Cutaneous melanoma remains the most lethal of the primary cutaneous neoplasms, and although the incidence of primary melanoma continues to rise, the mortality from metastatic disease remains unchanged, in part through advances in treatment. Major developments in immunomodulatory and targeted therapies have provided robust improvements in response and survival trends that have transformed the clinical management of patients with metastatic melanoma. Additional advances in immunologic and cancer cell biology have contributed to further optimization in (1) risk stratification, (2) prognostication, (3) treatment, (4) toxicity management, and (5) surveillance approaches for patients with an advanced melanoma diagnosis. In this review, we provide a comprehensive overview of the historical and future advances regarding the translational and clinical implications of advanced melanoma and share multidisciplinary recommendations to aid clinicians in the navigation of current treatment approaches for a variety of patient cohorts.

BackgroundImmune checkpoint inhibitors (ICI) have emerged as a front-line therapy for a variety of solid tumors. With the widespread use of these agents, immune-associated toxicities are increasingly being recognized, including fatal myocarditis. There are limited data on the outcomes and prognostic utility of biomarkers associated with ICI-associated myocarditis. Our objective was to examine the associations between clinical biomarkers of cardiomyocyte damage and mortality in patients with cancer treated with ICIs.MethodsWe retrospectively studied 23 patients who developed symptomatic and asymptomatic troponin elevations while receiving ICI therapy at a National Cancer Institute-designated comprehensive cancer center. We obtained serial ECGs, troponin I, and creatine kinase-MD (CK-MB), in addition to other conventional clinical biomarkers, and compared covariates between survivors and non-survivors.ResultsAmong patients with myocarditis, higher troponin I (p=0.037) and CK-MB (p=0.034) levels on presentation correlated with progression to severe myocarditis. Higher troponin I (p=0.016), CK (p=0.013), and CK-MB (p=0.034) levels were associated with increased mortality, while the presence of advanced atrioventricular block on presentation (p=0.088) trended toward increased mortality. Weekly troponin monitoring lead to earlier hospitalization for potential myocarditis (p=0.022) and was associated with decreased time to steroid initiation (p=0.053) and improved outcomes.ConclusionsRoutine troponin surveillance may be helpful in predicting mortality in ICI-treated patients with cancer in the early phase of ICI therapy initiation. Early detection of troponin elevation is associated with earlier intervention and improved outcomes in ICI-associated myocarditis. The recommended assessment and diagnostic studies guiding treatment decisions are presented.

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The clinical and immunologic implications of the SARS-CoV-2 pandemic for patients with cancer receiving systemic anticancer therapy have introduced a multitude of clinical challenges and academic controversies. This review summarizes the current evidence, discussion points, and recommendations regarding the use of immune checkpoint inhibitors (ICIs) in patients with cancer during the SARS-CoV-2 pandemic, with a focus on patients with melanoma and renal cell carcinoma (RCC). More specifically, we summarize the theoretical concepts and available objective data regarding the relationships between ICIs and the antiviral immune response, along with recommended clinical approaches to the management of melanoma and RCC patient cohorts receiving ICIs throughout the course of the COVID-19 pandemic. Additional insights regarding the use of ICIs in the setting of current and upcoming COVID-19 vaccines and broader implications toward future pandemics are also discussed.

Background Venous thromboembolism ( VTE ) is a major cause of morbidity, mortality, and hospitalization in cancer patients. Objectives To evaluate the feasibility of an electronic alert to identify and screen at‐risk individuals and gather rates of early detection of deep vein thrombosis ( DVT ). Patients/Methods An alert was built into the electronic medical record based on a validated risk tool (Khorana Score [ KS ]) and outcomes evaluated in an initial silent phase. The alert functioned in real time to warn physicians of high‐risk patients ( KS ≥ 3) and suggested lower extremity screening ultrasonography in a subsequent active phase. Results Of 194 consecutive patients identified as high risk in the silent phase, 14 (7.2%) developed subsequent DVT or pulmonary embolism ( PE ) over 90‐day follow‐up, with a median of 27 days. Mean 90‐day emergency room ( ER ) visits, all‐cause admissions, and length of stay (days) for patients with DVT were 1.2, 1.6, and 9.1 compared to 0.89, 0.93, and 5.1 for all patients, respectively. In the active phase, 197 consecutive alerts met inclusion criteria, and 40 patients (20.3%) received a screening ultrasound. Five (12.5%) had a DVT and were started on therapeutic anticoagulation. Of patients with alerts who had screening deferred, 13 (8.3%) were later diagnosed with DVT (median 50.5 days) and 7 (4.5%) with PE . Conclusion An automated alert may have value in early detection of DVT in high‐risk cancer patients leading to earlier intervention, and could potentially prevent VTE ‐related morbidity.

