Resection For Gastric Carcinoma Research Articles

Valoración de la 5. a edición de la clasificación TNM para el cáncer gástrico en nuestro medio

To estimate the proportion of patients with gastric carcinoma that can be classified using the criteria of the fifth edition of the TNM system and to analyze which factors could be related to the finding of an adequate number of nodes. The influence of distinct factors that could influence the number of lymph nodes isolated was evaluated in 164 patients who underwent resection of gastric carcinoma. These factors included tumor size, surgical resection, grade, histological type, variability among the pathologists who analyzed the surgical specimens, and the surgeon's experience. The mean number of lymph nodes examined by the pathologists was 11.4 (10.12-12.66). Applying the criteria of the fifth edition of the TNM classification, only 31% of the patients could be correctly classified. A positive correlation was found between tumor size and the number of resected nodes (p = 0.0018). In addition, a greater number of lymph nodes were found in total gastrectomies than in subtotal gastrectomies (p = 0.034). No significant association was found with the pathologist who analyzed the surgical specimen or with the experience of the surgeon who performed the resection. The fifth edition of the TNM system is easily reproducible, although the number of lymph nodes required to evaluate metastatic node involvement is difficult to obtain in our environment. Our results suggest that a combined effort between surgeons and pathologists is needed to increase the number of patients that can be reliably staged with this TNM edition.

793 PUBLICATION Salvage therapy with bevacizumab, capecitabin, and mitomycin C (BECAM) for patients with metastatic colorectal or gastric cancer refractory to 5-fluorouracil, oxaliplatin, irinotecan, and cetuximab

Purpose: To define the maximum-tolerated dose of oxaliplatin given with cisplatin, protacted 96-h infusion of fluorouracil, and radiotherapy for patients with advanced esophageal cancer.Patients and Methods: Seventeen patients with locally advanced esophageal cancer and 2 patients with local recurrence were treated. Escalating doses of oxaliplatin, cisplatin, and fluorouracil were administered on Days 1 and 29 of radiotherapy. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy. Dose-limiting toxicity was defined as a Grade 4 hematologic or Grade 3–4 nonhematologic toxicity.Results: Dose-limiting toxicity caused by diarrhea and asthenia was observed at the IV level. The recommended dose was 85 mg/m- oxaliplatin, 55 mg/m2 cisplatin, and 3000 mg/m2 96-h fluorouracil infusion. Two pathologic complete responses were observed in 12 patients selected for surgery (16%).Conclusions: Oxaliplatin, cisplatin, fluouracil, and radiotherapy can be administered together with acceptable toxicity. A Phase II trial is ongoing with resectable esophageal and gastric carcinoma.

Expression of Trefoil Factor Family Members Correlates with Patient Prognosis and Neoangiogenesis

Trefoil factor family (TFF) peptides are thought to contribute to epithelial protection and restitution by virtue of their protease-resistant nature and their strong affinity for mucins. However, they are often overexpressed in tumors, where they seem to be negative prognostic factors, possibly contributing to tumor spread, although the precise mechanisms have not been defined. Tissue sections from 111 patients with curatively resected advanced gastric carcinoma were immunohistochemically stained for TFF2, ITF (TFF3), and CD34. Microvessel density was expressed as number and area of microvessels. Results were correlated with clinicopathological characteristics and patient survival. Forty-nine (44.1%) and 41 (36.9%) tumors were immunohistochemically positive for TFF3 and TFF2, respectively. Among the various clinicopathologic variables, overexpression of TFF3 had a significant correlation with patient age only. In addition, a significantly higher prevalence of positive TFF2 staining was detected in large, diffuse tumors and in tumors with lymph node metastasis. The number of microvessels had a significant correlation with both TFF3 and TFF2 staining, whereas the area of microvessels had a significant correlation only with TFF3 staining. Both TFF3 and TFF2 were independent predictors of a worse disease-free survival. TFF3 had a gender-specific negative survival advantage, with a 91.3% disease-free survival in female patients with TFF3-negative advanced gastric carcinoma. Induction of increased tumor vascularity might be one of the mechanisms by which TFFs confer metastatic phenotype and frequent disease recurrence in gastric carcinomas. Female patients with TFF3-negative advanced gastric carcinoma have comparable survival as that reported for patients with early gastric carcinoma.

