Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients - A GIRCG study.

BACKGROUND: Gastric gastrointestinal stromal tumors (GISTs) represent a subgroup of GISTs with a better prognosis than those located in other areas. In this retrospective study we performed a molecular characterization of a large series of patients with gastric GISTs in relation to clinical-pathological characteristics and prognosis. METHODS: DNA was extracted from paraffin-embedded sections from 221 gastric GIST patients submitted to surgery. Exons 9, 11, 13 and 17 of KIT, exons 12 and 18 of PDGFRA and exons 11 and 15 of BRAF were analyzed by direct sequencing. Cox regression analysis adjusted for clinical-pathological factors was performed to evaluate KIT and PDGFRA mutations in relation to the composite endpoint of relapse or death. RESULTS: KIT and PDGFRA mutations were observed in 119 (53.8%) and 56 (25.3%) patients, respectively, whereas 46 (20.8%) patients had wild type (wt) disease. Univariable analyses showed that a high Miettinen risk category and the presence of ulceration and KIT deletions were associated with increased risk of relapse or death (p < 0.001; p = 0.0389 and p = 0.002, respectively). After adjusting for Miettinen risk score, KIT deletions remained an independent prognostic factor (HRadj = 2.65, 95% CI [1.15-6.13], p = 0.023). Moreover, KIT deletions in exon 11 codons 557, 558 or 559 were associated with a higher risk of relapse or death than wt tumors (HRadj = 3.29 95% CI [1.64-6.64], p = 0.001). CONCLUSIONS: KIT deletions in exon 11, especially those involving codons 557, 558 or 559, were correlated with a more aggressive gastric GIST phenotype and increased risk of relapse or death.

Extended lymphadenectomy in elderly and/or highly co-morbid gastric cancer patients: A retrospective multicenter study.

BACKGROUND: Gastrectomy with extended lymphadenectomy is considered the gold standard treatment for advanced gastric cancer, with no age- or comorbidity-related limitations. We evaluated the safety and efficacy of curative gastrectomy with extended nodal dissection, verifying survival in elderly and highly co-morbid patients. METHODS: In a retrospective multicenter study, we examined 1322 non-metastatic gastric-cancer patients that underwent curative gastrectomy with D2 versus D1 lymphadenectomy from January 2000 to December 2009. Postoperative complications, overall survival (OS), and disease-specific survival (DSS) according to age and the Charlson Comorbidity Score were analyzed in relation to the extent of lymphadenectomy. RESULTS: Postoperative morbidity was 30.4%. Complications were more frequent in highly co-morbid elderly patients, and, although general morbidity rates after D2 and D1 lymphadenectomy were similar (29.9% and 33.2%, respectively), they increased following D2 in highly co-morbid elderly patients (39.6%). D2-lymphadenectomy significantly improved 5-year OS and DSS (48.0% vs. 37.6% in D1, p < 0.001 and 72.6% vs. 58.1% in D1, p < 0.001, respectively) in all patients. In elderly patients, this benefit was present only in 5-year DSS. D2 nodal dissection induced better 5-year OS and DSS rates in elderly patients with positive nodes (29.7% vs. 21.2% in D1, p = 0.008 and 47.5% vs. 30.6% in D1, p = 0.001, respectively), although it was present only in DSS when highly co-morbid elderly patients were considered. CONCLUSION: Extended lymphadenectomy confirmed better survival rates in gastric cancer patients. Due to high postoperative complication rate and no significant improvement of the OS, D1 lymphadenectomy should be considered in elderly and/or highly co-morbid gastric cancer patients.

VEGF-A clinical significance in gastric cancers: immunohistochemical analysis of a wide Italian cohort.

PURPOSE: The clinical significance of VEGF-A expression in gastric cancer (GC) has been reported with contradicting results. We analyzed the expression and clinical significance of VEGF-A in a wide Italian cohort of GC specimens. METHODS: VEGF-A expression was tested by immunohistochemistry in 507 patients with GC of all clinical stages. The impact of VEGF-A on overall survival (OS) was evaluated in conjunction with clinical and pathological parameters. RESULTS: In the Italian cohort we studied VEGF-A was not an independent prognostic factor neither at the univariate nor at multivariate analysis. CONCLUSIONS: Although frequently expressed, in our study VEGF-A was not able to discriminate between groups of patients with different risk.

