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Background While post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) benefits patients with teratoma or viable germ cell tumors (GCT), it becomes overtreatment if necrosis is detected in PC-RPLND specimens. Serum microRNA-371a-3p correctly predicts residual viable GCT with 100% sensitivity but residual teratoma in PC-RPLND specimens using current modalities remains difficult. Therefore, we developed a machine learning model using CT imaging and clinical variables to predict the presence of residual teratoma in PC-RPLND specimens. Methods We included 58 patients who underwent PC-RPLND between 2005 and 2019 at the University of Tsukuba Hospital. On CT imaging, 155 lymph nodes were identified as regions of interest (ROIs). The ResNet50 algorithm and/or Support Vector Machine (SVM) classification were applied and a nested, 3-fold cross-validation protocol was used to determine classifier accuracy. Results PC-RPLND specimen analysis revealed 35 patients with necrosis and 23 patients with residual teratoma while histology of 155 total ROIs showed necrosis in 84 ROIs and teratoma in 71 ROIs. The ResNet50 algorithm, using CT imaging, achieved a diagnostic accuracy of 80.0%, corresponding to a sensitivity of 67.3%, a specificity of 90.5%, and an AUC of 0.84 while SVM classification using clinical variables achieved a diagnostic accuracy of 74.8%, corresponding to a sensitivity of 59.0%, a specificity of 88.1%, and an AUC of 0.84. Conclusions Our machine learning models reliably distinguish between necrosis and residual teratoma in clinical PC-RPLND specimens.

Background This retrospective multicenter study aimed to evaluate the survival benefit of upfront cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (RCC) patients stratified by International Metastatic RCC Database Consortium (IMDC) risk criteria. Methods We reviewed the medical records in the Michinoku Database between 2008 and 2019. Patients who received upfront CN, systemic therapy without CN (no CN) and CN after drug therapy (deferred CN) were analyzed. To exclude selection bias due to patient characteristics, baseline clinical data were adjusted by inverse probability of treatment weighting (IPTW). Overall survival (OS) was compared between upfront CN and non-upfront CN (no CN plus deferred CN). Associations between time-varying covariates including systemic therapies and OS stratified by IMDC risk criteria were analyzed by IPTW-adjusted Cox regression method. Results Of 259 patients who fulfilled the selection criteria, 107 were classified in upfront CN and 152 in non-upfront CN group. After IPTW-adjusted analysis, upfront CN showed survival benefit compared to non-upfront CN in patients with IMDC intermediate risk (median OS: 52.5 versus 31.3 months, p p p = 0.03) and in patients with IMDC poor risk (0.26, 0.11–0.59, p Conclusions Upfront CN may confer survival benefit in RCC patients with IMDC intermediate and poor risk.

In metastatic renal cell carcinoma (mRCC), the clinical response to immune checkpoint inhibitors (ICIs) is limited in a subset of patients and the need exists to identify non-invasive, blood-based, predictive biomarkers for responses. We performed RNA sequencing using whole-blood samples prospectively collected from 49 patients with mRCC prior to the administration of ipilimumab (IPI) and/or nivolumab (NIVO) to determine whether gene expression profiles were associated with responses. An analysis from 33 mRCC patients with complete responses (n = 5), partial responses (n = 14), and progressive disease (n = 14) showed 460 differentially expressed genes (DEGs) related to immune responses between the responder and non-responder groups with significant differences. A set of 14 genes generated from the initial 460 DEGs accurately classified responders (sensitivity 94.7% and specificity 50.0%) while consensus clustering defined clusters with significantly differing response rates (92.3% and 35.0%). These clustering results were replicated in a cohort featuring 16 additional SD patients (49 total patients): response rates were 95.8% and 48.0%. Collectively, whole-blood gene expression profiles derived from mRCC patients treated with ICIs clearly differed by response and hierarchical clustering using immune response DEGs accurately classified responder patients. These results suggest that such screening may serve as a predictor for ICI responses in mRCC patients.

