Evaluating RB1 and p53 as diagnostic markers in treatment-related neuroendocrine prostate cancer through immunohistochemistry and genomic analysis of RB1 and TP53.

BACKGROUND: The diagnosis of treatment-related neuroendocrine prostate cancer (t-NEPC) often involves a pathological assessment and immunohistochemistry (IHC) for neuroendocrine markers. Genomic alterations in RB1 and TP53 are frequently observed in NEPC and are believed to play a crucial role in the transformation of adenocarcinoma to NEPC. In this study, we examined the clinicopathologic, immunohistochemical, and genetic features of patients with t-NEPC to better understand their prognosis and diagnostic utility. METHODS: This retrospective study reviewed the records of patients diagnosed with t-NEPC at Kobe University Hospital between October 2018 and December 2022. Clinical data, including age, serum neuroendocrine marker levels, and treatment history, were collected. IHC was performed for conventional neuroendocrine markers (synaptophysin, chromogranin A, and CD56) and RB1 and p53 expression. Next-generation sequencing (NGS) was conducted using FoundationOne® CDx to identify mutations in RB1 and TP53. RESULTS: This study included 20 patients with t-NEPC. The median time from ADT initiation to development was 42.8 months. IHC revealed RB1 loss in 75% of cases and p53 abnormalities in 75% of cases. NGS identified RB1 mutations in 55% and TP53 mutations in 75% of cases. The concordance between NGS and IHC results was high, with 70% (14/20) agreement for RB1/RB1 and 80% (16/20) for p53/TP53. The immunostaining and genomic analysis of RB1/RB1 and p53/TP53 showed abnormal findings for the four negative cases for conventional neuroendocrine markers. CONCLUSIONS: This study indicated high concordance between IHC and NGS findings for RB1/RB1 and p53/TP53 in t-NEPC. We provide a comprehensive benchmark of NGS performance compared with IHC, and these findings may help increase the diagnostic sensitivity of t-NEPC.

Prognostic Importance of Lymphovascular Invasion for Specific Subgroup of Patients with Prostate Cancer After Robot-Assisted Radical Prostatectomy (The MSUG94 Group).

OBJECTIVE: This study aimed to investigate whether lymphovascular invasion (LVI) was associated with oncological outcomes in patients with prostate cancer (PCa) undergoing robotic-assisted radical prostatectomy (RARP). METHODS: This retrospective multicenter cohort study was conducted on 3195 patients with PCa who underwent RARP in nine institutions in Japan. The primary endpoints were the associations between biochemical recurrence (BCR) and LVI and between BCR and clinicopathological covariates, while the secondary endpoints were the association between LVI and the site of clinical recurrence and metastasis-free survival (MFS). RESULTS: In total, 2608 patients met the inclusion criteria. At the end of the follow-up period, 311 patients (11.9%) were diagnosed with BCR and none died of PCa. In patients with pathological stage T2 (pT2) + negative resection margins (RM-), and pT3+ positive RM (RM+), LVI significantly worsened BCR-free survival (BRFS). For patients with PCa who had pT3 and RM+, the 2-year BRFS rate in those with LVI was significantly worse than in those without LVI. Patients with LVI had significantly worse MFS than those without LVI with respect to pT3, RM+, and pathological Gleason grade (pGG). In multivariate analysis, LVI was significantly associated with BRFS in patients with pT3 PCa, and with worse MFS in PCa patients with pT3, RM+, and pGG ≥ 4. CONCLUSIONS: LVI was an independent prognostic factor for recurrence and metastasis after RARP, particularly in patients with pT3 and RM+ PCa. Locally advanced PCa with positive LVI and RM+ requires careful follow-up because of the high likelihood of recurrence.

Prognostic factors among patients with pathological Grade Group 5 prostate cancer based on robot-associated radical prostatectomy specimens from a large Japanese cohort (MSUG94).

