Targeting beta-adrenergic receptor pathways in melanoma: how stress modulates oncogenic immunity.

The intricate pathways of the sympathetic nervous system hold an inherently protective role in the setting of acute stress. This is achieved through dynamic immunomodulatory and neurobiological networks. However, excessive and chronic exposure to these stress-induced stimuli appears to cause physiologic dysfunction through several mechanisms that may impair psychosocial, neurologic, and immunologic health. Numerous preclinical observations have identified the beta-2 adrenergic receptor (ß2-AR) subtype to possess the strongest impact on immune dysfunction in the setting of chronic stressful stimuli. This prolonged expression of ß2-ARs appears to suppress immune surveillance and promote tumorigenesis within multiple cancer types. This occurs through several pathways, including (1) decreasing the frequency and function of CD8 + T-cells infiltrating the tumor microenvironment (TME) via inhibition of metabolic reprogramming during T cell activation, and (2) establishing an immunosuppressive profile within the TME including promotion of an exhausted T cell phenotype while simultaneously enhancing local and paracrine metastatic potential. The use of nonselective ß-AR antagonists appears to reverse many chronic stress-induced tumorigenic pathways and may also provide an additive therapeutic benefit for various immune checkpoint modulating agents including commonly utilized immune checkpoint inhibitors. Here we review the translational and clinical observations highlighting the foundational hypotheses that chronic stress-induced ß-AR signaling promotes a pro-tumoral immunophenotype and that blockade of these pathways may augment the therapeutic response of immune checkpoint inhibition within the scope of melanoma.

Use of artificial intelligence chatbots in clinical management of immune-related adverse events.

BACKGROUND: Artificial intelligence (AI) chatbots have become a major source of general and medical information, though their accuracy and completeness are still being assessed. Their utility to answer questions surrounding immune-related adverse events (irAEs), common and potentially dangerous toxicities from cancer immunotherapy, are not well defined. METHODS: We developed 50 distinct questions with answers in available guidelines surrounding 10 irAE categories and queried two AI chatbots (ChatGPT and Bard), along with an additional 20 patient-specific scenarios. Experts in irAE management scored answers for accuracy and completion using a Likert scale ranging from 1 (least accurate/complete) to 4 (most accurate/complete). Answers across categories and across engines were compared. RESULTS: Overall, both engines scored highly for accuracy (mean scores for ChatGPT and Bard were 3.87 vs 3.5, p<0.01) and completeness (3.83 vs 3.46, p<0.01). Scores of 1-2 (completely or mostly inaccurate or incomplete) were particularly rare for ChatGPT (6/800 answer-ratings, 0.75%). Of the 50 questions, all eight physician raters gave ChatGPT a rating of 4 (fully accurate or complete) for 22 questions (for accuracy) and 16 questions (for completeness). In the 20 patient scenarios, the average accuracy score was 3.725 (median 4) and the average completeness was 3.61 (median 4). CONCLUSIONS: AI chatbots provided largely accurate and complete information regarding irAEs, and wildly inaccurate information ("hallucinations") was uncommon. However, until accuracy and completeness increases further, appropriate guidelines remain the gold standard to follow.

Differences in systemic immune parameters in individuals with lung cancer according to race.

Introduction: Racial and ethnic disparities in the presentation and outcomes of lung cancer are widely known. To evaluate potential factors contributing to these observations, we measured systemic immune parameters in Black and White patients with lung cancer. Methods: Patients scheduled to receive cancer immunotherapy were enrolled in a multi-institutional prospective biospecimen collection registry. Clinical and demographic information were obtained from electronic medical records. Pre-treatment peripheral blood samples were collected and analyzed for cytokines using a multiplex panel and for immune cell populations using mass cytometry. Differences between Black and White patients were determined and corrected for multiple comparisons. Results: A total of 187 patients with non-small cell lung cancer (Black, 19; White, 168) were included in the analysis. There were no significant differences in baseline characteristics between Black and White patients. Compared to White patients, Black patients had significantly lower levels of CCL23 and CCL27, and significantly higher levels of CCL8, CXCL1, CCL26, CCL25, CCL1, IL-1 b, CXCL16, and IFN-γ (all P <0.05, FDR<0.1). Black patients also exhibited greater populations of non-classical CD16+ monocytes, NKT-like cells, CD4+ cells, CD38+ monocytes, and CD57+ gamma delta T cells (all P <0.05). Conclusions: Black and White patients with lung cancer exhibit several differences in immune parameters, with Black patients exhibiting greater levels of numerous pro-inflammatory cytokines and cell populations. The etiology and clinical significance of these differences warrant further evaluation.

Evolving Management of Stage IV Melanoma.

