Gastrectomy with or without omentectomy for cT3-4 gastric cancer: a multicentre cohort study.

BACKGROUND: Omentectomy is performed widely for locally advanced gastric cancer to prevent disease recurrence. However, its clinical benefit is unknown. METHODS: This retrospective cohort study compared the outcome of gastrectomy with preservation of the omentum (GPO) and gastrectomy with resection of the omentum (GRO) among patients with cT3-T4 gastric cancer who underwent gastrectomy between 2006 and 2012 in one of five participating institutions. A consensus conference identified 28 variables potentially associated with outcome after gastrectomy for the estimation of propensity scores, and propensity score matching (PSM) was undertaken to control for possible confounders. Postoperative surgical outcomes, overall survival and disease recurrence were compared between GPO and GRO. RESULTS: A total of 1758 patients were identified, of whom 526 remained after PSM, 263 in each group. Median follow-up was 4·9 (i.q.r. 3·1-5·9) years in the GRO group and 5·0 (2·5-6·8) years in the GPO group. The incidence of postoperative complications of Clavien-Dindo grade III or more was significantly higher in the GRO group (17·5 versus 10·3 per cent; P = 0·016). Five-year overall survival rates were 77·1 per cent in the GRO group and 79·4 per cent in the GPO group (P = 0·749). There were no significant differences in recurrence rate or pattern of recurrence between the groups. CONCLUSION: Overall survival and disease recurrence were comparable in patients with cT3-4 gastric cancer who underwent GPO or GRO.

ANTECEDENTES: La omentectomía se realiza ampliamente en el cáncer gástrico localmente avanzado para prevenir la recidiva de la enfermedad. Sin embargo, se desconoce su beneficio clínico. MÉTODOS: Este estudio retrospectivo comparó el resultado de la gastrectomía con preservación del omento (gastrectomy with preservation of the omentum, GPO) con la gastrectomía con resección del omento (gastrectomy with resection of the omentum, GRO) para el cáncer gástrico con estadio clínico T3/T4. Se incluyeron pacientes sometidos a gastrectomía por cáncer gástrico clínico T3/T4 (2006-2012) y se recogieron datos relevantes de 5 hospitales participantes. A través de una conferencia de consenso se identificaron 28 variables potencialmente asociadas con el resultado tras la gastrectomía, mediante las cuales se estimaron las puntuaciones de propensión, utilizándose el emparejamiento por puntuación de propensión (propensity score matching, PSM) para el control de posibles factores de confusión. Los resultados quirúrgicos postoperatorios, la supervivencia global y la recidiva de la enfermedad se compararon entre las gastrectomías con GPO y GRO. RESULTADOS: En total, se identificaron 1.758 pacientes, seleccionándose 526 (263 GRO y 263 GPO) tras el PSM. La mediana (rango intercuartílico) de seguimiento fue de 4,9 años (3,1-5,9) en el grupo GRO y de 5,0 años (2,5-6,8) en el grupo GPO. La incidencia de complicaciones postoperatorias de Clavien-Dindo grado III o más alto fue significativamente más elevada en el grupo GRO que en el grupo GPO (17,1% versus 9,1%; P = 0,010). La supervivencia global a los 5 años fue del 77,1% para el grupo GRO y del 79,4% para el grupo GPO (P = 0,749). No hubo diferencias estadísticamente significativas en la tasa de recidiva o patrón de recidiva entre ambos grupos. CONCLUSIÓN: La supervivencia global y la recidiva de la enfermedad son comparables en pacientes con cáncer gástrico estadio clínico T3-4 sometidos a GPO o GRO.

Molecular Biomarker Study in a Randomised Phase III Trial of Irinotecan Plus S-1 versus S-1 for Advanced Gastric Cancer (GC0301/TOP-002).

