Francesca Ferraraccio

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.

DETERMINATION OF MOLECULAR MARKER EXPRESSION CAN PREDICT CLINICAL OUTCOME IN COLON CARCINOMAS

Purpose: Conventional staging procedures are often unable to precisely predict prognosis in colorectal cancer (CRC). In this study, we set out to investigate the possible role of molecular/structural indicators involved in cell cycle regulation (p27 and p53), apoptosis (p53 and p27), and tumor neoangiogenesis [p53, vascular endothelial growth factor (VEGF), and microvessel count] in predicting tumor behavior and clinical outcome in CRC patients Experimental Design: Analysis of the above indicators was performed by immunohistochemistry on 104 CRC patient samples and 25 normal colon mucosa specimens. Results: Intense p27 nuclear staining was found in normal colon mucosa, with p53 nuclear staining and VEGF cytoplasmic accumulation <10%, and low microvessel count. In contrast, in CRC samples, p27 was down-regulated in 53.8%, p53 protein was overexpressed in 52%, and VEGF stained positive in 67.3% of the cases, respectively. Multiple regression analysis showed that molecular markers were strongly correlated. In patients treated with curative surgery, a significant relationship was seen between p27 down-regulation and Dukes’ stage, nodal status, and the presence of distant metastases. VEGF overexpression correlated significantly with Dukes’ stage, tumor (t) and metastasis (m) parameters, and left site. Stepwise regression selected p27, p53, VEGF, and Dukes’ stage as the best combination of variables capable of predicting both disease-specific and disease-free survival. Conclusions: The investigated indicators may be useful for the prediction of outcome and recurrence rate in curatively treated CRC patients. In conjunction with clinical and pathological staging, they may provide a stronger indication of clinical outcome than staging alone and help better select therapeutic options in CRC 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.

Prognostic Value of p27, p53, and Vascular Endothelial Growth Factor in Dukes A and B Colon Cancer Patients Undergoing Potentially Curative Surgery

PURPOSEEarly-stage colon cancer patients (Dukes A or B; pT1–T3 pNO pMO) are excluded from adjuvant chemotherapy following potentially curative surgery because they are expected to have good long-term survival. However, 20 percent to 30 percent of these patients ultimately succumb from recurrent disease. This indicates that the conventional staging procedures may be unable to precisely predict cancer prognosis.METHODSIn 65 early-stage colon cancers, we investigated by immunohistochemistry the role of molecular markers such as p27, p53, and vascular endothelial growth factor in identifying high-risk patients who may benefit from adjuvant treatments.RESULTSNo clinicopathologic factor, namely Dukes stage, t parameter, number of resected nodes, and vascular or lymphatic invasion, was found be an independent significant predictor of disease-specific and disease-free survival. In contrast, each molecular marker predicted survival and recurrence rates much better than the conventional Dukes staging system. The best combination of variables for prediction of long-term outcome and recurrence rate included p27, p53, and vascular endothelial growth factor. Interestingly, the greater the number of molecular alterations, the lower the five-year estimated survival function. Nearly all cancer-related deaths were observed among patients whose colon cancers expressed all three molecular alterations. Regardless of Dukes stage, the recurrence rate was found to increase with the increase in the number of molecular alterations. Early-stage colon cancers expressing p27 down-regulation and high p53 and vascular endothelial growth factor immunoreactivity showed a 100 percent actuarial four-year recurrence rate.CONCLUSIONSAssessment of molecular alterations may be useful to identify a higher-risk group of early-stage colon cancer patients who may benefit from adjuvant chemotherapy.

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.

Preventing seroma formation after axillary dissection for breast cancer: a randomized clinical trial.

BACKGROUND Seroma formation after axillary dissection remains the most common early sequel to breast cancer surgery. Different surgical approaches have been performed to reduce seroma collection. Therefore, we aimed to assess the outcome of patients operated on using an ultrasound scalpel according to a standardized operative technique before accepting it as a routine procedure. METHODS A randomized controlled trial was designed to compare the outcome of patients undergoing breast surgery and axillary dissection using either standard scalpel blades, scissors, ligations, and electrocautery or the ultrasound scalpel only. Each arm of the trial consisted of 30 patients. RESULTS A statistically significant benefit in terms of axillary and chest wall drainage volume, the number of axilla seromas, intraoperative bleeding, and hospitalization stay was recorded in the harmonic scalpel group. No significant differences were found between the 2 groups in terms of operative time. Finally, no postoperative hematoma, wound infections, and chest wall seroma were observed. CONCLUSIONS The use of the harmonic scalpel was shown to reduce the magnitude of seromas in axilla and hospitalization stay. The harmonic scalpel can be used alone in axillary dissection with a safe and effective hemostasis. Our results must be confirmed by larger series.