Background: Adrenergic stress (AS) reduces anti-tumor response by decreasing the frequency and function of CD8+ T- cells in the tumor microenvironment (TME), resulting in an increase in those with an “exhausted” phenotype.1 Additionally, AS increases the quantity and immunosuppressive phenotype of myeloid-derived suppressor cells (MDSC) in the TME.2 The data above suggests that β-2 AR acts akin to a tumorigenic IC which can be abrogated by using P, a well-known and highly cost efficient non-selective β-blocker. Synergistic activity of anti-PD-1 with P has been reported in several murine tumor models, including the B-16 OVA mouse model.3,4 A retrospective study has shown an improvement in overall survival (OS) in patients (pts) with metastatic melanoma (MM) treated concurrently with non-selective β-blocker and immunotherapy.5 This formed the basis for our phase I study of the combination of P (at dose levels; 10 mg, 20 mg BID, and 30mg BID) and pem 200 mg every 3 weeks in pts with MM. Our published phase I results found all 3 dose levels of P to be well tolerated, and an objective response was observed in 7/9 pts.6 A decrease in perceived stress score (PSS) in pts over time was observed. Intra-tumor ratio of (CD4+T cells + CD8+T-cells)/(MDSC+ Treg) >1 in the pre-treatment biopsy was predictive of treatment response. Based on the results of the phase I study, we chose P 30 mg BID as the recommended phase II dose. These results, though preliminary, strongly support our subsequent phase II clinical trial. Methods: In this prospective, single-arm, phase II, multicenter trial, pts with unresectable stage III/IV MM and measurable disease per RECIST v1.1 will be treated with P (30 mg BID) + Pem. Pts with active CNS disease, prior therapy with PD-1/PD-L1 inhibitors, or contraindications to β-blocker are excluded. The primary objective is to evaluate the overall response rate (ORR) by immune-modified RECIST v1.1. The secondary objectives are the assessment of progression free survival and OS. A Simon two-stage design will be employed, requiring a minimum of 29 pts (17 in stage 1 and 12 in stage 2) to achieve approximately 80% power to detect a 20% increase (0.35 to 0.55) in the ORR. As an exploratory analysis, we will further report a) Baseline and on-treatment PSS and b) Chronotropic effect of P after 5-minute treadmill walk as a biomarker of response; c) Post therapy changes in the TME, with a 12 week on therapy optional biopsy d) Peripheral blood changes in T cell and MDSC subsets, and cytokines/chemokines. To date, 10 pts have been accrued on the study (NCT0384836). Citation Format: Benjamin Switzer, Manu R. Pandey, Alexandra Valentine, Agnieszka Witkiewicz, Erik Knudsen, Kristopher Attwood, Joseph Tario, Pauline Funchain, Joseph J. Drabick, Hemn Mohammadpour, Marc S. Ernstoff, Igor Puzanov, Elizabeth A. Repasky, Shipra Gandhi. β-2 adrenergic receptor (AR): Another immune checkpoint (IC)" A phase II clinical trial of propranolol (P) with pembrolizumab (Pem) in patients with unresectable stage III and stage IV melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT568.

BackgroundBreaking bad news (BBN) is a critically important skill set for residents. Limited formal supervision and unpredictable timing of bad news delivery serve as barriers to the exchange of meaningful feedback.Purpose of studyThe goal of this educational innovation was to improve internal medicine residents’ communication skills during challenging BBN encounters. A formal BBN training programme and innovative on-demand task force were part of this two-phase project.Study designInternal medicine residents at a large academic medical centre participated in an interactive workshop focused on BBN. Workshop survey results served as a needs assessment for the development of a novel resident-led BBN task force. The task force was created to provide observations at the bedside and feedback after BBN encounters. Training of task force members incorporated video triggers and a feedback checklist. Inter-rater reliability was analysed prior to field testing, which provided data on real-world implementation challenges.Results148 residents were trained during the 2-hour communications skills workshop. Based on survey results, 73% (108 of 148) of the residents indicated enhanced confidence in BBN after participation. Field testing of the task force on a hospital ward revealed potential workflow barriers for residents requesting observations and prompted troubleshooting. Solutions were implemented based on field testing results.ConclusionsA trainee-led BBN task force and communication skills workshop is offered as an innovative model for improving residents’ interpersonal and communication skills in BBN. We believe the model is both sustainable and reproducible. Lessons learnt are offered to aid in implementation in other settings.

PURPOSE: Cardiopulmonary resuscitation in hospitalized patients with advanced cancer is associated with high rates of morbidity and mortality. Although advance care planning (ACP) in this population improves quality, patient satisfaction, hospice use, rates of harm, and health care costs, ACP documentation rates remain low. We observed changes in ACP documentation by internal medicine residents within a tertiary hospital’s inpatient oncology service after a mandatory training module and enterprise-wide modification in electronic health medical records (EHMR). METHODS: For patients admitted to the Cleveland Clinic oncology service, this 16-week retrospective review observed resident code status (CS) documentation through admission notes and direct EHMR orders before and after implementation of an ACP training module and CS best practice alert (BPA). In addition, residents were surveyed on perceived barriers to CS documentation. RESULTS: In 535 unique admissions (244 before BPA, 291 after BPA), residents exhibited a 14.4% increase (from 47.1% to 61.5%) in admission note CS documentation and an 18.2% increase (from 12.7% to 30.9%) in CS orders at time of discharge. The most common self-reported barrier to ACP documentation was forgetting to discuss, with first-, second-, and third-year residents admitting to feeling uncomfortable in orchestrating ACP conversations at rates of 58%, 6%, and 5%, respectively. CONCLUSION: Resident ACP documentation remains suboptimal in the high-risk cohort of hospitalized patients with advanced cancer. However, rates seem to be positively influenced by online modules and EHMR-based interventions. Additional efforts to improve the current practice and culture of ACP remain a crucial aspect in the quality and safety of our approach to patient care.