Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.

BACKGROUND: Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to VHL gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α). METHODS: In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan. RESULTS: After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl). CONCLUSIONS: Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).

Oral HIF-2α Inhibitor Belzutifan in Ocular von Hippel-Lindau Disease: Subgroup Analysis of the Single-Arm Phase 2 LITESPARK-004 Study.

OBJECTIVE: To report the efficacy of oral HIF-2α inhibitor belzutifan in participants with von Hippel-Lindau disease-associated retinal hemangioblastomas in LITESPARK-004. DESIGN: Subgroup analysis of the phase 2, single-arm, open-label LITESPARK-004 study. PARTICIPANTS: Adults with ≥1 von Hippel-Lindau disease-associated measurable renal cell carcinoma tumor not requiring immediate surgical intervention were eligible. METHODS AND INTERVENTION: Participants received oral belzutifan 120 mg once daily until disease progression or unacceptable treatment-related toxicity. MAIN OUTCOME MEASURES: Efficacy of belzutifan in retinal hemangioblastomas was a secondary end point, measured as response (improved, stable, or progressed) by independent reading center certified graders based on color fundus imaging performed every 12 weeks using the investigator's preferred imaging standards. Additional assessments, where available, included optical coherence tomography and ultra-widefield fluorescein angiography. RESULTS: Among 61 participants in LITESPARK-004, 12 had ≥1 evaluable active retinal hemangioblastoma in 16 eyes at baseline per independent reading center. As of April 1, 2022, the median follow-up for participants with ocular von Hippel-Lindau disease at baseline was 37.3 months. All 16 eyes were graded as improved, with a response rate of 100.0% (95% confidence intervals, 79.4-100.0). No new retinal hemangioblastomas or ocular disease progression were reported as of data cutoff date. Eight participants had additional multimodal eye assessments performed at the National Institutes of Health study site. Among this subgroup, 10 of 24 hemangioblastomas in 8 eyes of 6 participants measured ≥500 µm in greatest linear dimension at baseline and were further analyzed. All 10 hemangioblastomas had a mean area reduction of ≥15% by month 12 and ≥30% by month 24. CONCLUSIONS: Belzutifan showed promising activity against ocular von Hippel-Lindau disease, including capacity to control retinal hemangioblastomas, with effects sustained for >2 years while on treatment.

E-cadherin is downregulated in benign prostatic hyperplasia and required for tight junction formation and permeability barrier in the prostatic epithelial cell monolayer.

BACKGROUND: We previously reported the presence of prostate-specific antigen (PSA) in the stromal compartment of benign prostatic hyperplasia (BPH). Since PSA is expressed exclusively by prostatic luminal epithelial cells, PSA in the BPH stroma suggests increased tissue permeability and the compromise of epithelial barrier integrity. E-cadherin, an important adherens junction component and tight junction regulator, is known to exhibit downregulation in BPH. These observations suggest that the prostate epithelial barrier is disrupted in BPH and E-cadherin downregulation may increase epithelial barrier permeability. METHODS: The ultra-structure of cellular junctions in BPH specimens was observed using transmission electron microscopy (TEM) and E-cadherin immunostaining analysis was performed on BPH and normal adjacent specimens from BPH patients. In vitro cell line studies using benign prostatic epithelial cell lines were performed to determine the impact of small interfering RNA knockdown of E-cadherin on transepithelial electrical resistance and diffusion of fluorescein isothiocyanate (FITC)-dextran in transwell assays. RESULTS: The number of kiss points in tight junctions was reduced in BPH epithelial cells as compared with the normal adjacent prostate. Immunostaining confirmed E-cadherin downregulation and revealed a discontinuous E-cadherin staining pattern in BPH specimens. E-cadherin knockdown increased monolayer permeability and disrupted tight junction formation without affecting cell density. CONCLUSIONS: Our results indicate that tight junctions are compromised in BPH and loss of E-cadherin is potentially an important underlying mechanism, suggesting targeting E-cadherin loss could be a potential approach to prevent or treat BPH.

