Angelo Restivo

MiR-1 Downregulation Cooperates with MACC1 in Promoting MET Overexpression in Human Colon Cancer.

Purpose: MET, the tyrosine kinase receptor for hepatocyte growth factor, is frequently overexpressed in colon cancers with high metastatic tendency. We aimed to evaluate the role of its negative regulators, miR-1 and miR-199a*, and its transcriptional activator, the metastasis-associated in colon cancer 1 (MACC1), in controlling MET expression in human colon cancer samples. Experimental Design: The expression of MET, miR-1, miR-199a*, and MACC1 was evaluated by real-time PCR in 52 matched pairs of colorectal cancers and nontumoral surrounding tissues. The biological role of miR-1 in controlling MET expression and biological activity was assessed in colon cancer cells either by its forced expression or by AntagomiR-mediated inhibition. Results: MiR-1 was downregulated in 84.6% of the tumors and its decrease significantly correlated with MET overexpression, particularly in metastatic tumors. We found that concurrent MACC1 upregulation and miR-1 downregulation are required to elicit the highest increase of MET expression. Consistent with a suppressive role of miR-1, its forced in vitro expression in colon cancer cells reduced MET levels and impaired MET-induced invasive growth. Finally, we identified a feedback loop between miR-1 and MET, resulting in their mutual regulation. Conclusions: This study identifies an oncosuppressive role of miR-1 in colorectal cancer in which it acts by controlling MET expression through a feedback loop. Concomitant downregulation of miR-1 and increase of MACC1 can thus contribute to MET overexpression and to the metastatic behavior of colon cancer cells. Clin Cancer Res; 18(3); 737–47. ©2011 AACR.

Thymosin β-4 in colorectal cancer is localized predominantly at the invasion front in tumor cells undergoing epithelial mesenchymal transition

Objective Thymosin β-4 (Tβ4) is a ubiquitous peptide that plays pivotal roles in the cytoskeletal system and in cell differentiation during embryogenesis. Recently, a role for Tβ4 has been proposed in experimental and human carcinogenesis. This study was aimed at evaluating the correlation between Tβ4 immunoractivity and colorectal cancer, with particular attemption to tumor cells undergoing epithelial-mesenchymal transition. Methods and Results 86 intestinal biopsies were retrospectively analyzed including 76 colorectal adenocarcinomas with evident features of epithelial-mesenchymal transition, and 10 samples of normal colorectal mucosa. Paraffin sections were immunostained for Tβ4 and for E-cadherin. Total RNA was isolated from frozen specimens obtained, at surgery, from the normal colon mucosa, the deeper regions and the superficial tumor regions in four cases of colon cancer. Tβ4 immunoreactivity was detected in the vast majority (59/76) of colon carcinomas, showing a patchy distribution, with well differentiated areas significantly more reactive than the less differentiated tumor zones. We also noted a zonal pattern in the majority of tumors, characterized by a progressive increase in immunostaining for Tβ4 from the superficial toward the deepest tumor regions. The strongest expression for Tβ4 was frequently detected in invading tumor cells with features of epithelial-mesenchymal transition. The increase in reactivity for Tβ4 matched with a progressive decrease in E-cadherin expression in invading cancer cells. At mRNA level, the differences in Tβ4 expression between the surrounding colon mucosa and the tumors samples were not significant. Conclusions Our data show that Tβ4 is expressed in the majority of colon cancers, with preferential immunoreactivity in deep tumor regions. The preferential expression of the peptide and the increase in intensity of the immunostaining at the invasion front suggests a possible link between the peptide and the process of epithelial mesenchymal transition, suggesting a role for Tβ4 in colorectal cancer invasion and metastasis.

Aspirin as a neoadjuvant agent during preoperative chemoradiation for rectal cancer.

