Clinical Outcomes of Operating an Acute Palliative Care Unit at a Comprehensive Cancer Center.

PURPOSE: Acute palliative care units (APCUs) are inpatient services in tertiary hospitals that provide intensive symptom management and assist in hospital discharge for transitions to hospice care. We aimed to analyze the clinical outcomes of operating an APCU at a comprehensive cancer center. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 1,440 consecutive patients admitted to the APCU and analyzed demographic and clinical information, discharge outcomes, symptom assessments using the Edmonton Symptom Assessment System, spiritual distress, and financial distress. RESULTS: The median age of patients was 67.0 (range, 23-97) years, and 41% were female. The most common primary cancer types were lung (21.9%), hepatopancreatobiliary (14.1%), and colorectal cancers (12.9%). The median length of stay was 8.0 days (range, 1-60 days), and 31.0% of patients died in the APCU. Death in the APCU showed a significant decrease over time, and overall inpatient death in oncology wards did not increase after APCU opening. In total, 44.7% of patients were discharged to government-certified hospice centers. The proportion of patients discharged to certified hospice centers increased from 32.2% in 2015 to 62.4% in 2018. Among 715 patients with a follow-up evaluation 1 week after admission, Edmonton Symptom Assessment System symptom scores, spiritual distress, and financial distress showed statistically significant improvements compared with the baseline symptom scores (P < .001). This improvement was limited to patients who did not die in the APCU. CONCLUSION: Patients with advanced cancer admitted to the APCU may experience significant improvements in distressing symptoms. The majority of patients requiring transition to hospice were successfully transferred to certified hospice centers. The percentage discharged alive improved over time.

Metformin ameliorates olanzapine-induced disturbances in POMC neuron number, axonal projection, and hypothalamic leptin resistance.

Antipsychotics have been widely accepted as a treatment of choice for psychiatric illnesses such as schizophrenia. While atypical antipsychotics such as aripiprazole are not associated with obesity and diabetes, olanzapine is still widely used based on the anticipation that it is more effective in treating severe schizophrenia than aripiprazole, despite its metabolic side effects. To address metabolic problems, metformin is widely prescribed. Hypothalamic proopiomelanocortin (POMC) neurons have been identified as the main regulator of metabolism and energy expenditure. Although the relation between POMC neurons and metabolic disorders is well established, little is known about the effects of olanzapine and metformin on hypothalamic POMC neurons. In the present study, we investigated the effect of olanzapine and metformin on the hypothalamic POMC neurons in female mice. Olanzapine administration for 5 days significantly decreased Pomc mRNA expression, POMC neuron numbers, POMC projections, and induced leptin resistance before the onset of obesity. It was also observed that coadministration of metformin with olanzapine not only increased POMC neuron numbers and projections but also improved the leptin response of POMC neurons in the olanzapine-treated female mice. These findings suggest that olanzapine-induced hypothalamic POMC neuron abnormality and leptin resistance, which can be ameliorated by metformin administration, are the possible causes of subsequent hyperphagia. [BMB Reports 2022; 55(6): 293-298].

Treatment strategy and outcomes in locally advanced head and neck squamous cell carcinoma: a nationwide retrospective cohort study (KCSG HN13-01).

BACKGROUND: By investigating treatment patterns and outcomes in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), we aimed at providing valuable insights into the optimal therapeutic strategy for physicians in real-world practice. METHODS: This is a multi-institutional study enrolled the patients with stage III to IVB LA-HNSCC, except for nasopharyngeal carcinoma, from 2004 to 2015 in thirteen referral hospitals capable of multidisciplinary care. RESULTS: A total of 445 LA-HNSCC patients were analyzed. The median age was 61 years (range, 24-89). The primary tumor location was the oropharynx in 191 (43%), oral cavity in 106 (24%), hypopharynx in 64 (14%), larynx in 57 (13%) and other sites in 27 (6%). The most common stage was T2 in 172 (39%), and N2 in 245 (55%). Based on treatment intents, 229 (52%) of the patients received definitive concurrent chemoradiotherapy (CCRT) and 187 (42%) underwent surgery. Approximately 158 (36%) of the study population received induction chemotherapy (IC). Taken together, 385 (87%) of the patients underwent combined therapeutic modalities. The regimen for definitive CCRT was weekly cisplatin in 58%, 3-weekly cisplatin in 28% and cetuximab in 3%. The preferred regimen for IC was docetaxel with cisplatin in 49%, and docetaxel, cisplatin plus fluorouracil in 27%. With a median follow-up of 39 months, one-year and two-year survival rates were 89 and 80%, respectively. Overall survival was not significantly different between CCRT and surgery group (p = 0.620). CONCLUSIONS: In patients with LA-HNSCC, the majority of patients received combined therapeutic modalities. Definitive CCRT, IC then definitive CCRT, and surgery followed by adjuvant CCRT or radiotherapy are the preferred multidisciplinary strategies in real-world practice.

