Prognostic factors for survival in patients with pT1 N+ or T2-3 N0 gastric cancer in Japan.

BACKGROUND: The outcome for pT1 N+ or pT2-3 N0 gastric cancer is favourable, but some patients suffer from recurrent disease. The aim of this study was to identify prognostic factors in patients with pT1 N+ or pT2-3 N0 gastric cancer. METHODS: This was a multicentre, retrospective cohort study. All patients with pT1 N+ or pT2-3 N0 gastric cancer who underwent curative gastrectomy at five high-volume, specialized cancer centres in Japan between 2000 and 2008 were included. Demographic, clinical, surgical and pathological data were collected. Independent prognostic factors were identified using a Cox proportional hazards regression model. RESULTS: Some 1442 patients were included. The 5-year overall survival rate for patients with pT1 N+ or pT2-3 N0 gastric cancer was 92·0 per cent. Multivariable analysis for overall survival identified age (hazard ratio (HR) 2·67, 95 per cent c.i. 2·09 to 3·43), sex (HR 0·57, 0·39 to 0·83) and clinical tumour depth (cT) (HR 1·45, 1·06 to 1·98) as independent prognostic factors. CONCLUSION: Survival of patients with pT1 N+ or pT2-3 N0 gastric cancer is good. Age 65 years or above, male sex and cT2-4 category are associated with worse overall survival.

The clinical significance of para-aortic nodal dissection for advanced gastric cancer.

BACKGROUND: Advanced gastric cancer with the risk of extensive nodal involvement has a poor prognosis even after radical surgery. We aimed to comprehensively review the clinical significance of extended radical dissection. METHODS: Between 1990 and 1999, 232 patients underwent radical gastrectomy with D2 plus para-aortic lymph node dissection at the National Cancer Center Hospital in Tokyo. We analyzed the short-term surgical and long-term oncological outcomes of these operations. RESULTS: Major complications occurred in 34 patients (14.7%). Median operation time was 325 min (range: 182-555) and median blood loss was 715 ml (range: 95-4457). There were 2 (0.9%) hospital deaths. Nodal involvement of the para-aortic area was seen in 33 patients (14.2%). The overall 5- and 10-year survival rates in patients with para-aortic node involvement were 21.2 and 15.2%, respectively. Multivariate analysis of patients with para-aortic node involvement revealed advanced age and metastasis in the interaorticocaval lymph nodes above the left renal vein to be independent risk factors impacting overall survival. CONCLUSIONS: PAN dissection has limited applicability and effectiveness to the patients with advanced gastric cancer. Above all, advanced age and metastasis in the interaorticocaval lymph nodes above the left renal vein are significant poor prognostic factor even after radical resection.

Integrated genomic and functional analyses reveal glyoxalase I as a novel metabolic oncogene in human gastric cancer.

Chromosomal abnormalities are good guideposts when hunting for cancer-related genes. We analyzed copy number alterations of 163 primary gastric cancers using array-based comparative genomic hybridization and simultaneously performed a genome-wide integrated analysis of copy number and gene expression using microarray data for 58 tumors. We showed that chromosome 6p21 amplification frequently occurred secondary to ERBB2 amplification, was associated with poorer prognosis and caused overexpression of half of the genes mapped. A comprehensive small interfering RNA knockdown of 58 genes overexpressed in tumors identified 32 genes that reduced gastric cancer cell growth. Enforced expression of 16 of these genes promoted cell growth in vitro, and six genes showing more than two-fold activity conferred tumor-forming ability in vivo. Among these six candidates, GLO1, encoding a detoxifying enzyme glyoxalase I (GLO1), exhibited the strongest tumor-forming activity. Coexpression of other genes with GLO1 enhanced growth-stimulating activity. A GLO1 inhibitor, S-p-bromobenzyl glutathione cyclopentyl diester, inhibited the growth of two-thirds of 24 gastric cancer cell lines examined. The efficacy was found to be associated with the mRNA expression ratio of GLO1 to GLO2, encoding glyoxalase II (GLO2), another constituent of the glyoxalase system. GLO1 downregulation affected cell growth through inactivating central carbon metabolism and reduced the transcriptional activities of nuclear factor kappa B and activator protein-1. Our study demonstrates that GLO1 is a novel metabolic oncogene of the 6p21 amplicon, which promotes tumor growth and aberrant transcriptional signals via regulating cellular metabolic activities for energy production and could be a potential therapeutic target in gastric cancer.

Development and external validation of a nomogram for overall survival after curative resection in serosa-negative, locally advanced gastric cancer.

