Survival Impact of Adjuvant Therapy in Salivary Gland Cancers following Resection and Neck Dissection

Objective To evaluate the impact of postoperative radiotherapy (PORT) and chemotherapy on survival in salivary gland cancer (SGC) treated with curative-intent local resection and neck dissection. Study Design Retrospective population-based cohort study. Setting National Cancer Database. Subjects and Methods Patients with SGC who were undergoing surgery were identified from the National Cancer Database between 2004 and 2013. Neck dissection removing a minimum of 10 lymph nodes was required. Because PORT violated the proportional hazards assumption, this variable was treated as a time-dependent covariate. Results Overall, 4145 cases met inclusion criteria (median follow-up, 54 months). PORT was associated with improved overall survival in multivariable analysis, both 9 months (HR, 0.75; 95% CI, 0.66-0.86; P <.001). In propensity score-matched cohorts, 5-year overall survival was 67.1% and 60.6% with PORT and observation, respectively (P <.001). Similar results were observed in landmark analysis of patients surviving at least 6 months following diagnosis. Adjuvant chemotherapy was not associated with improved survival (HR, 1.15; 95% CI, 0.99-1.34; P = .06). Conclusion PORT, but not chemotherapy, is associated with improved survival among patients with SGC for whom neck dissection was deemed necessary. These results are not applicable to low-risk SGCs not requiring neck dissection.Peer reviewe

Significance of undissected retromaxillary air cells as a risk factor for revision endoscopic sinus surgery

Background: Retromaxillary air cells (RMC) are posterior ethmoid cells that separate the maxillary and ethmoid sinuses. The clinical significance of these cells in contributing to revision functional endoscopic sinus surgery (FESS) is unknown. Objectives: To investigate the prevalence, anatomic dimensions, and radiographic characteristics of RMC in patients with recalcitrant chronic rhinosinusitis after previous FESS. Methods: A retrospective review of patients who underwent revision FESS at a tertiary medical center between January 1, 2012, and December 31, 2014. Computed tomographies of patients who underwent revision FESS, including posterior ethmoidectomies, were reviewed. Each side of the scan was assessed for residual RMCs. The radiographic dimensions and Lund-Mackay (LM) scores of these cells were recorded. Results: Sixty-nine patients who underwent revision FESS were identified. The median age of the patient population was 51 years (range, 21'79 years). Forty-two percent of the patients had nasal polyps. The mean number of previous FESS was 2 (range, 1'10). Incompletely dissected RMCs were identified in 101 of 138 analyzed sides (73%), despite documented previous posterior ethmoidectomies. Sixty-five percent of RMCs had an LM score of ≥1; RMCs of patients with polyps were more likely to have an LM score of 2 (p = 0.049). There was a significant correlation between the number of previous FESS procedures and whether the RMCs had been dissected (p = 0.010). There also was a significant correlation between RMC height and the number of previous FESS procedures (p = 0.015). Conclusion: RMCs seemed to often be undissected during primary FESS and, thus, were commonly encountered in revision FESS. The majority of analyzed cells in this cohort demonstrated an LM score of =1, which indicated that these cells frequently harbor residual diseased mucosa that may contribute to the need for revision surgery.5 page(s

The association between facility volume and overall survival in patients with Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma is an uncommon malignancy often requiring multidisciplinary management. The purpose of this study was to determine whether high-volume facilities have improved outcomes in patients with Merkel cell carcinoma relative to lower-volume facilities. METHODS: A total of 5304 patients from the National Cancer Database with stage I-III Merkel cell carcinoma undergoing surgery were analyzed. High-volume facilities were the top 1% by case volume. Multivariable Cox regression and propensity score-matching were performed to account for imbalances between groups. RESULTS: Treatment at high-volume facilities (hazard ratio: 0.74; 95% confidence interval: 0.65-0.84, P \u3c .001) was independently associated with improved overall survival (OS) in multivariable analyses. In propensity score-matched cohorts, 5-year OS was 62.3% at high-volume facilities vs 56.8% at lower-volume facilities (P \u3c .001). Median OS was 111 months at high-volume facilities vs 79 months at lower-volume facilities. CONCLUSION: Treatment at high-volume facilities is associated with improved OS in Merkel cell carcinoma. Given the impracticality of referring all elderly patients with Merkel cell carcinoma to a small number of facilities, methods to mitigate this disparity should be explored

