Domenico D’Ugo

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.

Long-Term Follow-Up of a Pilot Phase II Study with Neoadjuvant Epidoxorubicin, Etoposide and Cisplatin in Gastric Cancer

Objective: The prognosis in T3–T4 or N+ gastric cancer is dismal, and the role of adjuvant therapy remains uncertain. Neoadjuvant chemotherapy could improve both resectability and survival. Here, we report the results of the long-term follow-up of a pilot study aimed at evaluating a neoadjuvant treatment in a group of patients carefully staged by computed tomography (CT), endoscopic ultrasound and laparoscopy. Methods: Twenty-five stage II–III patients with histologically proven gastric adenocarcinoma were enrolled in the study. All patients gave informed consent and were thoroughly staged. Patients were treated with epidoxorubicin (40 mg/m2 i.v.) on days 1 and 4, etoposide (VP-16; 100 mg/m2) on days 1, 3 and 4 and cisplatinum (80 mg/m2) on day 2, every 21–28 days for 3 pre-operative cycles before CT clinical restaging followed by laparotomy and D2 gastrectomy. Three further cycles of chemotherapy were planned after radical surgery. Results: Twenty-four patients received the planned pre-operative chemotherapy and underwent surgical resection; total (13 patients) or subtotal (7 patients) R0 D2 gastrectomy was possible in 20 patients. One patient died as a result of gastric bleeding. Perioperative complications occurred in 5 patients (failure of anastomosis in 1 patient and wound infection in the other 4). The pathologic response rate included 7 partial responses (29.1%) and 10 patients with stable disease (41.7%). The main toxicity was grade 3/4 neutropenia (68%), which occurred more frequently during the postoperative chemotherapy, and fatigue (68%). Fever or infection, however, were never observed. The median disease-free survival was 37 months, and median survival has not been reached after 40 months of median follow-up. One-, 2- and 3-year survival rates were 80, 64 and 60%, respectively. Conclusion: The notable long-term survival in the present study suggests a comparison between the neoadjuvant approach, including new drug combinations, and adjuvant chemo- or chemoradio-therapy in locally advanced gastric cancer.

Impact of the latest TNM classification for gastric cancer: Retrospective analysis on 94 D2 gastrectomies

The aim of this study was to determine whether the latest edition of tumor-node-metastasis (TNM) classification provides reliable prognostic information. The fifth edition of TNM Classification of Malignant Tumors has introduced for gastric cancer the numeric count of involved lymph nodes whereas their topographic location was considered in earlier editions. For our study, data from 94 patients who underwent D2-gastrectomy were reviewed. The N-factor was scored according to both the Japanese Research Society for Gastric Cancer (JRSGC) classification (n) and, retrospectively, the latest TNM classification (N). Actuarial survival was calculated for both groups. The two staging systems showed similar stratification of actuarial survival with relation to N-stage; in the JRSGC classification no statistical differences were observed between nl and n2 patients (62.7% vs. 52.5%; p=NS), whereas the 5th TNM classification showed a significant difference between Nl and N2 patients (68.5% vs. 45.0%; p=0.04), and between Nl and the new category of N3 patients (68.5% vs. 45.0%, p=0.03). It appears, therefore, that the numeric count of involved nodes may represent a more reliable indicator for single-case prognosis. Reclassification of all node-positive patients in our series caused an overall stage modification in 32.9% (31/94); 22 of those patients were reclassified to a less favorable stage (23.4%). In addition, 11.7% of patients (6/51) who were previously designated nl were reclassified as N2, shifting from an expected actuarial survival after 72 months of 62.7% to 33.3%.RésuméLa cinquième édition de la classification TNM pour cancer gastrique a introduit la notion d’un certain nombre de ganglions envahis, et au lieu d’une classification uniquement en rapport avec le site. Le but de cette étude a été de vérifier si la dernière classification TNM permettait une information pronostique fiable. On a recueilli les données provenant de 94 patients ayant eu une gastrectomie D2. Le facteur ganglionnaire a été évalué selon la classification japonaise (Japanese Research Society for Gastric Cancer) (JRSGC) («n») et, rétrospectivement, selon la dernière classification TNM («N»). La survie actuarielle a été calculée pour les deux groupes. Les deux systèmes de staging ont montré une stratification similaire de survie actuarielle en rapport avec le stade N. Selon le système de classification JRSGC, on n’a noté aucune différence statistiquement significative entre les patients ni et n2 (62.7% vs. 52.5%; p=NS) alors que selon la 5è classification TNM, on a trouvé une différence statistiquement significative entre les patients NI et N2 (68.5% vs. 45.0%; p 0.04) ainsi qu’entre les patients NI et la nouvelle catégorie N3 (68.5% vs. 45.0%, p=0.03). Le compte numérique des ganglions envahis pourrait donc représenter un indicateur plus fiable. La reclassification de tous les patients ayant des ganglions envahis dans notre série a été responsable d’une modification de stade chez 32.9% (31/94) patients; 22 de ces patients ont eu une classificaiton moins favorable (23.4%). 11.7% des patients (6/51) qui ont été classés antérieurement “n1” ont été reclassés N2; dans ces cas, la survie actuarielle à 72 mois est passée de 62.7% à 33.3%.ResumenLa 5a edición TNM para el cáncer gástrico introduce el concepto del número de adenopatías afectadas ya que la localización topográfica de las mismas fue tenida en cuenta anteriormente. El objetivo de este estudio fue verificar si la última clasificación TNM permite obtener una información pronostica fiable. Se revisó toda la información de 94 pacientes que sufrieron una gastrectomía D2. El factor N se atribuyó de acuerdo tanto con la clasificación (n) de la Sociedad japonesa de investigación para el cáncer gástrico (JRSGC) como, retrospectivamente, de acuerdo con la última clasificación TNM (N). La curva actuarial de supervivencia se calculó para ambos grupos. Ambos sistemas de estadificación mostraron una estratificación similar, desde el punto de vista de supervivencia actuarial, para los pacientes en estadio N. Por lo que se refiere a la clasificación JRSGC no se observaron diferencias entre los pacientes ni y n2 (62.7% vs 52.5%,p=NS). Mientras que con la 5a clasificación TNM se constató una diferencia significativa entre los pacientes NI y N2 (68.5% vs 45.0%, p 0.04) y también entre los NI y la nueva categoría N3 (68.5% vs 45.0%, p=0.003). El número de adenopatías afectadas podría representar un indicador fiable en el pronóstico de casos aislados. La reclasificación de todos los pacientes con ganglios positivos de nuestra serie ocasionó una modificación global de estadio en el 32.9% (31/94); 22 de estos pacientes estaban hipergraduados hacia un estadio menos favorable (23.4%). El 11.7% de los pacientes (6/51) que se habían asignado previamente a la categoría ni se reclasificaron en la N2, desplazándose, de una expectativa actuarial de supervivencia tras 72 meses, del 62.7% al 33.3%.

