Tyrosine kinase inhibitors (TKIs) are key drugs in advanced renal cell carcinoma. Their prolonged efficacy is expected to translate directly into improved prognosis for patients with advanced renal cell carcinoma. In our previous studies, we identified important metabolic pathways related to sunitinib resistance. In this study, we examined whether TKI resistance could be overcome by controlling the glutamine metabolic pathway involved in sunitinib resistance. We established multiple renal cancer cell lines resistant to sunitinib and cabozantinib. We analyzed changes in the glutamine metabolic pathway associated with drug resistance. Furthermore, we inhibited the glutamine metabolic pathway using a glutaminase inhibitor (GLSi) and examined the antitumor effects of these TKIs on resistant renal cancer cells in vitro and in vivo. We also analyzed the mechanism of the antitumor effect of GLSi. In all established TKI-resistant cell lines, TKI resistance was associated with increased glutamine metabolism. GLSi showed significant antitumor effects on proliferation, invasion, and migration in all resistant cell lines. Immunostaining of resected TKI-resistant tumors demonstrated that GLSi-resistant TKIs exhibited sufficient antiangiogenic effects. VEGFR signal analysis suggested that the reduction of glutamate by GLSi activated PETN, which reduced VEGFR expression and its signaling, resulting in antitumor effects. GLSi has the potential to resensitize TKIs in TKI-resistant renal cancer cells. Therefore, controlling glutamine metabolism may extend the efficacy of existing TKIs and further improve the prognosis of patients with advanced renal cancer.

INTRODUCTION: Fumarate hydratase-deficient renal cell carcinoma is a rare and aggressive subtype associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, characterized by germline mutations in the fumarate hydratase (FH) gene. Here, we report a case of HLRCC with early recurrence during adjuvant therapy following radical nephrectomy. CASE PRESENTATION: A 34-year-old woman with FH-deficient RCC presented with fever, right flank pain, and a large renal mass with a tumor thrombus. Open radical nephrectomy and IVC tumor thrombectomy were performed. Pathological findings and genetic analyses confirmed the diagnosis of HLRCC. Despite adjuvant pembrolizumab therapy after nephrectomy, bone metastases were detected within 9 weeks. The patient was treated with stereotactic body radiotherapy (SBRT), followed by systemic therapy with nivolumab and cabozantinib. After 16 months since the recurrence, no further disease progression was observed. Genetic counseling revealed the same FH mutation in her daughter, prompting annual surveillance. CONCLUSION: This case highlights the potential efficacy of combining tyrosine kinase inhibitor therapy with SBRT in managing aggressively progressive HLRCC.

Introduction: Although immune checkpoint inhibitor-associated myocarditis is relatively rare, it has the highest mortality rate among all immune-related adverse events, at 30–50%. Case Presentation: We encountered a case of advanced renal cancer in which immune checkpoint inhibitor-associated myocarditis was confirmed on autopsy. A 78-year-old man was diagnosed with a left renal tumor secondary to hematuria. A tumor biopsy was performed, and the tumor was diagnosed as cT4N0M1 clear cell renal carcinoma, which was classified as poor risk by the International mRCC Database Consortium. Combination therapy with pembrolizumab and axitinib was initiated. One month later, the patient developed anorexia, dizziness, and fatigue, which were judged to be adverse events due to systemic therapy, and the patient was admitted to the hospital urgently. After admission, the patient experienced a sudden drop in blood pressure and loss of consciousness and was referred to a cardiologist for treatment. Blood tests showed elevated brain‐type natriuretic peptide levels, but echocardiography showed good cardiac function. However, soon thereafter, the patient developed tachycardia, and echocardiography revealed a significant decline in systolic function, leading to the diagnosis of immune checkpoint inhibitor-associated myocarditis. Despite intensive care in the cardiac high-care unit and steroid administration, the patient died. An autopsy revealed necrotic changes in the myocardium, loss of myocardial cells, and severe lymphocyte infiltration, leading to a diagnosis of inhibitor-associated myocarditis. Conclusion: Delay in the initiation of treatment is considered a risk factor for poor prognosis, and the administration of high-dose steroids within 24 h of onset contributes to a better outcome. Herein, we discuss the pathology, diagnosis, and treatment of immune checkpoint inhibitor-associated myocarditis.

