SETD2 regulates SLC family transporter-mediated sodium and glucose reabsorptions in renal tubule.

A regulatory mechanism for SLC family transporters, critical transporters for sodium and glucose reabsorptions in renal tubule, is incompletely understood. Here, we report an important regulation of SLC family transporter by SETD2, a chromatin remodeling gene whose alterations have been found in a subset of kidney cancers. Kidney-specific inactivation of Setd2 resulted in hypovolemia with excessive urine excretion in mouse and interestingly, RNA-sequencing analysis of Setd2-deficient murine kidney exhibited decreased expressions of SLC family transporters, critical transporters for sodium and glucose reabsorptions in renal tubule. Importantly, inactivation of Setd2 in murine kidney displayed attenuated dapagliflozin-induced diuresis and glucose excretion, further supporting that SETD2 might regulate SLCfamily transporter-mediated sodium and glucose reabsorptions in renal tubule. These data uncover an important regulation of SLC family transporter by SETD2, which may illuminate a crosstalk between metabolism and epigenome in renal tubule.

Patient-specific simulations and navigation systems for partial nephrectomy.

Partial nephrectomy (PN) is the standard treatment for T1 renal cell carcinoma. PN is affected more by surgical variations and requires greater surgical experience than radical nephrectomy. Patient-specific simulations and navigation systems may help to reduce the surgical experience required for PN. Recent advances in three-dimensional (3D) virtual reality (VR) imaging and 3D printing technology have allowed accurate patient-specific simulations and navigation systems. We reviewed previous studies about patient-specific simulations and navigation systems for PN. Recently, image reconstruction technology has developed, and commercial software that converts two-dimensional images into 3D images has become available. Many urologists are now able to view 3DVR images when preparing for PN. Surgical simulations based on 3DVR images can change surgical plans and improve surgical outcomes, and are useful during patient consultations. Patient-specific simulators that are capable of simulating surgical procedures, the gold-standard form of patient-specific simulations, have also been reported. Besides VR, 3D printing is also useful for understanding patient-specific information. Some studies have reported simulation and navigation systems for PN based on solid 3D models. Patient-specific simulations are a form of preoperative preparation, whereas patient-specific navigation is used intraoperatively. Navigation-assisted PN procedures using 3DVR images have become increasingly common, especially in robotic surgery. Some studies found that these systems produced improvements in surgical outcomes. Once its accuracy has been confirmed, it is hoped that this technology will spread further and become more generalized.

CD70-Targeted Micelles Enhance HIF2α siRNA Delivery and Inhibit Oncogenic Functions in Patient-Derived Clear Cell Renal Carcinoma Cells.

The majority of clear cell renal cell carcinomas (ccRCCs) are characterized by mutations in the Von Hippel−Lindau (VHL) tumor suppressor gene, which leads to the stabilization and accumulation of the HIF2α transcription factor that upregulates key oncogenic pathways that promote glucose metabolism, cell cycle progression, angiogenesis, and cell migration. Although FDA-approved HIF2α inhibitors for treating VHL disease-related ccRCC are available, these therapies are associated with significant toxicities such as anemia and hypoxia. To improve ccRCC-specific drug delivery, peptide amphiphile micelles (PAMs) were synthesized incorporating peptides targeted to the CD70 marker expressed by ccRCs and anti-HIF2α siRNA, and the ability of HIF2α-CD27 PAMs to modulate HIF2α and its downstream targets was evaluated in human ccRCC patient-derived cells. Cell cultures were derived from eight human ccRCC tumors and the baseline mRNA expression of HIF2A and CD70, as well as the HIF2α target genes SLC2A1, CCND1, VEGFA, CXCR4, and CXCL12 were first determined. As expected, each gene was overexpressed by at least 63% of all samples compared to normal kidney proximal tubule cells. Upon incubation with HIF2α-CD27 PAMs, a 50% increase in ccRCC-binding was observed upon incorporation of a CD70-targeting peptide into the PAMs, and gel shift assays demonstrated the rapid release of siRNA (>80% in 1 h) under intracellular glutathione concentrations, which contributed to ~70% gene knockdown of HIF2α and its downstream genes. Further studies demonstrated that knockdown of the HIF2α target genes SLC2A1, CCND1, VEGFA, CXCR4, and CXCL12 led to inhibition of their oncogenic functions of glucose transport, cell proliferation, angiogenic factor release, and cell migration by 50−80%. Herein, the development of a nanotherapeutic strategy for ccRCC-specific siRNA delivery and its potential to interfere with key oncogenic pathways is presented.

