Prevalence of germline BRCA1/2 pathogenic variants in Japanese patients treated with castration-resistant prostate cancer and efficacy of CRPC treatment in real-world clinical practice.

OBJECTIVE: The companion diagnosis for olaparib, a poly (ADP-ribose) polymerase inhibitor for prostate cancer, aims to detect BRCA1/2 gene variants. In clinical practice, the frequency of germline BRCA1/2 variants in patients receiving castration-resistant prostate cancer treatment is unknown. We aimed to evaluate the prevalence of germline BRCA1/2 variants and their relationship to prognosis and treatment efficacy in castration-resistant prostate cancer. METHODS: Between June 2021 and 2023, 92 patients receiving castration-resistant prostate cancer treatment were examined for germline BRCA1/2 variants using BRACAnalysis CDx®. Furthermore, the associations between BRCA1/2 pathogenic variants and clinical outcomes were assessed. RESULTS: Of the 92 patients referred for genetic testing, 6 (6.5%) carried germline pathogenic variants in BRCA1/2. The BRCA2 variant was the most frequent (n = 5), followed by BRCA1 variant (n = 1). Among the five variants in BRCA2, the p.Asp427Thrfs*3 variant was identified for the first time in prostate cancer. Overall survival from castration-resistant prostate cancer for patients with BRCA1/2 variants was significantly shorter than for patients without BRCA1/2 variants (P = 0.043). Progression-free survival of androgen receptor signaling inhibitors for patients with BRCA1/2 variants was significantly shorter than for those without (P = 0.003). Progression-free survival of taxane chemotherapy was significantly shorter in patients with BRCA1/2 variants than in those without (P = 0.0149). CONCLUSIONS: In clinical practice, 6.5% of patients treated with castration-resistant prostate cancer carried germline BRCA1/2 pathogenic variants. Japanese castration-resistant prostate cancer patients with germline BRCA1/2 mutants have a poor prognosis and may be less responsive to treatment with androgen receptor signaling inhibitors and taxane-based chemotherapy for castration-resistant prostate cancer.

[A Case of Metastatic Renal Cell Carcinoma with Arthritis and Colitis Due to Immune-Related Adverse Events During Ipilimumab-Nivolumab Combination Therapy].

A 73-year-old man with renal cell carcinoma underwent a left-sided open radical nephrectomy at our center. The pathological diagnosis was Fuhrman Grade 2, stage pT3a, clear cell renal cell carcinoma. A follow-up computed tomography (CT) scan revealed lung metastases 9 months after the surgery. The patient was started on ipilimumab with nivolumab combination therapy; however, after two cycles of administration, he developed arthralgia and swelling of the knee. Furthermore, he developed diarrhea almost simultaneously, resulting in the interruption of the ipilimumab plus nivolumab treatment. We diagnosed arthritis and colitis with immune-related adverse events (irAE) and initiated steroid therapy with rehabilitation. His condition improved dramatically, and nivolumab treatment could be resumed after 3 months of treatment interruption.

[A Case of Retroperitoneal Bronchogenic Cyst].

A 75-year-old male visited a clinic with the chief complaint of pollakiuria. A computed tomography scan revealed, a left adrenal mass, and the patient was then referred to our hospital. Since a malignant tumor could not be ruled out. We performed laparoscopic left adrenal resection. Postoperative histopathological findings revealed the mass to be a bronchogenic cyst, which had no continuity with the normal adrenal gland. The postoperative course was uneventful, and recurrence has not been observed. Retroperitoneal bronchogenic cysts are rare and often difficult to diagnose preoperatively using imaging studies.

Improvement of three-dimensional motion sickness using a virtual reality simulator for robot-assisted surgery in undergraduate medical students: A prospective observational study.

