Retrospective Analysis of Retroperitoneal-Abdominal-Pelvic Ganglioneuromas: An International Study by the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG).

OBJECTIVE: The Transatlantic Australasian Retroperitoneal Sarcoma Working Group conducted a retrospective study on the disease course and clinical management of ganglioneuromas. BACKGROUND: Ganglioneuromas are rare tumors derived from neural crest cells. Data on these tumors remain limited to case reports and single-institution case series. METHODS: Patients of all ages with pathologically confirmed primary retroperitoneal, intra-abdominal, and pelvic ganglioneuromas between January 1, 2000, and January 1, 2020, were included. We examined demographic, clinicopathologic, and radiologic characteristics, as well as clinical management. RESULTS: Overall, 328 patients from 29 institutions were included. The median age at diagnosis was 37 years with 59.1% of patients being female. Symptomatic presentation comprised 40.9% of cases, and tumors were often located in the extra-adrenal retroperitoneum (67.1%). At baseline, the median maximum tumor diameter was 7.2 cm. One hundred sixteen (35.4%) patients underwent active surveillance, whereas 212 (64.6%) patients underwent resection with 74.5% of operative cases achieving an R0/R1 resection. Serial tumor evaluations showed that malignant transformation to neuroblastoma was rare (0.9%, N=3). Tumors undergoing surveillance had a median follow-up of 1.9 years, with 92.2% of ganglioneuromas stable in size. With a median follow-up of 3.0 years for resected tumors, 84.4% of patients were disease free after resections, whereas recurrences were observed in 4 (1.9%) patients. CONCLUSIONS: Most ganglioneuromas have indolent disease courses and rarely transform to neuroblastoma. Thus, active surveillance may be appropriate for benign and asymptomatic tumors particularly when the risks of surgery outweigh the benefits. For symptomatic or growing tumors, resection may be curative.

Surgery is Associated With Improved Overall Survival in Patients With Metastatic Gastric Cancer: A National Cancer Database Analysis.

BACKGROUND: The 5-year overall survival (OS) rate for patients with metastatic gastric cancer (mGC) is 5.3%. Surgery for mGC is controversial. METHODS: We identified all mGC patients who received chemotherapy using the National Cancer Database (2004-2015). Patients were grouped according to surgery of: (1) the primary site (PS) only, (2) primary and distant sites (PDS), (3) distant site only (DS), or (4) no surgery (NS). A propensity score adjustment and multivariate regression was used to compare OS. RESULTS: Overall, 18,772 patients met the inclusion criteria: (1) PS (n = 962, 5.1%), (2) PDS (n = 380, 2.1%), (3) DS (n = 984, 5.2%), and 16,446 NS (87.6%). Surgery was associated with improved OS in the PS and PDS groups (hazard ratios: .489 (95% CI: .376-.636); .583 (95% CI: .420-.811), P < .001) (median OS 15.8 and 15.9 months vs 8.6 for NS patients, respectively). CONCLUSIONS: Gastrectomy with or without metastasectomy is associated with improved survival in stage IV gastric cancer patients receiving chemotherapy. This warrants further prospective studies.

National Trends in Treatment for Retroperitoneal Soft Tissue Sarcoma: A Modern Appraisal of Variability in Therapeutic Strategies.

BACKGROUND: Little level 1 evidence exists to guide multimodality treatment in retroperitoneal soft tissue sarcoma (RPS), which may lead to significant variation in therapeutic approaches. This analysis aimed to describe national RPS treatment trends and explore potential variability among low-/high-volume hospitals (LVH/HVHs). PATIENTS AND METHODS: In total, 5992 patients who underwent resection for primary RPS were retrospectively identified in the National Cancer Database (2004-2017). Time trend analyses examined rates of multivisceral resection (MVR), radiation, and chemotherapy use. LVHs were defined as those carrying out fewer than ten resections per year (N = 5433), whereas HVHs were defined as those carrying out ten or more (N = 559). Descriptive statistics and logistic regression models compared trends between groups. RESULTS: MVR was more frequent at HVHs (63.7% versus 43.5%, p < 0.001). Use of radiation varied widely by hospital volume. HVHs more frequently employed preoperative radiation as compared with LVHs (14.7% versus 8.1%, p < 0.001). Throughout the study period, LVHs increased utilization of preoperative radiation (2.6% to 12.0%, p < 0.001) whereas rates at HVHs remained stable. Overall, LVHs utilized postoperative radiation significantly more frequently as compared with HVHs (14.7% versus 2.7%, respectively, p < 0.001). Postoperative radiation at LVHs remained stable until 2013 and sharply declined thereafter (16.7% to 6.9%, p < 0.001). Rates of postoperative radiation use at HVHs remained lower than those at LVHs at all time points. CONCLUSIONS: Strategies for resection and radiation use at LVHs have trended towards those of HVHs. Current national implementation of preoperative radiation, MVR, and chemotherapy remains heterogeneous. These findings inform future trial design and support standardization of care.

