TNFSF9 Is Associated with Favorable Tumor Immune Microenvironment in Patients with Renal Cell Carcinoma Who Are Treated with the Combination Therapy of Nivolumab and Ipilimumab.

Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is desirable to identify biomarkers to predict treatment responses in advance. We examined the tumor microenvironment (TME)-related gene expression in mRCC patients treated with NIVO + IPI, between the response and non-response groups, using tumor tissues, before administering NIVO + IPI. In TME-related genes, TNFSF9 expression was identified as a candidate for the predictive biomarker. Its expression discriminated between the response and non-response groups with 88.89% sensitivity and 87.50% specificity (AUC = 0.9444). We further analyzed the roles of TNFSF9 in TME using bioinformatics from The Cancer Genome Atlas (TCGA) cohort. An adaptive immune response was activated in the TNFSF9-high-expression tumors. Indeed, T follicular helper cells, plasma B cells, and tumor-infiltrating CD8+ T cells were increased in the tumors, which indicates the promotion of humoral immunity due to enhanced T-B interactions. However, as the number of regulatory T cells (Treg) increased in the tumors, the percentage of dysfunctional T cells also increased. This suggests that not only PD-1 but also CTLA-4 inhibition may have suppressed Treg activation and improved the therapeutic effect in the TNFSF9 high-expression tumors. Therefore, TNFSF9 may predict the therapeutic efficacy of NIVO + IPI for mRCC and allow more appropriate patient selection.

A Machine Learning Model to Predict the Histology of Retroperitoneal Lymph Node Dissection Specimens.

BACKGROUND/AIM: 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; however, prediction of 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. PATIENTS AND METHODS: This study 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, whereas 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. CONCLUSION: Our machine learning models reliably distinguish between necrosis and residual teratoma in clinical PC-RPLND specimens.

Patient characteristics correlate with diagnostic performance of photodynamic diagnostic assisted transurethral resection of bladder tumors: A retrospective, single-center study.

BACKGROUND: Identification of patient subclasses that correlate with the diagnostic performance of photodynamic diagnostic (PDD)-assisted transurethral resection of bladder tumors (TURBT) may improve outcomes. METHODS: Data were extracted from patients that underwent PDD-assisted TURBT at the University of Tsukuba Hospital between 2018 and 2023. Sensitivity and specificity were evaluated based on PDD findings (excluding WL findings) and pathology results. Cluster analysis using uniform manifold approximation and projection and k-means methods was performed, focusing on patients with malignant lesions. RESULTS: A total of 267 patients and 2082 specimens were extracted. Sensitivity was lowest with regard to BCG treatment (53.7 %), followed by flat lesions (57.2 %), urine cytology class ≥ III (62.9 %), and recurrent tumors (64.5 %). In the cluster analysis of 231 patients with malignant lesions, two showed lower sensitivity: Cluster 3 (62.4 %), consisting of patients with recurrent tumors and post-BCG treatment, and Cluster 4 (55.7 %), consisting of patients with primary tumors and urine cytology class ≥ III. Clusters 1 and 2, consisting of patients without BCG treatment and patients with lower urine cytology classes, exhibited higher sensitivities (94.4 % and 87.7 %). Among all clusters, Cluster 4 had the highest proportion of specimens which were negative for both PDD and white light (WL) findings but actually had malignant lesions (20.8 %). CONCLUSIONS: PDD-assisted TURBT sensitivity was lower in subclasses after BCG treatment or with cytology class III or higher. Random biopsy for PDD/WL double-negative lesions may improve diagnostic accuracy in these subclasses.

Adult genitourinary sarcoma: analysis using hospital-based cancer registry data in Japan.