[A Case of Lymphoepithelioma-Like Carcinoma of the Ureter].

Lymphoepithelioma-like carcinoma (LELC) of the ureter is very rare and only 14 previous cases have been reported. Here, we report a case of LELC of the ureter. A 76-year-old woman was admitted to our hospital complaining of gross hematuria. Left ureteral cancer was suspected by the imaging examination, and laparoscopic left total nephroureterectomy was performed. Histopathological examination showed pure type of LELC in the ureter. She is alive without disease recurrence at fifteen months after surgery.

Prediction of Time to Castration-Resistant Prostate Cancer Using Low-Molecular-Weight Protein Tyrosine Phosphatase Expression for Men with Metastatic Hormone-Naïve Prostate Cancer.

INTRODUCTION: Low-molecular-weight protein tyrosine phosphatase (LMW-PTP) expression affects carcinogenesis in various cancers and has been associated with determining the overall survival among men with metastatic hormone-naïve prostate cancer (mHNPC). In this study, we analyzed the value of LMWPTP for prediction of time to castration-resistant prostate cancer (CRPC) for men with mHNPC. MATERIALS AND METHODS: We retrospectively enrolled 45 men with mHNPC who were diagnosed from 2003 to 2009. All patients had received androgen deprivation therapy as first-line treatment. Prostate cancer tissues (pre-treatment needle biopsies) were immunohistochemically stained for LMW-PTP. Multivariate analyses (Cox proportional hazard model) were used to correlate baseline clinical factors of age, prostate-specific antigen (PSA), Gleason scores, T stage, N stage, extent of disease on bone scan (EOD), LMW-PTP expression and time to CRPC. Continuous variables were classified as dichotomous. RESULTS: Median age and PSA were 70.0 years and 87.8 ng/mL respectively. Median time to CRPC was 40.2 months. Median time to CRPC was significantly shorter in the high LMW-PTP group (14.8 months) than that in the low LMW-PTP group (86.3 months, p < 0.01). In multivariate analysis, age ≥70 years and high LMW-PTP expression were significant predictors of time to CRPC.

Significant response to nivolumab for metastatic chromophobe renal cell carcinoma with sarcomatoid differentiation: a case report.

BACKGROUND: The treatment of advanced or metastatic renal cell carcinoma (RCC) has drastically changed since the approval of immune checkpoint therapy. Nivolumab is a treatment option for patients with metastatic RCC, previously treated with targeted antiangiogenic therapy. The efficacy of nivolumab for patients with RCC was established by the Checkmate 025 clinical trial. Chromophobe RCC (CRCC) represents around 5% of RCC cases, but non-clear cell RCC (non-ccRCC) subtypes were excluded from the Checkmate 025 clinical trial. We report a case in which the use of nivolumab as the seventh-line therapy elicited a significant response in the treatment of metastatic CRCC with sarcomatoid differentiation. CASE PRESENTATION: We report a case of a 41-year-old woman with metastatic CRCC with sarcomatoid differentiation. She was treated with sunitinib, pazopanib, everolimus, sorafenib, axtinib, and temsirolimus, but treatment was discontinued because of disease progression or strong adverse events. Seventh-line treatment with nivolumab was initiated and significant clinical improvement was noted after 4 cycles. The treatment was well-tolerated with no significant side effects and the patient continues with nivolumab treatment at present. CONCLUSIONS: Nivolumab may be an attractive treatment option for non-ccRCC patients with sarcomatoid differentiation that exhibited aggressive characteristics and poor prognosis. Further investigation is warranted.