Modified versus standard D2 lymphadenectomy in total gastrectomy for nonjunctional gastric carcinoma with lymph node metastasis

BACKGROUND Although D2 lymphadenectomy has been shown to improve outcomes in gastric cancer, it may increase postoperative morbidity, mainly owing to splenopancreatic complications. In addition, the effects of nodal dissection along the proper hepatic artery have not been extensively elucidated. We hypothesized that modified D2 (ie, D1+) lymphadenectomy may decrease surgical risks without impairing oncologic adequacy. METHODS Patients with node-positive gastric cancer undergoing curative total gastrectomy were intraoperatively randomized to D1+ (group 1, 36 patients) or standard D2 lymphadenectomy (group 2, 37 patients), the latter including splenectomy and nodal group 12a. The index of estimated benefit was used to assess the efficacy of dissection of each nodal station. The primary endpoint for oncologic adequacy was the disease-free survival (DFS) rate. RESULTS Surgical complications were significantly more common in group 2, which also included 2 postoperative deaths. Overall, 35 patients (49%) experienced tumor recurrence. The primary site of tumor relapse and the 5-year DFS rate were not different between the 2 groups. Involvement of the second nodal level was associated with a worse DFS rate; however, patients undergoing more extensive lymphadenectomy did not show a better DFS rate. The incidence of involvement of nodal stations 10, 11d, and 12a was 5%, and the 5-year DFS rate was zero. Consequently, the benefit to dissect such lymph nodes was null. CONCLUSION These findings suggest that modified D2 lymphadenectomy confers the same oncologic adequacy as standard D2 lymphadenectomy, with a significant reduction of postoperative morbidity.

Adjuvant chemoradiotherapy in patients with stage III or IV radically resected gastric cancer: a pilot study.

BACKGROUND Adjuvant chemoradiotherapy does not represent the standard of care in patients with resected high-risk gastric cancer; however, results from phase 2 and randomized trials suggest improvement in overall survival. We assessed the feasibility and toxic effects of chemoradiotherapy as adjuvant treatment in locally advanced gastric cancer. DESIGN Pilot study. SETTING University hospital. PATIENTS Twenty-nine patients with T4N+ or any TN23 gastric cancer previously treated with potentially curative surgery were enrolled. All of the patients received combined adjuvant chemotherapy with FOLFOX-4 (ie, a combination of folinic acid [leucovorin], fluorouracil, and oxaliplatin [Eloxatin]) for 8 cycles and concomitant radiotherapy (45 Gy in 25 daily fractions over 5 weeks). Radiotherapy was begun after the first 2 cycles of FOLFOX-4, which was reduced by 25% during the period of concomitant radiotherapy. MAIN OUTCOME MEASURES Treatment toxic effects according to the National Cancer Institute-Common Toxicity Criteria classification, overall and disease-free survival rates, and identification of prognostic indicators. RESULTS All of the patients completed treatment. Severe hematologic and gastrointestinal toxic effects occurred in 10% and 33%, respectively. No acute hepatic or renal toxic effects were observed; 1 patient experienced severe neurotoxicity. Disease-free and overall survival rates at 1, 2, and 3 years were 79%, 35%, and 35% and 85%, 62.6%, and 50.1%, respectively, and were shown to be substantially better than those observed in untreated patients. Long-term outcome was related to TNM stage, basal serum tumor marker level, and, particularly, lymph node ratio. CONCLUSION A multimodal approach with FOLFOX-4 and radiotherapy is feasible and effective for the treatment of patients with resected high-risk gastric cancer.

Serum Vascular Endothelial Growth Factor (VEGF) Levels Correlate with Tumor VEGF and p53 Overexpression in Endocrine Positive Primary Breast Cancer

Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, associated with unfavorable clinical characteristics in breast cancer. The aim of this study was to evaluate different angiogenic markers in endocrine-positive breast cancer patients. The authors analyzed serum and tumor samples from 71 patients with endocrine-positive operable primary breast cancer to determine the expression and the possible relationship between circulating serum VEGF levels, tumor VEGF expression, microvessel density (MVD), and other immunohistochemical parameters. Basal VEGF serum levels were significantly higher in breast cancer patients than in healthy controls. A significant correlation was observed between basal VEGF serum concentrations, microvessel density (p = 0.01) and p53 status (p = 0.004). Intratumoral VEGF expression was significantly associated with neoplastic embolization (p = 0.041) and circulating VEGF levels (p = 0.047). The results confirm that in primary endocrine-positive breast cancer serum VEGF levels are elevated and show a positive relationship with tumor VEGF and p53 overexpression.