Validation of the new AJCC TNM staging system for gastric cancer in a large cohort of patients (n = 2,155): focus on the T category.

BACKGROUND: The prognostic value of T subclassification in patients with gastric carcinoma has been just implemented in the new AJCC TNM staging system, which has reclassified T2a and T2b into T2 and T3 tumors, respectively. The aim of the present study was to validate the prognostic significance of the new T categorization within the frame of the latest TNM staging system. METHODS: We retrospectively reviewed the records of 686 T2/T3 patients among 2155 subjects who underwent radical resection for gastric carcinoma at six Italian centers from 1988 through 2006. RESULTS: Upon multivariate analysis, the new T categories, extent of lymph node dissection (D) and patient's age were retained by the survival model as independent prognostic factors. In particular, the death risk for patients with T3 tumors was higher than that of patients with T2 tumors (HR: 1.42, P = 0.005). Among the 686 patients previously classified as having T2 tumors, patients with T2 and T3 disease were 270 (39.4%) and 416 (60.6%), respectively. After a median follow-up of 55 months, the 5-year overall survival rates were 67.3% and 52.3% for patients with T2 and T3 tumors, respectively (P < 0.001). The survival advantage for the T2 as compared to T3 category was maintained even when N0 and N+ patients were separately considered (P = 0.0154 and P < 0.001, respectively). CONCLUSIONS: Our data confirm the prognostic difference between the newly proposed T2 and T3 categories, which should be implemented in the routine clinical practice to improve risk stratification of patients with gastric cancer.

Changing clinical and pathological features of gastric cancer over time.

BACKGROUND: The aim of the present multicentre observational study was to evaluate potential changes in clinical and pathological features of patients with gastric cancer (GC) treated in a 15-year interval. METHODS: A centralized prospective database including clinical, surgical, pathological and follow-up data from 2822 patients who had resection of a primary GC was analysed. The analysis focused on three periods: 1991-1995 (period 1), 1996-2000 (period 2) and 2001-2005 (period 3). Surgical procedure, pathological classification and follow-up were standardized among centres. RESULTS: The number of resections decreased from 1024 in period 1 to 955 and 843 in periods 2 and 3 respectively. More advanced stages and a smaller number of intestinal-type tumours of the distal third were observed over time. Five-year survival rates after R0 resection (2320 patients) did not change over time (overall: 56·6 and 51·2 per cent in periods 1 and 3; disease-free: 66·8 and 61·1 per cent respectively). Decreases in survival in more recent years were related particularly to more advanced stage, distal tumours and tumours in women. Multivariable analysis showed a lower probability of overall and disease-free survival in the most recent interval: hazard ratio 1·22 (95 per cent confidence interval 1·06 to 1·40) and 1·29 (1·06 to 1·58) respectively compared with period 1. Recurrent tumours were more frequently peritoneal rather than locoregional. CONCLUSION: Overall and disease-free survival rates after R0 resection of GC were unchanged over time.

Resection line involvement after gastric cancer surgery: clinical outcome in nonsurgically retreated patients.

PURPOSE: Resection line infiltration (RLI) after surgical treatment represents an unfavorable prognostic factor in advanced gastric cancer. We performed a retrospective analysis of 89 patients with resection line involvement who did not undergo reoperation. METHODS: On behalf of the Italian Research Group for Gastric Cancer, we present the characteristics and outcome of 89 patients who were submitted to surgical resection for gastric cancer from 1988 to 2001 and did not undergo reoperation because of disease extension or associated pathologies. RESULTS: RLI was significantly higher in patients with T4 tumors and diffuse histological type. Anastomotic leakages were observed in 4.8% of infiltrated esophageal resection margins, whereas 1.9% of infiltrated duodenal resection lines showed duodenal fistulas. Five-year overall survival of patients with RLI was 29%. Prognosis was not affected by RLI in early forms (100% 5-year survival); however, 5-year survival in T2 and T3 stages was significantly lower with respect to the same stages without residual tumor. The influence of RLI on prognosis was confirmed in N0 as well as in N1 and N2 patients. RLI also was an independent prognostic at multivariate analysis (odds ratio = 1.5; 95% confidence interval, 1.08-2.08; P = 0.0144). CONCLUSIONS: RLI significantly affects long-term survival of advanced gastric cancer. The impact on prognosis is independent of lymph node involvement. Patients in good general condition for whom radical surgery is possible should be considered for reoperation.