PURPOSE: There are no definitive prognostic factors for patients with pathological Grade Group 5 (pGG 5) prostate cancer (PCa) undergoing robot-associated radical prostatectomy (RARP). This study aimed to explore the prognostic factors among patients with pGG 5 PCa in a large Japanese cohort (MSUG94). METHODS: This retrospective, multi-institutional cohort study was conducted between 2012 and 2021 at ten centers in Japan and included 3195 patients. Patients with clinically metastatic PCa (cN1 or cM1) and those receiving neoadjuvant and/or adjuvant therapy were excluded. Finally, 217 patients with pGG5 PCa were analyzed. RESULTS: The median follow-up period was 28.0 months. The 3- and 5-year biochemical recurrence-free survival (BCRFS) rates of the overall population were 66.1% and 57.7%, respectively. The optimal threshold value (47.2%) for the percentage of positive cancer cores (PPCC) with any GG by systematic biopsy was chosen based on receiver operating characteristic curve analysis. Univariate analysis revealed that the prostate-specific antigen level at diagnosis, pT, pN, positive surgical margins (PSMs), lymphovascular invasion, and PPCC were independent prognostic factors for BCRFS. A multivariate analysis revealed that PSMs and PPCC were independent prognostic factors for BCRFS. Using these two predictors, we stratified BCRFS, metastasis-free survival (MFS), and castration-resistant PCa-free survival (CRPC-FS) among patients with pGG 5 PCa. CONCLUSION: The combination of PSMs and PPCC may be an important predictor of BCRFS, MFS, and CRPC-FS in patients with pGG 5 PCa undergoing RARP.

Temporal declines in bone mineral density and trabecular bone score during androgen deprivation therapy.

INTRODUCTION: The trabecular bone score (TBS) has emerged as a convenient measure for assessing the microstructure of trabecular bone in the second through fourth lumbar vertebrae (L2-4) and can be conducted concurrently with bone mineral density (BMD) assessment. This study was performed to evaluate changes in BMD and the TBS during ADT for prostate cancer. MATERIALS AND METHODS: Consecutive patients who had prostate cancer without bone metastases at Kobe University Hospital were studied from March 2020 to December 2021. BMD and TBS were measured every 6 months from the start of treatment using Hologic Horizon devices (Hologic, Inc., Marlborough, MA, USA). RESULTS: Thirty-four patients were followed for 2 years. Significant declines in BMD (-3.8% for femoral neck, -4.2% for total hip, and -6.1% for lumbar spine) and TBS (-16.6%) were noted after 2 years of ADT. Correlation analyses revealed a weak correlation between lumbar spine BMD and TBS at ADT initiation, but this correlation strengthened after 2 years. The multiple regression analysis results suggested that the rate of BMD loss may be slower in patients with a preserved pretreatment TBS. CONCLUSION: In patients without bone metastases undergoing ADT for prostate cancer, notable decreases were found in both BMD and TBS over a 2-year treatment period. Factors influencing the TBS decline remain unclear; however, patients with a lower pretreatment TBS exhibited a more rapid decline in BMD.

Adrenalectomy for pheochromocytoma: Surgical outcomes and preoperative risk factors for hemodynamic instability.

BACKGROUND: Surgical resection for pheochromocytoma (PCC) is still challenging. This study assessed the perioperative outcomes of adrenalectomy for PCC and investigated the risk factors for intraoperative hemodynamic instability (HI). METHODS: This retrospective study included 571 patients with adrenal tumors who underwent adrenalectomy at Kobe University Hospital and other related hospitals between April 2008 and October 2023. The perioperative outcomes of laparoscopic adrenalectomy were compared between PCC (n = 92) and non-PCC (n = 464) groups. In addition, we investigated several potential risk factors for intraoperative HI in patients with PCC (n = 107; open, n = 11; laparoscopic, n = 92; robot-assisted, n = 4). RESULTS: While patients with PCC had a significantly larger amount of blood loss in comparison to those with non-PCC (mean, 70 and 30 mL, respectively; p = 0.004), no significant difference was observed in the rate of perioperative grade ≥III complications (1.1% vs. 0.6%; p = 0.516), and no perioperative mortality was observed in either group. A tumor size of ≥40 mm, with preoperative hypertension and urinary metanephrines at a level ≥3 times the upper limit of the normal value, were found to be significant predictors of HI, with odds ratios of 2.74 (p = 0.025), 3.91 (p = 0.005), and 3.83 (p = 0.004), respectively. CONCLUSIONS: Our data suggest that laparoscopic adrenalectomy for PCC may be as safe as that for other types of adrenal tumors and that large tumors and hormonally active disease may be risk factors for intraoperative HI. The optimal perioperative management for PCC with these risk factors should be established.

