MYC Induces Immunotherapy and IFNγ Resistance Through Downregulation of JAK2.

Immunotherapy has revolutionized the treatment of advanced melanoma. Because the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of preimmunotherapy tumor biopsies from patients with melanoma that received PD-1 blockade or adoptive cell therapy with tumor-infiltrating lymphocytes. We identified two melanoma-intrinsic, mutually exclusive gene programs, which were controlled by IFNγ and MYC, and the association with immunotherapy outcome.

Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response.

Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use.

Elective neck dissection versus observation in patients with head and neck cutaneous squamous cell carcinoma.

Background: The survival benefit of elective neck dissection (END) for patients with cutaneous squamous cell carcinoma (cSCC) of the head and neck and no evidence of regional metastasis (cN0) has never been reported. The aim of this study was to determine the effect of END on patient survival.

Methods: The authors included patients with head and neck cSCC who had undergone primary surgery from 1995 to 2017.

Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade.

Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models.

Gut Microbiota and Antitumor Immunity: Potential Mechanisms for Clinical Effect.

Several landmark preclinical studies have shown an association between the gut microbiota and the effectiveness of immunotherapy for cancer. These studies have sparked clinical trials aimed at modulating the gut microbiota in order to improve clinical response rates to immunotherapy. Despite this, the mechanisms through which the gut microbiota influences the effectiveness of immunotherapy are still incompletely characterized.

Inclusion of extranodal extension in the lymph node classification of cutaneous squamous cell carcinoma of the head and neck.

Background: The prognostic performance of the recently updated American Joint Committee on Cancer lymph node classification of cutaneous head and neck squamous cell carcinoma (HNSCC) has not been validated. The objective of this study was to assess the prognostic role of extranodal extension (ENE) in cutaneous HNSCC.

Methods: This was a retrospective analysis of 1258 patients with cutaneous HNSCC who underwent surgery with or without adjuvant therapy between 1995 and 2019 at The University of Texas MD Anderson Cancer Center.

Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients.

The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma.

Immune co-culture cell microarray - a feasible tool for high-throughput functional investigation of lymphocyte-cancer interactions.

Omics analyses often result in dozens to hundreds of potential targets, requiring validation for their biological relevance. Current high-throughput functional investigation methods are frequently labor-intensive, expensive, and display low reproducibility. The Immune Co-Culture Cell Microarray (ICCM) is a formalin-fixed paraffin-embedded cell block microarray based on co-cultures of patient-derived tumor-infiltrating lymphocytes and their autologous melanoma cells.

Immune-Related Adverse Events (irAEs): Diagnosis, Management, and Clinical Pearls.

Purpose Of Review: While immune checkpoint inhibitor (ICI) therapy has improved melanoma patient outcomes, it has also resulted in the rise of unique immune-related adverse events (irAEs). Here, we review and synthesize irAE management recommendations from several oncological societies into a streamlined format to aid in diagnosis and management. We also include clinical pearls highlighting several recent research studies in this field.

TNFSF4 (OX40L) expression and survival in locally advanced and metastatic melanoma.

Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease.

Proteomics of Melanoma Response to Immunotherapy Reveals Mitochondrial Dependence.

Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. Here, we investigated mechanisms of response by profiling the proteome of clinical samples from advanced stage melanoma patients undergoing either tumor infiltrating lymphocyte (TIL)-based or anti- programmed death 1 (PD1) immunotherapy. Using high-resolution mass spectrometry, we quantified over 10,300 proteins in total and ∼4,500 proteins across most samples in each dataset.

Locally advanced rectal adenocarcinoma: Are preoperative short and long course radiotherapy truly equivalent?

In the neoadjuvant treatment of locally advanced rectal adenocarcinoma, long- and short-course radiotherapy are considered to be of equivalent efficacy based upon several randomized trials. The present study assessed the effect of radiotherapy dose on overall survival. Using the National Cancer Database (2006-2013) 458 individuals with clinical stage II/III rectal adenocarcinoma treated were identified, with either short- (25 Gy) or long- (45 or 50.

Recurrent Pneumonitis in Patients with Melanoma Treated with Immune Checkpoint Inhibitors.