The prognostic value of N-ratio in patients with gastric cancer: validation in a large, multicenter series.

AIMS: The proportion between metastatic and examined lymph nodes (N-ratio) has been proposed as an independent prognostic factor in patients with gastric cancer. In the present work we validated the reliability of N-ratio in a large, multicenter series. PATIENTS AND METHODS: We retrospectively reviewed the data of 1853 patients who underwent radical resection for gastric carcinoma. Survival of patients with >15 (Group-1, n=1421) and those with < or =15 (Group-2, n=432) lymph nodes examined was separately analyzed in order to evaluate the influence of lymph node dissection on disease staging. N-ratio categories (N-ratio 0, 0%; N-ratio 1, 1-9%; N-ratio 2, 10-25%; N-ratio 3, >25%) were determined by the best cut-off approach. RESULTS: At multivariate analysis, N-ratio (but not TNM N-category) was retained as an independent prognostic factor both in Group-1 and Group-2 (HR for N-ratio 1, N-ratio 2 and N-ratio 3=1.67, 2.96 and 6.59, and 1.56, 2.68 and 4.28, respectively). After a median follow-up of 45.5 months, the 5-year overall survival rates of TNM N0, N1 and N2 patients were significantly different in Group-1 vs Group-2. This was not the case when adopting the N-ratio classification, suggesting that a low number of excised lymph nodes can lead to patients being understaged using the N-category, but not N-ratio. Moreover, N-ratio identified subsets of patients with significantly different survival rates within TNM N1 and N2 categories in both groups. CONCLUSIONS: N-ratio is a simple and reproducible prognostic tool that can stratify patients with gastric cancer, including those cases with limited lymph node dissection. These data support the rationale to propose the implementation of N-ratio into the current TNM staging system.

Prospective study of peritoneal recurrence after curative surgery for gastric cancer.

BACKGROUND: Peritoneal carcinomatosis is a common cause of failure after surgery for gastric cancer. The present longitudinal study was designed to evaluate the incidence and potential predictors of peritoneal recurrence after curative resection for gastric cancer. METHODS: Four hundred and forty-one patients who underwent potentially curative resections for gastric cancer in three surgical centres between 1988 and 1996 were evaluated. All patients were followed using a standard protocol following discharge from hospital. The correlation between tumour recurrence and clinicopathological variables was studied by univariate and multivariate analyses. RESULTS: Gastric cancer recurred in 215 (49 per cent) of 441 patients. Peritoneal recurrence was observed in 77 patients (17 per cent), locoregional recurrence in 96 patients and haematogenous recurrence in 75. Multivariate logistic regression analysis of factors associated with peritoneal recurrence identified diffuse-mixed histological type (relative risk (RR) 4.31, P < 0.001), infiltration of the serosa (RR 3.36, P = 0.001), lymph node involvement (RR 2.67, P = 0.023) and tumour size (RR 1.11, P = 0.050) as significant independent variables. In the diffuse-mixed histological subtype, the 5-year cumulative risk of peritoneal recurrence was 12 per cent in the absence of serosal invasion, and 69 per cent in patients with infiltration of the serosa; in the intestinal subtype, the cumulative risk in patients with serosa-negative and -positive tumours was 4 and 21 per cent respectively. CONCLUSION: Radical surgery offers a low probability of cure in patients with diffuse-mixed type of gastric cancer and involvement of the serosa, due to a high risk of peritoneal recurrence. These patients might benefit from adjuvant therapies to prevent peritoneal carcinomatosis.

[Expression of p27 and proliferative (MIB-1), mitotic (MI) and apoptotic indices in early-phase (EGF) gastric carcinoma. Results of a study by the Italian Gastric Cancer Research Group (IRGGC)]. / Espressione di p27, indici proliferativo (MIB-1), mitotico (MI) e apoptotico (AI) nel carcinoma gastrico in fase iniziale (EGC). Risultati di uno studio del Gruppo Italiano di Ricerca del Cancro Gastrico (IRGGC).

