In Memoriam: Nicholas J. Vogelzang MD1
Abstract
Dr. Nick Vogelzang passed away on September 20th, 2022. He was 72. He lived a life well spent.
Nick received his medical degree from the University of Illinois in Chicago, then completed his internship and residency at Rush University Medical Center. He then went on to a fellowship in oncology at the University of Minnesota.
Nick was an extraordinary force of nature in the decades that followed. He served as Director of the NCI designated University of Chicago Comprehensive Cancer Center and later as founding Director of the Nevada Cancer Institute.
He was a fierce champion for clinical research and clinical trials that changed standards of care. Among his countless leadership roles, he chaired the CALGB GU committee and served as a visionary vice-chair of our own SWOG GU Committee. He was a staunch advocate for the mentorship of early career investigators.
Most importantly, he was a master clinician with an impeccable bedside manner. He himself was a cancer survivor. He personally knew what people with cancer had to go through. He had to deal with the long term adverse effects of chemotherapy and radiation. He was known for giving his personal cell phone number to the patients he cared for. Needless to say, his patients adored him.
On a personal level, Nick was a true gentleman. Respectable. Caring. Knowledgeable. Empathetic. Qualities that many of us can only aspire to achieve. When I faced my own professional career crossroads, I had sought and benefited from Nick’s sage counsel, just like countless others.
Today, we mourn Nick Vogelzang’s passing, yet we are comforted by the thought that he is still very much alive. His legacy and inspiration live on in those whose lives he had touched: his colleagues, mentees, patients, and caregivers. Thank you again, Professor Vogelzang. Rest in peace.
Disparities in Clinical Care and Research in Renal Cell Carcinoma
Abstract
Disparities in cancer screening, prevention, therapy, clinical outcomes, and research are increasingly recognized and pervade all malignancies. In response, several cancer research and clinical care organizations have issued policy statements to acknowledge and address barriers to achieving health equity in cancer care. The increasingly specialized nature of oncology warrants a disease-focused appraisal of existing disparities and potential solutions. Although clear improvements in clinical outcomes have been recently observed for patients with renal cell carcinoma (RCC), these improvements have not been equally shared across diverse populations. This review describes existing RCC cancer disparities and their potential contributing factors and discusses opportunities to improve health equity in clinical research for all patients with RCC.
Chimeric Antigen Receptor (CAR) T-cell Treatment in Renal Cell Carcinoma: Current Clinical Trials and Future Directions
Abstract
Renal cell carcinoma (RCC) has long been found to be responsive to immunotherapy. While high dose interleukin-2 resulted in some durable remissions, this treatment has largely been replaced by immune checkpoint inhibitor therapy, due to the safer toxicity profile and emerging evidence for long term remissions. However, the majority of patients continue to face disease progression and death from metastatic RCC. Chimeric antigen receptor T-cells (CAR T) represent the next step in immunotherapy for this malignancy and hold promise for a higher rate of durable remissions. The realization of this therapeutic strategy for RCC will require identification of the best tumor antigen and T cell modifications and will depend on achieving remissions with an acceptable toxicity profile. This review summarizes current CAR T-cell treatment targets and clinical trials for metastatic RCC, highlighting the potential therapeutic impact as well as obstacles to successful development.
Logical Imputation to Optimize Prognostic Risk Classification in Metastatic Renal Cell Cancer
Abstract
BACKGROUND:
Application of the MSKCC and IMDC models is recommended for prognostication in metastatic renal cell cancer (mRCC). Patient classification in MSKCC and IMDC risk groups in real-world observational studies is often hampered by missing data on required pre-treatment characteristics.
OBJECTIVE:
To evaluate the effect of application of easy-to-use logical, or deductive, imputation on MSKCC and IMDC risk classification in an observational study setting.
PATIENTS AND METHODS:
We used data on 713 mRCC patients with first-line sunitinib treatment from our observational European multi-centre study EuroTARGET. Pre-treatment characteristics and follow-up were derived from medical files. Hospital-specific cut-off values for laboratory measurements were requested. The effect of logical imputation of missing data and consensus versus hospital-specific cut-off values on patient classification and the subsequent models’ predictive performance for progression-free and overall survival (OS) was evaluated.
RESULTS:
45% of the patients had missing data for≥1 pre-treatment characteristic for either model. Still, 72% of all patients could be unambiguously classified using logical imputation. Use of consensus instead of hospital-specific cut-offs led to a shift in risk group for 12% and 7% of patients for the MSKCC and IMDC model, respectively. Using logical imputation or other cut-offs did not influence the models’ predictive performance. These were in line with previous reports (c-statistic ∼0.64 for OS)
CONCLUSIONS:
Logical imputation leads to a substantial increase in the proportion of patients that can be correctly classified into poor and intermediate MSKCC and IMDC risk groups in observational studies and its use in the field should be advocated.