PD-1 and PD-L1 are more highly expressed in high-grade bladder cancer than in low-grade cases: PD-L1 might function as a mediator of stage progression in bladder cancer.

BACKGROUND: Bladder cancers have been characterized as a tumor group in which the immunological response is relatively well preserved. Programmed death ligand 1 (PD-L1, B7-H1, CD274) has been shown to be expressed in several malignancies, including bladder cancer. However, the clinicopathological impact of this biomarker has not yet been established. In the present study, a quantitative real-time polymerase chain reaction (qPCR) was performed using paired normal and cancerous bladder cancer tissue to investigate PD-1/PD-L1 gene expression. METHODS: We examined the mRNA expression of PD-1/PD-L1 by a qPCR using 58 pairs of normal and cancerous human bladder tissue specimens. We also examined the correlation with the expressions of the STAT1 and NFAT genes, which are thought to be upstream and downstream of the PD-L1 pathway, respectively. RESULTS: There were no significant differences between normal and cancerous tissue in the expression of the PD-1 and PD-L1 genes (p = 0.724 and p = 0.102, respectively). However, PD-1 and PD-L1 were both more highly expressed in high-grade bladder cancer than in low-grade bladder cancer (p < 0.050 and p < 0.010). PD-L1 was positively correlated with the expressions of both the STAT1 (r = 0.681, p < 0.001) and the NFATc1 genes (r = 0.444. p < 0.001). CONCLUSIONS: PD-1 and PD-L1 might be a new biomarker that correlates with the pathological grade of bladder cancer. PD-L1 might function as a mediator of stage progression in bladder cancer and STAT1-NFAT pathway might associate this function.

Neutrophil-to-lymphocyte ratio is a prognostic marker in bladder cancer patients after radical cystectomy.

BACKGROUND: There is no reliable biomarker for predicting the prognosis of patients who undergo radical cystectomy for bladder cancer. Recent studies have shown that the neutrophil-to-lymphocyte ratio (NLR) could function as a useful prognostic factor in several types of malignancies. This study aimed to assess the usefulness of NLR in bladder cancer. METHODS: A total of 74 patients who underwent radical cystectomy in our institutions from 1999 to 2014 were analyzed. The NLR was calculated using the patients' neutrophil and lymphocyte counts before radical cystectomy. An immunohistochemical analysis was also performed to detect tumor infiltrating neutrophils (CD66b) and lymphocytes (CD8) in bladder cancer specimens. RESULTS: A univariate analysis showed that the patients with a high NLR (≥2.38; HR = 4.84; p = 0.007), high C-reactive protein level (>0.08; HR = 10.06; p = 0.030), or pathological lymph node metastasis (HR = 4.73; p = 0.030) had a significantly higher risk of cancer-specific mortality. Kaplan-Meier and log-rank tests further revealed that NLR was strongly correlated with overall survival (p = 0.018), but not progression-free survival (p = 0.137). In a multivariate analysis, all of these were found to be independent risk factors (HR = 4.62, 10.8, and 12.35, respectively). The number of CD8-positive lymphocytes was significantly increased in high-grade (p = 0.001) and muscle-invasive (p = 0.012) tumors, in comparison to low-grade and non-muscle-invasive tumors, respectively. CONCLUSIONS: The NLR predicted the prognosis of patients who underwent radical cystectomy and might therefore function as a reliable biomarker in cases of invasive bladder cancer.

[A Case of Abdominal Wall Desmoid Tumor after Radical Nephrectomy for Renal Cancer].

A 71-year-old man with a right renal tumor underwent nephrectomy. The procedure was converted from laparoscopy to open surgery due to profound bleeding from the renal vein. Pathological diagnosis was clear cell carcinoma G2pT3b v1 ly1 INFα. Three years after surgery, a 5 cm tumor in the abdominal wall was found on computed tomography (CT). A mild uptake was shown on positron emission tomography/CT and as the tumor was located near the surgical wound, recurrence of the renal cell carcinoma was suspected. However, desmoid tumor was suggested by the pathological examination of the tumor biopsy. En-bloc resection of the mass was carried out and the pathological examination showed an array of proliferating and tangling atypical spindle-shaped tumor cells. Immunohistochemical staining of the tumor cells was positive for vimentin, but negative for CD34, c-kit, and s100. Pathological diagnosis was desmoid tumor. There has been no recurrence so far. Desmoid tumor, despite its extremely low incidence, should be considered in a postoperative neoplasm.