The aims of this study were to investigate prognosis and validate prognostic models [Memorial Sloan-Kettering Cancer Center (MSKCC), International Metastatic Renal Cell Carcinoma Data Consortium (IMDC), and Japanese metastatic renal cancer (JMRC) models] in the targeted therapy era in Japanese patients with metastatic renal cell carcinoma. We retrospectively analyzed 692 patients who were diagnosed with mRCC from January 2008 to August 2018 in the Michinoku Japan Urological Cancer Study Group database. Nivolumab as sequential therapy was widely used. Other immune checkpoint inhibitors were excluded from this study. The median overall survival (95% confident interval) in all, MSKCC favorable, intermediate, and poor risk patients was 41.0 months (33.9–46.8), not reached (63.5 to not estimable), 46.8 months (37.1–52.9), and 10.4 months (8.9–14.4), respectively. The median overall survival (95% confident interval) in IMDC favorable, intermediate, and poor risk patients was not reached (61.6 to not estimable), 47.4 months (41.4–56.5), and 11.5 (9.9–16.3), respectively. The c-index of the MSKCC, IMDC, and JMRC models calculated at mRCC diagnosis was 0.680, 0.689, and 0.700, respectively. No statistical differences were found in the c-index among the models. While the real-world overall survival in Japanese patients with mRCC in the targeted therapy era improved compared to that previously reported in the cytokine era, there was no clear difference in the survival of poor risk patients between these eras. There were no differences in the superiority among the models.

Objectives To evaluate the histologic findings and clinical outcomes of post-chemotherapy retroperitoneal lymph node dissection for advanced germ cell tumor. Methods We analyzed the medical records of 66 patients who underwent post-chemotherapy retroperitoneal lymph node dissection between 2005 and 2019 at Tsukuba University Hospital. Results The proportions of necrosis, teratoma, and viable germ cell tumor in the specimens were 62.1%, 36.4%, and 1.5%, respectively. The 5-year progression-free and overall survival rates were 82.3% and 91.3%, respectively. The 5-year overall survival rate of patients with residual teratoma was significantly worse than that of patients with necrosis only (74.1% vs 100%). Overall, three patients died: one from cancer and two from teratoma with somatic-type malignancy. Of these, two patients relapsed after incomplete resection of residual teratoma. When limited to patients with completely resected teratoma, the 5-year overall survival rate was 91.7%, which did not differ from that for patients with necrosis only. Multivariate analysis showed that presence of teratoma in the primary site and decrease in retroperitoneal lymph node mass to less than 50% of the initial tumor size were independent factors for residual teratoma. However, the absence of these factors could not reliably predict necrosis only in retroperitoneal lymph node dissection specimens. Conclusions In our series, 98% of post-chemotherapy retroperitoneal lymph node dissection pathology was either necrosis or teratoma, with viable germ cell tumor only found in 2% of patients. Residual teratoma was associated with poorer prognosis, especially in cases of incomplete resection.

OBJECTIVE To examine the discrepancy between clinical and pathological T stages in patients with urothelial carcinoma of the upper urinary tract treated with radical surgery, and to compare them with the corresponding discrepancy in urothelial carcinoma of the bladder. METHODS We used the Hospital-Based Cancer Registry data in Japan to extract urothelial carcinoma of the bladder cases (n = 3747) and urothelial carcinoma of the upper urinary tract cases (n = 6831), including urothelial carcinoma of the renal pelvis (n = 3295) and urothelial carcinoma of the ureter (n = 3536) with cT1-4N0M0 diagnosed in 2012-2015, histologically confirmed, and treated with radical surgery without chemotherapy or radiotherapy. We compared the T-stage discrepancy among different tumor locations. RESULTS The proportions of overall T-stage discrepancy in the urothelial carcinoma of the renal pelvis (40.8%) and urothelial carcinoma of the ureter (42.9%) groups tended to be higher compared with that in the urothelial carcinoma of the bladder (38.8%) group. The upstaging rate from clinical non-muscle-invasive cancer (≤cT1) to pathological muscle-invasive cancer (≥pT2) was significantly higher in the urothelial carcinoma of the renal pelvis and urothelial carcinoma of the ureter groups compared with the urothelial carcinoma of the bladder group (P = 0.002, P

Peripheral clocks function to regulate each organ and are synchronized though various molecular and behavioral signals. However, signals that entrain the bladder clock remain elusive. Here, we show that glucocorticoids are a key cue for the bladder clock in vitro and in vivo. A pBmal1-dLuc human urothelial cell-line showed significant shifts in gene expression after cortisol treatment. In vivo, rhythmic bladder clock gene expression was unchanged by bilateral adrenalectomy but shifted 4 hours forward by corticosterone administration at the inactive phase. Moreover, the bladder clock shifted 8–12 hours in mice that underwent both bilateral adrenalectomy and corticosterone administration at the inactive phase. These mice saw decreases in the diurnal rhythm of volume voided per micturition, while maintaining diurnal activity rhythms. These results indicate that the diurnal rhythm of glucocorticoid signaling is a zeitgeber that overcomes other bladder clock entrainment factors and coordinates the diurnal rhythm of volume voided per micturition.