A Randomized Phase II Study of Perioperative Chemotherapy Plus Bevacizumab Versus Postoperative Chemotherapy Plus Bevacizumab in Patients With Upfront Resectable Hepatic Colorectal Metastases.

INTRODUCTION: Whether patients with resectable colorectal liver metastases (CRLM) gain a survival benefit from perioperative chemotherapy remains controversial. The benefit of including bevacizumab in chemotherapy also remains unclear. MATERIAL AND METHODS: Seventy-six patients with CRLM were randomly assigned to either 6 cycles of FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin)/FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) with bevacizumab before and after surgery or 12 cycles after surgery. Progression-free survival (PFS) was estimated using the Kaplan-Meier method and compared by the log-rank test. RESULTS: The median PFS of all patients was 37.4 months at 5.4 years follow-up, and the median overall survival (OS) was not reached. The PFS between the perioperative group and the postoperative group did not reveal a statistical difference (P = .280). The OS was significantly better in the perioperative group (hazard ratio [HR], 0.60; 95% confidence interval [CI],) 0.35-1.02; P = .049). In subgroup patients with carcinoembryonic antigens (CEA) ≥ 5 ng/mL or those with over 2 liver metastases, perioperative group had longer OS than postoperative group (CEA: HR, 0.49; 95% CI, 0.25-0.93; P = .030; number of liver metastases: HR, 0.55; 95% CI, 0.30-0.99; P = .049). The largest liver metastases size, disease-free interval, and sidedness did not affect PFS or OS. There was no difference between the 2 groups in postoperative complications with bevacizumab or adverse events during chemotherapy. CONCLUSIONS: In patients with resectable CRLMs, perioperative chemotherapy had no effect on PFS, but improved OS. Patients with high CEA levels or over 2 liver metastases may benefit from perioperative chemotherapy.

Oxaliplatin-Based Adjuvant Chemotherapy for Rectal Cancer After Preoperative Chemoradiotherapy (ADORE): Long-Term Results of a Randomized Controlled Trial.

PURPOSE: We evaluated the role of oxaliplatin as adjuvant chemotherapy in patients with rectal cancer who received preoperative chemoradiotherapy (CRT) with fluoropyrimidine monotherapy and total mesorectal excision (TME). METHODS: The ADORE trial (adjuvant oxaliplatin in rectal cancer) is a multicenter, randomized trial in patients with postoperative ypStage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after fluoropyrimidine-based preoperative CRT and TME. Patients were randomly assigned (1:1) to receive adjuvant chemotherapy either with FL (fluorouracil 380 mg/m2 and leucovorin 20 mg/m2) or FOLFOX (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil bolus 400 mg/m2 on day 1, fluorouracil infusion 2,400 mg/m2 for 46 hours). Stratification factors included ypStage and participating center. Primary end point was disease-free survival (DFS). RESULTS: A total of 321 patients were enrolled between November 19, 2008, and June 12, 2012. Six-year DFS rates were 68.2% in the FOLFOX arm versus 56.8% in the FL arm, with a stratified hazard ratio of 0.63 (95% CI, 0.43 to 0.93; P = .018) by intention-to-treat analysis. In the subgroup analysis for DFS, FOLFOX was favorable versus FL in patients with ypStage III, ypN1b, ypN2, high-grade histology, minimally regressed tumor, and an absence of lymphovascular or perineural invasion. Six-year overall survival rate was 78.1% in the FOLFOX arm versus76.4% in the FL arm (hazard ratio, 0.73; 95% CI, 0.45 to 1.19; P = .21). In the subgroup analysis for OS, FOLFOX was favorable versus FL in patients with ypN2 and minimally regressed tumor. CONCLUSION: Adjuvant FOLFOX improved DFS in patients with rectal cancer with ypStage II and III disease after preoperative CRT. Adjuvant FOLFOX may be considered on the basis of the postoperative pathologic stage in those who received preoperative CRT and TME.

