Biomedical subjects

Atsushi Ohtsu

Publications and source records attributed to Atsushi Ohtsu.

At least 37 records · Page 2Linked to original sources

PubMed2005

Risk of multiple squamous cell carcinomas both in the esophagus and the head and neck region.

While multiple squamous cell carcinomas are often observed in the esophagus and the head and neck region and confound us about the favorable treatments, the reason why some patients are more likely to develop multiple cancers remains obscure. We statistically analyzed clinical factors in 203 patients with newly diagnosed squamous cell carcinoma, to assess the risk of multiple cancers for the establishment of an effective prevention and screening programs. Widespread epithelial oncogenic alterations were assessed as multiple lugol-voiding lesions (multiple LVL) using lugol chromoendoscopy. Genetic polymorphisms of alcohol dehydrogenase type 3 (ADH3) and aldehyde dehydrogenase type 2 (ALDH2) were identified by PCR-restriction fragment length polymorphism analysis. Forty patients had synchronous multiple cancers and the remaining 163 had solitary cancer. Presence of multiple LVL was the only independent risk factor for multiple cancers [relative risk (RR) = 67; 95%CI, 15-310]. Multiple LVL was observed in only smoking drinkers. Among them, a multivariate analysis demonstrated that the ALDH2 deficiency allele (RR = 5.7; 95%CI, 2.8-11.6) and the slow metabolizing ADH3 allele (RR = 1.9; 95%CI, 1.1-7.9) were the independent risk factors for multiple LVL. Combination of these alleles lead to increase the risk of multiple LVL. In conclusion, an episode of multiple LVL is a remarkable high risk for multiple cancers both at the esophagus and the head and neck region. The interaction between drinking and the ALDH2 deficiency allele increases the risk. In addition, the slow metabolizing ADH3 allele enhances the risk. Prohibiting the use of alcohol and early detection of cancer are strongly recommended for such individuals.

Alcohol Dehydrogenase↗

PubMed2005

Japanese nationwide post-marketing survey of S-1 in patients with advanced gastric cancer.

BACKGROUND: It is likely that there are some discrepancies in the safety and efficacy results for anticancer agents between those shown in registration studies for approval and those shown in clinical practice after market release. The aim of this survey was to confirm the safety and efficacy of S-1 for advanced gastric cancer after market release. METHODS: After the approval of S-1 in 1999, all patients had to be registered with the manufacturer for a post-marketing survey, according to the government recommendation. All patients were monitored for safety and survival. The data for all registered patients were updated 1 year after each registration. RESULTS: During this survey, a total of 4177 patients with advanced gastric cancer were registered. The incidences of all adverse events and of grade 3 or worse adverse events in the 3808 patients evaluable for safety were 74.3% and 25.0%, respectively. In patients with lower creatinine clearance at baseline, the incidences of adverse reactions were higher for all grades combined, as well as for grades 3 or worse. There were 90 (2.4%) early deaths (within 30 days of the initiation of the treatment) and 5 (0.1%) deaths possibly related to the treatment. The median survival time and the 1-year survival rate for all patients evaluable for efficacy (n = 3801) were 8.3 months (95% confidence interval [CI], 8.0-8.6 months) and 33.3% (95% CI, 31.8-34.9%), respectively. CONCLUSION: This nationwide survey confirmed that the safety and efficacy profiles of S-1 were similar to those seen in the registration study. These results have proven the utility of this post-marketing survey in assessing the reproducibility of the safety and efficacy results obtained from prior clinical studies.

Aged↗

PubMed2005

Current status and future prospects of chemotherapy for metastatic gastric cancer: a review.

