Core Exchange: A Professional Development Program for Shared Resource Personnel.

Introduction/objective: Academic institutions often struggle to meet the unique professional development needs of shared resource personnel, who require business skills, project and people management expertise, and an active, collaborative network of shared resource colleagues.

Materials And Methods: We launched the Vanderbilt Core Exchange professional development and networking program in 2020. The program was intentionally designed with core personnel input and supports faculty and staff from more than 80 shared resources across Vanderbilt University and Vanderbilt University Medical Center.

Professional Identity Formation of Basic Science Medical Educators: A Qualitative Study of Identity Supports and Threats.

Purpose: Basic science medical educators (BSME) play a vital role in the training of medical students, yet little is known about the factors that shape their professional identities. This multi-institutional qualitative study investigated factors that support and threaten the professional identity formation (PIF) of these medical educators.

Method: A qualitative descriptive study was conducted with a purposive sample of 58 BSME from 7 allopathic medical schools in the U.

Training Tomorrow's Physicians in Value Conscious Medicine.

Problem: Future physicians will practice medicine in an increasingly complex health care system. To become effective leaders of value-based teams and to practice cost-conscious care, medical students need training in and exposure to value conscious medicine (VCM).

Approach: A student-led initiative to enhance education in VCM led to the development of the 4-week elective course (High Value Care: In Policy and in Practice) for postclerkship third- and fourth-year students, introduced in 2021 at Vanderbilt University School of Medicine.

Safety and Efficacy of Avelumab in Small Bowel Adenocarcinoma.

Introduction: Small bowel adenocarcinomas (SBAs) are rare and frequently treated like large intestinal adenocarcinomas. However, SBAs have a very different microenvironment and could respond differently to the same therapies. Our previous data suggested that SBAs might benefit from targeting the PD-1/PD-L1 axis based on PD-L1 staining in almost 50% of SBA tissue samples tested.

High Sensitivity Troponin T and NT-proBNP in Patients Receiving Chimeric Antigen Receptor (CAR) T-Cell Therapy.

Retrospective studies suggest that chimeric antigen receptor T-cell (CAR T) therapy may lead to cardiac injury, but this has not been assessed systematically or prospectively. In this prospective study of 40 patients who received CAR T, we systematically measured high-sensitivity troponin T (hsTropT) and N-terminal pro-B natriuretic peptide (NTproBNP) at baseline and on day 1, days 7, and 21 after CAR T. Biomarker elevations with respect to timepoint and cytokine release syndrome (CRS) status were examined using repeated measure analysis of variance.

Precision Cancer Medicine: Dynamic Learning of Cancer Biology in a Clinically Meaningful Context.

Purpose: Precision medicine is revolutionizing healthcare practices, most notably in oncology. With cancer being the second leading cause of death in the USA, it is important to integrate precision oncology content in undergraduate medical education.

Methods: In 2015, we launched a Integrated Science Course (ISC) for post-clerkship medical students at Vanderbilt University School of Medicine (VUSM).

CMV exposure drives long-term CD57+ CD4 memory T-cell inflation following allogeneic stem cell transplant.

Donor and recipient cytomegalovirus (CMV) serostatus correlate with transplant-related mortality that is associated with reduced survival following allogeneic stem cell transplant (SCT). Prior epidemiologic studies have suggested that CMV seronegative recipients (R-) receiving a CMV-seropositive graft (D+) experience inferior outcomes compared with other serostatus combinations, an observation that appears independent of viral reactivation. We therefore investigated the hypothesis that prior donor CMV exposure irreversibly modifies immunologic function after SCT.

Clinical Features and Multiplatform Molecular Analysis Assist in Understanding Patient Response to Anti-PD-1/PD-L1 in Renal Cell Carcinoma.

Predicting response to ICI therapy among patients with renal cell carcinoma (RCC) has been uniquely challenging. We analyzed patient characteristics and clinical correlates from a retrospective single-site cohort of advanced RCC patients receiving anti-PD-1/PD-L1 monotherapy (N = 97), as well as molecular parameters in a subset of patients, including multiplexed immunofluorescence (mIF), whole exome sequencing (WES), T cell receptor (TCR) sequencing, and RNA sequencing (RNA-seq). Clinical factors such as the development of immune-related adverse events (odds ratio (OR) = 2.

Metastatic Melanoma Patient-Derived Xenografts Respond to MDM2 Inhibition as a Single Agent or in Combination with BRAF/MEK Inhibition.

Purpose: Over 60% of patients with melanoma respond to immune checkpoint inhibitor (ICI) therapy, but many subsequently progress on these therapies. Second-line targeted therapy is based on mutation status, but no available agents are available for , and mutations. Over 70% of melanoma tumors have activation of the MAPK pathway due to or mutations, while loss or mutation of occurs in approximately 40% of melanomas, resulting in unregulated MDM2-mediated ubiquitination and degradation of p53.

