Margherita Pinto

Expression of Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) is an Independent Prognostic Indicator of Worse Outcome in Gastric Cancer Patients

BackgroundUnlike other human tumors, gastric cancer remains a great therapeutic challenge since no standardized postoperative treatment exists. Knowledge of molecular pathways determining the behavior of individual gastric tumors seems to be crucial for therapeutic decisions, and evaluation of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression might be critical for prognosis, assessment, and identification of patients that could be treated with tailored therapies.MethodsVEGF and EGFR determination was performed in 88 gastric cancer samples as well as 25 normal gastric mucosa specimens from non-cancer patients using a commercially available immunohistochemistry kit. In all samples, the correlation of VEGF and EGFR expression was investigated with each other, and with other prognostic indicators in all samples, and, finally, with survival rates in 69 patients undergoing potentially curative surgery.ResultsForty-eight per cent (42 cases) of gastric cancers expressed VEGF, and 44% (39 cases) stained for EGFR. In curatively treated patients, VEGF and EGFR expression was demonstrated to correlate with worse survival in both univariate and multivariate analyses. Molecular profiling was shown to more accurately estimate the risk of cancer-related death than TNM stage, and, of most interest, to allow sorting out high-risk patients within the same stage.ConclusionsThese findings provide evidence that contemporary evaluation of VEGF and EGFR expression may be crucial to select gastric cancer patients with poor prognosis who may benefit of tailored treatments.

Epidermal Growth Factor Receptor (EGFR) Expression is Associated With a Worse Prognosis in Gastric Cancer Patients Undergoing Curative Surgery

BackgroundIn gastric cancer, the recurrence rate is high even after curative surgery. A relevant issue is the identification of independent prognostic factors to select high-risk patients; such features can be used as predictive factors for tailored therapies. In this study we have investigated the role of epidermal growth factor receptor (EGFR) expression as a prognostic marker for predicting cancer behavior and clinical outcome in gastric cancer patients undergoing potentially curative surgery.MethodsEpidermal growth factor receptor determination using a commercially available immunohistochemistry (IHC) kit was performed in tissues from 82 gastric cancer patients receiving primary surgical treatment and in 25 normal gastric mucosa specimens from noncancer patients. The EGFR positivity was correlated with disease recurrence and survival in univariate and multivariate analyses.ResultsForty-four percent (36 cases) of gastric cancers were EGFR positive. In 66 curatively treated patients, EGFR expression correlated with disease recurrence and poorer survival in both univariate and multivariate analyses. In a multivariate model for predicting recurrence and survival, advanced tumor extension (T3 or T4), nodal metastases, and EGFR expression were the only independent covariates. In particular, EGFR expression was shown to be a significant predictor of poor prognosis among gastric cancer patients having the same stage according to the current TNM staging system.ConclusionsThese findings suggest that EGFR expression may be useful in identifying high-risk gastric cancer patients undergoing potentially curative surgery. Multimodal treatments should be considered in the adjuvant treatment of these patients.

Prognostic Significance of Epidermal Growth Factor Receptor Expression in Colon Cancer Patients Undergoing Curative Surgery

BackgroundTo investigate the role of epidermal growth factor receptor (EGFR) expression as a prognostic marker for prediction of cancer behavior and clinical outcomes in colon cancer patients undergoing potentially curative surgery.MethodsEGFR determination using a commercially available immunohistochemistry kit was performed in tissues from 149 colon cancer patients receiving primary surgical treatment and in 25 normal colon mucosa specimens from noncancer patients. EGFR positivity was correlated in univariate and multivariate analyses with disease recurrence and survival. In addition, p27, p53, and vascular endothelial growth factor expression were assessed by immunohistochemistry in 104 patients and correlated with EGFR tumor expression and clinical outcome.ResultsEGFR expression was detected in approximately one third of colon cancer patients (53 of 149; 35.6%). In 126 curatively treated patients, EGFR expression was correlated with disease recurrence and worse survival in both univariate and multivariate analyses. In a multivariate model for predicting recurrence and survival, Dukes’ staging, p27, and EGFR expression were the only independent covariates. In particular, in Dukes’ A and B patients the 5-year survival probability was 96% for EGFR-negative and high p27 expression cases and was 30.7% for EGFR-positive and low p27 expression cases.ConclusionsEGFR expression was an independent prognostic indicator of disease recurrence and poor survival in colon cancer patients undergoing curative surgery. In the context of novel therapeutic options such as molecularly targeted therapies, these findings suggest that anti-EGFR drugs could be evaluated in the adjuvant treatment of EGFR-positive colon cancer patients.