EZH2 couples pancreatic regeneration to neoplastic progression

Although the polycomb group protein Enhancer of Zeste Homolog 2 (EZH2) is well recognized for its role as a key regulator of cell differentiation, its involvement in tissue regeneration is largely unknown. Here we show that EZH2 is up-regulated following cerulein-induced pancreatic injury and is required for tissue repair by promoting the regenerative proliferation of progenitor cells. Loss of EZH2 results in impaired pancreatic regeneration and accelerates KRas(G12D)-driven neoplasia. Our findings implicate EZH2 in constraining neoplastic progression through homeostatic mechanisms that control pancreatic regeneration and provide insights into the documented link between chronic pancreatic injury and an increased risk for pancreatic cancer

Mast cell dipeptidyl peptidase I mediates survival from sepsis

Sepsis is a common, life-threatening disease for which there is little treatment. The cysteine protease dipeptidyl peptidase I (DPPI) activates granule-associated serine proteases, several of which play important roles in host responses to bacterial infection. To examine DPPI’s role in sepsis, we compared DPPI(–/–) and DPPI(+/+) mice using the cecal ligation and puncture (CLP) model of septic peritonitis, finding that DPPI(–/–) mice are far more likely to survive sepsis. Outcomes of CLP in mice lacking mast cell DPPI reveal that the absence of DPPI in mast cells, rather than in other cell types, is responsible for the survival advantage. Among several cytokines surveyed in peritoneal fluid and serum, IL-6 is highly and differentially expressed in DPPI(–/–) mice compared with DPPI(+/+) mice. Remarkably, deleting IL-6 expression in DPPI(–/–) mice eliminates the survival advantage. The increase in IL-6 in septic DPPI(–/–) mice, which appears to protect these mice from death, may be related to reduced DPPI-mediated activation of mast cell tryptase and other peptidases, which we show cleave IL-6 in vitro. These results indicate that mast cell DPPI harms the septic host and that DPPI is a novel potential therapeutic target for treatment of sepsis

In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-α

Hepatic fibrosis occurs during most chronic liver diseases and is driven by inflammatory responses to injured tissue. Because DCs are central to modulating liver immunity, we postulated that altered DC function contributes to immunologic changes in hepatic fibrosis and affects the pathologic inflammatory milieu within the fibrotic liver. Using mouse models, we determined the contribution of DCs to altered hepatic immunity in fibrosis and investigated the role of DCs in modulating the inflammatory environment within the fibrotic liver. We found that DC depletion completely abrogated the elevated levels of many inflammatory mediators that are produced in the fibrotic liver. DCs represented approximately 25% of the fibrotic hepatic leukocytes and showed an elevated CD11b+CD8– fraction, a lower B220+ plasmacytoid fraction, and increased expression of MHC II and CD40. Moreover, after liver injury, DCs gained a marked capacity to induce hepatic stellate cells, NK cells, and T cells to mediate inflammation, proliferation, and production of potent immune responses. The proinflammatory and immunogenic effects of fibrotic DCs were contingent on their production of TNF-α. Therefore, modulating DC function may be an attractive approach to experimental therapeutics in fibro-inflammatory liver disease

Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor

The liver is the most common site of adenocarcinoma metastases, even in patients who initially present with early disease. We postulated that immune-suppressive cells in the liver of tumor-bearing hosts inhibit anti-tumor T cells, thereby accelerating the growth of liver metastases. Using models of early preinvasive pancreatic neoplasia and advanced colorectal cancer, aims of this study were to determine immune phenotype, stimulus for recruitment, inhibitory effects, and tumor-enabling function of immune-suppressive cells in the liver of tumor-bearing hosts. We found that in mice with intra-abdominal malignancies, two distinct CD11b+Gr1+ populations with divergent phenotypic and functional properties accumulate in the liver, becoming the dominant hepatic leukocytes. Their expansion is contingent on tumor expression of KC. These cells are distinct from CD11b+Gr1+ populations in other tissues of tumor-bearing hosts in terms of cellular phenotype and cytokine and chemokine profile. Liver CD11b+Gr1+ cells are highly suppressive of T cell activation, proliferation, and cytotoxicity and induce the development of Tregs. Moreover, liver myeloid-derived suppressor cells accelerate the development of hepatic metastases by inactivation of cytotoxic T cells. These findings may explain the propensity of patients with intra-abdominal cancers to develop liver metastases and suggest a promising target for experimental therapeutics