AIMS: Gastric cancer is a common and heterogeneous disease; however, global standard and biomarkers for selecting chemotherapy regimens have not been established. This study was designed retrospectively to identify molecular biomarkers for irinotecan plus S-1 (IRI-S) and S-1 therapy from subset analyses in GC0301/TOP-002, a randomised phase III trial for advanced gastric cancer. MATERIALS AND METHODS: Paraffin-embedded primary tumour specimens were collected from 126 of 326 randomised patients in GC0301/TOP-002. The mRNA was measured for thymidylate synthase, dihydropyrimidine dehydrogenase, topoisomerase I, excision repair cross-complementing gene 1 (ERCC1) and thymidine phosphorylase; categorised into low and high to analyse their association with efficacy end points. RESULTS: There was no significant difference in each mRNA between S-1 and IRI-S groups, whereas there were differences among some clinical characteristics. Multivariate analyses for overall survival showed that mRNA levels were not correlated with prognosis. By comparison, between IRI-S and S-1 arms, low thymidylate synthase, low ERCC1 and high thymidine phosphorylase were associated with better prognosis for IRI-S versus S-1 (hazard ratio = 0.653, 0.702 and 0.709, respectively; P < 0.15 for each interaction). CONCLUSION: Low thymidylate synthase, low ERCC1 and high thymidine phosphorylase are candidates for predictive biomarkers for first-line treatment in advanced gastric cancer by IRI-S. Further study is warranted to confirm these results in other clinical trials and cohort studies.

[A case of remnant gastric cancer responding to neoadjuvant TS-1 therapy].

We report the case a 77-year-old male with remnant gastric cancer successfully treated with TS-1 as neoadjuvant chemotherapy. His treatment was daily oral administration of 100 mg TS-1 for 28 days. This therapy was safely carried out on an outpatient basis. The histological diagnosis of the resected stomach revealed complete disappearance of cancer cells in the stomach and the regional lymph nodes. This case suggests that TS-1 may have a potent therapeutic effect in neoadjuvant chemotherapy for recurrent gastric cancer.

[A patient with obstructive jaundice due to recurrence after gastric cancer surgery responding remarkably to FLP combination therapy].

The patient was a 67-year-old man who had undergone distal gastrectomy because of early gastric cancer without lymph node metastasis two years earlier. The postoperative course was uneventful, but he was admitted again to our hospital because of abrupt jaundice. A CT scan of the abdomen showed obstructive jaundice due to the enlargement of the lymph nodes around the hepatoduodenal ligament, pancreas head, portal vein, and celiac axis. After percutaneous transhepatic cholangio-drainage (PTCD), 5 cycles of FLP combination therapy (5-fluorouracil, leucovorin, cisplatin) were performed. Consequently, the tumor marker level returned to the normal range and the shrinkage of the metastatic lymph nodes was remarkable. A reopening of the biliary tract was attained, so the PTCD tube could be removed. As an outpatient without recurrence he has received oral administration of uracil plus tegafur. The FLP combination therapy was effective for obstructive jaundice due to intraperitoneal lymph node recurrence of the gastric cancer.

[A case of AFP-producing gastric cancer after curative operation effectively treated with chemotherapies including hepatic arterial infusion therapy].

A 63-year-old woman was admitted complaining of epigastralgia. An endoscopic examination revealed a Borrmann type 2 lesion at the greater curvature of the middle third in the stomach. Abdominal computed tomography detected no liver metastasis. The preoperative serum alpha-phetoprotein (AFP) level was elevated to 242.9 ng/ml. 5-fluorouracil (5-FU) was given 200 mg/day for 26 days orally. Distal gastrectomy with D3+ No. 16b1 lymph node dissection, cholecystectomy and hepatic arterial canulation were performed, and mitomycin C 20 mg was injected intravenously during the operation. Immunohistochemical staining of the specimen for AFP by the SAB method was positive in the cancer lesion. After the operation, FP (cisplatin 100 mg on day 1, 5-FU 750 mg on days 1-3) therapy of one course and intrahepatic arterial infusion therapy using adriamycin 10-20 mg every 2 weeks for 7 months were conducted. Moreover, the patient took UFT 400 mg/day for 26 months orally on an outpatient basis as an adjuvant chemotherapy. The only toxicity was neutropenia (grade 3), but it abated without an interruption in the chemotherapy. The AFP level declined gradually, and returned to the normal range 1 month after surgery. The patient is still alive with no sign of hepatic metastasis or recurrence 7 years and 7 months after the gastrectomy.

