Domenico D'Ugo

The Role of Acid and Alkaline Reflux in Laryngeal Squamous Cell Carcinoma

Hypothesis At present, main factors considered responsible for the onset of squamous cell carcinoma are tobacco smoking, alcohol abuse, and exposure to viral and toxic agents. In last years, great interest has been focused on gastroesophageal reflux as independent carcinogenic factor and co‐carcinogen in association with smoking and alcohol assumption.

Polymorphisms in metabolic genes, their combination and interaction with tobacco smoke and alcohol consumption and risk of gastric cancer: a case-control study in an Italian population

BackgroundThe distribution and the potential gene-gene and gene-environment interaction of selected metabolic genetic polymorphisms was investigated in relation to gastric cancer risk in an Italian population.MethodsOne hundred and seven cases and 254 hospital controls, matched by age and gender, were genotyped for CYP1A1, CYP2E1, mEH, GSTM1, GSTT1, NAT2 and SULT1A1 polymorphisms. Haplotype analysis was performed for EPHX1 exons 3 and 4, as well as CYP2E1 RsaI (*5 alleles) and CYP2E1 DraI (*5A or *6 alleles). The effect modification by alcohol and cigarette smoking was tested with the heterogeneity test, while the attributable proportion (AP) was used to measure the biological interaction from the gene-gene interaction analysis.ResultsGastric cancer risk was found to be associated with the inheritance of GSTT1 null genotype (OR = 2.10, 95%CI: 1.27–3.44) and the SULT1A1 His/His genotype (OR = 2.46, 95%CI: 1.03–5.90). No differences were observed for the haplotype distributions among cases and controls. For the first time an increased risk was detected among individuals carrying the *6 variant allele of CYP2E1 if ever-drinkers (OR = 3.70; 95%CI: 1.45–9.37) with respect to never-drinkers (OR = 0.18; 95% CI: 0.22–1.46) (p value of heterogeneity among the two estimates = 0.001). Similarly, the effect of SULT1A1 variant genotype resulted restricted to ever-smokers, with an OR of 2.58 (95%CI: 1.27–5.25) for the carriers of His allele among smokers, and an OR of 0.86 (95%CI: 0.45–1.64) among never-smokers (p value of heterogeneity among the two estimates = 0.03). The gene-gene interaction analyses demonstrated that individuals with combined GSTT1 null and NAT2 slow acetylators had an additional increased risk of gastric cancer, with an OR of 3.00 (95%CI: 1.52–5.93) and an AP of 52%.ConclusionGSTT1, SULT1A1 and NAT2 polymorphisms appear to modulate individuals susceptibility to gastric cancer in this Italian population, particularly when more than one unfavourable genotype is present, or when combined with cigarette smoke. The increased risk for the carriers of CYP2E1*5A or *6 alleles among drinkers need to be confirmed by larger prospective studies.

Immunohistochemical analysis of pRb2/p130, VEGF, EZH2, p53, p16INK4A, p27KIP1, p21WAF1, Ki-67 expression patterns in gastric cancer†

Although the considerable progress against gastric cancer, it remains a complex lethal disease defined by peculiar histological and molecular features. The purpose of the present study was to investigate pRb2/p130, VEGF, EZH2, p53, p16INK4A, p27KIP1, p21WAF1, Ki‐67 expressions, and analyze their possible correlations with clinicopathological factors. The expression patterns were examined by immunohistochemistry in 47 patients, 27 evaluated of intestinal‐type, and 20 of diffuse‐type, with a mean follow up of 56 months and by Western blot in AGS, N87, KATO‐III, and YCC‐2, ‐3, ‐16 gastric cell lines. Overall, stomach cancer showed EZH2 correlated with high levels of p53, Ki‐67, and cytoplasmic pRb2/p130 (P < 0.05, and P < 0.01, respectively). Increased expression of EZH2 was found in the intestinal‐type and correlated with the risk of distant metastasis (P < 0.05 and P < 0.01, respectively), demonstrating that this protein may have a prognostic value in this type of cancer. Interestingly, a strong inverse correlation was observed between p27KIP1 expression levels and the risk of advanced disease and metastasis (P < 0.05), and a positive correlation between the expression levels of p21WAF1 and low‐grade (G1) gastric tumors (P < 0.05), confirming the traditionally accepted role for these tumor‐suppressor genes in gastric cancer. Finally, a direct correlation was found between the expression levels of nuclear pRb2/p130 and low‐grade (G1) gastric tumors that was statistically significant (P < 0.05). Altogether, these data may help shed some additional light on the pathogenetic mechanisms related to the two main gastric cancer histotypes and their invasive potentials. J. Cell. Physiol. 210: 183–191, 2007.

