Is the writing on the wall? The relationship between the number of disease-modifying anti-inflammatory bowel disease drugs used and the risk of surgical resection.

BACKGROUND: Disease-modifying anti-inflammatory bowel disease drugs (DMAIDs) revolutionized the management of ulcerative colitis (UC). This study assessed the relationship between the number and timing of drugs used to treat UC and the risk of colectomy and postoperative complications. METHODS: This was a retrospective review of adult patients with UC treated with disease-modifying drugs between 2005 and 2020 in the MarketScan database. Landmark and time-varying regression analyses were used to analyze risk of surgical resection. Multivariable Cox regression analysis was used to determine risk of postoperative complications, emergency room visits, and readmissions. RESULTS: A total of 12,193 patients with UC and treated with disease-modifying drugs were identified. With a median follow-up time of 1.7 years, 23.8% used >1 drug, and 8.3% of patients required surgical resection. In landmark analyses, using 2 and ≥3 drugs before the landmark date was associated with higher incidence of surgery for each landmark than 1 drug. Multivariable Cox regression showed hazard ratio (95% CIs) of 4.22 (3.59-4.97), 11.7 (9.01-15.3), and 22.9 (15.0-34.9) for using 2, 3, and ≥4 drugs, respectively, compared with using 1 DMAID. That risk was constant overtime. The number of drugs used preoperatively was not associated with an increased postoperative risk of any complication, emergency room visits, or readmission. CONCLUSION: The use of multiple disease-modifying drugs in UC is associated with an increased risk of surgical resection with each additional drug. This provides important prognostic data and highlights the importance of patient counseling with minimal concern regarding risk of postoperative morbidity for additional drugs.

Survival outcomes of anal adenocarcinoma versus rectal adenocarcinoma: A retrospective cohort study.

BACKGROUND: Anal adenocarcinoma (AA) is a rare malignancy with decreased survival compared to rectal adenocarcinoma (RA). However, AA continues to be treated with similar algorithms compared to rectal cancer with minimal data regarding the efficacy of these treatment algorithms. METHODS: A retrospective chart review of patients with non-metastatic AA at a single tertiary-care institution from 1995 to 2020. This cohort was matched 2:1 to a group of RA patients for comparison. The primary outcome of interest was overall survival rates. RESULTS: Sixteen patients with stages I-III AA were matched to a cohort of RA. There were no significant differences between the cohorts with regard to patient demographics, comorbidities, disease stage or histologic features. There were also no significant differences in treatment modalities between the two cohorts with a majority undergoing multimodal therapy with chemoradiation and surgery. All patients with AA demonstrated significantly worse survival than all patients with rectal adenocarcinoma (five-year survival 47.7% vs. 82.3%, respectively. p < 0.05). When looking at a sub-group of patients who underwent combination chemoradiation and surgery from each cohort, anal adenocarcinoma continued to exhibit lower overall survival (five-year survival 41.6% and 86.4%, respectively. p < 0.05). In a multi-variable model that adjusted for location, American Joint Committee on Cancer (AJCC) stage and treatment pathway, tumor location in the anal canal was an independent predictor of overall survival (Hazard ratio [HR] 2.7, p < 0.05). CONCLUSION: AA has worse survival as compared to RA despite similar treatment. This study highlights the need to evaluate the current classification and treatment pathways to improve outcomes.

Changing disposition patterns in the era of COVID-19 after colon resections: A National Surgical Quality Improvement Program colectomy study.

BACKGROUND: The COVID-19 pandemic severely impacted post-hospitalization care facilities in the United States and hindered their ability to accept new patients for various reasons. This study aimed to assess the impact of the pandemic on discharge disposition after colon surgery and associated postoperative outcomes. METHODS: A retrospective cohort study was performed using the National Surgical Quality Improvement Participant Use File and targeted colectomy. Patients were divided into the following 2 cohorts: (1) pre-pandemic (2017-2019) and (2) pandemic (2020). The primary outcomes included discharge disposition-post-hospitalization facility versus home. The secondary outcomes were rates of 30-day readmissions and other postoperative outcomes. The multivariable analysis assessed for confounders and effect modification on discharge to home. RESULTS: Discharge to posthospitalization facilities decreased by 30% in 2020 compared to 2017 to 2019 (7% vs 10%, P < .001). This occurred despite an increase in emergency cases (15% vs 13%, P < .001) and open surgical approach (32% vs 31%, P < .001) in 2020. Multivariable analysis revealed that patients in 2020 had 38% lower odds of going to post-hospitalization facilities (odds ratio 0.62, P < .001) after adjusting for surgical indications and underlying comorbidities. This decrease in patients going to a post-hospitalization facility was not associated with an increased length of stay or an increase in 30-day readmissions or postoperative complications. CONCLUSION: During the pandemic, patients undergoing colonic resection were less likely to be discharged to a post-hospitalization facility. This shift was not associated with an increase in 30-day complications. This should prompt further research to assess the reproducibility of these associations, especially in a setting without a global pandemic.