Long-term rivaroxaban for the treatment of acute venous thromboembolism in patients with active cancer in a prospective multicenter trial.

BACKGROUND/AIMS: Limited data are available regarding the efficacy of rivaroxaban for the treatment of cancer-associated venous thromboembolism (VTE). The aim of this study was to evaluate the effectiveness and safety of rivaroxaban for the treatment of VTE in active cancer patients. METHODS: In this prospective, multicenter, open-label trial (NCT01989845), we enrolled patients with active cancer and objectively diagnosed lower-extremity deep vein thrombosis, pulmonary embolism (PE), or both from November 2013 to June 2016. Active cancer was defined as a histologically confirmed malignancy, which was diagnosed or treated within the previous 6 months, or as a recurrent/ metastatic cancer. Patients received oral rivaroxaban 15 mg twice daily for first 3 weeks, followed by 20 mg once daily for 6 months. The primary outcome was the symptomatic recurrent VTE and the secondary outcomes included any recurrent VTE, major or clinically relevant non-major (CRNM) bleeding events, and overall mortality. All study outcomes were validated by blinded central adjudication. RESULTS: Of 124 patients enrolled, 110 (88.7%) had solid cancer, 93 (75.0%) had metastatic disease, and 110 (88.7%) were receiving chemotherapy or radiotherapy. During the 6-month study period, seven patients experienced symptomatic recurrent VTE (cumulative incidence, 5.9%), and two patients experienced incidental recurrent PE (cumulative incidence of any recurrent VTE, 7.6%). Major bleeding events occurred in six patients (cumulative incidence, 5.3%) and CRNM bleeding events in 11 patients (cumulative incidence, 10.2%). Twenty-eight patients (overall mortality, 24.0%) died. CONCLUSION: Rivaroxaban is effective and safe for the treatment of VTE in patients with active cancer.

Aronia melanocarpa Concentrate Ameliorates Pro-Inflammatory Responses in HaCaT Keratinocytes and 12-O-Tetradecanoylphorbol-13-Acetate-Induced Ear Edema in Mice.

Abnormal expression of pro-inflammatory mediators such as cell adhesion molecules and cytokines has been implicated in various inflammatory skin diseases, including atopic dermatitis. In this study, we investigated the anti-inflammatory activity of Aronia melanocarpa concentrate (AC) and its action mechanisms using in vivo and in vitro skin inflammation models. Topical application of AC on mouse ears significantly suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema formation, as judged by measuring ear thickness and weight, and histological analysis. Topical administration of AC also reduced the expression of pro-inflammatory cytokines such as TNF-α, IL-1ß, and IL-6 in TPA-stimulated mouse ears. Pretreatment with AC suppressed TNF-α-induced ICAM-I expression and subsequent monocyte adhesiveness in human keratinocyte cell line HaCaT. In addition, AC significantly decreased intracellular reactive oxygen species (ROS) generation as well as mitogen-activated protein kinase (MAPK) activation in TNF-α-stimulated HaCaT cells. AC and its constituent cyanidin 3-glucoside also attenuated TNF-α-induced IKK activation, IκB degradation, p65 phosphorylation/nuclear translocation, and p65 DNA binding activity in HaCaT cells. Overall, our results indicate that AC exerts anti-inflammatory activities by inhibiting expression of pro-inflammatory mediators in vitro and in vivo possibly through suppression of ROS-MAPK-NF-κB signaling pathways. Therefore, AC may be developed as a therapeutic agent to treat various inflammatory skin diseases.