BACKGROUND: A virtual reality (VR) simulator is utilized as an inexpensive tool for gaining basic technical competence in robotic-assisted surgery (RAS). We evaluated operator 3D motion sickness while using a VR simulator and assessed whether it can be reduced by repeating the training. METHODS: This prospective observational study was conducted at the Department of Urology, Iwate Medical University, a tertiary training hospital in an urban setting. A total of 30 undergraduate medical students participated in the study. We compared whether the VR simulator improved the students' skills in operating the da Vinci robot. Fifteen students underwent training with a VR simulator for 4 h a day for 5 days. Then, motion sickness was determined using the Visual Analog Scale and Simulator Sickness Questionnaire (SSQ) before and after the training. RESULTS: Manipulation time significantly improved after training compared to before training (293.9 ± 72.4 versus 143.6 ± 18.4 s; p < 0.001). Although motion sickness worsened after each training session, it gradually improved with continuous practice with the VR simulator. SSQ subscores showed that the VR simulator induced nausea, disorientation, and oculomotor strain, and oculomotor strain was significantly improved with repeated training. CONCLUSIONS: In undergraduate students, practice with the VR simulator improved RAS skills and operator 3D motion sickness caused by 3D manipulation of the da Vinci robot.

Prognostic outcomes and safety in patients treated with pembrolizumab for advanced urothelial carcinoma: experience in real-world clinical practice.

BACKGROUND: Prognostic outcomes and safety following treatment with pembrolizumab in patients with advanced urothelial carcinoma (UC) have not been fully elucidated in clinical practice. The aim of this study was to evaluate the oncological efficacy and safety of pembrolizumab after failure of platinum-based chemotherapy in Japanese patients with advanced UC in a routine clinical setting. METHODS: This retrospective study included 41 consecutive Japanese patients with advanced UC treated with pembrolizumab as second-line or greater therapy at Iwate Medical University Hospital from January 2018 to April 2019. RESULTS: The mean follow-up period was 6.2 months. The objective response rate, median progression-free survival, and median overall survival were 15%, 2.5 months, and 11.9 months, respectively. Univariate analysis identified poor performance status (> 1), liver metastasis, two or more metastatic organs, low hemoglobin levels, two or more prior regimens, high baseline C-reactive protein levels, higher relative C-reactive protein level change after 6 weeks, and higher relative neutrophil-to-lymphocyte ratio change after 6 weeks as significant predictors of overall survival. Among these factors, poor performance status (> 1), two or more metastatic organs, and higher relative neutrophil-to-lymphocyte ratio change after 6 weeks were identified as independent predictors of overall survival in multivariate analysis. CONCLUSIONS: The introduction of pembrolizumab can result in favorable cancer control outcomes in Japanese patients with advanced UC, and the prognosis of these patients can be stratified according to three potential parameters, including poor performance status, high number of metastatic organs, and higher relative neutrophil-to-lymphocyte ratio change.

Predictive factors for short-term biochemical recurrence-free survival after robot-assisted laparoscopic radical prostatectomy in high-risk prostate cancer patients.

BACKGROUND: We aimed to assess the short-term oncological outcomes of robot-assisted laparoscopic radical prostatectomy to determine the predictive factors associated with biochemical recurrence in high-risk prostate cancer patients. METHODS: A total of 331 patients with localized prostate cancer underwent robot-assisted laparoscopic radical prostatectomy. Of them, 113 patients were diagnosed with high-risk prostate cancer according to the D'Amico risk group classification. We evaluated the association between pre- or postoperative predictive factors and biochemical recurrence using Cox regression analysis. RESULTS: The 2-year biochemical recurrence-free survival rate was 65.0% in the high-risk group. On univariate analyses, PSA level > 20 ng/mL, Gleason pattern 5 component on biopsy, pathological stage T3 or higher, perineural invasion, and positive surgical margin were predictive factors for biochemical recurrence. On multivariate analysis, PSA level > 20 ng/mL, Gleason pattern 5 component on biopsy, perineural invasion, and positive surgical margin were identified as independent predictive factors. The 2-year biochemical recurrence-free survival rate was 36.5% for patients with PSA level > 20 ng/mL and/or Gleason pattern 5 component on biopsy. CONCLUSIONS: PSA level > 20 ng/mL and/or presence of the Gleason pattern 5 component on biopsy are predictive factors for early biochemical recurrence after robot-assisted laparoscopic radical prostatectomy in high-risk prostate cancer patients. We considered that these patients require a combined modality therapy to improve their prognosis.

Single-stage laparoscopic surgery for bilateral organ tumors using a transumbilical approach with a zigzag incision: a report of two cases.

BACKGROUND: Reduced port laparoscopic surgery (RPLS) is comparable to conventional multiport laparoscopic surgery and has the potential to provide improved cosmesis and decreased pain; as such, it satisfies a growing demand for less invasive surgical procedures. Moreover, a zigzag incision of the umbilicus results in a less visible scar in plastic surgery. Here we report a series of two cases with bilateral organ tumors treated by single-stage RPLS using a combination of a transumbilical approach and a zigzag incision. CASE PRESENTATION: Case 1: A 63-year-old man was diagnosed with right renal cell carcinoma (RCC) (clear cell carcinoma, pT1a, venous invasion (-)) and a splenic tumor (cavernous hemangioma). Case 2: An 84-year-old woman was diagnosed with concurrent left RCC (clear cell carcinoma, pT1b, 65 × 65 mm, venous invasion (+)) and ascending colon cancer (adenocarcinoma pT3 with no nodal involvement (0/48)). The perioperative course was uneventful in both cases. However, an additional incision was required in Case 2 for specimen excision. Therefore, the scars were more obvious in Case 2 than in Case 1. CONCLUSIONS: Although more cases are required to evaluate the superiority of this technique, this novel procedure could be considered for patients with bilateral lesions.

Appropriate preoperative membranous urethral length predicts recovery of urinary continence after robot-assisted laparoscopic prostatectomy.

PURPOSE: We investigated that preoperative membranous urethral length (MUL) would be associated with the recovery of urinary continence after robot-assisted laparoscopic prostatectomy (RALP). PATIENTS AND METHODS: We studied 204 patients who underwent RALP between May 2013 and March 2016. All patients underwent pelvic magnetic resonance imaging (MRI) preoperatively to measure MUL. Urinary continence was defined as the use of one pad or less (safety pad). The 204 patients were divided into two groups: continence group, those who achieved recovery of continence at 3, 6, and 12 months after RALP, and incontinence group, those who did not. We retrospectively analyzed the patients in terms of preoperative clinical factors including age, body mass index (BMI), estimated prostate volume, neurovascular bundle salvage, history of preoperative hormonal therapy, and MUL. RESULTS: The safety pad use rate was 69.6%, 86.9%, and 91.1% at 3, 6, and 12 months, respectively. On univariate and multivariate analyses, MUL were significant factors in every term of recovery of urinary continence in both groups. According to the receiver operating characteristic (ROC) curve analysis, the preoperative MUL that could best predict early recovery of urinary continence at 3 months after RALP was 12 mm. CONCLUSIONS: We suggest that preoperative MUL > 12 mm would be a predictor of early recovery of urinary continence after RALP.

Characteristics of early-onset hematotoxicity of sunitinib in Japanese patients with renal cell carcinoma.

BACKGROUND: A high incidence of severe hematological adverse events during sunitinib treatment complicates decision making on dose and treatment cycle. We identified the characteristics of early-onset hematotoxicity of sunitinib in Japanese patients with renal cell carcinoma (RCC). METHODS: Seventy-nine patients were treated with sunitinib as 6-week cycles of "4-week on 2-week off" schedule. To evaluate early-onset hematotoxicity, we compared patients with dose reduction during the first cycle (dose-reduced group, n = 57) and those who maintained the initial dose (dose-maintained group, n = 22). ABCG2 and FLT3 genotypes were analyzed for association between hematotoxicity and reported gene polymorphisms. RESULTS: Mean relative dose intensity (RDI) was similar in the two groups during the first 2 weeks of dosing in the first cycle, but was significantly lower in the dose-reduced group during the last 2 weeks. Lymphocytopenia and thrombocytopenia were observed in the dose-reduced group within the first 2 weeks. Genetic analysis indicated a significantly higher frequency of FLT3 738 T/C polymorphism in the dose-reduced group, but no significant difference in the ABCG2 421 C/A polymorphism. CONCLUSIONS: This study showed a high incidence of sunitinib-induced hematotoxicity in Japanese patients with RCC, many of whom need dose adjustment during the first cycle. Further studies should verify whether dose adjustment based on early-onset thrombocytopenia prolongs sunitinib treatment.