COVID-19 is Affecting the Presentation and Treatment of Melanoma Patients in the Northeastern United States.

BACKGROUND: Covid-19 significantly affected healthcare delivery over the past year, with a shift in focus away from nonurgent care. Emerging data are showing that screening for breast and colon cancer has dramatically decreased. It is unknown whether the same trend has affected patients with melanoma. METHODS: This is a retrospective cohort study of melanoma patients at two large-volume cancer centers. Patients were compared for 8 months before and after the lockdown. Outcomes focused on delay in treatment and possible resultant upstaging of melanoma. RESULTS: A total of 375 patients were treated pre-lockdown and 313 patients were treated post-lockdown (17% decrease). Fewer patients presented with in situ disease post-lockdown (15.3% vs. 17.9%), and a higher proportion presented with stage III-IV melanoma (11.2% vs. 9.9%). Comparing patients presenting 2 months before versus 2 months after the lockdown, there was an even more significant increase in Stage III-IV melanoma from 7.1% to 27.5% (p < 0.0001). Finally, in Stage IIIB-IIID patients, there was a decrease in patients receiving adjuvant therapy in the post lockdown period (20.0% vs. 15.2%). CONCLUSIONS: As a result of the recent pandemic, it appears there has been a shift away from melanoma in situ and toward more advanced disease, which may have significant downstream effects on prognosis and could be due to a delay in screening. Significantly patients have presented after the lockdown, and fewer patients are undergoing the recommended adjuvant therapies. Patient outreach efforts are essential to ensure that patients continue to receive preventative medical care and screening as the pandemic continues.

Optimal care and survival for signet-ring cell and non-signet-ring cell gastric cancer are more achievable at academic cancer centers.

BACKGROUND: Western literature lacks large-scale population studies comparing the influence of academic and high-volume (HV) versus low-volume (LV) cancer centers on gastric cancer oncologic outcomes. METHODS: The National Cancer Database from 2004 to 2016 was used. RESULTS: 22871 patients were studied. Patients with stage III signet-ring cell gastric carcinoma (SRGC) received neoadjuvant treatment (NAT) more frequently at academic and HV comprehensive cancer centers (OR: 4.27 and 2.42; p < 0.0001 and 0.009) compared to community centers. Patients with stage III non-SRGC (NSRGC) had a 2.4 times higher odds of receiving NAT at academic centers. The R1 resection rate for NSRGC was lower at academic centers (OR: 0.67; p = 0.0018). Lymph node harvest ≥15 nodes was 1.6 and 1.9 times higher at academic centers for NSRGC and SRGC, respectively. Patients treated at academic centers had a significantly improved overall survival (OS). CONCLUSIONS: Treatment at academic centers is associated with significant improvements in oncologic metrics and OS.

Partial Gastrectomy is Associated with Improved Overall Survival in Signet-Ring Cell Gastric Cancer.

BACKGROUND: Signet-ring cell gastric cancer (SRGC) is a histological variant of gastric adenocarcinoma (GAC) with a worse prognosis compared to non-signet-ring cell gastric cancer (NSRGC). To our knowledge, the overall survival (OS) among patients with SRGC undergoing total/near-total (TG) versus partial gastrectomy (PG) has never been reported from a large-scale Western database. METHODS: We performed a retrospective analysis of patients with both SRGC and NSRGC using The National Cancer Database. RESULTS: In total, 17,086 patients were included. Patients who underwent TG versus PG were 25.5% (n = 770) versus 74.5% (n = 2246) for SRGC, and 20.9% (n = 2943) versus 79.1% (n = 11,127) for NSRGC, respectively. Patients who had SRGC were more likely to undergo TG (25.5% versus 20.9% P< 0.0001). Patients with distal gastric tumors were less likely to undergo TG (16.5% versus 25.4% P < 0.0001). Patients undergoing PG for the SRGC histological variant had better OS (HR = 0.68, CI=0.61-0.76; P < 0.0001) versus those who underwent TG. Similarly, NSRGC patients undergoing PG also had improved OS, but to a lesser extent (HR = 0.91, CI = 0.85-0.96; P= 0.002). Overall, PG for GAC was associated with improved OS compared to TG, although the OS benefit is more profound in the SRGC histological variant (P < 0.0001). CONCLUSIONS: Our results show that TG is not associated with improved OS in patients who undergo gastrectomy for GAC, even when adjusted for tumor location. The survival differences are more pronounced in the SRGC histology variant. The worst survival is observed in patients with SRGC who undergo TG after adjusting for different covariates.