Although many randomized trials of chemotherapy for metastatic gastric cancer have been reported during the past two decades, no standard regimens worldwide have been established yet. Reference arms vary depending on the region and cultural differences. To date, a combination of 5-fluorouracil (5-FU) and cisplatin is most widely used. However, no confirmation of survival advantage over single-agent 5-FU in a randomized trial has been proved yet, and there remain limitations of efficacy results in older-generation regimens. Recently developed new agents such as irinotecan, taxanes (paclitaxel and docetaxel), and new oral fluorouracil (S-1 and capecitabine) provided more promising results: a response rate over 50% and median survival time (MST) over 10 months in their preliminary combination studies. These newer combination regimens are now being investigated in various randomized phase III studies, which will clarify whether the newer-generation regimens provide survival advantage over older-generation regimens. The MST of the new standard should exceed 11 months to be considered a definite improvement, and overall survival seems to be a more desirable primary end point than progression-free survival in a randomized trial. Molecular targeting agents are another concern to improve the treatment outcomes of this disease and are now under investigation in combination with conventional cytotoxic agents. Both clinical and biological research will be more important in future studies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Local recurrence of squamous-cell carcinoma of the esophagus after EMR.

BACKGROUND: Multicentric squamous dysplasia is frequent in the esophagus and can be visualized by chromoendoscopy (Lugol's solution) as multiple Lugol-voiding lesions (LVLs). Although EMR commonly is used to treat superficial esophageal cancer, new lesions can arise and incomplete resection can result in residual disease. Little is known about the risk factors for local recurrence or the appropriate treatment for recurrent lesions. METHODS: A total of 116 consecutive patients with a total of 165 esophageal squamous-cell carcinomas were studied retrospectively. Follow-up examination by means of chromoendoscopy (Lugol's solution) and biopsies was performed every 3 months during the first year after EMR and every 6 months thereafter. Lesions were defined as a local recurrence when cancer was detected at the site of the EMR scar. Risk factors associated with local recurrence were investigated by using logistic analysis. RESULTS: At a median follow-up of 35 months (range 12-110 months), local recurrence was detected for 33 (20%) of 165 lesions. Of the patient-related factors, multivariate logistic analysis showed that multiple LVLs (OR 3.1: 95% CI[1.1, 8.5]; p = 0.03) was an independent risk factor for local recurrence after EMR. The cumulative local recurrence rates at 3 years in patients with multiple LVLs and those without multiple LVLs were 39% and 14% (p < 0.01), respectively. All of the recurrent lesions except two could be removed by EMR, which was not associated with any serious complication. The remaining two patients had chemoradiotherapy. Overall cause-specific survival at 3 years was 100%. CONCLUSIONS: Patients with multiple LVLs are at risk of local recurrence after EMR. Although careful long-term endoscopic follow-up is needed for such patients, EMR is potentially curative for recurrent lesions.

Adult↗

PubMed2005

Photodynamic therapy as salvage treatment for local failures after definitive chemoradiotherapy for esophageal cancer.

BACKGROUND: Although definitive chemoradiotherapy for esophageal cancer shows a high response rate, persistent or recurrent locoregional disease remains a major problem. Salvage esophagectomy is the only curative intent treatment option; however, it carries higher morbidity and mortality rates than primary esophagectomy. Response to second-line chemotherapy is quite dismal. METHODS: From December 2002 to November 2003, we applied salvage photodynamic therapy to 13 patients with local failures after completion of chemoradiotherapy, 4 patients had local recurrence after achieving a complete response, and 9 had a persistent tumor after chemoradiotherapy. The decision to treat was based on patients' refusal of salvage surgery or chemotherapy. After the intravenous administration of 2 mg/kg of Photofrin, photoradiation treatment with an excimer dye laser was performed for 48 hours and 72 hours after the injection. Written informed consent was obtained from all patients. RESULTS: Eight patients (62%) achieved a complete response. After a median follow-up period of 12 months after photodynamic therapy, 6 patients were still free of disease, and the overall survival rate at 1 year was 68.4%. There were no treatment-related deaths. CONCLUSIONS: Our results show that salvage photodynamic therapy could be a promising curative intent treatment option with low morbidity and mortality rates.

Aged↗

PubMed2005

Overview of adjuvant therapy for resected gastric cancer: differences in Japan and the United States.