Intravesical Bovis bacillus Calmette-Guerin (BCG) therapy is the most effective immunotherapy for bladder cancer, but it sometime causes serious side effects because of its inclusion of live bacteria. It is necessary to develop a more active but less toxic immunotherapeutic agent. Trehalose 6,6'-dimycolate (TDM), the most abundant hydrophobic glycolipid of the BCG cell wall, has been reported to show various immunostimulatory activities such as granulomagenesis and adjuvant activity. Here, we developed cationic liposomes incorporating TDM purified from Mycobacterium bovis BCG Connaught, and we investigated the antitumor effect of the cationic liposome TDM (Lip-TDM). Lip-TDM exerted an antitumor effect in bladder cancer, colon cancer, and melanoma-bearing mouse models that was comparable or even superior to that of BCG, with no body weight loss or granuloma formation. The antitumor effect of Lip-TDM disappeared in two types of mice: those with depletion of CD8+ T cells, and those with knockout of macrophage-inducible C-type lectin (Mincle) which recognize TDM. Lip-TDM treatment enhanced the maturation and migration of dendritic cells in the tumor microenvironment in a Mincle-dependent manner. Our results elucidate mechanisms that underlie Lip-TDM treatment and suggest that Lip-TDM has potential as a safe and effective treatment for various cancers.

Objectives To compare overall survival between patients with metastatic renal cell carcinoma treated by cytoreductive nephrectomy and those not treated by cytoreductive nephrectomy. Methods We retrospectively evaluated 278 patients with metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitors between January 2008 and November 2019. Patients were divided into two groups: a cytoreductive nephrectomy group (immediate or deferred cytoreductive nephrectomy) and a group who received systemic tyrosine kinase inhibitor therapies alone without cytoreductive nephrectomy (control group). Overall survival comparisons were made in all patients in the control versus the cytoreductive nephrectomy group, the control versus the immediate cytoreductive nephrectomy group, the control versus the deferred cytoreductive nephrectomy group, and the deferred cytoreductive nephrectomy versus the immediate cytoreductive nephrectomy group. Analyses were weighted using the propensity score-based inverse probability of treatment weighting method to adjust for group imbalances. Results The median (range) age of the patients was 65 (59-73) years. Of the 278 patients, 132 and 146 were in the control group and the cytoreductive nephrectomy (immediate, n = 107 and deferred, n = 39) group, respectively. A significant difference was noted between the control and cytoreductive nephrectomy groups in age, clinical stage, International Metastatic Renal Cell Carcinoma Database Consortium risk factors, and the number of metastatic sites. Inverse probability of treatment weighting-adjusted Cox regression analysis showed a significant difference in overall survival between the control and the cytoreductive nephrectomy groups and between the control and the immediate or deferred cytoreductive nephrectomy groups. However, there was no significant difference in overall survival between the immediate and the deferred cytoreductive nephrectomy groups. Conclusions Our findings suggest that metastatic renal cell carcinoma patients undergoing cytoreductive nephrectomy are more likely to have longer overall survival than those who receive tyrosine kinase inhibitor therapy only.

OBJECTIVES To identify the prognosis of patients with non-urothelial carcinoma of the upper urinary tract and compare it with that of patients with urothelial carcinoma. METHODS We used hospital-based cancer registry data in Japan to extract histologically confirmed non-urothelial carcinoma and urothelial carcinoma cases of the upper urinary tract diagnosed in 2008-2009. We estimated the 5-year overall survival by a Kaplan-Meier analysis. The Cox proportional hazards regression analysis was used to evaluate prognostic factors. RESULTS A total of 2567 upper urinary tract cancer patients with confirmed histological subtypes were identified. The most common histology of non-urothelial carcinoma was squamous cell carcinoma (n = 88, 3.4%) followed by adenocarcinoma (n = 33, 1.3%) and small cell carcinoma (n = 10, 0.4%). The proportion of advanced stage in the squamous cell carcinoma patients was significantly higher than that in the urothelial carcinoma patients (P = 0.003). In stage IV, the proportion of patients who received a combination of surgery + chemotherapy in the urothelial carcinoma group was higher than that in the non-urothelial carcinoma group (34% vs 16%, respectively). The 5-year overall survival rates of the non-urothelial carcinoma patients at stages I-III and stage IV were significantly worse than those of the urothelial carcinoma patients (P = 0.003, P

