Profiling Fibroblast Growth Factor Receptor 3 Expression Based on the Immune Microenvironment in Upper Tract Urothelial Carcinoma.

BACKGROUND: Although several studies have shown favorable outcomes in upper tract urothelial carcinoma (UTUC) with fibroblast growth factor receptor 3 (FGFR3) mutations and/or expression, the relationship between immune cell markers and FGFR3 expression remains unknown. OBJECTIVE: To clarify the FGFR3-based immune microenvironment and investigate biomarkers to predict the treatment response to pembrolizumab (Pem) in patients with UTUC. DESIGN, SETTING, AND PARTICIPANTS: We conducted immunohistochemical staining in 214 patients with UTUC. The expression levels of FGFR3, CD4, CD8, CD68, CD163, CD204, and programmed cell death ligand 1 (PD-L1) were examined. INTERVENTION: All UTUC patients underwent radical nephroureterectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the relationship between these immune markers and patient prognosis. RESULTS AND LIMITATIONS: A total of 109 (50.9%) patients showed high FGFR3 expressions and a favorable prognosis compared with the remaining patients. Among the six immune markers, CD8 high expression was an independent favorable factor, whereas CD204 expression was an independent prognostic factor for cancer death. From the FGFR3-based immune clustering, three immune clusters were identified. Cluster A showed low FGFR3 with tumor-associated macrophage-rich components (CD204+) followed by a poor prognosis due to a poor response to Pem. Cluster B showed low FGFR3 with an immune hot component (CD8+), followed by the most favorable prognosis owing to a good response to Pem. Cluster C showed high FGFR3 expression but an immune cold component, followed by a favorable prognosis due to the high FGFR3 expression, but a poor response was confirmed with Pem. CONCLUSIONS: Although most patients exhibit a poor response to Pem, individuals with low FGFR3 expression and immune hot status may benefit clinically from Pem treatment. PATIENT SUMMARY: We conducted immunohistochemical staining to evaluate fibroblast growth factor receptor 3 (FGFR3)-related immune microenvironment by evaluating the expressions of CD4, CD8, CD68, CD163, CD204, and PD-L1 in 214 upper tract urothelial carcinoma patients. We identified three distinct immune clusters based on FGFR3 expressions and found that patients with a low FGFR3 expression but immune hot status received the maximum benefit from an immune checkpoint inhibitor.

Site-Specific Differences in PD-1 Blockade Success and Biomarkers in Urothelial Carcinoma Treated with Pembrolizumab.

INTRODUCTION: Since tumors in different human organs may have different tumor microenvironments, we evaluate time-course changes in all tumor locations after pembrolizumab treatment in urothelial carcinoma (UC) to examine the differences in efficacy of pembrolizumab per organ. Further, we uncover the usefulness of inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), CRP, and kinetics of these markers to predict pembrolizumab success and relation to overall survival (OS) in UC. PATIENTS AND METHODS: A total of 115 cancerous lesions from 44 UC patients were measurable based on RECIST 1.1 criteria. The serum CRP and NLR levels were measured at baseline prior to pembrolizumab treatment and at least every 3 weeks just prior to pembrolizumab administration. RESULTS: Site-specific success (ie, patients with CR/PR/SD by RESIST 1.1) rates for pembrolizumab treatments were as follows: primary tumors: 67%, lymph node: 70%, lung: 44%, liver: 40%, and peritoneal metastasis: 56%. Focusing on the major metastasis sites, lymph nodes and lungs, we examined the relationships between NLR, CRP, or that kinetics and pembrolizumab success. In lymph nodes, both early NLR kinetics (P = .005) and CRP kinetics (P = .035) was a predictor for pembrolizumab success. On the other hand, none of 4 was not in lung metastases. Regarding to the mortality, the multivariate analysis revealed that early NLR kinetics was a prognostic biomarker for OS among the 4, independent of performance status and liver metastasis. CONCLUSION: We revealed that site-specific pembrolizumab success in UC. Early NLR kinetics was a predictor for lymph node pembrolizumab success and OS in our cohorts.

A low subcutaneous fat mass is a risk factor for the development of inguinal hernia after radical prostatectomy.

