UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

UNASSIGNED: Few studies have reported on administering enfortumab vedotin to patients with metastatic urothelial carcinoma and end-stage renal disease requiring hemodialysis.
UNASSIGNED: Case 1: An 85-year-old man underwent hemodialysis for progressive renal failure 4 months after right laparoscopic radical nephroureterectomy. Case 2: A 73-year-old man underwent hemodialysis after two laparoscopic radical nephroureterectomies for recurrent urothelial carcinoma. In both cases, enfortumab vedotin was administered due to postoperative recurrence and progression despite platinum-based chemotherapy and pembrolizumab. Partial response and disease progression were observed in cases 1 and 2, respectively. Adverse events included a mild skin rash in both patients and neutropenia in Case 1, both of which resolved with symptomatic treatment.
UNASSIGNED: The efficacy and safety of enfortumab vedotin in patients with metastatic urothelial carcinoma, and end-stage renal disease undergoing hemodialysis, were confirmed.

The increasing incidence of urothelial carcinoma, coupled with advancements in its therapeutic landscape, has resulted in improved survival rates for patients. This, in turn, has led to a growing population of patients requiring specialized oncological care, with Enfortumab vedotin (EV) emerging as a pivotal treatment for metastatic urothelial carcinoma. While EV is associated with hyperglycemia, ketoacidosis is exceedingly rare. To the best of our knowledge, the link between EV and hemophagocytic lymphohistiocytosis (HLH) has not yet been explored. A 56-year-old patient diagnosed with metastatic urothelial carcinoma underwent EV treatment as a third-line treatment after progression following treatment with cisplatin/gemcitabine and pembrolizumab. Notably, after receiving two doses of EV, the patient exhibited refractory insulin resistance, leading to ketoacidosis. Subsequently, HLH emerged, necessitating a treatment regimen involving dexamethasone and etoposide. Despite intensive efforts, the patient experienced septic shock, resulting in death. The present case report highlights refractory insulin resistance and ketoacidosis, followed by reactive HLH, in the context of EV therapy. The limited literature on these complications demonstrates the need for further research to improve the understanding of the underlying mechanisms. With growing evidence of the efficacy of EV and evolving survival rates in urothelial carcinoma, healthcare professionals must remain vigilant for potential adverse effects, ensuring early recognition and optimal patient care.

Among upper urinary tract urothelial carcinoma (UUTUC) cases, there are few reports of the clear cell variant. Systemic chemotherapy will be given according to the usual treatment for urothelial cancer unless lymph nodes or organ metastases make surgical treatment inappropriate. Here, we report a clear cell variant of UUTUC of the left renal pelvis with aortic lymph node metastasis. The patient in this case was treated with systemic chemotherapy, anti-programmed death-ligand 1 (PD-L1) maintenance treatment, radiation therapy, and enfortumab vedotin (EV) therapy. To determine which of the treatments contributed to the therapeutic effect, immunostaining was used. The results indicated that Nectin-4 was expressed in clear cell variant tissues, while programmed cell death protein 1 (PD-1) and PD-L1 expression levels were weak in these tissues. The patient maintained complete remission with these treatments. Two years after the initial treatment, the patient was still alive with no progression or metastasis.

There are very few therapeutic options to treat patients with locally advanced or metastatic Urothelial Cancer (UC). Enfortumab vedotin (EV) was recently approved by the FDA and has become a new therapeutic option for patients previously managed with conventional treatments. Despite its efficacy, EV carries the potential for infrequent yet severe adverse effects. In this report, we present a case of a patient undergoing EV treatment for urothelial carcinoma who developed refractory diabetic ketoacidosis (DKA) unresponsive to escalating insulin doses and necessitating continuous renal replacement therapy. While DKA was resolved, the patient eventually succumbed to progressive maculopapular skin rash, liver failure, and respiratory failure. Additionally, the study delves into a review of cases of EV-induced refractory DKA in the literature, shedding light on the similarities in patient profiles, timelines of adverse effects and the treatment strategies employed to manage the ensuing complications.

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Enfortumab vedotin is a novel breakthrough therapy that received accelerated US Food and Drug Administration approval in 2019 for the treatment of metastatic urothelial carcinoma in patients who have failed other lines of treatment. The characteristics of its adverse effects are not well understood. Diabetic ketoacidosis has been reported in 2 postmarketing reports presented as abstracts at the 2020 American Thoracic Society Conference and the 2021 American Society of Nephrology Conference. Both cases progressed rapidly and expired in <3 days. We present a similar case of a man in his late 50s with no history of diabetes who was diagnosed with urothelial carcinoma 2 years prior. Despite several lines of treatment, including platinum-based chemotherapy and immune checkpoint inhibitors, he developed metastasis and was started on enfortumab vedotin. After his second dose of enfortumab vedotin, he was admitted to the intensive care unit for diabetic ketoacidosis with an initial A1C level of 7.7%. He was intubated for airway protection, started on pressors, and developed oliguric acute kidney injury requiring continuous venovenous hemodialysis. Despite aggressive treatment, the patient died on hospital day 2. The lethality of this aggressive diabetic ketoacidosis despite therapy suggests some other effect of enfortumab vedotin on glucose metabolism in addition to insulin resistance and the need for prior diabetes screening.

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.

A 39-year-old Japanese male patient presented with a chief complaint of gross hematuria persistent for two months. However, no relevant findings in the patient\'s medical and family history were observed. He was diagnosed with muscle-invasive bladder cancer, clinical stage T2bN0M0. After four courses of neoadjuvant chemotherapy with gemcitabine and cisplatin, the tumor size reduced by approximately 30%. The patient underwent robot-assisted radical cystectomy with standard lymph node dissection followed by intracorporeal ileal conduit reconstruction. Histologically, the tumor was diagnosed as a high-grade urothelial carcinoma invading the fatty tissue surrounding the bladder and metastasizing to the lymph nodes, with a pathological stage of ypT3aypN2M0. Four months after surgery, multiple metastases were detected, and treatment with pembrolizumab was initiated immediately. However, the patient did not respond to pembrolizumab. Therefore, a third-line treatment with enfortumab vedotin (EV) was initiated. Thereafter, the metastatic lesion shrank quickly, and the metastatic lesions almost disappeared after two courses of EV administration. Although new metastases were observed at other sites, there has been no regrowth to date. EV-related adverse events were not observed during follow-up. Eighteen months after the surgery, the patient remains alive with multiple metastases. Therefore, the sequence of treatment should be considered to maximize the therapeutic effect of EV, and, consequently, administering EV as early as possible may be important.

Enfortumab vedotin (EV) is an antibody-drug conjugate and a promising agent for metastatic urothelial carcinoma (mUC). However, evaluations in end-stage renal disease patients undergoing hemodialysis are unreported. Here, we report such a case. A 74-year-old woman with mUC, on hemodialysis for complete urinary tract extirpation, was diagnosed with multiple pulmonary metastases after treatment with gemcitabine-carboplatin followed by pembrolizumab. As third-line therapy, she received a standard dose of EV. She achieved complete response after 2 cycles without grade 3 or higher adverse events, demonstrating the utility of EV in this setting.