Significance of Skp2 expression in human gastric carcinoma and the relationship between Skp2, p27 and PTEN expression

Objective: S-phase kinase-associated protein 2 (Skp2) is a positive regulator of G1-S transition and promotes ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. Its overexpression has been implicated in cell transformation and oncogenesis. In this study, we investigated significance of Skp2 expression in human gastric carcinoma and the relationship between Skp2, p27 and PTEN expression. Methods: Immunohistochemical analysis was performed on 138 surgical resected primary gastric carcinoma specimens, 102 paired metastasis carcinoma tissue specimens in lymph node from the same set of 138 surgical resected primary gastric carcinoma specimens, 30 dysplasia specimens, 30 intestinal metaplasia specimens, and 20 normal gastric mucosa specimens for Skp2 and performed on the same set of 138 surgical resected primary gastric carcinoma specimens for p27 and PTEN. Results: Skp2 labeling frequency % was increased dramatically in intestinal metaplasia, dysplasia, and primary gastric carcinoma compared with normal gastric mucosa (P=0.000, all the same). Skp2 labeling frequency % in metastasis gastric carcinoma in lymph node was significantly higher than primary gastric carcinoma (P=0.037). Skp2 labeling frequency % was positively associated with differentiated degree (rho=0.315, P=0.000), vessel invasion (rho=0.303, P=0.000) and lymph node metastasis (rho=0.254, P=0.000) respectively. An inverse correlation of Skp2 was observed with both its biochemical target p27 expression in gastric carcinoma (rho=−0.451, P=0.000) and with its putative negative regulator, the PTEN tumor suppressor protein (rho=−0.480, P=0.000). p27 expression had positive relationship with PTEN expression in gastric carcinoma (rho=0.642, P=0.000). Conclusion: Skp2 overexpression is correlated with carcinogenesis and progression of gastric carcinoma: elevated Skp2 expression is correlated with decreased p27 and PTEN in gastric carcinoma, and p27 expression is parallel with PTEN expression. These suggest that PTEN may regulate expression of p27 through the Skp2 pathway, and the effects of Skp2, p27 and PTEN together play an important role in carcinogenesis and progression of gastric carcinoma.

Early prediction of tumor recurrence after curative resection of gastric carcinoma by measuring soluble E‐cadherin

Currently, to the authors' knowledge, there is no serum marker to predict disease recurrence after patients undergo curative resection for gastric carcinoma. Previous reports have indicated that serum levels of soluble E-cadherin had prognostic value in these patients. The objective of the current study was to determine whether soluble E-cadherin levels could predict disease recurrence in patients with gastric carcinoma who underwent curative surgery. Sixty-nine patients who underwent curative surgery for gastric carcinoma after December 1997 were followed prospectively. Venous blood samples were collected preoperatively, 1 month after surgery, and every 3 months thereafter. The blood samples were assayed for soluble E-cadherin and for carcinoembryonic antigen (CEA) using commercial enzyme-linked immunosorbent assay kits. Receiver operating characteristic (ROC) curves were used to define a cut-off level of E-cadherin for the optimal sensitivity and specificity for predicting disease recurrence. The median follow-up was 21 months for patients with recurrent disease (n = 17 patients) and 36 months for patients without recurrent disease (n = 52 patients; P = 0.007). The optimal cut-off level of E-cadherin was 10,000 ng/mL. The sensitivity for predicting prediction disease recurrence using this cut-off level at 3 months and at 6 months postsurgery was 47% and 59% respectively, which was significantly better compared with the sensitivity of CEA using the conventional cut-off level (6% at 3 months postsurgery and 6% at 6 months postsurgery; P = 0.004 and P < 0.0001, respectively). The median time between the elevated E-cadherin level and documented disease recurrence was 13 months (range, 3-20 months), compared with 4 months (range, 1-20 months) for CEA. Serum soluble E-cadherin was a good marker for predicting disease recurrence in the first 3-6 months after surgery, with a median of 13 months before clinical recurrence. The use of this marker may allow time for vigilant surveillance and consideration of adjuvant therapy.

Perioperative adjunctive treatment in the management of operable gastric cancer

Outcome in the management of clinically resectable gastric carcinoma has been disappointing, at least in Western populations, despite increasingly radical surgery and extensive experience with adjunctive perioperative treatment with innumerable single and combined modality regimens. The United States Intergroup Study, a prospective, randomized, controlled trial of adjuvant chemoradiation, demonstrated significant improvement in disease-free and overall survival. Consequently, this regimen of postoperative fluoruracil plus leucovorin and locoregional radiation has been incorporated into current clinical practice. In hopes of further improving cure rates, many other regimens are under investigation, including the efficacy of neoadjuvant therapy alone, combined neoadjuvant and adjuvant therapy, and adjuvant therapy alone. In these clinical trials, therapeutic agents are prescribed alone or in multimodal regimens and include systemic chemotherapy, intraperitoneal (IP) chemotherapy with or without hyperthermia, intraoperative radiotherapy (IORT), and postoperative external beam irradiation. Several molecular markers have been identified, which seem to predict that a given tumor may be effective or resistant to a drug, raising the possibility of customized chemotherapy regimens. Preclinical studies suggest potential efficacy of angiogenesis inhibitors, monoclonal antibodies, and antisense agents.

Lebensqualit�t nach subtotaler Magenresektion und Gastrektomie beim Magenkarzinom

Recently, quality of life has become a main objective in surgical therapy. Apart from the oncological consequences, the quality of results after gastric carcinoma resection are mainly determined by social and psychological aspects of life, early postoperative complications, and long-term nutritive/functional parameters. Of 338 patients who underwent gastric resection for adenocarcinoma of the stomach, quality of life was assessed in 73 recurrence-free patients by means of the Gastrointestinal Life Quality Index (GLQI). The median age was 71.9 years, and surgery had been carried out at least 1 year prior to the investigation (median follow-up 4.5 years). Patients with subtotal gastric resection displayed significantly higher GLQI scores (120 [97-138] points) than patients with gastrectomy (116 [70-139] points;p=0.047). Among partial parameters of the life quality index, physical functions were significantly better after subtotal resection (p=0.040), while the emotional status (p=0.147) and social activities (p=0.337) did not differ between the two groups. Abdominal symptoms (p=0.081) and the nutritional function (p=0.228) were insignificantly different. The number of meals (4 vs. 5 meals per day) and the loss of weight since surgery (5 vs. 10 kg) were less after subtotal resection than after gastrectomy. However, the latter parameter did not reach statistical significance.

Validation of a nomogram for predicting disease‐specific survival after an R0 resection for gastric carcinoma

A statistical model for predicting disease-specific survival in patients with gastric carcinoma, based on a single U.S. institution experience, was tested for validity in a sample of patients treated at different institutions. The authors analysed 459 patients from the Dutch Gastric Cancer trial that compared limited (D1) with extended (D2) lymph node dissection. The discrimination ability of the nomogram with respect to 5 and 9-year disease-specific survival probabilities was superior to that of the American Joint Committee on Cancer (AJCC) staging system. There was considerable heterogeneity of risk within many of the AJCC stages. Calibration plots suggested that predicted probabilities from the nomogram corresponded closely to actual disease-specific survival. The gastric carcinoma nomogram performed well when applied to patients treated in a large number of institutions. The nomogram provided predictions that discriminated better than the AJCC staging system, regardless of the extent of lymph node dissection. Patient counseling and adjuvant therapy decision-making should benefit from use of the nomogram.