Effects of modifying hinotori™ surgical robot system on perioperative outcome of robot-assisted radical prostatectomy.

OBJECTIVES: One of the main advantages of the hinotori™ surgical robot system (HSRS) is that it can be easily adjusted. This study aimed to clarify the effects of modifying the HSRS on the perioperative outcomes of robotic-assisted radical prostatectomy (RARP). METHODS: Overall, 158 cases of RARP using the HSRS were classified into three groups based on the modification to the system: group A (no modification, 70 cases), group B (addition of the ability to switch between two types of scopes and to adjust the arm base tilt back and forth, left and right, 42 cases), and group C (reduction of arm floating sensation, mitigation of emergency stop during arm collision, and addition of clutch function via hand switch in addition to foot pedal, 46 cases). The perioperative outcomes of each group were compared. RESULTS: The median of operation time, cockpit time, and cockpit time excluding the time required for lymph node dissection of group C were 223, 146, and 135 min, respectively, where are significantly shorter than those of group A (308, 228, and 208 min, p < 0.0001, respectively) and group B (319, 241, and 214 min, p < 0.0001, respectively). There was no significant difference in the rate of positive margin rates and the pad-free rate before the first follow-up visit among these three groups. The complication rates in groups A, B, and C were 11.4%, 9.4%, and 8.4% (Clavien-Dindo grades I-II), and 4.3%, 2.4%, and 0% (grade III), respectively. CONCLUSIONS: The modifications to the HSRS have enabled smoother surgical procedures for RARP.

Nomogram Predicting Locally Advanced Prostate Cancer in Patients with Clinically Organ-Confined Disease Who Underwent Robot-Assisted Radical Prostatectomy: A Retrospective Multicenter Cohort Study in Japan (The MSUG94 Group).

PURPOSE: We created a clinically applicable nomogram to predict locally advanced prostate cancer using preoperative parameters and performed external validation using an external independent validation cohort. PATIENTS AND METHODS: From a retrospective multicenter cohort study of 3622 Japanese patients with prostate cancer who underwent robot-assisted radical prostatectomy at ten institutions, the patients were divided into two groups (MSUG cohort and validation cohort). Locally advanced prostate cancer was defined as pathological T stage ≥ 3a. A multivariable logistic regression model was used to identify factors strongly associated with locally advanced prostate cancer. Bootstrap area under the curve was calculated to assess the internal validity of the prediction model. A nomogram was created as a practical application of the prediction model, and a web application was released to predict the probability of locally advanced prostate cancer. RESULTS: A total of 2530 and 427 patients in the MSUG and validation cohorts, respectively, met the criteria for this study. On multivariable analysis, initial prostate-specific antigen, prostate volume, number of cancer-positive and cancer-negative biopsy cores, biopsy grade group, and clinical T stage were independent predictors of locally advanced prostate cancer. The nomogram predicting locally advanced prostate cancer was demonstrated (area under the curve 0.72). Using a nomogram cutoff of 0.26, 464 of 1162 patients (39.9%) could be correctly diagnosed with pT3, and 2311 of 2524 patients (91.6%) could avoid underdiagnosis. CONCLUSIONS: We developed a clinically applicable nomogram with external validation to predict the probability of locally advanced prostate cancer in patients undergoing robot-assisted radical prostatectomy.

ANXA10 Expression Is Inversely Associated with Tumor Stage, Grade, and TP53 Expression in Upper and Lower Urothelial Carcinoma.

