Claudio Belluco

Ratio Between Metastatic and Examined Lymph Nodes Is an Independent Prognostic Factor After D2 Resection for Gastric Cancer: Analysis of a Large European Monoinstitutional Experience

Background: In view of the lack of consensus on the level and number of lymph nodes to be examined for accurate staging of patients with gastric cancer, our aim was to evaluate the prognostic significance of lymph node status in a large European monoinstitutional experience.Methods: A review was made of our prospective database from 1980 to 2000, when 314 of 445 patients operated for gastric adenocarcinoma underwent radical resection (R0) with D2 lymphadenectomy. Survival was determined by the Kaplan-Meier method and differences were assessed by the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model in forward stepwise regression.Results: In 277 evaluable patients, 5-year survival was 57% (median follow-up, 48 months; range, 2–251). A total of 7668 lymph nodes were examined (median, 27; range, 11–62). The 5-year survivals according to the metastatic/examined lymph nodes ratio (N ratio) were 14%, 50%, 61%, and 82% in the group of patients with N ratio >25%, 11%–25%, 1%–10%, and 0%, respectively (P < .0001). At multivariate analysis, the N ratio was the best single independent prognostic factor (P = .000).Conclusions: After R0 resection for gastric cancer, the N ratio is a potent prognostic factor. It should therefore be considered in the clinical decision making process.

Interleukin-6 blood level is associated with circulating carcinoembryonic antigen and prognosis in patients with colorectal cancer

AbstarctBackground: Interleukin-6 (IL-6) is an important proinflammatory cytokine that has multiple effects on stimulating inflammation and cell growth. Experimental data suggest that carcinoembryonic antigen (CEA) induces the systemic production of IL-6 and that IL-6 may stimulate tumor cell growth at metastatic sites. We tested the hypothesis that blood concentrations of IL-6 are associated with the amount of circulating CEA and with prognosis in patients with colorectal cancer.Methods: CEA and IL-6 concentrations were measured by using enzyme immunoassay in preoperative serum samples from 208 patients with stages I through IV colorectal cancer.Results: Linear regression analysis showed a significant association between serum values of CEA and IL-6 (r = .544; R2 = .296; P < .001). Patients with stage III and stage IV disease had a significantly higher IL-6 serum concentration than those with stage I and stage II disease. In patients with stages I through III, 5-year survival was 83% in cases with concentrations of IL-6 at 10xa0pg/ml or less (n = 94) and 56% in cases with IL-6 concentrations of more than 10 pg/ml (n = 54; P = .001; median follow-up time, 46 months). By using multivariate analysis, an IL-6 concentration of more than 10xa0pg/ml was an independent prognostic factor of survival (relative risk = 1.820; P = .020).Conclusions: In patients with colorectal cancer, blood concentration of IL-6 is associated with high circulating CEA and advanced stage. Furthermore, an IL-6 concentration of more than 10 pg/ml is an independent negative prognostic marker of survival.

Metastatic transcriptional pattern revealed by gene expression profiling in primary colorectal carcinoma

Metastatic spread to the liver is the major contributor to mortality in patients with colorectal carcinoma (CRC). In order to seek for gene expression patterns associated with metastatic potential in primary CRC, we compared the transcriptional profiles of 10 radically resected primary CRCs from patients who did not develop distant metastases within a 5‐year follow‐up period with those of 10 primary/metastatic tumor pairs from patients with synchronous liver metastases. To focus selectively on neoplastic cells, the study was conducted on laser‐microdissected bioptic tissues. Arrays of 7,864 human cDNAs were utilized. While a striking transcriptional similarity was observed between the primary tumors and their distant metastases, the nonmetastasizing primary tumors were clearly distinct from the primary/metastatic tumor pairs. Of 37 gene expression differences found between the 2 groups of primary tumors, 29 also distinguished nonmetastasizing tumors from metastases. The gene encoding for mannosyl (α‐1,3‐)‐glycoprotein β‐1,4‐N‐acetyl‐glucosaminyl‐transferase (GnT‐IV) became significantly upregulated in primary/metastatic tumor pairs (p < 0.001). GnT‐IV upregulation was confirmed by RT‐PCR. These data support the existence of a specific transcriptional signature distinguishing primary colon adenocarcinomas with different metastatic potential, the further pursuit of which may lead to relevant clinical and therapeutic applications.