AIMS: Since the Japanese Society for Gastroenterology and Endoscopy (JSGE) introduced the definition of Early Gastric Cancer (EGC), much more and deeper studies were done, which demonstrated that EGC was a more complex phase of the neoplastic disease with different morphologic characteristics, tightly linked to the prognosis. We evaluated the clinical impact of some prognostic factors, known being important in the advanced lesions, in a series of EGC patients with special reference to the clinicomorphological features. METHODS AND RESULTS: We analysed the mitotic (MI) and apoptotic (AI) indices and the immunohistochemical expression of p27 and MIB-1 in 83 EGC cases consecutively recruited in the hospitals of Forlì, Verona, Siena and Milan (IRGGC) in the period 1994-95. The classifications of JSGE, Lauren and Kodama were used to define the macroscopic, microscopic and growth pattern types, respectively. Decreased p27 expression correlated with the macroscopic escavated lesions and diffused mixed histotypes; the increase of MIB-1 detection with tumour size larger than 2 cm, but lesser than 4 cm; MI with intestinal histologic types and AI with mucosal and penetrating lesions, according to Kodama. Statistical analysis showed significative correlations among MIB-1, MI and AI, but not with p27 and the other variables. All these factors did not influence the prognosis of our patients. CONCLUSIONS: In our series, p27, MIB-1, MI, and AI did not add any useful clinical. So, in EGC patients the morphological features have still the most important role in influencing the prognosis and treatment of patients.

Small bowel perforation after incomplete removal of percutaneous endoscopic gastrostomy catheter.

Percutaneous endoscopic gastrostomy (PEG) is a well-established technique for providing long-term nutritional support. The advantages and most frequent complications have been widely documented, but less is known about the danger of removing or replacing a PEG by cutting the device at skin level without endoscopic assistance to ensure the removal of the inner part. Laparotomy is often required in elderly and high-risk patients to relieve an intestinal obstruction or perforation. We describe a fatal case of small bowel perforation, resulting from the inability to remove an inner bumper.

Gastric cancer in young patients with no alarm symptoms: focus on delay in diagnosis, stage of neoplasm and survival.

BACKGROUND: The test and treat strategy for Helicobacter pylori infection has raised some concern since young gastric cancer patients may have no alarm symptoms. In this study the frequency of alarm symptoms was assessed in a series of young gastric cancer patients, as well as the impact of absence of alarm symptoms on delay in diagnosis and stage of gastric cancer at diagnosis and survival. METHODS: A retrospective study was carried out on 92 gastric cancer patients < or = 45 years of age identified from databases in four hospitals between January 1985 and December 2001. Characteristics analysed included duration and features of dyspeptic symptoms, presence of alarm symptoms, time interval from the onset of symptoms to diagnosis, pTNM stage and survival. RESULTS: Of the 92 patients, 54 (58.7%) presented uncomplicated dyspepsia and 38 (41.3%) alarm symptoms. In those with uncomplicated dyspepsia, epigastric pain was the most common complaint (64.1%) followed by vomiting (30.4%), heartburn and nausea. Weight loss was the most common alarm symptom (30.4%), followed by anorexia (10.9%), dysphagia or anaemia (7.6%). The mean delay from first symptoms to final diagnosis was 16.8 +/- 13.9 weeks in patients with alarm symptoms and 29.3 +/- 39.9 weeks in patients without alarm symptoms (P:ns). Patients without alarm symptoms showed significantly less aggressive gastric cancer compared to patients with alarm symptoms in relation to TNM stage and survival (cumulative 5-year survival rate: 76% versus 49% P: 0.01). The survival rate, at 5 years, of patients without alarm symptoms, and with a history of dyspepsia of more than 24 weeks, was higher than that in patients with early diagnosis (93.4% versus 66.5%: P: 0.05). CONCLUSIONS: A large proportion of young gastric cancer patients present without alarm symptoms. Despite the delay in diagnosis, these patients have a better outcome than those with alarm symptoms. Thus the delay in diagnosis of patients without alarm symptoms does not affect survival.

The new TNM classification of lymph node metastasis minimises stage migration problems in gastric cancer patients.

