Citations

Abstract The 6th Edition of the World Health Organization Classification of Digestive System Tumours has introduced two new categories of gastric neuroendocrine tumors, reflecting recent data on subtypes that do not conform to the three established subtypes: type 1 (associated with autoimmune gastritis), type 2 (associated with Zollinger-Ellison Syndrome) and type 3 (sporadic). The new type 4 category is exceptionally rare and is caused by endogenous dysfunction of parietal cell proton pumps, potentially secondary to mutation of ATP4A. Type 5 gastric NETs are caused by chronic pharmacologic inhibition of the parietal cell proton pump, typically due to proton pump inhibitor use, and are increasingly common. Given the relatively low malignant potential of the new subtypes compared to sporadic (type 3) gastric NETs, it is important that clinicians and pathologists recognize these entities, limiting radical surgical resections when unnecessary.

Multidisciplinary case conferences have been shown to improve patient outcomes. However, such case conferences may be unavailable in some settings. This multidisciplinary discussion of 4 challenging hepatobiliary cases was presented at the 2023 Society of Advanced Body Imaging Annual Meeting in Dallas, TX. The cases include an “imaging occult” pancreatic tumor, a large pancreatic mass, an intraductal biliary mass, and a polypoid intraluminal gallbladder mass.

AimsWe compiled two cohorts of colorectal adenosquamous carcinoma (ASC) to describe its histologic and molecular aspects using modern parameters to compare them with literature reports using meta‐analysis of cohorts and individual case series.Methods and ResultsWe identified 53 colorectal ASC from 19 North American academic medical centres, in addition to national database reports on 94 Dutch cases. We analysed available clinical, histologic, and immunohistochemical features and patient outcome. ASC comprised 0.02% of colorectal cancers in the Dutch database. The median cohort patient ages at resection were 65 and 69 years (North American and Dutch cohorts, respectively), with a roughly equal male:female ratio. The squamous component represented between 5% and 95% of each tumour, with a median of 50%. Tumour‐infiltrating lymphocytes (TILs) were generally low (66%), and tumour budding was often Bd1 (64%). Most cases were pT3 (55%) or pT4 (40%), with nodal metastases in more than half (58%). Twenty‐three cases (43%) metastasized distantly, most commonly to the liver. Mismatch repair (MMR) deficiency was identified in 34% of the cases. Follow‐up was available for 48 patients; 13 (27%) had recurrent disease and 29 (60%) died. A total of 31 patients progressed, with median time to progression of 18 months. Available data for the Dutch cohort revealed largely similar findings, as did review of cases in the literature.ConclusionColorectal ASC usually presents at an advanced stage. Despite high rates of MMR deficiency and low tumour budding, TILs were generally low, and there is a high recurrence rate and poor prognosis.

Abstract Both metachronous and synchronous tumors pose a diagnostic and clinical challenge, more so when one of the specimens demonstrates the rare neuroendocrine histology. We describe a patient with sarcoidosis who was treated for endometrial and ovarian neoplasm, recurred with two separate histologies (adenocarcinoma and high grade neuroendocrine), both associated with microsatellite instability (MSI)-high status. Targeted next-generation sequencing of tumor with synonymous somatic alterations pointed to a common ancestry of all three tumors and patient was successfully treated with a tailored immunotherapy regimen. Her sarcoidosis worsened only slightly, and immunotherapy did not need to be discontinued. This case highlights the importance of molecular testing for the optimal therapy of complex synchronous tumors and the need for communication between surgical and medical oncologists in patients with MSI-high cancer. Key Points The case of a patient with a recurrent gynecological cancer presenting as microsatellite instability (MSI)-high endometrial adenocarcinoma and MSI-high neuroendocrine tumor is reported. This case demonstrated a common genetic lineage with good response to checkpoint inhibition without clinical worsening of autoimmune disease. This article adds to the literature, suggesting tumor evolution with neuroendocrine differentiation in some cancers, and argues that a molecular-based approach to treatment might achieve better understanding and possibly superior treatment outcomes.

Abstract Obesity is a risk factor for Pancreatic Ductal Adenocarcinoma (PDAC), but the molecular mechanisms involved are unclear. Oncogenic mutation of K-Ras occurs early and nearly universally in patients with this disease. However, recent evidence indicates that oncogenic Ras is not fully active and for activity to surpass the threshold required to engage a Ras-inflammation feed-forward loop, it requires a stimulus. We hypothesized that high-fat intake acts as an inflammatory stimulus, increasing K-Ras activity and that cyclooxygenase -2 (COX2) expression is required in the inflammatory loop. LSL-K-Ras mice were crossed with elastase-CreER (acinar cell-specific) or Pdx1-Cre (pancreatic cell-specific) to “knock-in” expression of oncogenic K-Ras. Additionally, acinar cell-specific -Ras mice were crossed with COX2 conditional knockout mice. All mice were fed isocaloric diets with different amounts of fat and a COX2 inhibitor was administered to some acinar cell-specific -Ras mice. Pancreata were analyzed for Ras activity, Phospho-ERK levels, inflammation, fibrosis, PanIN and PDAC development. We observed that consumption of a high fat diet (HFD) led to increased K-Ras activity, PanIN formation, fibrotic stroma and PDAC development compared to a control diet. Additionally, we observed a significant reduction in the survival of mice fed a HFD. Genetic deletion of COX2 in acinar cells and COX2 systemic inhibition prevented the HFD-induced effects in acinar cell-specific -Ras mice. These findings indicated that a HFD stimulates activation of oncogenic K-Ras and initiates an inflammatory feed-forward loop requiring the expression of COX2 leading to pancreatic inflammation, fibrosis, PanINs and PDAC. This mechanism may explain the PDAC risks associated with consumption of a HFD. Citation Format: Bincy Philip, Christina L. Roland, Jarek Daniluk, Yan Liu, Deyali Chatterjee, Sobeyda Berenice Gomez, Baoan Ji, Huang Haojie, Huamin Wang, Jason B. Fleming, Craig D. Logsdon, Zobeida Cruz-Monserrate. High fat triggers oncogenic K-Ras activity and a COX2 dependent feed-forward loop to induce pancreatic ductal adenocarcinoma development. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C61.