INTRODUCTION: Urothelial carcinoma (UC) is a common type of malignant disease, but little is known about the diagnostic and prognostic markers of upper urinary tract urothelial cancer (UTUC) because of its rarity. To clarify the significance of ANXA10 in UTUC, we studied ANXA10 expression with immunohistochemistry (IHC). METHODS: The expression of ANXA10 was analyzed in the upper and lower urinary tract of UC by IHC in combination with The Cancer Genome Atlas (TCGA) data analysis. The association between ANXA10 expression and representative cancer-related molecules was also evaluated. RESULTS: ANXA10 expression was weak in normal upper tract urothelium but was positive in 39/117 (33%) UTUCs. ANXA10 was more frequently positive in tumors with pure UC (36%, p < 0.05), papillary morphology (50%, p < 0.01), low grade (G1/2: 57%, p < 0.01), and pTa/is/1 stage (55%, p < 0.01) than in those with histological variants (0%), nodular morphology (9%), G3 (16%), and pT2/3/4 (13%), respectively. ANXA10-positive patients showed better cancer-specific survival and progression-free survival than ANXA10-negative patients (p < 0.05). IHC showed that ANXA10 positivity was detected more in cases with the low expression of TP53 (p < 0.01) and Ki-67 labeling index <20% (p < 0.01). In TCGA dataset of muscle-invasive bladder cancer, higher ANXA10 expression correlated with papillary morphology, lower grade/stage, luminal papillary subtype, wild-type TP53, and FGFR3 gene mutation. CONCLUSION: We revealed that ANXA10 expression was increased during carcinogenesis and was observed more frequently in papillary UC of lower grade and stage. However, its expression decreased as cancer progressed. Therefore, the ANXA10 expression in UTUC might be clinically useful for decision-making.

Prognostic differences among the positive surgical margin locations following robot-assisted radical prostatectomy in a large Japanese cohort (the MSUG94 group).

BACKGROUND: To investigate whether subgroups of prostate cancer patients, stratified by positive surgical margin locations, have different oncological outcomes following robot-assisted radical prostatectomy. METHODS: A retrospective multicenter cohort study in prostate cancer patients undergoing robot-assisted radical prostatectomy was conducted at 10 institutions in Japan. Pre- and post-operative outcomes were collected from enrolled patients. Biochemical recurrence and clinical and pathological variables were evaluated among subgroups with different positive surgical margin locations. RESULTS: A total of 3195 patients enrolled in this study. Data from 2667 patients (70.1% [N = 1869] with negative surgical margins and 29.9% [N = 798] with positive surgical margins based on robot-assisted radical prostatectomy specimens) were analyzed. The median follow-up period was 25.0 months. The numbers of patients with apex-only, middle-only, bladder-neck-only, seminal-vesicle-only and multifocal positive surgical margins were 401, 175, 159, 31 and 32, respectively. In the multivariate analysis, PSA level at surgery, pathological Gleason score based on robot-assisted radical prostatectomy specimens, pathological T stage, pathological N stage and surgical margin status were independent risk factors significantly associated with biochemical recurrence-free survival. Patients undergoing robot-assisted radical prostatectomy with multifocal positive surgical margins and seminal-vesicle-only positive surgical margins were associated with worse biochemical recurrence-free survival than those with apex-only, middle-only and bladder-neck-only positive surgical margins. Patients undergoing robot-assisted radical prostatectomy with apex-only positive surgical margins, the most frequent positive surgical margin location, were associated with more favorable biochemical recurrence-free survival that those with middle-only and bladder-neck-only positive surgical margins. The study limitations included the lack of central pathological specimen evaluation. CONCLUSIONS: Although positive surgical margin at any locations is a biochemical recurrence risk factor after robot-assisted radical prostatectomy, positive surgical margin location status should be considered to accurately stratify the biochemical recurrence risk after robot-assisted radical prostatectomy.

Association of hospital volume with perioperative and oncological outcomes of robot-assisted laparoscopic radical prostatectomy: a retrospective multicenter cohort study.

BACKGROUND: This retrospective multicenter cohort study investigated the association of hospital volume with perioperative and oncological outcomes in patients treated with robot-assisted radical prostatectomy (RARP). METHODS: We collected the clinical data of patients who underwent RARP at eight institutions in Japan between September 2012 and August 2021. The patients were divided into two groups based on the treatment site-high- and non-high-volume hospitals. We defined a high-volume hospital as one where RARP was performed for more than 100 cases per year. RESULTS: After excluding patients who received neoadjuvant therapy, a total of 2753 patients were included in this study. In the high-volume hospital group, console time and estimated blood loss were significantly (p < 0.001) lower than that of the non-high-volume hospital group. However, the continence rate at 3 months after RARP, positive surgical margins, and prostate-specific antigen (PSA)-relapse-free survival showed no significant differences between the two groups. Furthermore, the console time was significantly shorter after 100 cases in the non-high-volume hospital group but not in the high-volume hospital group. CONCLUSIONS: A higher hospital volume was significantly associated with shorter console time and less estimated blood loss. However, oncological outcomes and early continence recovery appear to be comparable regardless of the hospital volume in Japan.