Genomic landscape of a metastatic malignant proliferating tricholemmal tumor and its response to PI3K inhibition.

Proliferating tricholemmal tumors (PTTs) are rare benign neoplasms that arise from the outer sheath of a hair follicle. Occasionally, these PTTs undergo malignant transformation to become malignant proliferating tricholemmal tumors (MPTTs). Little is known about the molecular alterations, malignant progression, and management of MPTTs.

The RUNX1/IL-34/CSF-1R axis is an autocrinally regulated modulator of resistance to BRAF-V600E inhibition in melanoma.

Resistance to current therapies still impacts a significant number of melanoma patients and can be regulated by epigenetic alterations. Analysis of global cytosine methylation in a cohort of primary melanomas revealed a pattern of early demethylation associated with overexpression of oncogenic transcripts. Loss of methylation and associated overexpression of the CSF 1 receptor (CSF1R) was seen in a majority of tumors and was driven by an alternative, endogenous viral promoter in a subset of samples.

Class Matters: Sensitivity of -Mutant Melanoma to MAPK Inhibition.

Mutations in outside of the 600 codons ( non- V600) occur across cancer types, including in 3% to 5% of melanomas. The optimal treatment strategies are not clear but based on preclinical studies could include MEK inhibitors. Combining BRAF and MEK inhibitors in this population may provide additional benefit.

BRAF and MEK inhibitor therapy eliminates Nestin-expressing melanoma cells in human tumors.

Little is known about the in vivo impacts of targeted therapy on melanoma cell abundance and protein expression. Here, 21 antibodies were added to an established melanoma mass cytometry panel to measure 32 cellular features, distinguish malignant cells, and characterize dabrafenib and trametinib responses in BRAF melanoma. Tumor cells were biopsied before neoadjuvant therapy and compared to cells surgically resected from the same site after 4 weeks of therapy.

Integrating Foundational Sciences in a Clinical Context in the Post-Clerkship Curriculum.

Purpose: To design, implement, and launch courses that integrate foundational science learning and clinical application in a post-clerkship undergraduate medical school curriculum.

Method: In Academic Year (AY) 15-16, as part of a comprehensive curricular revision, Vanderbilt University School of Medicine (VUSM) formally implemented "Integrated Science Courses" (ISCs) that combined rigorous training in the foundational sciences with meaningful clinical experiences. These courses integrated foundational sciences that could be leveraged in the clinical environment, utilized a variety of instructional modalities, and included quantitative and qualitative (competency-based milestones) student assessments.

Frequent BRAF mutations suggest a novel oncogenic driver in colonic neuroendocrine carcinoma.

Background And Objectives: The World Health Organization (WHO) 2010 has classified GI neuroendocrine neoplasms into neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). The genetic underpinnings of NEC are poorly understood. The aim of the study was to perform genomic profiling of NEC to better characterize this aggressive disease.

Functional KRAS mutations and a potential role for PI3K/AKT activation in Wilms tumors.

Wilms tumor (WT) is the most common renal neoplasm of childhood and affects 1 in 10 000 children aged less than 15 years. These embryonal tumors are thought to arise from primitive nephrogenic rests that derive from the metanephric mesenchyme during kidney development and are characterized partly by increased Wnt/β-catenin signaling. We previously showed that coordinate activation of Ras and β-catenin accelerates the growth and metastatic progression of a murine WT model.

A phase I trial investigating pulsatile erlotinib in combination with gemcitabine and oxaliplatin in advanced biliary tract cancers.

Advanced biliary tract cancers (ABTC) are among the deadliest malignancies with limited treatment options after progression on standard-of-care chemotherapy, which includes gemcitabine (GEM) and oxaliplatin (OX). The epidermal growth factor receptor inhibitor erlotinib has been explored in ABTC with modest efficacy. Erlotinib given continuously may antagonize the action of chemotherapy against cycling tumor cells, but pulsatile dosing of erlotinib with chemotherapy may improve efficacy.

Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance.

Clinically acquired resistance to MAPK inhibitor (MAPKi) therapies for melanoma cannot be fully explained by genomic mechanisms and may be accompanied by co-evolution of intra-tumoral immunity. We sought to discover non-genomic mechanisms of acquired resistance and dynamic immune compositions by a comparative, transcriptomic-methylomic analysis of patient-matched melanoma tumors biopsied before therapy and during disease progression. Transcriptomic alterations across resistant tumors were highly recurrent, in contrast to mutations, and were frequently correlated with differential methylation of tumor cell-intrinsic CpG sites.

Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides.

The pathogenesis of mycosis fungoides (MF), the most common cutaneous T-cell lymphoma (CTCL), is unknown. Although genetic alterations have been identified, none are considered consistently causative in MF. To identify potential drivers of MF, we performed whole-genome sequencing of MF tumors and matched normal skin.

Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction.

Combined BRAF- and MEK-targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation.