Prognostic impact of histological discordance between transurethral resection and radical cystectomy.

OBJECTIVE: To analyse the impact of histological discordance of subtypes (subtypes or divergent differentiation [DD]) in specimens from transurethral resection (TUR) and radical cystectomy (RC) on the outcome of the patients with bladder cancer receiving RC. PATIENTS AND METHODS: We analysed data for 2570 patients from a Japanese nationwide cohort with bladder cancer treated with RC between January 2013 and December 2019 at 36 institutions. The non-urinary tract recurrence-free survival (NUTR-FS) and overall survival (OS) stratified by TUR or RC specimen histology were determined. We also elucidated the predictive factors for OS in patients with subtype/DD bladder cancer. RESULTS: At median follow-up of 36.9 months, 835 (32.4%) patients had NUTR, and 691 (26.9%) died. No statistically significant disparities in OS or NUTR-FS were observed when TUR specimens were classified as pure-urothelial carcinoma (UC), subtypes, DD, or non-UC. Among 2449 patients diagnosed with pure-UC or subtype/DD in their TUR specimens, there was discordance between the pathological diagnosis in TUR and RC specimens. Histological subtypes in RC specimens had a significant prognostic impact. When we focused on 345 patients with subtype/DD in TUR specimens, a multivariate Cox regression analysis identified pre-RC neutrophil-lymphocyte ratio and pathological stage as independent prognostic factors for OS (P = 0.016 and P = 0.001, respectively). The presence of sarcomatoid subtype in TUR specimens and lymphovascular invasion in RC specimens had a marginal effect (P = 0.069 and P = 0.056, respectively). CONCLUSION: This study demonstrated that the presence of subtype/DD in RC specimens but not in TUR specimens indicated a poor prognosis. In patients with subtype/DD in TUR specimens, pre-RC neutrophil-lymphocyte ratio and pathological stage were independent prognostic factors for OS.

Real-world prostate-specific antigen response and progression to castration-resistant prostate cancer among men with metastatic castration-sensitive prostate cancer treated with apalutamide: a multi-institutional study in the Chu-shikoku Japan Urological Consortium.

BACKGROUND: Japanese men receiving apalutamide often experience skin-adverse events (AEs), possibly requiring treatment interruption or dose reduction. However, concerns have arisen regarding the impact of these adjustments on the efficacy of apalutamide. Our study evaluated the efficacy, safety, and persistence of apalutamide in men with metastatic castration-sensitive prostate cancer (mCSPC). METHODS: We retrospectively reviewed the medical records of 108 men with mCSPC from 14 Japanese institutions. The primary outcomes were the efficacy of apalutamide: prostate-specific antigen (PSA) response (50%, 90% and < 0.2 decline) and progression to castration-resistant prostate cancer (CRPC). The secondary outcomes were the skin-AE and compliance of apalutamide. RESULTS: PSA50%, PSA90% and PSA < 0.2 declines were observed in 89.8, 84.3 and 65.7%, and the median time to CRPC progression was not reached. PSA < 0.2 decline and an initial full dose of apalutamide were significantly associated with a longer time to CRPC. The most common AE was skin-AE (50.9%), and there was no association between the occurrence of skin-AE and the time to CRPC (P = 0.72). The median apalutamide persistence was 29 months, which was longer in the initial full dose recipients than in the reduced dose recipients. The dosage is reduced in about 60% of patients within the first year of treatment in the initial full dose recipients. CONCLUSIONS: Our findings indicate the effectiveness of apalutamide in Japanese men with mCSPC, despite a substantial portion requiring dose reduction within a year among the initial full dose recipients.

Peripheral neuropathy and nerve electrophysiological changes with enfortumab vedotin in patients with advanced urothelial carcinoma: a prospective multicenter cohort study.

