Clinical practice pattern in patients with advanced urothelial cancer who had progressed on pembrolizumab in the pre-enfortumab vedotin era.

OBJECTIVES: Pembrolizumab, an anti-PD-1 monoclonal antibody, revolutionized the treatment for advanced urothelial carcinoma. However, the standard treatment for patients after disease progression with pembrolizumab had not been established until the recent approval of enfortumab vedotin. We analyzed the treatment of these patients in the real world, and the patient background and outcomes. METHODS: We extracted data from 543 patients who experienced progressive disease after pembrolizumab initiation from a Japanese nation-wide cohort of platinum-refractory, metastatic urothelial carcinoma. RESULTS: The median overall survival of the 543 patients was 3.5 months (95% confidence interval 3.0-4.1). Of these, only 20.6% (n = 112) received chemotherapy as a subsequent systemic treatment after progressive disease. The regimen of chemotherapy was very diverse. The median overall survival was 11.9 months (95% confidence interval 9.2-14.7) for patients who received chemotherapy, compared to 2.4 months for those who did not receive chemotherapy (95% confidence interval 2.1-2.9; P < 0.0001). Patients who received subsequent chemotherapy were more likely to have better performance status, neutrophil-to-lymphocyte ratio <3, hemoglobin >11 mg/dL, and history of a single chemotherapeutic regimen at pembrolizumab initiation. CONCLUSIONS: This report highlights the real-world practice of the management after pembrolizumab treatment failure in the pre-enfortumab vedotin era, characterized by infrequent use of subsequent anticancer therapy comprising various regimens, reflecting the lack of a standard treatment. Clinical introduction of enfortumab vedotin is expected to improve treatment outcomes in this setting. The present study will provide important baseline data for evaluating the influence of enfortumab vedotin on clinical practices and outcomes.

Development of novel and non-invasive diagnostic markers for lower urinary tract symptoms using urothelial cells in voided urine.

OBJECTIVES: We evaluated the association between lower urinary tract symptoms (LUTS) and the expression of connexin (Cx) and transient receptor potential (TRP) channel on urothelial cells non-invasively collected from voided urine in humans. METHODS: A total of 55 patients (36 males and 19 females, median age: 71 years old), who were followed up at University of Yamanashi Hospital, were enrolled in the present study. Urothelial cells were collected from voided urine of patients, and the mRNA expression of each subtype of Cxs and TRP channels was measured using quantitive real-time reverse transcription polymerase chain reaction. We then analyzed the correlation between the expression of Cxs and TRP channels and symptom scores in International Prostate Symptom Scoreand Overactive Bladder Symptom Score, in addition to Interstitial Cystitis Symptom Index (ICSI) from only interstitial cystitis (IC) patients. RESULTS: Non-adjusted statistical procedure using Spearman's rank-correlation showed that there were significant correlations between the following expressions and symptom scores; (positive correlations) Cx26 versus urgency score, Cx40 versus nocturia, TRPM2 versus intermittency, TRPV1 versus urge incontinence, (negative correlation) Cx40 versus intermittency, TRPM7 versus pollakisuria. However, a multiple comparison adjustment using Bonferroni correction showed that only Cx40 had a trend of correlation with nocturia in ICSI. CONCLUSIONS: The expressions of Cxs and TRP channels on urothelial cells in voided urine could be related to LUTS. Further analysis of urothelial cells in voided urine has the potential to reveal the mechanism of the LUTS and develop new markers with non-invasive methods.

Robot-assisted radical nephroureterectomy for right renal pelvic tumor post sacrocolpopexy with mesh: A case report.

INTRODUCTION: Robot-assisted nephroureterectomy for upper tract urothelial carcinoma has been increasingly performed as a minimally invasive procedure recently. However, there are concerns regarding its adoption in highly complex cases with dense adhesions. PRESENTATION OF CASE: An 86-year-old woman presented to our hospital with gross hematuria one year after having undergone robot-assisted sacrocolpopexy using a mesh for pelvic organ prolapse. Cystoscopy revealed hematuria from the right ureteral orifice. Computed tomography suggested right hydronephrosis; retrograde pyelography showed a defect in the right renal pelvis with class V urine cytology of the urine from the right kidney. Based on these findings, a right renal pelvic tumor was diagnosed, and robot-assisted nephroureterectomy was performed. The patient was discharged on postoperative day 7 without complications. DISCUSSION: To the best of our knowledge, this is the first case report in which robot-assisted radical nephroureterectomy was performed after robot-assisted sacrocolpopexy with a mesh. Dense tissue adhesions are encountered not only between the bladder and the anterior vaginal wall but also around the right ureter in the pelvis. In this case, dense adhesions were confirmed around the right ureter in the pelvis. CONCLUSION: Robot-assisted nephroureterectomy may be considered an option for minimally invasive surgery in cases with a history of pelvic organ prolapse surgery using mesh.