Phase I trial of oxaliplatin in combination with cisplatin, protacted-infusion fluorouracil, and radiotherapy in advanced esophageal and gastroesophageal carcinoma

To define the maximum-tolerated dose of oxaliplatin given with cisplatin, protacted 96-h infusion of fluorouracil, and radiotherapy for patients with advanced esophageal cancer. Seventeen patients with locally advanced esophageal cancer and 2 patients with local recurrence were treated. Escalating doses of oxaliplatin, cisplatin, and fluorouracil were administered on Days 1 and 29 of radiotherapy. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy. Dose-limiting toxicity was defined as a Grade 4 hematologic or Grade 3-4 nonhematologic toxicity. Dose-limiting toxicity caused by diarrhea and asthenia was observed at the IV level. The recommended dose was 85 mg/m- oxaliplatin, 55 mg/m2 cisplatin, and 3000 mg/m2 96-h fluorouracil infusion. Two pathologic complete responses were observed in 12 patients selected for surgery (16%). Oxaliplatin, cisplatin, fluouracil, and radiotherapy can be administered together with acceptable toxicity. A Phase II trial is ongoing with resectable esophageal and gastric carcinoma.

COX-2 correlates with F-box protein, Skp2 expression and prognosis in human gastric carcinoma

The expression of cyclooxygenase (COX)-2 is induced by growth factors, tumor promoters and cytokines, and is correlated with carcinogenesis, tumor progression and inhibition of apoptosis. To clarify the pathological significance of COX-2, we examined the effect of a selective COX-2 inhibitor, NS398, on two human gastric carcinoma cell lines, MKN-45 and KATO-III, and the expression of Skp2, P27/Kip1 and COX-2 protein in human gastric carcinomas. NS398 inhibited cell growth in a time- and dose-dependent manner and exerted cell cycle arrest in the G0/G1 phase without induction of apoptosis in MKN-45, but had no effect in KATO-III. In MKN-45, NS398 induced up-regulation of P27/Kip1 and down-regulation of COX-2, cyclin D1 and Skp2. Immunohistochemistry using 63 surgically resected gastric carcinomas disclosed that COX-2 expression was correlated with Skp2 expression and that P27/Kip1 expression was inversely correlated with COX-2 and Skp2 expression. High levels of COX-2 or Skp2 were significantly correlated with poor survival (P=0.02 and P=0.004). Our results suggested that: a) NS398 induced inhibition of cell proliferation through cell cycle arrest and suppressed the expression of Skp2 in COX-2-expressing gastric carcinoma cells, and b) COX-2 contributes to the expression of Skp2 and poor survival in human gastric carcinomas.

Prognostic Significance of CpG Island Methylator Phenotype and Microsatellite Instability in Gastric Carcinoma

The influence of molecular characteristics in prognosis of gastric cancer remains unclear. The aim of this study was to evaluate the prognostic value of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in gastric cancer. We studied the methylation profiles of tumor suppressor gene p16, DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using bisulfite/methylation-specific PCR, and MSI using five microsatellite markers in 83 resected gastric carcinomas. The CIMP and MSI status were compared with clinicopathologic features and overall survival. Concordant methylation of multiple genes/loci (CIMP-high) was present in 31% of tumors and in 4% of non-neoplastic mucosa, CIMP-low in 55% and 17%, and CIMP-negative in 13% and 79%, respectively (P < 0.001). The prevalence of MSI-high, MSI-low, and MS-stable in tumor was 19%, 17%, and 64%, respectively. MSI status was closely associated with hMLH1 hypermethylation and CIMP status (P = 0.001). In univariate analysis, overall survival was predicted by pathologic stage (P < 0.0001), R0 resection (P = 0.0002), MINT31 methylation (P = 0.04), and CIMP-high status (P = 0.04). MSI status of tumor was not a significant predictor of prognosis. Although CIMP status seemed to be a prognostic predictor of gastric cancer, only pathologic stage remained a significant predictor of prognosis on multivariate analysis (P < 0.001). Our results indicate that there is an association between CIMP status and MSI status in gastric cancer. Concordant methylation of multiple genes/loci (CIMP-H) is associated with better survival but is not an independent predictor of prognosis in resected gastric cancer.

