Epidemiology of adverse drug events and medication errors in four nursing homes in Japan: the Japan Adverse Drug Events (JADE) Study.

BACKGROUND: Worldwide, the emergence of super-ageing societies has increased the number of older people requiring support for daily activities. Many elderly residents of nursing homes (NHs) take drugs to treat chronic conditions; however, there are few reports of medication safety in NHs, especially from non-western countries. OBJECTIVE: We examined the incidence and nature of adverse drug events (ADEs) and medication errors (MEs) in NHs for the elderly in Japan. DESIGN, SETTING, AND PARTICIPANTS: The Japan Adverse Drug Events Study for NHs is a prospective cohort study that was conducted among all residents, except for short-term admissions, at four NHs for older people in Japan for 1 year. MEASUREMENTS: Trained physicians and psychologists, five and six in number, respectively, reviewed all charts of the residents to identify suspected ADEs and MEs, which were then classified by the physicians into ADEs, potential ADEs and other MEs after the exclusion of ineligible events, for the assessment of their severity and preventability. The kappa score for presence of an ADE and preventability were 0.89 and 0.79, respectively. RESULTS: We enrolled 459 residents, and this yielded 3315 resident-months of observation time. We identified 1207 ADEs and 600 MEs (incidence: 36.4 and 18.1 per 100 resident-months, respectively) during the study period. About one-third of ADEs were preventable, and MEs were most frequently observed in the monitoring stage (72%, 433/600), with 71% of the MEs occurring due to inadequate observation following the physician's prescription. CONCLUSION: In Japan, ADEs and MEs are common among elderly residents of NHs. The assessment and appropriate adjustment of medication preadmission and postadmission to NHs are needed to improve medication safety, especially when a single physician is responsible for prescribing most medications for the residents, as is usually the case in Japan.

Over Half of Falls Were Associated with Psychotropic Medication Use in Four Nursing Homes in Japan: A Retrospective Cohort Study.

Medication use can increase the risk of falls and injuries in nursing homes, creating a significant risk for residents. We performed a retrospective cohort study over one year to identify the incidence of drug-related falls with and without injury among four Japanese nursing homes with 280 beds. We evaluated the relationship between potential risk factors for falls and fall-related injuries while considering well-known risks such as ADLs and chronic comorbidities. By collaboratively reviewing care records, we enrolled 459 residents (mean age, 87) and identified 645 falls, including 146 injurious falls and 16 severe injurious falls requiring inpatient care, incidence: 19.5, 4.4, 0.5 per 100 resident-months, respectively. Medication influenced around three-quarters of all falls, >80% of which were psychotropic drugs. Regularly taking ≥5 medications was a risk factor for the initial falls (HR 1.33: CI 1.00−1.77, p = 0.0048) and injuries after falls (OR 2.41: CI 1.30−4.50, p = 0.006). Our findings on the incidence of falls with and without injury were similar to those in Western countries, where the use of psychotropic medication influenced >50% of falls. Discontinuing unnecessary medication use while simultaneously assessing patient ADLs and comorbidities with physicians and pharmacists may help to avoid falls in nursing homes.

Effects of the dipeptide L-glutamic acid-L-tryptophan on dermatitis in mice and human keratinocytes.

Allergic contact dermatitis (ACD) and atopic dermatitis (AD) are inflammatory eczematous skin diseases caused by various factors. Here, we report that topical application of the dipeptide, L-glutamic acid-L-tryptophan (L-Glu-L-Trp), improved symptoms in both ACD and AD in mice. Using a mouse model of ACD induced by repeated application of 2,4-dinitorofluorbenzene (DNFB), we demonstrated that L-Glu-L-Trp attenuated DNFB-induced skin thickening. In addition, quantification of cytokines in serum revealed that L-Glu-L-Trp suppressed the DNFB-induced increase in the interleukin (IL)-22 level. Moreover, L-Glu-L-Trp attenuated mite antigen extract-induced AD model symptoms such as the increase of skin thickening and elevation of serum IL-22. We also confirmed that the dipeptide structure rather than the individual amino acid components was important for the therapeutic effects of L-Glu-L-Trp. Furthermore, we showed that IL-22 decreased the expression level of filaggrin mRNA in human epidermal keratinocytes, and L-Glu-L-Trp attenuated that effect. These results suggested that the topical application of the dipeptide, L-Glu-L-Trp, to the skin may be useful for treating ACD and AD.