[A patient with advanced gastric cancer who obtained downstaging and underwent radical surgery by neoadjuvant chemotherapy].

The patient was a 74-year-old man with extremely advanced gastric cancer. A CT scan of the abdomen showed enlargement of many huge abdominal para-aortic lymph nodes. Neoadjuvant chemotherapy (NAC) was planned in order to reduce or eliminate the tumor. Two cycles of FLP combination therapy (5-fluorouracil, leucovorin, cisplatin) were given. After NAC, a CT scan revealed marked shrinkage of the No. 16 lymph nodes, and a distal gastrectomy with extended radical lymph node dissection including the No. 16 nodes was performed. The histological effect was judged to be grade 2. There were no viable cancer cells in the No. 16 lymph nodes. The FLP combination therapy as NAC was so effective that it induced downstaging from stage IVb to IIIb.

[A case of advanced gastric cancer with abdominal para-aortic lymph node metastasis successfully treated with FLP therapy].

A 73-year-old woman was admitted to our hospital in June 1998, suffering from upper abdominal pain. The upper G-I series and endoscopic examination revealed stenosis of the pylorus and antrum by a type 2 cancer, and a poorly differentiated adenocarcinoma and a signet-ring cell carcinoma were confirmed on endoscopic biopsy. A CT scan showed the enlargement of many regional and abdominal para-aortic lymph nodes. FLP therapy combined with cisplatin (50 mg/m2 drip i.v., day 1-8), 5-fluorouracil (333 mg/m2 drip i.v.) and leucovorin (30 mg/body i.v., day 1-8) was planned for neoadjuvant chemotherapy (NAC) in order to reduce or eliminate the tumor and increase curability. After two cycles of the FLP therapy, the tumor size shrunk remarkably and the enlargement of the para-aortic lymph nodes disappeared. Distal gastrectomy with extended lymphadenectomy and cholecystectomy was performed. The histological findings of the primary tumor and metastatic lymph nodes demonstrated massive cancer cell degeneration such as pycnosis and vacuolation, xanthogranulomatous inflammation and dense fibrosis. The effect of NAC was judged to be grade 2 histologically. FLP therapy is an effective and safe regimen for NAC.

Apoptosis and Bbcl-2 expression in gastric carcinomas: correlation withclinicopathological variables, p53 expression, cell proliferation and prognosis.

We investigated apoptosis and Bcl-2 expression in 221 advanced gastric carcinomas in correlation with clinicopathological variables, p53 expression, cell proliferation and prognosis, using the in situ DNA nick end labeling method and immunohistochemistry. Apoptosis was associated with high immunoreactivity of proliferating cell nuclear antigen. Bcl-2 expression correlated with a low apoptotic index and less malignant behavior of tumors. Prognostically, Bcl-2 expression was associated with a better prognosis, whereas p53 expression was the most important prognostic risk factor. Thus, apoptosis in gastric carcinomas is associated with cell proliferation, and Bcl-2 expression may have a prognostic importance as well as p53 expression.

Chemotherapy of human alpha-fetoprotein-producing gastric carcinomas grown in nude mice.