BACKGROUND: Enfortumab vedotin is a novel antibody-drug conjugate used as a third-line therapy for the treatment of urothelial cancer. We aimed to elucidate the effect of enfortumab vedotin-related peripheral neuropathy on its efficacy and whether enfortumab vedotin-induced early electrophysiological changes could be associated with peripheral neuropathy onset. METHODS: Our prospective multicenter cohort study enrolled 34 patients with prior platinum-containing chemotherapy and programmed cell death protein 1/ligand 1 inhibitor-resistant advanced urothelial carcinoma and received enfortumab vedotin. The best overall response, progression-free survival, overall survival, and safety were assessed. Nerve conduction studies were also performed in 11 patients. RESULTS: The confirmed overall response rate and disease control rate were 52.9% and 73.5%, respectively. The median overall progression-free survival and overall survival were 6.9 and 13.5 months, respectively, during a median follow-up of 8.6 months. The patients with disease control had significantly longer treatment continuation and overall survival than did those with uncontrolled disease. Peripheral neuropathy occurred in 12.5% of the patients. The overall response and disease control rates were 83.3% and 100%, respectively: higher than those in patients without peripheral neuropathy (p = 0.028 and p = 0.029, respectively). Nerve conduction studies indicated that enfortumab vedotin reduced nerve conduction velocity more markedly in sensory nerves than in motor nerves and the lower limbs than in the upper limbs, with the sural nerve being the most affected in the patients who developed peripheral neuropathy (p = 0.011). CONCLUSION: Our results indicated the importance of focusing on enfortumab vedotin-induced neuropathy of the sural nerve to maximize efficacy and improve safety.

Reproductive organ involvement in women undergoing radical cystectomy for urothelial bladder cancer: a nationwide multicenter study.

BACKGROUND: Radical cystectomy in women generally includes the removal of the uterus, ovaries, and anterior vaginal wall, but the criteria for reproductive organ sparing are not clear. METHODS: A total of 2674 patients with bladder cancer were retrospectively reviewed, having undergone cystectomy at this nationwide multicenter from January 2013 to December 2019. We evaluated the incidence of malignancy in reproductive organs in a cohort of 417 women and analyzed the clinicopathological features of reproductive organ involvement. Recurrence-free survival and overall survival were reported using Kaplan-Meier survival curves. RESULTS: Median follow-up was 36.9 months. Of the 417 patients with urothelial carcinoma of the bladder, 325 underwent hysterectomy, and 92 had a spared uterus and anterior wall of the vagina. Twenty-nine (8.9%) patients exhibited reproductive organ involvement; this consisted of 22 (6.8%) uteri, 16 (4.9%) vaginas, and two (0.6%) ovaries. Incidental primary reproductive malignancies were found in only two (0.6%) patients. Recurrence-free survival and overall survival were significantly shorter in patients with reproductive organ involvement than in those without. Patients with reproductive organ involvement were more likely to have tumors with ≥ cT3 or sub-localization at the posterior/trigone/bladder neck. CONCLUSIONS: The risk of reproductive organ involvement cannot be ignored in women undergoing radical cystectomy for urothelial carcinoma of the bladder, therefore, the eligibility criteria for reproductive organ preservation should be considered carefully.

Retroperitoneal cutaneous ureterostomy following radical cystectomy: A multicenter comparative study of robotic versus open surgery.

INTRODUCTION: The aim of this study was to evaluate the differences in perioperative outcomes of cutaneous ureterostomy (CUS) between open surgery (open radical cystectomy, ORC) and robot-assisted surgery (robot-assisted radical cystectomy, RARC), including the stent-free rate, readmission rates due to urinary tract infection (UTI), and changes in renal function. METHODS: Between 2005 and 2023, a total of 37 patients underwent CUS following ORC, while 24 patients underwent CUS following RARC. Perioperative outcomes were compared between these two groups. RESULTS: The patients in the RARC group were significantly older (p = 0.007) and had a significantly higher proportion of high-risk cases with ASA-PS ≥3 (p = 0.002). In addition, RARC was associated with a significantly lower estimated blood loss (p < 0.001) and a reduced transfusion rate (p = 0.003). Postoperative complication rates and the stent-free rate were comparable between the ORC and RARC groups. Throughout a median follow-up period of 2.6 years, rates of readmission due to UTI did not differ significantly between the two groups. Moreover, there were no differences in the change in estimated glomerular filtration rate before and after surgery and the 3-year survival rates were similar across both groups. CONCLUSIONS: CUS following RARC appears to offer a safer alternative compared with CUS following ORC, and the stent-free rates are comparable. The significantly lower estimated blood loss and transfusion rate associated with RARC are particularly favorable for elderly patients, those who are frail, and individuals with multiple comorbidities.

