Near Complete Response to Platinum-based Systemic Chemotherapy in High-risk Upper Tract Urothelial Carcinoma With an ERBB2 Gene Mutation: A Case Report.

In bladder urothelial carcinoma, ERBB2 mutations have been associated with favorable response to platinum-based neoadjuvant chemotherapy. However, this association has not been reported in upper tract urothelial carcinoma (UTUC). We describe an excellent response to cisplatin-based chemotherapy in metastatic UTUC with an ERBB2 mutation. Our patient is a 54-year-old female with metastatic UTUC who received systemic cisplatin and gemcitabine. Postchemotherapy imaging demonstrated decreased size of pyelocaliceal mass and decreased retroperitoneal adenopathy compared to initial imaging. Surgical pathology from consolidative resection showed 3 mm residual renal tumor and no viable lymph node disease. Genomic testing demonstrated an ERBB2 gain of function mutation.

Molecular characterization of plasmacytoid urothelial carcinoma and the impact on treatment implications.

Bladder cancer researchers and clinicians have increasingly viewed tumor biology through the lens of genomic and molecular alterations, drastically improving our knowledge of the underlying disease biology. This understanding has led to significant advances in treatment options that allow implementation of a personalized approach to cancer treatment. Large-scale genomic studies initially focused on the most common forms of bladder cancer. However, as genomic and molecular technologies become more widespread and are applied to less common variant histologies, we are gaining additional insight into the unique molecular and genomic characteristics driving the biology of variant histologies of bladder cancer. In this review, we summarize the current state of knowledge of molecular alterations underlying the distinct tumor biology of plasmacytoid urothelial carcinoma and how these alterations may impact treatment options.

The effect of treatment on work productivity in patients with bladder cancer.

OBJECTIVE: To describe the impact of bladder-preserving treatment vs. cystectomy on work productivity and activity impairment (WPAI) among patients with bladder cancer. METHODS: Using cross-sectional survey data, we constructed 2-part models involving both logistic and linear prediction to describe the relationship between WPAI and treatment modality among patients with non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). RESULTS: A total of 848 patients were included in the analysis. Patients with NMIBC who had cystectomy were more likely to experience activity impairment compared with those receiving bladder-preserving treatment (OR: 4.25, 95% CI: 2.28-7.93). Among patients with MIBC, cystectomy was protective against increasing presenteeism (e^ß: 0.41, 95% CI: 0.23-0.71) and productivity loss (e^ß: 0.44, 95% CI: 0.21-0.88); however, the opposite effect was seen for absenteeism treatment (e^ß: 4.82, 95% CI: 1.72-13.49). CONCLUSION: Cystectomy increased the odds of experiencing activity impairment for patients with NMIBC. However, for patients with MIBC, cystectomy appears to be protective for presenteeism and productivity loss. Further work is needed in order to better understand these important relationships and improve both patient counseling and shared decision-making.

PBRM1 Inactivation Promotes Upregulation of Human Endogenous Retroviruses in a HIF-Dependent Manner.

Clear cell renal cell carcinoma (ccRCC) is considered an immunotherapy-responsive disease; however, the reasons for this remain unclear. Studies have variably implicated PBRM1 mutations as a predictive biomarker of immune checkpoint blockade (ICB) response, and separate studies demonstrate that expression of human endogenous retroviruses (hERV) might be an important class of tumor-associated antigens. We sought to understand whether specific mutations were associated with hERV expression. Two large, annotated genomic datasets, TCGA KIRC and IMmotion150, were used to correlate mutations and hERV expression. PBRM1 mutations were consistently associated with increased hERV expression in primary tumors. In vitro silencing of PBRM1, HIF1A, and HIF2A followed by RNA sequencing was performed in UMRC2 cells, confirming that PBRM1 regulates hERVs in a HIF1α- and HIF2α-dependent manner and that hERVs of the HERVERI superfamily are enriched in PBRM1-regulated hERVs. Our results uncover a role for PBRM1 in the negative regulation of hERVs in ccRCC. Moreover, the HIF-dependent nature of hERV expression explains the previously reported ccRCC-specific clinical associations of PBRM1-mutant ccRCC with both a good prognosis as well as improved clinical outcomes to ICB. See related Spotlight by Labaki et al., p. 274.

