Docetaxel 75 mg/m(2) is active and well tolerated in patients with metastatic or recurrent gastric cancer: a phase II trial

OBJECTIVE: The aim of the present study was to confirm the efficacy and tolerability of docetaxel 75 mg/m(2) in a population of Korean patients with advanced gastric cancer. METHODS: Patients with metastatic or locally recurrent gastric cancer received docetaxel 75 mg/m(2) by intravenous infusion every 3 weeks. Objective response rate was the primary endpoint. RESULTS: Forty-five patients were enrolled. Most showed adenocarcinomas of the gastric antrum and/or body of the stomach. All showed metastases and two-thirds retained the primary tumour. Forty-four patients received at least one docetaxel infusion ('treated' population), with 40 patients evaluable for response. A total of 159 cycles (median three cycles) were administered, with mean duration of treatment 10.9 weeks. The objective response rate in the treated population was 15.9% (17.5% in the per protocol population), with stable disease in 25.0% of patients and progressive disease in 50.0%. Grade 3-4 neutropenia occurred in 36 (81.8%) patients and 36.1% of cycles. However, febrile neutropenia occurred in only two (4.5%) patients and 1.3% of cycles. Grade 3 anorexia, experienced by two patients (4.5%) and during 1.9% of cycles, was the most frequent non-haematological adverse event possibly or probably related to docetaxel. No grade 4 non-haematological events occurred. CONCLUSION: This study suggests that docetaxel 75 mg/m(2) is active in metastatic or locally recurrent adenocarcinoma with a low incidence of grade 3-4 adverse events. Docetaxel warrants further study in combination regimens for advanced gastric cancer.     

Differential associations of body mass index and adiposity with all-cause mortality among men in the first and second National Health and Nutrition Examination Surveys (NHANES I and NHANES II) follow-up studies

OBJECTIVE: The frequently observed U-shaped relationship between body mass index (BMI; kg/m(2)) and mortality rate may be due to the opposing effects of fat mass (FM) and fat-free mass (FFM) components of BMI on mortality rate. The purpose is to test the hypothesis stated above. DESIGN: Longitudinal prospective cohort studies. The mortality follow-up of the first and second National Health and Nutrition Examination Surveys (NHANES I and NHANES II). SUBJECTS: A total of 10 169 male subjects aged 25-75 who participated in NHANES I and II were selected for analyses. Follow-up continued until 1992. The mean follow-up time was 14.6 y for NHANES I and 12.9 y for NHANES II. Ninety-eight percent of the participants were successfully followed representing a total of 3722 deaths. MEASUREMENTS: Subscapular and triceps skinfolds thickness were used as FM indicators, whereas upper arm circumference was used as a FFM indicator. The Cox proportional hazards model tested the relationships of BMI, FM and FFM with all-cause mortality adjusting for age, smoking status, race and education levels. RESULTS: BMI had a U-shaped relationship with mortality, with a nadir of approximately 27 kg/m(2). However, when indicators of FM and FFM were added to the model, the relationship between BMI and mortality became more nearly monotonic increasing. Moreover, the relationship between FM indicator and mortality was monotonic increasing and the relationship between FFM indicator and mortality was monotonic decreasing. CONCLUSION: These results support the hypothesis that the apparently deleterious effects of marked thinness may be due to low FFM and that, over the observed range of the data, marked leanness (as opposed to thinness) has beneficial effects.     

RET oligonucleotide microarray for the detection of RET mutations in multiple endocrine neoplasia type 2 syndromes.

