Trends in surgical complexity and treatment modalities utilized in the management of ovarian cancer in an era of neoadjuvant chemotherapy.

OBJECTIVES: To investigate the impact of the increased use of neoadjuvant chemotherapy on the complexity of cytoreductive surgeries for ovarian cancer. METHODS: Using the National Cancer Database, we performed a retrospective cohort study of women diagnosed between 2004 and 2015 with stage III or IV epithelial ovarian cancer who underwent either primary cytoreductive surgery (PDS) followed by adjuvant chemotherapy, neoadjuvant chemotherapy (NACT) followed by interval debulking surgery. Cases were assigned a surgical complexity category as 1) Inadequate, 2) Low, 3) Moderate and, 4) High complexity. The primary outcome was the trend in surgical complexity over time. Secondary outcomes included temporal trends in treatment modality, perioperative mortality, and survival. RESULTS: At total of 52,582 (76.3%) underwent PDS and 16,307 (23.7%) underwent NACT. The utilization of NACT increased from 7.7% in 2004 to 27.8% in 2015 (p-trend < 0.001). Patients undergoing moderate complexity surgeries increased from 28.9% to 33.5% and high complexity surgeries from 26.3% to 30% (p-trend < 0.001, for both). Trends in increasing surgical complexity were seen in both NACT and PDS cohorts. This increase in surgical complexity was seen most profoundly at the high-volume centers. Overall 30-day mortality decreased from 3.4% in 2004 to 1.4% in 2015; and 90-day mortality decreased from 7.6% to 4%. During the same time, 5-year survival increased from 39.7% to 49%. CONCLUSIONS: Increase in the utilization of NACT is associated with decreased 30- and 90-day mortality and increase in five-year survival. Moreover, the overall complexity of ovarian cancer surgery has increased in both PDS and NACT cohorts.

Inhibition of Fas ligand in NOD mice unmasks a protective role for IL-10 against insulitis development.

Type 1 diabetes mellitus (T1D) is an autoimmune disease caused by the destruction of pancreatic insulin-producing ß cells by autoreactive T cells early in life. Despite daily insulin injections, patients typically develop cardiovascular and other complications; and intensive efforts are being directed toward identifying therapeutic targets to prevent the disease without directly impinging on the host defense. Fas ligand (FasL) is one potential target. Fas-FasL interactions primarily regulate T-cell homeostasis, not activation. Nevertheless, spontaneous gene mutation of Fas (called lpr mutation) or FasL (called the gld mutation) prevents autoimmune diabetes in nonobese diabetic (NOD) mice, the widely used model for T1D. Furthermore, although homozygous gld mutations cause age-dependent lymphoproliferation, limiting the gld mutation to one allele (NOD-gld/+) or treating NOD-wild-type mice with FasL-neutralizing monoclonal antibody completely prevents the disease development without causing lymphoproliferation or immune suppression. Herein, we show that the heterozygous gld mutation inhibits the accumulation of diabetogenic T cells in the pancreas, without interfering with their proliferation and expansion in the draining pancreatic lymph nodes. Pancreata from NOD-gld/+ mice contained B cells that expressed CD5 and produced IL-10, which was critical for maintenance of the disease resistance because its neutralization with an IL-10 receptor-blocking monoclonal antibody allowed accumulation of CD4 T cells in the pancreas and led to insulitis development. The results provide novel insights into the pathogenesis of T1D that could have important therapeutic implications.