Altered mitochondrial function and energy metabolism is associated with a radioresistant phenotype in oesophageal adenocarcinoma

Neoadjuvant chemoradiation therapy (CRT) is increasingly the standard of care for locally advanced oesophageal cancer. A complete pathological response to CRT is associated with a favourable outcome. Radiation therapy is important for local tumour control, however, radioresistance remains a substantial clinical problem. We hypothesise that alterations in mitochondrial function and energy metabolism are involved in the radioresistance of oesophageal adenocarcinoma (OAC). To investigate this, we used an established isogenic cell line model of radioresistant OAC. Radioresistant cells (OE33 R) demonstrated significantly increased levels of random mitochondrial mutations, which were coupled with alterations in mitochondrial function, size, morphology and gene expression, supporting a role for mitochondrial dysfunction in the radioresistance of this model. OE33 R cells also demonstrated altered bioenergetics, demonstrating significantly increased intracellular ATP levels, which was attributed to enhanced mitochondrial respiration. Radioresistant cells also demonstrated metabolic plasticity, efficiently switching between the glycolysis and oxidative phosphorylation energy metabolism pathways, which were accompanied by enhanced clonogenic survival. This data was supported in vivo, in pre-treatment OAC tumour tissue. Tumour ATP5B expression, a marker of oxidative phosphorylation, was significantly increased in patients who subsequently had a poor pathological response to neoadjuvant CRT. This suggests for the first time, a role for specific mitochondrial alterations and metabolic remodelling in the radioresistance of OAC

Metastatic Insulinoma in a Patient with Type 2 Diabetes Mellitus: Case Report and Review of the Literature

Pancreatic neuroendocrine tumors (NETs) are extremely rare, and although insulinomas are the commonest, less than 10% of insulinomas are malignant. Most patients with insulinomas present with neuroglycopenic symptoms and weight gain attributable to insulin excess. Here, we report a case where a 67-year-old lady with a background history of type 2 diabetes mellitus and breakthrough hyperinsulinism who presented with coma. The biochemical profile revealed features typical of insulinoma, and CT and endosonography confirmed a pancreatic tumor with large volume right-sided liver metastases (biopsy confirming a neuroendocrine tumor). The patient underwent successful one-step RO surgical resection, distal pancreatectomy, splenectomy, and right hepatectomy, and 9 months postoperatively, she remains free of recurrent disease. She remains a diabetic

Presentation and management of gastrointestinal stromal tumours.

Duodenal gastrointestinal stromal tumors (GIST) have been described primarily in isolated case reports. In order to learn more about duodenal GIST, a retrospective review of patients with GIST managed at a single institution between 2000 and 2005 was conducted. Thirty-eight GIST of the stomach and small bowel were analyzed. Eight (21%) were duodenal GIST. The median size of duodenal GIST (6.0 cm) and small bowel GIST (6.3 cm) was larger than the median size of gastric GIST (3.0 cm). The most common presentation of duodenal GIST was bleeding (50%) which was similar to other small bowel GIST (49%) but different from gastric GIST which were most commonly an incidental finding (62%). Two patients (25%) with duodenal GIST had a history of neurofibromatosis. The duodenal GIST were located in the 2nd (n = 5, 63%) and 3rd portion of duodenum (n = 3, 37%). Seven of 8 patients underwent complete resection of duodenal GIST. Pancreaticoduodenectomy was the most common operation performed (n = 5); 2 patients were treated with partial duodenal resection. No patients undergoing pancreaticoduodenectomy (n = 5) were found to have lymph node metastases. No patients received neo-adjuvant or adjuvant therapy with Imatinib. Following resection, 2 patients have recurred (12 and 48 mo.), 4 patients are without disease (1, 6, 6, and 24 mo.), 1 patient died postoperatively. Duodenal GIST are relatively rare tumors that present most commonly with gastrointestinal bleeding. Duodenal GIST are associated with neurofibromatosis. Many duodenal GIST require pancreaticoduodenectomy for complete removal

HER2 positive gastric and gastroesophageal adenocarcinoma; An Irish tertiary center experience