Introduction: Enfortumab vedotin (EV) has been approved for the treatment of many types of cancer, and its use is still expanding. It is an essential drug used as a standard treatment for advanced and metastatic urothelial carcinoma but is known to cause various adverse events (AEs). Case Presentation: We report a patient with metastatic urothelial carcinoma who experienced multiple AEs associated with diabetic ketoacidosis (DKA) during EV treatment. The onset of DKA during EV treatment has been reported to be associated with poor prognosis. Although strict management was required in the intensive care unit, we were able to save the patient’s life. Conclusion: Although the detailed mechanism that induced insulin resistance remains unclear, the patient required high-dose insulin because of a marked increase in insulin resistance. If hyperglycemia is observed during EV therapy, DKA may lead to the occurrence of serious AEs. We report on the pathogenesis and management of drug-induced DKA caused by EV based on our case and a literature review.

INTRODUCTION: Female pelvic organ prolapse (POP) is considered a borderline disease between urology and gynecology and is treated by reconstructive surgery, which restores the organs to their original positions. CASE PRESENTATION: An 82-year-old woman with bladder and uterine prolapse at POP-Q Stage IV was treated with an indwelling catheter for voiding dysfunction. Eventually, the catheter has been often spontaneously removed when pelvic organ prolapse occurs, resulting in a diagnosis of bladder inversion. Because of bladder inversion and low bladder capacity at the time of bladder retraction, the patient underwent total cystectomy, combined with total hysterectomy, colpopexy, and posterior colporraphy, and ileal conduit. CONCLUSION: The cases of complete bladder and uterine prolapse combined with bladder inversion, total hysterectomy, colpopexy, posterior colporraphy, and ileal conduit were performed safely. Considering urinary function, surgery without organ preservation with urinary diversion may be an option.

INTRODUCTION: Pelvic arteriovenous malformation is often a source of intraoperative bleeding. Here, we report our experience with a case of ureteral cancer with pelvic arteriovenous malformation treated using laparoscopic nephroureterectomy with temporary intraoperative occlusion of the internal iliac artery. CASE PRESENTATION: A 75-year-old man presented to our hospital with asymptomatic macro-hematuria. Contrast-enhanced computed tomography revealed right ureteral tumor with no apparent metastases, and right pelvic arteriovenous malformation. Three months later, multiple bladder cancers were identified and the patient underwent trans-urethral resection of bladder tumor. The pathological diagnosis was urothelial carcinoma, pTa. We performed right laparoscopic nephroureterectomy with temporary intraoperative occlusion of the internal iliac artery. There was little intraoperative bleeding, and the surgery was safely completed. The pathological diagnosis was urothelial carcinoma, pT2 + Tis. CONCLUSION: A patient showing ureteral cancer with pelvic arteriovenous malformation was safely treated using laparoscopic nephroureterectomy with temporary occlusion of the internal iliac artery.

INTRODUCTION: Distant recurrence of non-muscle invasive bladder cancer is a rare condition that is poorly understood and difficult to detect in follow-up protocols. CASE PRESENTATION: A 73-year-old female with a history of T1N0M0 bladder cancer 8 years ago suffered from a left axillary tumor, a left lung tumor, left mediastinal lymph node swelling, and bilateral adrenal gland tumors. Initially, she was diagnosed with metastatic left breast cancer of the left accessory mamma by needle biopsy of an axillary tumor. Subsequent bronchoscopic biopsy of the mediastinal lymph node revealed metastatic urothelial carcinoma, although no recurrence was detected in the urinary tract. She underwent systemic therapy, and all regions shrank without reprogression. CONCLUSION: Non-muscle invasive bladder cancer should be managed considering distant metastasis. If the origin of the metastatic lesions is unknown, this disease should be considered as a possible origin, even in the absence of urinary tract recurrence.