Small cell bladder cancer: should we consider prophylactic cranial irradiation?

PURPOSE: To describe the clinical characteristics, treatment patterns, and outcomes in patients with small cell bladder cancer at our institution, including those who received prophylactic cranial irradiation (PCI) for the prevention of intracranial recurrence. MATERIALS AND METHODS: Patients with small cell bladder cancer treated at a single institution between January 1990 and August 2015 were identified and analyzed retrospectively for demographics, tumor stage, treatment, and overall survival. RESULTS: Of 44 patients diagnosed with small cell bladder cancer, 11 (25%) had metastatic disease at the time of presentation. Treatment included systemic chemotherapy (70%), radical surgery (59%), and local radiation (39%). Six patients (14%) received PCI. Median overall survival was 10 months (IQR 4 - 41). Patients with extensive disease had worse overall survival than those with organ confined disease (8 months vs. 36 months, respectively, p = 0.04). Among those who received PCI, 33% achieved 5 - year survival. CONCLUSION: Outcomes for patients with small cell bladder cancer remain poor. Further research is indicated to determine if PCI increases overall survival in small call bladder cancer patients, especially those with extensive disease who respond to chemotherapy.

The comparative effectiveness of quadratus lumborum blocks and paravertebral blocks in radical cystectomy patients.

INTRODUCTION: Multimodal analgesia is an effective way to control pain and limit opioid use after surgery. The quadratus lumborum block and paravertebral block are two regional anesthesia techniques that leverage multimodal analgesia to improve postoperative pain control. We sought to compare the efficacy of these blocks for pain management following radical cystectomy. MATERIALS AND METHODS: We performed a retrospective review of radical cystectomy patients who received bilateral continuous paravertebral blocks (n = 125) or bilateral single shot quadratus lumborum blocks (n = 50) between 2014-2016. The primary outcome was postoperative opiate consumption on day 0. Secondary outcomes included self-reported pain scores and hospital length of stay. RESULTS: Quadratus lumborum block patients had similar opioid use on postoperative day 0 compared with paravertebral block patients (29 mg versus 30 mg, p = 0.90). Pain scores on postoperative day 0 were similar between quadratus lumborum block and paravertebral block groups (4.0 versus 3.8, p = 0.72); however, the paravertebral block group had lower pain scores on days 1-3 compared with the quadratus lumborum block group (all p < 0.05). Hospital length of stay was similar between groups (6.6 days versus 6.2 days, p = 0.41). CONCLUSIONS: There were no differences in opioid consumption among patients receiving bilateral single shot quadratus lumborum blocks and bilateral continuous paravertebral blocks after radical cystectomy. These data suggest that the quadratus lumborum block is a viable alternative for delivering multimodal analgesia in cystectomy patients.

Genomic investigation of etiologic heterogeneity: methodologic challenges.

BACKGROUND: The etiologic heterogeneity of cancer has traditionally been investigated by comparing risk factor frequencies within candidate sub-types, defined for example by histology or by distinct tumor markers of interest. Increasingly tumors are being profiled for molecular features much more extensively. This greatly expands the opportunities for defining distinct sub-types. In this article we describe an exploratory analysis of the etiologic heterogeneity of clear cell kidney cancer. Data are available on the primary known risk factors for kidney cancer, while the tumors are characterized on a genome-wide basis using expression, methylation, copy number and mutational profiles. METHODS: We use a novel clustering strategy to identify sub-types. This is accomplished independently for the expression, methylation and copy number profiles. The goals are to identify tumor sub-types that are etiologically distinct, to identify the risk factors that define specific sub-types, and to endeavor to characterize the key genes that appear to represent the principal features of the distinct sub-types. RESULTS: The analysis reveals strong evidence that gender represents an important factor that distinguishes disease sub-types. The sub-types defined using expression data and methylation data demonstrate considerable congruence and are also clearly correlated with mutations in important cancer genes. These sub-types are also strongly correlated with survival. The complexity of the data presents many analytical challenges including, prominently, the risk of false discovery. CONCLUSIONS: Genomic profiling of tumors offers the opportunity to identify etiologically distinct sub-types, paving the way for a more refined understanding of cancer etiology.