Background: Trastuzumab has been approved for patients with human epidermal growth factor receptor 2 (HER2) over expression and gene amplification metastatic gastric cancer. Here we present the prevalence of HER2 positive gastric cancer in an Irish population, the use of Trastuzumab in first line and beyond progression. Methods: The study was conducted in St James's Hospital, Dublin. A retrospective analysis of the date of patients with HER2 positive gastric cancer over a period of 3 years was carried out. Her2 positive was defined as immunohistochemistry (IHC) score of +3, of IHC score of +2 and increased gene copy number by fluorescence in situ hybridization (FISH). Overall survival was calculated from the day of initiation of treatment with Trastuzumab until death. Results: During the study period 140 patients with gastric and gastro-esophageal junction adenocarcinoma were treated. Out of those, 30 (21.4%) had HER2 positive disease. Among HER2 positive disease patients 18 (12.8%) were treated with first line Trastuzumab containing regimen with a median overall survival of 13 months. Nine (50%) developed progressive disease while on Trastuzumab and of those, 4 (22.2%) patients continued on Trastuzumab beyond progression, two (11.1%) of whom achieved stable disease and a prolonged survival. Conclusion: HER2 positivity rate in an Irish population with advanced gastric and gastro-esophageal junction adenocarcinoma is 21.4%. Treatment with Trastuzumab in the first line in combination with chemotherapy is a reasonable approach. Continuation of Trastuzumab beyond progression is a feasible strategy that requires further exploration

Prognostic significance of neuroepithelial transforming gene 1 in adenocarcinoma of the oesophagogastric junction.

BACKGROUND: Neuroepithelial transforming gene 1 (NET1) mediates tumour invasion and metastasis in a number of cancers, including gastric adenocarcinoma. It is an indicator of poor prognosis in breast cancer and glioma. This study examined NET1 expression and its prognostic significance in patients with adenocarcinoma of the oesophagogastric junction (AOG). METHODS: NET1 expression was measured by immunohistochemistry in a tissue microarray, constructed from biobanked tissue collected over a 10-year interval, and linked to a prospectively maintained clinical database. RESULTS: Using the Siewert classification for AOG, type I tumours expressed significantly higher levels of NET1, with lowest expression in type III and intermediate levels in type II (P = 0.001). In patients with AOG type III, NET1-positive patients were more likely to be female (P = 0.043), have advanced stage cancer (P = 0.035), had a higher number of transmural cancers (P = 0.006) and had a significantly higher median number of positive lymph nodes (P = 0.029). In this subgroup, NET1-positive patients had worse median overall (15 versus 23 months; P = 0?025) and disease-free (11 versus 36 per cent; P = 0.025) survival compared with NET1-negative patients. CONCLUSION: Although existing data show differences in clinical and prognostic indices across AOG subtypes, there are no studies showing differences in tumour biology. These data suggest NET1, a known mediator of an aggressive tumour phenotype in a number of gastrointestinal cancers, is expressed differentially across AOG subtypes and may be of prognostic significance in the clinical management of this condition

Serum proteomic profiling reveals that pretreatment complement protein levels are predictive of esophageal cancer patient response to neoadjuvant chemoradiation

OBJECTIVE: To identify serum-based biomarkers predicting response to neoadjuvant chemoradiotherapy (neo-CRT) in esophageal cancer. PURPOSE: Increasingly, the standard of care for esophageal cancer involves neo-CRT followed by surgery. The identification of biomarkers predicting response to therapy may represent a major advance, enabling clinical trials and improved outcomes. BACKGROUND DATA: Patients with esophageal cancer (n = 31) received a standard neo-CRT regimen. Histopathologic response to therapy was assessed by using the Mandard tumor regression grade (TRG) classification. Serum was collected pretreatment and at 24-hour and 48-hour time points into treatment. Serum samples were analyzed by using Surface-enhanced laser desorption/ ionization time-of-flight mass spectrometry and enzyme-linked immunosorbent assay. A leave-one-out cross-validation predictive algorithm assessed the ability of validated biomarkers to correctly predict therapeutic outcome. RESULTS: Fifty-one percent (16) of patients were poor responders (TRG 3-5), whereas 49% (15) responded well (TRG 1-2). On CM10 biochips, serum expression of 9 protein peaks was significantly different between the response groups. Two differential spectrum peaks were identified as complement C4a and C3a and were subsequently analyzed by enzyme-linked immunosorbent assay. Pretreatment serum C4a and C3a levels were significantly higher in poor responders versus good responders. Subdivision of the response groups by TRG indicated an inverse correlation between levels of C4a and C3a and pathological response to neo-CRT. The leave-one-out cross-validation analysis revealed that these serum proteins could predict response to neo-CRT with a sensitivity and specificity of 78.6% and 83.3%, respectively. CONCLUSIONS: This translational application of proteomics technology identifies pretreatment serum levels of C4a and C3a as predictive biomarkers of response. Large validation studies in an independent cohort are merited. Copyright © 2011 by Lippincott Williams &Wilkins

Outcomes in gastric and junctional cancer using neoadjuvant and adjuvant chemotherapy (epirubicin, oxaliplatin, and capecitabine) and radical surgery