Insulin-like growth factor-1 directly mediates expression of mitochondrial uncoupling protein 3 via forkhead box O4.

OBJECTIVE: The objective of our study was to examine the direct action of insulin-like growth factor-1(IGF-1) signaling on energy homeostasis in myocytes. DESIGN: We studied the IGF-1 stimulation of mitochondrial uncoupling protein 3 (UCP3) expression in the HEK 293 derived cell line TSA201, murine C2C12 skeletal muscle myoblasts, and rat L6 skeletal myoblasts. We also investigated the direct effect of IGF-1 on the Insulin/IGF-1 receptor (IGF-1R)/phosphatidylinositol 3 (PI3)-Akt/forkhead box O4 (FOXO4) pathway using a combination of a reporter assay, semi-quantitative polymerase chain reaction, western blotting, and animal experiments. RESULTS: We demonstrated that IGF-1 regulates UCP3 expression via phosphorylation of FOXO4, which is a downstream signal transducer of IGF-1. UCP3 expression increased with activated FOXO4 in a dose-dependent manner. We also examined the functional FOXO4 binding site consensus sequences and identified it as the -1922 bp site in the UCP3 promoter region. UCP3 was also found to be concomitantly expressed with IGF-1 during differentiation of C2C12 myoblasts. Our animal experiments showed that high fat diet induced IGF-1 levels which likely influenced UCP3 expression in the skeletal muscle. CONCLUSION: Our findings demonstrate that that IGF-1 directly stimulates UCP3 expression via the IGF-1/IGF-1R/PI3-Akt/FOXO4 pathway.

Association between circadian and chemotherapeutic cycle effects on plasma concentration of 5-fluorouracil and the clinical outcome following definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in patients with esophageal squamous cell carcinoma.

Therapeutic drug monitoring (TDM) of 5-fluorouracil (5-FU) is believed to be a clinical option for improving clinical responses. Evaluating the potential factors contributing to plasma 5-FU concentration is important to develop TDM of 5-FU. Our aim was to evaluate the association of the circadian and treatment cycle effects on plasma 5-FU concentration with the clinical response. A post hoc population analysis was performed using the plasma concentration of 5-FU and clinical response data, including prognosis from 49 patients with esophageal squamous cell carcinoma after treatment with definitive 5-FU/cisplatin-based chemoradiotherapy, consisting of prolonged infusion of 5-FU at 400 mg/(m2·day) for 5 days. The circadian rhythm and treatment cycle were applied as covariates to the model equation. The plasma 5-FU concentration in the evening was 1.3-fold higher compared with the morning, and in the second cycle, it was 1.5-fold increased compared with the first cycle, with relatively small inter-individual variations (23.3 and 16.8%). Clinical efficacy depended on the plasma 5-FU concentration, excluding the covariate effects (P=0.025), which correlated with age and height but not body surface area. Circadian variation did not contribute to the clinical response, and the increase in 5-FU plasma concentration in the second cycle significantly correlated with leucocyte counts obtained before chemoradiotherapy. The higher plasma concentration of 5-FU in the early phase of treatment may be the key determinant of clinical efficacy, whereas the variations in the plasma concentration of 5-FU owing to the time of day and treatment cycle are small contributors.

IGF-1 regulate the expression of uncoupling protein 2 via FOXO1.

Mitochondria uncoupling protein2 (UCP2) expressed ubiquitously is a key molecule of energy metabolism. Insulin-like growth factor-1 (IGF-1) is a hormone, a target molecule of growth hormone (GH) signal pathway, which is also known as the drug "mecasermin" for clinical usages. IGF-1 is seemed to be closely related to metabolic diseases, such as adult GH deficiency. However, there has not been reports depicted possible relationship with each other. So, we sought to elucidate the mechanisms by which expression of UCP2 is regulated by IGF-1 via FOXO1. The findings suggested that three sequences in the consensus UCP2 promoter play complementary functional roles in the functional expression of FOXO1. So, we found that FOXO1 is involved in IGF-1-mediated energy metabolism greater than that of direct action of GH via STAT5. Our findings suggested that IGF-1 was involved in energy metabolism by regulating the expression of UCP2 via the PI3K/Akt/FOXO1 pathway.