[A case of pneumatosis cystoides intestinalis secondary to sunitinib treatment for renal cell carcinoma].

A 78-year-old man was diagnosed as having right renal cell carcinoma (RCC) with metastasis to the right lung. He received sunitinib and the treatment reduced the size of both RCC and lung metastasis. Then he received right radical nephrectomy. The pathological diagnosis was clear cell RCC. After the initial surgery, he was diagnosed with polymyalgia rheumatic and steroid therapy was started. During follow-up, local recurrence was discovered and sunitinib was then started at a dose of 25 mg/day. Two months after the treatment, abdominal computed tomography (CT) revealed colonic pneumatosis cystoides intestinalis. Administration of sunitinib was stopped and the patient was observed carefully without pursuing surgical intervention. A follow-up CT demonstrated resolution of the colonic pnumatosis.

[Four cases of penile fracture].

Penile fracture is not common but is an emergency disease. We report 4 cases of penile fracture treated at the Department of Urology, Yokohama City University between 2005 and 2012. The age of the patients ranged between 26 and 67 years (mean age, 41.5 years). Of the patients in our series, 3 sustained injury during sexual intercourse, and 1 while rolling over in bed. All patients were treated surgically and cured without any functional disturbance after treatment. Reports before 2002 and 99 cases after 2002 were also reviewed. The number of patients between 40 and 60 years was increasing. Magnetic resonance imaging was useful to detect the site of penile fracture and immediate surgical treatment was important.

[Vesical tuberculosis after Bacillus Calmette-Guerin intravesical instillation therapy for bladder cancer].

An 82-year-old man who had undergone transurethral resection (TUR) for superficial bladder cancer (pT1 G3) in June and Luly 2011 received intravesical Bacillus Calmette-Guerin therapy (80 mg weekly for 6 weeks) in September 2011. Seven months later, a follow-up cystoscopy revealed a slowly growing torose lesion at the site of the previous TUR. The lesion was removed by TUR in June 2012. Pathological examination showed an inflammatory response with small granulomatous lesions. The specimen stained positive for TB DNA-RTPCR. Mycobacterium bovis was detected from the bladder specimen and urine. He was administered antituberculous agents, isoniazid 300 mg and rifampicin 450 mg daily, for 3 months. He is well with no recurrence of bladder carcinoma and urinary cultures were negative during the follow-up.

Perioperative Nephrectomy Outcomes for Patients with Liver Disease: Implications for Liver Transplant Candidates.

OBJECTIVE: To improve the management of cirrhotic patients diagnosed with new renal masses, we used a nationally representative cohort to assess the perioperative outcomes of nephrectomy in the setting of liver disease. The incidences of liver disease and renal masses are both rising in the US. Delaying liver transplantation to address other health concerns may have life changing consequences in these patients, thus these results help to guide treatment decisions at this critical junction in care. METHODS: A retrospective study of the 2016-2019 Nationwide Readmissions Database was performed in adults undergoing nephrectomy for non-emergent indications. Outcomes were compared between 3 cohorts: no chronic liver disease (no CLD), chronic liver disease (CLD), and decompensated cirrhosis (DC). Mixed regression models were used to evaluate the association between CLD and DC with outcomes of interest including morbidity, mortality, readmission rates, non-home discharges, length of stay, and costs. RESULTS: A total of 183,362 patients were evaluated. The mortality rate in the DC cohort (7%) was higher than with CLD (0.4%) and no CLD (0.3%), (P <.001). DC was associated with higher mortality (OR 8.29, 95% CI 4.07 - 16.88), postoperative bleeding requiring transfusion (OR 5.55, 95% CI 3.72 - 8.26), non-home discharge (OR 5.12, 95% CI 3.16 - 8.30) and readmission (OR 1.79, 95% CI 1.09 - 2.94) compared to no CLD. The DC cohort had the greatest length of stay and costs. CONCLUSION: Patients undergoing nephrectomy with DC have increased morbidity, mortality, readmission rates, non-home discharges, LOS and costs. Alternative management strategies may be considered in these patients.