We have examined the effects of chemotherapeutic drugs on tumor growth and metastasis of human alpha-fetoprotein-producing gastric carcinoma (AFPGC) xenografts growing in nude mice. These xenografts consisted of 3 hepatoid adenocarcinomas and 2 non-hepatoid, poorly differentiated adenocarcinomas. Mitomycin C and cisplatin inhibited the tumor growth and liver metastasis of hepatoid adenocarcinomas in nude mice. 5-fluorouracil also inhibited the growth of hepatoid adenocarcinomas but did not exhibit a significant antimetastatic action. Doxorubicin was effective only against non-hepatoid adenocarcinomas. These results indicate that chemotherapeutic drugs for AFPGC should be used according to the subtype of the tumor.

Phylogenetic relationships of entomopathogenic nematophilic bacteria: Xenorhabdus spp. and Photorhabdus sp.

Phylogenetic relationships of Xenorhabdus spp. and Photorhabdus sp. were investigated on the basis of 16S rRNA gene sequences. Xenorhabdus spp. and Photorhabdus sp. were grouped together with Proteus vulgaris and Arsenophonus nasoniae. This group was distant from other members of the family Enterobacteriaceae. Xenorhabdus japonicus, previously proposed as a new species, was nearly located to Xenorhabdus nematophilus. Signature nucleotides of X. japonicus were identified that distinguish it other members of the family Enterobacteriaceae.

Modulation of cisplatin sensitivity and resistance by buthionine sulfoximine and cyclosporin A in human esophageal cancer cells.

We established a 2.4-fold cisplatin (CDDP)-resistant human esophageal cancer cell line (TE2R) from the parent TE2 line. CDDP accumulation was reduced in TE2R. The Na+, K+-ATPase inhibitor ouabain inhibited CDDP accumulation in TE2 but not TE2R, suggesting that TE2R may have alterations in the Na+, K+-ATPase and defective CDDP uptake mechanism. Buthionine sulfoximine (BSO) enhanced CDDP sensitivity of both cell lines and cyclosporin A (CsA) modified CDDP resistance in TE2R. These effects were associated with increased CDDP accumulation. Thus, BSO and CsA may be useful for modulation of CDDP sensitivity or resistance in esophageal cancer.

Chemotherapy of human small-cell gastrointestinal carcinoma xenografts in nude mice.

We established two xenografts of small-cell carcinoma (SCC) arising in the oesophagus or the stomach, designated TEG13 and TSG15, and investigated the responses to experimental chemotherapy on these strains. Both tumours were classified as the intermediate cell type of SCC composed of small cells having neuroendocrine features in terms of morphology, argyrophil property, and immunoreactivity for neuron-specific enolase. Mitomycin C, cisplatin, and cyclophosphamide were judged to be effective against both strains. Particularly, cisplatin produced almost complete regression of tumour growth of the TEG13 strain. Etoposide proved effective only against the TSG15 strain. Moreover, the combined treatment with etoposide and cisplatin produced the most pronounced antitumour effect against the TSG15 strain. These studies suggest that cisplatin may be a key drug for chemotherapy of oesophageal SCC, and etoposide plus cisplatin treatment may be especially recommended in the treatment of gastric SCC. Mitomycin C should be re-evaluated in gastrointestinal SCC.

Inhibition of tumor-cell invasion and gelatinase production in metastatic human gastric-carcinoma cells by retinoic Acid and bestatin.

We have selected a human variant gastric carcinoma cell line (MKN45H) with increased metastatic potential in nude mice to study the properties of metastatic cells, and investigated the effects of retinoic acid (RA), interferon-gamma and bestatin on invasion and gelatinase production by MKN45H cells. The MKN45H cells showed increased invasive phenotypes and greater secretion of gelatinases as compared to the parental cells. Treatment with RA and bestatin significantly decreased invasion through Matrigel and production of gelatinases by MKN45H cells. These results suggest that RA and bestatin may be useful for the inhibition of invasive potential of gastric carcinoma.

Different characteristics of hepatoid and non-hepatoid alpha-fetoprotein-producing gastric carcinomas: an experimental study using xenografted tumors.