Prostate carcinoma and green tea: PSA-triggered basement membrane degradation and MMP-2 activation are inhibited by (-)epigallocatechin-3-gallate

Prostate‐specific antigen (PSA) is a serine‐protease that, in addition to cleaving semenogelins in the seminal coagulum, is able to cleave extracellular matrix glycoproteins, thereby affecting cell migration and metastasis. We here report some new activities of PSA that deserve careful consideration in the cancer context: degradation of gelatin, degradation of type IV collagen in reconstituted basement membrane (Matrigel) and activation of progelatinase A (MMP‐2), but not pro‐MMP‐9, in a cell‐free system. Since consumption of green tea has been reported to lower the risk of prostate cancer, we investigated the effects of the major flavanol of green tea, (−)epigallocatechin‐3‐gallate (EGCG), on expression and activity of PSA by prostate carcinoma cells. In addition to restraint of PSA expression, EGCG was found to inhibit in a dose‐dependent manner all the above PSA activities, at concentrations lower than the cytotoxic serine‐protease inhibitor PMSF and close to levels measured in the serum following ingestion of green tea. The activity of PSA was suppressed also by the elastase released by the inflammatory leukocytes. These results highlight new PSA activities, suggest gelatin zymography as a new convenient assay for PSA, propose EGCG as natural inhibitor of prostate carcinoma aggressiveness, but also stimulate further investigation on the role of prostatic inflammation.

Stoma Adjustable Silicone Gastric Banding: Results in 111 Consecutive Patients

From April 1990 through December 1992, 111 patients (80 females, 31 males, mean age 38 years, range 16-60) underwent stoma adjustable silicone gastric banding (SASGB) at the Department of Surgery, University Hospital, Padua, Italy. Patients characteristics were: mean height 166 ± 8 cm; mean body weight (BW) 129.1 ± 21.6 kg; mean body mass index (BMI) 46.4 ± 6.3 kg/m2; mean percentage of ideal body weight (%IBW) 206.2 ± 27. Eighty-eight patients were morbidly obese and 23 super obese. All patients were available for follow-up. Median follow-up was 18.8 months (range 12-44). At 1 year (103 patients), mean postoperative BW, BMI, %IBW and excess weight lost (%EWL) were 101.5 ± 20 kg, 36.5 ± 6 kg/m2, 164 ± 30 and 40.8 ± 19 respectively; at 2 years (58 patients) 92.3 ± 19 kg, 33.1 ± 6 kg/m2, 148.8 ± 28, 52 ± 23, respectively, and at 3 years (26 patients) 86.9 ± 14 kg, 31.4 ± 5 kg/m2, 141.5 ± 25 and 63.6 ± 20 respectively. The overall postoperative mortality rate was zero and the early morbidity rate 9%. Late complications were band slippage (two patients), stoma stenosis with pouch dilatation (seven patients), band erosion (one patient), reservoir leakage (three patients) and reservoir infection (two patients). Surgical revision was performed in ten (9%) patients, two of whom required band removal. Most complications occurred in patients who underwent SASGB during our initial experience. Our findings confirm that SASGB is a safe and effective surgical means of achieving weight reduction.

Adjustable Silicone Gastric Banding (ASGB): the Italian experience

Adjustable silicone gastric banding (ASGB) is a recently introduced gastric restrictive procedure. From April 1990 to April 1992, 85 patients underwent ASGB at our Department. Patients characteristics were: 65 females, 20 males, mean age 39.6 years (range 17-60 years); body weight (BW) 127.9 ± 23 kg; % ideal body weight (%IBW) 205 ± 29; body mass index (BMI) 46 ± 7; morbidly obese 68, super-obese 17. Mean follow-up is 353 days. Twelve months after the operation BW was 95.2 ± 23 kg, % loss of excess BW 52.1 ± 22, and %IBW 152.2 ± 30 (45 patients). Mortality rate was zero and postoperative morbidity was insignificant. As late morbidity, we experienced two slippages of the band and six stoma-stenosis with pouch dilatation. Therefore, a surgical revision without removal of the band was performed in eight patients. The band was removed in one patient because of band erosion. In conclusion, ASGB is a safe and effective bariatric procedure. The weight loss is comparable to that produced by more extensive operations. Moreover, ASGB is fully reversible and adjustable to the patients needs.

