Renal cell carcinoma histologic subtypes exhibit distinct transcriptional profiles.

Molecular profiling of clear cell renal cell carcinoma (ccRCC) tumors of patients in a clinical trial has identified distinct transcriptomic signatures with predictive value, yet data in non-clear cell variants (nccRCC) are lacking. We examined the transcriptional profiles of RCC tumors representing key molecular pathways, from a multi-institutional, real-world patient cohort, including ccRCC and centrally reviewed nccRCC samples. ccRCC had increased angiogenesis signature scores compared with the heterogeneous group of nccRCC tumors, while cell cycle, fatty acid oxidation/AMPK signaling, and fatty acid synthesis/pentose phosphate signature scores were increased in one or more nccRCC subtypes. Among both ccRCC and nccRCC tumors, T effector scores statistically correlated with increased immune cell infiltration and were more commonly associated with immunotherapy-related markers (PD-L1+/TMBhi/MSIhi). In conclusion, this study provides evidence of differential gene transcriptional profiles among ccRCC versus nccRCC tumors, providing insights for optimizing personalized and histology-specific therapeutic strategies for patients with advanced RCC.

Analysis of treatment of muscle invasive bladder cancer using the national cancer database: Factors associated with receipt of aggressive therapy.

OBJECTIVES: To characterize the treatments received by muscle-invasive bladder cancer (MIBC) patients, analyze their use according to sociodemographic, clinical, pathologic, and facility variables, and identify possibilities for improvement in care, with the understanding that patients with MIBC face a potentially lethal disease, yet often do not receive guideline-concordant potentially curative therapies. MATERIALS AND METHODS: Using the National Cancer Data Base (NCDB), we analyzed 102,119 patients with MIBC diagnosed from 2009 to 2018. Treatments included cystectomy, radiation, chemotherapy (CT), or observation. Treatments including cystectomy or radiotherapy (RT) ≥50 Gy were considered aggressive therapy (AT). A multivariable generalized estimating equation model was used to assess the impact of the independent variables with receiving AT, using SAS version 9.4. RESULTS: The median age was 73 years, with 72.9% male, 84.3% White, and 7.1% Black. Stage distribution was 59.4% stage II, 23.0% stage III, and 17.6% stage IV. Overall, 55.2% of patients received AT, while 41.1% did not, with 26.6% receiving observation alone after transurethral resection of bladder tumor. 45.4% received cystectomy, 9.8% received RT, and 12.8% received CT as primary treatment. Notably, over 30% of patients ages 50 to 70 did not receive aggressive therapy. On multivariate analysis, factors associated with nonreceipt of AT included age >70 (OR < 0.79, P < 0.0001), Black race (OR 0.70, P < 0.0001), underinsured status (OR 0.62, P < 0.0001), high comorbidity (OR 0.74, P < 0.0001), and treatment at low volume (OR 0.72 P < 0.0001) or nonacademic cancer program (OR 0.54, P < 0.0001). Long-term trends included increases in utilization of perioperative CT (17.5% in 2009 to 46.7% in 2018, P < 0.001), and chemoradiation (5.4% in 2009 to 8.8% in 2018, P < 0.001). Using Cox regression analysis to control for confounding variables, receipt of aggressive therapy was associated with improved overall survival. CONCLUSIONS: Over a third of patients did not receive AT for MIBC, with many of these patients seemingly eligible by age and comorbidity status. Prospective studies are needed to determine why these patients do not receive AT. A better understanding of patient vs. access to care vs. provider factors will help to focus efforts to improve care for MIBC patients.

Mechanisms of tyrosine kinase inhibitor resistance in renal cell carcinoma.