OBJECTIVES To investigate the clinical characteristics of patients with penile cancer in Japan using the nationwide hospital-based cancer registry database. METHODS Using hospital-based cancer registry data, we described the distribution of age, pathology, tumor-node-metastases classification, and first-course treatment in patients treated between 2012 and 2015. We compared the patterns of first-line treatment between elderly and non-elderly patients. RESULTS A total of 1012 patients were diagnosed with squamous cell carcinoma among 1773 patients with penile tumors who registered under topography code C60. The median age at diagnosis was 74 years, and 85.9% of patients were aged >60 years. The most common pathology was usual-type squamous cell carcinoma (91.9%), followed by verrucous carcinoma (5.0%), sarcomatoid carcinoma (1.1%), papillary carcinoma (0.7%), basaloid carcinoma (0.6%), adenosquamous carcinoma (0.4%), warty carcinoma (0.2%) and mixed carcinoma (0.1%). A total of 61.3% of patients were diagnosed with localized disease. In contrast, the proportions of patients with lymph node and distant metastases were 27.5% and 2.1% at diagnosis, respectively. The proportion of patients who were treated with chemotherapy as the first-course treatment was significantly lower among elderly patients (≥80 years) with clinical stage III (27.6% vs 7.1%, P = 0.0312) and clinical stage IV (53.2% vs 14.3%, P = 0.0086). CONCLUSIONS Most penile cancer patients in Japan are diagnosed with usual-type squamous cell carcinoma, and those with human papilloma virus-related squamous cell carcinomas are

Renal cell carcinoma (RCC) features altered lipid metabolism and accumulated polyunsaturated fatty acids (PUFAs). Elongation of very long-chain fatty acid (ELOVL) family enzymes catalyze fatty acid elongation, and ELOVL5 is indispensable for PUFAs elongation, but its role in RCC progression remains unclear. Here, we show that higher levels of ELOVL5 correlate with poor RCC clinical prognosis. Liquid chromatography/electrospray ionization-tandem mass spectrometry analysis showed decreases in ELOVL5 end products (arachidonic acid and eicosapentaenoic acid) under CRISPR/Cas9-mediated knockout of ELOVL5 while supplementation with these fatty acids partially reversed the cellular proliferation and invasion effects of ELOVL5 knockout. Regarding cellular proliferation and invasion, CRISPR/Cas9-mediated knockout of ELOVL5 suppressed the formation of lipid droplets and induced apoptosis via endoplasmic reticulum stress while suppressing renal cancer cell proliferation and in vivo tumor growth. Furthermore, CRISPR/Cas9-mediated knockout of ELOVL5 inhibited AKT Ser473 phosphorylation and suppressed renal cancer cell invasion through chemokine (C-C motif) ligand-2 downregulation by AKT-mTOR-STAT3 signaling. Collectively, these results suggest that ELOVL5-mediated fatty acid elongation promotes not only cellular proliferation but also invasion in RCC.

Adrenocortical oncocytic tumors are rare. As the Weiss criteria overestimate the malignancy of oncocytic tumor due to histological hallmarks, the Lin-Weiss-Bisceglia system (LWB system) is required for an accurate diagnosis of the malignant potential of an oncocytic tumor. We report two cases diagnosed as an oncocytic tumor with uncertain malignant potential (borderline) and an oncocytic tumor (benign) based on the LWB system, both of which were diagnosed as malignant based on the Weiss criteria. Case 1 : A man in his 20s was referred to our hospital for treatment of a left adrenal tumor. A non-functional pheochromocytoma or adrenal cancer was suspected. He underwent surgical resection of the left adrenal tumor and left kidney. The specimen was positive for 3 of the 9 Weiss criteria, but met one minor criterion in the LWB system. He was diagnosed with an oncocytic tumor with uncertain malignant potential (borderline). Case 2 : A woman in her 40s was referred to our hospital for treatment of a left adrenal tumor. Under the possibility of adrenal cancer, she underwent surgical resection of the left adrenal tumor. The specimen was positive for 3 of the 9 Weiss criteria, but the specimen met no criteria in the LWB system. She was diagnosed with an oncocytic tumor (benign). There has been no recurrence of the oncocytic tumor as of 2 years of follow-up in the two patients.