Therapeutic Implications of Mesenchymal Stem Cells in Liver Injury

Mesenchymal stem cells (MSCs), represent an attractive tool for the establishment of a successful stem-cell-based therapy of liver diseases. A number of different mechanisms contribute to the therapeutic effects exerted by MSCs, since these cells can differentiate into functional hepatic cells and can also produce a series of growth factors and cytokines able to suppress inflammatory responses, reduce hepatocyte apoptosis, regress liver fibrosis, and enhance hepatocyte functionality. To date, the infusion of MSCs or MSC-conditioned medium has shown encouraging results in the treatment of fulminant hepatic failure and in end-stage liver disease in experimental settings. However, some issues under debate hamper the use of MSCs in clinical trials. This paper summarizes the biological relevance of MSCs and the potential benefits and risks that can result from translating the MSC research to the treatment of liver diseases.

Selection of locally advanced gastric carcinoma by preoperative staging laparoscopy

AbstractBackground: The present study is a prospective evaluation of immediate preoperative laparoscopy compared to ultrasound/computed tomography (US/CT) staging for gastric cancer in a series of 100 patients observed at two major Italian hospitals from April 1995 through September 1996. Methods: After a complete preoperative work-up all c-M0 patients underwent laparoscopy immediately prior to an eventual surgical exploration. pTNM was considered as the gold standard for the evaluation of the results. Results: Laparoscopy detected 21 unsuspected M+ cases out of 100. As regards locally advanced tumors, laparoscopy showed a sensibility of 69.7% for T3 and 89.6% for T4, significantly higher than US/CT staging (23.2% and 48.3%, respectively; p < 0.02). In this series laparoscopic staging altered clinical staging in 58% of cases. Conclusions: This procedure plays two crucial roles in the preoperative evaluation of advanced gastric cancer: It makes it possible to avoid unnecessary surgical exploration in M+ cases and, to date, it represents the most reliable and economic tool for the selection of locally advanced tumors in the light of neoadjuvant treatment.

Determinants of surgical morbidity in gastric cancer treatment

BACKGROUND The occurrence of early surgical complications after gastrectomy as a treatment for gastric cancer has been reported to have a negative impact on longterm survival. The aim of this study was to identify treatment-related factors that can predict morbidity and mortality in patients undergoing operations for gastric cancer. STUDY DESIGN The charts of 388 patients who underwent different operations for gastric cancer at A Gemelli General Hospital, Catholic University of Rome, Italy, between January 1992 and April 2007, were reviewed. Patients were grouped according to the type of surgical treatment performed. The study end points were postoperative morbidity, mortality, and the length of hospital stay after surgery. RESULTS Overall morbidity and mortality rates were 16.2% (63 patients) and 2.3% (9 patients), respectively. Overall morbidity rates were higher in patients more than 64 years of age, when a gastric tumor was resected along with the spleen, and when an extended lymphadenectomy was performed. Patients older than 64 years had longer postoperative hospital stays, and Roux-en-Y gastrojejunostomy was predictive of a shorter stay. Mortality was not influenced by any surgically related factors. CONCLUSIONS Age, splenectomy, and extended lymphadenectomy were independently associated with the development of complications after gastric cancer operations. After subtotal gastrectomy, Roux-en-Y gastrojejunostomy was associated with a shorter postoperative length of stay than conventional Billroth I and Billroth II reconstructions.

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and susceptibility to gastric adenocarcinoma in an Italian population