Renal cell carcinoma (RCC), the most prevalent type of kidney cancer, is a significant cause of cancer morbidity and mortality worldwide. Antiangiogenic tyrosine kinase inhibitors (TKIs), in combination with immune checkpoint inhibitors (ICIs), are among the first-line treatment options for patients with advanced RCC. These therapies target the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase pathway and other kinases crucial to cancer proliferation, survival, and metastasis. TKIs have yielded substantial improvements in progression-free survival (PFS) and overall survival (OS) for patients with advanced RCC. However, nearly all patients eventually progress on these drugs as resistance develops. This review provides an overview of TKI resistance in RCC and explores different mechanisms of resistance, including upregulation of alternative proangiogenic pathways, epithelial-mesenchymal transition (EMT), decreased intracellular drug concentrations due to efflux pumps and lysosomal sequestration, alterations in the tumor microenvironment including bone marrow-derived cells (BMDCs) and tumor-associated fibroblasts (TAFs), and genetic factors such as single nucleotide polymorphisms (SNPs). A comprehensive understanding of these mechanisms opens the door to the development of innovative therapeutic approaches that can effectively overcome TKI resistance, thereby improving outcomes for patients with advanced RCC.

Emerging perioperative therapeutic approaches in muscle invasive bladder cancer.

Bladder cancer is a significant healthcare burden with more than 17,000 deaths in the United States in 2018. Patients who are diagnosed with muscle invasive bladder cancer (MIBC) have a high rate of micro-metastatic disease and have a much poorer prognosis compared with patients who have less advanced lesions. Historically, neoadjuvant administration of cisplatin-based therapy followed by surgery has been the mainstay of treatment. Unfortunately, of patients who come in with initially diagnosed MIBC, more than 50% are ineligible for traditional cisplatin-based therapy. Today, new modalities of treatment such as immune checkpoint inhibitors are beginning to radically improve outcomes in this population. The addition of immune checkpoint therapy to traditional chemotherapy appears to augment pathologic complete response rates in the bladder during surgery. Immunotherapy combinations also provide novel trimodality approaches with excellent outcomes in those pursuing non-surgical management. Pure immunotherapy approaches appear promising in the neoadjuvant and adjuvant setting, and the immune checkpoint inhibitor nivolumab is now approved in the adjuvant setting for high-risk patients. Antibody drug conjugates, such as enfortumab vedotin, and targeted therapies, such as infigratinib, are in trials in the perioperative setting. This review article summarizes the current evidence and likely future developments for the management of muscle invasive bladder cancer in 2022 and beyond.

Understanding the Uptake and Challenges of Genetic Testing Guidelines for Prostate Cancer Patients.

BACKGROUND: Multiple studies have confirmed a high prevalence of prognostic germline mutations in prostate cancer. In recognition, the NCCN guidelines and recommendations for genetic counselling (GC) in prostate cancer patients were expanded. METHODS: Data on prostate cancer patients at a single tertiary cancer center from January 2019 - June 2019 were queried. The cohort of patients from the queried list were evaluated for their eligibility for genetic testing. From the patients that were eligible for testing, the rate of referrals was ascertained. A 10-item questionnaire was concurrently sent to providers to understand germline genetic testing patterns and potential barriers. RESULTS: Only 39% of the eligible prostate cancer patients were referred, with testing completed in 11% with indications. 30% of providers reported they would be comfortable completing genetic counseling themselves. The identified barriers to provide genetic testing themselves were lack of time and expertise (50%). Other barriers included: lack of genetic counselor workforce (70%), lack of knowledge of genetic testing and the inadequate co-ordination of referrals (60%). CONCLUSION: In this retrospective study, many patients met the criteria for GC, however, the referrals for this patient population are inconsistent, and only a handful of the eligible patients completed testing. Identified barriers were provider's knowledge and comfort with guidelines and testing, systemic bottlenecks such as limited capacity of genetic counsellors, and the creation of improved workflows.

Multi-institutional Analysis of the Clinical and Genomic Characteristics of Black Patients with Metastatic Hormone-Sensitive Prostate Cancer.