Insulin receptor expression to predict resistance to axitinib and elucidation of the underlying molecular mechanism in metastatic renal cell carcinoma.

BACKGROUND: The study aimed to examine the significance of insulin receptor (INSR) expression in predicting resistance to axitinib in clear cell renal cell carcinoma (ccRCC). METHODS: Clinicopathological data were collected from 36 consecutive patients with metastatic RCC who received axitinib. Thirty-three primary tumours were obtained for immunohistochemistry. Patient-derived xenograft (PDX) models were created by transplanting primary tumours into immunodeficient mice, establishing axitinib-resistant PDX models. RCC cell lines were co-cultured with human renal glomerular endothelial cells (HGECs) treated with siRNA of INSR (HGEC-siINSR). Gene expression alteration was analysed using microarray. RESULTS: The patients with low INSR expression who received axitinib had a poorer outcome. Multivariate analysis showed that INSR expression was the independent predictor of progression-free survival. INSR expression decreased in axitinib-resistant PDX tumours. RCC cell lines showed upregulated interferon responses and highly increased interferon-ß levels by co-culturing with HGEC-siINSR. HGECs showed decreased INSR and increased interferon-ß after axitinib administration. RCC cell lines co-cultured with HGEC-siINSR showed high programmed death-ligand 1 (PD-L1) expression, which increased after interferon-ß administration. CONCLUSIONS: Decreased INSR in RCC could be a biomarker to predict axitinib resistance. Regarding the resistant mechanism, vascular endothelial cells with decreased INSR in RCC may secrete interferon-ß and induce PD-L1.

A propensity score matching study on robot-assisted radical cystectomy for older patients: comparison of intracorporeal ileal conduit and cutaneous ureterostomy.

BACKGROUND: Robot-assisted radical cystectomy (RARC) and intracorporeal urinary diversion are less invasive than conventional procedures. However, for older patients, cutaneous ureterostomy (CUS) may be preferred because urinary diversion using the intestine has a high incidence of perioperative complications and is highly invasive. The purpose of this study was to demonstrate the safety and efficacy of intracorporeal ileal conduit (ICIC) compared with CUS in patients aged 75 years or older who underwent RARC. METHODS: From October 2014 to December 2021, 82 patients aged 75 years or older who underwent RARC at Tokushima University Hospital, Tokushima Prefectural Central Hospital, or Ehime Prefectural Central Hospital were retrospectively reviewed. Of these, 52 and 25 patients who underwent ICIC and CUS, respectively, were included. After adjusting the patients' characteristics using propensity score-matching, surgical results and prognoses were retrospectively compared. The propensity score was based on age, Eastern Cooperative Oncology Group Performance Status Scale (ECOG-PS), American Society of Anesthesiologists physical status classification (ASA-PS), clinical tumor stage, and neoadjuvant chemotherapy. RESULTS: The median age was lower in the ICIC group compared with the CUS group, and the proportion of high-risk cases (ECOG-PS ≥ 2 or ASA-PS ≥ 3) did not differ. The median operation time was longer in the ICIC group, and estimated blood loss was higher, compared with the CUS group. There were no significant differences in the incidence of complications within the first 30 postoperative days, incidence of complications 30-90 days after surgery, 2-year overall survival, 2-year cancer-specific survival, and 2-year recurrence-free survival. The stent-free rate was significantly lower in the CUS group than that in the ICIC group. CONCLUSION: In older patients, the ICIC group showed non-inferior surgical and oncological outcomes compared with the CUS group. Urinary diversion following RARC in older patients should be carefully selected by considering not only the age but also the general condition (including comorbidities) of the patient.

Real-world analysis of apalutamide-associated skin adverse events in Japanese patients with advanced prostate cancer: a multi-institutional study in the Chu-shikoku Japan Urological Consortium.