Treatment at an Academic Cancer Center Confers Better Survival by Stage for Signet-Ring Cell and Non-signet-Ring Cell Gastric Cancer.

BACKGROUND: The literature lacks large-scale population studies comparing survival outcomes between signet-ring cell gastric carcinoma (SRGC) and non-SRGC (NSRGC) when treatment is delivered at academic versus community cancer centers. METHODS: The National Cancer Database (NCDB) from 2004 to 2016 was queried to examine the association between treatment facility category and overall survival of patients who underwent gastrectomy for resectable gastric adenocarcinoma (GAC). RESULTS: The study investigated 22,871 patients. Upstaging of resectable GAC to pathologic stage 4 was more evident at community centers (3.5%) than at academic centers (2.8%) for the NSRGC variant (p = 0.211), whereas it was comparable between the two facility categories for the SRGC variant (5.9% vs 6%, respectively). Patients with pathologic stage 1 or 3 NSRGC who underwent gastrectomy at academic programs had better overall survival (OS) (hazard ratio [HR], 0.68; p < 0.0001) than those who underwent gastrectomy at community centers (HR, 0.79; p < 0.0065). Similarly, patients with stage 2 SRGC had better OS when treated at academic versus community centers (HR, 0.54; p = 0.0019). No statistically significant improvement in OS was observed between patients with stage 2 NSRGC (HR, 0.84; p = 0.083) and those with stage 3 SRGC (HR, 0.78; p = 0.054) who were treated at academic centers. No survival benefit was demonstrated for stage 1 SRGC when academic and community centers were compared (p = 0.56). CONCLUSIONS: This is the first study based on a large-scale database in the Western population that addressed the overall survival-by-stage of two distinct GAC histologic variants. Treatment at academic centers was associated with significant improvements in OS.

Neoadjuvant therapy is associated with lower margin positivity rates after Pancreaticoduodenectomy in T1 and T2 pancreatic head cancers: An analysis of the National Cancer Database.

BACKGROUND: Neoadjuvant therapy (NAT) for T1/T2 pancreatic adenocarcinoma (PDAC) prior to pancreaticoduodenectomy remains controversial. We compared positive margin rates in patients with clinical T1&T2 tumors who did and did not receive NAT. METHODS: The National Cancer Database (NCDB) found clinical T1&T2 PDAC patients who underwent pancreaticoduodenectomy from 2004 to 2014. Univariate and multivariate regression determined factors associated with a positive margin and survival. RESULTS: 9795 patients underwent surgery for clinical T1 or T2 pancreatic head adenocarcinoma. 8472 patients had data regarding use of neoadjuvant and adjuvant therapies; of which, 774 (9.1%) received NAT and 435 (5.1%) received both chemotherapy and radiation therapy. NAT was found to lower positive margin rates from 21.8 to 15.5% (p < 0.0001) and when radiation was added this rate dropped to 13.4%. Positive margins were associated with worse overall survival (14.9 vs. 23.9 months; HR 1.702, p < 0.0001). CONCLUSIONS: NAT is associated with a reduced positive margin rate in patients with T1 and T2 tumors. These findings support ongoing and future clinical trials of NAT in T1 and T2, early stage PDAC to determine impacts on survival.

How to Review a Surgical Scientific Paper: A Guide for Critical Appraisal.

It is important for surgeons to participate in the peer-review process of scientific literature. As the number of published manuscripts continues to increase, there is a great need for volunteerism in this arena. However, there is little formal or informal training, which can help surgeons provide unbiased and meaningful reviews. Therefore, it is critical to provide more resources and guidelines to aid surgeons during the review process. The purpose of this paper is to provide a structured guide for a quality review of a surgical paper. This review represents the work of the Association of Women Surgeons Publications Committee.

Subcategorizing T1 Staging in Pancreatic Adenocarcinoma Predicts Survival in Patients Undergoing Resection: An Analysis of the National Cancer Database.