Survival in adjuvant chemotherapy following resected gastric cancer has been studied by both Japanese and Western investigators using varied chemotherapy regimens in different target patients. Gastrectomy with D2 lymphadenectomy is the standard in Japan, and trials of adjuvant therapy in these patients have shown no survival advantages over surgery alone. In the United States, where 5-year survival rates in patients with gastric cancer are much lower following potentially curative surgery, adjuvant therapy has shown a survival benefit. The differences observed in these trials may result from the additional experience that Japanese surgeons have gained because of the higher incidence of gastric cancer there, or because of this increased incidence, there are more stringent screening guidelines in place and these cancers are possibly being diagnosed at an earlier stage. The Japanese viewpoint on the use of adjuvant therapy in patients with gastric cancer following potentially curative resection is that the quality of surgery, including diagnostic and pathologic procedures, is a more important prognostic factor than adjuvant chemotherapy. Also, they have determined from previously conducted clinical trials that patients with stage 1-2 tumors should be excluded from the target populations of randomized trials. Until the results of INT-0116 became available, there had been no improvement, or only marginal improvement, in overall or disease-free survival for patients receiving adjuvant chemotherapy following gastric cancer resection in the United States and Europe.

Adenocarcinoma↗

PubMed2005

Japanese multicenter phase II study of CHOP followed by radiotherapy in stage I-II, diffuse large B-cell lymphoma of the stomach.

CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) followed by radiotherapy is regarded as standard care for localized aggressive lymphoma; however, prospective confirmation of its applicability to localized primary gastric lymphoma is inadequate, and most patients in Japan have been initially treated with gastrectomy. We conducted a multicenter phase II study to evaluate the feasibility and efficacy of the non-surgical treatment. Eligibility criteria required primary gastric diffuse large B-cell lymphoma, stage I-II(1), age 20-75, performance status 0-1 and adequate organ function. Treatment consisted of three cycles of CHOP followed by radiotherapy 40.5 Gy. Fifty-five patients were enrolled between December 1999 and February 2003, and 52 eligible patients were analyzed. Patient characteristics were as follows: median age, 61 years; 28 men, 24 women; 36 with stage I, 16 with stage II(1); 47 with a low International Prognostic Index (IPI) and five with a low-intermediate IPI. All but one patient completed planned treatment. No serious complications including massive hemorrhage or perforation were observed. A complete response was achieved in 48 of the 52 patients (92%, 95% confidence interval: 82-98%) and progressive disease in three. Two patients underwent salvage gastrectomy due to disease persistence or recurrence. With a median follow-up period of 28 months, 2-year progression-free and overall survivals were 88 and 94%, respectively. CHOP followed by radiotherapy is safe and highly effective in localized gastric diffuse large B-cell lymphoma. This organ-preserving treatment should be considered as a very reasonable therapeutic option.

Administration, Oral↗

PubMed2005

Genetic variations and haplotypes of UGT1A4 in a Japanese population.

Nineteen genetic variations, including 11 novel ones, were found in exon 1 and its flanking region of the UDP-glucuronosyltransferase (UGT) 1A4 gene from 256 Japanese subjects, consisting of 60 healthy volunteers, 88 cancer patients and 108 arrhythmic patients. These variations include -217T>G and -36G>A in the 5'-flanking region, 30G>A (P10P), 127delA (43fsX22; frame-shift from codon 43 resulting in the termination at the 22nd codon, codon 65), 175delG (59fsX6), 271C>T (R91C), 325A>G (R109G), and 357T>C (N119N) in exon 1, and IVS1+1G>T, IVS1+98A>G and IVS1+101G>T in the following intron. Among them, 127delA and 175delG can confer early termination of translation, resulting in an immature protein that probably lacks enzymatic activity. Variation IVS1+1G>T is located at a splice donor site and thus may lead to aberrant splicing. Since we did not find any significant differences in the frequencies of all the variations among the three subject groups, the data were analyzed as one group. The allele frequencies of the novel variations were 0.006 for IVS1+101G>T, 0.004 for 30G>A (P10P) and 357T>C (N119N), and 0.002 for the 8 other variations. In addition, the two known nonsynonymous single nucleotide polymorphisms (SNPs), 31C>T (R11W) and 142T>G (L48V), were found at 0.012 and 0.129 frequencies, respectively. The SNP 70C>A (P24T), mostly linked with 142T>G (L48V) in German Caucasians, was not detected in this study. Sixteen haplotypes were identified or inferred, and some haplotypes were confirmed by cloning and sequencing. It was shown that most of 142T>G (L48V) was linked with -219C>T, -163G>A, 448T>C (L150L), 804G>A (P268P), and IVS1+43C>T, comprising haplotype *3a; haplotype *4a harbors 31C>T (R11W); 127delA (43fsX22) and 142T>G (L48V) were linked (haplotype *5a); 175delG (59fsX6) was linked with 325A>G (R109G) (*6a haplotype); and -219C>T, -163G>A, 142T>G (L48V), 271C>T (R91C), 448T>C (L150L), 804G>A (P268P), and IVS1+43C>T comprised haplotype *7a. Our results provide fundamental and useful information for genotyping UGT1A4 in the Japanese and probably Asian populations.

