Is Endoscopic Submucosal Dissection the Option for Early Gastric Cancer Patients with Contraindication to Surgery?

Surgical therapy is the traditional approach for early gastric cancer. Patients with comorbidities cannot benefit from this treatment because of high surgical morbidities and mortalities. Endoscopic submucosal dissection is a new technique for complete en bloc resection of early gastric cancer. We report the case of a patient with severe cardiomyopathy who developed early gastric cancer without metastases present on CT scan. The patient underwent endoscopic submucosal dissection because of the high risk associated to surgery due to severe comorbidity. The patient had complete submucosal dissection with complete en bloc resection. The lateral and deep margins were free of cancerous cells based on histopathology study. The patient was controlled every 6 months for 30 months by endoscopy. Systematic biopsies were done. No recurrences were diagnosed. This report supports the application of endoscopic treatment for patients with early gastric cancer and at high risk for surgery due to comorbidities

Cyclooxygenase-2 expression and recurrence of colorectal adenomas: effect of aspirin chemoprevention

Background Low-dose aspirin reduces the incidence of colorectal cancer and recurrence of adenomas. Cyclooxygenase-2 (COX-2), one of its main target enzymes, is reportedly over-expressed in colorectal adenomas.Aim To assess COX-2 expression, in relation to adenoma recurrence and the protective effect of aspirin, in a large series of colorectal adenomas, recruited from a double-blind randomised controlled trial comparing recurrences after low-dose aspirin or placebo. Methods Follow-up colonoscopies were performed after 1 and 4 years to assess adenoma recurrence. COX-2 expression was assessed by immunohistochemistry for each adenoma obtained at baseline colonoscopy, separately for epithelium, deep stroma and overall. Architecture, grade of dysplasia, K-ras mutation, p53 and cyclin D1 expression were studied. Results COX-2 expression could be assessed in 219 adenomas from 136 patients: 128 adenomas (58%) from 59 patients strongly expressed COX-2. Strong COX-2 expression predominated in adenomas larger than 10 mm (84/129 vs 44/90; p=0.02) and in adenomas showing high-grade dysplasia (22/29 vs 104/188; p=0.04). Deep stromal but not epithelial initial expression of COX-2 predicted adenoma recurrence in the whole population (30/72 patients or 42% strongly expressed deep stromal COX-2 compared with16/64 or 25% without recurrent adenoma; p=0.04). The protective effect of aspirin was mainly observed in patients in whom COX-2 initial expression was low (RR for recurrence in patients taking aspirin with low COX-2 expression: 0.59; 95% CI 0.39 to 0.90; p=0.02). There was no significant effect of aspirin at the end of the trial. Conclusion Over-expression of COX-2 was frequent and predominated in large and high-grade dysplasia adenomas. Deep stromal but not epithelial initial expression of COX-2 predicted recurrence of adenomas. Aspirin did not act preferentially on patients whose initial adenomas strongly expressed COX-2

Importance of histological tumor response assessment in predicting the outcome in patients with colorectal liver metastases treated with neo-adjuvant chemotherapy followed by liver surgery

Background: The purpose of the study was to characterize histological response to chemotherapy of hepatic colorectal metastases (HCRM), evaluate efficacy of different chemotherapies on histological response, and determine whether tumor regression grading (TRG) of HCRM predicts clinical outcome. Patients and methods: TRG was evaluated on 525 HCRM surgically resected from 181 patients, 112 pretreated with chemotherapy. Disease-free survival (DFS) and overall survival (OS) were correlated to TRG. Results: Tumor regression was characterized by fibrosis overgrowing on tumor cells, decreased necrosis, and tumor glands (if present) at the periphery of HCRM. With irinotecan/5-fluorouracil (5-FU), major (MjHR), partial (PHR), and no (NHR) histological tumor regression were observed in 17%, 13%, and 70% of patients, respectively. With oxaliplatin/5-FU, MjHR, PHR, and NHR were observed in 37%, 45%, and 18% of patients, respectively. Five patients, treated with oxaliplatin, had complete response in all their metastases. MjHR was associated with an improved 3-year DFS compared with PHR or NHR. MjHR and PHR were associated with an improved 5-year OS compared with NHR. Conclusion: Histological tumor regression of HCRM to chemotherapy corresponds to fibrosis overgrowth and not to increase of necrosis. TRG should be considered when evaluating efficacy of chemotherapy for HCRM. Histological tumor regression was most common among oxaliplatin-treated patients and associated with better clinical outcom

Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer

Background: In advanced metastatic colorectal adenocarcinoma, the addition of a neo-adjuvant systemic treatment to surgery might translate into a survival advantage, although this is yet to be confirmed by ongoing randomized trials. The objective of this study was to assess the effects of preoperative systemic chemotherapy on the morphology of non-tumoral liver. Patients and methods: A large series of surgically resected liver metastases (n = 153) was selected. Light microscopy, electron microscopy, and immunohistochemistry using antibodies against endothelial cells (CD31) and hepatic stellate cells (α-SM actin, CRBP-1) were performed to identify sinusoidal wall integrity. Results: We found that 44 (51%) of the 87 post-chemotherapic liver resection specimens had sinusoidal dilatation and hemorrhage, related to rupture of the sinusoidal barrier. In contrast, the 66 livers treated by surgery alone remained normal. In 21 out of the 44 post-chemotherapy patients (48%), perisinusoidal and veno-occlusive fibrosis also developed. Sinusoidal injury persisted several months after end of chemotherapy, and fibrosis may progress. Development of lesions was strongly correlated to the use of oxaliplatin; 34 out of 43 patients (78%) treated with this drug showed striking sinusoidal alterations. Conclusions: Systemic neo-adjuvant chemotherapy in metastatic colorectal cancer frequently causes morphological lesions involving hepatic microvasculature. Sinusoidal obstruction, complicated by perisinusoidal fibrosis and veno-occlusive lesion of the non-tumoral liver revealed by this study, should be included in the list of the adverse side-effects of colorectal systemic chemotherapy, in particular related to the use of oxaliplati

Prevention by daily soluble aspirin of colorectal adenoma recurrence: 4-year results of the APACC randomised trial

Background Aspirin inhibits colorectal carcinogenesis. In a randomised double-blind placebo-controlled trial, daily soluble aspirin significantly reduced recurrence of colorectal adenomas at 1-year follow-up. In this study the results of daily intake of low-dose aspirin on polyp recurrence at 4-year follow-up are presented.Methods 272 patients (naive for chronic aspirin use) with colorectal adenomas were randomly assigned to treatment with lysine acetylsalicylate 160 mg/day (n=73) or 300 mg/day (n=67) or placebo (n=132) for 4 years. The primary endpoints were adenoma recurrence and adenomatous polyp burden at year 4, comparing aspirin at either dose with placebo. The same endpoints were also assessed at year 1 or 4 (last colonoscopy performed for each patient). Results At the final year 4 colonoscopy the analysis included 185 patients (55 receiving aspirin 160 mg/day, 47 aspirin 300 mg/day and 83 placebo). There was no difference in the proportion of patients with at least one recurrent adenoma between patients receiving aspirin at either dose and those treated with placebo (42/102 (41%) vs 33/83 (40%); NS) or in the adenomatous polyp burden (3.1±5.8 mm vs 3.4±6.2 mm; NS). Also, the proportion of patients with at least one advanced recurrent adenoma did not differ (10/182 (10%) in the aspirin group vs 7/83 (7%) in the placebo group; NS). Conclusion Daily low-dose aspirin decreased adenoma recurrence significantly at 1 year but not at year 4. This discrepancy might be explained by a differential effect of aspirin according to the natural history of the polyp. Trial Registration Number NCT 00224679

Inactivation of class II PI3K-C2 alpha induces leptin resistance, age-dependent insulin resistance and obesity in male mice

AIMS/HYPOTHESIS: While the class I phosphoinositide 3-kinases (PI3Ks) are well-documented positive regulators of metabolism, the involvement of class II PI3K isoforms (PI3K-C2α, -C2β and -C2γ) in metabolic regulation is just emerging. Organismal inactivation of PI3K-C2β increases insulin signalling and sensitivity, whereas PI3K-C2γ inactivation has a negative metabolic impact. In contrast, the role of PI3K-C2α in organismal metabolism remains unexplored. In this study, we investigated whether kinase inactivation of PI3K-C2α affects glucose metabolism in mice. METHODS: We have generated and characterised a mouse line with a constitutive inactivating knock-in (KI) mutation in the kinase domain of the gene encoding PI3K-C2α (Pik3c2a). RESULTS: While homozygosity for kinase-dead PI3K-C2α was embryonic lethal, heterozygous PI3K-C2α KI mice were viable and fertile, with no significant histopathological findings. However, male heterozygous mice showed early onset leptin resistance, with a defect in leptin signalling in the hypothalamus, correlating with a mild, age-dependent obesity, insulin resistance and glucose intolerance. Insulin signalling was unaffected in insulin target tissues of PI3K-C2α KI mice, in contrast to previous reports in which downregulation of PI3K-C2α in cell lines was shown to dampen insulin signalling. Interestingly, no metabolic phenotypes were detected in female PI3K-C2α KI mice at any age. CONCLUSIONS/INTERPRETATION: Our data uncover a sex-dependent role for PI3K-C2α in the modulation of hypothalamic leptin action and systemic glucose homeostasis. ACCESS TO RESEARCH MATERIALS: All reagents are available upon request

Sarcopenia Predicts Early Dose-Limiting Toxicities and Pharmacokinetics of Sorafenib in Patients with Hepatocellular Carcinoma

