An SNP linkage scan identifies significant Crohn's disease loci on chromosomes 13q13.3 and, in Jewish families, on 1p35.2 and 3q29.

Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score=3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score=3.5) and 3q29 (peak LOD score=3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score=2.57) and Jewish UC on chromosome 2q24 (peak LOD score=2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score=4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score=2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.

Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucovorin in patients with organ dysfunction.

BACKGROUND: Patients with hepatic or renal dysfunction are often treated with 5-fluorouracil (5-FU), but there are few data to confirm the safety of this practice. PATIENTS AND METHODS: Patients with solid tumors were eligible if they were able to fit into one of three organ dysfunction cohorts: I, creatinine >1.5 but < or =3.0 mg/dl and normal bilirubin; II, bilirubin >1.5 but <5.0 mg/dl with normal creatinine; or III, bilirubin > or =5.0 mg/dl with normal creatinine. 5-FU doses were escalated separately within each of the three cohorts. Leucovorin (LV) dosage was fixed at 500 mg/m(2). 5-FU was given as a 24-h infusion at 1000, 1800 or 2600 mg/m(2), and plasma concentrations were measured every 3 h during the first two infusions for each patient. RESULTS: Sixty-four patients were treated. Toxicities did not appear to be related to organ dysfunction cohort. A weekly dose of of 5-FU 2600 mg/m(2) produced dose-limiting toxicity (DLT) in six of 20 evaluable patients. These DLTs included grade 3 fatigue (n = 3), grade 2 neutropenia precluding weekly dosing (n = 1), grade 3 thrombocytopenia (n = 1) and grade 3 mental status changes (n = 1). There was no relationship between serum bilirubin or serum creatinine and 5-FU clearance. CONCLUSIONS: Patients with elevated bilirubin may be safely started on a weekly regimen of 5-FU 2600 mg/m(2) with leucovorin 500 mg/m(2) as a 24-h continuous infusion.

Phase I/II investigation of paclitaxel, ifosfamide and carboplatin for advanced non-small-cell lung cancer.

BACKGROUND: The aim of this study was to evaluate feasibility and tolerability of the three-drug combination of paclitaxel, ifosfamide and carboplatin (TIC) in patients with advanced non-small-cell lung cancer. The specific objectives of the study were: (i) to define the dose-limiting toxicities (DLTs) and the maximum-tolerated dose of ifosfamide administered as part of the combination; and (ii) to determine the overall response rate and overall survival of patients treated with this regimen. PATIENTS AND METHODS: Patients with untreated, stage IIIB (pleural effusion) or stage IV non-small-cell lung cancer were enrolled in one of three cohorts. Patients received paclitaxel 200 mg/m(2) as a 1-h infusion on day 1 with carboplatin at an area under the concentration-time curve (AUC) of 6 mg.min/ml on day 2. For dose level I, ifosfamide was administered at a dose of 2 g/m(2) on days 1 and 2. For dose levels II and III, the dose of ifosfamide was decreased to 1.5 g/m(2) on days 1 and 2 and the dose of carboplatin was decreased to AUC 5 mg.ml/min. Therapy for dose levels I and III included filgrastim support (5 micro g/kg/day), which was initiated on day 3 and continued until after day 11 or until an absolute neutrophil count >10 000/ micro l. Treatment cycles were repeated every 21 days. Once the phase II dose was established, a full cohort of patients received therapy at this dose level to examine further the regimen's activity and tolerability. RESULTS: Neutropenia was the DLT encountered for dose levels I and II. No DLT was encountered in the initial six patients treated at dose level III, and therefore this dose level was declared the recommended phase II dose. A total of 49 patients were treated at the recommended phase II dose. The predominant non-hematological toxicity encountered with this triplet regimen was cumulative peripheral neuropathy. Of the 65 eligible patients enrolled in this study, 17 (26%) responded. There were 15 patients with partial responses (23%), two with regression, and 26 with stabilization of disease (40%). Median progression-free and overall survival were 4.8 and 9.4 months, respectively. CONCLUSIONS: The combination TIC is well-tolerated. This triplet regimen produced response and survival rates in advanced non-small-cell lung cancer similar to those of other current combination chemotherapy regimens.

Self-reports of stress in Asian immigrants: effects of ethnicity and acculturation.