Arrhythmias, Cardiac↗

PubMed2005

Novel genetic polymorphisms in the NR3C1 (glucocorticoid receptor) gene in a Japanese population.

Glucocorticoid receptor, encoded by NR3C1, is a transcriptional regulator of many drug metabolizing enzymes and anti-inflammatory molecules. In order to identify genetic variations of the NR3C1 gene, genomic DNA from 265 Japanese individuals was sequenced. Fifty genetic polymorphisms were identified, including 32 novel ones [3 were in coding exons, 17 in the introns, 4 in the 5'-untranslated region (UTR), and 8 in the 5'-flanking region]. The novel nonsynonymous variation was 420G>T (Lys140Asn), and the allele frequency was 0.004. We did not detect any nonsynonymous polymorphism reported previously in other races, including a relatively frequent SNP Asn363Ser found in Caucasians and African-Americans. Thus, ethnic differences between Japanese and other races are suggested to exist in NR3C1.

Amino Acid Substitution↗

PubMed2005

Genetic polymorphisms of UGT1A6 in a Japanese population.

Thirteen single nucleotide polymorphisms (SNPs), including 6 novel ones, were found in exon 1 and its flanking region of UDP-glucuronosyltransferase (UGT) 1A6 from 195 Japanese subjects. Several novel SNPs were identified, including 269G>A (R90H), 279A>G (S93S), and 308C>A (S103X) in exon 1, and IVS1+109C>T, IVS1+120A>G, and IVS1+142C>T in the intron downstream of exon 1. Among these SNPs, 308C>A confers termination of translation at codon 103, resulting in the production of an immature protein that probably lacks enzymatic activity. The allele frequencies were 0.003 for all the 6 SNPs. In addition, the 3 known nonsynonymous SNPs were detected: 19T>G (S7A), 541A>G (T181A), and 552A>C (R184S) with frequencies of 0.226, 0.218, and 0.226, respectively. High linkage disequilibrium was observed among 19T>G (S7A), 315A>G (L105L), 541A>G (T181A), 552A>C (R184S), and IVS1+130G>T, as reported in Caucasian and African-American populations. Then, 11 haplotypes in UGT1A6 were estimated. The novel nonsynonymous variant, 269A or 308A, was shown to be located on the same DNA strand together with 19G, 315G, 541G, 552C, and IVS1+130T. Our results provide fundamental and useful information for genotyping UGT1A6 in the Japanese, and probably Asian populations.

Asian People↗

PubMed2004

Squamous cell carcinoma in situ at oropharyngeal and hypopharyngeal mucosal sites.

BACKGROUND: Head and neck squamous cell carcinoma typically is diagnosed at an advanced stage, and the prognosis for patients with this type of malignancy is poor. Detection of these lesions at an earlier stage (e.g., as carcinoma in situ) would be of clear benefit to patients. However, it has been extremely difficult to detect carcinoma in situ at head and neck mucosal sites during routine endoscopy, even after numerous passes of the endoscope through the oral cavity and the pharynx. METHODS: The current clinical investigation was performed during routine endoscopic screening or surveillance procedures. The authors used a novel optical technique, known as narrowband imaging (NBI) that allows noninvasive visualization of the microvascular structure of an organ's surface using reflected light. RESULTS: Between April 2002 and August 2003, 34 consecutive superficial lesions were found in 18 patients. Multifocal carcinoma was found in 5 patients (28%). The median age of the patients examined was 59.5 years (range, 43-71 years), and 83% of all patients were male. All lesions exhibited a microvascular proliferation pattern on magnified NBI. Thirteen patients with a combined total of 29 lesions underwent endoscopic resection under general anesthesia. The pyriform sinus was the most frequent primary site (66%; 19 of 29 lesions). The median tumor diameter was 20 mm (range, 1.3-40 mm). Twenty-one lesions (72%) were histologically confirmed to be carcinoma in situ, and the remaining lesions showed evidence of microinvasion (0.05-1 mm) beneath the epithelium. Vascular invasion was observed in only one lesion. The median hospital stay was 10 days (range, 4-18 days). All patients were discharged without severe complications. After a median follow-up period of 8 months (range, 1-16 months), there were no cases of local disease recurrence. CONCLUSION: The authors stress the importance of endoscopic detection of superficial carcinoma at oropharyngeal and hypopharyngeal mucosal sites. NBI is a promising and potentially powerful tool for identifying carcinomas at an earlier stage during routine endoscopic examination.