Effect of muscle mass on toxicity and survival in patients with colon cancer undergoing adjuvant chemotherapy.

PURPOSE: The purpose of this study was to elucidate the effect of decreased muscle mass on the toxicity and survival of patients with colon cancer treated with adjuvant chemotherapy after surgery. METHODS: We reviewed the data of 229 consecutive patients with stage III colon cancer who received adjuvant oxaliplatin, 5-fluorouracil, and leucovorin chemotherapy at a single center between 2003 and 2010. Baseline muscle mass was assessed by measuring the cross-sectional area of the psoas muscle at the level of the fourth lumbar vertebra on computed tomography images. Effects of muscle mass on toxicity of chemotherapy and survival were assessed. RESULTS: The median age of the 229 patients was 61 years (range, 28-80) and 134 (58.5 %) were men. The mean psoas muscle mass index (PI, psoas muscle area divided by height(2) [mm(2)/m(2)]) was 548.3. A 1 SD decrement in the PI was associated with an increase in all grade 3-4 toxicities in univariate (OR = 1.69, 95 % CI = 1.18-2.27) and multivariate (OR = 1.56, 95 % CI = 1.05-2.38) analyses. In univariate analysis, the PI was not associated with overall survival. However, multivariate analysis showed that a 1 SD decrement in the PI increased the hazard of overall mortality by 85 % (HR = 1.85, 95 % CI = 1.10-3.13). This effect of the PI on mortality was maintained in subgroup analyses, especially in older and obese patients. CONCLUSIONS: Decreased muscle mass was associated with increased risk of grade 3-4 toxicity and poor prognosis in patients with stage III colon cancer.

S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: updated results from a phase 3 trial.

BACKGROUND: We report updated progression-free survival (PFS) and overall survival (OS) data from a trial that compared capecitabine plus oxaliplatin (CapeOX) versus S-1 plus oxaliplatin (SOX) for the first-line treatment of metastatic colorectal cancer. METHODS: This trial was a randomized, two-armed, non-inferiority phase 3 comparison of CapeOX (capecitabine 1000 mg/m2 twice daily on days 1-14 and oxaliplatin 130 mg/m2 on day 1) versus SOX (S-1 40 mg/m2 twice daily on days 1-14 and oxaliplatin 130 mg/m2 on day 1). The primary end point was to show non-inferiority of SOX relative to CapeOX in terms of PFS. Thus, a follow-up exploratory analysis of PFS and OS was performed. RESULTS: The intention to treat (ITT) population was comprised of 340 patients (SOX arm: 168 and CapeOX arm: 172). The updated median PFS was 7.1 months (95% CI 6.4-8.0) in the SOX group and 6.3 months (95% CI 4.9-6.7) in the CapeOX group (hazard ratio [HR], 0.83 [0.66-1.04], p = .10). The median OS was 19.0 months (95% CI 15.3-23.0) in the SOX group and 18.4 months (95% CI 14.1-20.7) in the CapeOX group (HR, 0.86 [0.68-1.08], p = .19). Subgroup analyses according to principal demographic factors such as sex, age, ECOG (Eastern Cooperative Oncology Group) performance status, primary tumor location, measurability, previous adjuvant therapy, number of metastatic organs, and liver metastases showed no interaction between any of these characteristics and the treatment. CONCLUSIONS: Updated survival analysis shows that SOX is similar to CapeOX, confirming the initial PFS analysis. Therefore, the SOX regimen could be an alternative first-line doublet chemotherapy strategy for patients with metastatic colorectal cancer. TRIAL REGISTRATION: NCT00677443 and May 12 2008.

Pharmacogenetic analysis of adjuvant FOLFOX for Korean patients with colon cancer.

