Approximately 50% of melanomas harbor an activating BRAF mutation. Combined BRAF and MEK inhibitors such as dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib are US Food and Drug Administration (FDA)-approved to treat patients with BRAFV600-mutated advanced melanoma. Both genetic and epigenetic alterations play a major role in resistance to BRAF inhibitors by reactivation of the MAPK and/or the PI3K–Akt pathways. The role of BRAF inhibitors in modulating the immunomicroenvironment and perhaps enhancing the efficacy of checkpoint inhibitors is gaining interest. This article provides a comprehensive review of mechanisms of resistance to BRAF and MEK inhibitors in melanoma and summarizes landmark trials that led to the FDA approval of BRAF and MEK inhibitors in metastatic melanoma.

Scurvy is a nutritional disorder caused by vitamin C deficiency. It was a notorious disease in the ancient world, especially among the sailors, and is of rare occurrence in contemporary, developed countries due to increased access and advancement in nutrition services. Scurvy primarily affects the skin and soft tissue, presenting with a myriad of clinical manifestations ranging from musculoskeletal to bleeding-related complaints and even sudden death in later stages. In this article, we present the case of an elderly female with scurvy-related weakness and gait instability leading to mechanical falls, easy bruising, fatigue, and petechial rash. She had improvement in her constitutional symptoms after the initiation of vitamin C supplements. This case reinforces the need to consider scurvy as one of the differentials for petechial rash and easy bruising apart from bleeding diathesis and vasculitis in the contemporary world, especially in atrisk populations.

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Introduction: Copper deficiency or hypocupraemia is a rare cause of anaemia and neutropenia. Case description: We hereby present the case of a 34-year-old female with gastric bypass surgery who presented with neutropenic fever, abdominal pain and diarrhoea, later found to have extended-spectrum beta-lactamase resistant Escherichia coli urinary tract infection and small bowel bacterial overgrowth syndrome, with her anaemia and neutropenia being caused by copper deficiency due to hyperzincaemia induced by using zinc denture adhesive cream. Discussion: Various causes of copper deficiency have been recognized including, but not limited to, malnutrition, gastrectomy, gastric bypass surgery, protein-losing enteropathies (coeliac disease, tropical sprue), Wilson disease and Menkes syndrome. Copper deficiency caused by zinc overuse is not very prevalent. The haematologic abnormalities associated with copper deficiency are neutropenia, sideroblastic anaemia and/or pancytopenia. Conclusion: Because of its low prevalence and nonspecific haematologic and clinical manifestations, the diagnosis of zinc-induced copper deficiency (ZICD) can be missed.

INTRODUCTION Aggressive NK-cell leukemia ( ANKL) is a systemic lymphoproliferative disorder of natural killer (NK) cells frequently associated with Epstein-Barr virus (EBV) which has been grouped under histiocytic/dendritic neoplasms in the 2008 WHO classification of hematopoietic neoplasms. Due to rarity of diagnosis, the current available literature is limited to case reports and case series. This population-based study using Surveillance Epidemiology and End result program (SEER) is the largest to explore demographic characteristics, survival patterns and long-term outcomes in patients with ANKL in the United States. MATERIALS AND METHODS We utilized SEER 18 November 2020 submission database to select all patients (> 1 years of age) diagnosed from 2000-2018 with ANKL using International Classification of Diseases for Oncology edition 3 (ICD-O-3) code of 9948/3. Patients were divided into various cohorts based on age (<60 years, 60-79 years, >80 years), sex, race (Caucasians, African American, Asian/Pacific islander and American Indians/Alaska natives) and median household income of county of residence (< $ 50,000 vs > $50,000). We used SEER*stat to calculate age adjusted incidence rate using 2000 US standard population. Kaplan Meier curve was utilized to calculate 5-year overall survival. Cox proportional hazard model was used for multivariate analysis of factors associated with survival and p<0.05 was considered significant. RESULTS A total of 140 patients were identified with ANKL. The median age at diagnosis is 58 years. The crude, age-adjusted to 2000 US standard population and age-specific incidence rate of HCD in Unites states is < 1/100, 000 respectively. The incidence in males is 1.9 times that of females- 92 males (65.7%) and 48 females (34.2%). Between 2001-2018, minimum number of cases were diagnosed in 2010 (n=2).Out of the cohort, 107 patients were White (76.4%), 21 patients were Asian or Pacific islander (15 %), 9 patients were African Americans (6.4%) and 3 patients were American Indian/Alaska native (2.1%). The median overall survival was 7 months (95% CI; 0-16). Survival rates at 1year, 2 years and 5 years were found to be 45.3% , 37.1 % and 31.1% respectively [Figure 1]. 5 year overall survival rates are as follows- Whites ( 69.7% ), Blacks ( 63.1%), American Indian (59.9%), Asian or Pacific Islander ( 66.8%). On multivariate analysis, black race was associated with poor outcomes (p 0.008), whereas sex, income and age had no significant effect on cancer outcomes. CONCLUSIONS Our study shows that ANKL is a rare hematological malignancy in general population with a poor median survival of less than one year. Males are twice more likely to be affected than females with poor outcomes in africo-americans. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.