Impact of low and high body mass index on predicting therapeutic efficacy and prognosis in patients with metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitors.

OBJECTIVE: To evaluate the significance of both low and high body mass index (BMI) as a biomarker in first-line tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC). METHODS: The oncological outcome of 235 patients with mRCC treated with TKI from 2007 to 2018 was reviewed retrospectively. All patients received first-line TKI as therapy. We analyzed the relationship between BMI (low and high) and disease control rate. The primary outcome was progression free survival and overall survival, and the association between BMI and survival prognosis was evaluated. RESULTS: The median BMI was 22.5 kg/m2 , and 25 patients (10.7%) had a low BMI (<18.5 kg/m2 ), 158 patients (67.2%) had a normal BMI (18.5-25 kg/m2 ), and 52 patients (22.1%) had a high BMI (≥ 25 kg/m2 ). Patients in the low BMI group had a significantly lower disease control rate, whereas patients in the high BMI group had a significantly higher disease control rate (p = 0.002 and p = 0.030, respectively). A log-rank test showed prognosis to be significantly poorer in the low BMI group and to be significantly better in the high BMI group than that in the normal BMI group. Multivariable Cox regression analysis showed that low BMI was an independent indicator of poor prognosis, whereas high BMI was an independent indicator of favorable prognosis. CONCLUSION: We showed the impact of both low and high BMI on predicting therapeutic efficacy and prognosis in mRCC patients treated with TKI.

Prevalence of immune-related adverse events and anti-tumor efficacy following immune checkpoint inhibitor therapy in Japanese patients with various solid tumors.

BACKGROUND: While immune checkpoint inhibitors (ICIs) occasionally cause immune-related adverse events (irAEs) in various organs, the prevalence of irAEs and potential risk factors have not been clarified. We identified irAE predictive factors and examined the relationship between the effect of ICIs and irAEs for patients with malignancies. METHODS: A total of 533 cases treated with ICIs, including programmed death 1 (PD-1), PD-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), for various malignancies were included retrospectively. We recorded irAEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 5. Prevalence and predictive factors associated with immune-related liver injury and the relationship between irAE and treatment response were analyzed. RESULTS: During a median of 10 (1-103) cycles with a median follow-up after several ICI initiations of 384 (21-1715) days, irAEs with all grades and with grade ≥ 3 developed in 144 (27.0%) and 57 (10.7%) cases. Cumulative irAE development rates were 21.9, 33.5, and 43.0% in all grades and 8.8, 14.9, and 20.7% in grade ≥ 3 at 5, 10, and 20 cycles, respectively. Patients who received anti-CTLA4 therapy were more likely to develop irAEs compared to those who received anti-PD-1 or anti-PD-L1 monotherapy. Liver injury was the most common irAE. Multivariate analysis identified the combination of PD-1 and anti-CTL-4 antibodies (hazard ratio [HR], 17.04; P < 0.0001) and baseline eosinophil count ≥130/µL (HR, 3.01 for < 130; P = 0.012) as independent risk factors for the incidence of immune-related liver injury with grade ≥ 2. Patients who developed irAEs had a higher disease control rate (P < 0.0001) and an increased overall survival rate compared to those without irAEs (P < 0.0001). CONCLUSION: Combination therapy with anti-PD-1 and anti-CTL-4 antibodies resulted in higher a frequency of irAEs. Baseline absolute eosinophil count was found to be a predictive factor for immune-related liver injury. Occurrence of irAEs may be associated with higher efficacy of ICI treatment and longer survival among patients who receive ICI therapy.

Longitudinal analysis of trifecta outcome in Japanese patients with prostate cancer following robot-assisted laparoscopic radical prostatectomy.

