Mucosal colonization of gastric endocrine tumors mimicking mixed neoplasms

Two cases of gastric tumors showing mixed composition of endocrine cell clusters and exocrine glands and originally diagnosed as mixed neoplasms are described. In both cases, the exocrine glandular component was restricted to the upper third of the neoplasms being consistently absent in areas of muscular wall invasion and, in case 2, in nodal metastases. These glands were in close anatomical contiguity with the glands of the overlying gastric mucosa or, in case 1, apparently derived from deep pouch-like invaginations of the mucosa. They showed either lack of dysplasia (case 1) or mild dysplasia (case 2) with a Ki67 proliferation index consistently lower than that of the intramucosal glands. The intratumoral glands presented intestinal metaplastic features confirmed by intense Cdx2 immunostaining that, conversely, was absent in the endocrine component of the tumors. The latter showed intense vesicular monoamine transporter 2 immunoreactivity consistent with its origin from the enterochromaffin-like cells of the gastric oxyntic mucosa. On the basis of these findings, it is proposed that the exocrine glands do not represent a true neoplastic component of the tumors. Although mucosal entrapment by the tumor cannot be ruled out, they more likely reflect a hitherto unrecognized mechanism of mucosal colonization of gastric endocrine tumors

Occurrence of gastric cancer and carcinoids in atrophic gastritis during prospective long-term follow up

Objective. Atrophic gastritis (AG) is a risk condition for gastric cancer and type I gastric carcinoids. Recent studies assessing the overall risk of gastric cancer and carcinoids in AG at long-term follow up are lacking. This study aimed to investigate in a prospective cohort of AG patients the occurrence of gastric cancer and carcinoids at long-term follow up. Methods. A total of 200 AG patients from a prospective cohort (67% female, median age 55 years) with a follow up of 7.5 (range: 4-23.4) years were included. Inclusion criteria were presence of AG and at least one follow-up gastroscopy with biopsies at ≥4 years after AG diagnosis. Follow-up gastroscopies at 4-year intervals were performed. Results. Overall, 22 gastric neoplastic lesions were detected (crude incidence 11%). Gastric cancer was diagnosed in four patients at a median follow up of 7.2 years (crude incidence 2%). Eleven type I gastric carcinoids were detected at a median follow up of 5.1 years (crude incidence of 5.5%). In seven patients, six low-grade and one high-grade dysplasia were found. The annual incidence rate person-year were 0.25% (95% confidence interval [CI]: 0.067-0.63%), 0.43% (95% CI: 0.17-0.89%), and 0.68% (95% CI: 0.34-1.21%) for gastric cancer, dysplasia, and type I-gastric carcinoids, respectively. The incidence rates of gastric cancer and carcinoids were not different (p = 0.07). Conclusion. This study shows an annual incidence rate of 1.36% person-year for gastric neoplastic lesions in AG patients at long-term follow up. AG patients are similarly exposed to gastric cancer and type I gastric carcinoids

Alternative polyadenylation of ZEB1 promotes its translation during genotoxic stress in pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor prognosis. The standard chemotherapeutic drug, gemcitabine, does not offer significant improvements for PDAC management due to the rapid acquisition of drug resistance by patients. Recent evidence indicates that epithelial-to-mesenchymal transition (EMT) of PDAC cells is strictly associated to early metastasization and resistance to chemotherapy. However, it is not exactly clear how EMT is related to drug resistance or how chemotherapy influences EMT. Herein, we found that ZEB1 is the only EMT-related transcription factor that clearly segregates mesenchymal and epithelial PDAC cell lines. Gemcitabine treatment caused upregulation of ZEB1 protein through post-transcriptional mechanisms in mesenchymal PDAC cells within a context of global inhibition of protein synthesis. The increase in ZEB1 protein correlates with alternative polyadenylation of the transcript, leading to shortening of the 3' untranslated region (UTR) and deletion of binding sites for repressive microRNAs. Polysome profiling indicated that shorter ZEB1 transcripts are specifically retained on the polysomes of PDAC cells during genotoxic stress, while most mRNAs, including longer ZEB1 transcripts, are depleted. Thus, our findings uncover a novel layer of ZEB1 regulation through 3'-end shortening of its transcript and selective association with polysomes under genotoxic stress, strongly suggesting that PDAC cells rely on upregulation of ZEB1 protein expression to withstand hostile environments

Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and incurable disease. Poor prognosis is due to multiple reasons, including acquisition of resistance to gemcitabine, the first-line chemotherapeutic approach. Thus, there is a strong need for novel therapies, targeting more directly the molecular aberrations of this disease. We found that chronic exposure of PDAC cells to gemcitabine selected a subpopulation of cells that are drug-resistant (DR-PDAC cells). Importantly, alternative splicing (AS) of the pyruvate kinase gene (PKM) was differentially modulated in DR-PDAC cells, resulting in promotion of the cancer-related PKM2 isoform, whose high expression also correlated with shorter recurrence-free survival in PDAC patients. Switching PKM splicing by antisense oligonucleotides to favor the alternative PKM1 variant rescued sensitivity of DR-PDAC cells to gemcitabine and cisplatin, suggesting that PKM2 expression is required to withstand drug-induced genotoxic stress. Mechanistically, upregulation of the polypyrimidine-tract binding protein (PTBP1), a key modulator of PKM splicing, correlated with PKM2 expression in DR-PDAC cell lines. PTBP1 was recruited more efficiently to PKM pre-mRNA in DR- than in parental PDAC cells. Accordingly, knockdown of PTBP1 in DR-PDAC cells reduced its recruitment to the PKM pre-mRNA, promoted splicing of the PKM1 variant and abolished drug resistance. Thus, chronic exposure to gemcitabine leads to upregulation of PTBP1 and modulation of PKM AS in PDAC cells, conferring resistance to the drug. These findings point to PKM2 and PTBP1 as new potential therapeutic targets to improve response of PDAC to chemotherapy.Oncogene advance online publication, 3 August 2015; doi:10.1038/onc.2015.270

Evaluation of the relationships between computed tomography features, pathological findings, and rrognostic risk assessment in gastrointestinal stromal tumors

Objectives The aim of this study was to correlate computed tomography (CT) findings with pathology in gastrointestinal stromal tumors (GISTs). Methods A retrospective evaluation of CT images of 44 patients with GISTs was performed. Computed tomography findings analyzed were location, size, margins, degree and pattern of contrast enhancement, angiogenesis, necrosis, signs of invasion, peritoneal effusion, peritoneal implants, surface ulceration, and calcifications. Associations between CT features and mitotic rate, Miettinen classes of risk, lesions size, and among CT features were investigated. χ 2 Test and Fisher test were performed. Results Mitotic rate was associated with margins (P = 0.016) and with adjacent organ invasion (P = 0.043). Pattern of contrast enhancement (P = 0.002), angiogenesis (P = 0.006), necrosis (P = 0.006), invasion of adjacent organs (P = 0.011), and margins (P = 0.006) were associated with classes of risk. Several associations (P < 0.05) between lesion size and CT features and among all the investigated CT features were found. Conclusions Computed tomography features could reflect GIST biology being associated with the mitotic rate and with classes of risk

What’s hidden under the gastric intestinal metaplasia? Diffuse-type adenocarcinoma dscovered by targeted biopsies: a case-report

Gastric corpus atrophy and intestinal metaplasia are two well established gastric precancerous conditions and scientific evidence shows a confidential relationship between this precancerous condition and intestinal type gastric cancer, according to Lauren classification. Differently, the background histological gastric mucosa characteristics from whom diffuse type gastric cancer may arise, need to be clarified. In this case, report we present a case of an 81-year-old female with corpus atrophic gastritis in whom we arrived at the diagnosis of diffuse type gastric cancer by following specific guidelines related to the characterization and the endoscopic-histological surveillance of gastric precancerous conditions

UCN-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing DNA damage response

Colorectal cancer (CRC) is one of the most common and lethal cancers worldwide. Despite recent progress, the prognosis of advanced stage CRC remains poor, mainly because of cancer recurrence and metastasis. The high morbidity and mortality of CRC has been recently ascribed to a small population of tumor cells that hold the potential of tumor initiation, i.e. cancer stem cells (CSCs), which play a pivotal role in cancer recurrence and metastasis and are not eradicated by current therapy. We screened CRC-SCs in vitro with a library of protein kinase inhibitors and showed that CRC-SCs are resistant to specific inhibition of the major signaling pathways involved in cell survival and proliferation. Nonetheless, broad-spectrum inhibition by the staurosporin derivative UCN-01 blocks CRC-SC growth and potentiates the activity of irinotecan in vitro and in vivo CRC-SC-derived models. Reverse-Phase Protein Microarrays (RPPA) revealed that, albeit CRC-SCs display individual phospho-proteomic profiles, sensitivity of CRC-SCs to UCN-01 relies on the interference with the DNA damage response mediated by Chk1. Combination of LY2603618, a specific Chk1/2 inhibitor, with irinotecan resulted in a significant reduction of CRC-SC growth in vivo, confirming that irinotecan treatment coupled to inhibition of Chk1 represents a potentially effective therapeutic approach for CRC treatment

Gastrointestinal stromal tumors: correlation between symptoms at presentation, tumor location and prognostic factors in 47 consecutive patients