The present study aimed at investigating whether in gastric cancer patients stage migration occurs with extension of lymphadenectomy, when node metastases are staged according to the new pN classification (UICC 1997). The investigation involved 921 patients, who underwent R0 gastric resection for gastric cancer between 1988 and 1998 in three different Italian centres: Verona (n=236), Forlì (n=409), Siena (n=276). The relation among lymphadenectomy and pN category was assessed by Kendall's partial rank-order correlation coefficient, controlling for depth of tumour invasion. A direct evaluation of the Will Rogers phenomenon was accomplished in the Verona series, by comparing the number of positive nodes actually observed with the number of positive nodes which would have been retrieved by a less extended lymphadenectomy (D1). The number of positive nodes increased remarkably with the enlargement of lymphadenectomy, especially in pT2 patients (from 2.2+/-3.9 in D1 to 3.9+/-5.0 in D3) and in pT3/pT4 patients (from 5.1+/-5.9 in D1 to 11.3+/-12.6 in D3). Non-parametric statistics highlighted a weak (Kendall's partial T=0.128) but significant (P<0.001) correlation between pN category and extension of lymphadenectomy. In the direct analysis of the Verona series, 22 patients out of 230 (9.6%) migrated to a lower pN tier when ignoring positive nodes retrieved from the second and third level. This percentage increased to 39.1% (90 out of 230) when adopting the TNM 87 classification. In conclusion stage migration is of minor importance in gastric cancer patients, staged according to the new pN classification.

Risk factors for lymph node metastases and their prognostic significance in early gastric cancer (EGC) for the Italian Research Group for Gastric Cancer (IRGGC).

BACKGROUND: Lymph node metastases are present in only about 15% of patients with early gastric cancer (EGC) and for this reason, the majority of these patients do not require lymphadenectomy. In Japan, EGC patients undergo less invasive treatment (endoscopic mucosal resection, wedge resection, laparoscopy). However, the indications for and results of these types of treatment are still uncertain. METHODS: In a multicentre retrospective study, we analysed the clinicopathological data referring to 584 early gastric cancer patients who underwent D2 gastrectomy. A comparison was made between patients with and without lymph node metastases in relation to numerous pre- and postoperative variables. Long-term survival and risk factors for lymph node metastases were analysed. The primary aim was to compare our results with those of Western and Japanese authors; we also evaluated the possibility of identifying a subset of patients at low risk of lymph node metastases who may be candidates for endoscopic treatment. RESULTS: The incidence of lymph node metastasis was 14.4%. Univariate and multivariate analyses showed that submucosal infiltration, diffuse histotype, tumour size and Kodama Pen A type were all related to the presence of lymph node metastases. Patients with types I, IIa and IIb mucosal tumours did not present lymph node metastases. Postoperative mortality was 2.2%. Five-year survival in relation to lymph node groups was 95% in N0 patients, 77% in N1 patients and 60% in N2 patients (p = 0.0001, Japanese N-stage). The number of positive lymph nodes also had a prognostic value. Patients with three or fewer positive lymph nodes presented a better 5-year prognosis (83%) than those with more than three positive lymph nodes (48%) (p = 0.0001). CONCLUSIONS: Our study confirms that lymph node involvement is an extremely important prognostic factor. For this reason, the therapeutic strategy of our surgical units is as follows: 1) D2 gastrectomy is the standard treatment even in early gastric cancer (EGC); 2) endoscopic mucosal resection (EMR) could be considered first in types I, IIa and IIb tumours that are diagnosed as limited to the mucosal layer.

[Influence of histologic type on prognosis of patients undergoing curative intervention for gastric adenocarcinoma. Italian multicenter study]. / Influenza del tipo istologico sulla prognosi dei pazienti sottoposti ad intervento curativo per adenocarcinoma gastrico. Studio multicentrico italiano.

