Anna Zamboli

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.

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.

CD66c is a novel marker for colorectal cancer stem cell isolation, and its silencing halts tumor growth in vivo

Despite the well recognized expression of the cell surface markers cluster of differentiation 44 (homing cell adhesion molecule) and CD133 (Prominin 1) on human colorectal cancer stem cells (CCSCs), these molecules do not appear to be effective targets for stem cell‐directed therapies. Because the surface marker CD66c (also known as carcinoembryonic antigen‐related cell adhesion molecule 6) has demonstrated promise as a therapeutic target in pancreatic malignancy, the authors evaluated its potential as a target for stem cell‐directed treatment of colorectal cancer.

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.

Neutrophil to lymphocyte ratio is a strong predictor of tumor recurrence in early colon cancers: A propensity score-matched analysis.

BACKGROUND Systemic inflammation and immune response play a crucial role in tumor growth, and the neutrophil to lymphocyte ratio (NLR) may be a simple way to assess the host inflammatory response. The NLR has been shown to be a prognostic indicator in many human tumors; in early colon cancers, it has been evaluated only in a few studies and its role remains controversial. METHODS We analyzed data from 503 colon cancer patients. The best cutoff value for NLR was defined by receiver operating characteristic curve analysis. We grouped 276 Dukes A/B colon cancers, not receiving adjuvant chemotherapy, into low (<2.36) and high (>2.36) NLR and subjected to further analyses related to disease-free survival (DFS). A propensity score-matched analysis and the inverse probability of treatment weighting (IPTW) were performed to avoid confounding bias. RESULTS The NLR correlated with tumor stage and oncologic outcome. The best NLR cutoff value was identical in the whole cohort and in Dukes A/B patients. Low NLR patients had a significantly better DFS rate than high NLR patients (hazard ratio [HR], 0.27; P = .0001); along with elevated carcinoembryonic antigen levels and Dukes B stage, high NLR was an independent prognostic factor of worse prognosis (HR, 2.86; P = .0033). Even in Dukes A patients, NLR discriminated between relapsing and nonrelapsing patients. Propensity score and IPTW analyses confirmed such results, thus excluding possible misinterpretation. CONCLUSION Preoperative NLR, an inexpensive and readily available biomarker, can predict tumor relapse and should be assessed for implementation of tailored therapy in early stage colon cancer.

Behavior of Circulating CD4+CD25+Foxp3+ Regulatory T Cells in Colon Cancer Patients Undergoing Surgery

CD4+CD25+Foxp3+ regulatory T cells (Treg) specialize in suppressing immune responses. In this study, 47 consecutive colon cancer patients were subjected to circulating Treg frequency assessment by flow cytometry before and after cancer resection. Thirty-two healthy subjects served as controls. Circulating Treg frequencies were significantly higher in colon cancer patients with respect to healthy controls. When patients were subgrouped according to Dukes stages, a linear relationship was observed between Dukes stages and Treg frequencies. In radically resected patients, Treg frequencies were shown to have significantly dropped down. Patients with advanced colon cancer were more likely to have significantly higher proportions of circulating Treg frequencies than Dukes A and B patients when compared to healthy subjects. Of note, nonradically resected patients were found to display reductions in—but not normalization of—Treg frequencies. These results suggest that cancer itself may be able to drive Treg recruitment as a strategy of immunoevasion.

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.

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.