PURPOSE: Ethnic diversity of genetic polymorphism can result in individual differences in the efficacy and toxicity of cancer chemotherapy. METHODS: We analyzed 20 germline polymorphisms in 10 genes (TS, MTHFR, ERCC1, XPD, XRCC1, ABCC2, AGXT, GSTP1, GSTT1 and GSTM1) from prospectively enrolled 292 Korean patients treated with adjuvant oxaliplatin plus leucovorin plus 5-fluorouracil (FOLFOX) for colon cancer. RESULTS: In contrast to previous studies in Caucasians, neutropenia (grade 3-4, 60.5 %) was frequently observed, whereas only 16.4 % experienced grade 2 or more sensory neuropathy. Neutropenia was more frequent in MTHFR 677TT [adjusted odds ratio (OR) 2.32, 95 % confidence interval (CI) 1.19-4.55] and ERCC1 19007TT (adjusted OR 4.58, 95 % CI 1.20-17.40) genotypes. Patients harboring XRCC1 23885GG experienced less grade 2-4 neuropathy [adjusted OR 0.52, 95 % CI 0.27-0.99]. MTHFR 677TT (p = 0.002) and XRCC1 23885GG (p = 0.146) genotypes were also more prevalent in Koreans compared to Caucasians. TS 'low' genotype (adjusted HR 1.83, 95 % CI 1.003-3.34) was significantly related to shorter disease-free survival. Overall survival was not significantly different according to the polymorphisms. CONCLUSIONS: Polymorphisms in MTHFR, XRCC1 and TS are related to toxicities and disease-free survival in patients with colon cancer. The ethnic differences in frequencies of genotypes may explain the ethnic difference in toxicity profile following adjuvant FOLFOX chemotherapy.

Practical outcome of adjuvant FOLFOX4 chemotherapy in elderly patients with stage III colon cancer: single-center study in Korea.

OBJECTIVE: Elderly patients derive similar benefits from 5-fluorouracil-based adjuvant chemotherapy in Stage III colon cancer; however, conflicting data exist regarding additional benefit from oxaliplatin, fluorouracil and leucovorin (FOLFOX) chemotherapy. METHODS: Single-center, retrospective analysis was performed to compare the safety and efficacy of adjuvant oxaliplatin, fluorouracil and leucovorin-4 chemotherapy in older patients (age ≥65 years) with younger patients with Stage III colon cancer after surgical resection. RESULTS: Among 391 patients with Stage III colon cancer, 229 patients received adjuvant oxaliplatin, fluorouracil and leucovorin chemotherapy (87 (43.5%) ≥65 years old versus 142 (74.3%) <65 years old). Older patients had similar clinico-pathological characteristics as younger patients except for higher Charlson-Age comorbidity score (median 3.44 versus 2.85, P < 0.01). The estimated 3-year disease-free survival (76.5 versus 80.0%, P = 0.88) and 3-year overall survival (90.9 versus 92.7%, P = 0.98) were similar. Grade 3-4 neutropenia was the only toxicity with higher frequency in the elderly patients (62.1 versus 46.5%, P = 0.02). Elderly patients received a lower relative dose intensity of oxaliplatin (0.76 versus 0.79) and 5-fluorouracil (0.75 versus 0.80, P = 0.009). CONCLUSIONS: Adjuvant oxaliplatin, fluorouracil and leucovorin chemotherapy resulted in similar efficacy without significant increase in toxicity in older patients aged ≥65 when compared with younger patients with curatively resected Stage III colon cancer. Therefore, for colon cancer patients aged ≥65, oxaliplatin, fluorouracil and leucovorin chemotherapy can be recommended as safe and effective adjuvant chemotherapy after curative surgery in Asia.

S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial.