Expression ofp16gene and Rb protein in gastric carcinoma and their clinicopathological significance

To analyze the correlation between the protein expression of p16 and Rb genes in gastric carcinoma (GC), to investigate the role of p16 gene in invasion and lymph node metastasis of GC, and to examine the deletion and mutation in exon 2 of p16 gene in GC. The protein expression of p16 and Rb genes was examined by streptavidin-peroxidase conjugated method (S-P) in normal gastric mucosa, dysplastic gastric mucosa and GC. The deletion and mutation of p16 gene were examined by polymerase chain reaction (PCR) and polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) respectively in normal gastric mucosa and GC. The positive rates of P16 and Rb protein expression respectively were 96% (77/80) and 99% (79/80) in normal gastric mucosa, 92% (45/50) and 80% (40/50) in dysplastic gastric mucosa, 48% (58/122) and 60% (73/122) in GC. The positive rates of P16 and Rb protein expression in GC were significantly lower than that in normal gastric mucosa and dysplastic gastric mucosa (P<0.05). The positive rate of P16 protein expression in mucoid carcinoma (10%, 1/10) was significantly lower than that in poorly differentiated carcinoma (51%, 21/41), undifferentiated carcinoma (58%, 15/26) and signet ring cell carcinoma (62%, 10/16) (P<0.05). The positive rates of P16 protein in 30 cases of paired primary and lymph node metastatic GC were 47% (14/30) and 17% (5/30) respectively, being significantly lower in the later than in the former (P<0.05). There was no mutation in exon 2 of p16 gene in the 25 freshly resected primary GCs. But five cases in the 25 freshly resected primary GCs displayed deletion in exon 2 of p16 gene. The positive rate of both P16 and Rb proteins was 16% (14/90), and the negative rate of both P16 and Rb proteins was 8% (7/90) in 90 GCs. The rate of positive P16 protein with negative Rb protein was 33% (30/90). The rate of negative P16 protein with positive Rb protein was 43% (39/90). There was reverse correlation between P16 and Rb expression in 90 GCs (P<0.05). The loss protein expression of p16 and Rb genes is related to GC. The loss expression of P16 protein is related to the histopathologic subtypes and lymph node metastasis of GC. Expression of P16 and Rb proteins in GC is reversely correlated. The deletion but not mutation in exon 2 of p16 gene may be involved in GC.

Increased expression of mitogen-activated protein kinase and its upstream regulating signal in human gastric cancer