BACKGROUND: Few nomograms can predict overall survival (OS) after curative resection of advanced gastric cancer (AGC), and these nomograms were developed using data from only a few large centers over a long time period. The aim of this study was to develop and externally validate an elaborative nomogram that predicts 5-year OS after curative resection for serosa-negative, locally AGC using a large amount of data from multiple centers in Japan over a short time period (2001-2003). PATIENTS AND METHODS: Of 39 859 patients who underwent surgery for gastric cancer between 2001 and 2003 at multiple centers in Japan, we retrospectively analyzed 5196 patients with serosa-negative AGC who underwent Resection A according to the 13th Japanese Classification of Gastric Carcinoma. The data of 3085 patients who underwent surgery from 2001 to 2002 were used as a training set for the construction of a nomogram and Web software. The data of 2111 patients who underwent surgery in 2003 were used as an external validation set. RESULTS: Age at operation, gender, tumor size and location, macroscopic type, histological type, depth of invasion, number of positive and examined lymph nodes, and lymphovascular invasion, but not the extent of lymphadenectomy, were associated with OS. Discrimination of the developed nomogram was superior to that of the TNM classification (concordance indices of 0.68 versus 0.61; P < 0.001). Moreover, calibration was accurate. CONCLUSIONS: We have developed and externally validated an elaborative nomogram that predicts the 5-year OS of postoperative serosa-negative AGC. This nomogram would be helpful in the assessment of individual risks and in the consideration of additional therapy in clinical practice, and we have created freely available Web software to more easily and quickly predict OS and to draw a survival curve for these purposes.

Surgical treatment of gastric cancer in Japan, trend from standardization to individualization.

Japan has a huge number of patients with gastric cancer and has developed various surgical treatments for this disease.This paper intends to introduce our strategies against gastric cancer. The Japanese Gastric Cancer Association was established in 1962. Its major purposes are promotion of basic and clinical researches and popularization of the latest knowledge and technologies. For the purposes, the association organized the annual scientific meeting and the nationwide registry by member hospitals, and published the Japanese Classification of Gastric Cancer (1) and the Treatment Guide Line (2). The nationwide registry reported that proportion of Stage-I cancer was 22.5% in 1963-66,which increased to 59.3% in 2008 (3,4,5). 11,261 patients with gastric resection were registered by 187 hospitals in 2008. 63 patients were died within 30 postoperative days and the direct death rate was 0.55%. 5 year survival rate (5YSR) was 37.5% for resected cases in 1963-66, which was improved to 70.1% in 2008. 5YSR was improved from 55.1% to 74.1% for Stage-II, and from 39.1% to 48.8% for Stage-III in the period. According to remarkable increase of early stage cancer, principle of surgical treatments was shifted from "€œextended and standardized surgery for radicality" €to "€œreasonable and individual surgery considering safety and quality of life"€. This trend produced a large variation in surgical treatments; namely 1) minimally invasive surgeries,2) function preserving surgeries, 3) optimal extent of lymph node dissection, and 4) aggressive but safe surgeries.Intention of this paper is to explain these procedures, the intentions, the indications, and the treatment results.

Feasibility study of adjuvant chemotherapy with S-1 plus cisplatin for gastric cancer.

PURPOSE: To evaluate the feasibility of S-1 plus cisplatin as adjuvant chemotherapy for stage III gastric cancer after curative resection. METHODS: Japanese patients with stage III gastric cancer who underwent gastrectomy with D2 lymph node resection were enrolled. Treatment consisted of 3 cycles of S-1 (80 mg/m(2)/day, b.i.d.) for 21 days followed by a 14-day rest, and cisplatin (60 mg/m(2) iv) on day 8. After that, S-1 monotherapy was given on days 1-28 every 6 weeks until 1-year postsurgery. After protocol amendment, the first chemotherapy cycle consisted of S-1 monotherapy; cisplatin was added to cycles 2, 3, and 4, followed by S-1 monotherapy up to 1-year postsurgery. The primary endpoint was the completion rate of three cycles of S-1 plus cisplatin. RESULTS: A total of 63 enrolled patients have been evaluated. Grade 3/4 toxicities included neutropenia (40%), anorexia (28%), and febrile neutropenia (4%) before protocol amendment (n = 25), and neutropenia (37%), anorexia (8%), and febrile neutropenia (3%) after amendment implementation (n = 38). Excluding ineligible cases, treatment completion rates were 57% (12/21) before and 81% (30/37) after the protocol amendment. CONCLUSIONS: The amended S-1 plus cisplatin is more feasible than the original protocol because of early dose reduction of S-1 prior to cisplatin addition and greater recovery time from surgery prior to cisplatin. This treatment should be considered as a feasible experimental arm for the next postoperative adjuvant phase III trial.

