ontario (Canada). Methods:All patients who were diagnosed with TB and treated at West Park Healthcare Centre between January 2010 and December 2016 were included in this retrospective cohort study. Characteristics of patients with isoniazid mono-resistant (INH-R) TB and multidrug resistant (MDR) TB were compared to patients with drug-susceptible TB with bivariate and multivariable logistic regression. Results:Risk factors for INH-R TB included younger age (younger than 35 years), prior TB treatment, non-diabetic and birth in a non-South-East Asian country, but only the latter two factors were significant in multivariable analysis. On the other hand, we found younger generation (younger than 65 years), birth in European region, recent arrival to Canada (fewer than 120 months), prior treatment and human immunodeficiency virus (HIV) infection were associated with MDR-TB, among which younger age (younger than 35 years), more recent immigration (fewer than 24 months), prior treatment and HIV infection were significant in multivariable analysis. Conclusion:These findings may be of use to TB clinicians in the province by informing the initial empiric antibiotic regimen prescribed while awaiting phenotypic drug susceptibility testing and assisting in decisions regarding whether to request rapid molecular drug susceptibility testing.

Caveolins are integral membrane proteins that are the principal structural component of caveolae. Newly synthesized caveolin self-associates into oligomers that further assemble into higher-order structures. Imaging fluorescently labeled caveolin at the plasma membrane with total internal reflection fluorescence (TIRF) microscopy reveals a spatially heterogeneous distribution with aggregates of various sizes. In this chapter, we present a set of image-processing tools to quantify the spatial organization and mobility of caveolin aggregates seen in TIRF images. We apply a spot detection algorithm to identify punctate features on multiple length scales, and computationally estimate the area and integrated fluorescence signal of each detected feature. We then partition the original image into two disjoint sets: one containing pixels within punctae, and the other containing pixels on the rest of the plasma membrane. From these partitions, we estimate the relative fraction of caveolin that is punctate versus diffuse. Finally, we analyze the mobility of caveolin aggregates by tracking them and classify individual trajectories as diffusive or subdiffusive using a moment scaling spectrum analysis. Together, these analyses capture multiple facets of caveolin organization and dynamics. To demonstrate their utility, we quantify the distribution of fluorescent Caveolin 1 stably transfected in HeLa cells. We analyze cells at baseline and after being exposed to the anesthetic Dibucaine that is known to scramble membrane phospholipids. Our analysis shows how this perturbation dramatically alters caveolin aggregation and mobility.

Lung transplant recipients are at risk of developing many kinds of lung infection, such as community-acquired, nosocomial, opportunistic, and endemic. Here, we report a young lung transplant recipient who developed blastomycosis, which had most likely occurred following eculizumab treatment for atypical hemolytic uremia syndrome. We hypothesize that the agent interfering with C5 would influence the immune response against Blastomyces species.Although eculizumab has opened a new era for treatment of atypical hemolytic uremia syndrome and has led to the understanding that complementmediated pathology is needed, the risk of potentially fatal infections by blocking the complement pathway has not been fully elucidated. Careful follow-up and frequent tests to look for infections are needed after using this monoclonal antibody.

BACKGROUND: Recipients of solid organ transplants are prone to various complications that are seldom encountered in immunocompetent individuals. Post-transplant lymphoproliferative disorder (PTLD) is the best known and commonest Epstein-Barr Virus (EBV)-associated malignancy post solid organ transplant. EBV-associated smooth muscle tumors (EBV-SMT) including leiomyomas and leiomyosarcomas are rare and much less studied than PTLD. We recently encountered two cases of EBV-SMT post lung transplantation and here we summarize their clinical features and course together with a literature review. METHOD: Clinical data and treatment details of two patients who developed EBV-SMT were reviewed and retrieved up to December 31, 2017. English literature was searched through the PubMed database from 1965 to 2017 for studies of the association between lung transplant and EBV-SMT. RESULTS: The incidence of PTLD is higher among lung transplant recipients compared to kidney transplant recipients, an observation that has been attributed to stronger immune suppression in the lung patients. EBV-SMT showed a higher incidence among kidney recipients than among lung recipients, suggesting that the degree of immunosuppression may be a less important factor in the development of EBV-SMT. EBV-SMT has most often been seen among lung transplant recipients with EBV mismatch. CONCLUSIONS: Because EBV-SMT is a rare tumor, its incidence, risk factors, and optimal management have not been well-defined and further study is needed.

Mycobacterium xenopi pulmonary disease (Mxe-PD) is common among nontuberculous mycobacterial infections in Europe and Canada. Associations between radiological pattern and clinical features and outcomes are inadequately studied in Mxe-PD. We sought to investigate clinical characteristics and outcomes according to the dominant radiological pattern among patients with Mxe-PD. We retrospectively studied patients with Mxe-PD seen in our clinic, categorizing their predominant CT pattern as nodular bronchiectasis, fibrocavitary, or unclassifiable, and compared clinical characteristics, treatment, and outcomes between radiologic groups. Of 94 patients with Mxe-PD, CT patterns comprised nodular bronchiectasis (40/94, 42.6%), fibrocavitary (37/94, 39.4%), and unclassifiable (17/94, 18.1%). Compared with fibrocavitation, patients with nodular bronchiectasis were female dominant, less often had COPD, less often had AFB smear-positive sputum, and more frequently had co-isolation of Pseudomonas. Patients with nodular bronchiectasis were less often treated (65% versus 91.9%) and when treated, they received fewer anti-mycobacterial drugs (on average 3 versus 4). Outcomes did not differ significantly by radiological pattern. Nodular bronchiectasis was common among Mxe-PD patients in our clinic. Compared with fibrocavitary disease, patients with nodular bronchiectasis had features suggestive of milder disease and were less often treated. Among treated patients, outcomes did not differ by radiologic pattern.

UNLABELLED: Identification of the causative pathogen(s) of pneumonia would allow the selection of effective antibiotics and thus reduce the mortality rate and the emergence of drug-resistant pathogens. To identify such pathogens and to obtain these benefits, it is necessary that a clinical test is rapid, accurate, easily performed, and cost-effective. Here, we devised a PCR-based test, named HIRA-TAN, which is able to discriminate therapeutic targets from commensal organisms (e.g. Streptococcus pneumoniae or Haemophilus influenzae) and to detect foreign organisms (e.g. Mycoplasma pneumoniae or Legionella pneumophila) in the sputum. The utility of this system was validated in a prospective study, using sputum samples from patients with pneumonia. 568 patients were enrolled and the HIRA-TAN assay identified the causative pathogens with an accuracy of 96.7% for H. influenzae; 93.2% for Pseudomonas aeruginosa; 80.6% for Klebsiella pneumoniae; 90.9% for Moraxella catarrhalis; 87.5% for Escherichia coli; 78.1% for MRSA and 91.6% for S. pneumoniae. Overall the HIRA-TAN procedure was able to identify the causative pathogens of pneumonia in 60% of the cases. Additionally, this procedure was able to determine when the pneumonia-causing organism was a commensal organism or a foreign organism in a single assay. The HIRA-TAN approach yielded reproducible results and provided valuable information to plan the course of treatment of pneumonia. Through the rapid identification of the causative pathogens, the HIRA-TAN will promote targeted treatments for pneumonias. CLINICAL TRIALS REGISTRATION: UMIN000001694.