To investigate the expression of mitogen-activated protein kinases (MAPKs) and its upstream protein kinase in human gastric cancer and to evaluate the relationship between protein levels and clinicopathological parameters. Western blot was used to measure the expression of extracellular signal-regulated kinase (ERK)-1, ERK-2, ERK-3, p38 and mitogen or ERK activated protein kinaseMEK-1 proteins in surgically resected gastric carcinoma, adjacent normal mucosa and metastatic lymph nodes from 42 patients. Immunohistochemistry was employed for their localization. Compared with normal tissues, the protein levels of ERK-1 (integral optical density value 159 526+/-65 760 vs 122 807+/-65 515, P = 0.001), ERK-2 (168 471+/-95 051 vs 120 469+/-72 874, P<0.001), ERK-3 (118 651+/-71 513 vs 70 934+/-68 058, P<0.001), P38 (104 776+/-51 650 vs 82 930+/-40 392, P = 0.048) and MEK-1 (116 486+/-45 725 vs 101 434+/-49 387, P = 0.027) were increased in gastric cancer tissues. Overexpression of ERK-3 was correlated to TNM staging (average ratio of integral optic density (IOD)(tumor): IOD(normal) in TNM I, II, III, IV tumors was 1.43+/-0.34, 5.08+/-3.74, 4.99+/-1.08, 1.44+/-1.02, n = 42, P = 0.023) and serosa invasion (4.31+/-4.34 vs 2.00+/-2.03, P = 0.037). In poorly differentiated cancers (n = 33), the protein levels of ERK-1 and ERK-2 in stage III and IV tumors were higher than those in stage I and II tumors (2.64+/-3.01 vs 1.01+/-0.33, P = 0.022; 2.05+/-1.54 vs 1.24+/-0.40, P = 0.030). Gastric cancer tissues with either lymph node involvement (2.49+/-2.91 vs 1.03+/-0.36, P = 0.023; 1.98+/-1.49 vs 1.24+/-0.44, P = 0.036) or serosa invasion (2.39+/-2.82 vs 1.01+/-0.35, P = 0.022; 1.95+/-1.44 vs 1.14+/-0.36, P = 0.015) expressed higher protein levels of ERK-1 and ERK-2. In Borrmann II tumors, expression of ERK-2 and ERK-3 was increased compared with Borrmann III tumors (2.57+/-1.86 vs 1.23+/-0.60, P = 0.022; 5.50+/-5.05 vs 1.83+/-1.21, P = 0.014). Borrmann IV tumors expressed higher p38 protein levels. No statistically significant difference in expression of MAPKs was found when stratified to tumor size or histological grade (P>0.05). Protein levels of ERK-2, ERK-3 and MEK-1 in metastatic lymph nodes were 2-7 folds higher than those in adjacent normal mucosa. The immunohistochemistry demonstrated that ERK-1, ERK-2, ERK-3, p38 and MEK-1 proteins were mainly localized in cytoplasm. The expression of MEK-1 in gastric cancer cells metastasized to lymph nodes was higher than that of the primary site. MAPKs, particularly ERK subclass are overexpressed in the majority of gastric cancers. Overexpression of ERKs is correlated to TNM staging, serosa invasion, and lymph node involvement. The overexpression of p38 most likely plays a prominent role in certain morphological subtypes of gastric cancers. MEK-1 is also overexpressed in gastric cancer, particularly in metastatic lymph nodes. Upregulation of MAPK signal transduction pathways may play an important role in tumorigenesis and metastatic potential of gastric cancer.

Membranous Levels of C-Erbb-2 Oncoprotein in Gastric Cancer: Their Relationship with Clinicopathological Parameters and Their Prognostic Significance

The protein encoded by the c-erbB-2 gene is a membrane receptor expressed in a variety of solid human cancers and directly related to poor prognosis. The objective of this work was to evaluate the clinical value of the quantification of membranous oncoprotein levels in gastric cancer. Membranous c-erbB-2 levels were examined by means of a sandwich immunoenzymatic assay in 82 patients with gastric cancer. The median follow-up period for these patients was 16 months. In addition, c-erbB-2 expression was analyzed by immunohistochemistry in 57 gastric carcinomas. Membranous c-erbB-2 levels ranged widely in the studied tumors (44-112,000 NHU/mg protein). Median c-erbB2 content was significantly higher in intestinal-type tumors than in diffuse-type tumors (p = 0.01). In addition, high levels of c-erbB-2 were significantly associated with shorter relapse-free survival and overall survival in patients with resectable gastric carcinomas (p = 0.01 and p = 0.04, respectively). However, the correlation between immunohistochemistry and ELISA determinations did not reach statistical significance. Our results suggest a potential prognostic value of membranous c-erbB-2 quantification by immunoenzymatic assay in gastric cancer. However, its possible role in the selection of patients with a view to the possible introduction of Herceptin as a novel drug against gastric cancer is at present uncertain.

Time to Death and Pattern of Death in Recurrence following Curative Resection of Gastric Carcinoma: Analysis Based on Depth of Invasion

It is difficult to predict recurrence in patients who undergo curative gastrectomy for gastric carcinoma. If the timing and site of recurrence can be predicted, it becomes easier to detect recurrent disease. Records of 290 patients who died of tumor recurrence after curative gastrectomy for gastric carcinoma were retrospectively analyzed to determine whether the depth of carcinoma invasion is independently correlated with the time to death due to tumor recurrence. Additionally, the relation between the pattern of recurrence and the depth of invasion of the gastric wall was examined. Postoperative survival in patients with tumors with deep invasion was shorter than that of patients with tumors with shallow invasion. Depth of invasion was a predictor of survival on multivariate analysis. When carcinoma invaded into deeper layers, the incidence of peritoneal metastasis and local recurrence rose and that of hematogenous metastasis fell. In conclusion, the timing of death and the site of recurrence after gastrectomy for gastric carcinoma might be predicted by the depth of invasion of the gastric wall.