PURPOSE: To analyze the trifecta outcome (continence, potency, and cancer control) longitudinally using robot-assisted laparoscopic radical prostatectomy (RARP). METHOD: We prospectively obtained 1-year longitudinal Expanded Prostate Cancer Index Composite (EPIC) data (preoperative and at 3, 6, 9, and 12 months after RARP) from 291 patients who underwent RARP by a single surgeon. Continence was defined as the use of 'zero or one pads'. Potency was defined as the ability to achieve and maintain satisfactory erections firm enough for sexual activity or sexual intercourse. Continence and potency were subjectively determined from patient-reported outcomes (EPIC question nos. 5 and 18). The biochemical recurrence (BCR) rate was defined as two consecutive PSA levels of > 0.2 ng/mL after RARP. Outcomes of the pentafecta were complications and positive surgical margins combined with the trifecta outcomes. RESULTS: Trifecta was achieved in 4.6, 5.6, 8.1, and 9.6% of all patients at 3, 6, 9, and 12 months, respectively. Pentafecta rates were 2.3, 3.0, 5.1, and 6.1%, respectively. Trifecta rates in the nerve-sparing (NS) group were 12.5, 12.7, 18.9, and 23.6%, respectively. The BCR-free rates maintained a high level and were 94.4, 93.9, 93.9, and 90.9%, respectively. Continence rates were improved to 55.2, 75.5, 81.6, and 85.0%, while the potency rate was extremely low at 7.5, 7.8, 9.8, and 10.9%. Even in the NS group, potency rates remained low at 18.1, 18.6, 21.9, and 26.1%, respectively. CONCLUSION: This longitudinal analysis of trifecta outcomes may be beneficial and should be used when counseling patients with clinically localized PCa.

Impact of adherence to criteria on oncological outcomes of radical prostatectomy in patients opting for active surveillance: data from the PRIAS-JAPAN study.

OBJECTIVES: This study aimed to evaluate whether oncological outcomes of radical prostatectomy differ depending on adherence to the criteria in patients who opt for active surveillance. MATERIALS AND METHODS: We retrospectively reviewed the data of 1035 patients enrolled in a prospective cohort of the PRIAS-JAPAN study. After applying the exclusion criteria, 136 of 162 patients were analyzed. Triggers for radical prostatectomy due to pathological reclassification on repeat biopsy were defined as on-criteria. Off-criteria triggers were defined as those other than on-criteria triggers. Unfavorable pathology on radical prostatectomy was defined as pathological ≥T3, ≥GS 4 + 3 and pathological N positivity. We compared the pathological findings on radical prostatectomy and prostate-specific antigen recurrence-free survival between the two groups. The off-criteria group included 35 patients (25.7%), half of whom received radical prostatectomy within 35 months. RESULTS: There were significant differences in median prostate-specific antigen before radical prostatectomy between the on-criteria and off-criteria groups (6.1 vs. 8.3 ng/ml, P = 0.007). The percentage of unfavorable pathologies on radical prostatectomy was lower in the off-criteria group than that in the on-criteria group (40.6 vs. 31.4%); however, the differences were not statistically significant (P = 0.421). No significant difference in prostate-specific antigen recurrence-free survival was observed between the groups during the postoperative follow-up period (median: 36 months) (log-rank P = 0.828). CONCLUSIONS: Half of the off-criteria patients underwent radical prostatectomy within 3 years of beginning active surveillance, and their pathological findings were not worse than those of the on-criteria patients.

Clinicopathological significance of the overexpression of MUC1 in upper tract urothelial carcinoma and possible application as a diagnostic marker.

Mucin 1 (MUC1) overexpression has been reported in many malignancies and is associated with a poor prognosis. However, the clinicopathological significance of MUC1 in upper tract urothelial carcinoma (UTUC) has not been investigated. We analyzed the expression and distribution of MUC1 in UTUC by immunohistochemistry. In normal urothelium, MUC1 expression was observed on the surface of umbrella cells. Meanwhile, the strong expression of MUC1 was observed in cell membranes and cytoplasm in UTUC tissues, and it was detected in 64 (58%) of a total of 110 UTUC cases. MUC1-positive UTUC cases were associated with nodular/flat morphology, high grade, high T stage, and lymphatic and venous invasion and poor prognosis. Additionally, MUC1 expression was associated with high expression of Ki-67, programmed death-ligand 1 (PD-L1), CD44 variant 9 (CD44v9), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and p53 in UTUC. Furthermore, immunocytochemistry for MUC1 on urine cytology slides demonstrated that the strong staining of MUC1 was more frequently found in tumor cells than in nonneoplastic cells. The diagnostic accuracy of urine cytology was improved by combining MUC1 immunostaining with cytology. These results suggest that MUC1 may be a prognostic biomarker in UTUC, and MUC1 exression has a potential application as a diagnostic immunomarker for urine cytology.