BACKGROUND: The outcomes of metastatic hormone-sensitive prostate cancer (mHSPC) have significantly improved through treatment intensification, yet Black representation in those studies is suboptimal. METHODS: A multi-institutional, retrospective analysis of Black men with mHSPC was conducted, focusing on baseline demographics, treatment patterns, genomic profiles, clinical outcomes including prostate-specific antigen response, time to castrate-resistant prostate cancer (CRPC), and subsequent treatments. RESULTS: A total of 107 patients, median age 64 years, 62% with de novo metastases at diagnosis and 64% with high-volume disease, were included. Twenty-nine patients (27%) were treated with androgen deprivation therapy (ADT) with and without first generation anti-androgens, while 20%, 38% and 5% received chemotherapy, abiraterone, and enzalutamide, respectively. At time of data cut-off, 57 (54%) patients had developed CRPC, with a median time to CRPC of 25.4 months (95% CI 20.3-30.4). The median time to CRPC was 46.3 months (18.9-73.7) and 23.4 months (18.6-28.2) for patients who received ADT with or without first-generation anti-androgens and treatment intensification, respectively. The 2-year survival rate was 93.3%, and estimated median overall survival of was 74.9 months (95% CI, 68.7-81.0). Most patients (90%) underwent germline testing; the most frequent known alterations were found within the DNA repair group of genes. Somatic testing revealed pathogenic alterations of interest, notably TP53 (24%) and CDK12 (12%). CONCLUSION: In our cohort, Black men with mHSPC presented with a high proportion of de novo metastases and high-volume disease. Treatment outcomes were very favorable with ADT-based regimens. The genomic landscape suggests different molecular profile relative to White patients with potential therapeutic implications.

Efficacy of enfortumab vedotin in advanced urothelial cancer: Analysis from the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study.

BACKGROUND: Enfortumab vedotin (EV) is a novel antibody-drug conjugate approved for advanced urothelial cancer (aUC) refractory to prior therapy. In the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study, the authors looked at the experience with EV in patient subsets of interest for which activity had not been well defined in clinical trials. METHODS: UNITE was a retrospective study of patients with aUC treated with recently approved agents. This initial analysis focused on patients treated with EV. Patient data were abstracted from chart reviews by investigators at each site. The observed response rate (ORR) was investigator-assessed for patients with at least 1 post-baseline scan or clear evidence of clinical progression. ORRs were compared across subsets of interest for patients treated with EV monotherapy. RESULTS: The initial UNITE analysis included 304 patients from 16 institutions; 260 of these patients were treated with EV monotherapy and included in the analyses. In the monotherapy cohort, the ORR was 52%, and it was >40% in all reported subsets of interest, including patients with comorbidities previously excluded from clinical trials (baseline renal impairment, diabetes, and neuropathy) and patients with fibroblast growth factor receptor 3 (FGFR3) alterations. Progression-free survival and overall survival were 6.8 and 14.4 months, respectively. Patients with a pure urothelial histology had a higher ORR than patients with a variant histology component (58% vs 42%; P = .06). CONCLUSIONS: In a large retrospective cohort, responses to EV monotherapy were consistent with data previously reported in clinical trials and were also observed in various patient subsets, including patients with variant histology, patients with FGFR3 alterations, and patients previously excluded from clinical trials with an estimated glomerular filtration rate < 30 mL/min and significant comorbidities. LAY SUMMARY: Enfortumab vedotin, approved by the Food and Drug Administration in 2019, is an important new drug for the treatment of patients with advanced bladder cancer. This study looks at the effectiveness of enfortumab vedotin as it has been used at multiple centers since approval, and focuses on important patient populations previously excluded from clinical trials. These populations include patients with decreased kidney function, diabetes, and important mutations. Enfortumab vedotin is effective for treating these patients. Previously reported clinical trial data have been replicated in this real-world setting, and support the use of this drug in broader patient populations.

Outcomes With First-Line PD-1/PD-L1 Inhibitor Monotherapy for Metastatic Renal Cell Carcinoma (mRCC): A Multi-Institutional Cohort.