BACKGROUND: Sorafenib induces frequent dose limiting toxicities (DLT) in patients with advanced hepatocellular carcinoma (HCC). Sarcopenia has been associated with poor performance status and shortened survival in cancer patients. PATIENTS AND METHODS: The characteristics of Child Pugh A cirrhotic patients with HCC receiving sorafenib in our institution were retrospectively analyzed. Sorafenib plasma concentrations were determined at each visit. Toxicities were recorded during the first month of treatment, and sarcopenia was determined from baseline CT-scans. RESULTS: Forty patients (30 males) were included. Eleven (27.5%) were sarcopenic. Eighteen patients (45%) experienced a DLT during the first month of treatment. Sarcopenic patients experienced significantly more DLTs than non-sarcopenic patients did (82% versus 31%, p = 0.005). Grade 3 diarrhea was significantly more frequent in sarcopenic patients than in non-sarcopenic patients (45.5% versus 6.9%, p = 0.01), but not grade 3 hand foot syndrome reaction (9% versus 17.2%, p = 1). On day 28, median sorafenib AUC (n = 17) was significantly higher in sarcopenic patients (102.4 mg/l.h versus 53.7 mg/l.h, p = 0.013). CONCLUSIONS: Among cirrhotic Child Pugh A patients with advanced HCC, sarcopenia predicts sorafenib exposure and the occurrence of DLT within the first month of treatment

The impact of laxative use upon symptoms in patients with proven slow transit constipation

<p>Abstract</p> <p>Background</p> <p>Constipation severity is often defined by symptoms including feelings of complete evacuation, straining, stool frequency and consistency. These descriptors are mostly obtained in the absence of laxative use. For many constipated patients laxative usage is ubiquitous and long standing. Our aim was to determine the impact of laxative use upon the stereotypic constipation descriptors.</p> <p>Methods</p> <p>Patients with confirmed slow transit constipation completed 3-week stool diaries, detailing stool frequency and form, straining, laxative use and pain and bloating scores. Each diary day was classified as being under laxative affect (laxative affected days) or not (laxative unaffected days). Unconditional logistic regression was used to assess the affects of laxatives on constipation symptoms.</p> <p>Results</p> <p>Ninety four patients with scintigraphically confirmed slow transit constipation were enrolled in the study. These patients reported a stool frequency of 5.6 ± 4.3 bowel motions/week, only 21 patients reported <3 bowel motions/week. Similarly, 21 patients reported a predominant hard stool at defecation. The majority (90%) of patients reported regular straining. A regular feeling of complete evacuation was reported in just 7 patients. Daily pain and/or bloating were reported by 92% of patients. When compared with laxative unaffected days, on the laxative affected days patients had a higher stool frequency (OR 2.23; <it>P </it><0.001) and were more likely to report loose stools (OR 1.64; <it>P </it><0.009). Laxatives did not increase the number of bowel actions associated with a feeling of complete evacuation. Laxative use had no affect upon straining, pain or bloating scores</p> <p>Conclusions</p> <p>The reporting of frequent and loose stools with abdominal pain and/or bloating is common in patients with slow transit constipation. While laxative use is a significant contributor to altering stool frequency and form, laxatives have no apparent affect on pain or bloating or upon a patients feeling of complete evacuation. These factors need to be taken into account when using constipation symptoms to define this population.</p

Differential effects of the phosphatidylinositol 4-kinases, PI4KIIα and PI4KIIIβ, on Akt activation and apoptosis

In this study, we investigated the role of PI4P synthesis by the phosphatidylinositol 4-kinases, PI4KIIα and PI4KIIIβ, in epidermal growth factor (EGF)-stimulated phosphoinositide signaling and cell survival. In COS-7 cells, knockdown of either isozyme by RNA interference reduced basal levels of PI4P and PI(4,5)P2, without affecting receptor activation. Only knockdown of PI4KIIα inhibited EGF-stimulated Akt phosphorylation, indicating that decreased PI(4,5)P2 synthesis observed by loss of either isoform could not account for this PI4KIIα-specific effect. Phospholipase Cγ activation was also differentially affected by knockdown of either PI4K isozyme. Overexpression of kinase-inactive PI4KIIα, which induces defective endosomal trafficking without reducing PI(4,5)P2 levels, also reduced Akt activation. Furthermore, PI4KIIα knockdown profoundly inhibited cell proliferation and induced apoptosis as evidenced by the cleavage of caspase-3 and its substrate poly(ADP-ribose) polymerase. However, in MDA-MB-231 breast cancer cells, apoptosis was observed subsequent to knockdown of either PI4KIIα or PI4KIIIβ and this correlated with enhanced proapoptotic Akt phosphorylation. The differential effects of phosphatidylinositol 4-kinase knockdown in the two cell lines lead to the conclusion that phosphoinositide turnover is inhibited through PI4P substrate depletion, whereas impaired antiapoptotic Akt signaling is an indirect consequence of dysfunctional endosomal trafficking