BACKGROUND: Apalutamide-associated skin adverse events are more common in the Japanese than in the global population. However, limited clinical data have hampered further understanding. This real-world study investigated the clinical characteristics of skin adverse events in patients with advanced prostate cancer. METHODS: We retrospectively reviewed 119 patient records from 16 institutions in Japan. Skin adverse events were graded according to the Common Terminology Criteria for Adverse Events (v5.0). The incidence and characteristics of skin adverse events (along with the clinical risk factors for their incidence, worsening, and recurrence) were evaluated. RESULTS: Fifty-five patients (46.2%) experienced skin adverse events. The median times to the incidence and remission of skin adverse events were 62 and 30 days, respectively. Grade 3 skin adverse events were observed in 15 patients (12.6%). The median time from the first incidence to apalutamide interruption was significantly longer in patients with progression to grade 3 skin adverse events than in those without such a progression (8 vs. 0 days, p = 0.005). Skin adverse events were observed in 45.2% of patients who resumed apalutamide treatment (median treatment interruption time: 31.5 days). Sixteen patients (13.4%) permanently discontinued apalutamide due to skin adverse events. No significant clinical risk factors for the incidence, worsening and recurrence of apalutamide-associated skin adverse events were observed. CONCLUSIONS: Nearly half of the Japanese patients in this study experienced skin adverse events following apalutamide administration. The time to apalutamide discontinuation after the incidence of skin adverse events was positively correlated with the worsening of these events.

Effects of undernutrition and low energy availability on reproductive functions and their underlying neuroendocrine mechanisms.

It has been well established that undernutrition and low energy availability disturb female reproductive functions in humans and many animal species. These reproductive dysfunctions are mainly caused by alterations of some hypothalamic factors, and consequent reduction of gonadotrophin-releasing hormone (GnRH) secretion. Evidence from literature suggests that increased activity of orexigenic factors and decreased activity of anorexigenic/satiety-related factors in undernourished conditions attenuate GnRH secretion in an integrated manner. Likewise, the activity of kisspeptin neurons, which is a potent stimulator of GnRH, is also reduced in undernourished conditions. In addition, it has been suggested that gonadotrophin-inhibitory hormone, which has anti-GnRH and gonadotrophic effects, may be involved in reproductive dysfunctions under several kinds of stress conditions. It should be remembered that these alterations, i.e., promotion of feeding behavior and temporary suppression of reproductive functions, are induced to prioritize the survival of individual over that of species, and that improvements in metabolic and nutritional conditions should be considered with the highest priority.

Appropriate management reduces radiation exposure in daily urological practice.

OBJECTIVES: To identify and raise awareness of the radiation exposure of urologists due to X-ray fluoroscopic procedures in daily practice. METHODS: This was a single-center, cohort study of 30 consecutive patients who underwent periodic percutaneous or transurethral replacements of urinary tract catheters. A total of 55 replacements every 3 months with cases aligned were performed by a single urologist. The urologist's radiation exposure and the incident dose to patients per case were measured with thermoluminescent dosimeters. In the latter 3-month period, the pulse fluoroscopy condition was changed from 15 to 7.5 pulses per second, and collimation was added to the field of view. RESULTS: In the analysis of all patients, the use of a modified pulse rate and collimation did not affect the fluoroscopy time, but it did significantly reduce the air kerma and dose area product; in addition, with respect to the medical exposure dose during percutaneous catheter replacement, fluoroscopy time was longer, but air kerma and dose area product showed significant decreases. As with decreases in medical exposure of patients, the equivalent dose for eye lenses of the urologist decreased from 1.2 mSv in the first 3-month period to 0.2 mSv in the second 3-month period. Similarly, the exposure dose for the extremities also decreased significantly, from 33.9 mSv to 8.1 mSv. CONCLUSIONS: Urologists are exposed to non-negligible amounts of radiation due to fluoroscopy. Appropriate management such as modified pulse fluoroscopy condition and precautions are required.

[A Case of Pappilary Renal Cell Caircinoma which Responded Well to the Combination Therapy of Ipilimumab and Nivolumab --A CASE REPORT-].

We report a case of papillary renal cell carcinoma that responded well to the combination of ipilimumab and nivolumab. The patient was a 68-year-old male who was being followed up for a small left renal mass without treatment. Two years later, computed tomography (CT) showed enlarged cervical and para-aortic lymph nodes, and lymph node biopsy suggested metastases of the cancer. After resection of the renal tumor, we performed pararenal aortic lymph node biopsy, and we diagnosed the case as papillary renal cell carcinoma type 1 with lymph node metastasis. The combination of ipilimumab and nivolumab each metastatic site showed regression on CT. Since immune-related adverse events occurred during the therapy nivolumab was discontinued, but partial response of the metastases was maintained.