Abstract Lipocalin-2 (LCN2) promotes malignant development in many cancer types. LCN2 is upregulated in patients with pancreatic ductal adenocarcinoma (PDAC) and in obese individuals, but whether it contributes to PDAC development is unclear. In this study, we investigated the effects of Lcn2 depletion on diet-induced obesity, inflammation, and PDAC development. Mice with acinar cell–specific expression of KrasG12D were crossed with Lcn2-depleted animals and fed isocaloric diets with varying amounts of fat content. Pancreas were collected and analyzed for inflammation, pancreatic intraepithelial neoplasia (PanIN), and PDAC. We also used a syngeneic orthotopic PDAC mouse model to study tumor growth in the presence or absence of Lcn2 expression. In addition, to understand the mechanistic role of how LCN2 could be mediating PDAC, we studied LCN2 and its specific receptor solute carrier family 22 member 17 (SLC22A17) in human pancreatic cancer stellate cells (PSC), key mediators of the PDAC stroma. Depletion of Lcn2 diminished extracellular matrix deposition, immune cell infiltration, PanIN formation, and tumor growth. Notably, it also increased survival in both obesity-driven and syngeneic orthotopic PDAC mouse models. LCN2 modulated the secretion of proinflammatory cytokines in PSC of the PDAC tumor microenvironment, whereas downregulation of LCN2-specific receptor SLC22A17 blocked these effects. Our results reveal how LCN2 acts in the tumor microenvironment links obesity, inflammation, and PDAC development. Cancer Res; 77(10); 2647–60. ©2017 AACR

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) is lethal cancer whose primary tumor is characterized by dense composition of cancer cells, stromal cells, and extracellular matrix (ECM) composed largely of collagen. Within the PDAC tumor microenvironment, activated pancreatic stellate cells (PSC) are the dominant stromal cell type and responsible for collagen deposition. Lumican is a secreted proteoglycan that regulates collagen fibril assembly. We have previously identified that the presence of lumican in the ECM surrounding PDAC cells is associated with improved patient outcome after multimodal therapy and surgical removal of localized PDAC. Experimental Design: Lumican expression in PDAC from 27 patients was determined by IHC and quantitatively analyzed for colocalization with PSCs. In vitro studies examined the molecular mechanisms of lumican transcription and secretion from PSCs (HPSCs and HPaSteC), and cell adhesion and migration assays examined the effect of lumican on PSCs in a collagen-rich environment. Results: Here we identify PSCs as a significant source of extracellular lumican production through quantitative IHC analysis. We demonstrate that the cytokine, TGF-β, negatively regulates lumican gene transcription within HPSCs through its canonical signaling pathway and binding of SMAD4 to novel SBEs identified within the promoter region. In addition, we found that the ability of HPSCs to produce and secrete extracellular lumican significantly enhances HPSCs adhesion and mobility on collagen. Conclusions: Our results demonstrate that activated pancreatic stellate cells within PDAC secrete lumican under the negative control of TGF-β; once secreted, the extracellular lumican enhances stellate cell adhesion and mobility in a collagen-rich environment. Clin Cancer Res; 22(19); 4934–46. ©2016 AACR.

Abstract Purpose: To evaluate the relevance between lumican expression patterns and the clinical course of patients with pancreatic ductal adenocarcinoma (PDAC), and to investigate the role of lumican in PDAC progression. Experimental Design: One hundred thirty-one patient tumors were chosen for tissue microarray staining, and Cox regression analysis was used to test the associations between lumican expression and clinical, pathologic, and oncologic outcomes in all patients. Primary PDAC cells and recombinant human lumican protein were used to establish a working model to mimic the in vivo interactions between stromal lumican and PDAC cells. Using this model, we tested the effects of lumican on EGFR signaling via Akt and hypoxia-inducible factor-1α (HIF1α) and its subsequent influence on glucose consumption, lactate production, intracellular ATP, and apoptotic cell death. Results: Lumican was present in the stroma surrounding PDAC cells in roughly one-half of primary tumors and the direct xenografts. Patients with stromal lumican were associated with a profound reduction in metastatic recurrence after surgery and 3-fold longer survival than patients without stromal lumican. In PDAC cells, extracellular lumican reduced EGFR expression and phosphorylation through enhanced dimerization and internalization of EGFR and the resultant inhibition of Akt kinase activity. Lumican also reduced HIF1α expression and activity via Akt. PDAC cells with enhanced HIF1α activity were resistant to lumican-induced inhibition of glucose consumption, lactate production, intracellular ATP, and apoptosis. Conclusions: There is a positive association between stromal lumican in primary PDAC tumors and prolonged survival after tumor resection. Lumican plays a restrictive role in EGFR-expressing pancreatic cancer progression. Clin Cancer Res; 20(24); 6529–40. ©2014 AACR.