Abstract Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the metabolism of folate, which provides a methyl donor for DNA methylation and deoxynucleoside synthesis. We performed a case–control study to explore the relationship between two common MTHFR polymorphisms (C677T and A1298C), their combination and interaction with environmental exposures, on gastric adenocarcinoma susceptibility and progression in an Italian population. One hundred and two cases and 254 hospital controls, matched by age and gender, were enrolled. Individuals carrying the MTHFR 677T allele showed an increased risk of gastric cancer (odds ratio (OR) 1.62, 95% confidence interval (CI) 0.98–2.67), particularly among ever smokers (OR 2.10, 95% CI 1.07–5.33) and, among 677 TT individuals, those with a low intake of fruit and vegetables (OR 2.18, 95% CI 1.05–4.54). The strongest effect, however, was noted for the MTHFR 677 TT genotype among the diffuse gastric cancer histotype (OR 2.92, 95% CI 1.12–7.60). No association was detected for the effect of MTHFR A1298C polymorphism. Survival analysis did not show any association between each polymorphism on the overall survival, although when the analysis was restricted to the first year of follow-up after the surgical intervention an improved survival was noted among MTHFR 677 CC subjects compared with the T allele carriers (p value for log-rank test 0.02). In conclusion, MTHFR 677 (any T genotype) appears to modulate an individuals susceptibility to gastric cancer, particularly when combined with cigarette smoking and among those with a low intake of fruit and vegetables. Our results also suggest that an aberrant DNA methylation pattern, through impaired folate metabolism, might play a key role in gastric carcinogenesis. A possible survival effect of the MTHFR C677T genotype in gastric cancer patients deserves further investigations with larger sample sizes.

Surgical treatment of achalasia: a retrospective comparative study.

A retrospective study carried out on 74 patients among 101 consecutive cases of achalasia of the esophagus operated from 1967 to 1989 is reported. On 21 patients observed between 1967 and 1975, a standard transabdominal Heller cardiomyotomy was performed (group A). From 1976 to 1989, the treatment of choice was a Heller myotomy associated with a modified Dors fundoplication. In 80 consecutive cases (group B) the extension of myotomy was regulated by intraoperative monitoring of lower esophageal sphincter pressure. A 5-year follow-up with questionnaires, physical examination, and barium swallows was carried out on 16 patients in group A and on 58 patients in group B. In 75.6% of the cases (56 patients) follow-up examinations included esophageal manometry and 24-hour esophageal pH monitoring. Recurrence of dysphagia was recognized in 3 cases in group A (18.7%) and in 2 cases in group B (3.4%) (P=0.053); postoperative gastroesophageal reflux, measured as a percentage of total reflux time, showed a significantly lower mean value in group B than in group A (1.8% vs. 4.1%. P<0.01). This study suggests that an anti-reflux procedure lowers post-operative gastroesophageal reflux after Heller myotomy. Due to the low incidence of postoperative reflux and the negligible recurrence of dysphagia, Heller myotomy associated with a modified Dors fundoplication may represent the surgical treatment of choice for achalasia of the esophagus.

Outcomes of clinical T4M0 extra-peritoneal rectal cancer treated with preoperative radiochemotherapy and surgery: A prospective evaluation of a single institutional experience

BACKGROUND Our objective was evaluate the outcome of primary clinical T4M0 extraperitoneal rectal cancer treated by neoadjuvant radiochemotherapy. Prognosis of clinical T4 rectal cancer is poor. Preoperative chemoradiation therapy may be beneficial. The results obtained are unclear due to lack of objective and strictly applied staging methods. METHODS Patients with primary, clinical, T4MO, extraperitoneal rectal cancer, defined by transrectal ultrasonography, computed tomography or magnetic resonance imaging, were considered. Intraoperative radiotherapy and adjuvant chemotherapy were employed in some patients after curative resection (R0). Variables influencing the possibility to perform an R0 resection and a sphincter-saving procedure were investigated as predictors of outcome. RESULTS 100 patients were included. R0 resection was performed in 78 patients. R0 resection rate was greater in females (93% vs 67%) and in responders to neoadjuvant chemoradiation (94% vs 60%). The ability to perform a sphincter-saving procedure was 57%, greater in middle rectal location (85% vs 51%) and in responders to the chemoradiation (70% vs 47%). Median follow-up was 31 months (range, 4-136). Local recurrences were found in 7 patients (10%). Five-year local control in R0 patients was 90% and better in the IORT group (100%). Distant relapse occurred in 24 patients (30%). Five-year overall survival was 59%, and was better after an R0 versus an R1 or R2 resection (68% vs 22%). Overall and disease free survival in R0 patients improved after overall downstaging. Adjuvant chemotherapy given in addition to the neoadjuvant therapy did not appear to offer benefit in improving survival. CONCLUSION A multimodal approach enabled us to obtain a 5-year overall survival of about 60%. IORT increased local control. The role of adjuvant chemotherapy needs to be further investigated.

Prognostic implications of the lymph node count after neoadjuvant treatment for rectal cancer

The aim of this study was to investigate the effect of neoadjuvant chemoradiotherapy on the lymph node yield of rectal cancer surgery.