PURPOSE: Inguinal hernia (IH) after radical prostatectomy (RP) is a complication that impairs quality of life; however, the factors contributing to IH after RP remain unclear. Therefore, we herein attempted to identify the factors responsible for the development of IH after RP. METHODS: We reviewed 622 patients who underwent laparoscopic or robot-assisted laparoscopic RP at our hospital between December 2011 and April 2020. The total fat area and visceral fat area were calculated at the level of the umbilicus using computed tomography, and the subcutaneous fat area (SFA) was calculated by subtracting the visceral fat area from the total fat area. The psoas muscle area was measured at the third lumbar vertebrae level using computed tomography to calculate the psoas muscle mass index, which is used in sarcopenia as an index of muscle mass. We investigated the risk factors for IH after laparoscopic or robot-assisted laparoscopic RP. RESULTS: IH developed in 88 patients (16.7%). Fifty-seven of these patients underwent hernia repair at our hospital, and 56 (98.2%) had indirect hernias. A multivariate analysis identified SFA (odds ratios: 0.383, p < 0.001) as an independent predictor for the development of IH. Two-year IH-free survival rates were 77.3% in the small SFA group (SFA < 123 cm2) and 88.7% in the large SFA group (SFA ≥ 123 cm2) (p < 0.001). CONCLUSION: Subcutaneous fat was associated with the development of IH, particularly indirect IH, after laparoscopic or robot-assisted laparoscopic RP. An indirect IH prevention technique needs to be considered, particularly for patients with less subcutaneous fat.

Does neoadjuvant chemotherapy have therapeutic benefit for node-positive upper tract urothelial carcinoma? Results of a multi-center cohort study.

OBJECTIVE: The indications of neoadjuvant chemotherapy (NAC) for lymph node-positive upper tract urothelial carcinoma (UTUC) have not been investigated regarding improved survival outcomes. Our specific aim was to compare the clinical outcomes of clinically node-positive UTUC patients who were treated by NAC followed by radical nephroureterectomy (RNU) or upfront RNU followed by adjuvant chemotherapy (AC). MATERIALS AND METHODS: Among 966 UTUC patients, we identified 89 with clinical nodal involvement who received either NAC before RNU nor AC after upfront RNU. Cox proportional hazard models were employed to evaluate the impact of chemotherapy modality on the oncological outcomes. RESULTS: Of the patient cohort, 36 (40.4%) received NAC followed by RNU, whereas 53 (59.6%) underwent RNU followed by AC. Multivariate analysis revealed that tumor size ≥3 cm, clinical T4, and gemcitabine and cisplatin regimen were independent risk factors for disease recurrence, whereas NAC followed by RNU was an independent factor for favorable RFS. Furthermore, regarding cancer-specific survival (CSS), NAC followed by RNU remained an independent factor for favorable CSS. According to Kaplan-Meier analysis, the 1-year and 2-year RFS were 67.9% and 47.0%, respectively, in the NAC+RNU group, which were significantly higher than those in the RNU+AC group (43.9% and 24.6%, respectively, P = 0.006). Moreover, the 1-year and 2-year CSS were 80.5% and 64.2%, respectively, in the NAC+RNU group, which were higher than those in the RNU+AC group (68.6% and 48.2%, respectively, P = 0.016). CONCLUSION: For node-positive UTUC patients, NAC followed by RNU was more clinically beneficial than RNU followed by AC.

The clinicopathological characteristics of muscle-invasive bladder recurrence in upper tract urothelial carcinoma.

This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle-invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa-4N0-2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2-4N0-2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer-specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non-MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC.

Hand-assisted laparoscopic ileal ureter substitution for ureteral obstruction after right ureteral rupture: A case report.

Iatrogenic ureteral rupture is a serious complication. In the past, ileal ureter substitution was performed with open, laparoscopic, and robot-assisted procedure; however, there are problems with operation invasiveness and difficulty. We present a 72-year-old female whose ureter was completely injured at the ureteropelvic junction and torn longitudinally in full length at the time of transurethral lithotripsy. Although initially she had nephrostomy, we were able to internalize with hand-assisted laparoscopic ileal ureter substitution for obstruction over the full length of the ureter.

A Japanese patient with ductal carcinoma of the prostate carrying an adenomatosis polyposis coli gene mutation: a case report.

BACKGROUND: Ductal carcinoma of the prostate is a histological subtype with a higher mortality than acinar adenocarcinoma. The number of cases is small and there are no treatment guidelines. We believe that this is the first report of ductal carcinoma of the prostate with an adenomatosis polyposis coli (APC) gene mutation in Japan. CASE PRESENTATION: An 85-year-old man presented with gross hematuria, and a papillary tumor in the prostatic urethra that was diagnosed as ductal carcinoma of the prostate following transurethral resection. Genetic analysis found an APC mutation with loss of heterozygosity. Immunostaining revealed focal nuclear translocation of ß-catenin. APC mutations associated with loss of ß-catenin degradation in the Wnt signaling pathway and result in over accumulation of ß-catenin are thought to increase mortality. In this patient, ß-catenin migrated into tumor cell nuclei. CONCLUSION: To the best of our knowledge, this is the first report of ductal carcinoma of the prostate with an APC mutation in Japan. The development of a therapeutic Wnt inhibitor is discussed.