Background:Recently, many studies have suggested a possible adjuvant role of aspirin in colorectal cancer, reporting a positive prognostic effect with its use in patients with established disease. The aim of this study was to investigate the anticancer effect of aspirin use during preoperative chemoradiation for rectal cancer.Methods:Two hundred and forty-one patients with stage II–III rectal cancer and candidates for chemoradiation (CRT) were selected and assigned to two groups: group 1, patients taking aspirin at the time of diagnosis, and group 2, all others. Treatment and oncological outcomes were explored.Results:Aspirin use was associated with a higher rate of tumour downstaging (67.6% vs 43.6%, P=0.01), good pathological response (46% vs 19%; P<0.001), and a slightly, although not significant, higher rate of complete pathological response (22% vs 13%; P=0.196). Aspirin use was also associated with a better 5-year progression-free survival (86.6% vs 67.1%; hazard rate (HR)=0.20; 95% CI=0.07–0.60) and overall survival (90.6% vs 73.2%; HR=0.21; 95% CI=0.05–0.89). Although chance of local relapse was similar (HR=0.6; 95% CI=0.06–4.5), aspirin use was associated with a lower risk of developing metastasis (HR=0.30; 95% CI=0.10–0.86).Conclusions:Aspirin might have anticancer activity against rectal cancer during preoperative CRT. This finding could be clinically relevant and should be further investigated with randomised trials.

Does long-course radiotherapy influence postoperative perineal morbidity after abdominoperineal resection of the rectum for cancer?

Aim  The aim of the study was to define risk factors for perineal wound complications after abdominoperineal resection (APR), with particular reference to preoperative radiotherapy.

A meta-analysis of prospective randomized trials comparing minimally invasive and open distal gastrectomy for cancer

Current literature suggests that minimally invasive distal gastrectomy (MIDG) may enhance post‐operative recovery and decrease morbidity compared to open surgery (ODG) in patients with gastric cancer. A meta‐analysis of six Prospective Randomized Trials comparing MIDG (343 patients) and ODG (323 patients) for gastric cancer was conducted. MIDG was associated with increased operative time, reduced blood loss and overall morbidity. There was not sufficient data to draw solid conclusions about the oncologic quality of MIDG. J. Surg. Oncol. 2011; 104:544–551.

Routine preoperative chest computed tomography does not influence therapeutic strategy in patients with colorectal cancer

Aim  Patients with lung metastasis from colorectal cancer (CRC) may benefit from surgical resection. Chest computed tomography (CT) is often included in the preoperative staging. Interpretation of the nature of pulmonary lesions is not always easy and many question its clinical value.

MUTYH-associated colon disease: adenomatous polyposis is only one of the possible phenotypes. A family report and literature review.

AIMS AND BACKGROUND The MutY human homologue gene (MUTYH) is responsible for about a quarter of attenuated familial adenomatous polyposis. Occasionally, it has been associated with hyperplastic polyps and serrated adenoma. We report a family where the same MUTYH mutation determined four different phenotypes, including a case of hyperplastic polyposis syndrome. PATIENTS AND METHODS A family with a history of right-sided colon cancer and multiple colonic polyposis was investigated. Genetic tests were correlated with clinical findings to define phenotypic manifestations of MUTYH mutations. The pertinent English-language literature was reviewed to evaluate the risk of malignancy of MUTYH and the role of prophylactic surgery. RESULTS Three male siblings carried a biallelic MUTYH mutation (G382D-exon13), while the fourth was heterozygote. One developed an isolated cecal cancer at the age of 48. Another, aged 38, was diagnosed with numerous minute colonic and rectal polyps and underwent a proctocolectomy, with final pathology showing a picture of hyperplastic and lymphoid polyposis. The third biallelic brother, 46 years old, developed four hyperplastic lesions, while the heterozygote brother had a large flat serrated adenoma of the right colon removed at the age of 50. CONCLUSION Many aspects of MUTYH mutation still need to be clarified and one of them regards the different phenotypic expressions. Although the majority of reported cases manifested attenuated adenomatous polyposis, hyperplastic polyps and serrated adenomas appear to be more common than expected. Presenting hyperplastic polyposis syndrome is very unusual and may represent a clinical dilemma for correct management. Current evidence suggests to handle MUTYH-associated polyposis as typical FAP.