Laparoscopic Placement of Adjustable Silicone Gastric Banding: Early Experience

Background: the authors describe a laparoscopic technique for the positioning of stoma adjustable silicone gastric banding (SASGB), which respects the main steps of the open procedure. Methods: (1) patient position: supine with thighs abducted and 30° reverse Trendelenburg; (2) Four 10 mm trocars (supra-umbilical, sub-xiphoid, right upper quadrant, left upper quadrant) and an 18 mm trocar (left subcostal); (3) exposure of the subcardial area; (4) measurement of the pouch; (5) dissection of the lesser and greater curvatures; (6) retrogastric tunnel; (7) introduction and placement of the band; (8) band closure and stoma calibration; (9) retention sutures. Results: results obtained in a first (1992) series of five patients who underwent the laparoscopic application of the regular SASGB and results of a second series (1993-1994) of seven patients in whom the new LAP-ASGB was utilized are reported. Conclusion: this new approach can represent a major achievement in bariatric surgery, as it combines the minimal invasiveness of the laparoscopic approach with the reversibility of SASGB.

Absence of the cell cycle inhibitor p27Kip1 protein predicts poor outcome in patients with stage I-III colorectal cancer.

Background: The p27Kip1 protein regulates the G1 to S phase transition of cell cycle by binding to and inhibiting the cyclin E/Cdk2 complex. This study explores the prognostic significance of the absence of the p27Kip1 protein in patients with colorectal cancer (CRC).Methods: Formalin-fixed tumor sections from 124 patients who underwent curative resection for stage I-III CRC were analyzed by immunohistochemistry using MoAb anti-p27Kip1.Results: Detectable levels of p27Kip1 protein were found in 86% of tumors. Median follow-up was 55 months. Actuarial 5-year disease-free survival (DFS) and overall survival (OS) were 76% and 85%, respectively, in patients with tumors with p27Kip1 protein expression and 34% and 40%, respectively, in those whose tumors lacked p27Kip1 protein expression (P < .001). At multivariate analysis, tumor stage (III vs. I-II) and p27Kip1 protein status (absence vs. presence) were found to be independent prognostic factors for DFS and OS.Conclusions: Lack of p27Kip1 protein expression in CRC is a negative prognostic marker and may therefore be useful in selecting early-stage patients more likely to benefit from adjuvant treatment.

Acute effects of HMG-CoA reductase inhibitors on biliary lipids in patients with interrupted enterohepatic circulation

Abstract. HMG‐CoA reductase inhibitors decrease serum cholesterol by inhibiting hepatic cholesterol synthesis, but their influence on biliary lipids is not well characterized. In the present study Pravastatin (80 mg) was administered as a single oral dose to 10 patients with external bile fistula, after 1 week of interruption of the enterohepatic circulation, in order to assess the effect of inhibition of hepatic cholesterol synthesis on biliary lipids in conditions of stimulated bile acid synthesis. Bile was collected every hour for 12 h. On the day before, the same procedure was applied with a placebo, and collected bile used as control. Pravastatin decreased both bile acid and phospholipid concentration to about 60% of basal values; this change was still significant after 10 h. Cholesterol concentration was also decreased to about 70% of basal values, but this change was significant only from the 5th to the 7th h. The per cent of cholic and chenodeoxycholic acid was not affected by the drug, but the ratio of glyco‐ to tauroconjugated bile acids was decreased to about half the initial values. Bilirubin concentration exhibited a late increase, suggesting a reduction in the bile flow. These results suggest that, in patients with interrupted enterohepatic circulation, biliary excretion of bile acids can be largely dependent on hepatic cholesterol synthesis.

p53 gene alterations and protein accumulation in colorectal cancer

Aim—To correlate immunohistochemical staining with single strand conformation polymorphism (SSCP) analysis of the p53 gene in colorectal cancer in order to understand how the findings provided by the two techniques complement each other in defining p53 functional status. Methods—Frozen tumour tissue from 94 patients with colorectal cancer was studied for p53 protein accumulation and gene mutations. Accumulation of p53 protein was detected by immunohistochemistry using PAb1801 and BP53-12-1 monoclonal antibodies. The findings were then compared with SSCP analysis of exons 5 to 8 of the p53 gene. All cases with a positive result by SSCP analysis were confirmed by sequencing. Results—Nuclear staining was observed in 51 (54.2%) cases. SSCP analysis of the DNA amplified by PCR revealed that the electrophoretic pattern had shifted in 30 cases; sequence analysis confirmed the occurrence of a mutation in 29 cases and of a polymorphism in one. In 27 cases both assays gave a positive result, and in 40 both were negative; therefore, concordance between PCR-SSCP and immunohistochemistry was seen in 72% of cases. Conclusion—The data indicate that positive immunostaining corresponds with the presence of a mutation in most, but not all, cases studied; other mechanisms could be responsible for stabilisation and accumulation of p53 protein in the nucleus. Nonsense mutations which do not confer stability on the protein will not be detected by immunohistochemistry and false negative results can also occur with SSCP analysis.