Interacting Genetic Lesions of Melanoma in the Tumor Microenvironment: Defining a Viable Therapy

Melanoma is the most aggressive form of skin cancer with an estimated 106,110 newly diagnosed cases in the United States of America in 2021 leading to an approximated 7180 melanoma-induced deaths. Cancer typically arises from an accumulation of somatic mutations and can be associated with mutagenic or carcinogenic exposure. A key characteristic of melanoma is the extensive somatic mutation rate of 16.8 mutations/Mb, which is largely attributed to UV exposure. Bearing the highest mutational load, many of them occur in key driver pathways, most commonly the BRAFV600E in the mitogen-activated protein kinase (MAPK) pathway. This driver mutation is targeted clinically with FDA-approved therapies using small molecule inhibitors of oncogenic BRAFV600E and MEK, which has greatly expanded therapeutic intervention following a melanoma diagnosis. Up until 2011, therapeutic options for metastatic melanoma were limited, and treatment typically fell under the spectrum of surgery, radiotherapy, and chemotherapy.Attributed to the extensive mutation rate, as well as having the highest number of neoepitopes, melanoma is deemed to be extremely immunogenic. However, despite this highly immunogenic nature, melanoma is notorious for inducing an immunosuppressive microenvironment which can be relieved by checkpoint inhibitor therapy. The two molecules currently approved clinically are ipilimumab and nivolumab, which target the molecules CTLA-4 and PD-1, respectively.A plethora of immunomodulatory molecules exist, many with redundant functions. Additionally, these molecules are expressed not only by immune cells but also by tumor cells within the tumor microenvironment. Tumor profiling of these cell surface checkpoint molecules is necessary to optimize a clinical response. The presence of immunomodulatory molecules in melanoma, using data from The Cancer Genome Atlas and validation of expression in two model systems, human melanoma tissues and patient-derived melanoma cells, revealed that the expression levels of B and T lymphocyte attenuator (BTLA), TIM1, and CD226, concurrently with the BRAFV600E mutation status, significantly dictated overall survival in melanoma patients. These molecules, along with herpesvirus entry mediator (HVEM) and CD160, two molecules that are a part of the HVEM/BTLA/CD160 axis, had a higher expression in human melanoma tissues when compared to normal skin melanocytes and have unique roles to play in T cell activation. New links are being uncovered between the expression of immunomodulatory molecules and the BRAFV600E genetic lesion in melanoma. Small molecule inhibitors of the MAPK pathway regulate the surface expression of this multifaceted molecule, making BTLA a promising target for immuno-oncology to be targeted in combination with small molecule inhibitors, potentially alleviating T regulatory cell activation and improving patient prognosis

Monitoring and Developing a Volunteer Patient Navigation Intervention to Improve Mammography Compliance in a Safety Net Hospital

PURPOSE: Although mammography screening is crucial for cancer detection, screening rates have been declining, particularly in patients of low socioeconomic status and minorities. We sought to evaluate and improve the compliance rates at our safety net hospital through a prospective randomized controlled trial of a volunteer-run patient navigation intervention. METHODS: Baseline 90-day institutional mammography compliance rates were evaluated for patients who received a physician order for screening mammograms over a 1-month period. This analysis aided in the creation of a prospective randomized controlled trial of a volunteer-run patient navigation intervention to improve compliance, with 49 total participants. The primary outcome was 14-day mammography compliance rates. Secondary analysis examined the efficacy of the intervention with respect to patient demographics, prior mammography compliance, family history of cancer, beliefs on mammography, and past medical history. RESULTS: Analysis of baseline institutional compliance revealed a 47.87% compliance rate, with the majority of compliance occurring within 14 days of order placement. The patient navigation intervention significantly improved compliance by 34% (42% in the control group, 76% in the intervention group). Additional findings included significantly improved compliance in patients who believed they had a low susceptibility to cancer, those who understood the benefits of mammography and early diagnosis, those who had a prior mammogram, those who were employed, and those with a family history of cancer. CONCLUSION: A system to monitor compliance and intervene using patient navigation significantly improved mammography compliance of patients in a safety net hospital. The relatively straightforward design of this volunteer-based intervention makes it affordable, easily replicable, and perhaps beneficial at other institutions

Thoracoscopy in acquired immunodeficiency syndrome

AbstractObjective: The role of thoracic surgery in patients with acquired immunodeficiency syndrome (AIDS) continues to evolve. This review seeks to evaluate the outcome, morbidity, and mortality associated with videoassisted thoracoscopic surgery for empyema and pneumothorax in patients with AIDS. Methods: A retrospective review was conducted of patients with AIDS in whom video-assisted thoracoscopic surgery was performed for empyema (group 1) or intractable pneumothorax (group 2). Results: Twenty patients with AIDS (95% male, mean age 37.4 years, mean CD4 count 76 cells/ml3) underwent thoracoscopy. Surgery was performed for empyema (group 1) in 11 (55%) and intractable pneumothorax (group 2) in nine (45%). Three patients (15%) died within 30 days of the operation. At mean follow-up (29 months), overall survival was 55%. For those who survived the hospitalization and died within the follow-up period (35.3%), mean survival time was 8.2 months (range 1 month to 27 months). In group 1, surgical procedures were performed after 8 days of chest tube drainage and included pleural debridement and mechanical pleurodesis (n = 11) along with lung biopsy (n = 6). Survivals at 30 days and 29 months' follow-up were 90.9% and 45.4%, respectively. In group 2, significantly depressed CD4 counts (average 33.2 cells/ml3) were noted along with a more prolonged preoperative hospitalization (18.5 days) with 14.2 days spent with a chest tube before the operation. In this group, operative procedures included mechanical pleurodesis and talc poudrage (n = 9), bleb resection (n = 7), and lung biopsy (n = 1). Two deaths (22%) occurred within 30 days of the operation and survival at 29 months' follow-up was 66% Conclusion: Video-assisted thoracoscopic surgery performed in patients with AIDS for the treatment of empyema and intractable pneumothorax is effective, can be performed with little operative morbidity and mortality, and is associated with acceptable long-term survival. Video-assisted thoracoscopic surgery is best performed soon after the diagnosis of intractable pneumothorax or empyema has been established. (J Thorac Cardiovasc Surg 1997;114:361-6