Background The MAGIC/UK Medical Research Council (MRC) trial set the standard of care for treatment of resectable gastric and junctional adenocarcinoma, demonstrating that perioperative chemotherapy with epirubicin, cisplatin and 5-fluorouracil (ECF) confers a survival benefit over surgery alone. The randomized ECF for advanced and locally advanced esophagogastric cancer (REAL-2) trial showed that, in the metastatic setting, the EOX regimen (epirubicin, oxaliplatin and capecitabine) is as effective as ECF, with a favourable toxicity profile. Methods Consecutive patients with resectable gastric or junctional adenocarcinoma treated with perioperative EOX, between 2007 and 2012, were retrospectively analysed. Results Fifty-nine patients (12 female, 47 male), commenced EOX therapy; 47 underwent surgery. A good pathological response was seen in 34 %, (16/47). Disease recurrence occurred in 19 patients (19/47, 40 %). Median overall survival was 22 months, with 4-year survival of 47 %. Chemotoxicities were consistent with those previously reported for this regimen. Conclusion This study in a high-volume centre demonstrates that EOX in resectable gastric and junctional adenocarcinoma is associated with a reasonable safety profile, and efficacy consistent with that reported for ECF

Differential pathologic variables and outcomes across the spectrum of adenocarcinoma of the esophagogastric junction

Background \ud Adenocarcinoma of the esophagogastric junction (AEG) as described by Siewert et al. is classified as one entity in the latest (7th Edition) American Joint Cancer Committee/International Union Against Cancer (AJCC/UICC) manual, compared with the previous mix of esophageal and gastric staging systems. The origin of AEG tumors, esophageal or gastric, and their biology remain controversial, particularly for AEG type II (cardia) tumors. \ud \ud Methods \ud We adapted a large prospective database (n = 520: 180 type I, 182 type II, 158 type III) to compare AEG tumors under the new TNM system Pathological variables associated with prognosis were compared (pT, pN, stage, differentiation, R status, lymphovascular invasion, perineural involvement, number of positive nodes, percent of positive nodes, and tumor length), as well as overall survival. \ud \ud Results \ud Compared with AEG type I tumors, type II and type III tumors had significantly (p\0.05) more advanced pN stages, greater number and percentage of positive nodes, poorer differentiation, more radial margin involvement, and more perineural invasion. In AEG type I, 14/180 patients (8%) had[6 involved nodes (pN3), compared with 16 and 30% of patients classified type II and III, respectively. Median survival was significantly (p = 0.03) improved for type I patients (38 months) compared with those with tumors classified as type II (28 months) and type III (24 months). In multivariate analysis node positivity and pN staging but not AEG site had an impact on survival. \ud \ud Conclusions \ud In this series AEG type I is associated with more favorable pathologic features and improved outcomes compared with AEG type II and III. This may reflect earlier diagnosis, but an alternative possibility, that type I may be a unique paradigm with more favorable biology, requires further study. © Société Internationale de Chirurgie 2010

Gene expression analysis of diagnostic biopsies predicts pathological response to neoadjuvant chemoradiotherapy of esophageal cancer

OBJECTIVE:This study explored gene expression differences in predicting response to chemoradiotherapy in esophageal cancer. PURPOSE:A major pathological response to neoadjuvant chemoradiation is observed in about 40% of esophageal cancer patients and is associated with favorable outcomes. However, patients with tumors of similar histology, differentiation, and stage can have vastly different responses to the same neoadjuvant therapy. This dichotomy may be due to differences in the molecular genetic environment of the tumor cells. BACKGROUND DATA:Diagnostic biopsies were obtained from a training cohort of esophageal cancer patients (13), and extracted RNA was hybridized to genome expression microarrays. The resulting gene expression data was verified by qRT-PCR. In a larger, independent validation cohort (27), we examined differential gene expression by qRT-PCR. The ability of differentially-regulated genes to predict response to therapy was assessed in a multivariate leave-one-out cross-validation model. RESULTS:Although 411 genes were differentially expressed between normal and tumor tissue, only 103 genes were altered between responder and non-responder tumor; and 67 genes differentially expressed >2-fold. These included genes previously reported in esophageal cancer and a number of novel genes. In the validation cohort, 8 of 12 selected genes were significantly different between the response groups. In the predictive model, 5 of 8 genes could predict response to therapy with 95% accuracy in a subset (74%) of patients. CONCLUSIONS:This study has identified a gene microarray pattern and a set of genes associated with response to neoadjuvant chemoradiation in esophageal cancer. The potential of these genes as biomarkers of response to treatment warrants further investigation