Multiple endocrine neoplasia type 2 (MEN2) syndromes are inherited in an autosomal dominant fashion with high penetrance. There are three subtypes, namely, MEN2A (multiple endocrine neoplasia type 2A), MEN2B (multiple endocrine neoplasia type 2B), and familial medullary thyroid carcinoma. The variations in the RET gene play an important role in the MEN2 syndromes. In this work, we have developed a RET oligonucleotide microarray of 67 oligonucleotides to quickly detect RET mutations in MEN2 syndromes. The predominant RET mutations are missense mutations and are restricted to nine codons (codons 609, 611, 618, 620, 630, 634, 768, 804, and 918) in MEN2 syndromes. Missense mutations at codons 609, 611, 618, 620, and 634 have been identified in 98% of MEN2A families and in 85% of familial medullary thyroid carcinoma families. More than 95% of MEN2B patients also had a predominant mutation type at codon 918 (Met-->Thr). RET oligonucleotide microarray can detect RET missense mutations at these nine codons. Theoretically, a total of 55 missense mutation types can occur at eight codons (codons 609, 611, 618, 620, 630, 634, 768, and 804). RET oligonucleotide microarray is designed to detect all of these 55 missense mutation types at these eight codons and one predominant type at codon 918. Fifty-six oligonucleotides were designed for the 56 mutation types at nine codons, and 11 oligonucleotides were designed for the wild types and positive controls. We found RET mutations in all eight of the Korean MEN2A families (a total of 75 members; 27 affected members, 19 gene carriers, and 29 unaffected members) using the developed RET oligonucleotide microarray and an automatic sequencing. Because we found only five mutation types from eight MEN2A families, the international collaborations are required to see whether the RET oligonucleotide microarray may be used as a genetic diagnostic tool. Taken together, the RET oligonucleotide microarray can function as a fast and reliable genetic diagnostic device, which simplifies the process of detecting RET mutations.     

Hepatitis B virus infection and B-cell non-Hodgkin's lymphoma in a hepatitis B endemic area: a case-control study.

Several studies have reported a higher prevalence of chronic hepatitis C virus (HCV) infection in patients with B-cell non-Hodgkin's lymphoma and suggested a pathogenic role for HCV, but studies on hepatitis B virus (HBV) infection and non-Hodgkin's lymphoma are limited. To determine the association between HBV infection and non-Hodgkin's lymphoma, we performed a case-control study in Korea, a hepatitis B endemic area. We recruited 222 patients newly diagnosed with non-Hodgkin's lymphoma at Seoul National University Hospital between January 1997 and December 1998 as cases. Four age- and sex-matched controls were selected for each case, and the control groups comprised of 439 patients with non-hematological malignancy (control group 1) and 444 subjects with non-malignant conditions (control group 2). Relative risk of developing non-Hodgkin's lymphoma among individuals tested positive for hepatitis B surface antigen was calculated after controlling for other potential risk factors of lymphoma, such as smoking, alcohol drinking, transfusion history and HCV infection. Hepatitis B surface antigen was positive in 28 of 222 patients (12.6%) with non-Hodgkin's lymphoma compared with 32 of 439 (7.3%) in control group 1, and 21 of 444 (4.7%) in control group 2 (P = 0.001). The crude odds ratio for B-cell non-Hodgkin's lymphoma among the HBV carriers was 2.54 (1.46 - 4.45) and the adjusted odds ratio was 3.30 (1.69 - 6.45) by multivariate analysis. The present study suggests that the risk of B-cell non-Hodgkin's lymphoma is increased in HBV carriers and warrants further investigation of the possible role of hepatitis B virus in the pathogenesis of B-cell non-Hodgkin's lymphoma.     