Implementation of Postoperative Standard Opioid Prescribing Schedules Reduces Opioid Prescriptions Without Change in Patient-reported Pain Outcomes.

OBJECTIVE: To implement Standard Opioid Prescribing Schedules (SOPS) based on opioid use following urologic surgeries and to evaluate how evidence-based prescribing schedules affect opioid use and patient reported outcomes. METHODS: Patients who underwent urologic surgeries within 6 procedure subtypes at UNC Health during the 2 study time periods ("pre-SOPS": 7/2017-1/2018, "post-SOPS": 7/2018-1/2019) were invited to complete a survey analyzing postoperative opioid usage, storage and disposal, and patient reported outcomes (including pain interference using a validated questionnaire). A pharmacy database provided medication prescribing data and patient demographics. During the pre-SOPS time period, baseline outcomes were measured. Following the pre-SOPS period, usage amounts were analyzed and Standard Opioid Prescribing Schedules were developed to guide prescriptions during the post-SOPS period. Descriptive summary statistics and appropriate t test or r2 were calculated. RESULTS: A total of 438 patients within 6 procedure types completed the survey (pre-SOPS: 282 patients, post-SOPS: 156 patients). Pre-SOPS, patients were prescribed significantly more 5-mg oxycodone tablets than used (20.9 vs 7.8, P <.001). Post-SOPS, compared to pre-SOPS amounts, patients were prescribed significantly fewer tablets (12.7 vs 20.9, P <.001) and used fewer tablets (5.3 vs 7.8, P = .003). No difference was observed in pain interference (average t-score (standard deviation): 54.33 (10.9) pre-SOPS vs 55.89 (9.1) post-SOPS, P = .125) or patient satisfaction (95% pre-SOPS vs 94% post-SOPS). CONCLUSION: Adherence to data-driven postoperative opioid prescribing schedules reduce opioid prescriptions and use without compromising pain interference or patient satisfaction. These results have important implications for urologists' ability to decrease opioid prescriptions and fight the opioid epidemic.

Correction: SETD2 loss sensitizes cells to PI3Kß and AKT inhibition.

[This corrects the article DOI: 10.18632/oncotarget.26567.].

SETD2 loss sensitizes cells to PI3Kß and AKT inhibition.

Upregulation of the PI3K pathway has been implicated in the initiation and progression of several types of cancer, including renal cell carcinoma (RCC). Although several targeted therapies have been developed for RCC, durable and complete responses are exceptional. Thus, advanced RCC remains a lethal disease, underscoring the need of robust biomarker-based strategies to treat RCC. We report a synthetic lethal interaction between inhibition of phosphatidylinositol 3-kinase beta (PI3Kß) and loss of SETD2 methyltransferase. Clear cell RCC (ccRCC)-derived SETD2 knockout 786-0 and SETD2 mutant A498 cells treated with TGX221 (PI3Kß-specific) and AZD8186 (PI3Kß- and δ-specific) inhibitors displayed decreased cell viability, cell growth, and migration compared to SETD2 proficient 786-0 cells. Inhibition of the p110 δ and α isoforms alone had modest (δ) and no (α) effect on ccRCC cell viability, growth, and migration. In vivo, treatment of SETD2 mutant A498 cells, but not SETD2 proficient 786-0 cells, with AZD8186 significantly decreased tumor growth. Interestingly, inhibition of the downstream effector AKT (MK2206) recapitulated the effects observed in AZD8186-treated SETD2 deficient cells. Our data show that specific inhibition of PI3Kß causes synthetic lethality with SETD2 loss and suggest targeting of the AKT downstream effector pathway offers a rationale for further translational and clinical investigation of PI3Kß-specific inhibitors in ccRCC.