DLK1: a novel target for immunotherapeutic remodeling of the tumor blood vasculature.

Tumor blood vessels are frequently inefficient in their design and function, leading to high interstitial fluid pressure, hypoxia, and acidosis in the tumor microenvironment (TME), rendering tumors refractory to the delivery of chemotherapeutic agents and immune effector cells. Here we identified the NOTCH antagonist delta-like 1 homologue (DLK1) as a vascular pericyte-associated antigen expressed in renal cell carcinomas (RCC), but not in normal kidney tissues in mice and humans. Vaccination of mice bearing established RCC against DLK1 led to immune-mediated elimination of DLK1(+) pericytes and to blood vessel normalization (i.e., decreased vascular permeability and intratumoral hypoxia) in the TME, in association with tumor growth suppression. After therapeutic vaccination, tumors displayed increased prevalence of activated VCAM1(+)CD31(+) vascular endothelial cells (VECs) and CXCL10, a type-1 T cell recruiting chemokine, in concert with increased levels of type-1 CD8(+) tumor-infiltrating lymphocytes (TIL). Vaccination against DLK1 also yielded (i) dramatic reductions in Jarid1B(+), CD133(+), and CD44(+) (hypoxia-responsive) stromal cell populations, (ii) enhanced tumor cell apoptosis, and (iii) increased NOTCH signaling in the TME. Coadministration of a γ-secretase inhibitor (N-[N-(3,5-Difluorophenacetyl-l-alanyl)]-(S)-phenylglycine t-butyl ester (DAPT)) that interferes with canonical NOTCH signaling resulted in the partial loss of therapeutic benefits associated with lentivirus encoding full-length murine (lvDLK1)-based vaccination.

Belzutifan for von Hippel-Lindau Disease: Pancreatic Lesion Population of the Phase 2 LITESPARK-004 Study.

PURPOSE: Primary analysis of the ongoing, single-arm, phase 2 LITESPARK-004 study (NCT03401788) showed clinically meaningful antitumor activity in von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) and other neoplasms with belzutifan treatment. We describe results of belzutifan treatment for VHL disease-associated pancreatic lesions [pancreatic neuroendocrine tumors (pNET) and serous cystadenomas]. PATIENTS AND METHODS: Adults with VHL diagnosis based on germline VHL alteration, ≥1 measurable RCC tumor, no renal tumor >3 cm or other VHL neoplasm requiring immediate surgery, Eastern Cooperative Oncology Group performance status of 0 or 1, and no prior systemic anticancer treatment received belzutifan 120 mg once daily. End points included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and linear growth rate (LGR) in all pancreatic lesions and pNETs per RECIST version 1.1 by independent review committee, and safety. RESULTS: All 61 enrolled patients (100%) had ≥1 pancreatic lesion and 22 (36%) had ≥1 pNET measurable at baseline. Median follow-up was 37.8 months (range, 36.1-46.1). ORR was 84% [51/61; 17 complete responses (CR)] in pancreatic lesions and 91% (20/22; 7 CRs) in pNETs. Median DOR and median PFS were not reached in pancreatic lesions or pNETs. After starting treatment, median LGR for pNETs was -4.2 mm per year (range, -7.9 to -0.8). Eleven patients (18%) had ≥1 grade 3 treatment-related adverse event (AE). No grade 4 or 5 treatment-related AEs occurred. CONCLUSIONS: Belzutifan continued to show robust activity and manageable safety in VHL disease-associated pNETs.

An uncommon cause of gross hematuria: two cases of ureteroarterial fistula.