Germline mutations of the dpc4 gene in Korean juvenile polyposis patients

Juvenile polyposis is an uncommon condition characterized by the development of multiple (usually more than 5) juvenile polyps in the gastrointestinal tract, especially in the colon. This disease usually occurs during childhood, and is inherited in an autosomal dominant fashion. It has been suggested that the dpc4 (deleted in pancreatic carcinoma, locus 4) gene, which is located on chromosome 18q21.1, might cause juvenile polyposis. The dpc4 (smad4) gene is a candidate tumor-suppressor gene and may play a role in the TGF-beta-signaling pathway. To confirm the idea that alterations of the dpc4 gene may result in juvenile polyposis, we screened 5 Korean juvenile-polyposis patients by PCR-SSCP (single-strand conformation polymorphism) analysis and bi-directional sequencing. There were germline mutations of the dpc4 gene in 3 out of the 5 patients: 2 had a genetic alteration in exon 9 and the third had a mutation in exon 8. These germline mutations occurred in the C-terminus of the dpc4 gene, similar to most published mutations. One patient exhibited a non-sense mutation (codon 388), which changed a glutamine codon (CAG) to a stop codon (TAG). The second patient harbored a mis-sense mutation (codon 390), causing a non-conservative amino-acid change . The third patient had a mis-sense mutation in exon 8 (codon 361), which altered an arginine codon (CGC) into a histidine codon (CAC).     

The expression of MHC class I, TAP1/2, and LMP2/7 gene in human gastric cancer cell lines

Intracellular antigens are presented to CD8+ T cells through major histocompatibility complex (MHC) class I molecule. For stable MHC class I expression, several molecules as well as the MHC molecule itself have to express simultaneously and function well. To determine a gene associated with MHC class I surface expression, the expressions of LMP2/7 and TAP1/2 including MHC I gene were analyzed in ten human gastric cancer cell lines, using RT-PCR and Northern blot analysis. Although LMP2, TAP1/2, and MHC class I gene expression were reduced in some cells, this was not significantly associated with MHC class I surface expression. By comparison, the expression of LMP7 was significantly reduced in three of ten cell lines, which also showed low levels of MHC class I surface expression, and increased in four of ten cell lines, which also showed high levels of MHC class I surface expression. These results suggest that the level of MHC class I surface expression is associated, in most cases, with the expression of the LMP7 gene regardless of the LMP2, TAP1, TAP2, or MHC class I genes.     

Paclitaxel/Platinum-based perioperative chemotherapy and surgery in stage IIIA non-small cell lung cancer

OBJECTIVE: The objectives of the present study were to assess the efficacy and tolerability of perioperative paclitaxel/platinum-based chemotherapy and surgery in patients with stage IIIA clinical N2 (cN2) non-small cell lung cancer (NSCLC). METHODS: Clinical N2 was defined as either >15 mm or >10 mm and multiple nodes on computed tomography (CT) scan. Thirty-four chemotherapy-naive patients with stage IIIA cN2 received preoperative paclitaxel/cisplatin for two cycles and then underwent surgery. The treatment with paclitaxel/carboplatin was repeated for three cycles after the operation. RESULTS: Of the 34 patients, none achieved a complete response (CR) and 22 achieved a partial response (PR), resulting in a response rate of 65%. Among 29 patients (85%) who had received thoracotomy, 25 (74%) underwent complete resection. Two pathological CRs were observed and mediastinal nodes were free of tumor in 21%. Grade 3-4 toxicity was uncommon and treatment-related mortality was not observed. The median time to progression (TTP) was 12.1 months [95% confidence interval (CI) 8.3-15.9 months] and median overall survival (OS) was 23.6 months (95% CI 17.7-30.2 months). CONCLUSIONS: Paclitaxel/platinum-based perioperative chemotherapy and surgery for patients with stage IIIA cN2 NSCLC is effective and well tolerated.     

Phase II trial of low-dose paclitaxel and cisplatin in patients with advanced gastric cancer