Non-machinery dialysis that achieves blood purification therapy without using full-scale dialysis machines.

An electrical or water supply and a blood purification machine are required for renal replacement therapy. There is a possibility that acute kidney injury can occur in large numbers and on a wide scale in the case of a massive earthquake, and there is the potential risk that the current supply will be unable to cope with acute kidney injury cases. However, non-machinery dialysis requires exclusive circuits and has the characteristic of not requiring the full-scale dialysis machines. We performed perfusion experiments that used non-machinery dialysis and recent blood purification machines in 30-min intervals, and the effectiveness of non-machinery dialysis was evaluated by the assessing the removal efficiency of potassium, which causes lethal arrhythmia during acute kidney injury. The non-machinery dialysis potassium removal rate was at the same level as continuous blood purification machines with a dialysate flow rate of 5 L/h after 15 min and continuous blood purification machines with a dialysate flow rate of 3 L/h after 30 min. Non-machinery dialysis required an exclusive dialysate circuit, the frequent need to replace bags, and new dialysate exchanged once every 30 min. However, it can be seen as an effective renal replacement therapy for crush-related acute kidney injury patients, even in locations or facilities not having the full-scale dialysis machines.

Efficacy of everolimus in patients with advanced renal cell carcinoma refractory or intolerant to VEGFR-TKIs and safety compared with prior VEGFR-TKI treatment.

OBJECTIVE: Everolimus is positioned as second-line treatment for metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitors. We investigated retrospectively the efficacy and safety of everolimus in Japanese patients with advanced renal cell carcinoma in the clinical setting. METHODS: Nineteen patients who discontinued treatment with vascular endothelial growth factor receptor-tyrosine kinase inhibitors because of disease progression or adverse events were administered everolimus. We evaluated progression-free survival, overall survival and tumor response rate of everolimus treatment. We also compared laboratory abnormalities and adverse events of everolimus treatment with those of prior vascular endothelial growth factor receptor-tyrosine kinase inhibitors therapy. RESULTS: In all patients, median progression-free survival was 8.4 months and median overall survival was not reached at 25 months. The best objective response was complete response in 1 patient and stable disease in 15 patients. Eleven patients (58%) were intolerant and 8 (42%) were refractory to prior vascular endothelial growth factor receptor-tyrosine kinase inhibitors treatment. Median overall survival was significantly longer (P < 0.01) in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-intolerant (>25 months) than in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-refractory subjects (4.3 months), and median progression-free survival tended to be better (P= 0.06) in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-intolerant (10.0 months) than in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-refractory subjects (2.5 months). Two patients discontinued everolimus treatment because of adverse events. CONCLUSIONS: In this study, the overall survival and progression-free survival were better in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-intolerant than in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-refractory subjects. The adverse event profiles of everolimus and vascular endothelial growth factor receptor-tyrosine kinase inhibitors were different. Patients intolerant to vascular endothelial growth factor receptor-tyrosine kinase inhibitors may tolerate everolimus well and have greater survival benefit from switching to everolimus than those refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitors.

Changes in Renal Function After Nephroureterectomy for Upper Tract Urothelial Cancer in Elderly Patients.

Introduction Decreased renal function after radical nephroureterectomy is one of the most important complications because it contributes to the decision to initiate adjuvant chemotherapy. This study aimed to investigate clinical factors associated with changes in renal function after radical nephroureterectomy in elderly patients. Methodology A total of 145 patients who underwent radical nephroureterectomy for upper tract urothelial carcinoma were evaluated. The renal function was calculated preoperatively, postoperatively, and one month postoperatively, and the long-term change in renal function was investigated once a year. The association between clinical factors and changes in renal function following radical nephroureterectomy in univariate and multivariate analyses was stratified by age ≥75 years and <75 years. Results The median age of the patients was 71 years, with 94 patients (65%) aged <75 years and 51 patients (35%) aged ≥75 years. The median estimated glomerular filtration rates (eGFRs) were 57.1 (21.8-100) preoperatively, 36.1 (9.1-100) postoperatively, and 42.4 (19.5-100) in one month after radical nephroureterectomy. The median eGFRs in elderly patients were 50.8 (21.8-85.4) preoperatively. In the elderly group, only 8% had an eGFR of ≥50 as cisplatin-eligible at one month postoperatively. The long-term renal function in the elderly may decline further than during the stable postoperative periods. In the multivariate analysis, hydronephrosis (HN) was a significant predictor of decreased renal function in patients aged ≥75 years between the pre- and postoperative periods. Conclusions Elderly patients with HN who have upper tract urothelial carcinoma have a lower risk of decreased renal function after radical nephroureterectomy. This result may be useful in determining adjuvant therapy.