Transcriptomic recurrence score improves recurrence prediction for surgically treated patients with intermediate-risk clear cell kidney cancer.

BACKGROUND: Risk stratification of kidney cancer patients after nephrectomy may tailor surveillance intensity and selection for adjuvant therapy. Transcriptomic approaches are effective in predicting recurrence, but whether they add value to clinicopathologic models remains unclear. METHODS: Data from patients with clear cell renal cell carcinoma (ccRCC) was downloaded from The Cancer Genome Atlas. Clinicopathologic variables were used to calculate SSIGN (stage, size, grade, and necrosis) scores. The 16 gene recurrence score (RS) signature was generated using RNA-seq data. Transcriptomic risk groups were calculated using the original thresholds. SSIGN groups were divided into low, intermediate, and high risk. Disease-free status was the primary endpoint assessed. RESULTS: SSIGN and RS were calculated for 428 patients with non-metastatic ccRCC. SSIGN low-, intermediate-, and high-risk groups demonstrated 2.7%, 15.2%, and 27.5%, 3-year recurrence risk, respectively. On multivariable analysis, the RS was associated with disease-free status (sub-distribution hazard ratio (sHR) 1.43 per 25 RS [95% CI (1.00-1.43)], p = 0.05). By risk groups, RS further risk stratified the SSIGN intermediate-risk group (sHR 2.22 [95% CI 1.10-4.50], p = 0.03). SSIGN intermediate-risk patients with low and high RS had a 3-year recurrence rate of 8.0% and 25.2%, respectively. Within this risk group, the area under the curve (AUC) at 3 years was 0.69 for SSIGN, 0.74 for RS, and 0.78 for their combination. CONCLUSIONS: Transcriptomic recurrence scores improve risk prediction even when controlling for clinicopathologic factors. Utility may be best suited for intermediate-risk patients who have heterogeneous outcomes and further refinement for clinical utility is warranted.

Comparative analyses define differences between BHD-associated renal tumour and sporadic chromophobe renal cell carcinoma.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome, caused by germline alteration of folliculin (FLCN) gene, develops hybrid oncocytic/chromophobe tumour (HOCT) and chromophobe renal cell carcinoma (ChRCC), whereas sporadic ChRCC does not harbor FLCN alteration. To date, molecular characteristics of these similar histological types of tumours have been incompletely elucidated. METHODS: To elucidate renal tumourigenesis of BHD-associated renal tumours and sporadic renal tumours, we conducted whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) of sixteen BHD-associated renal tumours from nine unrelated BHD patients, twenty-one sporadic ChRCCs and seven sporadic oncocytomas. We then compared somatic mutation profiles with FLCN variants and RNA expression profiles between BHD-associated renal tumours and sporadic renal tumours. FINDINGS: RNA-seq analysis revealed that BHD-associated renal tumours and sporadic renal tumours have totally different expression profiles. Sporadic ChRCCs were clustered into two distinct clusters characterized by L1CAM and FOXI1 expressions, molecular markers for renal tubule subclasses. Increased mitochondrial DNA (mtDNA) copy number with fewer variants was observed in BHD-associated renal tumours compared to sporadic ChRCCs. Cell-of-origin analysis using WGS data demonstrated that BHD-associated renal tumours and sporadic ChRCCs may arise from different cells of origin and second hit FLCN alterations may occur in early third decade of life in BHD patients. INTERPRETATION: These data further our understanding of renal tumourigenesis of these two different types of renal tumours with similar histology. FUNDING: This study was supported by JSPS KAKENHI Grants, RIKEN internal grant, and the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research.

Objective assessment of laparoscopic targeting skills using a Short-Time Power of Difference (STPOD) method.