[Two Cases of Robot-Assisted Total Pelvic Exenteration and Intracorporeal Ileal Conduit for Locally Advanced Rectal Cancer].

We describe two cases of locally advanced rectal cancer (LARC) treated with robot-assisted total pelvic exenteration (Ra-TPE) and intracorporeal ileal conduit (ICIC). The first case was in a 71-year-old man with LARC (RbP, T4bN2bM0, cStage IIIc). He was started on bevacizumab+S-1/oxaliplatin therapy in July 2019. In April 2020, he developed Fournier's gangrene due to subcutaneous penetration of rectal cancer. Emergency drainage and colostomy were performed simultaneously, and a percutaneous vesical fistula was created. In May 2020, Ra-TPE and ICIC were performed. Histopathological analysis revealed moderately differentiated tubular adenocarcinoma (ypT3N0, RM0). At postoperative 9 months, thoracoscopic right upper lobectomy was performed for a right metastatic lung tumor. At present, ie, at postoperative 12 months, the patient has been free of recurrence and metastasis, with a carcinoembryonic antigen (CEA) level of 1.4 ng/ml and carcinoma antigen (CA) 19-9 level of 11 U/ml. The second case was in a 61-year-old man with fistula-associated anal cancer (PRb, T4N3M1b, cStage IVb). In April 2019, he was started on FOLFOXIRI+cetuximab therapy. In August 2020, Ra-TPE, ICIC, and transperineal total mesenteric excision were performed. Histopathological analysis revealed adenocarcinoma (ypT4N0, RM0). At postoperative 11 months, thoracoscopic left lower lobectomy was performed for a left metastatic lung tumor. At present, ie, at postoperative 12 months, the patient remains free of recurrence and metastasis, with a CEA level of 7.3 ng/ml and CA19-9 level of 12 U/ml. Ra-TPE, which allows transperineal removal of a specimen, can be performed as a minimally invasive surgery in combination with ICIC.

[A Case of Robot-Assisted Radical Cystoprostatectomy for Locally Advanced Prostate Cancer with Bladder Infiltration].

While robot-assisted radical cystoprostatectomy (RARC) for locally advanced prostate cancer (LAPC) may sometimes prove to be excessive treatment, it can significantly reduce the risk of positive surgical margins and lower urinary tract obstruction in some cases. Here, we report a case of LAPC treated with RARC in a patient with right hydronephrosis due to bladder infiltration and left hypoplastic kidney. A 71-year-old man presented with frequent urination in August 2019. Prostate-specific antigen (PSA) level was 8.633 ng/ml, and magnetic resonance imaging led to the suspicion that the prostate cancer extended beyond the prostate capsule without distant metastasis. Prostatic biopsy revealed Gleason score 10 (5＋5) adenocarcinoma in 8 out of 8 specimens. We diagnosed left hypoplastic kidney and LAPC with right hydronephrosis due to bladder infiltration. We performed percutaneous right nephrostomy and started neoadjuvant hormone therapy. RARC and intracorporeal ileal conduit were performed in March 2020. The prostate was adherent to the anterior surface of the rectum and was difficult to remove. At present, five months after the surgery, the patient remains free of recurrence and metastasis with PSA level ＜0.003 ng/ml. RARC for LAPC with bladder infiltration can be an effective therapeutic strategy in some cases.

[A Case of Desmoid Tumor Initially Diagnosed as a Metastasis from Renal Cell Carcinoma --A CASE REPORT-].

We report a case of desmoid tumor that was initially diagnosed as metastasis from renal cell carcinoma. A follow-up computed tomographic (CT) scan after nephrectomy for renal cell carcinoma in a 64-year-old man revealed a right retroperitoneal tumor 3.5 cm in diameter. Though the CT density of the tumor was similar to that of muscles, we first suspected metastasis from renal cell carcinoma or other cancer because the tumor growth was relatively fast. We resected the tumor. The pathological diagnosis was desmoid type fibromatosis. We also review six cases of desmoid tumors after nephrectomy for renal cell carcinoma reported in Japan. Careful followup is required for the patients with desmoid tumors because of frequent recurrence.