A case-control study on the effect of Apolipoprotein E genotypes on gastric cancer risk and progression

BackgroundApolipoprotein E (ApoE) is a multifunctional protein playing both a key role in the metabolism of cholesterol and triglycerides, and in tissue repair and inflammation. The ApoE gene (19q13.2) has three major isoforms encoded by ε2, ε3 and ε4 alleles with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. An inverse relationship between cholesterol levels and gastric cancer (GC) has been previously reported, although the relationship between apoE genotypes and GC has not been explored so far.MethodsOne hundred and fifty-six gastric cancer cases and 444 hospital controls were genotyped for apoE polymorphism (ε2, ε3, ε4 alleles). The relationship between GC and putative risk factors was measured using the adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) from logistic regression analysis. A gene-environment interaction analysis was performed. The effect of the apoE genotypes on survival from GC was explored by a Kaplan–Meier analysis and Cox proportional hazard regression model.ResultsSubjects carrying at least one apoE ε2 allele have a significant 60% decrease of GC risk (OR=0.40, 95% CI: 0.19 – 0.84) compared with ε3 homozygotes. No significant interaction emerged between the ε4 or ε2 allele and environmental exposures, nor ε2 or ε4 alleles affected the median survival times, even after correcting for age, gender and stadium.ConclusionsOur study reports for the first time a protective effect of the ε2 allele against GC, that might be partly attributed to the higher antioxidant properties of ε2 compared with the ε3 or ε4 alleles. Given the study’s sample size, further studies are required to confirm our findings.

Gastric cancer: Current status of lymph node dissection

D2 procedure has been accepted in Far East as the standard treatment for both early (EGC) and advanced gastric cancer (AGC) for many decades. Recently EGC has been successfully treated with endoscopy by endoscopic mucosal resection or endoscopic submucosal dissection, when restricted or extended Gotodas criteria can be applied and D1+ surgery is offered only to patients not fitted for less invasive treatment. Furthermore, two randomised controlled trials (RCTs) have been demonstrating the non inferiority of minimally invasive technique as compared to standard open surgery for the treatment of early cases and recently the feasibility of adequate D1+ dissection has been demonstrated also for the robot assisted technique. In case of AGC the debate on the extent of nodal dissection has been open for many decades. While D2 gastrectomy was performed as the standard procedure in eastern countries, mostly based on observational and retrospective studies, in the west the Medical Research Council (MRC), Dutch and Italian RCTs have been conducted to show a survival benefit of D2 over D1 with evidence based medicine. Unfortunately both the MRC and the Dutch trials failed to show a survival benefit after the D2 procedure, mostly due to the significant increase of postoperative morbidity and mortality, which was referred to splenopancreatectomy. Only 15 years after the conclusion of its accrual, the Dutch trial could report a significant decrease of recurrence after D2 procedure. Recently the long term survival analysis of the Italian RCT could demonstrate a benefit for patients with positive nodes treated with D2 gastrectomy without splenopancreatectomy. As nowadays also in western countries D2 procedure can be done safely with pancreas preserving technique and without preventive splenectomy, it has been suggested in several national guidelines as the recommended procedure for patients with AGC.