Presence of vascular adventitial fibroblastic cells in diffuse-type gastric carcinomas

Aim: To investigate morphological changes in the tumour vessel adventitia, particularly the distribution of vascular adventitial fibroblastic cells (VAFCs)—namely, CD34 positive fibroblastic cells just outside the vascular media—in diffuse-type gastric...

A proposal for diagnostically meaningful criteria to classify increased epidermal growth factor receptor and c-erbB-2 gene copy numbers in gastric carcinoma, based on correlation of fluorescence in situ hybridization and immunohistochemical measurements

Amplification of the epidermal growth factor receptor (EGFR) and/or c-erbB-2 oncogenes and overexpression of their proteins are detected in 30% of gastric carcinomas, but there are few reports regarding the correlation between gene amplification and protein overexpression. We examined the correlation between amplification of the EGFR and c-erbB-2 genes, detected using fluorescence in situ hybridization, and overexpression of their proteins, detected using immunohistochemistry, in formalin-fixed tissue sections of 54 surgically resected gastric carcinomas. A mean EGFR copy number per nucleus of four or more and an EGFR/chromosome 7 centromere (CEP7) ratio of 1.7 or more were each detected in 4 specimens (7%). The sensitivity and specificity of both criteria for EGFR protein overexpression were 75% and 92%, respectively. A mean c-erbB-2 copy number per nucleus of 7.0 or more and a c-erbB-2/chromosome 17 centromere (CEP17) ratio of 2.0 or more were detected in six (11%) and eight (15%) specimens, respectively. The sensitivity and specificity of the former criterion to c-erbB-2 overexpression were 83% and 98%, respectively, while those of the latter were 63% and 98%. A mean EGFR gene copy number of 4.0 or more and/or an EGFR/CEP7 ratio of 1.7 and a mean c-erbB-2 gene copy number of 7.0 or more and/or a c-erbB-2/CEP17 ratio of 2.0 or more would be useful in defining increased EGFR and c-erbB-2 gene copy numbers, respectively, in gastric carcinomas.

Multi-Institutional Trial of Preoperative Chemoradiotherapy in Patients With Potentially Resectable Gastric Carcinoma

In the West, curative (R0) resection is achieved in approximately 50% of patients with localized gastric carcinoma, and more than 60% die of cancer following an R0 resection. A multi-institutional study of preoperative chemoradiotherapy was done to assess the R0 resection rate, pathologic complete response (pathCR) rate, safety, and survival in patients with resectable gastric carcinoma. Operable patients with localized gastric adenocarcinoma were eligible. Staging also included a laparoscopy and endoscopic ultrasonography (EUS). Patients received up to two 28-day cycles of induction chemotherapy of fluorouracil, leucovorin, and cisplatin, followed by 45 Gy of radiation plus concurrent fluorouracil. Patients were then staged and surgery was attempted. Thirty-four patients were registered at three institutions. One ineligible patient was excluded. Most patients had a promixal cancer and EUST3N1 designation. Twenty-eight (85%) of 33 patients underwent surgery. The R0 resection rate was 70% and pathCR rate was 30%. A pathologic partial response (< 10% residual carcinoma in the primary) occurred in eight patients (24%). EUS T plus N and postsurgery T plus N correlation showed significant downstaging (P = <.01). The median survival time for 33 patients was 33.7 months. Patients achieving a pathCR or pathPR had a significantly longer median survival time (63.9 months) than those achieving less than pathPR (12.6 months; P =.03). There were two treatment-related deaths. Our data suggest that the three-step strategy of preoperative induction chemotherapy followed by chemoradiotherapy resulted in substantial pathologic response that resulted in durable survival time. This strategy is worthy of a direct comparison with postoperative adjuvant chemoradiotherapy.