To improve treatment outcomes in real practice, useful biomarkers are desired when predicting postoperative recurrence for renal cell carcinoma (RCC). We collected data from patients who underwent definitive surgery for RCC and for benign urological tumor at our department between November 2016 and December 2019. We evaluated the differences in pre- and postoperative urinary metabolites with our precise quantitative method and identified predictive factors for RCC recurrence. Additionally, to clarify the significance of metabolites, we measured the intracellular metabolite concentration of three RCC cell lines. Among the 56 patients with RCC, nine had a recurrence (16.0%). When comparing 27 patients with T1a RCC and 10 with benign tumor, a significant difference was observed between pre- and postoperative concentrations among 10 urinary metabolites. In these 10 metabolites, multiple logistic regression analysis identified five metabolites (lactic acid, glycine, 2-hydroxyglutarate, succinic acid, and kynurenic acid) as factors to build our recurrence prediction model. The values of area under the receiver operating characteristic curve, sensitivity, and specificity in this predictive model were 0.894%, 88.9%, and 88.0%, respectively. When stratified into low and high risk groups of recurrence based on this model, we found a significant drop of recurrence-free survival rates among the high risk group. In in vitro studies, intracellular metabolite concentrations of metastatic tumor cell lines were much higher than those of primary tumor cell lines. By using our quantitative evaluation of urinary metabolites, we could predict postoperative recurrence with high sensitivity and specificity. Urinary metabolites could be noninvasive biomarkers to improve patient outcome.

Metabolomics analysis possibly identifies new therapeutic targets in treatment resistance by measuring changes in metabolites accompanying cancer progression. We previously conducted a global metabolomics (G-Met) study of renal cell carcinoma (RCC) and identified metabolites that may be involved in sunitinib resistance in RCC. Here, we aimed to elucidate possible mechanisms of sunitinib resistance in RCC through intracellular metabolites. We established sunitinib-resistant and control RCC cell lines from tumor tissues of RCC cell (786-O)-injected mice. We also quantified characteristic metabolites identified in our G-Met study to compare intracellular metabolism between the two cell lines using liquid chromatography-mass spectrometry. The established sunitinib-resistant RCC cell line demonstrated significantly desuppressed protein kinase B (Akt) and mesenchymal-to-epithelial transition (MET) phosphorylation compared with the control RCC cell line under sunitinib exposure. Among identified metabolites, glutamine, glutamic acid, and α-KG (involved in glutamine uptake into the tricarboxylic acid (TCA) cycle for energy metabolism); fructose 6-phosphate, D-sedoheptulose 7-phosphate, and glucose 1-phosphate (involved in increased glycolysis and its intermediate metabolites); and glutathione and myoinositol (antioxidant effects) were significantly increased in the sunitinib-resistant RCC cell line. Particularly, glutamine transporter (SLC1A5) expression was significantly increased in sunitinib-resistant RCC cells compared with control cells. In this study, we demonstrated energy metabolism with glutamine uptake and glycolysis upregulation, as well as antioxidant activity, was also associated with sunitinib resistance in RCC cells.