Adult↗

PubMed2004

Phase II study of oral S-1 for treatment of metastatic colorectal carcinoma.

BACKGROUND: The goal of the current study was to evaluate the objective response rate and toxicity associated with the oral fluoropyrimidine S-1 (a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate) in patients with previously untreated metastatic colorectal carcinoma. METHODS: Thirty-eight patients were enrolled in the study. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 days, followed by a 14-day rest period. Treatment was repeated every 6 weeks unless disease progression was observed. RESULTS: A combined total of 173 courses of S-1 were administered to the 38 enrolled patients. The median number of courses administered to a given patient was 3.5 (range, 1-18). Although no patient exhibited a complete response to treatment, 15 had partial responses (response rate, 39.5%; 95% confidence interval, 24.0-56.6%). In addition, 5 patients had minor responses, and 14 had stable disease. Four patients were found to have progressive disease after two courses of treatment. The median survival time was 358 days (95% confidence interval, 305-490 days), and the 1-year survival rate was 47.4%. The most common adverse reactions included myelosuppression and gastrointestinal toxicity; most cases involved Grade 1 or 2 toxicity, but Grade 3 toxicities (anemia [7.9% of patients], neutropenia [5.3% of patients], diarrhea [2.6% of patients], and abnormal bilirubin levels [7.9% of patients]) also were noted. Neither Grade 4 toxicity nor treatment-related death was observed during the study. CONCLUSIONS: Orally administered S-1 is active against metastatic colorectal carcinoma and has an acceptable toxicity profile. This promising agent has the potential to become a valuable chemotherapeutic option.

Adenocarcinoma↗

PubMed2004

Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population.

In order to identify single nucleotide polymorphisms (SNPs) and haplotype frequencies of CYP3A4 in a Japanese population, the distal enhancer and proximal promoter regions, all exons, and the surrounding introns were sequenced from genomic DNA of 416 Japanese subjects. We found 24 SNPs, including 17 novel ones: two in the distal enhancer, four in the proximal promoter, one in the 5'-untranslated region (UTR), seven in the introns, and three in the 3'-UTR. The most common SNP was c.1026+12G>A (IVS10+12G>A), with a 0.249 frequency. Four non-synonymous SNPs, c.554C>G (p.T185S, CYP3A4(*)16), c.830_831insA (p.E277fsX8, (*)6), c.878T>C (p.L293P, (*)18), and c.1088 C>T (p.T363M, (*)11) were found with frequencies of 0.014, 0.001, 0.028, and 0.002, respectively. No SNP was found in the known nuclear transcriptional factor-binding sites in the enhancer and promoter regions. Using these 24 SNPs, 16 haplotypes were unambiguously identified, and nine haplotypes were inferred by aid of an expectation-maximization-based program. In addition, using data from 186 subjects enabled a close linkage to be found between CYP3A4 and CYP3A5 SNPs, especially among the SNPs at c.1026+12 in CYP3A4 and c.219-237 (IVS3-237, a key SNP site for CYP3A5(*)3), c.865+77 (IVS9+77) and c.1523 in CYP3A5. This result suggested that CYP3A4 and CYP3A5 are within the same gene block. Haplotype analysis between CYP3A4 and CYP3A5 revealed several major haplotype combinations in the CYP3A4-CYP3A5 block. Our findings provide fundamental and useful information for genotyping CYP3A4 (and CYP3A5) in the Japanese, and probably Asian populations.