Successful treatment of eosinophilia associated with dialysis-related renal cancer with radical nephrectomy.

Introduction: Secondary eosinophilia due to solid tumors is a rare case. This is the first study to report secondary eosinophilia due to renal cancer in a patient on dialysis. Case presentation: A 70-year-old man, on long-term hemodialysis was incidentally detected with right renal cancer, and workup performed revealed eosinophilia. Allergic symptoms caused by hemodialysis were initially considered; however, treatment did not lead to any improvement in eosinophilia. Therefore, nephrectomy for renal cancer was performed. The resolution of symptoms and eosinophilia after surgery suggested renal cancer as the cause of eosinophilia. Conclusion: As demonstrated in this patient with dialysis-related renal cancer, eosinophilia associated with solid tumors may be addressed by treating the tumor.

A case of severe ureteral injury repaired by renal autotransplantation with an iliac vein patch using bovine pericardium.

Introduction: Renal autotransplantation is considered a surgical procedure for extensive ureteral defects. Herein, we report a case of severe ureteral injury repaired by laparoscopic nephrectomy and renal autotransplantation with an iliac vein patch using bovine pericardium. Case presentation: A 56-year-old woman who had previously undergone gynecological surgery complained of right-sided abdominal pain. She was then later diagnosed with a right middle ureteral injury with a 5-cm long defect. We performed retroperitoneal laparoscopic nephrectomy and renal autotransplantation. As the iliac vein was fragile, venous patching using bovine pericardium was performed. The patient's renal function was well preserved after surgery. Conclusion: Laparoscopic nephrectomy and renal autotransplantation is an effective method for repairing severe ureteral injury with the preservation of renal function. A venous patch using bovine pericardium might be considered as a replacement for a fragile vein.

Avelumab plus axitinib for translocation renal cell carcinoma: A case series and literature review.

Introduction: Patients with translocation renal cell carcinoma (tRCC) have a poor prognosis without standardized treatment. Case presentation: The first case was of a 72-year-old woman who underwent robot-assisted partial nephrectomy for a left renal tumor and was pathologically diagnosed with tRCC. Recurrence was observed in the left retroperitoneal soft tissue. After treatment with avelumab-axitinib, continued progression-free survival was confirmed at the 90-week follow-up. The second case was of a 41-year-old woman referred to our hospital and presented with translocation renal cell carcinoma metastasis to a para-aortic lymph node. After treatment with avelumab-axitinib, continued progression-free survival was confirmed at the 43-week follow-up. Conclusion: The outcomes of these cases indicate that avelumab-axitinib therapy has a long-term antitumor effect in some patients with tRCC.

Pathological complete response to neoadjuvant chemotherapy may improve antitumor immune response via reduction of regulatory T cells in muscle-invasive bladder cancer.

The prognosis for patients who achieve a pathologic complete response in bladder cancer is excellent, but the association between their prognosis and the tumor microenvironment is unclear. We investigated the tumor immune microenvironment of those with pathological complete response after platinum-based neoadjuvant chemotherapy for cT2-4aN0M0 bladder cancer using multiplex fluorescence immunohistochemistry. Our retrospective study included 12 patients with pathological complete response who underwent radical cystectomy following neoadjuvant chemotherapy for cT2-4aN0M0 muscle-invasive bladder cancer. We assessed the density of several immune cell types in pretreatment and posttreatment tissues via multiplex fluorescence immunohistochemical analysis. The median age was 67 years; 10 patients were male. Nine (75%) and 3 (25%) patients were cT2 and cT3, respectively. The 5-year progression-free and overall survivals were 90% and 100%, respectively. The densities of regulatory T cells (Treg; CD3+CD4+FoxP3+ cell) were significantly decreased and almost disappeared in the tumor microenvironment of posttreatment tissue compared with pretreatment tissue. Other immune cells, such as effector T cells or M2 macrophages, were not significantly changed between posttreatment and pretreatment tissues. In pathological complete response, Tregs in the tumor immune microenvironment were significantly decreased after platinum-based chemotherapy for muscle-invasive bladder cancer. The temporary arresting of immune response in the tumor microenvironment may reflect a favorable prognosis due to the decrease of Tregs with tumor shrinkage and improve the host tumor immune response.