Lower Body Mass Index is a Risk Factor for In-Hospital Mortality of Elderly Japanese Patients Treated with Ampicillin/sulbactam.

Objectives: A retrospective examination was conducted to identify risk factors for in-hospital mortality of elderly patients (65 years or older) treated with the beta-lactam/beta-lactamase inhibitor combination antibiotic, ampicillin/sulbactam (ABPC/SBT). Methods: Clinical data from 96 patients who were hospitalized with infectious diseases and treated with ABPC/SBT (9 g/day or 12 g/day) were analyzed. Risk factors examined included demographic and clinical laboratory parameters. Parameter values prior to treatment and changes after treatment were compared between survivors and non-survivors. Results: The study patients had an average age of 81.9±8.4 years (±SD) and body mass index (BMI) of 19.9±4.2 kg/m2. They were characterized by anemia (low hemoglobin and hematocrit levels), inflammation (high leukocyte count, neutrophil count, C-reactive protein level, and body temperature), and hepatic and renal dysfunction (high aspartate aminotransferase, alanine aminotransferase and blood urea nitrogen levels). The BMI of non-survivors, 16.2±2.9 kg/m2, was lower than that of survivors, 20.4±4.1 kg/m2. In addition, the hematological parameters deteriorated more remarkably, inflammation markers were not altered (or the decrease was marginal), and hepatic function was not improved, in non-survivors. Conclusions: A lower BMI value is a risk factor for in-hospital mortality of elderly patients treated with ABPC/SBT.

Transport of Azithromycin into Extravascular Space in Rats.

Recent clinical trials showed a prolonged retention of subinhibitory concentrations of unbound azithromycin in the interstitial fluid of soft tissues despite the fact that azithromycin is extensively distributed in tissues. In these clinical trials, interstitial fluid samples were obtained by using the microdialysis method, and it was established that drug concentrations represent protein-unbound drug concentrations. The present study was designed to measure total azithromycin concentrations in the interstitial fluid of the skin of rats by directly collecting interstitial fluid samples from a pore formed on the skin by a dissolving microneedle array. The total azithromycin concentrations in interstitial fluid of the skin were about 4 to 5 times higher than those in plasma throughout the experimental period, and stasis of the azithromycin concentration in interstitial fluid was observed when the concentration of azithromycin in plasma was at the lower limit of quantification. In addition, the skin/plasma concentration ratio transiently increased after dosing (from 4.3 to 83.1). Our results suggest that azithromycin was trapped inside white blood cells and/or phagocytic cells in not only blood but also interstitial fluid, resulting in a high total azithromycin concentration and the retention of its antimicrobial activity at the primary infection site. The stasis of azithromycin in interstitial fluid and skin would lead to long-lasting pharmacological effects (including those against skin infection) at concentrations exceeding the MIC.

[A three-week regimen of S-1 monotherapy reduced gastrointestinal toxicity and maintained efficacy in patients with gemcitabine-refractory advanced pancreatic cancer].

S-1 administration for 28 consecutive days followed by 14 days of rest (6-week cycle) is often chosen as second-line chemotherapy for advanced pancreatic cancer (PC), but it causes gastrointestinal toxicity. In comparison, in gastric cancer or head and neck cancer, S-1 administration for 14 consecutive days followed by a 7-day rest period (3-week cycle) reduced gastrointestinal toxicity. This study retrospectively evaluated the efficacy and safety of a 3-week S-1 schedule compared to a 6-week schedule in patients with gemcitabine (GEM)-refractory advanced PC. Fifty-seven patients were treated with the 6- week S-1 schedule and 68 patients were treated with the 3-week S-1 schedule. There were no statistical differences in overall survival (p=0.13) and progression-free survival (p=0.190). With regard to adverse events, the rates of nausea (p<0.01) and vomiting (p=0.04) were lower with the 3-week schedule than with the 6-week schedule. Thus, S-1 therapy with a 3- week schedule as second-line chemotherapy in patients with GEM-refractory advanced PC was associated with reduced gastrointestinal toxicity and similar efficacy, when compared to a 6-week schedule.

Prognostic factors in patients with hepatocellular carcinoma refractory or intolerant to sorafenib.