BACKGROUND: Paclitaxel has shown promising activity in gastric cancer and has synergism with cisplatin. This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel (145 mg/m(2)) plus cisplatin chemotherapy in metastatic or relapsed gastric cancer. METHODS: Chemotherapy-na?ve patients with metastatic or relapsed gastric cancer were enrolled. Paclitaxel 145 mg/m(2) was administered intravenously over 3 h, followed by cisplatin 60 mg/m(2) on Day 1 every 3 weeks in the outpatient setting. RESULTS: Of 39 patients enrolled, 17 (44%) had partial responses. Twelve (31%) had stable disease and eight (21%) progressive disease. Two patients (5%) were not evaluable because of early drop-out. The median time to progression was 4.7 months and the median overall survival was 12.1 months. The most common hematologic toxicity was anemia (41%). Grade 3/4 neutropenia and thrombocytopenia developed in 14 and 3%, respectively. The most common non-hematologic toxicities were peripheral neuropathy (43%) and emesis (43%). Grade 3/4 non-hematologic toxicities included emesis (11%), peripheral neuropathy (3%), diarrhea (3%) and hepatotoxicity (3%). CONCLUSIONS: Low-dose paclitaxel and cisplatin chemotherapy was active and well-tolerated in chemotherapy-na?ve gastric cancer patients. This regimen seems to have comparable efficacy to previously reported higher-dose paclitaxel plus cisplatin-containing regimens and fewer toxicities.     

Efficacy of platinum-based chemotherapy after cranial radiation in patients with brain metastasis from non-small cell lung cancer

This study was conducted to assess the efficacy of systemic chemotherapy in patients with brain metastasis from non-small cell lung cancer. Sixty-three consecutive patients who were diagnosed as having non-small cell lung cancer (NSCLC) with synchronous brain metastasis (BM) and had not been previously treated were included in this study. After cranial radiation therapy (RT), all patients in 'the chemotherapy arm' (CTX) were treated with platinum-based combination chemotherapy, and best supportive care was selected for patients in 'the no-chemotherapy arm' (no-CTX). Thirty-one of the 63 patients received systemic chemotherapy. The median age of all patients was 55 years. The performance status of all patients was ECOG grade 1-2. Twenty-two patients had a solitary brain metastasis, 37 patients had more than two masses, and 38 patients had extracranial metastatic lesions. In the CTX arm, a paclitaxel-based combination chemotherapy was administered in 38.7%, gemcitabine-based in 25.8%, and vinorelbine-based in 25.8% as the first-line chemotherapy. Seventeen patients were treated with a second-line chemotherapy, and paclitaxel plus gemcitabine was used in 8 patients. For the first-line and second-line chemotherapies, extracranial overall responses were 36 and 35%, the median response durations were 29.1 weeks (range: 9.1-58.1 weeks) and 30.4 weeks (range: 19.4-44.0 weeks), respectively. 'Progression of the extracranial lesion' (58.1%) was more frequent than an 'aggravation of neurologic status' (19.4%) for the pattern of treatment failure in the first-line chemotherapy. The causes of failure were identical in the second-line chemotherapy. The median survival of the CTX arm was longer than that of the no-CTX arm (58.1 vs. 19.0 weeks, p<0.001). Toxicity in the CTX arm was tolerable. The systemic chemotherapy showed an effectiveness to increase the survival of patients with BM from NSCLC, and extracranial progression was the main cause of chemotherapeutic failure, although consideration for non-randomized methods should be made in this study.     

Performance of a mixed effects logistic regression model for binary outcomes with unequal cluster size

When a clustered randomized controlled trial is considered at a design stage of a clinical trial, it is useful to consider the consequences of unequal cluster size (i.e., sample size per cluster). Furthermore, the assumption of independence of observations within cluster does not hold, of course, because the subjects share the same cluster. Moreover, when the clustered outcomes are binary, a mixed effect logistic regression model is applicable. This article compares the performance of a maximum likelihood estimation of the mixed effects logistic regression model with equal and unequal cluster sizes. This was evaluated in terms of type I error rate, power, bias, and standard error through computer simulations that varied treatment effect, number of clusters, and intracluster correlation coefficients. The results show that the performance of the mixed effects logistic regression model is very similar, regardless of inequality in cluster size. This is illustrated using data from the Prevention Of Suicide in Primary care Elderly: Collaborative Trial (PROSPECT) study.