Long-term results of gastrectomy for alpha-fetoprotein-producing gastric cancer.

BACKGROUND: alpha-Fetoprotein (AFP)-producing gastric cancer is a rare tumour. It is said to have a high incidence of liver metastasis and poor prognosis. This study sought to evaluate long-term outcomes in such patients. METHODS: Records of consecutive patients with gastric carcinoma who underwent preoperative measurement of serum AFP levels and gastrectomy were reviewed to identify those who satisfied the following criteria: preoperative AFP level exceeding 40 ng/ml with a decrease after gastrectomy, or raised preoperative AFP level (10-39 ng/ml) and resected tumour showing histologically characteristic features or immunohistochemically positive AFP production. RESULTS: Of 3374 patients with gastric cancer, 53 (1.6 per cent) met the selection criteria. Tumours were characterized by a high incidence of nodal (79 per cent) or liver (53 per cent) metastasis. Preoperative serum AFP levels showed no correlation with tumour size, depth of invasion, disease stage or survival. The 5-year survival rate was 34 per cent. Five patients survived after recurrence following multimodal treatment. A rising AFP level during follow-up always led to tumour recurrence, but the level remained normal in 11 of 31 patients with recurrence. CONCLUSION: AFP-producing tumours represent a small subgroup of gastric cancer with high metastatic potential. Postoperative serum AFP level can help predict recurrence but a normal level does not mean absence of recurrence. Prognosis is not as poor as previously thought, and multimodal treatment may be worthwhile even in patients with recurrent tumour.

Long-term outcome after proximal gastrectomy with jejunal interposition for suspected early cancer in the upper third of the stomach.

BACKGROUND: Proximal gastrectomy was introduced as a function-preserving operation for early gastric cancer (EGC). The aim of this study was to investigate long-term outcomes after this procedure. METHODS: Between 1993 and 2005, patients with suspected EGC in the upper third of the stomach underwent proximal gastrectomy. The long-term oncological and surgical outcomes were assessed. RESULTS: Of 128 patients thought to have EGC, 14 had advanced disease. Nodal involvement was seen in 13 patients (10.2 per cent). Postoperative complications developed in 20 (15.6 per cent). Anastomotic stricture was the most frequent complication, occurring in 13 patients (10.2 per cent). There were no postoperative deaths. During follow-up, nine patients (7.0 per cent) were hospitalized owing to bowel obstruction. Eight (6.3 per cent) developed a second primary gastric carcinoma. The overall 5-year survival rate was 90.5 per cent. CONCLUSION: Proximal gastrectomy is well tolerated, with excellent outcomes in patients with suspected EGC. It is recommended as a standard procedure for the treatment of EGC in the upper third of the stomach.

The prognostic impact of isolated tumor cells in lymph nodes of T2N0 gastric cancer: comparison of American and Japanese gastric cancer patients.

BACKGROUND: The clinical significance of immunohistochemically detected isolated tumor cells (ITC) in lymph nodes of gastric cancer patients is controversial. This study examined the prognostic impact of ITC on patients with early-stage gastric cancer in two large volume centers in the United States and Japan. METHODS: Fifty-seven patients with T2N0M0 gastric carcinoma who underwent gastric resection between January 1987 and January 1997 at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York and 107 patients resected at National Cancer Center Hospital (NCCH) in Tokyo between January 1984 and December 1990 were studied. The sections were newly prepared from each lymph node for immunohistochemical staining for cytokeratin. Lymph nodes and original specimens from MSKCC were examined by pathologists in NCCH. The prognostic significance of the presence of ITC in lymph nodes was investigated in patients of both institutions. RESULTS: ITC were identified in 30 of 57 patients (52.6%) at MSKCC and in 38 of 107 patients (35.5%) at NCCH. In both institutions, there was no significant difference in the prognosis of the studied patients with or without ITC (P= .22, .86 respectively). CONCLUSIONS: The presence of ITC detected by immunohistochemistry in the regional lymph nodes did not affect the prognosis of American and Japanese patients with T2N0M0 gastric carcinoma who underwent gastrectomy with D2 lymph node dissection.

Treatment strategy after non-curative endoscopic resection of early gastric cancer.

