Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib. Treatment with BRAF and MEK inhibitors has met challenges as patient responses began to drop due to the development of resistance to these inhibitors which paved the way for development of immunotherapies and other small molecule inhibitor approaches to address this. Resistance to these inhibitors continues to push the need to expand our understanding of novel mechanisms of resistance associated with treatment therapies. This review focuses on the current landscape of how resistance occurs with the chronic use of BRAF and MEK inhibitors in BRAF-mutant melanoma and progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma.

The use of BRAF and MEK inhibitors for patients with BRAF-mutant melanoma is limited as patients relapse on treatment as quickly as 6 months due to acquired resistance. We generated trametinib and dabrafenib resistant melanoma (TDR) cell lines to the MEK and BRAF inhibitors, respectively. TDR cells exhibited increased viability and maintenance of downstream p-ERK and p-Akt as compared to parental cells. Receptor tyrosine kinase arrays revealed an increase in p-IGF1R and p-IR in the drug resistant cells versus drug sensitive cells. RNA-sequencing analysis identified IGF1R and INSR upregulated in resistant cell lines compared to parental cells. Analysis of TCGA PanCancer Atlas (skin cutaneous melanoma) showed that patients with a BRAF mutation and high levels of IGF1R and INSR had a worse overall survival. BMS-754807, an IGF1R/IR inhibitor, suppressed cell proliferation along with inhibition of intracellular p-Akt in TDR cells. Dual inhibition of IGF1R and INSR using siRNA reduced cell proliferation. The combination of dabrafenib, trametinib, and BMS-754807 treatment reduced in vivo xenograft tumor growth. Examining the role of IGF1R and IR in mediating resistance to BRAF and MEK inhibitors will expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients.

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required by patients while on ECMO therapy along with final outcomes of patients. Results: Nineteen patients required ECMO therapy secondary to ARDS in the year 2014 at our institution. Overall survival was 47.37%. Patients required transfusion of 1.21 blood products/ECMO day out of which they received 0.80 units of packed red blood cells (PRBC)/ECMO day and 0.42 units of platelets/ECMO day. People who survived ECMO received only 0.67 blood products/ECMO day consisting of 0.56 PRBC and 0.11 platelet units / ECMO day compared to 1.71 blood products/ ECMO day consisting of 1.01 PRBC and 0.70 platelet units/ECMO day. Conclusions: This is the first study delineating the impact of blood product transfusions on survival in patients with ARDS requiring ECMO therapy. In our retrospective analysis patients with ARDS on ECMO therapy requiring less blood transfusions had a better survival compared to patients who required more transfusions. Further prospective studies would be required to validate our findings.Learning Objectives: Tidal volume (TV) has been correlated with mortality (Am J Respir Crit Care Med 2015;191(2):177-185). TV may be normalized several ways: dosage (TV/weight); strain (TV/FRC); driving pressure (TV/compliance). The unifying assumption is that the lower the TV, the less risk of ventilator induced lung injury (VILI, suggesting that a strategy of minimizing TV may be an effective way to minimize risk of VILI. Therefore, we sought to determine the ability of conventional ventilators to reduce TV by increasing frequency (f ) to their maximum capabilities. The purpose of this study was to describe the relationship between normalized TV and frequency for a constant level of ventilation in a simulated passive adult patient with ARDS. Methods: A math model showed ideal relationship of TV and f. Lung model: Rin = 11 cm H2O/L/s, Rout =16 cm H2O/L/s, C = 29 mL/cm H2O; Effort model: Pmus = 0; patient weight = 60 kg; height = 163 cm, CO2 production = 207 mL/min; dead space = 100 mL; target minute alveolar ventilation = 4.8 L/min. A physical model (IngMar ASL 5000) was used to test the performance of 3 ventilators (Maquet Servo-i, Dräger Evita XL, Covidien PB840) in pressure control ventilation with fixed I:E at 1:1.4. With constant minute ventilation and total PEEP, we recorded TV (from ventilator) and end expiratory volume (from simulator) for f = 15-100 bpm. Mean normalized TV were compared at the extremes of f using t-test or ANOVA with P < 0.05 used for significance. Results: For all models TV decreased exponentially with f. There were no differences in mean airway pressure or total PEEP (P = 0.05). All comparisons of TV showed significant differences (P < 0.01). Differences among ventilators were not clinically important at either f (< 0.25 mL/kg). There was a clinically important difference in mean TV at f = 100 (7.5 mL/kg) than f = 15 (2.6 mL/kg).Conclusions: Using 3 conventional ventilators, VT can be reduced as much as 65% using f up to 100 bpm in a passive model of ARDS. If TV dosage is linearly related ...