OBJECTIVE: The aim of this study was to identify the prognostic factors in patients with advanced hepatocellular carcinoma (HCC) who are refractory or intolerant to sorafenib and to exclude unsuitable candidates from subsequent therapy. METHODS: The study cohort consisted of 111 patients who had discontinued sorafenib therapy. Uni- and multivariate analyses were conducted to identify the prognostic factors for survival after discontinuation of sorafenib therapy. RESULTS: The median age of the patients was 70 years, and 96 of them (86%) were male. The Eastern Cooperative Oncology Group performance status was 0-1 in 94 patients (85%). Forty patients (36%) were classified as Child-Pugh class A and 57 (51%) as Child-Pugh class B. The median survival time after discontinuation of sorafenib therapy was 146 days. Hepatitis C viral antibody negativity, presence of ascites, absence of a history of previous treatment excluding sorafenib, elevated serum total bilirubin level, and elevated serum α-fetoprotein level were identified as the independent unfavorable prognostic factors by multivariate analysis. The median survival time of the patients with 4 or 5 unfavorable prognostic factors was 59 days. CONCLUSIONS: We should judge the indication of any subsequent therapy carefully in patients with 4 or 5 of the aforementioned factors.

Serum lactate dehydrogenase levels as a predictive marker of oxaliplatin-induced hypersensitivity reactions in Japanese patients with advanced colorectal cancer.

OBJECTIVE: Clinical laboratory test data obtained prior to treatments were previously analyzed from the standpoint of susceptibility to hypersensitivity reactions in patients treated with the platimun anticancer agent, oxaliplatin (L-OHP). In the present study, the time course from the first to last cycle of the treatment was additionally analyzed to determine a better predictor of these reactions. METHODS: A total of 20 laboratory test data were obtained from 108 Japanese patients with advanced colorectal cancer who were treated with the L-OHP-containing regimens, FOLFOX4 and/or mFOLFOX6. The averages and variation coefficients (CV%) of the data until the last cycle of the treatment were compared between patients with hypersensitivity reactions and those without. RESULTS: The average serum lactate dehydrogenase (LDH) level was lower in patients with grade 1/2 reactions (P=0.016), whereas its CV% value was higher in patients with grade 3/4 reactions (P=0.005) than in those without reactions. An increase in serum LDH levels was observed in some patients with grade 3/4 reactions as the cycle number increased, and thereafter hypersensitivity reactions occurred. This phenomenon was not always observed, but was never detected in patients with grade 1/2 reactions. CONCLUSIONS: Serum LDH levels may be a predictive marker of hypersensitivity reactions in patients treated with L-OHP. Further extensive examinations with a larger number of patients are needed to establish a patient management strategy.

Genetic polymorphisms in SLC23A2 as predictive biomarkers of severe acute toxicities after treatment with a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma.

OBJECTIVE: Definitive chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and cisplatin (CDDP) is one of the standard therapies for esophageal squamous cell carcinoma (ESCC); however, inter-individual variations in clinical outcomes have yet to be investigated. In the present study, single nucleotide polymorphisms (SNPs) in SLC23A2 gene were retrospectively evaluated in 49 Japanese patients with ESCC who were treated with a definitive 5-FU/CDDP-based CRT, and the predictive values for the clinical response, severe acute toxicities, and long-term survival were assessed. METHODS: A course consisted of the continuous infusion of 5-FU at 400 mg/m(2)/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course being repeated after a 2-week interval. The SLC23A2 SNPs rs2681116, rs13037458, rs1715364, rs4987219, and rs1110277 were evaluated. RESULTS: The rs2681116 and rs13037458 had a tendency to predict the clinical response (p=0.144 and 0.085, respectively) and long-term survival (p=0.142 and 0.056, respectively). The rs4987219 and rs1110277 correlated with severe acute leukopenia (p=0.025) and stomatitis (p=0.019), respectively. CONCLUSIONS: Further investigations with a larger number of patients or an in vitro study are needed to confirm the predictive values of genetic polymorphisms in SLC23A2.

Efficacy of sorafenib in patients with hepatocellular carcinoma refractory to transcatheter arterial chemoembolization.

BACKGROUND: The efficacy of sorafenib for hepatocellular carcinoma (HCC) patients refractory to transcatheter arterial chemoembolization (TACE) has not yet been clarified. We investigated the efficacy of sorafenib in HCC patients who were refractory to TACE (sorafenib group) and retrospectively compared the results with those of patients treated with hepatic arterial infusion chemotherapy using cisplatin (cisplatin group). METHODS: We evaluated the anti-tumor effect, the time to progression, and the overall survival in 48 patients in the sorafenib group and 66 patients in the cisplatin group. RESULTS: The disease control rate to sorafenib was 60.4 %, the median time to progression was 3.9 months, and the median survival time was 16.4 months in patients who were refractory to TACE. When compared with the cisplatin group, significant differences in the patient characteristics were not observed between the two groups with the exception of patient age; however, the disease control rate (cisplatin group 28.8 %, P = 0.001), time to progression (cisplatin group: median 2.0 months, hazard ratio 0.44, P < 0.01), and overall survival (cisplatin group: median 8.6 months, hazard ratio 0.57, P < 0.001) were significantly superior in the sorafenib group. The multivariate analysis also showed the sorafenib treatment to be the most significant factor contributing to prolongation of time to progression and overall survival. CONCLUSIONS: Sorafenib showed favorable treatment results in patients refractory to TACE. When compared with hepatic arterial infusion chemotherapy using cisplatin, sorafenib demonstrated a significantly higher disease control rate, a longer time to progression and increased overall survival.

Early relapse of unresectable gallbladder cancer after discontinuation of gemcitabine monotherapy administered for 5 years in a patient who had complete response to the treatment.

The tumor shrinkage effect of gemcitabine is considered to be limited in cases of advanced gallbladder cancer, and there are few reports of complete response to gemcitabine therapy in patients with this cancer. Therefore, the treatment continuation strategy in these patients, after a complete response has been achieved, still remains to be established. Here, we present the case of a 77-year-old patient with unresectable gallbladder cancer, who after showing complete response to gemcitabine monotherapy administered for 5 years, showed early relapse within only 11 months of discontinuation of the drug. Thus, it is necessary to establish a suitable treatment continuation strategy for patients who show complete response to gemcitabine treatment.

TNF-α -857C>T genotype is predictive of clinical response after treatment with definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma.

BACKGROUND: Genotypes of tumor necrosis factor alpha (TNF-α) and its surface receptors, TNFRSF1A and TNFRSF1B, have been examined in terms of the progression, metastasis, clinical efficacy, and prognosis of various cancers; however, little is known about their effects on clinical outcome in patients with esophageal squamous cell carcinoma (ESCC). In this study, TNF-α and TNFRSF1A genotypes were retrospectively evaluated in terms of predicting clinical response, long-term survival, and severe acute toxicities in 46 male Japanese ESCC patients treated with definitive 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT). METHODS: A course consisted of the continuous infusion of 5-FU at 400 mg/m(2)/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1-5, 8-12, and 15-19, with a second course being repeated after a 2-week interval. The TNF-α -1031T>C (rs1799964), -863C>A (rs1800630), -857C>T (rs1799724), -308G>A (rs1800629), -238G>A (rs361525), TNFRSF1A -609G>T (rs4149570), and 36A>G (rs767455) genotypes were evaluated. RESULTS: The TNF-α -857C>T genotype was found to be predictive of clinical response, i.e., complete response or not (P = 0.010, Fisher's exact test), but had no effect on long-term survival (CC(-857) vs. CT(-857) + TT(-857), P = 0.072, Fisher's exact test, P = 0.070, Log-rank test). CONCLUSIONS: The TNF-α -857C>T genotype was found to be predictive of clinical response and was more likely to predict long-term survival in Japanese ESCC patients receiving definitive 5-FU/CDDP-based CRT. Further clinical investigations with a larger number of patients or experiments in vitro should be performed to assess the predictive value of this genotype following CRT.

Current status of hepatocellular carcinoma in Japan.