PURPOSE: To ensure that the use of surgical training tools results in improvement of surgical skills, it is necessary to be able to measure and assess surgeons' skills. We established the Short-Time Power of Difference (STPOD) method as an evaluation tool for evaluating targeting technique. The STPOD method evaluates the distance from the actual movement of the forceps to the shortest linear path between two points in a short time period. We examined the effectiveness of the STPOD method as a new forceps kinematic analysis. METHODS: Six residents were categorized as novices and six urologists as experts. All participants performed box trainer training and LapPASS® Simulator training. During the procedure, objective scores (time, distance, and STPOD) were recorded. STPOD (Power) evaluated motion smoothness and STPOD (Stop) evaluated the stop time of the forceps. RESULTS: STPOD (Stop) on the right side of the experts was significantly lower than that of the novices in the box trainer. Furthermore, there were significant differences in the distances of left side and STPOD (Power) between the experts and the novices in the simulator. In the correlation of parameters between the box trainer and the simulator, time showed the strongest correlation, STPOD (Power) and distance showed a mild correlation. CONCLUSION: We showed the construct validity of STPOD (Power) and STPOD (Stop) using both the box trainer and the simulator. This method is a good evaluation tool for assessing a physician's skill; however, there are much more complex motions that are performed in actual surgery. Future studies are needed to focus on evaluation in an environment closer to actual surgery and comparing with other existing methods.

Training on a virtual reality laparoscopic simulator improves performance of live laparoscopic surgery.

INTRODUCTION: To determine whether training laparoscopic nephrectomy (LN) with a virtual reality (VR) simulator improves the performance of porcine LN. METHODS: Twelve urological residents were assigned to two groups: a training and a non-training group. All participants performed baseline assessments of LN skills and time on the LapPASS® simulator. The training group received preoperative LapPASS® training. Both groups then performed LN using a porcine model. The operations were videotaped and evaluated using the Global Operative Assessment of Laparoscopic Skills (GOALS) system. After porcine LN, the training group performed a final LN with the LapPASS® simulator. RESULTS: There was no significant difference in the operation time required for porcine LN. There were no significant differences in the total A (autonomy), B (bimanual dexterity), D (depth perception), or T (tissue handling) GOALS scores. However, the total E (efficiency) score in the training group was higher than that in the non-training group (P = .030). The final LN score with LapPASS® was significantly higher than the baseline (P = .004). CONCLUSIONS: The results of this study demonstrated that VR LN training improved performance in an actual operation. VR-based procedural simulation could become a vital part of the laparoscopic training program for residents.

Understanding the Impact of Belzutifan on Treatment Strategies for Patients with VHL.

Belzutifan was recently approved for the management of Von Hippel-Lindau disease (VHL). Given the morbidity of recurrent treatment, systemic therapy to reduce or eliminate the need for surgery has been long-awaited. Herein, we sought to gain insight about future utilization by surveying VHL kidney cancer experts in the United States. A survey developed by members of the VHL Alliance (VHLA) Clinical Advisory Council was distributed to kidney cancer providers at VHLA and National Comprehensive Cancer Network (NCCN) centers. Surveys were administered on a secure web-based platform. A total of 60 respondents from 29 institutions participated. Urologists (50%) and medical oncologists (43%) represented the majority of participants. The majority (98%) of respondents anticipated that belzutifan's approval would significantly change the current treatment landscape. Most reported that therapy should be continuous (76%). There was a difference in willingness to prescribe belzutifan by specialty (38% of urologists vs 91% of medical oncologists (P = 0.02)). In individuals with renal tumors <3 cm, 36% would still recommend surveillance, while 36% would initiate belzutifan to prevent growth. In those with multifocal renal lesions and growth of a solitary tumor on belzutifan, 50% would proceed with only treatment of that site. In conclusion, VHL kidney cancer specialists anticipate a paradigm shift with the approval of belzutifan. Provider roles may change with movement away from surgical management. Opinions on treatment indications, such as when to initiate therapy and how to best salvage, vary widely and therefore collaborative efforts among experts may assist in the development of new clinical guidelines.