Roberto Persiani

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.

Diffusion-Weighted Magnetic Resonance Imaging in Monitoring Rectal Cancer Response to Neoadjuvant Chemoradiotherapy

PURPOSE To prospectively monitor the response in patients with locally advanced nonmucinous rectal cancer after chemoradiotherapy (CRT) using diffusion-weighted magnetic resonance imaging. The histopathologic finding was the reference standard. METHODS AND MATERIALS The institutional review board approved the present study. A total of 62 patients (43 men and 19 women; mean age, 64 years; range, 28-83) provided informed consent. T(2)- and diffusion-weighted magnetic resonance imaging scans (b value, 0 and 1,000 mm(2)/s) were acquired before, during (mean 12 days), and 6-8 weeks after CRT. We compared the median apparent diffusion coefficients (ADCs) between responders and nonresponders and examined the associations with the Mandard tumor regression grade (TRG). The postoperative nodal status (ypN) was evaluated. The Mann-Whitney/Wilcoxon two-sample test was used to evaluate the relationships among the pretherapy ADCs, extramural vascular invasion, early percentage of increases in ADCs, and preoperative ADCs. RESULTS Low pretreatment ADCs (<1.0 × 10(-3)mm(2)/s) were correlated with TRG 4 scores (p = .0011) and associated to extramural vascular invasion with ypN+ (85.7% positive predictive value for ypN+). During treatment, the mean percentage of increase in tumor ADC was significantly greater in the responders than in the nonresponders (p < .0001) and a >23% ADC increase had a 96.3% negative predictive value for TRG 4. In 9 of 16 complete responders, CRT-related tumor downsizing prevented ADC evaluations. The preoperative ADCs were significantly different (p = .0012) between the patients with and without downstaging (preoperative ADC ≥1.4 × 10(-3)mm(2)/s showed a positive and negative predictive value of 78.9% and 61.8%, respectively, for response assessment). The TRG 1 and TRG 2-4 groups were not significantly different. CONCLUSION Diffusion-weighted magnetic resonance imaging seems to be a promising tool for monitoring the response to CRT.

Restaging locally advanced rectal cancer with MR imaging after chemoradiation therapy.

In recent years, preoperative therapy has become standard procedure for locally advanced rectal cancer. Tumor shrinkage due to preoperative chemotherapy-radiation therapy (CRT) is now a reality, and pathologically complete responses are not uncommon. Some researchers are now addressing organ preservation, thus increasing the demand for both functional and morphologic radiologic evaluation of response to CRT to distinguish responding from nonresponding tumors. On magnetic resonance (MR) images, post-CRT tumor morphologic features and volume changes have a high positive predictive value but a low negative predictive value for assessing response. Preliminary results indicate that diffusion-weighted MR imaging, especially at high b values, would be effective for prediction of treatment outcome and for early detection of tumor response. Some authors have reported that the use of apparent diffusion coefficient values in combination with other MR imaging criteria significantly improves discrimination between malignant and benign lymph nodes. Sequential determination of fluorodeoxyglucose uptake at positron emission tomography/computed tomography has proved useful in differentiating responding from nonresponding tumors during and at the end of CRT. However, radionuclide techniques have limitations, such as low spatial resolution and high cost. Large studies will be needed to verify the most effective morphologic and functional imaging modalities for post-CRT restaging of rectal cancer. Supplemental material available at http://radiographics.rsna.org/lookup/suppl/doi:10.1148/rg.303095085/-/DC1.