Ureteroarterial fistula (UAF) is a rare but potentially fatal cause of hematuria seen in patients with prolonged ureteral stenting in the setting of surgery or abdominal radiation. It presents as episodic, transfusion-dependent hematuria with formation of clots. There is no current consensus for the optimal way to diagnose or treat UAF. We report two cases of UAF that required repeated studies and provocative testing to confirm the diagnosis. Both were successfully managed by endovascular stenting. Clinicians must recognize the diagnostic difficulties involved and maintain a high index of suspicion for UAF in stented patients with intermittent, severe hematuria.

ACR Appropriateness Criteria® Post-Treatment Follow-up of Prostate Cancer: 2022 Update.

Prostate cancer has a wide spectrum ranging between low-grade localized disease and castrate-resistant metastatic disease. Although whole gland and systematic therapies result in cure in the majority of patients, recurrent and metastatic prostate cancer can still occur. Imaging approaches including anatomic, functional, and molecular modalities are continuously expanding. Currently, recurrent and metastatic prostate cancer is grouped in three major categories: 1) Clinical concern for residual or recurrent disease after radical prostatectomy, 2) Clinical concern for residual or recurrent disease after nonsurgical local and pelvic treatments, and 3) Metastatic prostate cancer treated by systemic therapy (androgen deprivation therapy, chemotherapy, immunotherapy). This document is a review of the current literature regarding imaging in these settings and the resulting recommendations for imaging. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Nox4 inhibition enhances the cytotoxicity of cisplatin in human renal cancer cells.

PURPOSE: Kidney cancer is notoriously chemo-resistant and abundantly expresses the Nox4 NADPH oxidase. To determine if Nox4 superoxide generation contributes to drug resistance, we assayed in vitro drug cytotoxicity following Nox4 shRNA silencing in human renal cancer cells. MATERIALS AND METHODS: Human conventional kidney cell lines, 786-0 and RCC4 expressing Nox4-specific shRNA or a non-targeting, control shRNA were grown in serial dilutions of cisplatin, vincristine, doxorubicin, or etoposide. Cell viability curves were generated and the concentration required to kill 50% of the cells (IC50) calculated for each drug. Apopotosis was estimated by TUNEL assay. Quantitative RT-PCR and Western blots were used to confirm Nox4 silencing and evaluate expression of apoptotic pathway proteins. RESULTS: Silencing significantly lowered the IC50 for cisplatin, vincristine and etoposide, and promoted drug-induced apoptosis by TUNEL assay. Improved sensitivity to cisplatin was reproduced by Nox inhibiton with diphenyliodonium, whereas induction of intracellular superoxide by dithiothreitol superoxide enhanced chemo-resistance. RT-PCR and Western blot revealed decreased expression of anti-apoptotic Bcl-XL and Bcl-2 and increased expression of pro-apoptotic Bax following Nox4 knockdown. CONCLUSION: Nox4 contributes to RCC chemo-resistance through modulation of pro-apoptotic and anti-apoptotic signaling, suggesting that Nox4 inhibition might enhance the efficacy of conventional cytotoxic drugs against RCC.

The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma.

Clear-cell renal carcinoma is associated with inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. VHL is the substrate recognition subunit of an E3 ligase, known to target the alpha subunits of the HIF heterodimeric transcription factor for ubiquitin-mediated degradation under normoxic conditions. We demonstrate that competitive inhibition of the VHL substrate recognition site with a peptide derived from the oxygen degradation domain of HIF1alpha recapitulates the tumorigenic phenotype of VHL-deficient tumor cells. These studies prove that VHL substrate recognition is essential to the tumor suppressor function of VHL. We further demonstrate that normoxic stabilization of HIF1alpha alone, while capable of mimicking some aspects of VHL loss, is not sufficient to reproduce tumorigenesis, indicating that it is not the critical oncogenic substrate of VHL.