Introduction: The treatment landscape of metastatic renal cell carcinoma has advanced significantly with the approval of combination regimens containing an immune checkpoint inhibitor (ICI) for patients with treatment-naïve disease. Little information is available regarding the activity of single-agent ICIs for patients with previously untreated mRCC not enrolled in clinical trials. Methods: This retrospective, multicenter cohort included consecutive treatment-naïve mRCC patients from six institutions in the United States who received ≥1 dose of an ICI outside a clinical trial, between June 2017 and October 2019. Descriptive statistics were used to analyze outcomes including objective best response rate (ORR), progression-free survival (PFS), and tolerability. Results: The final analysis included 27 patients, 70% men, median age 64 years (range 42-92), 67% Caucasian, and 33% with ECOG 2 or 3 at baseline. Most patients had intermediate risk (85%, IMDC) with clear cell (56%), papillary (26%), unclassified (11%), chromophobe (4%), and translocation (4%) RCC. All patients had evidence of metastatic disease involving the lungs (59%), lymph node (41%), CNS (19%), liver (11%), adrenal gland (11%), and bone (11%). The median time on ICI was 3.1 (0.1-26.8) months, and the median PFS was 6.3 (95% CI, 0-18.6) months. Among the 21 patients with an evaluable response, the best ORR was 33%, including two complete responses and five partial responses. The ORR was 29% (n = 1 complete response, n = 5 partial response) in clear cell and 5% (n = 1 complete response) in non-clear cell RCC. Adverse events (AEs) of any cause were reported in 37% and included fatigue (11%), dermatitis (11%), diarrhea (7%), and shortness of breath (7%). Significant AEs (30%) included shortness of breath (7%), acute kidney injury (4%), dermatitis (4%), Clostridium difficile infection (4%), cerebrovascular accident (4%), and fatigue (7%). Three patients discontinued therapy due to grade 4 AEs. Conclusions: In this multi-institutional case series, single-agent ICI demonstrated objective responses and was well tolerated in a heterogeneous treatment-naïve mRCC cohort. ICI monotherapy is not the standard of care for patients with mRCC, and further investigation is necessary to explore predictive biomarkers for optimal treatment selection in this setting.

Neoadjuvant Therapies for Bladder Cancer in Cisplatin-ineligible Patients: What Options Do We Have?

Neoadjuvant chemotherapy has proven clinical benefit in muscle- invasive bladder cancer. Cisplatin is the likely driver of this benefit. Textbook definitions of cisplatin ineligibility may restrict almost 50% of patients from therapy. Checkpoint inhibitors (anti- PD-1 antibodies and anti- CTLA-4 antibodies) are currently in clinical trials for neoadjuvant use. Initial data from these studies appear promising.

Nivolumab-induced hypophysitis leading to hypopituitarism and secondary empty sella syndrome in a patient with non-small cell lung cancer.

We describe the clinical course of a 64-year-old woman with stage IVa lung adenocarcinoma who presented with over 1 month of fatigue, unintentional weight loss and emesis. She initiated treatment with nivolumab immunotherapy 1 year prior and had been tolerating the treatment well. A comprehensive workup revealed multiple endocrinological abnormalities consistent with hypophysitis leading to hypopituitarism in the form of central adrenal insufficiency and hypogonadism as well as a partially empty sella on imaging. This case demonstrates that while receiving novel forms of treatment such as immunotherapy, patients should be monitored closely for a wide range of adverse effects.

Association of PD-L1, PD-L2, and Immune Response Markers in Matched Renal Clear Cell Carcinoma Primary and Metastatic Tissue Specimens.

Objectives: Immune checkpoint therapy has been promising in renal cell carcinoma, but no validated clinically relevant biomarkers exist. Metastatic deposits may have discordant biomarker expression. Methods: Fifty matched pairs of primary and metastatic kidney tumors were evaluated via immunohistochemistry for immune checkpoint proteins PD-1, PD-L1, and PD-L2 and the T-cell and macrophage surface markers CD3, FOXP3, and CD163. Semiquantitative scores incorporating prevalence of both tumor and nontumor labeling were compared between metastatic and primary kidney tumor specimens. Results: A large minority of patients had discordant expression of PD-1 (31.2%), PD-L1 (22.5%), or PD-L2 (21.5%) between primary and metastatic sites. The expression of the novel marker PD-L2 correlated with both PD-1 (r = 0.47, P = .02) and PD-L1 (r = 0.67, P < .001) in metastatic deposits. Conclusions: This study demonstrates that renal clear cell carcinoma primary tumors and metastatic deposits have some discordance in the expression of PD-L1, PD-1, and PD-L2.