First-Line Chemotherapy vs Bowel Tumor Resection Plus Chemotherapy for Patients With Unresectable Synchronous Colorectal Hepatic Metastases

HYPOTHESIS Bowel resection followed by chemotherapy is a better management strategy than immediate chemotherapy in asymptomatic patients with colorectal cancer and unresectable liver-only metastases at presentation. DESIGN Retrospective study. SETTING University hospital. PATIENTS Sixty-five consecutive symptom-free colorectal cancer patients with unresectable synchronous metastases confined to the liver undergoing bowel tumor resection plus systemic chemotherapy (42 patients [resection group]) or chemotherapy first (23 patients [chemotherapy group]). MAIN OUTCOME MEASURES Long-term survival and identification of prognostic indicators of outcome. RESULTS In the resection group, the mean and median overall survival times were shown to be significantly better than those in the chemotherapy group (P = .03). Performance status, basal serum levels of lactic dehydrogenase and alkaline phosphatase, percentage of liver involvement, potentially curative resection of the bowel tumor, and type of treatment (resection vs chemotherapy) were demonstrated to be the only variables significantly correlated with long-term survival. On multivariate analysis, performance status, extent of liver involvement, and type of treatment were shown to be the only covariates independently associated with survival rate. The rate of liver metastasis downstaging with subsequent curative hepatic resection was clearly associated with good performance status, limited liver involvement, and resection of the bowel tumor. CONCLUSIONS Achieving complete cure in asymptomatic colorectal cancer patients with unresectable synchronous liver-only metastases appears to be mostly the result of shrinkage and resection of hepatic metastases. In patients with good performance status and limited liver involvement, bowel tumor resection appears to be the best treatment option for this purpose.

Combined CD133/CD44 expression as a prognostic indicator of disease-free survival in patients with colorectal cancer.

HYPOTHESIS Because of some inconsistencies in the traditional model of human colorectal carcinogenesis, the cancer stem cell (CSC) model was recently proposed, in which tumor results from neoplastic transformation of stem cells, which become CSCs. Identification of CSCs by expression of surface antigens remains a critical issue because no biomarker has been shown to be completely reliable. CD133 and CD44 are commonly used as CSC markers, and correlation of their expression with colorectal cancer (CRC) clinicopathological features and outcomes may be useful. DESIGN Pilot study. SETTING University hospital. PATIENTS Thirty-six consecutive patients with CRC. CD133 and CD44 expression (alone or combined) was determined in nontumor cells and in tumor cells by flow cytometry, which identified viable cells only. MAIN OUTCOME MEASURES Correlation of CD133 and CD44 expression with each other, with other prognostic indicators, and with disease-free survival. RESULTS CD133 and CD44 expression was significantly higher in tumor cells than in nontumor cells, and expression of one did not necessarily correlate with expression of the other. CD133 or CD44 expression alone was variable, while combined CD133/CD44 expression identified a small subset of cells positive for CRC. CD133 or CD44 overexpression was not associated with CRC recurrence; only high frequencies of CD133(+)/CD44(+) cells were a strong indicator of worse disease-free survival and an independent risk factor for CRC recurrence. CONCLUSION Evaluation of combined CD133/CD44 expression could be useful to identify putative colorectal CSCs and tumors with a poor prognosis.