Carbohydrate antigens are associated with carcinogenesis, cancer invasion, and metastasis and their expression reflect biological activities of various cancers. We previously reported that expression of disialosyl globopentaosyl ceramide (DSGb5), one of carbohydrate antigens, in radical prostatectomy specimens independently predicted biochemical recurrence (i.e., elevating serum prostate specific antigen without recurrent lesions in the image) after radical prostatectomy. However, it is important to evaluate the prognosis at the diagnosis. In this study we investigated DSGb5 expression in prostate biopsy specimens to develop a novel biomarker for providing appropriate management. Between 2005 and 2011, patients who underwent both prostate biopsy and radical prostatectomy in our institution were included. The median follow-up period was 88 months. DSGb5 expression was assessed by immunohistochemical staining and defined 116 patients as high DSGb5 expression (42 patients) or low DSGb5 expression (74 patients). High DSGb5 expression was significantly associated with lymphovascular invasion in radical prostatectomy specimens on both univariate and multivariable analyses (p = 0.028, 0.027). On multivariable analysis, Gleason Score in prostatectomy specimen, positive resection margin, and DSGb5 expression in the biopsy specimen were independently associated with biochemical recurrence-free survival following radical prostatectomy (p = 0.004, 0.008, 0.024). When targeting only patients with negative resection margin, DSGb5 expression was significantly associated with biochemical recurrence-free survival on both univariate and multivariable analyses (p = 0.006, 0.007). DSGb5 expression in prostate biopsy specimens is predictive of lymphovascular invasion and biochemical recurrence-free survival following radical prostatectomy. DSGb5 is a potential biomarker for preoperatively predicting oncological outcomes of prostate cancer.

Using surgically resected tissue, we identified characteristic metabolites related to the diagnosis and malignant status of clear cell renal cell carcinoma (ccRCC). Specifically, we quantified these metabolites in urine samples to evaluate their potential as clinically useful noninvasive biomarkers of ccRCC. Between January 2016 and August 2018, we collected urine samples from 87 patients who had pathologically diagnosed ccRCC and from 60 controls who were patients with benign urological conditions. Metabolite concentrations in urine samples were investigated using liquid chromatography-mass spectrometry with an internal standard and adjustment based on urinary creatinine levels. We analyzed the association between metabolite concentration and predictability of diagnosis and of malignant status by multiple logistic regression and receiver operating characteristic (ROC) curves to establish ccRCC predictive models. Of the 47 metabolites identified in our previous study, we quantified 33 metabolites in the urine samples. Multiple logistic regression analysis revealed 5 metabolites (l-glutamic acid, lactate, d-sedoheptulose 7-phosphate, 2-hydroxyglutarate, and myoinositol) for a diagnostic predictive model and 4 metabolites (l-kynurenine, l-glutamine, fructose 6-phosphate, and butyrylcarnitine) for a predictive model for clinical stage III/IV. The sensitivity and specificity of the diagnostic predictive model were 93.1% and 95.0%, respectively, yielding an area under the ROC curve (AUC) of 0.966. The sensitivity and specificity of the predictive model for clinical stage were 88.5% and 75.4%, respectively, with an AUC of 0.837. In conclusion, quantitative analysis of urinary metabolites yielded predictive models for diagnosis and malignant status of ccRCC. Urinary metabolites have the potential to be clinically useful noninvasive biomarkers of ccRCC to improve patient outcomes.

Renal cell carcinoma (RCC) is a malignant tumor that currently lacks clinically useful biomarkers indicative of early diagnosis or disease status. RCC has commonly been diagnosed based on imaging results. Metabolomics offers a potential technology for discovering biomarkers and therapeutic targets by comprehensive screening of metabolites from patients with various cancers. We aimed to identify metabolites associated with early diagnosis and clinicopathological factors in RCC using global metabolomics (G-Met). Tumor and nontumor tissues were sampled from 20 cases of surgically resected clear cell RCC. G-Met was performed by liquid chromatography mass spectrometry and important metabolites specific to RCC were analyzed by multivariate statistical analysis for cancer diagnostic ability based on area under the curve (AUC) and clinicopathological factors (tumor volume, pathological T stage, Fuhrman grade, presence of coagulation necrosis and distant metastasis). We identified 58 metabolites showing significantly increased levels in tumor tissues, 34 of which showed potential early diagnostic ability (AUC >0.8), but 24 did not discriminate between tumor and nontumor tissues (AUC ≤0.8). We recognized 6 pathways from 9 metabolites with AUC >0.8 and 7 pathways from 10 metabolites with AUC ≤0.8 about malignant status. Clinicopathological factors involving malignant status correlated significantly with metabolites showing AUC ≤0.8 (p = 0.0279). The tricarboxylic acid cycle (TCA) cycle, TCA cycle intermediates, nucleotide sugar pathway and inositol pathway were characteristic pathways for the malignant status of RCC. In conclusion, our study found that metabolites and their pathways allowed discrimination between early diagnosis and malignant status in RCC according to our G-Met protocol.