Incidence of postoperative cytomegalovirus and BK-polyoma virus infections and graft loss in ABO-incompatible renal transplant recipients: a multicenter retrospective study.

OBJECTIVES: The current study aimed to examine the incidence of perioperative infections and graft viability in ABO-compatible and ABO-incompatible renal transplant recipients. METHODS: We included 643 living donor renal transplant recipients registered in the Michinoku Renal Transplant Network from 1998 to 2021. Patients were divided into the ABO-compatible and ABO-incompatible kidney transplantation groups. We compared the characteristics of the two groups and evaluated the incidence of postoperative viral infections (cytomegalovirus and BK virus), graft loss-free survival, and overall survival between the two groups. RESULTS: Of 643 patients, 485 (75%) and 158 (25%) were ABO-compatible and ABO-incompatible renal transplant recipients, respectively. Postoperative viral infections, rituximab use, and plasma exchange were significantly more common in ABO-incompatible than in ABO-compatible transplant recipients. However, there were no significant differences in terms of other background characteristics. The ABO-incompatible group was more likely to develop viral infections than the ABO-compatible group. Graft loss-free survival and overall survival did not significantly differ between the two groups. According to the multivariate Cox regression analysis, ABO compatibility was not significantly associated with graft loss-free survival and overall survival. CONCLUSION: Although the incidence of postoperative viral infections in ABO-incompatible renal transplant recipients increased, there was no significant difference in terms of rejection events, graft loss-free survival, and overall survival.

Metastatic bladder cancer forming a sigmoidorectal fistula after enfortumab vedotin therapy: a case report.

We report the case of a 68-year-old man who developed a sigmoidorectal fistula after marked response to enfortumab vedotin for advanced bladder cancer. The patient had undergone radical cystectomy with ileal conduit after neoadjuvant chemotherapy. Six months after surgery, local recurrence in the pelvic cavity and multiple lung metastases were found, and the patient was administered pembrolizumab as second-line therapy. Due to worsening local recurrence and suspected invasion of the sigmoid colon and rectum, enfortumab vedotin was initiated as third-line therapy and comprehensive genomic profiling was simultaneously performed. Enfortumab vedotin was remarkably effective, the lung metastases disappeared, and the local recurrent lesion shrank in volume although a sigmoidorectal fistula was found to form through the tumor cavity. Immunohistochemical analysis of the tumor specimens exhibited increased nectin-4 expression. This rare case of metastatic bladder cancer with sigmoidorectal fistula associated with effective enfortumab vedotin therapy suggests that nectin-4 expression and comprehensive genomic profiling might be useful in predicting treatment response to enfortumab vedotin.

Abnormal carnitine metabolism in hemodialysis patients on different anticoagulants.

INTRODUCTION: We aimed to determine whether unfractionated heparin (UH) and low molecular weight heparin (LH) contribute to aberrant carnitine metabolism in patients receiving hemodialysis. METHODS: The rate of increase in serum free fatty acids (FFAs) and the ratio of acylcarnitine to free carnitine (AC/FC) from before to after hemodialysis were determined in patients receiving UH and LH. Additionally, the effect of switching patients to UH from LH was examined. RESULTS: AC/FC was significantly higher in the UH group. In addition, serum FFAs in that group increased to 0.825 ± 0.270 after dialysis from 0.172 ± 0.160 before dialysis, showing a positive correlation with AC/FC. Furthermore, AC/FC was observed to be significantly higher in patients who were switched to UH from LH at 3 months after the change. CONCLUSION: Compared with UH, LH has a lesser effect on lipid metabolism, suggesting that it also has a lesser effect on carnitine metabolism.