BACKGROUND: Genitourinary sarcomas are rare in adults and few large-scale studies on adult genitourinary sarcoma are reported. We aimed to elucidate the clinical characteristics, survival outcomes, and prognostic factors for overall survival of adult genitourinary sarcoma in Japan. METHODS: A hospital-based cancer registry data in Japan was used to identify and enroll patients diagnosed with genitourinary sarcoma in 2013. The datasets were registered from 121 institutions. RESULTS: A total of 116 men and 39 women were included, with a median age of 66 years. The most common primary site was the kidney in 47 patients, followed by the paratestis in 36 patients. The most common histological type was liposarcoma in 54 patients, followed by leiomyosarcoma in 25 patients. The 5-year overall survival rates were 57.6%. On univariate analysis, male gender, paratestis as primary organ, and histological subtype of liposarcoma were predictive of favorable survival while primary kidney, bladder, or prostate gland location were predictive of unfavorable survival. On multivariate analysis, primary paratestis was an independent predictor of favorable survival while primary kidney, bladder, or prostate gland were independent predictors of unfavorable survival. CONCLUSIONS: This is the first report showing the clinical characteristics and survival outcomes of adult genitourinary sarcoma in Japan using a real-world large cohort database.

Retroperitoneal sarcoma: a 10-year follow-up analysis using hospital-based cancer registry data in Japan.

OBJECTIVES: We sought clinical characteristics, survival outcomes, and prognostic factors for overall survival of retroperitoneal sarcoma in Japan. METHODS: A Japanese hospital-based cancer registry database with a pivotal 10-year follow-up was used to identify and enroll patients, registered from 106 institutions, diagnosed with retroperitoneal sarcoma in 2008-2009. Treating hospitals were divided by hospital care volume; high-volume hospitals and low-volume hospitals were defined as ≥ 4 and < 4 cases/year, respectively. RESULTS: A total of 91 men and 97 women were included, with a median age of 64 years. The most common histological type was liposarcoma in 101 patients, followed by leiomyosarcoma in 38 patients. The 5-year and 10-year overall survival rates were 44.1 and 28.3%. The majority of patients (n = 152, 80.9%) were treated at low-volume hospitals. High-volume hospital patients had higher 10-year overall survival rates than low-volume hospital patients (51.2% vs 23.2%, P = 0.026). Multivariate analysis revealed age over 60 years, treatment in low-volume hospitals and chemotherapy were independent predictors of unfavorable survival while treatment with surgery was an independent predictor of favorable survival. CONCLUSIONS: The possibility of surgical removal was suggested to be the most important prognostic factor for retroperitoneal sarcoma. Better survival was shown in patients treated at high-volume hospitals in our series.

The prognostic impact of treatment centralization in patients with testicular germ cell tumors: analysis of hospital-based cancer registry data in Japan.

BACKGROUND: To identify the prognostic impact of treatment centralization in patients with testicular germ cell tumors (TGCT). METHODS: We used a hospital-based cancer registry data in Japan to extract seminoma and non-seminoma cases that were diagnosed in 2013, histologically confirmed, and received the first course of treatment. To compare the 5-years overall survival (OS) rates of patients stratified by institutional care volume, we performed a Cox proportional hazards regression analysis using inverse probability of treatment weighting (IPTW) method to adjust patient backgrounds. RESULTS: A total of 1767 TGCT patients were identified. The 5-years OS rates for stage II and III TGCT patients treated at low-volume institutions (< 7 cases) were significantly worse than high-volume institutions (≥ 7 cases) (91.2% vs. 83.4%, p = 0.012). Histological stratification revealed that 5-year OS rates for stage II and III seminoma patients in the low-volume group were significantly worse than the high-volume group (93.5% vs. 84.5%, p = 0.041). Multivariate OS analysis using an IPTW-matched cohort showed that institutional care volume was an independent prognostic factor (hazard ratio 2.13 [95% confidence interval: 1.23-3.71], p = 0.0072). CONCLUSION: Our results indicate that stage II and III TGCT patients experience lower survival rates at low-volume institutions and would benefit from treatment centralization.

Plasma circulating tumor DNA profiling in patients with chemo-refractory germ cell tumors.