The characteristics, including metastatic potential, of 5 xenografts of alpha-fetoprotein (AFP)-producing gastric carcinomas in nude mice, designated TSG1, TSG3, TSG11, TSG17 and TSG20, were examined. Of these xenografts, TSG1, TSG11 and TSG20 were regarded as hepatoid adenocarcinomas based on their morphological resemblance to hepatocellular carcinoma, frequent immunoreactivity for liver-cell markers, and excessive production of AFP with a high concanavalin A (Con-A)-binding property of hepatic type. On the other hand, TSG3 and TSG17 tumors showed the features of poorly differentiated medullary adenocarcinoma with scattered AFP-positive cells consistent with low AFP levels in mouse sera, and negative immunoreactivity for other liver-cell markers. Ultrastructurally, these tumors were composed of undifferentiated cells with a little adenocarcinomatous differentiation. Moreover, the AFP produced by TSG3 and TSG17 tumors had an extremely high Con-A nonbound fraction (80% to 90%), which was different from that of the hepatic or yolk-sac types. Therefore, both TSG3 and TSG17 tumors were regarded as non-hepatoid, poorly differentiated adenocarcinomas which could be differentiated from any types of AFP-producing gastric carcinoma. Furthermore, cells from hepatoid adenocarcinoma strains (TSG1, TSG11 and TSG20) injected into the spleens of nude mice produced liver metastases in all the mice examined, whereas cells from non-hepatoid carcinoma strains (TSG3 and TSG17) produced few or no liver metastases. Our data show that some non-hepatoid AFP-producing gastric carcinomas have lower liver-metastasizing potential than hepatoid AFP-producing gastric carcinomas.

Augmentation of 5-fluorouracil cytotoxicity by epidermal growth factor in a newly established human signet-ring cell carcinoma of the stomach in culture.

A cell line designated TSG6 was established from a signet-ring cell gastric carcinoma developed in a 57-year-old female patient. The TSG6 cells had well preserved the features of signet-ring cell carcinoma based on morphology. The cells exhibited both epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) immunoreactivities, and also secreted EGF. Moreover, the growth of TSG6 cells was stimulated in the presence of exogenous EGF. These results suggest that the possible presence of an EGF/EGFR autocrine growth mechanism is expressed in the TSG6 cells. The simultaneous treatment with EGF and 5-fluorouracil (5-FU) produced a nearly 2.4-fold enhancement of 5-FU cytotoxicity against TSG6 cells. A bromodeoxyuridine/DNA flow cytometry analysis revealed that EGF augmented 5-FU cytotoxicity by inducing the accumulation of S phase cells which might be more susceptible to 5-FU. Moreover, we found that the incorporation of 5-FU into the TSG6 cells was increased with the addition of EGF. These data indicate that EGF may be a potent agent as a biological response modifier for 5-FU against the tumors which express the EGF/EGFR autocrine mechanism, and that the TSG6 cell line is useful in furthering our understanding of the interaction between anticancer drugs and EGF.

[A carcinoma of the reconstructed gastric tube after a radical esophageal cancer operation].

Reported are five patients who developed a carcinoma of the reconstructed gastric tube. In 3 of the 5 patients, the esophageal cancer was preceded by a gastric cancer, and the intervals before the gastric cancer was detected were 34, 24, and 60 months. The gastric tube the had been reconstructed by the retrosternal rout was resected with a median sternotomy in cases 1 and 2. In case 3, since a liver and lung metastasis had been detected by routine examination, surgery was not performed. Cases 4 and 5 had an esophageal cancer associated with a simultaneous early gastric cancer located in the lesser curvature of the upper body. Thus, a esophagectomy and a partial gastrectomy were performed. Twenty-eight and 21 months later, respectively, an early gastric cancer was found at the stump of the gastric tube that had been reconstructed by the retrosternal route. Endoscopic laser therapy was subsequently employed for both patients. Because of these findings, the author have concluded that postoperative serial examination of the gastric tube are very important, since cases of a gastric tube cancer are increasing.