Molecular mechanisms of resistance to tyrosine kinase inhibitor in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC). Loss of von Hippel-Lindau tumor suppressor gene is frequently observed in ccRCC and increases the expression of hypoxia-inducible factors and their targets, including epidermal growth factor, vascular endothelial growth factor, and platelet-derived growth factor. Tyrosine kinase inhibitors (TKIs) offer a survival benefit in metastatic renal cell carcinoma (mRCC). Recently, immune checkpoint inhibitors have been introduced in mRCC. Combination therapy with TKIs and immune checkpoint inhibitors significantly improved patient outcomes. Therefore, TKIs still play an essential role in mRCC treatment. However, the clinical utility of TKIs is compromised when primary and acquired resistance are encountered. The mechanism of resistance to TKI is not fully elucidated. Here, we comprehensively reviewed the molecular mechanisms of resistance to TKIs and a potential strategy to overcome this resistance. We outlined the involvement of angiogenesis, non-angiogenesis, epithelial-mesenchymal transition, activating bypass pathways, lysosomal sequestration, non-coding RNAs, epigenetic modifications and tumor microenvironment factors in the resistance to TKIs. Deep insight into the molecular mechanisms of resistance to TKIs will help to better understand the biology of RCC and can ultimately help in the development of more effective therapies.

The Impact of Gleason Grade 3 as a Predictive Factor for Biochemical Recurrence after Robot-Assisted Radical Prostatectomy: A Retrospective Multicenter Cohort Study in Japan (The MSUG94 Group).

Background and Objectives: This study's objective was to examine patients treated with robot-assisted radical prostatectomy (RARP) for intermediate-risk prostate cancer (IR-PCa), and to identify preoperative risk factors for biochemical recurrence (BCR) in these patients in Japan. Materials and Methods: We conducted a retrospective multicenter cohort study of patients with PCa who underwent RARP at 10 institutions in Japan. A total of 3195 patients were enrolled in this study. We focused on patients with IR-PCa who underwent RARP. We obtained data on pre- and postoperative covariates from the enrolled patients. Biochemical recurrence-free survival was the primary endpoint of this study. We also identified useful preoperative predictive factors for BCR in patients with IR-PCa after RARP. Results: A total of 1144 patients with IR-PCa were enrolled in this study. The median follow-up period was 23.7 months. At the end of the follow-up period, 94 (8.2%) patients developed BCR. The 2 and 3 year biochemical recurrence-free survival (BRFS) rates were 92.2% and 90.2%, respectively. Using the Kaplan-Meier method, Gleason grade (GG) 3 was significantly associated with poor BRFS compared with ≤GG 2. In multivariate analysis, GG 3 was a significant predictive factor for BCR in patients with IR-PCa. Conclusions: The results of the study indicated a significant relationship between GG 3 and post-RARP BCR in patients with IR-PCa.

BUB1B Overexpression Is an Independent Prognostic Marker and Associated with CD44, p53, and PD-L1 in Renal Cell Carcinoma.

INTRODUCTION: BUB1 mitotic checkpoint serine/threonine kinase B encoded by BUB1B gene is a member of the spindle assembly checkpoint family. Several reports have demonstrated that overexpression of BUB1B is associated with cancer progression and prognosis. OBJECTIVE: This study aims to clarify the expression and function of BUB1B in renal cell carcinoma (RCC). METHODS: The expression of BUB1B was determined using immunohistochemistry and bioinformatics analysis in RCC. The effects of BUB1B knockdown on cell growth and invasion were evaluated. We analyzed the interaction between BUB1B, cancer stem cell markers, p53, and PD-L1 in RCC. RESULTS: In 121 cases of RCC, immunohistochemistry showed that 30 (25%) of the RCC cases were positive for BUB1B. High BUB1B expression was significantly correlated with high nuclear grade, T stage, and M stage. A Kaplan-Meier analysis showed that the high expression of BUB1B was associated with poor overall survival after nephrectomy. High BUB1B expression was associated with CD44, p53, and PD-L1 in RCC. Knockdown of BUB1B suppressed cell growth and invasion in RCC cell lines. Knockdown of BUB1B also suppressed the expression of CD44 and increased the expression of phospho-p53 (Ser15). In silico analysis showed that BUB1B was associated with inflamed CD8+, exhausted T-cell signature, IFN-γ signature, and the response to nivolumab. CONCLUSION: These results suggest that BUB1B plays an oncogenic role and may be a promising predictive biomarker for survival in RCC.

