Mast cells (MCs) are involved in host defenses against pathogens and inflammation. Stimulated MCs release substances stored in their granules via regulated exocytosis. In other cell types, Munc13 (mammalian homolog of uncoordinated gene 13) proteins play essential roles in regulated exocytosis. Here, we found that MCs express Munc13-2 and -4, and we studied their roles using global and conditional knock-out (KO) mice. In a model of systemic anaphylaxis, we found no difference between WT and Munc13-2 KO mice, but global and MC-specific Munc13-4 KO mice developed less hypothermia. This protection correlated with lower plasma histamine levels and with histological evidence of defective MC degranulation but not with changes in MC development, distribution, numbers, or morphology. assays revealed that the defective response in Munc13-4-deficient MCs was limited to regulated exocytosis, leaving other MC secretory effector responses intact. Single cell capacitance measurements in MCs from mouse mutants differing in Munc13-4 expression levels in their MCs revealed that as levels of Munc13-4 decrease, the rate of exocytosis declines first, and then the total amount of exocytosis decreases. A requirement for Munc13-2 in MC exocytosis was revealed only in the absence of Munc13-4. Electrophysiology and EM studies uncovered that the number of multigranular compound events ( granule-to-granule homotypic fusion) was severely reduced in the absence of Munc13-4. We conclude that although Munc13-2 plays a minor role, Munc13-4 is essential for regulated exocytosis in MCs, and that this MC effector response is required for a full anaphylactic response.

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Background: Thoracentesis with cytological examination of pleural fluid is the initial test of choice for evaluation of pleural effusions in patients with suspected malignant pleural effusion (MPE). There is limited data on the sensitivity of thoracentesis stratified by tumor type. A better understanding of stratified sensitivities is of clinical interest, and may guide early and appropriate referral for pleural biopsy. Objective: The primary objective was sensitivity of thoracentesis with pleural fluid cytology stratified by tumor type. Methods: This is a retrospective cohort study of consecutive patients with a solid tumor malignancy with proven or strong suspicion for metastatic disease with new pleural effusions that underwent an initial thoracentesis. Only patients with metastatic disease were included. Results: Of the 725 patients examined, 63% had pleural fluid cytology positive for malignancy. Sensitivity of thoracentesis varied from a low of 0.38 (95% CI 0.13–0.68) in head and neck malignancy, 0.38 (95% CI 0.15–0.65) in sarcoma, and 0.53 (95% CI 0.34–0.72) in renal cancer to a high of 93 (95% CI 88–97) in breast cancer, and 100 (95% CI 0.82–100) in pancreatic cancer. Factors associated with an increased risk of MPE included larger amount of fluid drained (p = 0.014) and higher pleural fluid protein (p = 0.002). The only factor associated with decreased risk of MPE if first cytology was negative for malignancy was the presence of contralateral effusion (p = 0.005). Conclusions: Sensitivity of thoracentesis for solid tumors varies significantly depending on the type of tumor and is lowest in those with sarcomas, head and neck malignancies, and renal cell cancers.

Episodes of peritonitis 1.4±2.6 0.8±1.3 0.6 Accumulated glucose load (kg) 156.1±287 84.3±66 0.6 Creatinine MTC (mL/min) 11.7±9 10.1±3 0.7 Urea MTC (mL/min) 22.1±13 24.4±7.1 0.7 Ultrafiltration (mL/4 hr, 2.27% glucose) 650±339 540±124 0.5 VEGR = vascular endothelial growth factor; PD = peritoneal dialysis; MTC = mass transfer coefficient.

Pleural effusion size, amount of pleural fluid drained, LDH and pleural fluid cytology were found to be risk factors for recurrence.

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