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Context Immune checkpoint inhibitors (ICIs) have gained a revolutionary role in management of many advanced malignancies. However, immune-related endocrine events (irEEs), have been associated with their use. irEEs have non-specific clinical presentations and variable timelines, making their early diagnosis challenging. Objective To identify risk factors, timelines, and prognosis associated with irEEs development. Design and setting Retrospective observational study within the Cleveland Clinic center. Patients Metastatic cancer adult patients who received ICIs were included. Methods 570 charts were reviewed to obtain information on demographics, ICIs used, endocrine toxicities, cancer response to treatment with ICI, and overall survival. Main Outcome Measures Incidence of irEEs, time to irEEs development, and overall survival of patients who develop irEEs. Results The final cohort included 551 patients. The median time for the diagnosis of irEEs was 11 weeks. Melanoma was associated with the highest risk for irEEs (31.3%). Ipilimumab appeared to have the highest percentage of irEEs (29.4%), including the highest risk of pituitary insufficiency (11.7%), the most severe (Grade 4 in 60%) and irreversible (100%) forms of irEEs. 45 % of patients with irEEs had adequate cancer response to ICI compared to 28.3 % of patients without irEEs (p= 0.002). Patients with irEEs had significantly better survival compared to patients without irEEs (P <0.001). Conclusions In the adult population with metastatic cancer receiving treatment with ICI, irEEs development may predict tumor response to immunotherapy and a favorable prognosis. Ipilimumab use, combination ICI therapy, and melanoma are associated with a higher incidence of irEEs.

Acute cholecystitis is the inflammation of the gallbladder, classically caused by gall stones obstructing the cystic duct. In contrast, acalculous cholecystitis is a gallbladder inflammation occurring in the absence of cholelithiasis with a reported prevalence of 10% of all cases of acute cholecystitis. Reactive acalculous cholecystitis is an extremely rare subset of this disease that results from an adjacent inflammatory or infectious intra-abdominal process that may lead to gallbladder stasis, ischemia, and subsequent wall inflammation. Many factors have been associated with acalculous cholecystitis, including (but not limited to) hemodynamic instability, altered immunity, and biliary tree anomalies. Lack of specific signs and symptoms of this particular entity often delays the diagnosis. Herein, we present a rare case of acute, reactive, acalculous cholecystitis secondary to a perforated duodenal ulcer found incidentally during laparoscopic cholecystectomy.

Background:Venous thromboembolism (VTE) is a highly prevalent complication of cancer and its treatment and is commonly treated with anticoagulation1. However, there are limited data regarding the use of therapeutic anticoagulation in patients with brain metastases, due to concerns for intracranial hemorrhage (ICH). Methods:We retrospectively identified cancer patients who were diagnosed with brain metastasis between 12/2005 and 7/2017, and subsequently underwent whole brain radiation at the Cleveland Clinic. Patients with primary brain tumors, leptomeningeal disease alone, and absence of follow-up brain imaging were excluded. Clinically significant ICH was defined as ICH resulting in focal neurologic deficit or required neurosurgery, as previously described2. Cumulative incidence of ICH from initial diagnosis of brain metastasis was calculated with death as competing risk. Difference between cumulative incidence estimates was tested using Gray's test. Overall survival (OS) calculated from initial diagnosis of brain metastasis, estimated by the Kaplan-Meier method, and compared by the log-rank test. Median follow-up time was calculated using reverse Kaplan-Meier method. Predictors identified as statistically significant on univariate logistic regression analysis (p<0.05) were selected for multivariate analysis. Results:We screened568 patients and identified 407 who meet inclusion criteria. Seventy-eight (19%) patients received therapeutic anticoagulation (AC) [enoxaparin: n = 46 (59%), warfarin: n = 27 (35%), apixaban/rivaroxaban: n = 3 (4%), unfractionated heparin: n = 2 (2%)] due to VTE after diagnosis of brain metastasis, whereas 329 (81%) patients did not receive any therapeutic dose of AC. There were more female patients in the AC cohort, but other baseline characteristics were similar in both cohorts (Table 1). In the AC cohort, 11 of 78 (14%) patients had ICH, of which 6 (55%) were clinically insignificant and 5 (45%) were clinically significant at initial diagnosis of brain metastasis. Five of 11 patients were already on AC before diagnosis of brain metastasis. In the no-AC cohort, 65 of 329 (20%) patients had ICH, of which 53 (82%) clinically insignificant and 12 (18%) clinically significant at initial diagnosis of brain metastasis. Median follow-up of patients was 28 months. The 3-year cumulative incidence of clinically insignificant ICH in AC and no-AC groups was 7.7 (95% CI: 1.8 - 13.6) and 21.3 (95% CI: 16.5 - 26.1), respectively (p = 0.017). The 3-year cumulative incidence of clinically significant ICH in AC and no-AC groups was 12.0 (95% CI: 4.6 - 19.4) and 4.9 (95% CI: 2.6 - 7.4), respectively (p = 0.044). The 3-year cumulative incidence of all ICH in AC and no-AC groups was 19.7 (95% CI: 10.7 - 28.7) and 25.8 (95% CI: 20.9 - 30.7), respectively (p = 0.27). The 3-year OS in AC and no-AC groups was 13.6 (95% CI: 6.9 - 26.4) and 17.6 (95% CI: 12.9 - 23.9), respectively (p = 0.64) (Figure 1). In univariable analysis, AC vs no-AC [OR: 2.39, 95% CI: 1.00 - 5.48, p = 0.044] and primary cancer (melanoma vs lung) [OR: 5.62, 95% CI: 1.78 - 16.49, p = 0.002] were predictors of clinically significant ICH after diagnosis of brain metastasis (Table 2). In multivariable analysis, only primary cancer (melanoma vs lung) [OR: 6.19, 95% CI: 1.92 - 18.88, p = 0.001]remained a statistically significant predictor of clinically significant ICH after diagnosis of brain metastasis. Conclusion: In this relatively large cohort of patients with brain metastasis, use of therapeutic anticoagulation did not influence the incidence of developing ICH but was associated with a greater risk of clinically significant ICH. This increase was, however, not linked to differences in overall survival. Nearly all patients in our AC cohort were treated with enoxaparin; ongoing studies will examine whether anticoagulation with DOACs is associated with similar outcomes. Disclosures Khorana: Bayer: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Pfizer: Consultancy.