BACKGROUND: Capecitabine plus oxaliplatin (CapeOX) is one of the reference doublet cytotoxic chemotherapy treatments for patients with metastatic colorectal cancer. We aimed to compare the efficacy and safety of CapeOX with that of S-1 plus oxaliplatin (SOX), a promising alternative treatment for patients with metastatic colorectal cancer. METHODS: In this open-label, multicentre, randomised phase 3 trial, we randomly assigned patients (1:1) from 11 institutions in South Korea to receive either CapeOX (capecitabine 1000 mg/m(2) twice daily on days 1-14 and oxaliplatin 130 mg/m(2) on day 1) or SOX (S-1 40 mg/m(2) twice daily on days 1-14 and oxaliplatin 130 mg/m(2) on day 1). Treatment was repeated every 3 weeks and continued for as many as nine cycles of oxaliplatin-containing chemotherapy, except in instances of disease progression, unacceptable toxicity, or a patient's refusal. Maintenance chemotherapy with S-1 or capecitabine was allowed after discontinuation of oxaliplatin. Randomisation was done with a computer-generated sequence (stratified by primary sites, previous adjuvant or neoadjuvant treatment, and the presence of measurable lesions). The primary endpoint was to show non-inferiority of SOX relative to CapeOX in terms of progression-free survival (PFS). The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00677443. FINDINGS: Between May 14, 2008, and Sept 23, 2009, we randomly assigned 168 patients to receive SOX and 172 to receive CapeOX. Median PFS was 8·5 months (95% CI 7·6-9·3) in the SOX group and 6·7 months (6·2-7·1) in the CapeOX group (hazard ratio, 0·79 [95% CI 0·60-1·04]; p(non-inferiority)<0·0001, p(log-rank)=0·09). The upper limit of the CI was below the predefined margin of 1·43, showing the non-inferiority of SOX to CapeOX. We recorded a higher incidence of grade 3-4 neutropenia (49 [29%] vs 24 [15%]), thrombocytopenia (37 [22%] vs 11 [7%]), and diarrhoea (16 [10%] vs seven [4%]) in the SOX group than in the CapeOX group. The frequency of any grade of hand-foot syndrome was greater in the CapeOX group than it was in the SOX group (51 [31%] vs 23 [14%]). INTERPRETATION: The SOX regimen could be an alternative first-line doublet chemotherapy strategy for patients with metastatic colorectal cancer. Further investigation is needed to explore its potential when used together with other targeted agents or as adjuvant chemotherapy. FUNDING: Korea Healthcare Technology Research and Development Project, Ministry of Health and Welfare, South Korea.

Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial.

BACKGROUND: D2 gastrectomy is recommended in US and European guidelines, and is preferred in east Asia, for patients with resectable gastric cancer. Adjuvant chemotherapy improves patient outcomes after surgery, but the benefits after a D2 resection have not been extensively investigated in large-scale trials. We investigated the effect on disease-free survival of adjuvant chemotherapy with capecitabine plus oxaliplatin after D2 gastrectomy compared with D2 gastrectomy only in patients with stage II-IIIB gastric cancer. METHODS: The capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study was an open-label, parallel-group, phase 3, randomised controlled trial undertaken in 37 centres in South Korea, China, and Taiwan. Patients with stage II-IIIB gastric cancer who had had curative D2 gastrectomy were randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of oral capecitabine (1000 mg/m(2) twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m(2) on day 1 of each cycle) for 6 months or surgery only. Block randomisation was done by a central interactive computerised system, stratified by country and disease stage. Patients, and investigators giving interventions, assessing outcomes, and analysing data were not masked. The primary endpoint was 3 year disease-free survival, analysed by intention to treat. This study reports a prespecified interim efficacy analysis, after which the trial was stopped after a recommendation by the data monitoring committee. The trial is registered at ClinicalTrials.gov (NCT00411229). FINDINGS: 1035 patients were randomised (520 to receive chemotherapy and surgery, 515 surgery only). Median follow-up was 34·2 months (25·4-41·7) in the chemotherapy and surgery group and 34·3 months (25·6-41·9) in the surgery only group. 3 year disease-free survival was 74% (95% CI 69-79) in the chemotherapy and surgery group and 59% (53-64) in the surgery only group (hazard ratio 0·56, 95% CI 0·44-0·72; p<0·0001). Grade 3 or 4 adverse events were reported in 279 of 496 patients (56%) in the chemotherapy and surgery group and in 30 of 478 patients (6%) in the surgery only group. The most common adverse events in the intervention group were nausea (n=326), neutropenia (n=300), and decreased appetite (n=294). INTERPRETATION: Adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer. FUNDING: F Hoffmann-La Roche and Sanofi-Aventis.