No standard procedure has been established for laparoendoscopic single-site surgery for urachal remnants (LESS-U). This study aimed to report the novel surgical techniques and initial outcomes of laparoendoscopic single-site surgery with an extraperitoneal approach through a suprapubic port for urachal remnants (spLESS).Fifty-five patients (median age, 27 years; range, 15-69 years) who underwent LESS-U were analyzed. To overcome the limitations inherent in the conventional procedure (LESS-U through an umbilical port: uLESS), we modified the port placement and approached via the extraperitoneal space. spLESS is a novel procedure which reduces intestinal damage caused by the extraperitoneal approach and overcomes incomplete resection of the urachal remnant, especially in the bladder dome. Three trocars are inserted into the extraperitoneal space through a suprapubic port in spLESS, and complete resection of the urachal remnant from the umbilicus to the bladder is performed with an appropriate incision line. Patient characteristics and perioperative results were retrospectively collected. Cosmetic outcomes were prospectively evaluated using self-administered questionnaires (body image and photo-series questionnaire).spLESS and uLESS were performed in 43 and 12 patients, respectively. No differences were observed between the perioperative results. The cosmetic outcomes were compared between the groups using body image and photo-series questionnaires. No patient developed major complications; there was no recurrence in either group.spLESS is a novel procedure which can completely resect the urachal remnant and reduce the risk of intestinal damage. spLESS is a safe, effective, and feasible procedure with high postoperative cosmesis.

Background Multiple common variants and also rare variants in monogenic risk genes such as BRCA2 and HOXB13 have been reported to be associated with risk of prostate cancer (PCa); however, the clinical setting in which germline genetic testing could be used for PCa diagnosis remains obscure. Herein, we tested the clinical utility of a 16 common variant–based polygenic risk score (PRS) that has been developed previously for Japanese men and also evaluated the frequency of PCa-associated rare variants in a prospective cohort of Japanese men undergoing prostate biopsy. Methods A total of 1336 patients undergoing first prostate biopsy were included. PRS was calculated based on the genotype of 16 common variants, and sequencing of 8 prostate cancer–associated genes was performed by multiplex polymerase chain reaction based target sequencing. PRS was combined with clinical factors in logistic regression models to assess whether addition of PRS improves the prediction of biopsy positivity. Results The top PRS decile was associated with an odds ratio of 4.10 (95% confidence interval = 2.46 to 6.86) with reference to the patients at average risk, and the estimated lifetime absolute risk approached 20%. Among the patients with prostate specific antigen 2-10 ng/mL who had prebiopsy magnetic resonance imaging, high PRS had an equivalent impact on biopsy positivity as a positive magnetic resonance imaging finding. Rare variants were detected in 19 (2.37%) and 7 (1.31%) patients with positive and negative biopsies, respectively, with BRCA2 variants being the most prevalent. There was no association between PRS and high-risk rare variants. Conclusions Germline genetic testing could be clinically useful in both pre- and post-PSA screening settings.

Germ cell tumors are highly susceptible to chemotherapy; however, there is a lack of established treatments for consistently relapsing germ cell tumor. Therefore, in this phase II study, we evaluated the efficacy and safety of nivolumab for relapsed germ cell tumor.Seventeen adult patients (median age 34 years) with refractory primary germ cell tumor after second-line or higher chemotherapy were enrolled. Nivolumab was administered over 30 min at 240 mg/body every 2 weeks until disease progression or intolerable adverse event occurrence. The primary endpoint was the overall response rate.We performed a biomarker analysis of programmed death ligand-1 expression and genomic sequencing. Tumor histology revealed nonseminoma and seminoma in 14 and three patients, respectively. Patients were pretreated with a median of three chemotherapy lines, and three patients received high-dose chemotherapy. The median number of nivolumab doses was 3 (range 2-46). One patient showed a partial response and three showed stable disease. Responses were durable in one patient with a partial response and one patient with stable disease (median 90 and 68 weeks, respectively). Nivolumab was well-tolerated, with only two Grade 3 adverse events observed. Programmed death ligand-1 expression was not associated with objective responses. Genomic sequencing revealed a high tumor mutation burden in a patient with a durable partial response. While a small subset of chemorefractory germ cell tumors may respond to nivolumab, programmed death ligand-1 is unreliable to measure response.Tumor mutation burden is a potential biomarker for future testing of germ cell tumor response.

A 17-year-old man received continuous ambulatory peritoneal dialysis (CAPD) catheter implantation and had started peritoneal dialysis. Perfusion failure of peritoneal dialysis catheter occurred one month after the catheter implantation. Transcatheter contrast examination revealed catheter obstruction about 4-5 cm from the catheter tip. We performed reduced port surgery to remove the obstruction. Laparoscopy revealed that the omentum was adhered to the abdominal wall and wrapped the catheter. We diagnosed the cause of catheter malfunction as omentum wrapping. We removed the omentum from the catheter, and repositioned the catheter into the Douglas fossa. Although CAPD worked successfully after the operation, perfusion failure recurred one month after the operation. The patient requested discontinuation of CAPD and change to hemodialysis. Therefore, we removed the CAPD catheter. The catheter was adhered to the omentum. Reduced port surgery for peritoneal dialysis catheter obstruction has the advantage of being minimally invasive and is a reliable procedure, but further studies are needed to reduce the recurrence rate of perfusion failure and to establish the procedure after perfusion failure.