The Lymph Node Ratio Is a Powerful Prognostic Factor of Node-Positive Colon Cancers Undergoing Potentially Curative Surgery

BackgroundThe number of harvested (LNs) and metastatic nodes (LNs+) represents the most significant factor to define postoperative treatment and prognosis in colon cancer. However, its assessment may be inadequate causing an incorrect cancer staging. The lymph node ratio (LNR: the ratio between metastatic and resected nodes) has shown prognostic significance in many tumors; however, its role in colon cancer is not clearly elucidated. This study investigated LNR as a prognostic factor in node-positive colon cancers.MethodsA total of 145 consecutive patients with node-positive colon cancer who underwent curative surgery and adjuvant chemotherapy in a single oncologic unit entered this study.ResultsLNR ranged from 0.0416 to 0.9; it was clearly lower in pN1 than pN2 patients, and increased as tumor stage worsened. ROC analysis selected 0.1818 as the best LNR cutoff value. Low LNR patients did significantly better than high LNR patients; this difference was not dependent on the number of LNs and stronger than differences observed by grouping patients according to LNs or LNs+. When stratified by low and high LNR value, pN1 and pN2 patients, as well as stage III subgroups were shown to display substantially different outcomes. LNR was an independent prognostic factor for disease-specific survival, and the only covariate related to disease-free survival.ConclusionsLNR was a robust prognostic indicator for node-positive colon cancers undergoing curative surgery. Because this ratio-based staging was demonstrated to reduce stage migration and to aid in identifying high-risk patients, it should be proposed as a standard tool for colon cancer staging.

The Over-The-Scope-Clip (OTSC) System is Effective in the Treatment of Chronic Esophagojejunal Anastomotic Leakage

IntroductionManagement of postoperative esophagojejunal anastomotic leakage after total gastrectomy represents a very challenging event. Surgical repair is difficult, and conservative treatment can predispose to more severe complications. Endoclips and self-expanding stents are useful endoscopic therapeutic options but present some drawbacks. The Over-The-Scope-Clip (OTSC) system has been shown to be appropriate to close acute small gastrointestinal perforations, but its use in the treatment of chronic leakage remains controversial.Case SeriesThe present series reports three consecutive chronic esophagojejunal anastomotic leaks successfully treated with OTSC. In all cases, clip application was simple, safe and effective, without early and late complications.DiscussionThe OTSC system may represent a new therapeutic option in the management of postoperative esophagojejunal anastomotic leakage.

Endoscopic Intraoperative Anastomotic Testing May Avoid Early Gastrointestinal Anastomotic Complications. A Prospective Study

BackgroundGastrointestinal anastomotic complications represent serious events; methods to evaluate anastomotic integrity seem to be suboptimal. Since endoscopic intraoperative anastomotic testing allows direct visualization of anastomosis, complication rates may be theoretically reduced by the use of this technique.MethodsA prospective study involving 118 consecutive oncologic patients undergoing endoscopically tested gastrointestinal stapled anastomoses was carried out. As controls, 148 historical patients without anastomotic testing were used for comparisons.ResultsIn the study group, anastomotic testing revealed 16 defects: 11 (9.3%) air leaks and five (4.3%) bleeding anastomoses. All leaks were oversewn and secured. Bleeding anastomoses were managed under direct visualization, and one non-patent anastomosis was redone. Forty-one (15.4%) postoperative anastomotic complications were observed: eight (3%) bleeding anastomoses, seven (2.6%) stenoses, and 26 (9.8%) clinical leaks. No early dehiscence or bleeding occurred if anastomoses were intraoperatively checked, while these complications were significantly more frequent in non-checked anastomoses (6.1% and 5.4%, respectively). Conversely, late leak and stenosis rates were similar between the two groups.ConclusionEndoscopic anastomotic testing was a safe and reliable method to assess integrity of gastrointestinal anastomoses, to correct any defect under direct visualization, and to avoid early complications. However, this method seemed inadequate to predict late anastomotic complications.