Meckel's Diverticulum Charading as Crohn's Disease: A Single-Institution Case Series.

Meckel's diverticulum is the most common gastrointestinal congenital anomaly and may present with lower gastrointestinal bleeding, abdominal pain, and nausea. Imaging and endoscopic findings can be similar to those of Crohn's disease, including transmural inflammation, stricturing, and superficial ulceration frequently in the distal ileum. Here, we present a case series of three patients who were initially diagnosed with Crohn's disease and ultimately found to have Meckel's diverticulum alone on final pathology. This single-institution case series, the largest in the literature, highlights the importance of maintaining a high index of suspicion for Meckel's diverticulum, especially in the absence of microscopic evidence of inflammatory bowel disease.

Neoadjuvant chemotherapy does not increase risk for anastomotic leak for simultaneous resection of primary colon cancer with synchronous liver metastasis: A NSQIP-colectomy analysis.

BACKGROUND AND OBJECTIVES: In patients with colon cancer with synchronous liver metastasis, treatment algorithms are complex and often require multidisciplinary evaluation. Neoadjuvant therapy is frequently utilized, but there is an unclear relationship with postoperative outcomes in patients with simultaneous resection. METHODS: This is a retrospective cohort study from the National Surgical Quality Improvement Program and Targeted Colectomy databases. All patients with stage IV colon cancer undergoing simultaneous colectomy with synchronous liver metastasis resection or ablation between 2015 and 2019 were identified and categorized into subgroups based on receipt of neoadjuvant chemotherapy. Multivariable logistic regression was utilized to assess for risk factors of anastomotic leaks and serious postoperative complications. RESULTS: We identified 1006 patients who underwent simultaneous colectomy and liver operations. Of those, 418 (41.6%) received neoadjuvant chemotherapy within 90 days of surgery, while 588 (58.4%) had simultaneous upfront surgery. On multivariable logistic regression, neoadjuvant therapy was not associated with postoperative anastomotic leaks (odds ratio [OR]: 1.30; p = 0.39) or serious complications (OR: 1.04; p = 0.82). CONCLUSION: Neoadjuvant therapy does not increase postoperative complications in simultaneous colon and liver resections. These results may alleviate concerns regarding postoperative morbidity in the decision-making process of administering neoadjuvant therapy.

Characteristics and Outcomes of Right- Versus Left-Sided Early-Onset Colorectal Cancer.