SETD2 Regulates the Methylation of Translation Elongation Factor eEF1A1 in Clear Cell Renal Cell Carcinoma1
Abstract
BACKGROUND:
SET domain-containing protein 2 (SETD2) is commonly mutated in renal cell carcinoma. SETD2 methylates histone H3 as well as a growing list of non-histone proteins.
OBJECTIVE:
Initially, we sought to explore SETD2-dependent changes in lysine methylation of proteins in proximal renal tubule cells. Subsequently, we focused on changes in lysine methylation of the translation elongation factor eEF1A1.
METHODS:
To accomplish these objectives, we initially performed a systems-wide analysis of protein lysine-methylation and expression in wild type (WT) and SETD2-knock out (KO) kidney cells and later focused our studies on eEF1A1 as well as the expression of lysine methyltransferases that regulate its lysine methylation.
RESULTS:
We observed decreased lysine methylation of the translation elongation factor eEF1A1. EEF1AKMT2 and EEF1AKMT3 are known to methylate eEF1A1, and we show here that their expression is dependent on SET-domain function of SETD2. Globally, we observe differential expression of hundreds of proteins in WT versus SETD2-KO cells, including increased expression of many involved in protein translation. Finally, we observe decreased progression free survival and loss of EEF1AKMT2 gene expression in SETD2-mutated tumors predicted to have loss of function of the SET domain.
CONCLUSION:
Overall, these data suggest that SETD2-mutated ccRCC, via loss of enzymatic function of the SET domain, displays dysregulation of protein translation as a potentially important component of the transformed phenotype.
EAU 2022 Highlights on Renal Cell Carcinoma
Abstract
The most debated topic on renal cell carcinoma (RCC) during the EAU 2022 in Amsterdam was the 30 month follow-up update of the Keynote-564 trial. In this trial patients with intermediate and high risk for recurrence after nephrectomy with curative intent, and with no evidence of disease at the time of inclusion were randomized between adjuvant treatment with pembroluzimab for 1 year or placebo. A small group of patients with M1 disease who underwent metastasectomy were also included. In the intermediate risk (pT2 with Grade 4 or sarcomatoid differentiation, N0, M0; pT3, any grade, N0, M0), the high risk (T4, any grade, N0, M0; any pT, any grade, N+, M0) and M1 (no evidence of disease after surgery) groups disease-free survival was better with pembrolizumab compared with placebo (HR 0.63 [95% CI 0.50–0.80]). Although the median disease-free survival was not reached in any of the groups, the estimated number of participants alive and disease free after 30 months was 75.2% (95% CI 70.8–79.1) in the pembrolizumab group and 65.5% (60.9–69.7) in the placebo group [1].
Clinical Trials Corner: Optimizing Papillary Renal Cell Carcinoma Care
Abstract
A Phase II Randomized Trial of Cabozantinib (NSC#761968) With or Without Atezolizumab (NSC#783608) in Patients with Advanced Papillary Renal Cell Carcinoma (PAPMET2)
Status: Recruiting
Clinicaltrials.gov identifier: NCT05411081
Sponsor: National Cancer Institute
Enrollment: 200
Rationale: The Phase II PAPMET was a landmark study in that it was the first randomized trial assessing targeted therapies in patients with papillary renal cell carcinoma (pRCC), a rare histologic subtype observed in 15% of patients with RCC. In the study, cabozantinib was found to have a longer progression free survival (PFS) compared with sunitinib in patients with metastatic pRCC. Since the initiation of that trial, immune checkpoint inhibitors (ICIs) have become a vital foundation of first-line treatment of advanced clear cell RCC, and some trials of ICI combinations have included a non-clear cell RCC cohort, a heterogeneous population. Thus, SWOG has initiated a clinical trial evaluating a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI) cabozantinib with or without a checkpoint inhibitor in this specific patient population.
Study Design: This study enrolls patients with metastatic histologically confirmed pRCC (either Type 1 or Type 2) with radiographically measurable disease who are ICI- and cabozantinib-naïve and who have been treated with one or fewer targeted therapies for pRCC. Following enrollment, patients are randomized to receive either 60 mg of cabozantinib orally or 60 mg of cabozantinib orally plus atezolizumab 1200 mg intravenously every 3 weeks, until the time of disease progression or unacceptable toxicity.
Endpoints: The primary endpoint of this trial is progression-free survival (PFS). Key secondary outcomes include overall survival (OS), objective response rate (ORR), and quantitative & qualitative adverse events observed in each treatment arm.