A Novel Risk-based Approach Simulating Oncological Surveillance After Radical Nephroureterectomy in Patients with Upper Tract Urothelial Carcinoma.

BACKGROUND: The current guideline lacks evidence for creating individualized surveillance strategies for upper tract urothelial carcinoma (UTUC) patients after radical nephroureterectomy (RNU). OBJECTIVE: To create a novel risk model and to simulate individualized surveillance duration that dynamically illustrates the changing risk relationship of UTUC-related death and non-UTUC death, considering the impact of cigarette smoking. DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study comprised 714 pTa-T4N0M0 UTUC patients, with a median follow-up duration of 65mo. There were 279 (39.1%) nonsmokers, 260 (36.4%) current smokers, and 175 (24.5%) ex-smokers. INTERVENTION: All patients underwent RNU. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The risks of UTUC death and non-UTUC death over time were estimated using parametric models for time to failure with Weibull distributions. Age-specific, stage-specific, and smoking status-specific surveillance durations were simulated based upon Weibull estimates. RESULTS AND LIMITATIONS: The hazard rate (HR) of non-UTUC death gradually increased over time in all age groups regardless of the smoking status, whereas that of UTUC-related death decreased markedly according to the pathological T (pT) stage and was affected by the smoking status. Among current smokers, the baseline HR of UTUC-related death in pT3/4 was higher than that of pT ≤2 and remained high even 10yr after RNU. Among heavy smokers, the HR of UTUC-related death in all pT stages was highest at baseline and remained high after RNU, compared with nonsmokers, current smokers, or ex-smokers. We simulated specific time points when the risk of non-UTUC death was greater than that of UTUC-related death. Among patients ≥80yr of with pT3N0M0, the risk of non-UTUC death was greater than that of UTUC-related death 1yr after RNU in nonsmokers, but 7yr for heavy smokers. CONCLUSIONS: Our result revealed that smokers bear a long-term risk burden of UTUC-related death more than the risk of non-UTUC death. For UTUC smokers, longer-term surveillance duration is recommended even in elderly stage. PATIENT SUMMARY: In the present study, we evaluated the risk transition of upper tract urothelial carcinoma (UTUC)-related death and non-cancer-related death over time. We found that smoking weighed a huge impact upon UTUC-related death compared with death from other cause, and therefore, we created a more individualized surveillance duration model.

Long-Term Oncologic Outcomes of Laparoscopic Versus Open Radical Nephroureterectomy for Patients with T3N0M0 Upper Tract Urothelial Carcinoma: A Multicenter Cohort Study with Adjustment by Propensity Score Matching.

BACKGROUND: This study aimed to investigate the long-term oncologic outcomes of laparoscopic radical nephroureterectomy (LRNU) and open radical nephroureterectomy (ORNU) for patients with clinical and pathologic T3N0M0 upper tract urothelial carcinoma (UTUC). METHODS: Among 375 UTUC patients who underwent radical nephroureterectomy, this study identified 144 pT3N0M0 patients as cohort 1 after propensity score (PS) matching. Among 399 UTUC patients, the study identified 110 cT3N0M0 patients as cohort 2 after PS matching. Oncologic outcomes such as intravesical recurrence-free survival (IVRFS) and cancer-specific survival (CSS) were assessed by multivariate Cox's regression analysis. RESULTS: Cohort 1 of pT3N0M0 UTUC had 3-year CSS and IVRFS rates of 67.9 and 52.7%, respectively, in the LRNU group, which were significantly lower than in the ORNU group (81.4%, p = 0.039 and 71.6%, p = 0.046). The multivariate Cox's regression analysis identified the type of surgical approach (LRNU vs. ORNU) as one of the independent prognostic factors for CSS (hazard rate [HR], 1.88, p = 0.043) and IVRFS (HR, 1.75, p = 0.049). Cohort 2 of cT3N0M0 UTUC had 3-year CSS and IVRFS rates of 48.5 and 41.4%, respectively, in the LRNU group, which were significantly lower than in the ORNU group (65.8%, p = 0.049 and 67.2%, p = 0.047), and the type of surgical approach (LRNU vs. ORNU) remained as one of the independent prognostic factors for CSS and IVRFS. CONCLUSIONS: Based on clinical and pathologic T3N0M0 UTUC populations after PS adjustments, LRNU resulted in poorer CSS and IVRFS than ORNU.