BACKGROUND: Early-onset colorectal cancers are increasing in incidence. Studies reported more left-sided cancers in patients aged <50 years. Some advocate for screening via flexible sigmoidoscopy at age 40 years. OBJECTIVE: The purpose of this study was to investigate characteristics and outcomes in sporadic right- and left-sided early-onset colorectal cancers. DESIGN: This was a retrospective cohort study. SETTINGS: This study was conducted at a single, tertiary care institution. PATIENTS: This study included patients aged <50 years diagnosed with colorectal cancer between 2000 and 2018. MAIN OUTCOME MEASURES: We analyzed patient demographics, tumor characteristics, and survival. RESULTS: A total of 489 patients aged 20 to 49 years were identified from 2000 to 2018. The majority of patients were white (90%) and male (57%). The median age at diagnosis was 44 years, and 75% were diagnosed at age 40-49 years. There was a predominance of left-sided tumors (80%). The majority of patients presented with stage 3 (35%) and stage 4 (35%) disease. Right-sided tumors were more likely to have mucinous (24% vs 7.4%; p < 0.001) and signet-ring cell (4.4% vs 1.7%; p < 0.001) histology. There was no difference in age, sex, race, ethnicity, and stage at presentation. Right-sided tumors were associated with lower 5-year overall survival (44% vs 61%; p < 0.005) with the decrease in survival most prominent in right-sided stage 3 tumors (41% vs 72%; p < 0.0001) and in ages 40 to 49 years (43% vs 61%; p = 0.03). Sex, tumor location, increasing stage, and signet-ring cell histology were independent prognostic factors of overall survival. There was no difference in disease-free survival. LIMITATIONS: This study was a retrospective review at a single institution. CONCLUSIONS: The majority of early-onset colorectal cancers arise from age 40 to 49 years with a left-sided predominance but higher mortality in right-sided tumors. These findings provide further evidence in favor of recommending earlier initial screening colonoscopy for colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B892 . CARACTERSTICAS Y RESULTADOS DEL CNCER COLORRECTAL DE INICIO TEMPRANO DEL LADO DERECHO FRENTE AL IZQUIERDO: ANTECEDENTES:Los cánceres colorrectales de aparición temprana están aumentando en incidencia. Los estudios han informado una preponderancia de cánceres en el lado izquierdo en pacientes <50 años, lo que ha llevado a algunos a abogar por la detección con sigmoidoscopia flexible a los 40 años.OBJETIVO:El propósito de nuestro estudio fue investigar las características del tumor y los resultados de los pacientes en cánceres colorrectales esporádicos del lado derecho e izquierdo de aparición temprana.DISEÑO:Este fue un estudio de cohorte retrospectivo.ENTORNO CLÍNICO:Este estudio se realizó en una única institución de atención terciaria.PACIENTES:Pacientes <50 años diagnosticados de cáncer colorrectal entre 2000 y 2018.RESULTADO PRINCIPAL:Analizamos los datos demográficos de los pacientes, las características del tumor, la supervivencia general y la supervivencia libre de enfermedad.RESULTADOS:Se identificaron un total de 489 pacientes de entre 20 y 49 años entre 2000 y 2018. La mayoría de los pacientes eran blancos (90%) y varones (57%). La mediana de edad en el momento del diagnóstico fue de 44 años y el 75% se diagnosticó entre los 40 y los 49 años. Predominó los tumores del lado izquierdo (80%). La mayoría de los pacientes presentaban enfermedad en estadio 3 (35%) y estadio 4 (35%). Los tumores del lado derecho tenían más probabilidades de tener histología mucinosa (24% frente a 7,4%, p < 0,001) y de células en anillo de sello (4,4% frente a 1,7%, p < 0,001). No hubo diferencia en edad, sexo, raza, etnia, estadio AJCC en la presentación. Los tumores del lado derecho se asociaron con una menor supervivencia general a 5 años (44% frente al 61%, p < 0,005) con la disminución de la supervivencia más prominente en los tumores del lado derecho en estadio 3 (41% frente al 72%, p < 0,0001) y en edades 40-49 (43% vs 61%, p = 0.03). El sexo, la ubicación del tumor, el estadio AJCC en aumento y la histología de las células en anillo de sello fueron factores pronósticos independientes de la supervivencia general. No hubo diferencias significativas en la supervivencia libre de enfermedad.LIMITACIONES:Este estudio fue una revisión retrospectiva en una sola institución.CONCLUSIONES:La mayoría de los cánceres colorrectales de aparición temprana surgen entre los 40 y los 49 años con un predominio en el lado izquierdo pero una mayor mortalidad en los tumores del lado derecho. Estos hallazgos proporcionan evidencia adicional a favor de recomendar una colonoscopia de detección inicial más temprana para el cáncer colorrectal. Consulte Video Resumen en http://links.lww.com/DCR/B892 . (Traducción-Dr. Ingrid Melo ).

Intraoperative Techniques for Gaining Ileoanal Pouch Reach.

Ileal pouch-anal anastomosis allows for reestablishing gastrointestinal continuity in patients after proctocolectomy. The technical elements of pouch creation and gaining reach into the pelvis are demanding and require a variety of surgical maneuvers to achieve a tension-free anastomosis. We present a brief review of the literature discussing various approaches aimed at improving ileal pouch reach into the low pelvis. Although these techniques are used with different frequencies, they serve as important adjuncts to the gastrointestinal surgeons' armamentarium.

Characteristics of Early-Onset vs Late-Onset Colorectal Cancer: A Review.

Importance: The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer. Observations: Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts. Conclusions and Relevance: The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.

Eurythermic Sprint and Immune Thermal Performance and Ecology of an Exotic Lizard at Its Northern Invasion Front.

AbstractThermal performance of immunity has been relatively understudied in ectotherms, especially in the context of invasive species or in relation to other fitness-related traits and thermoregulatory patterns in the field. For reptiles, thermal biology is a primary factor determining physiological performance and population viability, and suboptimal thermal conditions may limit the expansion of exotic species along the edges of their invasion fronts. This study examined thermoregulatory ecology and thermal performance of immunity and sprinting in a population of Mediterranean geckos (Hemidactylus turcicus) at the northern edge of their invasion front in a temperate zone of the United States. In the field, we quantified temperatures of geckos of varied age classes in relation to air, wall, and refugia temperatures. We also quantified temperature-dependent sprint performance and immune function in field-collected geckos to detail thermal performance patterns that may contribute to the capacity for this species to invade cool climates. Although body temperature (Tb) of wild-caught geckos correlated with wall temperature, average Tb exhibited wide distributions, suggesting eurythermy. Furthermore, the thermal performance of immune swelling responses to phytohemagglutinin injections and sprinting was optimized over a similarly wide temperature range that overlapped with the field Tb's that suggest eurythermy in this species. The wide thermal performance breadths in these traits could buffer against variation in factors such as pathogen exposure and environmental temperatures that could otherwise suppress functional performance. Thus, eurythermy of sprint and immune performance may facilitate the invasive potential of H. turcicus.