OBJECTIVES: To determine whether penile blood pressure (PBP) can be used to identify patients who can benefit from tadalafil treatment, the correlation between PBP at baseline and changes in lower urinary tract symptoms (LUTS) induced by tadalafil treatment was studied prospectively. PATIENTS AND METHODS: Patients with BPH who were poor responders to α1 -blockers and took tadalafil instead of an α1 -blocker were registered between 2014 and 2016. The patients were divided into two groups (low- and high-PBP groups) using the median baseline PBP of 110 mmHg as the threshold. The changes in the International Prostate Symptom Score (IPSS) between before and at 4 and 12 weeks after tadalafil treatment were compared between the low- and high-PBP groups. Multivariate analysis was performed to identify parameters associated with IPSS improvement with tadalafil treatment. RESULTS: In all, 51 patients were investigated. The IPSS in the low-PBP group decreased immediately after the start of treatment, and there was significant improvement in the IPSS from baseline at 4 and 12 weeks after the start of treatment, whilst the IPSS in the high-PBP group did not show significant changes. On multivariate analysis, PBP at baseline, anticholinergic drug use, and IPSS at baseline were significant predictors of a good IPSS response to tadalafil treatment. CONCLUSIONS: This study demonstrated that PBP could reliably identify patients with BPH who could benefit from tadalafil treatment. Patients with low PBP could be better responders to tadalafil.

Tubulointerstitial nephritis is primary injury to renal tubules and interstititum which could be resulting in decreased renal function. The acute and chronic forms are most often due to allergic drug reactions or to infections. Tubulointerstitial nephritis in Crohn's disease has rarely been reported. Imaging findings of a striated nephrogram on enhanced computed tomography (CT) could represent the clinical state of tubulointerstitial nephritis. This is the first report of tubulointerstitial nephritis caused by infliximab, monoclonal antibody against human tumor necrosis factor-α, showing striated nephrograms in Crohn's disease. The case of a 28-year-old man treated with infliximab for Crohn's disease is described. Infliximab was added to his maintenance therapy, and bowel symptoms were stable. The patient presented with a 2-month history of fever and an elevated C-reactive protein after infliximab administration for 4.5 years. Contrast-enhanced CT showed striated nephrograms in both kidneys. Urinalysis showed no abnormal findings. The pathological diagnosis on CT-guided percutaneous renal needle biopsy was drug-induced tubulointerstitial nephritis because of eosinophilic infiltration with neutrophils mainly in the tubulointerstitial areas. The imaging findings of striated nephrogram are important for the diagnosis of tubulointerstitial nephritis. Tubulointerstitial nephritis could be caused by drug-induced inflammation or direct extension of Crohn's disease as an extra-interstitial manifestation. The treatment strategies for these two diseases are contradictory to each other and inappropriate treatment could worsen the renal function. Needle biopsy is therefore indispensable for differential diagnosis.

(Objectives) We report the clinical features about polymicrobial bacteria detection cases in the uncomplicated urinary tract infection of the premenopausal woman from the voided midstream urine culture. (Methods) We retrospectively reviewed the premenopausal woman from 18-49 years patients visited Sendai City Hospital from April, 2006 to December, 2014, diagnosed uncomplicated cystitis or uncomplicated pyelonephritis. We analyzed for 375 specimens from the voided midstream urine culture. (Results) Among 375 specimens, the urine culture-positive for uropathogens were 211 specimens. The monomicrobial bacterial were detected in 184 specimens (87.2%) and polymicrobial bacterial specimens were 27 specimens (12.8%). The most combination group was the caused bacteria and periurethral microorganisms in 20 specimens (74.1%). Then 6 periurethral microorganisms specimens (22.2%), the caused bacteria were only 1 specimen was overlapped (3.7%). The case of urinary tract infections recurrence or revealed voiding dysfunction that need periodic treatment were more prevalent in the polymicrobial than the monomicrobial group (22.2% vs 9.8%, p=0.043). (Conclusions) When polymicrobial bacteria were detected in uncomplicated urinary tract infection in premenopausal woman, it was confirmed that there were the most combinations of caused bacteria and periurethral microorganisms. In these cases, treatment intended for only the caused bacteria. A risk of the infection recurrence and voiding dysfunction were statistically significant higher rate in the polymicrobial bacteria detection cases, and it might be necessary to consider that search to complicated urinary tract infection.