Optogenetic stimulation of neurons in the anterior cingulate cortex induces changes in intravesical bladder pressure and the micturition reflex.

Lower urinary tract (LUT) function is controlled by the central nervous system, including higher-order cognitive brain regions. The anterior cingulate cortex (ACC) is one of these regions, but the role of its activity in LUT function remains poorly understood. In the present study, we conducted optogenetic experiments to manipulate neural activity in mouse ACC while monitoring bladder pressure to elucidate how the activity of ACC regulates LUT function. Selective optogenetic stimulation of excitatory neurons in ACC induced a sharp increase in bladder pressure, whereas activation of inhibitory neurons in ACC prolonged the interval between bladder contractions. Pharmacological manipulation of ACC also altered bladder contractions, consistent with those observed in optogenetic experiments. Optogenetic mapping of the cortical area responsible for eliciting the increase in bladder pressure revealed that stimulation to ACC showed more potent effects than the neighboring motor cortical areas. These results suggest that ACC plays a crucial role in initiating the bladder pressure change and the micturition reflex. Thus, the balance between excitation and inhibition in ACC may regulate the reflex bidirectionally.

Effect of rechallenge nivolumab in a hemodialysis patient with multiple metastases from a rapidly progressed T1a renal clear cell carcinoma: An autopsy case.

Introduction: Distant metastasis of T1a renal cell carcinoma is rare and whether metastasis is more probable in patients undergoing hemodialysis remains unclear. We report the autopsy case of a patient undergoing hemodialysis with multiple metastases that rapidly progressed from T1a renal cell carcinoma treated with multimodal therapy including nivolumab. Case presentation: A 70-year-old male who underwent hemodialysis was diagnosed with clear cell carcinoma (pT1a, G2) after nephrectomy. Six months post-surgery, bone and lung metastases appeared and treated with radiotherapy and pazopanib, respectively. Nivolumab was administered as second- and fourth-line treatments for lung metastases. The patient died approximately 60 months after initial diagnosis; however, nivolumab controlled disease progression for 24 months. An autopsy revealed the lung's occupation with clear cell carcinoma tumor tissue. Conclusion: Nivolumab has potential to control lung metastasis progression. Additionally, rechallenge is possible in patients with renal cell carcinoma undergoing hemodialysis.

Hypopituitarism induced by pembrolizumab plus axitinib in the treatment of metastatic renal cell carcinoma: A case report.

Immune checkpoint inhibitor (ICI) therapies have broadened the armamentarium for metastatic renal cell carcinoma (mRCC). As the ICI therapy spreads in the clinical settings, immune-related adverse events are more of a concern for clinicians. The present study reports three cases of mRCC treated with pembrolizumab plus axitinib and diagnosed hypopituitarism based on clinical symptoms and hormonal profile. Acute methylprednisolone infusion therapy was necessary in one case because of severe adrenal hypofunction; however, the clinical symptoms of the other two cases were controlled with oral corticosteroid therapy. To the best of our knowledge, there is no report of pembrolizumab plus axitinib related hypopituitarism in the treatment of mRCC. The present cases suggests that hypopituitarism after pembrolizumab plus axitinib treatment for mRCC can be handled with steroid therapy even after the development of hypopituitarism.

Enfortumab Vedotin-Induced Febrile Neutropenia and Hyperglycemia Successfully Treated with Multidisciplinary Treatment Including Continuous Hemodialysis Filtration and Insulin Injection in a Patient with Chemo-Resistant Metastatic Urothelial Carcinoma: A Case Report.

Introduction: Enfortumab vedotin (EV) is an antibody-drug conjugate combining a monoclonal antibody targeting nectin-4 with a highly potent microtubule disrupting agent. EV is expected to be a candidate for the third-line treatment for urothelial carcinoma previously treated with platinum-based chemotherapy and PD-1/PD-L1 inhibitors. Very few cases of patients experienced hyperglycemia of unknown cause. Case Presentation: We describe a 72-year-old Asian man with mild obesity, type 2 diabetes, hyperlipidemia, hypertension, and chemo-resistant metastatic urothelial carcinoma. He developed hyperglycemia and febrile neutropenia after 3 doses of EV. He had hyperglycemia of 489 mg/dL and was started on continuous intravenous insulin infusion (CVII). The patient's intravenous insulin requirements peaked at 316 units per day. He also developed febrile neutropenia and consequent sepsis caused acute kidney injury. Continuous hemodialysis filtration (CHDF) together with antibiotics were started to treat the septic condition. The blood glucose level gradually decreased after CHDF treatment and CHDF was continued for 14 days. The timing of liberation from CHDF correlated with the elimination half-life of EV of 3.4 days. CVII was treated for 26 days and the patient was finally released from the intensive care unit. Conclusion: This case indicates that the uncontrollable hyperglycemia induced by EV during metastatic urothelial carcinoma treatment is effectively managed with CVII and CHDF until the elimination of the adverse effect of EV.