Post-treatment changes in hematological parameters predict response to nivolumab monotherapy in non-small cell lung cancer patients.

BACKGROUND: The absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count (AMC) and neutrophil to lymphocyte ratio (NLR) are known markers of inflammation. We evaluated whether ANC, ALC, AMC and NLR, both before and after treatment with nivolumab, are indicative markers of overall survival (OS) and evaluated change in NLR as a predictive marker of response in non -small cell lung cancer (NSCLC) patients treated with nivolumab. METHODS: A total of 109 patients with advanced NSCLC treated with nivolumab were included. ANC, ALC, AMC and NLR were examined at initiation of nivolumab therapy and after two cycles. The prognostic role of ANC, ALC, AMC and NLR with OS and changes in NLR ratio were examined with Kaplan-Meier curves and proportional hazard model. RESULT: Post-treatment NLR ≥5 after two cycles of nivolumab was associated with poor OS (median OS in NLR = <5 vs NLR = ≥5 was 29.1 (16.2-40.9) vs 24.2(16.1-36.2) months respectively, p<0.001). In addition NLR increased in non-responders after two cycles of nivolumab by 6.6±21.8 as compared to responders (p = 0.027). CONCLUSIONS: Post-treatment ANC, ALC and NLR are independent prognostic factors in NSCLC patients treated with nivolumab. Changes in NLR can be an early biomarker for response in NSCLC patients treated with nivolumab.

Primary proximal epithelioid sarcoma of the lung successfully treated with pneumonectomy and adjuvant chemotherapy.

Primary sarcomas of the lung and proximal epithelial sarcomas (PESs) are extremely rare. Inactivation of INI1 has been found in the majority of epithelioid sarcoma (ES). We report the third known case of a primary PES of the lung along with immunohistochemical data. A 41-year-old man with HIV infection, on highly active antiretroviral therapy, presented with haemoptysis, shortness of breath and progressive weight loss for 2 months. He was eventually diagnosed with stage IIA cT2bN0M0 grade-2 primary PES of the lung. This patient underwent pneumonectomy and adjuvant chemotherapy with ifosfamide and doxorubicin. He remains in remission 36 months since diagnosis. Our case stands to help other clinicians as treatment of such rare cases is often reliant on case reports. We also posit a possible pathogenic mechanism given a history of HIV infection in this patient. The association of INI1 mutation with other atypical sarcomas in patients with HIV infection merits further evaluation.

Beta catenin is degraded by both caspase-3 and proteasomal activity during resveratrol-induced apoptosis in HeLa cells in a GSK3ß-independent manner.

Increased activity of ß-catenin, an important transcriptional activator for survival and proliferation-associated genes has been linked with many cancers. We examined whether ß-catenin is a target of resveratrol and whether its degradation contributes to the pro-apoptotic effects of resveratrol. HeLa cells were exposed to 60 µM resveratrol for 48 h. Apoptosis was confirmed by measurement of annexin V externalization, caspase-3 activation and DNA fragmentation. Induction of apoptosis was observed as early as 12 h, when both caspase-3 activation and PARP (poly ADP ribose polymerase) cleavage occurred. Nuclear ß-catenin levels remained unchanged for 48 h during resveratrol exposure. However, extranuclear cell lysate ß-catenin underwent a decrease at a late stage of apoptosis namely at 36-48 h. Alterations in the phosphorylation status of Akt/GSK3ß were not observed during resveratrol-induced apoptosis. Furthermore, inhibition of GSK3ß activity which is. largely responsible for ß-catenin degradation failed to influence ß-catenin stability. However, inhibition of caspase-3 activity prevented the decline in ß-catenin levels at 36-48 h of resveratrol exposure. Lactacystin, a proteosomal inhibitor also prevented the degradation of ß-catenin by resveratrol. In conclusion, resveratrol induced apoptosis in HeLa cells in an Akt/GSK3ß-independent manner and down-regulated ß-catenin levels during apoptosis through action of caspase-3 and proteasomal degradation, independent of GSK3ß-mediated phosphorylation.