BACKGROUND: The prognostic significance of the histological type in gastric cancer is still debated. The correlation between intestinal-diffuse type and tumor recurrence was investigated in a prospective multicentric study which collects the cases from three surgical Departments of Italy. PATIENTS AND METHODS: Four-hundred and twelve patients who underwent a potentially curative resection between 1988 and 1995 were considered; 273 cases were classified as intestinal type (group A), and 139 cases as diffuse type (group B). Mixed cases were excluded from the study. All patients were included in a complete follow-up program for the early diagnosis of recurrence. Clinical, histopathological and surgical factors were examined for their influence on tumor recurrence by univariate and multivariate analysis. RESULTS: Recurrence rate was 41.4% in intestinal type, and 65.5% in diffuse type cases (p < 0.0001). In group A, multivariate analysis identified nodal status (p < 0.0001), depth of invasion (p < 0.005), lymph node dissection (D1 vs. D2-D4, p < 0.01), advanced age (p < 0.01) and male sex (p < 0.05) as significant prognostic factors. In group B, depth of invasion (p < 0.0005), lymph node dissection (p < 0.005), tumor size (p < 0.01) and nodal status (p < 0.05) resulted as significant variables; no preventive effect on tumor recurrence was found for D2 vs. D1 lymphadenectomy. Multivariate analysis performed on the totality of the cases demonstrated diffuse type as an independent predictor of poor prognosis (relative risk: 1.67, p < 0.001). CONCLUSIONS: Diffuse type of gastric cancer is an independent risk factor for tumor recurrence as compared with intestinal type; clinical and pathological variables play a different role as prognostic factors in the two histotypes.

Lymph node micrometastases in patients with early gastric cancer: experience with 139 patients.

BACKGROUND: Although lymph node metastases in patients with early gastric cancer (EGC) is an important prognostic factor, the prognostic relevance of lymph node micrometastases is still uncertain. METHODS: The authors studied 1488 lymph nodes, which were histologically confirmed as pN0, dissected from 139 patients who were treated for EGC between 1976-1994. Micrometastases were defined as a single or small cluster of neoplastic cells identifiable only by immunohistochemical methods. RESULTS: Lymph node micrometastases was observed in 24 of the 139 patients (17%). No significant correlation was observed between micrometastases and other clinicopathological characteristics. Analysis of overall survival showed no significant difference between the micrometastases positive and negative groups. CONCLUSION: The results of our study show that the presence of lymph node micrometastases in EGC does not have an influence on patient prognosis.

Identification of occult micrometastases in patients with early gastric cancer using anti-cytokeratin monoclonal antibodies.

The presence of occult micrometastases was evaluated in 1488 lymph nodes removed from 139 patients with node-negative early gastric cancer (EGC). Additional multiple levels of the lymph nodes were examined with haematoxylin-eosin staining and keratin immunostaining. Occult nodal micrometastases were detected in 24 patients (17%) in one or more lymph nodes dissected after a gastrectomy. The cases investigated were a small group from a total of 412 EGC patients who underwent surgical treatment in our hospital between 1976 and 1997; the mean follow-up period was 9 years (range 1-22). We found no significant differences between cytokeratin-negative and positive patients regarding the following clinicopathological parameters: age, gender, tumour size and site, macroscopic and microscopic type, depth of invasion and type of infiltration, according to Kodama's classification. The survival rate at 5 years was 88% and 87% for cytokeratin-negative and positive patients, respectively (log-rank = 0.6; ns). Our data suggest that occult micrometastases do not add useful information and immunohistochemical studies to detect them are probably unnecessary.

[Respiratory function tests as a predictive indicator of postoperative course in patients undergoing pneumonectomy because of neoplasms]. / Le prove di funzionalità respiratoria come indice predittivo del decorso postoperatorio nei pazienti pneumonectomizzati per neoplasia.

Postoperative morbidity and mortality were correlated with the preoperative results of three widely used pulmonary function tests (FVC, FEV1, FEV1/FVC) in 100 consecutive patients who underwent pneumonectomy for lung carcinoma. Factor analyzed following operation included thirty-day mortality, incidence of cardiovascular and respiratory complications, number of individuals requiring prolonged mechanical ventilation. Nineteen patients had a forced vital capacity (FVC) of 70% or less of the normal value, seven had a one-second forced expiratory volume (FEV1) of 1.5 liters or less, and thirty-three had a FEV1 of less than 2 liters. Fourteen patients had a FEV1/FVC ratio of 65% or less. There were no differences in morbidity or mortality between these patients and those presenting higher test scores. As a general rule, decisions regarding operability and extent of resection cannot be made solely on the basis of the three spirometry tests reviewed.