Significant advancements have been made in the treatment of advanced melanoma with the use of immune checkpoint inhibitors, novel immunotherapies, and BRAF/MEK-targeted therapies with numerous frontline treatment options. However, there remains suboptimal evidence to guide treatment decisions in many patients. These include patients with newly diagnosed disease, immune checkpoint inhibitor (ICI)-resistant/ICI-refractory disease, CNS metastases, history of autoimmune disease, and/or immune-related adverse events (irAEs). Uveal melanoma (UM) is a rare melanoma associated with a poor prognosis in the metastatic setting. Systemic treatments, including checkpoint inhibitors, failed to demonstrate any survival benefit. Tebentafusp, a bispecific molecule, is the first treatment to improve overall survival (OS) in patients with HLA A*02:01-positive metastatic UM.

Managing Metastatic Melanoma in 2022: A Clinical Review.

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.

Neural Net Modeling of Checkpoint Inhibitor Related Myocarditis and Steroid Response.

Background: Serious but rare side effects associated with immunotherapy pose a difficult problem for regulators and practitioners. Immune checkpoint inhibitors (ICIs) have come into widespread use in oncology in recent years and are associated with rare cardiotoxicity, including potentially fatal myocarditis. To date, no comprehensive model of myocarditis progression and outcomes integrating time-series based laboratory and clinical signals has been constructed. In this paper, we describe a time-series neural net (NN) model of ICI-related myocarditis derived using supervised machine learning. Methods: We extracted and modeled data from electronic medical records of ICI-treated patients who had an elevation in their troponin. All data collection was performed using an electronic case report form, with approximately 300 variables collected on as many occasions as available, yielding 6000 data elements per patient over their clinical course. Key variables were scored 0-5 and sequential assessments were used to construct the model. The NN model was developed in MatLab and applied to analyze the time course and outcomes of treatments. Results: We identified 23 patients who had troponin elevations related to their ICI therapy, 15 of whom had ICI-related myocarditis, while the remaining 8 patients on ICIs had other causes for troponin elevation, such as myocardial infarction. Our model showed that troponin was the most predictive biomarker of myocarditis, in line with prior studies. Our model also identified early and aggressive use of steroid treatment as a major determinant of survival for cases of grade 3 or 4 ICI-related myocarditis. Conclusion: Our study shows that a supervised learning NN can be used to model rare events such as ICI-related myocarditis and thus provide clinical insight into drivers of progression and treatment outcomes. These findings direct attention to early detection biomarkers and clinical symptoms as the best means of implementing early and potentially life-saving steroid treatment.

Clinical and immunologic implications of COVID-19 in patients with melanoma and renal cell carcinoma receiving immune checkpoint inhibitors.

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.

Teaching residents how to break bad news: piloting a resident-led curriculum and feedback task force as a proof-of-concept study.

Background: Breaking 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 study: The 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 design: Internal 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. Results: 148 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. Conclusions: A 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.

Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis.

BACKGROUND: Immune 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. METHODS: We 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. RESULTS: Among 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. CONCLUSIONS: Routine 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.

Impact of an Electronic Medical Record Alert on Code Status Documentation for Hospitalized Patients With Advanced Cancer.

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.

Higher Grit Scores Associated With Less Burnout in a Cohort of Internal Medicine Residents.

BACKGROUND: The association between grit, defined as perseverance and passion for long-term goals, and professional burnout has not been studied in internal medicine residents. Our objective was to examine whether internal medicine residents' scores on a grit scale were associated with various measures of burnout. METHODS: All residents from a single internal medicine program were invited to participate in a study of grit and burnout. Grit and burnout were measured using the Short Grit Scale and modified Maslach Burnout Inventory, respectively. In addition, demographics, last In-Training Examination (ITE) score, and interest in a subspecialty were captured. RESULTS: A total of 139 of 168 eligible residents (83%) participated. Emotional exhaustion and depersonalization (i.e., burn out) were identified in 63% and 42% of residents, respectively. Endorsement of emotional exhaustion was higher for residents living with family members, postgraduate year (PGY)1 and PGY2 compared with PGY3 residents, and residents scoring above the 50th percentile on the last ITE. Grit scores were higher for residents not reporting emotional exhaustion. As grit score increases, the odds of reporting emotional exhaustion significantly decreased, after adjustments for demographics, ITE scores, type of medical school, PGY level, and interest in a subspecialty (odds ratio = 0.36, 95% CI 0.15-0.84). CONCLUSIONS: Grit appeared to be an independent predictor of burnout in internal medicine residents in this sample, with lower grit scores associated with higher burnout scores. By measuring grit early in residency, programs can potentially identify residents at risk for symptoms of burnout, specifically emotional exhaustion, and implement targeted interventions.

Implementation of an electronic medical record tool for early detection of deep vein thrombosis in the ambulatory oncology setting.

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.