The SIC-GIRCG 2013 Consensus Conference on Gastric Cancer

The topic chosen by the Board of the Italian Society of Surgery for the 2013 annual Consensus Conference was gastric cancer. With this purpose, under the direction of 2 chairmen, 36 experts nominated by the Regional Societies of Surgery and by the Italian Research Group for Gastric Cancer (GIRCG) participated in an experts consensus exercise, preceded by a questionnaire and mainly held by telematic vote, in accordance with the rules of the Delphi method. The results of this Consensus Conference, presented to the 115th National Congress of the Italian Society of Surgery, and approved in plenary session, are reported in the present paper.

Transesophageal echocardiographic assessment of hemodynamic function during laparoscopic cholecystectomy in healthy patients

AbstractBackground: This study aimed by means of transesophageal echocardiography, to evaluate hemodynamic changes induced by pneumoperitoneum in patients with normal cardiac performance. Methods: In this study, 11 ASA I–II patients (mean age, 39 years) with normal cardiac performance undergoing laparoscopic cholecystectomy were evaluated. A 5-MHz transesophageal biplane phased-array transducer connected to an echocardiographer was inserted after induction of anesthesia. Data were collected at three different times: before insufflation (T1), 10 min after insufflation (T2), and 5 min after desufflation (T3). At these same times, heart rate, systolic blood pressure, diastolic blood pressure, end-tidal carbon dioxide (CO2), and peak airway pressure were recorded. Statistical analysis was performed using one-way and two-way analysis of variance (ANOVA). A p value less than 0.05 was considered significant. Results: End-systolic and end-diastolic diameters of the left ventricle, contractility, and performance parameters did not change significantly. Conversely, at insufflation, color Doppler area of the mitral backflow increased significantly (p < 0.05) when already present or showed up abruptly (T1: 0.22 ± 0.28 cm2; T2: 1.28 ± 1.02 cm2; T3: 0.49 ± 0.53 cm2). Conclusions: Such an event is not interpreted as a mitral insufficiency. It is possibly the result of a ``contrast effect’’ caused by the absorption of CO2 microbubbles in the blood.

Neo-adjuvant chemo(radio)therapy in gastric cancer: Current status and future perspectives

In the last 20 years, several clinical trials on neoadjuvant chemotherapy and chemo-radiotherapy as a therapeutic approach for locally advanced gastric cancer have been performed. Even if more data are necessary to define the roles of these approaches, the results of preoperative treatments in the combined treatment of gastric adenocarcinoma are encouraging because this approach has led to a higher rate of curative surgical resection. Owing to the results of most recent randomized phase III studies, neoadjuvant chemotherapy for locally advanced resectable gastric cancer has satisfied the determination of level I evidence. Remaining concerns pertain to the choice of the optimal therapy regimen, strict patient selection by accurate pre-operative staging, standardization of surgical procedures, and valid criteria for response evaluation. New well-designed trials will be necessary to find the best therapeutic approach in pre-operative settings and the best way to combine old-generation chemotherapeutic drugs with new-generation molecules.

cDNA-Microarray Analysis as a New Tool to Predict Lymph Node Metastasis in Gastric Cancer

BackgroundThe aim of the present study was to investigate whether microarray gene expression analysis can be used to predict lymph node status in gastric cancer.MethodsTwenty-nine patients undergoing gastrectomy for cancer were enrolled and subdivided according to the pathologic nodal involvement of their disease (N+ vs N0). Molecular profiling was performed by cDNA microarray on tumor tissue and healthy mucosa. Data were processed to identify differently expressed genes. Selected genes were categorized with gene ontology.ResultsCompared to healthy gastric mucosa, 52 genes were differently expressed in N+ patients, and 50 genes in N0 patients. Forty-five genes were similarly regulated in N+ and N0 patients, whereas 12 genes were differently expressed between N+ and N0 patients. Seven genes were exclusively expressed in N+ patients: Egr-1 was upregulated; Claudin-18, AKR1C2, Cathepsin E, CA II, TFF 1, and progastricsin were downregulated. Five genes were exclusively expressed in N0 patients: Complement C5 receptor 1, PLA2/VII, and MMP- 9 were upregulated; MAO-A and ID-4 were downregulated.ConclusionsMicroarray analysis could be a valuable tool to identify genes associated with lymph node metastasis in gastric cancer. This technique could improve the selection of patients with locally advanced disease who are candidates for extended lymph node dissection, multimodal treatment options, or alternative therapeutic strategies.