We report a histologically pure stage 1 seminoma with an elevated human chorionic gonadotropin (hCG). A 38 year-old man was referred for the evaluation of the left testicular swelling. He showed an elevated serum hCG level of 25,265 mIU/ml with normal a fetoprotein and lactate dehydrogenase. Imaging showed heterogeneous tumor without any metastatic lesions. We conducted 4 courses of chemotherapy before detecting hCG nadir. The final pathological report showed pure seminoma with syncytiotrophoblastic cells but no choriocarcinoma components. The patient remains disease free until present time. The case raised several questions regarding diagnosis and treatment strategy for bulky testicular seminoma.

BACKGROUND: We prospectively examined influence of androgen deprivation therapy (ADT) on lipid and glucose metabolisms in Japanese patients with prostate cancer. METHODS: Patients with prostate cancer who were hormone-naive and scheduled to receive long-term ADT were recruited between 2011 and 2013. Body weight, abdominal circumference and blood testing associated with lipid and glucose metabolism were recorded every 3 months during 1 year of ADT. Computed tomography (CT) was performed to measure areas of subcutaneous and visceral fat before and after 1 year of ADT. ADT was limited to a luteinizing hormone-releasing hormone (LHRH) agonist with or without bicalutamide. RESULTS: Of 218 patients registered, data were available from 177 patients who completed 1 year of ADT. Of these, CT was performed before and after 1 year of ADT in 88 patients. Median age was 75 years (range, 49-85 years). Median PSA before ADT was 16.7 ng ml(-1) (range, 0.3-3316). Clinical stage was B (54.2%), C (23.2%) and D (20.9%). Mean increases in body weight and abdominal circumference after 1 year of ADT were 2.9 and 3.0%, respectively. Mean increases in total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were 10.6, 14.3, 7.8 and 16.2%, respectively. Mean increases in fasting blood sugar and hemoglobin A1c (HbA1c) were 3.9 and 2.7%, respectively. Lipid alterations were noted in patients without comorbidities, whereas changes in HbA1c were noted in patients with diabetes mellitus at baseline. These lipid and glucose alterations were prominent in the early ADT period. Both visceral and subcutaneous fat, as measured by CT, increased by >20%. The increase in subcutaneous fat was significantly greater than that in visceral fat (P=0.028). CONCLUSIONS: One year of ADT significantly changed lipid and glucose metabolism in Japanese patients with prostate cancer. Patient characteristics or comorbidities at baseline may be associated with ADT-induced metabolic changes.

45歳女。常染色体優性多発性嚢胞腎症による慢性腎不全の悪化のため血液透析導入となり、同時期より腎嚢胞増大に起因する右腰背部痛が出現し、2回の右腎嚢胞穿刺固定術でも改善しなかった。硬膜外麻酔下に右大腿動脈からのアプローチで経カテーテル的動脈塞栓術を行い、術後にコントロール不良な疼痛が出現したためフェンタニル持続静注を3日間併用した。また、微熱も認めたが対症療法で解熱し、術後11日目に除痛、食欲改善が得られ退院となった。しかし、術後20日目に突然左腰背部痛、肉眼的血尿が出現して再入院となり、膀胱鏡、逆行性腎盂尿管造影で明らかな出血原因を特定できず、ヘモグロビン値が低下していたため濃厚赤血球2単位の輸血を行った。それ以降同様の症状はない。