Longitudinal evaluation of the frequency of sexual intercourse and sexual activity in patients after nerve-sparing robot-assisted laparoscopic radical prostatectomy.

OBJECTIVE: To evaluate the frequency of sexual intercourse and sexual activity of patients after nerve-sparing (NS) robot-assisted laparoscopic radical prostatectomy (RARP). PATIENTS AND METHODS: We prospectively obtained 2-years longitudinal Expanded Prostate Cancer Index Composite (EPIC) and Sexual Health Inventory for Men (SHIM) score data from 99 patients. We classified the frequency of sexual intercourse and sexual activity as 'none', 'less than once a week', 'about once a week', 'several times a week', and 'daily'. RESULTS: The percentages of patients who took part in sexual activity before and at 3, 6, 9, 12, 18, and 24 months after NS RARP were 55.6%, 27.9%, 38.8%, 42.5%, 44.4%, 41.7%, and 42.1%, respectively. The percentages of patients who took part in sexual intercourse before and at 3, 6, 9, and 12, 18, and 24 months after NS RARP were 41.4%, 9.0%, 13.3%, 16.3%, 16.7%, 22.2%, and 23.7%, respectively. Preoperative sexual status was classified into two groups: those who had sexual intercourse or those who only had sexual activity except sexual intercourse. Sexual function (SF) was investigated longitudinally using the EPIC and SHIM data between the two groups. The SHIM data showed an improvement in SF in the sexual intercourse group, but did not do so in the sexual activity except sexual intercourse group. On the other hand, SF in the EPIC data might reflect the postoperative improvement of SF in the sexual activity except sexual intercourse group. CONCLUSION: There was a large discrepancy between the percentages of patients taking part in sexual intercourse and sexual activity; therefore, surveys of postoperative SF are recommended to include not only sexual intercourse but also sexual activity.

Recurrence- and progression-free survival in intermediate-risk non-muscle-invasive bladder cancer: the impact of conditional evaluation and subclassification.

OBJECTIVES: To assess the change in rates of recurrence-free survival (RFS) and progression-free survival (PFS) based on the duration of survival without recurrence or progression among patients with intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC), and to examine the predictive factors for recurrence at different time points by assessing conditional RFS and PFS. PARTICIPANTS AND METHODS: A cohort of 602 patients treated with transurethral resection of bladder tumour and histopathologically diagnosed with IR NMIBC was included in this retrospective study. RESULTS: The conditional RFS rate at 1, 2, 3, 4 and 5 years improved with increased duration of RFS; however, the conditional PFS rate did not improve over time. Multivariable analyses showed that recurrent tumour, multiple tumours, tumour size (>3 cm), immediate postoperative instillation of chemotherapy, and administration of BCG were independent predictive factors for recurrence at baseline. The predictive ability of these factors disappeared with increasing recurrence-free survivorship. Subclassification of these patients with IR NMIBC into three groups using clinicopathological factors (recurrent tumour, multiple tumours, tumour size) demonstrated that the high IR group (two factors) had significantly worse RFS than the intermediate (one factor, P < 0.001) and low IR groups (no factor, P = 0.005) at baseline. This subclassification stratified conditional risk of RFS also at 1, 3 and 5 years, which provides the basis for distinct surveillance protocols among patients with IR NMIBC. CONCLUSION: Conditional survival analyses of patients with IR NMIBC demonstrate that RFS changes over time, while PFS does not change. These data support distinct surveillance protocols based on the subclassification of IR NMIBC.