Radiofrequency-Assisted Liver Resection With a Comb-Shaped Bipolar Device Versus Clamp Crushing A Clinical Study

Background. In liver surgery, clamp-crushing (CC) procedure has been shown to be the most efficient system for liver transection. Recently, it has been suggested that radiofrequency-assisted liver resection (RFALR) may be more advantageous, but sufficient evidence has yet to be accumulated. Method. The control group was constituted by 32 patients undergoing CC liver transection. The study group included 13 patients undergoing RFALR with a new fully automated radiofrequency generator supplying a comb-shaped bipolar multielectrode device. Results. RFALR allowed a faster hepatic transection and reduced both surgical time and intraoperative blood loss. RFALR was the only independent prognostic indicator of bleeding during liver transection. No significant liver damage and postoperative complications, particularly biliary leakage and stenosis, were experienced in the RFALR group. Conclusion. Compared with the CC procedure, this bipolar device was shown to be safe and effective in liver resections, allowing a very clean surgical field without increase of postoperative complications.

Prognostic Biomarkers and Targeted Therapy in Gastric Cancer: Reply

We very much appreciate the interest in our article, ‘‘Epidermal Growth Factor Receptor (EGFR) Expression Is Associated with a Worse Prognosis in Gastric Cancer Patients Undergoing Curative Surgery’’ (World Journal of Surgery, 2007; 31:1458–1468) expressed by Liakakos et al. (DOI:10.1007/s00268-9434-3), from the well-known and distinguished oncological team of the Ioannina University School of Medicine, Greece. Gastric cancer is the fourth most common cancer worldwide, with an estimated 934,000 new cases per year, and it is the second most common cause of cancer deaths worldwide, with an estimated 700,000 deaths annually [1]. Complete tumor removal by surgery, so called R0 resection, is the only available treatment to provide cure in localized, nonmetastatic gastric cancer [2]. However, even after a R0 resection, locoregional recurrence and metastatic spread frequently occur, accounting for the still modest 5-year survival rates (35%–45% in Western countries) [3, 4]. Integrated treatments have been advocated to reduce postoperative relapse rates. In the USA, adjuvant 5-fluorouracil (5-FU)based chemoradiotherapy after limited D1 gastrectomy is established as standard treatment [5]; and in the UK, since perioperative ECF (epirubicin, cisplatin, 5-FU) chemotherapy significantly improved survival after D2 gastrectomy [6], it was proposed as the standard treatment for gastric cancer patients undergoing potentially curative surgery [7]. Despite tremendous efforts to improve the clinical outcomes of resected patients, no definitive conclusions concerning the efficacy of adjuvant chemotherapy were reached until the recent report of a Japanese ACTS-GC trial that is the first study showing, in II and III TNM stages, a significantly better long-term survival in gastric cancer patients treated with radical surgery plus oral S-1 (tegafur, gimeracil, and oteracil) than in patients undergoing surgery alone (3-year survival rates were 80.5% and 70.1%, respectively; hazard ratio 0.68 [95% confidence interval 0.52–0.87], p = 0.0024) [8]. These combined-modality treatments have been highly questioned, however, because of eligibility criteria, very true benefits, and, limited to the single Japanese trial, doubts about the use of S-1 in Western patients who seem to tolerate this drug very poorly because of the genetic polymorphism of the tegafur-converting enzyme, CYP2A6 [9–12]. Moreover, different clinical outcomes among patients in the same TNM stage receiving the same integrated treatments suggest, on the one hand, biological and clinical heterogeneity of gastric cancer, and, on the other hand, an urgent need to investigate new prognostic factors capable of selecting patients with a high risk of recurrence [13]. Thus, controversy still exists about the best management of gastric cancer [14]. Recently, it has been suggested that molecularly based approaches may be critical in predicting clinical outcome G. Galizia (&) E. Lieto P. Castellano V. Imperatore M. Pinto A. Zamboli Division of Surgical Oncology, ‘‘F. Magrassi A. Lanzara’’ Department of Clinical and Experimental Medicine and Surgery, Second University of Naples School of Medicine, c/o II Policlinico, Edificio 17, Via Pansini, 5, 80131 Naples, Italy e-mail: gennaro.galizia@unina2.it