OBJECTIVES: Molecular analysis of tumor tissues has been extensively analyzed in germ cell tumors. However, genetic analysis of plasma circulating tumor DNA has been limited. Our objective was to analyze genetic alterations in circulating tumor DNA as well as its impact on prognosis in patients with chemo-refractory germ cell tumors. METHODS: We included 13 patients with chemo-refractory germ cell tumors who relapsed after second-line or higher previous chemotherapy and performed targeted sequencing of plasma cell-free DNA using an AVENIO Expanded kit. RESULTS: Tumor-specific genetic alterations were identified in all patients. The most frequently mutated gene was TP53 (53.4%), followed by PTEN (23.1%), GNAS (15.4%) and MTOR (15.4%). Moreover, EGFR amplification (38.5%) and MET amplification (15.4%) were also identified. We defined two or more single nucleotide variants detected in plasma cell-free DNA as circulating tumor DNA-positive. Kaplan-Meier analysis revealed that overall survival was significantly shorter in circulating tumor DNA-positive patients than circulating tumor DNA negative-patients (median overall survival 3.13 vs. 8.73 months; p = 0.042). CONCLUSION: Analysis of plasma circulating tumor DNA could detect genetic alterations in patients with chemo-refractory GCT. Moreover, detectable circulating tumor DNA in plasma was associated with poor prognosis in those patients. These results suggest that liquid biopsy using analysis of plasma circulating tumor DNA may be clinically useful for germ cell tumor patients.

Improved survival of poor-risk non-seminomatous germ cell tumor patients: real-world data from a single institute in Japan.

OBJECTIVES: The International Germ Cell Cancer Collaborative Group Update Consortium showed the improved survival of patients with a non-seminomatous germ cell tumor. We updated the survival data of the non-seminomatous germ cell tumor patients treated at our hospital. PATIENTS AND METHODS: We analyzed the outcomes of 138 patients treated in 1981-2018. We compared the survival of the patients treated in the early (1981-99) and later (2000-18) periods and determined the groups' progression-free survival and overall survival using the Kaplan-Meier method. We used a web-based application of the International Germ Cell Cancer Collaborative Group Update model to calculate each patient's predicted 3-year progression-free survival. RESULTS: The 5-year progression-free survival rates of the good, intermediate and poor prognosis groups were 91, 83 and 64%, and their 5-year overall survival rates were 97, 89 and 82%, respectively. There were no significant differences in the progression-free survival or overall survival of the good and intermediate prognosis groups by treatment year. The 5-year progression-free survival of the poor prognosis group was almost identical in both treatment year (60 and 65%, respectively). By contrast, the 5-year overall survival in the later period (85%) was higher than that in the early period (70%). The median-predicted 3-year progression-free survival rates of the good, intermediate and poor prognosis groups were 92, 83 and 51% (P < 0.01), respectively. The concordance index for the good, intermediate and poor prognosis groups were 0.56, 0.79 and 0.67, respectively. CONCLUSION: The survival of our poor prognosis non-seminomatous germ cell tumor patients improved over time. The 5-year overall survival of patients treated in 2000-18 reached 85%.

Whole-Blood Gene Expression Profiles Correlate with Response to Immune Checkpoint Inhibitors in Patients with Metastatic Renal Cell Carcinoma.

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.

Manual vacuum aspiration (women's MVA) for endometrial biopsy for patients with suspected endometrial malignancies.