Cytochrome P-450 CYP3A↗

PubMed2004

Chemoradiotherapy for esophageal cancer: current status and perspectives.

The optimal role of chemoradiotherapy in the multimodality treatment of esophageal cancer is still controversial. According to a series of clinical trials, definitive chemoradiotherapy is considered the standard of care for patients with medically inoperable or surgically unresectable esophageal cancer. This modality provides survivals comparable to those in Western series of surgery alone and is one of the standards of care even for resectable-stage disease. Recent reports of primary chemoradiotherapy from Japan suggest survival comparable to that of surgery in Japanese patients with stage I disease, but radical surgery is still the standard treatment for T2-3NanyM0 disease in Japan. However, it is clear that this approach has limitations in treatment outcomes. Trimodality therapy, i.e., preoperative chemoradiotherapy followed by surgery, is more favored than surgery alone in clinical practice, particularly in patients with adenocarcinoma, although current data from randomized trials are insufficient to support this approach. To improve the local control rate of chemoradiotherapy, intensification of the radiation dose has been attempted, but this has failed to demonstrate any superiority in terms of local control or survival. The addition of new agents, including molecular targeting agents, to the current standard chemoradiotherapy has shown more promising results and warrants further investigations in future studies. Salvage treatment for patients who do not achieve a complete response (CR) is necessary to improve the overall treatment results. Salvage surgery, as well as endoscopic resection, in selected patients, may provide an improvement in survival. Until high rates of local control can be consistently achieved with chemoradiotherapy alone, these salvage treatments will be an integral component of multimodality treatment for esophageal cancer, and should be active areas for clinical investigations.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer.

PURPOSE: A comprehensive haplotype analysis of UGT1A1 in the Japanese population was conducted, and the effects of these haplotypes were investigated with respect to UGT1A1-related phenotypic parameters in patients with cancer who received irinotecan. METHODS: The UGT1A1 gene, including the enhancer, the promoter, and all 5 exons and their flanking regions, was sequenced from 195 Japanese subjects. The gene was divided into 2 blocks, and the haplotypes of each block were assigned. The association of these haplotypes with area under the concentration-time curve (AUC) ratios (7-ethyl-10-hydroxycamptothecin glucuronide [SN-38G]/7-ethyl-10-hydroxycamptothecin [SN-38]) and pretreatment levels of serum total bilirubin was investigated in 85 cancer patients who received irinotecan. RESULTS: Four haplotype groups (*1, *60, *28, and *6) were assigned in block 1, and 2 haplotype groups (*IA and *IB) were in block 2. The majority of the *IB haplotypes in block 2 were linked to either the *1 or the *60 haplotype but not to *28 in block 1. Highly significant associations were obtained between the *28 haplotypes and both a reduced AUC ratio (P =.0014, Jonckheere-Terpstra [JT] test) and an increased total bilirubin level (P =.0007, JT test). Increased total bilirubin levels in the *60 (P =.0048, JT test) and *IB groups (P =.0224, JT test) were also observed. The reduction in the AUC ratio by the *6 group was moderate (P =.0372, JT test) but was remarkable in combination with *60 (*6/*60) or *28 (*6/*28) as compared with the *1 group (*1/*1) (P =.049 and P =.0071, respectively; nonparametric Dunnett test). CONCLUSION: This study identified several UGT1A1 haplotypes significantly associated with the reduced AUC ratio (*28 and *6) and with the increased total bilirubin level (*28, *60, and *IB) and suggested that the novel haplotype *IB might be functionally important. These findings will be useful for further pharmacogenetic studies on adverse reactions to irinotecan.

Aged↗

PubMed2004

Phase II study of sequential methotrexate and 5-fluorouracil chemotherapy against peritoneally disseminated gastric cancer with malignant ascites: a report from the Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group, JCOG 9603 Trial.