BACKGROUND: Endoscopic resection (ER) is indicated for patients with early gastric cancer who have a negligible risk of lymph node metastasis (LNM). Histological examination of the resected specimen may indicate a possible risk of LNM or a positive resection margin. These patients are considered to have undergone non-curative ER. The aim of this study was to determine the appropriate treatment strategy for such patients. METHODS: A total of 298 patients who had non-curative ER were classified into those with a positive lateral margin only (group 1; 72 patients) and those with a possible risk of LNM (group 2; 226 patients). RESULTS: Surgery was performed within 6 months of non-curative ER in 19 patients in group 1 and 144 in group 2. In group 1, nine patients were found to have local residual tumours, all limited to the mucosal layer without LNM. In Group 2, 13 patients had residual disease, including four local tumours without LNM, two local tumours with LNM and seven cases of LNM alone. The rate of LNM after surgery was 6.3 per cent in group 2. CONCLUSION: Surgery remains the standard treatment after non-curative ER in patients with a possible risk of LNM.

Outcome of pylorus-preserving gastrectomy for early gastric cancer.

BACKGROUND: Pylorus-preserving gastrectomy has been introduced as a function-preserving operation for early gastric cancer in Japan. The aim of this study was to investigate the safety and radicality of the procedure. METHODS: Between 1995 and 2004, 611 patients with apparent early gastric cancer in the middle third of the stomach had pylorus-preserving gastrectomy. The short-term surgical and long-term oncological outcomes of these operations were assessed. RESULTS: The accuracy of preoperative diagnosis of early gastric cancer was 94.3 per cent. Nodal involvement was seen in 62 patients (10.1 per cent). There were no postoperative deaths. Complications developed in 102 patients (16.7 per cent). Major complications, such as leakage and abscess, were observed in 19 (3.1 per cent). The most common complication was gastric stasis, occurring in 49 (8.0 per cent). The overall 5-year survival rate in patients with early gastric cancer was 96.3 per cent. CONCLUSION: Pylorus-preserving gastrectomy is a safe operation with an excellent prognosis in patients with early gastric cancer. It is recommended as the standard procedure for early gastric cancer in the middle third of the stomach.

Identification of the high-risk group for metastasis of gastric cancer cases by vascular endothelial growth factor receptor-1 overexpression in peripheral blood.

Identification of an isolated tumour cell with metastatic ability is important for predicting the recurrence and prognosis of gastric cancer. A biological marker for evaluating the metastatic ability of gastric cancer cells has not yet been identified. We assessed vascular endothelial growth factor receptor-1 mRNA expression by quantitative real-time reverse transcriptase-polymerase chain reaction. Vascular endothelial growth factor receptor-1 mRNA in peripheral blood was more highly expressed in perioperative metastasis-positive and postoperative recurrence cases than in normal control cases, early cancer cases and nonmetastatic advanced cancer cases. The peripheral blood vascular endothelial growth factor receptor-1 mRNA-positive group was associated with advanced clinical stage, deep invasion beyond the muscularis propria, lymphatic involvement, vascular involvement, lymph node metastasis, positive peritoneal lavage cytology, preoperative metastasis and postoperative recurrence. Flow cytometry analysis disclosed that vascular endothelial growth factor receptor-1 expressing cells in the peripheral blood were more abundant in cancer cases with metastases than in cases without metastases. Our data suggest that the amount of positive cells may provide information on the clinical features of gastric cancer, especially in regard to gastric cancer metastasis.

Surgical treatment of advanced gastric cancer: Japanese perspective.

The results of clinical trials regarding surgery of curable advanced gastric cancer and esophagogastric junction (EGJ) tumors are reviewed and summarized. Four clinical trials have evaluated D2 dissection for curable gastric cancer in the West. Two large trials in the UK and the Netherlands failed to prove the efficacy of D2 dissection. However, these trials had critical weak points. As they were carried out in a number of hospitals where there was no experience with this surgery, the quality of surgery and postoperative care were very poor making the hospital mortality unacceptably high. After these trials, an Italian group started a phase II study in 8 hospitals with a relatively high volume to confirm the safety of this procedure for Caucasians. They achieved 3% mortality, which was much smaller than that of even D1 in the former trials. These results first highlighted the importance of learning and hospital volume in D2 dissection. Survival results of the Dutch trial showed some difference between D1 and D2, but the difference was not statistically significant. This was attributed to the high hospital mortality and poor quality of surgery, especially low compliance of D2 and the high rate of extension of D1, making this comparison similar to that between D1.3 and D1.7. The results of the phase III study by the Italian group are awaited. Recently a Taiwanese trial proved the benefit of D2 dissection over D1 in a phase III trial. This was a single institutional trial with a sample size of 221 patients. The 5-year survival rate of D2 and D1 was 59.5 and 53.6%, respectively (p = 0.04). The Dutch trials for EGJ tumors showed a large difference in overall survival between the transthoracic and transhiatal approach for Siewert type 1 and 2 tumors, but this was not statistically significant, most likely due to the small sample size. In the subgroup analysis, they demonstrated that there was no survival difference in Siewert type 2 but a large difference in Siewert type 1. A Japanese study showed that there is no benefit to the thoraco-abdominal approach over the transhiatal approach for EGJ tumors whose invasion in the esophagus is 3 cm or less. These two trials clearly demonstrated that mediastinal dissection through a right thoracotomy is recommendable for Siewert type 1, while the transhiatal approach should be considered as standard for Siewert type 2.