[A Case of Pelvic Organ Prolapse and Bladder Diverticulum Surgically Treated at the Same Time].

We report a case of bladder diverticulum presumably caused by lower urinary tract dysfunction due to pelvic organ prolapse (POP) simultaneously treated with transurethral coagulation (TUC) of the bladder diverticulum and laparoscopic sacrocolpopexy (LSC). A literature search showed this is the first report of bladder diverticulum and POP surgically treated at the same time. A 71-year-old woman was referred to our hospital for the treatment of cystocele. She had both storage and voiding symptoms. She had a POPQ stage III cystocele and stage I uterine prolapse. Ultrasonography and computed tomographic scan showed a large volume of residual urine along with a bladder diverticulum. Since urodynamic studies revealed a low compliance bladder and obstruction, we opined that the lower urinary tract symptoms were induced by the cystocele. TUC of the bladder diverticulum and LSC were performed at the same time. After the operation, clean intermittent catheterization (CIC) was needed once a day for one month. Gradually, residual urine decreased and CIC became unnecessary. The bladder diverticulum disappeared, and there has been no recurrence of POP.

[Renal Angiomyolipoma Extending into the Renal Vein --A Case Report-].

We report a case of left renal angiomyolipoma extending into the renal vein. A 67-year-old woman showed a left renal tumor which was 6 cm in diameter and had density equal to fat tissue in computed tomography. We suspected liposarcoma and performed radical nephrectomy and resection of thrombus. The pathological diagnosis was angiomyolipoma with no malignancy. To our knowledge, renal angiomyolipoma with tumor thrombus has been reported in 62 cases, and pulmonary embolism developed in 9 of these cases. We conclude that surgical treatment is effective in treating angiomyolipoma with tumor thrombus.

Complications of Flexible Ureteroscopic Treatment for Renal and Ureteral Calculi during the Learning Curve.

BACKGROUND: The flexible ureterorenoscope (URS) and associated devices have developed rapidly. However, despite its therapeutic benefits, URS may be associated with some complications. To the best of our knowledge, there are no studies discussing the complications of flexURS during the learning curve. METHODS: A retrospective review of the records of patients who underwent flexURS from January 2005 to June 2013 was performed. To compare the complications after the introduction of flexURS, patients were divided into four groups based on the surgeon's training experience, that is, based on the number of cases performed by the surgeon. A total of 219 cases underwent flexURS. Groups 1, 2, 3, and 4 included 35, 50, 50, and 84 cases, respectively. The complications were classified using the Clavien system (I-IV). RESULTS: The mean operation time and stone-free rate were significantly different (p < 0.001, p = 0.013, respectively). The total complication rates were 13.6, 10, 8.3, and 3.2%, respectively (p = 0.068). The more the surgeon's experience, the less was the complication rate. Despite our best efforts, the incidence of urosepsis was not reduced (p = 0.902). CONCLUSIONS: To reduce severe complications, it is necessary to have performed about 100 cases. Increased surgeon experience tended to decrease the risk of severe complications, but the incidence of urosepsis was not reduced.

A case of an advanced renal collecting duct carcinoma in which initial therapeutic effect was achieved with pembrolizumab plus axitinib.

Introduction: Renal collecting duct carcinoma is often found in advanced cancers and has a poor prognosis. Here, we present the case of symptomatic metastatic collecting duct carcinoma in which we observed an initial therapeutic effect of immune checkpoint inhibitors plus tyrosine kinase inhibitors. Case presentation: The patient was a 69-year-old male who was referred to our hospital for examination of a right chest tumor and related pain. Contrast-enhanced computed tomography and tumor biopsy were performed, leading to a diagnosis of collecting duct carcinoma. A combination of pembrolizumab plus axitinib was initiated as first-line therapy; right chest pain decreased, and tumor shrinkage was observed. Seven months after treatment initiation, tumor progression was noted. Cabozantinib was initiated as second-line therapy; however, was discontinued due to patient fatigue. The patient died 15 months after the initiation of treatment. Conclusion: For symptomatic metastatic collecting duct carcinoma, pembrolizumab plus axitinib may have initial therapeutic effects.