AIM: Endometrial biopsy is generally performed with a metal uterine curette sonde; however, recently, many types of vacuum aspirators are available, including the manual vacuum aspiration (MVA) system. We used the women's MVA system for endometrial sampling and evaluated its effectiveness in determining the presence of endometrial malignancy. METHODS: Forty-seven samples were examined using the following procedures after measuring endometrial thickness by transvaginal ultrasonography: fractional curettage biopsy (Bx; 20 samples), total curettage under general anesthesia (T/C; 13 samples), and MVA (14 samples). The quality of the endometrial samples was classified into four types: 1-4, where 1 denoted poor and 4, good quality. RESULTS: The mean score of the MVA group was significantly higher than that of the partial curettage biopsy group (p = 0.0065). No differences were observed between the MVA and total curettage groups (p = 1.00). When patients were divided into two groups according to endometrial thickness (<10 mm or ≥10 mm) and analyzed, both the MVA and T/C groups did not show a significant difference in their scores compared to the Bx group when the endometrial thickness was <10 mm. However, when the endometrial thickness was ≥10 mm, the MVA and T/C groups had significantly better scores than the Bx group (p = 0.0225 and p = 0.0244, respectively). Vagal reflex, as an adverse event, was observed only in two patients in the Bx group (2/20, 10%). CONCLUSION: Considering its quality and safety, Karman-type MVA for endometrial sampling could be an alternative to fractional curettage using a metallic uterine curette sonde.

ELOVL5-mediated fatty acid elongation promotes cellular proliferation and invasion in renal cell carcinoma.

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.

Laparoendoscopic single-site surgery for urachal remnant with extraperitoneal approach through a suprapubic port.

INTRODUCTION: 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). METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

[Adrenocortical Oncocytic Tumor : A Report of Two Cases].

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.

Granulocyte colony-stimulating factor associated arteritis in a patient with castration-resistant prostate cancer.

INTRODUCTION: Granulocyte colony-stimulating factor-associated arteritis is a rare adverse event of granulocyte colony-stimulating factor, with an incidence of 0.47% among all patients who receive granulocyte colony-stimulating factor. We herein present a case of granulocyte colony-stimulating factor-associated arteritis. CASE PRESENTATION: A 72-year-old man with castration-resistant prostate cancer and multiple bone metastases was treated with docetaxel and pegfilgrastim. He developed a high fever on day 12 without other symptoms. His white blood cell count and C-reactive protein levels were high. Antibiotic therapy was ineffective, and contrast-enhanced computed tomography showed thickened subclavian and brachiocephalic artery walls. He was diagnosed with granulocyte colony-stimulating factor-associated arteritis. CONCLUSION: When patients receiving chemotherapy with granulocyte colony-stimulating factor develop an unexplained fever, granulocyte colony-stimulating factor associated arteritis should be considered.

ELOVL2 promotes cancer progression by inhibiting cell apoptosis in renal cell carcinoma.

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 very­long­chain 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/Cas9­mediated knockdown of ELOVL2 resulted in the suppression of the elongation of long­chain 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.

[A Case of Perfusion Failure of Peritoneal Dialysis Catheter Treated by Reduced Port Surgery].

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.

Advanced germ cell tumor patients undergoing post-chemotherapy retroperitoneal lymph node dissection: Impact of residual teratoma on prognosis.

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.

Discrepancy between clinical and pathological T stages in upper urinary tract urothelial carcinoma: Analysis of the Hospital-Based Cancer Registry data in Japan.

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 < 0.0001, respectively). Upstaging from clinical organ-confined disease (≤cT2) to pathological non-organ-confined disease (≥pT3) was significantly more frequent in the urothelial carcinoma of the renal pelvis (27.8%, P < 0.0001) and urothelial carcinoma of the ureter (22.3%, P < 0.0001) groups compared with the urothelial carcinoma of the bladder (17.8%) group. CONCLUSION: Discrepancy in T staging is significantly higher in patients with urothelial carcinoma of the upper urinary tract compared with those with urothelial carcinoma of the bladder, especially in those with organ-confined disease. As T-stage discrepancy might lead to missed opportunities to carry out perioperative treatment, more accurate diagnostic techniques are required to identify the appropriate urothelial carcinoma candidates for preoperative treatment.

PLD1 promotes tumor invasion by regulation of MMP-13 expression via NF-κB signaling in bladder cancer.

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.