Cancer of the gastric stump following distal gastrectomy for cancer.

BACKGROUND: Cancer of the gastric stump (CGS) after distal gastrectomy for cancer has not been characterized in a large study. The aim of this study was to investigate the clinicopathological features and outcome of CGS following distal gastrectomy for cancer. METHODS: Patients with CGS following distal gastrectomy for gastric cancer diagnosed between 1970 and 2002 were reviewed retrospectively. RESULTS: A total of 108 patients was identified. The median interval between the initial gastrectomy and resection for CGS was 7.5 (range 1-41) years. The depth of tumour invasion was T1 in 67 patients, T2 in 16, T3 in eight and T4 in 17 patients. Endoscopic mucosal resection was performed in 25 patients with T1 tumours. R0 resection was achieved in 103 patients. The overall 5-year survival rate was 53.1 per cent. The 5-year survival rates for patients with T1, T2, T3 and T4 disease were 76, 40, 13 and 9 per cent respectively. CONCLUSION: The outcome for patients with non-early CGS was poor. Early detection of CGS is important following distal gastrectomy for gastric cancer and strict surveillance is recommended for at least 10 years after the initial gastrectomy.

Extranodal metastasis is an indicator of poor prognosis in patients with gastric carcinoma.

BACKGROUND: The aim of this study was to determine the clinical significance and prognostic impact of extranodal metastasis (EM) in gastric carcinoma. METHODS: The study included 1023 patients who underwent gastrectomy with lymphadenectomy for primary gastric carcinoma between January 1993 and December 1996. EM was defined as the presence of tumour cells in extramural soft tissue that was discontinuous with either the primary lesion or locoregional lymph nodes. RESULTS: EM was detected in 146 (14.3 per cent) of the 1023 patients and in 1060 (3.0 per cent) of the 35 811 nodules that were retrieved as 'lymph nodes' from adipose connective tissues. The incidence of EM was significantly higher in patients with tumours that were large (diameter 10 cm or more), infiltrative, deeply invading or undifferentiated and in those with lymph node, peritoneal or liver metastases, or lymphatic or vascular involvement. After curative operation overall survival was significantly worse for patients with EM than those without (P < 0.001). Multivariate analysis identified EM as an independent prognostic factor (hazard ratio 1.82 (95 per cent confidence interval 1.23 to 2.71); P = 0.003). CONCLUSION: EM is an independent prognostic factor and should therefore be included in the tumour node metastasis (TNM) staging system.

Prospective study of proximal gastrectomy for early gastric cancer in the upper third of the stomach.

BACKGROUND: Total gastrectomy with D2 dissection is the standard treatment in Japan for early upper-third gastric cancer. The purpose of this study was to confirm the safety and radicality of proximal gastrectomy as an alternative operation. METHODS: Between 1993 and 1999, 45 patients with an apparent primary early gastric cancer in the upper third of the stomach were treated by proximal gastrectomy with jejunal interposition. The spleen was preserved, but the suprapancreatic nodes were cleared. RESULTS: Histology confirmed early gastric cancer in 37 patients while eight had advanced disease. Nodal metastasis was observed in six patients. There was no hospital death and no early postoperative complications. One patient died from nodal recurrence and two from unrelated causes. Two patients had reflux symptoms without endoscopic oesophagitis. Mean weight loss was 11.5 per cent of initial bodyweight. CONCLUSION: Proximal gastrectomy for early upper-third gastric cancer can be performed safely with an excellent cure rate. This procedure deserves further clinical evaluation to assess patients' quality of life.