Oxytocin Nasal Spray in the Treatment of Binge Eating Disorder and Obesity: A Pilot, Randomized, Double-Blind Trial

Background Preclinical studies suggest that the neuropeptide oxytocin reduces food intake and body weight, but only a few clinical studies have investigated the translatability of these findings in humans. The present study investigated the safety and efficacy of oxytocin nasal spray in patients affected by binge eating disorder and obesity. Methods Seventeen outpatients affected by binge eating disorder and obesity participated in a 8 week double-blind trial and received oxytocin (n=8; 24 IU, four times a day, 20 min before each of three meals and before going to bed) or placebo (n=9) with an energy-restricted diet. Primary outcomes included adverse events and the number of binge eating episodes per week. Secondary measures included body weight, BMI, severity of BED, craving for food, quality of sleep, quality of life, anxiety, and depressive symptoms. Results One patient of oxytocin group discontinued prematurely the trial before the first post-randomization efficacy measure. Among the other 16 participants, 13 (81.2%) completed the trial, and 3 (18.8%) discontinued [3 in the oxytocin group; 0 in the placebo group (p=0.0625, Fisher’s exact test)]. No significant difference between groups was found in any outcome evaluated. Patients of the placebo group performed slightly better than patients of the oxytocin group in some secondary outcomes, but these differences were not significant. Conclusion Oxytocin nasal spray resulted to be safe, including in women of childbearing age but did not significantly reduce the number of binge eating episodes per week in outpatients affected by binge eating disorder and obesity. These findings are discussed in light of the human oxytocin literature.

Disulfiram for binge eating disorder: an open trail.

OBJECTIVE To evaluate the efficacy and safety of disulfiram for treatment of binge eating disorder. METHOD Two hundred and fifty milligrams per day of disulfiram was administered to 12 patients affected by binge eating disorder for 16 weeks; the number of binge eating episodes per week and the number of participants who reported side effects were evaluated. RESULTS Nine participants (75.0%) completed the trial, while the other 3 (25.0%) discontinued prematurely. Disulfiram significantly decreased the mean frequency of binge eating episodes per week from 7.9±1.2 to 0.9±0.6 (p<.001). All patients (100.0%) reduced the frequency of binge eating episodes, and 7 participants (58.3%) achieved remission of binge eating. Eleven participants (91.7%) reported side effects [drowsiness (N=9), headache (N=7), dysgeusia (N=3), tachycardia (N=3), dizziness (N=2), and nausea (N=2)]. DISCUSSION While disulfiram reduced the frequency of binge eating episodes, side effects were observed in the majority of participants. Longer-term placebo-controlled studies are warranted to exclude the contribution of a placebo response from these results and to evaluate drugs with similar pharmacological activity but improved tolerability.

Second-line angiogenesis inhibition in metastatic colorectal cancer patients: Straightforward or overcrowded?

Although the number of therapeutic options targeting tumour angiogenesis is becoming increasingly relevant, the question of the optimal choice for second-line anti-angiogenic inhibition in combination with chemotherapy for metastatic colorectal cancer patients remains largely unanswered. In fact the lack of head to head comparison between consolidated options such as bevacizumab and new treatment alternatives such as aflibercept and ramucirumab makes the selection in the clinical practice challenging, particularly when the patient has already received an anti-angiogenic-based combination up-front. In the following pages we described the biological scenario validating second-line angiogenesis inhibition in colorectal cancer along with potential mechanism of resistance. We also critically described the available evidence recommending the use of the bevacizumab, aflibercept and ramucirumab in this setting with the final aim to guide the choice in the clinical practice.