Outcomes of > 1300 Nipple-Sparing Mastectomies with Immediate Reconstruction: The Impact of Expanding Indications on Complications.

BACKGROUND: The enhanced esthetics and demonstrated oncologic safety of nipple-sparing mastectomy (NSM) in selected patients have resulted in increased rates among patients with locally advanced breast cancer and/or additional risk factors (obesity, prior radiation, surgery). Limited data exist on complication and reconstruction success rates in a contemporary patient cohort with expanded indications for NSM. METHODS: With institutional review board (IRB) approval, patients treated from 2009 to 2017 with NSM were identified from our prospective breast surgery registry. Main outcomes were 30-day complications requiring treatment and 1-year reconstruction failure rates. Risk factors were assessed using logistic regression. RESULTS: We evaluated 1301 breasts in 769 women undergoing NSM for cancer (n = 555) or risk reduction (n = 746) with median age of 48 (range 21-77) years. The overall 30-day complication rate was 7.5% (97/1301 breasts) and declined from 14.8% in 2009 to 6.3% in 2017 (p < 0.001), while the proportion of patients with obesity (p = 0.007) and treated with neoadjuvant chemotherapy (p < 0.001) increased. Prior radiation [odds ratio (OR) 2.35, p = 0.04], recent/current smoking (OR 3.37, p < 0.001), and body mass index (BMI) (OR 1.28 per 5-kg/m2 increase, p = 0.03) significantly increased 30-day complication rates. Reconstruction success at 1 year was 96.7%. Prior radiation (OR 5.65, p < 0.001), axillary surgery (OR 2.55, p = 0.006), and postoperative adjuvant radiation (OR 3.22, p = 0.007) significantly affected 1-year reconstruction failure. CONCLUSION: The 30-day complication rates of NSM decreased, despite broadened indications among higher-risk patients over time. These data confirm a team learning curve with NSM and also demonstrate that the nipple-sparing approach is suitable for appropriately selected higher-risk patients for both risk reduction and cancer treatment.

Program Cell Death Receptor-1-Mediated Invariant Natural Killer T-Cell Control of Peritoneal Macrophage Modulates Survival in Neonatal Sepsis.

We have shown that invariant natural killer T (iNKT) cells mediate sepsis-induced end-organ changes and immune responses, including macrophage bacterial phagocytosis, a finding regulated by the check point protein program cell death receptor-1 (PD-1). Furthermore, PD-1 mediates mortality in both adult and neonatal murine sepsis as well as in surgical patients. Given our previous findings, we hypothesize that iNKT cells will also modulate neonatal sepsis survival, and that this effect is regulated in part through PD-1. We utilized a polymicrobial intra-peritoneal cecal slurry (CS) sepsis model in wild type (WT), iNKT-/- or PD-1-/- 5-7 day old neonatal pups. Typically, tissues were harvested at 24 h for various bioassays/histology and, in some cases, survival was assessed for up to 7 days. Interestingly, similar to what we recently reported for PD-1-/- mice following CS, iNKT-/--deficient animals exhibit a markedly improved survival vs. WT. Histologically, minor alterations in liver architectural, which were noted in WT pups, were attenuated in both iNKT-/- and PD-1-/- pups. Following CS, PECAM-1 expression was unchanged in the WT pups but increased in both iNKT-/- and PD-1-/- pups. In WT, following CS the emergence of a Ly6Clow subpopulation was noted among the influxed peritoneal macrophage population. Conversely, within iNKT-/- pups, there were fewer peritoneal macrophages and a greater percentage of Ly6Chigh macrophages. We show not only a key role for iNKT cells in affecting end-organ damage as well as alterations in phagocytes phenotypes in neonatal sepsis but that this iNKT cell mediated effect is driven by the central checkpoint protein PD-1.

Improved survival after induction of sepsis by cecal slurry in PD-1 knockout murine neonates.

BACKGROUND: Sepsis and the ensuing immune dysfunction continue to be major contributors to neonatal morbidity and mortality. Neonatal sepsis also is associated with profound immune dysfunction. We have recently identified a role for a family of coinhibitory molecules that are altered in murine sepsis and in critically ill adult patients, which may be a target for development of novel therapies. There is, however, a paucity of data pertaining to the role of coinhibitory checkpoint proteins in the control and modulation of neonatal sepsis. METHODS: The cecal slurry model consists of harvesting the cecal content of an adult, wild-type, male mouse and combining it with 5% dextrose to create a cecal slurry with a concentration of 80 mg/mL (LD70 at 7 days). Neonatal mice (5-7 days of age) underwent intraperitoneal injection of the cecal slurry or 0.9% saline for the sham procedure. Wild-type (C57BL/6) or PD-1-/- mice were used; a 7-day survival study was undertaken. Cytometric bead array was used for cytokine expression. Blood and peritoneal fluid was cultured for bacterial burden. Flow cytometry was used to assess the peritoneal cavity cell populations. RESULTS: There was no mortality after the sham procedure in either wild-type or PD-1-/- pups. PD-1 markedly affected sepsis survival with significantly improved survival in the PD-1-/- pups (40% vs 80%; P < .01). This survival improvement was not associated with any difference in bacterial clearance. The bacterial burden was equivalent between wild-type and PD-1-/- pups at 24 hours after cecal slurry. However, PD-1-/- pups did display an increased circulating cytokine response to the cecal slurry compared with wild type, with increased expression of IL-6, IL-10, and TNF-α levels. Within the peritoneal cavity, sepsis induced an influx of neutrophils, a finding that was increased in PD-1-/- pups. Although the T-cell response was unaffected by PD-1, it was noted that cecal slurry induced a loss of peritoneal B cells in WT, while the peritoneal B-cell population was preserved in PD-1-/- pups. CONCLUSION: Our data suggest that the checkpoint protein, PD-1, plays an important role in controlling the immune response to sepsis in the neonate, ultimately affecting sepsis-related mortality in this neonatal murine model of sepsis. Akin to adult studies, these data further emphasize the potential therapeutic target for PD-1 across a spectrum of septic patients.

Effect of PD-1: PD-L1 in Invariant Natural Killer T-Cell Emigration and Chemotaxis Following Sepsis.

Invariant natural killer T-cells (iNKT) are a subset of T-cells that play a regulatory role in sepsis. Following cecal ligation and puncture (CLP), iNKT cells emigrate from the liver and into the circulation and peritoneum in a manner dependent upon coinhibitory molecule Programmed Cell Death Receptor 1 (PD-1). We hypothesized that the effect of PD-1 on iNKT-cell emigration was dependent upon the direct PD-1:PD-L1 interaction, and that PD-1 and PD-L1 would play a role in chemotaxis and chemokine receptor expression. Adoptive transfer of Vybrant-labeled wild-type (WT) cells showed the donor iNKT cells migrated from the liver to the peritoneum following CLP, but PD-L1 deficient donor iNKT cells did not. In a chemotaxis assay, WT-iNKT cells chemotaxed to CXCL12, but PD-1 and PD-L1 deficient iNKT cells did not. Using flow cytometry to evaluate chemokine receptor expression, peritoneal iNKT expression of CXCR4 increased following CLP in the WT, PD-1, and PD-L1 deficient animals, and CXCR6 increased in the WT and PD-1 deficient animals. In conclusion here we document that the hepatic emigration of iNKT cells following CLP to the peritoneum appears dependent upon the direct PD-1:PD-L1 interaction; however, although PD-1 and PD-L1 appear to play a role in chemotaxis, this is unlikely a reflection of iNKT-cell chemokine receptor expression changes.