ACR Appropriateness Criteria® Staging and Surveillance of Testicular Cancer: 2021 Update.

The staging and surveillance of testicular cancer is a complex topic, which integrates clinical, biochemical, and imaging components. The use of imaging for staging and surveillance of testicular cancer is individually tailored to each patient by considering tumor histology and prognosis. This document discusses the rationale for use of imaging by imaging modality during the initial staging of testicular seminoma and nonseminoma tumors and during the planned surveillance of stage IA and IB testicular cancer by histological subtype integrating clinical suspicion for disease recurrence in surveillance protocols. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

A 25 year perspective on the evolution and advances in an understanding of the biology, evaluation and treatment of kidney cancer.

The diagnosis, evaluation and management of patients with renal cell carcinoma has transformed in the 21st century. Utilizing biological discoveries and technological advances, the field has moved from blunt surgical and largely ineffective medical treatments, to nuanced and fine-tuned approaches based on biology, extent of disease and patient preferences. In this review we will summarize the last 25 years of progress in kidney cancer.

ACR Appropriateness Criteria® Post-Treatment Surveillance of Bladder Cancer: 2021 Update.

Urothelial cancer is the second most common cancer, and cause of cancer death, related to the genitourinary tract. The goals of surveillance imaging after the treatment of urothelial cancer of the urinary bladder are to detect new or previously undetected urothelial tumors, to identify metastatic disease, and to evaluate for complications of therapy. For surveillance, patients can be stratified into one of three groups: 1) nonmuscle invasive bladder cancer with no symptoms or additional risk factors; 2) nonmuscle invasive bladder cancer with symptoms or additional risk factors; and 3) muscle invasive bladder cancer. This document is a review of the current literature for urothelial cancer and resulting recommendations for surveillance imaging. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Optimizing Outcomes in Urological Surgery: Intraoperative Patient Safety and Physiological Considerations.

INTRODUCTION: Intraoperative surgical outcomes are influenced by a wide variety of patient, surgeon and institutional factors. The current literature lacks comprehensive resources that describe best practices in preventing patient safety events and optimizing patient physiology during urological surgery. METHODS: A multidisciplinary panel of subject matter experts (urologists, nurses, anesthesiologists) was convened to evaluate the existing literature, create a white paper and disseminate this to urological providers. Focusing on intraoperative patient safety and physiology, a narrative review was undertaken and relevant guidelines and practical interventions were highlighted. RESULTS: Patient safety is optimized by preventing surgical site infections, wrong site surgery, venous thromboembolism, falls/positioning injuries, laser/fire injuries, excessive radiation exposure and harm from the adoption of new technology. Goals for intraoperative physiological parameters (temperature, glucose, fluid balance) are addressed as well as analgesic and anesthetic considerations in urological patients. In addition, practical tools are provided to assist in the quality improvement process. CONCLUSIONS: This article summarizes intraoperative factors related to patient safety and optimal physiology that can impact urological surgical outcomes. This overview can be used as a practical guide for process improvement to optimize the quality of intraoperative care.

ACR Appropriateness Criteria® Recurrent Lower Urinary Tract Infections in Females.

Urinary tract infections (UTIs) in women are common, with an overall lifetime risk over >50%. UTIs are considered recurrent when they follow complete clinical resolution of a previous UTI and are usually defined as at least three episodes of infection within the preceding 12 months. An uncomplicated UTI is classified as a UTI without structural or functional abnormalities of the urinary tract and without relevant comorbidities. Complicated UTIs are those occurring in patients with underlying structural or medical problems. In women with recurrent uncomplicated UTIs, cystoscopy and imaging are not routinely used. In women suspected of having a recurrent complicated UTI, cystoscopy and imaging should be considered. CT urography or MR urography are usually appropriate for the evaluation of recurrent complicated lower urinary tract infections or for women who are nonresponders to conventional therapy, develop frequent reinfections or relapses, or have known underlying risk factors. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.