Approximately 32,000 patients die of primary liver cancer each year in Japan. The annual number of deaths from primary liver cancer in Japan ranks second only to that in China in the world. In recent years, there has been a gradual trend towards decrease in the number of liver cancer patients from its peak in Japan, and this trend is expected to also continue in the future. The main reason for this decreasing trend was the establishment of screening of transfusion products for hepatitis B and hepatitis C viruses, which prevents transfusion-related transmission of the viral infection. Most patients with hepatocellular carcinoma (HCC) in Japan have underlying viral hepatitis, with hepatitis C accounting for about two-third of all the patients and hepatitis B accounting for about 15%. Regular screening of patients with viral hepatitis infection makes it possible to diagnose HCC early, and also enables effective loco-regional treatment, such as surgical resection, local ablative therapy and transcatheter arterial chemoembolization (TACE). However, HCC recurrence is encountered frequently even after these potentially effective treatments. After numerous loco-regional treatments for recurrent HCC, chemotherapy is administered for patients with highly advanced HCC. Among the modalities of chemotherapy, hepatic arterial infusion chemotherapy (HAIC) is employed more commonly than systemic chemotherapy, although no survival advantage has ever been demonstrated. Randomized controlled studies are currently under way to clarify the survival benefit of HAIC. Also, various novel systemic chemotherapeutic agents are currently under development in Japan, and further improvements in the treatment outcomes are expected.

THRB genetic polymorphisms can predict severe myelotoxicity after definitive chemoradiotherapy in patients with esophageal squamous cell carcinoma.

OBJECTIVE: Chemotherapy-related toxicities are difficult to predict before treatment. In this study, we investigated whether thyroid hormone receptor beta (THRB) genetic polymorphisms can serve as a potential biomarker in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Forty-nine Japanese patients with ESCC who received a definitive chemoradiotherapy (CRT) with 5-fluorouracil and cisplatin in conjunction with concurrent irradiation were retrospectively analyzed. Severe acute toxicities, including leukopenia, stomatitis, and cheilitis, were evaluated according to 6 single nucleotide polymorphisms (SNPs) in the gene; the intronic SNPs of rs7635707 G/T, rs6787255 A/C, rs9812034 G/T, and rs9310738 C/T and the SNPs in the 3'-untranslated region (3'-UTR) of rs844107 C/T and rs1349265 G/A. RESULTS: Distribution of the 4 intronic SNPs, but not the 2 SNPs in the 3'-UTR, showed a significant difference between patients with and without severe acute leukopenia. Stomatitis and cheilitis were not associated with any of the 6 analyzed SNPs. Frequency of haplotype of the 4 intronic SNPs reached approximately 97% with the 2 major haplotypes G-A-G-C (73.4%) and T-C-T-T (23.5%). CONCLUSIONS: THRB intronic SNPs can provide useful information on CRT-related severe myelotoxicity in patients with ESCC. Future studies will be needed to confirm these findings.

VEGF -634C/G genotype is predictive of long-term survival after treatment with a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma.

BACKGROUND: Reports have been accumulating that genetic properties are predictive of clinical response after and/or toxicity during cancer chemotherapy, but little information is available concerning effects on long-term survival. In this study, 49 Japanese patients with esophageal squamous cell carcinoma (ESCC) were followed up for 5 years after treatment with a definitive 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT), and the effects of genotypes of vascular endothelial growth factor (VEGF) were retrospectively revaluated in terms of prediction of long-term survival. METHODS: A course consisted of the continuous infusion of 5-FU at 400 mg/m(2)/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course repeated after a 2-week interval. The VEGF genotypes -1498T/C, -1154G/A, -634C/G, -7C/T, 936C/T, and 1612G/A were evaluated. RESULTS: The complete response (CR) rate was 46.9% (23/49). The 5-year survival rate was 42.9 % (21/49). There were 7 patients with a CR, but survival of less than 5 years. They died from myocardial infarction (N=1), sudden cardiac death after suffering from heart failure (N=1), acute myeloid leukemia that developed from myelodysplastic syndromes (N=1), factors not specified (N=2), oropharynx cancer (N=1), and tongue cancer (N=1). VEGF -634C/G had no effect on clinical response, but long-term survival depended on the genotype (p=0.033, Fisher's; p=0.038, Cochran-Armitage; p=0.079, Log-rank). The genotype frequency of 7 patients with a CR, but survival of less than 5 years was different from that for the other 42 patients (p=0.032, Fisher's). None of the other 5 genotypes evaluated affected either clinical response or survival. CONCLUSIONS: VEGF -634C/G is possibly predictive of long-term survival after treatment with a definitive 5-FU/CDDP-based CRT. Further clinical studies with a larger number of cases are needed to clarify the effects of this genotype.