Mucins (MUC) protect epithelial barriers from environmental insult to maintain homeostasis. However, their aberrant overexpression and glycosylation in various malignancies facilitate oncogenic events from inception to metastasis. Mucin-associated sialyl-Tn (sTn) antigens bind to various receptors present on the dendritic cells (DCs), macrophages, and natural killer (NK) cells, resulting in overall immunosuppression by either receptor masking or inhibition of cytolytic activity. MUC 1-mediated interaction of tumor cells with innate immune cells hampers crosspresentation of processed antigens on MHC class I molecules. MUC1 and MUC16 bind siglecs and mask Toll-like receptors (TLRs), respectively, on DCs promoting an immature DC phenotype that in turn reduces T cell effector functions. Mucins, such as MUC1, MUC2, MUC4, and MUC16, interact with or form aggregates with neutrophils, macrophages, and platelets, conferring protection to cancer cells during hematological dissemination and facilitate their spread and colonization to the metastatic sites. On the contrary, poor glycosylation of MUC1 and MUC4 at the tandem repeat region (TR) generates cancer-specific immunodominant epitopes. The presence of MUC16 neoantigen-specific T cell clones and anti-MUC1 antibodies in cancer patients suggests that mucins can serve as potential targets for developing cancer therapeutics. The present review summarizes the molecular events involved in mucin-mediated immunomodulation, and metastasis, as well as the utility of mucins as targets for cancer immunotherapy and radioimmunotherapy. Compliance with ethical standardsPublisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Key Points Question What are the morbidity and mortality of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) compared with other major oncologic surgical procedures? Findings In this cohort study of 1822 patients who received CRS/HIPEC compared with patients who received other high-risk surgical oncology procedures, overall 30-day mortality was lower in CRS/HIPEC (1.1%) compared with pancreaticoduodenectomy (2.5%), right lobe hepatectomy (2.9%), esophagectomy (3.0%), and trisegmental hepatectomy (3.9%). Meaning Comparative analysis revealed CRS/HIPEC to be safe across the spectrum of National Surgical Quality Improvement Project safety metrics when compared with oncologic procedures with similar inherent risk.

Extensive desmoplasia is a prominent feature of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Initially, studies demonstrated that desmoplasia promotes proliferation, invasion and chemoresistance in PDAC cells. While these findings suggested the therapeutic potential of targeting desmoplasia in PDAC, more recent studies utilizing genetically-engineered mouse models of PDAC, which lack key components of desmoplasia, demonstrated accelerated progression of PDAC. This contrast calls into question the paradigm that desmoplasia unilaterally promotes PDAC progression and the premise of desmoplasia-targeted therapy. This review briefly examines the major reports of the tumor-promoting and -restraining roles of desmoplasia in PDAC with commentary on the gaps in our current understanding of desmoplasia in PDAC. Additionally, we discuss the studies demonstrating the heterogeneous and multifaceted nature of desmoplasia in PDAC and advocate for future areas of research to thoroughly address the various facets of desmoplasia in PDAC, reconcile seemingly contradictory reports of the role of desmoplasia in PDAC progression, and discover aspects of desmoplasia that are therapeutically actionable.

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Introduction Pancreatic cancer (PC) is characterized by mucin overexpression. MUC4 is the most differentially overexpressed membrane-bound mucin that plays a functional role in disease progression and therapy resistance. Area covered We describe the clinicopathological significance of MUC4, summarize mechanisms contributing to its deregulated expression, review preclinical studies aimed at inhibiting MUC4, and discuss how MUC4 overexpression provides opportunities for developing targeted therapies. Finally, we discuss the challenges for developing MUC4-based therapeutics, and identify areas where efforts should be directed to effectively exploit MUC4 as a therapeutic target for PC. Expert opinion Studies demonstrating that abrogation of MUC4 expression reduces proliferation and metastasis of PC cells and enhances sensitivity to therapeutic agents affirm its utility as a therapeutic target. Emerging evidence also supports the suitability of MUC4 as a potential immunotherapy target. However, these studies have been limited to in vitro, ex vivo or in vivo approaches using xenograft tumors in immunodeficient murine models. For translational relevance,MUC4-targeted therapies should be evaluated in murine models with intact immune system and accurate tumor microenvironment. Additionally, future studies evaluating MUC4 as a target for immunotherapy must entail characterization of immune response in PC patients and investigate its association with immunosuppression and survival.

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BackgroundIn contrast to other cancers, survival rates for pancreatic ductal adenocarcinoma (PDAC) patients have improved but minimally over the past thirty years. The aim of this study was to perform a meta-analysis of clinical trials published since 1986 to determine trends in median overall survival in primarily metastatic PDAC.Materials and methodsAll Phase 2–4 clinical trials published during or after 1986 investigating first-line systemic chemotherapy in metastatic PDAC were included in the meta-analysis. Publications obtained through PubMed and www.ClinicalTrials.gov were cross-referenced to identify additional trials. Trials enrolling fewer than 50% of study participants with metastatic disease were excluded.ResultsOf 19,488 patients enrolled in 151 clinical trials, 84% had metastatic disease and 16% had locally advanced pancreatic cancer. In clinical trials published from 1986 to 2016, the weighted median overall survival (wMOS) increased by 3.0 months. The median wMOS was higher in combination therapy (7.31 months, IQR 5.4 to 8.5) compared to non-gemcitabine, single-agent therapy (4.76 months, IQR 3.5 to 6.0), gemcitabine monotherapy (6.48 months, IQR 5.9 to 7.2), and gemcitabine plus single-agent therapy (7.09 months, IQR 6.3 to 8.2). Of all regimens used in more than one study arm, FOLFIRINOX had the highest wMOS (10.9 months).ConclusionsRegardless of treatment regimen, survival rates in PDAC have minimally improved over time. Of drugs used in two or more study arms, only FOLFIRINOX has a wMOS greater than ten months. Emphasis should, therefore, be placed on identification of novel targets that promote early diagnosis and intervention.FundingThe authors on this manuscript are in parts, supported by grants from the National Institutes of Health (EDRN U01 CA200466, SPORE P50 CA127297, R01 CA183459, R21 AA026428 and R01 CA 195586).

Background: Anastomotic leak is the most common major complication after esophagectomy. We investigated the 2016 American College of Surgeons National Surgical Quality Improvement Program esophagectomy targeted database to identify risk factors for anastomotic leak.Methods: Patients who underwent esophagectomy for cancer were included. Patients experiencing an anstomotic leak were identified, and univariate and multivariable logistic regression was performed to identify variables independently associated with anastomotic leak.Results: Of 915 patients included, 83% were male and the median age was 64 years.Patients with anastomotic leak more frequently had additional complications (87% vs 36%, P < .001). Rates of reoperation (64% vs 11%, P < .001) and mortality (8% vs 2%, P = .001) were higher in patients with anastomotic leak. After adjusting for patient and procedure characteristics, prolonged operative time (for each additional 30-minutes; adjusted odds ratios (AOR) 1.068, 95% CI, 1.022-1.115, P = .003), increased preoperative WBC count (for each 3000/µL increase; AOR 1.323, 95% CI, 1.048-1.670, P = .019), pre-existing diabetes (AOR 1.601, 95% CI, 1.012-2.534, P = .045), and perioperative transfusion (AOR 1.777, 95% CI, 1.064-2.965, P = .028) were independently associated with anastomotic leak.Conclusion: Both patient and procedure-related factors are associated with anastomotic leak. Though frequently non-modifiable, these findings could facilitate risk stratification and early detection of anastomotic leak to reduce associated morbidity.