Introduction: Immune checkpoint inhibitors (ICIs) have changed the oncologic landscape in the past few years. Alongside impressive antitumor responses, new novel immune-related adverse events (irAEs) have emerged; pneumonitis is an irAE that can potentially be fatal and necessitates a proper management. No consensus exists regarding steroid treatment duration or drug rechallenge options.

Clinical Significance of Pancreatic Atrophy Induced by Immune-Checkpoint Inhibitors: A Case-Control Study.

Immune-checkpoint inhibitor (ICI)-related diarrhea is attributed to inflammatory colitis, with no other drug-related differential diagnosis. Here, we investigated the occurrence of pancreatic atrophy (PA) in ICI-treated cancer patients and its correlation to exocrine pancreatic insufficiency (EPI). Metastatic melanoma, non-small cell lung carcinoma, and head and neck squamous cell carcinoma patients ( = 403) treated with anti-PD-1 ( = 356) or anti-CTLA-4 ( = 47) were divided into a case group (radiologic evidence of PA); control group matched by age, gender, and previous lines of treatment; and colitis group (ICI-induced colitis).

Possible immune adverse events as predictors of durable response to BRAF inhibitors in patients with BRAF V600-mutant metastatic melanoma.

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are among the cornerstones of metastatic melanoma therapy demonstrating excellent response rates with duration of 7-12 m. Long-term benefit from these agents was reported in patients with normal lactate dehydrogenase (LDH) and less than three disease sites. However, a treatment-dependent marker for long-term efficacy is lacking.

ADAR1-mediated regulation of melanoma invasion.

Melanoma cells use different migratory strategies to exit the primary tumor mass and invade surrounding and subsequently distant tissues. We reported previously that ADAR1 expression is downregulated in metastatic melanoma, thereby facilitating proliferation. Here we show that ADAR1 silencing enhances melanoma cell invasiveness and ITGB3 expression.

Histopathological expression analysis of intercellular adhesion molecule 1 (ICAM-1) along development and progression of human melanoma.

Intercellular adhesion molecule 1 (ICAM-1) protein is an important adhesion molecule that facilitates metastasis on one hand, and on the other hand supports the immunological synapse necessary for T-cell mediated elimination. The expression pattern of ICAM-1 in melanoma was studied more than two decades ago, mainly in cell lines or in unmatched melanoma specimens. By using real time PCR we could not demonstrate a clear difference in ICAM-1 mRNA levels between primary melanocytes and primary cultures of metastatic melanoma.

Prehospital administration of freeze-dried plasma, is it the solution for trauma casualties?

Background: Hemorrhage is the leading cause of possible preventable death in the battlefield. There is an increasing evidence for the effectiveness of blood component therapy in general, and plasma infusion in particular but their use is less applicable in the prehospital setting due to logistic difficulties. Israeli Defense Force has implemented the use of freeze-dried plasma (FDP) at the point of injury (POI), this adoption of FDP use entailed doubts regarding the feasibility and effectiveness of this practice.

Adoptive T cell therapy: An overview of obstacles and opportunities.

The therapeutic potential of adoptive cell therapy (ACT) in cancer patients was first acknowledged 3 decades ago, but it was an esoteric approach at the time. In recent years, technological advancements have transformed ACT into a viable therapeutic option that can be curative in some patients. In fact, current ACT response rates are 80% to 90% for hematological malignancies and 30% for metastatic melanoma refractory to multiple lines of therapy.

Extending a Helping Hand: A Comparison of Israel Defense Forces Medical Corps Humanitarian Aid Field Hospitals.

Background: During the past 6 years the Israel Defense Forces Medical Corps (IDF-MC) deployed three humanitarian delegation field hospitals (HDFHs) in disaster zones around the globe: Haiti (2010), the Philippines (2013), and Nepal (2015).

Objectives: To compare the activity of these HDFHs and the characteristics of the patients they served.

Methods: This retrospective study was based on the HDFHs' operation logs and patients medical records.

Point of injury tourniquet application during Operation Protective Edge-What do we learn?

Background: Hemorrhage is a leading cause of preventable death on the battlefield. Timely tourniquet application to massively bleeding extremity wounds is critical for casualty survival albeit with reported adverse effects to extremity integrity. The aim of this study was to describe the immediate- and short-term outcomes of point of injury (POI) tourniquet applications during "Operation Protective Edge" (OPE).