A 59-year-old woman presented with a left adrenal tumor 4 cm in diameter. The ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy showed apparent accumulation in the left adrenal tumor. However, the patient had no sign or symptoms suggesting pheochromocytoma. No biochemical evidence of catecholamine excess was noticed. Computed tomography (CT) revealed relatively strong enhancement in the arterial phase, which persisted until the portal phase. The computed tomography (CT) and magnetic resonance imaging showed 2 liver nodule suspected to be metastatic tumors. No ¹²³I-MIBG accumulation was seen in these nodules. CT also showed thyroid nodules with calcification, which suggested papillary thyroid cancer. Based on the findings, open left adrenalectomy, partial hepatectomy and segmentectomy were performed under the clinical diagnosis of pheochromocytoma and metastatic liver tumors. Histopathological diagnosis was adrenocortical cancer. There was only lymphocyte infiltration in the liver nodules. Postoperative recovery was uneventful, and the patient underwent partial thyroidectomy 6 months later. The pathological diagnosis was papillary thyroid cancer. She has been without recurrence or metastases for 18 months after adrenalectomy. We found only 6 cases of MIBG scintigraphy-positive adrenocortical cancer in the literature. The mechanisms for MIBG uptake in adrenocortical cancer are discussed with a review of the literature.

Introduction A double inferior vena cava is a rare anomaly with an incidence ranging from 0.3% to 3.0%. In patients with a double inferior vena cava, it is important to understand the precise anatomy and possible irregular lymph node flow when performing surgery for malignancies. Case presentation A 60-year-old man with a non-seminoma was referred to our hospital after left high orchiectomy. Computed tomography revealed a double inferior vena cava and swollen masses in the para-aortic region. After four cycles of chemotherapy with etoposide and cisplatin, retroperitoneal lymph node dissection was safely performed with a modified template extended to the right side of the paracaval region by referring to three-dimensional images created by SYNAPSE VINCENT® software. Conclusion Preoperative three-dimensional images were useful to understand this patient's unusual and complicated anatomical positions.

LBA442 Background: Although most pts with HR NMIBC respond to BCG, pts whose cancer does not respond or who relapse within 12 mo have poor prognosis and require radical cystectomy (RC). The single-arm, multicohort phase 2 KEYNOTE-057 trial (NCT02625961) was designed to investigate the safety and efficacy of pembro monotherapy for pts with BCG-unresponsive HR NMIBC (per FDA) who were ineligible or declined to undergo RC. Results from cohort A (carcinoma in situ [CIS] ± papillary tumors) showed a clinical complete response rate of 41% at 3 mo and led to approval of pembro monotherapy for such pts in the United States. We describe the results from cohort B (papillary tumors without CIS). Methods: Pts were aged ≥18 y with BCG-unresponsive HR NMIBC with papillary tumors only (high-grade Ta or any-grade T1) at baseline and ECOG PS 0-2. Pts received pembro 200 mg every 3 wk (Q3W) for ≤35 cycles (~2 y). Cancer was assessed at 12 wk and Q12W thereafter if no recurrent HR NMIBC or progression was observed; CT urography was done Q24W. Primary end points for cohort B were 12-mo disease-free survival (DFS) rate of HR NMIBC as assessed by central pathology/radiology review and safety, assuming a 12-mo DFS of >20% for HR NMIBC. Secondary efficacy end points were 12-mo DFS rate of any disease; progression-free survival (PFS) to worsening of grade, stage, or death; PFS to muscle invasion, metastasis, or death; and overall survival (OS). Results: Overall, 132 pts received pembro for a median of 9.5 cycles (range, 1.0-35.0). Median age was 72 y (range, 37-87); 57 pts (43.2%) had T1 stage; all pts (100%) had urothelial histology; 104 pts (78.8%) were male; pts received a median of 10 (range, 6-33) prior BCG instillations. Median follow-up was 45.4 mo (range, 14.9-77.1). Efficacy data are shown in Table. Thirty-one pts (23.5%) had RC after stopping pembro. Treatment-related AEs occurred in 97 pts (73.5%); 19 (14.4%) had a grade 3/4 treatment-related AE and 14 pts (10.6%) discontinued due to a treatment-related AE. No deaths from treatment-related AEs occurred. Conclusions: Pembro showed notable antitumor activity in pts with BCG-unresponsive non-CIS papillary HR NMIBC after ~45 mo of follow-up. Toxicity was manageable and consistent with that in cohort A, with no new safety signals. Results suggest pts with non-CIS papillary HR NMIBC unresponsive to BCG who declined or were ineligible to undergo RC may also benefit from pembro monotherapy. Clinical trial information: NCT02625961 . [Table: see text]

Renal cell carcinoma (RCC) is an aggressive genitourinary malignancy which has been associated with a poor prognosis, particularly in patients with metastasis, its major subtypes being clear cell RCC (ccRCC), papillary PCC (pRCC) and chromophobe RCC (chRCC). The presence of intracellular lipid droplets (LDs) is considered to be a hallmark of ccRCC. The importance of an altered lipid metabolism in ccRCC has been widely recognized. The elongation of very-long-chain fatty acid (ELOVL) catalyzes the elongation of fatty acids (FAs), modulating lipid composition, and is required for normal bodily functions. However, the involvement of elongases in RCC remains unclear. In the present study, the expression of ELOVL2 in ccRCC was examined; in particular, high levels of seven ELOVL isozymes were observed in primary tumors. Of note, elevated ELOVL2 expression levels were observed in ccRCC, as well as in pRCC and chRCC. Furthermore, a higher level of ELOVL2 was significantly associated with the increased incidence of a poor prognosis of patients with ccRCC and pRCC. The CRISPR/Cas9-mediated knockdown of ELOVL2 resulted in the suppression of the elongation of long-chain polyunsaturated FAs and increased LD production in renal cancer cells. Moreover, ELOVL2 ablation resulted in the suppression of cellular proliferation via the induction of apoptosis in vitro and the attenuation of tumor growth in vivo. On the whole, the present study provides new insight into the tumor proliferation mechanisms involving lipid metabolism, and suggests that ELOVL2 may be an attractive novel target for RCC therapy.

ObjectiveWe retrospectively analyzed the incidence and localization of venous thromboembolism in patients undergoing chemotherapy for advanced germ cell tumor and separately evaluated the risk factors for venous thromboembolism development before and during chemotherapy.MethodsWe included 121 patients treated with cisplatin-based chemotherapy between 2005 and 2018. Venous thromboembolism was defined as venous thrombosis diagnosed using radiological imaging with or without thromboembolic symptoms. We analyzed the clinical parameters for identifying the possible venous thromboembolism risk factors. Khorana score was used to calculate the venous thromboembolism risk.ResultsThirteen patients showed prechemotherapy venous thromboembolism and 13 developed venous thromboembolism during chemotherapy. The most common venous thromboembolism was deep vein thrombosis (10 patients), followed by inferior vena cava thrombus (eight patients) and pulmonary thrombus (six patients). Compared to the group without venous thromboembolism, the group with prechemotherapy venous thromboembolism showed higher proportion of patients with tumors originating in the right testis (10 out of 13), significantly higher lactate dehydrogenase levels (828 IU/L versus 436 IU/L, P = 0.013), significantly higher proportion of patients with retroperitoneal lymph node (RPLN) metastases >5 cm in diameter (76.9% versus 33.7%, P = 0.003) and slightly higher proportion of patients with high-risk Khorana score (≥ 3; 30.8% versus 11.6%). No significant differences were observed between the clinical characteristics of patients with venous thromboembolism developed during chemotherapy and patients without venous thromboembolism.ConclusionsWe show that both RPLN mass > 5 cm and high lactate dehydrogenase levels are significant risk factors for prechemotherapy venous thromboembolism but not for venous thromboembolism development during chemotherapy.

We retrospectively evaluated the clinical outcomes of patients with histologic variants of muscle invasive bladder cancer (MIBC) treated with trimodal bladder-preserving therapy (TMT). Among 148 patients with clinical T2-3N0M0 MIBC treated with TMT at Tsukuba University Hospital from 1990 to 2015, 11 patients (7.4%) had pathological components of variant urothelial carcinoma (UC). The complete response (CR), overall survival (OS), cause-specific survival (CSS) and progression-free survival (PFS) rates were analyzed in these 11 patients. Among the 11 patients with variant UC, 7 (64%) had UC with squamous and/or glandular differentiation and 4 (36%) had sarcomatoid (n = 1), plasmacytoid (n = 1), signet ring cell (n = 1), or clear cell variant (n = 1). Median follow-up was 49.0 months. Nine (82%) out of 11 patients achieved CR and 2 (22%) out of the 9 developed recurrence. Among seven patients who had UC with squamous and/or glandular differentiation, two developed recurrence and one died of disease. In contrast, 2 (50%) out of four patients with other variants, which were sarcomatoid variant or signet ring cell, developed recurrence and died of disease. Overall, the 5-year OS, CSS, and PFS rates of variant UC were 75%, 75%, and 58%, respectively. TMT might provide acceptable clinical outcomes for well-selected MIBC patients with histologic variants, especially for those with squamous and/or glandular differentiation. However, we need to pay special attention to other variants such as sarcomatoid variant or signet ring cell. TMT might be an alternative treatment option for patients with histologic variants, although further experiments will be needed to confirm this.

The Tumor-Node-Metastasis (TNM) staging system, jointly developed by the American Joint Commission on Cancer (AJCC) and the Union for International Cancer Control (UICC), is widely employed in clinical practice and research on patients with cancer. The definitions of TNM classification have recently been changed, improving patient stratification for management and prognosis. As the feature of new editions, biomarkers which are necessary for the stratification of patients are included to adapt for personalized medicine. Although it would be ideal for the AJCC and UICC have identical TNM staging systems, there are some differences between these two publications. In this review, we introduce the significant changes and differences in the eighth edition of the AJCC and UICC TNM staging systems for urologic cancers and summarize the evidence supporting these changes.

Objectives This study aims to evaluate the utility of the scoring system of the Registry for Metastatic Renal Cell Carcinoma (REMARCC) model on the overall survival (OS) of patients undergoing cytoreductive nephrectomy (CN). Methods A total of 278 patients with primary metastatic renal cell carcinoma (mRCC) treated with first-line tyrosine kinase inhibitors (TKIs) between January 2008 and November 2019 were identified. The c-index and net benefit between the REMARCC score were compared with the International mRCC Database Consortium (IMDC) score in patients with CN (CN group, n = 146). The effect of the REMARCC score on OS was compared between the CN group and patients without CN (non-CN group, n = 132) using Cox regression analysis under the propensity score-based inverse probability of treatment weighting (IPTW) method to adjust for group imbalances. Results Of the 146 patients with CN, the c-index of the REMARCC model (0.60) was higher than the IMDC model (0.54). The decision curve analysis showed the advantage of REMARCC model predicting OS compared with the IMDC model. OS was significantly longer in the REMARCC low-score (0–2) than that in the high-score (3–6) among the patients with CN. IPTW-adjusted Cox regression analyses showed that OS was significantly longer in the CN group than that in the non-CN group among the patients with REMARCC low-score but was not significantly different between the groups among the patients with REMARCC high-score. Conclusions The REMARCC score may be active for selecting the CN candidate in patients treated with TKIs.

Invasion of bladder cancer (BC) cells from the mucosa into the muscle layer is canonical for BC progression while phospholipase D isoform 1 (PLD1) is known to mediate development of cancer through phosphatidic acid (PA) production. We therefore used in silico, in vitro and in vivo approaches to detail the effect of PLD1 on BC invasion. In BC patients, higher levels of PLD1 expression were associated with poor prognoses. PLD1 knockdown significantly suppressed cellular invasion by human BC cells and matrix metalloproteinase-13 (MMP-13) was observed to mediate this effect. In our mouse bladder carcinogenesis model, the development of invasive BCs was suppressed by PLD1 knockout and a global transcriptomic analysis in this model indicated MMP-13 as a potential tumor invasion gene with NF-κB (nuclear factor-kB) as its transcriptional regulator. Furthermore, PA administration increased MMP-13 expression in line with NF-κB p65 phosphorylation levels. Collectively, we demonstrate that PLD1 promotes tumor invasion of BC by regulation of MMP-13 expression through the NF-κB signaling pathway and that PLD1 might be a potential therapeutic target to prevent clinical progression in BC patients.

A 32-year-old woman was referred to our hospital for consultation with a suspected left adrenal tumor detected by ultrasonography at a health check. Computed tomography and magnetic resonance imaging revealed a 3×1×4 cm multilocular cystic mass arising from the diaphragmatic crura, suggesting a retroperitoneal bronchogenic cyst. The patient underwent excision of the cyst and adjacent diaphragm using a retroperitoneoscopic approach. Retroperitoneal bronchogenic cysts are rare. We review the cases of 26 patients who underwent laparoscopic resection of a retroperitoneal bronchogenic cyst.