<p>Abstract</p> <p>Background</p> <p>Gastrointestinal stromal tumors (GIST) are mesenchymal tumors of the gastrointestinal tract, usually kit-positive, that are believed to originate from interstitial cell of Cajal, or their related stem cells. The most common clinical presentation of these tumors is gastrointestinal bleeding, otherwise they may cause intestinal obstruction, abdominal pain, a palpable mass, or can be incidentally detected during surgery or endoscopic/radiological procedures. Prognosis is related to the size of the tumor and to the mitotic rate; other prognostic factors are tumor location, tumor resection margins, tumor rupture, and c-kit mutation that may interfere with molecular target therapy efficacy.</p> <p>Aim</p> <p>Primary aim of this study was to report our experience regarding GIST patients, correlating symptoms at presentation with tumor localization and risk factors.</p> <p>Patients and methods</p> <p>47 consecutive patients undergone to surgical resection for GISTs were enrolled in a prospective study from December 1999 to March 2009. Patient's clinical and pathological features were collected and analysed.</p> <p>Results</p> <p>The most common symptom was abdominal pain. Bleeding in the digestive tract and abdominal pain were more frequent in gastric GISTs (58% and 61%); acute abdominal symptoms were more frequent in jejunal and ileal GISTs (40% and 60%), p < 0.05. We reported a mild correlation between the mitotic rate index and symptoms at presentation (p 0.074): this correlation was stronger if GISTs causing "acute abdominal symptoms" were compared with GISTs causing "abdominal pain" as main symptom (p 0.039) and with "incidental" GISTs (p 0.022).</p> <p>We observed an higher prevalence of symptomatic patients in the "high risk/malignant group" of both the Fletcher's and Miettines's classification (p < 0.05).</p> <p>Conclusion</p> <p>According with our findings symptoms correlate to tumor location, to class risk criteria as mitotic index and risk classifications, however we cannot conclude that symptoms are <it>per se </it>predictive of survival or patient's outcome.</p

Utility of histopathological revision in the management of gastro-entero-pancreatic neuroendocrine neoplasia

Background: Histological evaluation and grading assessment are key points in the diagnostic work-up of gastroentero-pancreatic neuroendocrine neoplasms (GEP-NENs). Aim: To analyze the impact of histopathological revision on the clinical management of patients with GEP-NEN. Materials and methods: Patients referred to our Center of Excellence between 2015 and 2021 were included in this study. Immunohistochemical slides at the time of initial diagnosis were reviewed to assess tumor morphology, diagnostic immunohistochemistry, and Ki67. Results: 101 patients were evaluated, with 65 (64.4%) gastrointestinal, 25 (24.7%) pancreatic, and 11 (10.9%) occult neoplastic lesions suspected to be of GEP origin. The main changes resulting from the revision were: first Ki-67 assessment in 15.8% of patients, Ki-67 change in 59.2% of patients and grading modification in 23.5% of patients. An additional immunohistochemical evaluation was performed in 78 (77.2%) patients, leading to a confirmation of GEP origin in 10 of 11 (90.9%) of unknown primary site neoplastic lesions and an exclusion of NEN diagnosis in 2 (2%) patients. After histopathological revision, a significant modification in clinical management was proposed in 42 (41.6%) patients. Conclusions: Histopathological revision in a referral NEN center is strongly advised in newly diagnosed GEP-NENs to properly plan prognostic stratification and therapeutic choice

Clinical management of endoscopically resected pT1 colorectal cancer

Background Implementation of colorectal cancer (CRC) screening programs increases endoscopic resection of polyps with early invasive CRC (pT1). Risk of lymph node metastasis often leads to additional surgery, but despite guidelines, correct management remains unclear. Our aim that are diagnosed and treated endoscopically and this number is expected to increase [1,2].Methods We retrospectively reviewed patients undergoing endoscopic resection of pT1 CRC from 2006 to 2016. Clinical, endoscopic, surgical treatment, and follow-up data were collected and analyzed. Lesions were categorized according to endoscopic/histological risk-factors into low and high risk groups. Comorbidities were classified according to the Charlson comorbidity index (CCI). Surgical referral for each group was computed, and dissociation from current European CRC screening guidelines recorded. Multivariate analysis for factors affecting the post-endoscopic surgery referral was performed.Results Seventy-two patients with endoscopically resected pT1-CRC were included. Overall, 20 (27.7%) and 52 (72.3%) were classified as low and high risk, respectively. In the low risk group, 11 (55%) were referred to surgery, representing over-treatment compared with current guidelines. In the high risk group, nonsurgical endoscopic surveillance was performed in 20 (38.5%) cases, representing potential under-treatment. After a median follow-up of 30 (6-130) months, no patients developed tumor recurrence. At multivariate analysis, age (OR 1.21, 95 %CI 1.02 -1.42; P = 0.02) and CCI (OR 1.67, 95 %CI 1.12 -3.14; P= 0.04) were independent predictors for subsequent surgery.Conclusions A substantial rate of inappropriate post-endoscopic treatment of pT1-CRC was observed when compared with current guidelines. This was apparently related to an overestimation of patient-related factors rather than endoscopically or histologically related factors