Citations

We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained NCSTN and PSEN2 , genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of NCSTN and PSEN2 were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with an increasing incidence and extremely dismal prognosis. Discovery and mechanistic understanding of the genetic and epigenetic drivers of PDAC is therefore of critical importance. Here, we uncover serine protease inhibitor Kazal type 1 (SPINK1) as a putative determinant of clinical progression and demonstrate that it can have a non-canonical function as a regulator of epigenomic states of PDAC cells and associated extensive changes in gene expression. We show that SPINK1 expression, which varies in PDAC, is associated with key aggressive phenotypic cancer states and is correlated with the expression of stemness markers both in vitro and in patient samples. Mechanistically, our results strongly suggest that SPINK1 acts through a new signaling axis, by interacting with COL18A1 in the Golgi apparatus, promoting endostatin release and eventually inducing extensive histone H3 modifications. These results reveal a new function of SPINK1 in PDAC and suggest a potential therapeutic route to combat PDAC aggressiveness by targeting the SPINK1-COL18A1-endostatin signaling.

52 Background: When combination medical therapy incorporates both IV and oral anti-cancer agents, patients may experience compound side effects and face challenges with treatment adherence. To assess how community cancer programs may improve care coordination for patients receiving combination IV/oral systemic therapy, the Association of Community Cancer Centers (ACCC) conducted a mixed-methods study that involved healthcare professionals (HCPs), patients and caregivers. Methods: The study followed a sequential quantitative-qualitative design to answer questions around the barriers or challenges associated with combination IV/oral systemic therapy. The quantitative phase included an online survey of HCPs (by ACCC) and a survey of patients and caregivers (by Edge Research, in collaboration with several patient advocacy organizations). In the quantitative phase, the survey results were contextualized through two HCP focus groups and individual HCP interviews. Results: Comparing and contrasting the patient survey (n = 113) and HCP survey (n = 157) results revealed insights around the following themes: Top Challenges: Patients felt their top challenges were side effects (57.5%); inconvenience going to medical appointments (37.2%); and financial burden (36.3%). HCPs perceived top challenges as cost of care to the patient (24.0%); coordination and delivery of oral agents (22.1%); and health insurance coverage (21.9%). In focus groups, HCPs explained how they were investing significant staffing resources to prevent and mitigate financial toxicity, especially for patients receiving oral therapies. Methods of Communication: 35.4% of patients “highly preferred” using email to communicate with HCPs about their combination regimens. However, HCPs felt that email was one of the least effective methods of communicating with patients. In focus groups, HCPs agreed that email is convenient when communicating about non-urgent matters. However, they were concerned that some patients may use email to communicate about urgent issues. Treatment-related AEs: When patients experienced treatment-related AEs, 30.1% said their clinicians tried a dose modification or hold. HCPs had mixed perceptions regarding the effectiveness of dose holidays. Those who felt this was highly effective included: advanced practice providers (42.9%), nurses (28.1%); oncologists (16.7%); and pharmacists (16.7%). Conclusions: This study identifies opportunities to improve care coordination for patients receiving combination IV/oral systemic anti-cancer regimens. These findings may inform the creation and dissemination of effective practices and quality improvement projects. These results may also help cancer programs tailor resources and incorporate proactive steps to address some of the key challenges patients may face.

This review, based on the content of the 2020 US Gastrointestinal Pathology Society’s Rodger Haggitt Lecture, concerns an array of tubular gastrointestinal tract dysplastic or possible “predysplastic lesions” with an almost purely morphologic focus based on our collaborative efforts over the past few years. These processes include esophageal epidermoid metaplasia, Barrett esophagus-associated dysplasia, polypoid gastric dysplastic lesions, small intestinal dysplasia, and the ability of metastases to mimic it, the controversial “serrated epithelial change” encountered in the setting of long-standing ulcerative and Crohn colitis, and recently described anal columnar human papilloma virus-associated neoplasms.

AimsInverted appendices are rare, but have the potential to cause diagnostic confusion among endoscopists and pathologists. The aim of this study was to describe the clinicopathological features of inverted appendices seen at our institution over the last 30 years.Methods and resultsTwenty‐one inverted appendices were identified and the clinical and pathological features reviewed. Patients were predominantly middle‐aged women. Most cases were detected incidentally on colonoscopy. Endoscopically, inverted appendices appeared polypoid in the proximal caecum. All resections featured associated pathological processes, including endometriosis (n = 3), inflammatory mucocoele (n = 1), low‐grade appendiceal mucinous neoplasm (n = 2), traditional serrated adenoma (n = 1) and inflammatory fibroid polyp (n = 1). Five cases were endoscopically mischaracterised as caecal polyps and removed via polypectomy; initial pathological impressions were erroneous in most cases. All polypectomies featured a dome‐like configuration covered by mucosa on the convex surface; the majority had aggregates of ganglion cells and neural plexi embedded in muscularis propria. The vast majority of cases, regardless of the procedure, showed lymphoid aggregates. Among post‐polypectomy patients with follow‐up, none experienced perforation‐associated morbidity despite the histological presence of muscularis propria.ConclusionsThe diagnosis of an inverted appendix should be considered in polypectomy specimens from the caecum or appendiceal orifice with (i) dome‐like tissue configuration covered by mucosa on the convex surface, (ii) a deep, robust smooth muscle component with ganglion cells (muscularis propria) and (iii) associated lymphoid aggregates. Prompt recognition on H&E will avoid unnecessary time and resource investment.