Purpose: According to the American Joint Committee on Cancer (AJCC) 7th edition, T1 staging of pancreatic adenocarcinoma (PC) is defined as tumor limited to the pancreas, ≤2 cm. The AJCC 8th edition subcategorizes T1 staging into T1a (≤5 mm), T1b (≤1 cm), and T1c (≤2 cm) for PC despite the absence of supporting evidence. We sought to determine whether this new subcategorization has prognostic significance. Methods: A retrospective review of patients undergoing definitive surgery for PC was performed by using the National Cancer Database (NCDB) from 2004 to 2014. Kaplan-Meier survival was computed for the subcategories. Multivariable analysis (MVA) was performed by using stepwise regression. Results: The NCDB captured 41,552 stages I and II patients who underwent definitive surgery for PC in this 10-year period. A total of 2090 of these patients were pathological T1N0. The 5-year overall survival (OS) for patients with T1a (n = 319), T1b (n = 296), and T1c (n = 1309) PC was 68.8%, 57%, and 46.6%, respectively. This subcategorization lost significance on MVA and when focused on T1N1-2 patients. Recategorizing T stage into T1a (≤1 cm) and T1b (≤2 cm) resulted in statistical significance on MVA. Conclusion: Subcategorization of the T1 stage into T1a, T1b, and T1c in resected PC does differentiate OS in patients with node-negative disease. We support the AJCC 8th edition T1 stage subcategorization, while understanding that it does not differentiate OS on MVA. When this is further subcategorized into T1a (≤1 cm) and T1b (≤2 cm), it predicts OS in resected, node-negative patients on MVA.

Rethinking the Role of Radiation Therapy in the Treatment of Unresectable Hepatocellular Carcinoma: A Data Driven Treatment Algorithm for Optimizing Outcomes.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, with a majority of HCC patients not suitable for curative therapies. Approximately 70% of initially diagnosed patients cannot undergo surgical resection or transplantation due to locally advanced disease, poor liver function/underlying cirrhosis, or additional comorbidities. Local therapeutic options for patients with unresectable HCC, who are not suitable for thermal ablation, include transarterial embolization (bland, chemoembolization, radioembolization) and/or external beam radiation therapy (EBRT). Regarding EBRT specifically, technological advancements provide a means for safe and effective radiotherapy delivery in a wide spectrum of HCC patients. In multiple prospective studies, EBRT delivery in a variety of different fractionation schemes or in combination with transcatheter arterial chemoembolization (TACE) demonstrate improved outcomes, particularly with combination therapy. The Barcelona Clinic Liver Cancer classification provides a framework for treatment selection; however, given the growing complexity of treatment strategies, this classification system tends to simplify decision-making. In this review, we discuss the current literature regarding unresectable HCC and propose a modified treatment algorithm that emphasizes the role of radiation therapy for Child-Pugh score A or B patients with ≤3 nodules measuring >3 cm, multinodular disease or portal venous thrombosis.

Mincle Signaling Promotes Con A Hepatitis.

Con A hepatitis is regarded as a T cell-mediated model of acute liver injury. Mincle is a C-type lectin receptor that is critical in the immune response to mycobacteria and fungi but does not have a well-defined role in preclinical models of non-pathogen-mediated inflammation. Because Mincle can ligate the cell death ligand SAP130, we postulated that Mincle signaling drives intrahepatic inflammation and liver injury in Con A hepatitis. Acute liver injury was assessed in the murine Con A hepatitis model using C57BL/6, Mincle(-/-), and Dectin-1(-/-) mice. The role of C/EBPß and hypoxia-inducible factor-1α (HIF-1α) signaling was assessed using selective inhibitors. We found that Mincle was highly expressed in hepatic innate inflammatory cells and endothelial cells in both mice and humans. Furthermore, sterile Mincle ligands and Mincle signaling intermediates were increased in the murine liver in Con A hepatitis. Most significantly, Mincle deletion or blockade protected against Con A hepatitis, whereas Mincle ligation exacerbated disease. Bone marrow chimeric and adoptive transfer experiments suggested that Mincle signaling in infiltrating myeloid cells dictates disease phenotype. Conversely, signaling via other C-type lectin receptors did not alter disease course. Mechanistically, we found that Mincle blockade decreased the NF-κß-related signaling intermediates C/EBPß and HIF-1α, both of which are necessary in macrophage-mediated inflammatory responses. Accordingly, Mincle deletion lowered production of nitrites in Con A hepatitis and inhibition of both C/EBPß and HIF-1α reduced the severity of liver disease. Our work implicates a novel innate immune driver of Con A hepatitis and, more broadly, suggests a potential role for Mincle in diseases governed by sterile inflammation.

The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression.

Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle--its cognate receptor--was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.