WSES Jerusalem guidelines for diagnosis and treatment of acute appendicitis

Acute appendicitis (AA) is among the most common cause of acute abdominal pain. Diagnosis of AA is challenging; a variable combination of clinical signs and symptoms has been used together with laboratory findings in several scoring systems proposed for suggesting the probability of AA and the possible subsequent management pathway. The role of imaging in the diagnosis of AA is still debated, with variable use of US, CT and MRI in different settings worldwide. Up to date, comprehensive clinical guidelines for diagnosis and management of AA have never been issued. In July 2015, during the 3rd World Congress of the WSES, held in Jerusalem (Israel), a panel of experts including an Organizational Committee and Scientific Committee and Scientific Secretariat, participated to a Consensus Conference where eight panelists presented a number of statements developed for each of the eight main questions about diagnosis and management of AA. The statements were then voted, eventually modified and finally approved by the participants to The Consensus Conference and lately by the board of co-authors. The current paper is reporting the definitive Guidelines Statements on each of the following topics: 1) Diagnostic efficiency of clinical scoring systems, 2) Role of Imaging, 3) Non-operative treatment for uncomplicated appendicitis, 4) Timing of appendectomy and in-hospital delay, 5) Surgical treatment 6) Scoring systems for intra-operative grading of appendicitis and their clinical usefulness 7) Non-surgical treatment for complicated appendicitis: abscess or phlegmon 8) Pre-operative and post-operative antibiotics.

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.

Immediately preoperative laparoscopic staging for gastric cancer

AbstractBackground: This ongoing study is a prospective evaluation of immediately preoperative video-laparoscopy compared to ultrasound/computed tomography (US/CT) staging for gastric cancer. An analysis of the first 70 cases is reported. Methods: TNM staging is used to compare the US/CT findings and the laparoscopic findings with the gold standard for pathologic findings in resected specimens. Results: In our series 47 out of 70 cases are locally advanced cancers (stages III and IV): In this subset the predictive value of laparoscopic staging is 86.4%. Laparoscopy shows an overall staging accuracy of 68.6%, compared to 32.8% for US/CT. The difference is statistically significant as regards the T factor (T3: 69.7% vs 12.1%, p < 0.002; T4: 84.2% vs 42.1%, p < 0.05); as regards the M factor, laparoscopy appears the most specific method for detecting peritoneal seeding. Conclusions: This procedure plays a crucial role in determining the resectability of the tumor, thus avoiding unnecessary laparotomies. A meticulous staging becomes mandatory when applying modem treatment options (e.g., neo-adjuvant chemotherapy) to locally advanced cancers; in this context the use of staging laparoscopy will have a relevant impact on future treatment.

A case–control study on the effect of p53 and p73 gene polymorphisms on gastric cancer risk and progression

The p53 protein and its functional homologue p73 share several functions in modulating cell-cycle control and apoptosis. Based on the functional interaction between p53 and p73 in carcinogenesis, we investigated the combined effect of p73 G4C14-to-A4T14 and p53 gene polymorphisms and their interaction with selected environmental factors, on the risk for gastric cancer in a hospital-based case-control study conducted in Italy. The effect of these polymorphisms on cancer progression was also investigated. One hundred and fifteen gastric cancer cases and 295 hospital controls were genotyped for p73 G4C14-to-A4T14, and p53 exon 4 (Arg72Pro), intron 3 and intron 6 polymorphisms. An increased risk for gastric cancer was found to be associated with the inheritance of the p73 homozygous variant genotype among the gastric cancer intestinal histotype (odds ratio (OR)=6.75; 95% confidence interval (95% CI)=1.88-24.24). An effect modification of the p73 variant allele by gender was observed [(OR=2.82; 95%CI=1.24-6.40) among females, versus an OR of 0.70 (95%CI=0.32-1.54) among males; p-value for homogeneity among strata estimates =0.03]. Gene-gene interaction analyses demonstrated that individuals with combined p53 exon 4 and intron 6 variant alleles are borderline significantly protected from gastric cancer (OR=0.52; 95% CI=0.26-1.07; p-value for interaction =0.005), which was confirmed by the haplotype analysis. Finally, a poorer survival was observed among carriers of the variant allele of p53 intron 6 if compared with those carrying both wild-type alleles (p-value for log-rank test =0.02). This study shows that the p73 G4C14-to-A4T14 polymorphism may be a risk factor for gastric cancer, as reported from other studies in different tumour sites among Caucasians. Along with the protective effect of p53 exon 4-intron 6 allelic variants, already noted for breast and lung cancer, our results require confirmation from larger studies.

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.