Liver biopsies obtained for abnormal liver enzymes or unexplained ascites occasionally appear histologically almost normal. The differential diagnosis for these cases is challenging because literature addressing this topic is lacking. We aimed to establish a differential diagnosis and determine clinical associations and outcomes for almost-normal liver biopsies. Ninety-seven histologically almost-normal liver biopsies were collected from 2 institutions. All cases lacked significant inflammation, fatty change, biliary tract disease, vascular disease, nodular regenerative hyperplasia, iron overload, inherited metabolic or storage disorder, viral hepatitis, or fibrosis. Biopsies for follow-up of known liver diseases were excluded. Transplant biopsies, lesion-directed biopsies, biopsies obtained during bariatric surgery, liver donor biopsies, and biopsies to evaluate methotrexate toxicity were excluded. Clinical (including follow-up) and laboratory data were collected. The frequency of almost-normal liver biopsies was 0.6% and 3.7% at the 2 institutions. The most common biopsy indications were elevated liver biochemistries or clinical findings that suggested portal hypertension. In 70 patients (72%), an associated clinical abnormality was identified; the most common were autoimmune systemic inflammatory conditions (18%), vascular/ischemic events (13%), metabolic syndrome (11%), drug effects (8%), and inflammatory conditions of the gastrointestinal tract (7%). The median follow-up period was 4.3 years (range=0 to 10 y); detailed clinical follow-up was available for 66 patients (68%). Liver biochemistries normalized in 32 patients (48.5%) and remained elevated in 34 (51.5%). Seven patients (7.2%) eventually developed chronic liver disease (autoimmune hepatitis [n=3], primary biliary cirrhosis [n=3], cryptogenic cirrhosis [n=1]). This multicenter study determines the differential diagnosis for almost-normal liver biopsies; this will guide pathologists in subsequent workup efforts in these challenging cases.

Gastric polyps are found in 1% to 4% of patients undergoing gastroscopy. The vast majority are sporadic, but some gastric polyps indicate an underlying syndrome. Gastric polyps can manifest in each of the gastrointestinal polyposis syndromes, including the recently described gastric adenocarcinoma and proximal polyposis of the stomach syndrome. In addition, gastric polyps occur in Lynch syndrome and in a few rare conditions that are not primarily gastrointestinal. While some of these syndromes are clearly associated with an increased risk of gastric cancer, others are not. Interestingly, even in disorders with a well-established risk of gastric cancer, the neoplastic potential and the precursor status of these gastric polyps are not always clear. Although rare, recognition of syndromic gastric polyps is important for individual patient management. These conditions also serve as important models to study gastric homeostasis and gastric tumorigenesis.

Abstract Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genomes of 638 patients with familial pancreatic cancer and the tumor exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types. Significance: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer. Cancer Discov; 6(2); 166–75. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109

Abstract Background. The anticancer multikinase inhibitors (MKIs) are associated with cutaneous adverse events, including hand–foot skin reaction (HFSR), a condition affecting 20%–40% of patients. Symptoms are usually mild, but can evolve into a painful condition that limits function and impacts quality of life (QoL), resulting in shortened cancer treatment duration or intensity. The goal of this study was to systematically review the literature on the prevention and palliation of MKI-associated HFSR, to identify areas for further clinical study, and to provide a foundation for evidence-based guidelines for HFSR management. Methods. Systematic searches of the National Library of Medicine’s PubMed database, Cochrane Reviews, BIOSIS, CancerLit, and the American Society of Clinical Oncology website were conducted using search terms for cutaneous toxicities associated with chemotherapeutic agents. Articles were categorized (C) based on type of agent and cutaneous reaction as: C1 (MKI and HFSR); C2 (MKI and other cutaneous toxicity); C3 (other antineoplastic agents and HFSR); and C4, other. Results. Of the 2,069 abstracts screened, 350 (17%) met the criteria for C1–C4, with 56 (16%) coded as C1 with details of HFSR histology, pathogenesis, clinical outcome, QoL impact, and/or prevention and treatment approaches in MKI-treated patients. No randomized, controlled trials (RCTs) on prevention/palliation of HFSR were identified. Anecdotal evidence or expert opinion advocated protective measures, preventive and therapeutic skin care, systemic analgesics for pain, vitamin B6, and MKI dose modification. Conclusion. No articles containing evidence from RCTs on preventive/palliative approaches to MKI-associated HFSR have been published. Systematic study of optimal treatment strategies for HFSR is needed to advance development of evidence-based treatment guidelines.