Background Obesity has been linked to increased mortality in several cancer types; however, the relationship between obesity and survival in metastatic melanoma is unknown. The aim of this study was to examine the association between BMI, progression-free survival (PFS), and overall survival (OS) in metastatic melanoma. Methods This study included 6 independent cohorts for a total of 1918 metastatic melanoma patients. These included two targeted therapy cohorts [randomized control trials (RCTs) of dabrafenib and trametinib (n=599) and vemurafenib and cobimetinib (n=240)], two immunotherapy cohorts [RCT of ipilimumab + dacarbazine (DTIC) (n=207) and a retrospective cohort treated with anti-PD-1/PDL-1 (n=331)], and two chemotherapy cohorts [RCT DTIC cohorts (n=320 and n=221)]. BMI was classified as normal (BMI 18 to <25; n=694 of 1918, 36.1%) overweight (BMI 25-29.9; n=711, 37.1%) or obese (BMI≥30; n=513, 26.7%). The primary outcomes were the association between BMI, PFS, and OS, stratified by treatment type and sex. These exploratory analyses were based on previously reported intention-to-treat data from the RCTs. The effect of BMI on PFS and OS was assessed by multivariable-adjusted Cox models in independent cohorts. In order to provide a more precise estimate of the association between BMI and outcomes, as well as the interaction between BMI, sex, and therapy type, adjusted hazard ratios were combined in mixed-effects meta-analyses and heterogeneity was explored with meta-regression analyses. Findings In the pooled analysis, obesity, as compared to normal BMI, was associated with improved survival in patients with metastatic melanoma [average adjusted hazard ratio (HR) and 95% CI: 0.77 (0.66-0.90) and 0.74 (0.58-0.95) for PFS and OS, respectively]. The survival benefit associated with obesity was restricted to patients treated with targeted therapy [0.72 (0.57-0.91) and 0.60 (0.45-0.79) for PFS and OS, respectively] and immunotherapy [0.75 (0.56-1.00) and 0.64 (0.47-0.86)]. No associations were observed with chemotherapy [0.87 (0.65-1.17) and 1.03 (0.80-1.34); treatment p for interaction = 0.61 and 0.01, for PFS and OS, respectively]. The prognostic effect of BMI with targeted and immune therapies differed by sex with pronounced inverse associations in males [PFS 0.67 (0.53-0.84) and OS 0.53 (0.40-0.70)], but not females [PFS 0.92 (0.70-1.23) and OS 0.85 (0.61-1.18), sex p for interaction= 0.08 and 0.03, for PFS and OS, respectively] Interpretation Obesity is associated with improved PFS and OS in metastatic melanoma, driven by strong associations observed in males treated with targeted or immune therapy. The magnitude of the benefit detected supports the need for investigation into the underlying mechanism of these unexpected observations Funding ASCO/CCF Young Investigator Award and ASCO/CCF Career Development Award to JLM

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• Therapeutic enoxaparin was associated with a greater than threefold increased risk of major ICH in patients with glioma.• The PANWARDS risk score was a sensitive predictor of major ICH in glioma.Venous thromboembolism occurs in up to one-third of patients with primary brain tumors. Spontaneous intracranial hemorrhage (ICH) is also a frequent occurrence in these patients, but there is limited data on the safety of therapeutic anticoagulation. To determine the rate of ICH in patients treated with enoxaparin, we performed a matched, retrospective cohort study with blinded radiology review for 133 patients with high-grade glioma. After diagnosis of glioma, the cohort that received enoxaparin was 3 times more likely to develop a major ICH than those not treated with anticoagulation (14.7% vs 2.5%; P 5 .036; hazard ratio [HR], 3.37; 95% confidence interval [CI], 1.02-11.14). When enoxaparin was analyzed as a time-varying covariate, anticoagulation was associated with a >13-fold increased risk of hemorrhage (HR, 13.26; 95% CI, 3.33-52.85; P < .0001).Overall survival was significantly shorter for patients who suffered a major ICH on enoxaparin compared with patients not receiving anticoagulation (3.3 vs 10.2 months; log-rank P 5 .012). We applied a validated ICH prediction risk score PANWARDS (platelets, albumin, no congestive heart failure, warfarin, age, race, diastolic blood pressure, stroke), and observed that all major ICHs on enoxaparin occurred in the setting of a PANWARDS score ‡25, corresponding with a sensitivity of 100% (95% CI, 63% to 100%) and a specificity of 40% (95% CI, 25% to 56%). We conclude that caution is warranted when considering therapeutic anticoagulation in patients with high-grade gliomas given the increased risk of ICH and poor prognosis after a major hemorrhage on anticoagulation. The PANWARDS score may assist clinicians in identifying the patients at greatest risk of suffering a major intracranial hemorrhage with anticoagulation. (Blood. 2017;129(25):3379-3385)

Summary Intracranial hemorrhage (ICH) is common in patients with brain tumors. We compared rates of ICH with DOACs and low molecular weight heparin. DOACs were associated with a lower incidence of ICH in primary brain tumors. DOACs appear safe to administer to patients with brain tumors. Summary BackgroundDirect oral anticoagulants (DOACs) are efficacious in the treatment of cancer‐associated thrombosis but are associated with an increased risk of hemorrhage compared with low‐molecular‐weight heparin in certain malignancies. Whether the DOACs increase the incidence of intracranial hemorrhage (ICH) in patients with brain tumors is not established. ObjectivesTo determine the cumulative incidence of ICH in DOACs compared with Low‐molecular‐weight heparin (LMWH) in patients with brain tumors and venous thromboembolism. Patients and methodsA retrospective comparative cohort study was performed. Radiographic images for all ICH events were reviewed and the primary endpoint was cumulative incidence of ICH at 12 months following initiation of anticoagulation. Results and conclusionsA total of 172 patients with brain tumors were evaluated (42 DOAC and 131 LMWH). In the primary brain tumor cohort (n = 67), the cumulative incidence of any ICH was 0% in patients receiving DOACs vs. 36.8% (95% confidence interval [CI], 22.3–51.3%) in those treated with LMWH, with a major ICH incidence of 18.2% (95% CI, 8.4–31.0). In the brain metastases cohort (n = 105), DOACs did not increase the risk of any ICH relative to enoxaparin, with an incidence of 27.8% (95% CI, 5.5–56.7%) compared with 52.9% (95% CI, 37.4–66.2%). Similarly, DOAC did not increase the incidence of major ICH in brain metastases, with a cumulative incidence 11.1% (95% CI, 0.5–40.6%) vs. 17.8% (95% CI, 10.2–27.2%). We conclude that DOACs are not associated with an increased incidence of ICH relative to LMWH in patients with brain metastases or primary brain tumors.