Mincle suppresses Toll-like receptor 4 activation.

Regulation of Toll-like receptor responses is critical for limiting tissue injury and autoimmunity in both sepsis and sterile inflammation. We found that Mincle, a C-type lectin receptor, regulates proinflammatory Toll-like receptor 4 signaling. Specifically, Mincle ligation diminishes Toll-like receptor 4-mediated inflammation, whereas Mincle deletion or knockdown results in marked hyperresponsiveness to lipopolysaccharide in vitro, as well as overwhelming lipopolysaccharide-mediated inflammation in vivo. Mechanistically, Mincle deletion does not up-regulate Toll-like receptor 4 expression or reduce interleukin 10 production after Toll-like receptor 4 ligation; however, Mincle deletion decreases production of the p38 mitogen-activated protein kinase-dependent inhibitory intermediate suppressor of cytokine signaling 1, A20, and ABIN3 and increases expression of the Toll-like receptor 4 coreceptor CD14. Blockade of CD14 mitigates the increased sensitivity of Mincle(-/-) leukocytes to Toll-like receptor 4 ligation. Collectively, we describe a major role for Mincle in suppressing Toll-like receptor 4 responses and implicate its importance in nonmycobacterial models of inflammation.

Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways.

Dectin-1 is a C-type lectin receptor critical in anti-fungal immunity, but Dectin-1 has not been linked to regulation of sterile inflammation or oncogenesis. We found that Dectin-1 expression is upregulated in hepatic fibrosis and liver cancer. However, Dectin-1 deletion exacerbates liver fibro-inflammatory disease and accelerates hepatocarcinogenesis. Mechanistically, we found that Dectin-1 protects against chronic liver disease by suppressing TLR4 signaling in hepatic inflammatory and stellate cells. Accordingly, Dectin-1(-/-) mice exhibited augmented cytokine production and reduced survival in lipopolysaccharide (LPS)-mediated sepsis, whereas Dectin-1 activation was protective. We showed that Dectin-1 inhibits TLR4 signaling by mitigating TLR4 and CD14 expression, which are regulated by Dectin-1-dependent macrophage colony stimulating factor (M-CSF) expression. Our study suggests that Dectin-1 is an attractive target for experimental therapeutics in hepatic fibrosis and neoplastic transformation. More broadly, our work deciphers critical cross-talk between pattern recognition receptors and implicates a role for Dectin-1 in suppression of sterile inflammation, inflammation-induced oncogenesis, and LPS-mediated sepsis.

TLR9 ligation in pancreatic stellate cells promotes tumorigenesis.

Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid-derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis.

TGF-ß Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia.

Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-ß) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-ß inhibition using the anti-TGF-ß antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-ß inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.

Interleukin 17-producing γδT cells promote hepatic regeneration in mice.

BACKGROUND & AIMS: Subsets of leukocytes synergize with regenerative growth factors to promote hepatic regeneration. γδT cells are early responders to inflammation-induced injury in a number of contexts. We investigated the role of γδT cells in hepatic regeneration using mice with disruptions in Tcrd (encodes the T-cell receptor δ chain) and Clec7a (encodes C-type lectin domain family 7 member a, also known as DECTIN1). METHODS: We performed partial hepatectomies on wild-type C57BL/6, CD45.1, Tcrd(-/-), or Clec7a(-/-) mice. Cells were isolated from livers of patients and mice via mechanical and enzymatic digestion. γδT cells were purified by fluorescence-activated cell sorting. RESULTS: In mice, partial hepatectomy up-regulated expression of CCL20 and ligands of Dectin-1, which was associated with recruitment and activation of γδT cells and their increased production of interleukin (IL)-17 family cytokines. Recruited γδT cells induced production of IL-6 by antigen-presenting cells and suppressed expression of interferon gamma by natural killer T cells, promoting hepatocyte proliferation. Absence of IL-17-producing γδT cells or deletion of Dectin-1 prevented development of regenerative phenotypes in subsets of innate immune cells. This slowed liver regeneration and was associated with reduced expression of regenerative growth factors and cell cycle regulators. Conversely, exogenous administration of IL-17 family cytokines or Dectin-1 ligands promoted regeneration. More broadly, we found that γδT cells are required for inflammatory responses mediated by IL-17 and Dectin-1. CONCLUSIONS: γδT cells regulate hepatic regeneration by producing IL-22 and IL-17, which have direct mitogenic effects on hepatocytes and promote a regenerative phenotype in hepatic leukocytes, respectively. Dectin-1 ligation is required for γδT cells to promote hepatic regeneration.