Pseudoaneurysm of the Mesenteric Artery Status Post Drain Placement for Complicated Diverticulitis.

Perforated diverticulitis presents a challenging clinical scenario for the surgeon. Development of an abscess in those without an acute abdomen may be amendable to non-operative drainage. Furthermore, early intervention can dramatically alter the hospital course let alone the overall outcome. While relatively safe as a procedure, image-guided drainage does carry risk that needs to be calculated relative to benefit gained. One rare albeit possibly serious risk is pseudoaneurysm formation.

Speciation with introgression: Phylogeography and systematics of the Ameerega petersi group (Dendrobatidae).

The Tropical Andes contains exceptionally high diversity, much of it arising within the Quaternary period. The complex geology of the Andes and paleoclimate fluctuations within the Quaternary suggest complex speciation scenarios. This, in turn, has contributed to idiosyncratic speciation modes among shallowly diverged Amazonian taxa. Many relationships among these taxa remain poorly resolved. Here we use a sequence capture approach, ultraconserved elements (UCEs), to address the phylogenetic relationships among three recently diverged Peruvian Ameerega poison frog species (A. cainarachi, A. petersi, and A. smaragdina; family Dendrobatidae) and explore a possible mode of speciation in this group. We assess concordance among concatenated phylogenetic tree inference, gene-tree based species tree inference, SNP-based species tree inference, and Bayes factor lineage delimitation to resolve species boundaries. We complement these analyses with assessments of call divergence to address the presence of a prezygotic reproductive barrier. Additionally, we further explore the phylogeographic history of these species of Ameerega with demographic inference, considering evidence for admixture and population expansions. Our results support the synonymy of A. smaragdina as a junior synonym of A. petersi and we find that speciation in this group is characterized by admixture and signatures of a population bottleneck followed by expansion. We invoke the disturbance-vicariance hypothesis to explain the observed patterns and call for more, detailed investigations of in-situ speciation in the Tropical Andes.

Systematics of the Ameerega rubriventris complex (Anura: Dendrobatidae) with descriptions of two new cryptic species from the East-Andean versant of Peru.

We describe two new species of poison frog from central and southern Peru that have been referred to as Ameerega picta, A. hahneli, or A. altamazonica throughout the past thirty years. Our phylogenies generated with genomic data provide strong support that the two new species are successive sisters to two described taxa, A. rubriventris and A. altamazonica, and collectively comprise the Ameerega rubriventris complex. The first new taxon, Ameerega panguana sp. nov., can be distinguished from all other Ameerega by its combination of a unique white venter and an advertisement call of 1-2 notes per second. The second new taxon, Ameerega imasmari sp. nov., is the only cryptically colored Ameerega species that is disttributed across the Fitzcarrald Arch in Southern Peru which possesses a 'peep' advertisement call consisting of 3-4 notes per second and a dominant frequency of 4.3-4.5 kHz. Within the Ameerega rubriventris complex, we observed differences between species in their ventral coloration, tympanum diameter, and call, which suggest that these taxa are reproductively isolated from each other.

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.

A Detailed Protocol to Enable Safe-Handling, Preemptive Detection, and Systematic Surveillance of Rat-Vectored Pathogens in the Urban Environment.

We detail a five-stage protocol to address physical barriers and experimental limitations that have hindered routine pathogen monitoring of wild rats in urban settings. New York City potentially harbors from 2 to 32 million rats among its 8-million people. However, at a time, when people are most vulnerable to disease from over-crowdedness brought on by increased urbanization of society, the difficulty of studying wild rats has led to a paucity of ecological and epidemiological research. Challenges of safely handling animals and the difficulties of identifying individual animals and the emergence of their respective pathogen loads (timing of infection) have impeded progress. We previously reported a method using radio frequency identification paired with load cell and camera traps to enable the identification of individual animals and subsequent monitoring of the animals' weights (an indicator of health). However, efficient pathogen surveillance requires repeated captures of the same individual in order to isolate and document the emergence of new pathogens, or variations in pathogen load, over time. Most of these barriers are now addressed in our protocol, which is aided by the use of a mobile, outdoor laboratory, followed by incorporation of pheromone-based lures to attract individuals back to active sensors, within a camera trap. This approach allows for the assessment of individual animal health, behaviors under camera, and changing pathogen loads and weights in most urban environments (e.g., financial district, docks, sewers, and residential). Five phases are described and presented: (1) site selection and urban trapping, (2) anesthetization, (3) serological and ectoparasite collection, (4) microchip implantation, and (5) retrapping and luring animals back to active remote sensors. In order to fulfill the unmet call for preemptive pathogen surveillance, public health officials and researchers may wish to adapt, or modify, similar protocols to ensure early detection and monitoring of rat-borne zoonoses, before they become problematic.

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.