Tumor progression and chemosensitivity to uracil/tegafur in relation to the apoptosis related protens in gastric cancer

4072 Background: Apoptosis related proteins including p53 and p21 regulate cell cycle under exposure of anticancer drugs. The Bax and Mcl-1 gene are members of the Bcl-2 family. Bcl-2 and Mcl-1 are blockers of cell death, whereas Bax and Bcl-Xs are promoters of apoptosis. Methods: To study apoptosis related protein expression and their impact on patient's survival time and chemosensitivity to postoperative UFT [uracil/tegafur 4:1], we examined mutant p53, p21, bax and Mcl-1 protein expression using immunohistochemical staining in 125 surgically resected gastric carcinomas invading the serosa (T3). Results: Expression of mutant p53, p21, Bax and Mcl-1 proteins were detected in 64%, 48%, 39% and 75% of patients, respectively. Mutant p53(+), p21(-) or Mcl-1(+) tumor was frequently observed in more advanced carcinomas. Patients with mutant p53(-), p21(+) or Mcl-1(-) tumor had better survival rates than those with mutant p53(+), p21(-) or Mcl-1(+) tumor, respectively. More p21(+) or Bax(+) cases and less mutant p53(+) or Mcl-1(+) cases were found in differentiated carcinoma. In patients with mutant p53(+), p21(+), Bax(-), or Mcl-1(-) tumor, no survival benefit was obtained by using UFT. In patients with mutant p53 tumor, however, 5-year survival rate of those given UFT was 72%, significantly superior to 35% of those not given the drug (P<0.05). In patients with p21(-) tumor, 54% of patients given UFT survived for 5 year, whereas all patients not given UFT died within 4 years (P<0.05). In patients with Bax(+) tumor, 5-year survival rates were 61% in those given UFT and 31% in those not given UFT (P<0.05). In patients with Mcl-1(+) tumor, 5-year survival rate of those given UFT was 57%, being significantly better than 32% of those not given the drug (P<0.01). Conclusions: These results indicate that the relationship of expression levels of p53, p21, Bax and Mcl-1 is important for predicting the efficacy of postoperative UFT. Therefore, patients with T3 gastric carcinoma should be selected for UFT treatment based on the expression of apoptosis related proteins in tumor cells. No significant financial relationships to disclose.

Early-onset gastric carcinomas display molecular characteristics distinct from gastric carcinomas occurring at a later age.

Gastric cancer is thought to result from a combination of environmental factors and accumulation of specific genetic alterations, and consequently mainly affects older patients (>50 years of age). Fewer than 10% of patients present with the disease before 45 years of age and these young patients are thought to develop carcinomas with a different molecular genetic profile from that of sporadic carcinomas occurring at a later age. Forty early-onset gastric carcinoma resection specimens were characterized for microsatellite instability (MSI) and loss of heterozygosity status using 22 polymorphic microsatellite markers. Twenty-four biopsies were additionally evaluated for the presence of MSI. No MSI was observed in any of the cases analysed. Losses were infrequent, but were most common for the D1S234 (26.1%) and D1S1676 (17.4%) markers, flanking the RUNX3 gene; for the p53ALU (23.1%) and TP53 (15.4%) markers, near the TP53 gene; and for the D16S2624 (17.2%) marker, near the E-cadherin (CDH1) gene. All cases with loss of CDH1, as well as 6/7 cases with loss of TP53, displayed aberrant staining of the corresponding proteins, pointing to a functional role for these proteins in early-onset gastric carcinogenesis. No germline CDH1, TP53 or RUNX3 mutations were detected in any of the cases analysed. No correlation was observed between non-functional E-cadherin and the histological type of the tumours analysed. Finally, Epstein-Barr virus was not detected in any of the cases analysed. On the basis of these results, early-onset gastric carcinomas appear to have characteristics distinct from gastric carcinomas occurring at a later age.