Palliative care in low- and medium-resource countries.

Low- and medium-resource countries are facing a significant increase in the incidence of noncommunicable diseases such as cancer. Unfortunately, the majority of patients with cancer present with advanced disease, and disease-directed treatment may be unlikely to be effective and/or not available. Globally, there will be a growing need for palliative care services. There has been significant progress in the provision and integration of palliative care into the health care policy and systems. Nonetheless, palliative care services vary significantly between regions of the world and also between countries in the same region. Some common barriers to care include the lack of a trained workforce to provide palliative care, lack of availability of opioids or the restriction of their use, cultural attitudes of physicians and patients, and also funding. Despite these challenges, there are examples of low- and medium-resource countries that are providing excellent palliative care that is being integrated into the health care system and the cancer care continuum. This article provides an overview of the progress in providing palliative care in low- and medium-resource countries. In addition, more specific information is provided on palliative care in low-resource countries in Latin America, Asia, and Africa. Finally, a more personal perspective is presented on the development of palliative care in Ethiopia, as an example.

Characterization of antibodies induced by vaccination with hepatitis C virus envelope glycoproteins.

Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 were used with MF59 adjuvant as a candidate vaccine for a phase 1 safety and immunogenicity trial. Ten of 41 vaccinee serum samples displayed a neutralization titer of > or =1:20 against vesicular stomatitis virus (VSV)-HCV pseudotype, 15 of 36 serum samples tested had a neutralization titer of > or =1:400 against human immunodeficiency virus (HIV)-HCV pseudotype, and 10 of 36 serum samples tested had a neutralization titer of > or =1:20 against cell culture-grown HCV genotype 1a. Neutralizing serum samples had increased affinity levels and displayed >2-fold higher specific activity levels to well-characterized epitopes on E1/E2, especially to the hypervariable region 1 of E2.

High-throughput screening of viral entry inhibitors using pseudotyped virus.

Virus entry into a host cell is an attractive target for therapy because propagation of virus can be blocked at an early stage, minimizing chances for the virus to acquire drug resistance. Anti-infective drug discovery for BSL-4 viruses like Ebola or Lassa hemorrhagic fever virus presents challenges due to the requirement for a BSL-4 laboratory containment facility. Pseudotyped viruses provide a surrogate model in which the native envelope glycoprotein of a BSL-2 level virus (e.g., vesicular stomatitis virus) is replaced with envelope glycoprotein of a foreign BSL-4 virus (e.g., Ebola virus). Because the envelope glycoprotein determines interaction of virus with its cellular receptors, pseudotyped viruses can mimic the viral entry process of the original virus. Moreover, they are competent for only a single cycle of infection, and therefore can be used in BSL-2 facilities. Pseudotyped viruses have been used in high-throughput screening of entry inhibitors for a number of BSL-4 level viruses. This unit includes protocols for preparing pseudotyped viruses using lentiviral vectors and use of pseudotyped viruses for high-throughput screening of viral entry inhibitors.

Sulfated homologues of heparin inhibit hepatitis C virus entry into mammalian cells.

The mechanism of entry of hepatitis C virus (HCV) through interactions between the envelope glycoproteins and specific cell surface receptors remains unclear at this time. We have previously shown with the vesicular stomatitis virus (VSV)/HCV pseudotype model that the hypervariable region 1 of the HCV E2 envelope glycoprotein helps in binding with glycosaminoglycans present on the cell surface. In this study, we have examined the binding of HCV envelope glycoproteins with chemically modified derivatives of heparin. Furthermore, we have determined the functional relevance of the interaction of heparin derivatives with HCV envelope glycoproteins for infectivity by using a human immunodeficiency virus (HIV)/HCV pseudotype, a VSV/HCV pseudotype, and cell culture-grown HCV genotype 1a. Taken together, our results suggest that the HCV envelope glycoproteins rely upon O-sulfated esters of a heparin homologue to facilitate entry into mammalian cells.