BACKGROUND: The efficacy of systemic chemotherapy against peritoneal dissemination from advanced gastric cancer (AGC) remains unclear, because the peritoneal dissemination was not defined as a measurable lesion in conventional phase II studies. In this study, we evaluated the efficacy and toxicity of sequential MTX and 5FU therapy (MF) in chemotherapy-naive patients with AGC accompanied by malignant ascites in a phase II setting. METHODS: The treatment schedule comprised weekly administration of MTX (100 mg/m2, i.v. bolus) followed by 5FU (600 mg/m2, i.v. bolus) with a 3 h interval. Leucovorin rescue (10 mg/m2 every 6 h, for a total of six times) was commenced 24 h after MTX administration. RESULTS: Thirty-seven chemotherapy-naive patients with AGC presenting with malignant ascites were enrolled in this trial. The median age was 60 years (range, 25-74 years) and most patients (86%) had a performance status of 0-1. In total, 355 administrations of the sequential MTX/5FU therapy were performed. Major toxicity consisted of myelosuppression and gastrointestinal toxicity. Grade 4 neutropenia occurred in 10.8% of the patients. The overall objective response rate was 5.7% (two partial responses in 35 patients; 95% confidence interval: 0.7-19.2%). However, the response rate of ascites was 35.1% (complete disappearance in three patients and apparent decrease in 10 patients; 95% confidence interval: 20.2-52.5%). CONCLUSIONS: Sequential MTX/5FU therapy is effective against AGC with malignant ascites with acceptable toxicity and warrants further investigations in a phase III setting.

Adult↗

PubMed2004

Long-term survival and prognostic factors in patients with metastatic gastric cancers treated with chemotherapy in the Japan Clinical Oncology Group (JCOG) study.

BACKGROUND: The long-term survival of patients after chemotherapy for advanced gastric cancer remains unclear. The aim of this analysis was to investigate prognostic factors for patients with metastatic gastric cancer treated by chemotherapy, and to identify the characteristics of long-term survivors. METHODS: Six hundred and forty three patients were enrolled in four phase II studies and one phase III study by the Japan Clinical Oncology Group between January 1985 and April 1997. By adjusting patients' eligibility between the five studies, 497 patients (77%) were selected for the analysis. Univariate and multivariate analyses were performed using log-rank tests and Cox's proportional hazard model, respectively. RESULTS: Of the 497 patients analyzed, 39 (8%) and 11 (2%) patients have survived longer than 2 and 5 years, respectively. By multivariate analysis, better performance status, a small number of metastatic sites and macroscopically non-scirrhous type tumors were significantly associated with better prognosis. Characteristics of the 11 5-year survivors revealed eight with para-aortic node metastases alone. Eight of these patients received gastrectomy; four underwent it before chemotherapy, and the other four patients received it after achieving downstaging with successful chemotherapy. CONCLUSIONS: These results demonstrated that better performance status, a small number of metastatic sites and macroscopically non-scirrhous type tumors are independent favorable factors for survival. There were a few 5-year survivors with unresectable gastric cancers, most of whom had only abdominal lymph node metastases and received gastrectomy before or after chemotherapy.

Adult↗

PubMed2004

Genetic variations of the AHR gene encoding aryl hydrocarbon receptor in a Japanese population.

Aryl hydrocarbon receptor (AhR), encoded by the AHR gene, is a transcriptional factor that induces various drug metabolizing enzymes in response to diverse endogenous and exogenous ligands. In order to identify genetic variations of the AHR gene, genomic DNA from 242 Japanese individuals was sequenced. We identified 32 single nucleotide variations, including 25 novel ones [7 were in the coding exons, 7 in the introns, 1 in the 5'-untranslated region (UTR), 5 in the 3'-UTR, 2 in the 5'-flanking region, and 3 in the 3'-flanking region] and a GGGGC repeat polymorphism (a novel microsatellite marker) in the promoter region. The novel nonsynonymous variations were 50A>C (Lys17Thr), 1202A>G (Lys401Arg), 1459A>G (Asn487Asp), and 1541T>C (Ile514Thr). The allele frequencies were 0.010 for 1459A>G (Asn487Asp) and 0.002 for the other 3 variations. Also detected in this analysis was the known nonsynonymous single nucleotide polymorphism 1661G>A (Arg554Lys) at a 0.444 frequency.

Asian People↗