INTRODUCTION: Although the concept of stress is hard to define or measure, it is a phenomenon associated with a number of health conditions, including hypertension, heart disease, and decreased immunocompetency. Events such as migration are known to create stress; researchers refer to this as acculturative stress. Given that cultural background might influence a patient's recognition, interpretation, and coping mechanisms for stress, we wondered how self-reports of stress by Asian immigrants compare with those of non-Hispanic Whites, and how these self-reports vary with years since immigration, a proxy for acculturation. METHODS: Data from the National Health Information Survey for 1993 and 1995 were analyzed for six groups of Asian national origin, and were compared with non-Hispanic Whites. Using ordered logistic regression, we examined self-reports of stress over two weeks and twelve months, as well as the changes in these self-reports with years since immigration. RESULTS: Adjusted for age, income, educational level, marital status, and gender, Asian immigrants were uniformly less likely to report stress over a two-week period than were non-Hispanic Whites (OR ranges: 0.34[Asian Indian]-0.59[Korean], P values<.05). There were no significant differences in reported stress among Asian ethnic groups. Compared with immigrants who have lived in the United States for at least 15 years, recent immigrants (<1 year) were likely to report less stress over two weeks and twelve months, OR = 0.13 and 0.23, respectively, P values<.005. CONCLUSIONS: Despite their status as immigrants, Asians report less stress than non-Hispanic Whites. These reports of stress increase as years since immigration increase. One potential explanation for these discrepancies is under-reporting, which might reflect underlying cultural differences in the perception or definition of stress, differences that may diminish with "acculturation."

Enhanced eradication of local and distant tumors by genetically produced interleukin-12 and radiation.

Ionizing radiation (IR) is frequently unsuccessful in the treatment of cancer because of local failure or distant metastases. The efficacy of systemically administered cytokines for cancer therapy is often limited by toxicity. We report that intratumoral injection of an adenoviral vector with interleukin-12 (IL-12) enhances local anti-tumor effects of irradiation (IR). We demonstrate that microscopic tumor growth at a distant site is suppressed following treatment of the primary tumor with adeno-murine IL-12 (Adm.IL-12). The results support a model in which the anti-angiogenic effects of IL-12 contribute to the local anti-tumor effects of radiation, while IL-12 induced immunity suppresses growth of microscopic tumors distant from the primary irradiated site. These data suggest that combining radiotherapy with IL-12 improves both local and distant tumor control compared to either treatment alone. Immunoradiotherapy may be employed in addition to or in place of current conventional therapies to increase local control and decrease distant tumor growth.

Clinical trials in general surgical journals: are methods better reported?

BACKGROUND: Reports of clinical trials often lack adequate descriptions of their design and analysis. Thus readers cannot properly assess the strength of the findings and are limited in their ability to draw their own conclusions. A review of 6 surgical journals in 1984 revealed that the frequency of reporting 11 basic elements of design and analysis in clinical trials was only 59%. This study attempted to identify areas that still need improvement. METHODS: Eligible studies published from July 1995 through June 1996 included all reports of comparative clinical trials on human subjects that were prospective and had at least 2 treatment arms. A total of 68 articles published in 6 general surgery journals were reviewed. The frequency that the previously identified 11 basic elements of design and analysis were reported was determined. RESULTS: Seventy-four percent of all items were reported accurately (a 15% increase from the previous study), 4% were reported ambiguously, and 23% were not reported; improvement was seen in every journal. The reporting of eligibility criteria and statistical power improved the most. For 3 items, reporting was still not adequate; 32% of reports provided information about statistical power, 40% about the method of randomization, and 49% about whether the person assessing outcomes was blind to the treatment assignment. CONCLUSIONS: Improvements have been made in reporting surgical clinical trials, but in general methodologic questions poorly answered in the 1980s continue to be answered poorly in the 1990s. Editors of surgical journals are urged to provide authors with guidelines on how to report clinical trial design and analysis.

Monitoring AIDS and other rare population events: a network approach.

This paper replicates and extends an earlier attempt to use data from the General Social Survey (GSS) to track the distribution of AIDS across demographic subgroups. (The GSS asks respondents whether they know a person with AIDS [PWA].) The gender, racial, age, and regional composition of the set of PWAs reported by GSS respondents is compared with that of the official AIDS cases reported to the Centers for Disease Control (CDC). In an attempt to assess the accuracy of the GSS estimates, a similar analysis is performed in which GSS respondents are asked whether they know a homicide victim. Data from four consecutive GSS samples (1988, 1989, 1990, and 1991) are used, permitting a more detailed exploration of potential biases and problems with the network technique. In addition, time series data from the National Health Interview Survey on the percentage of people who know at least one PWA are used to validate the GSS data. Our earlier findings, that the GSS identifies proportionately more White and midwestern cases than are reported to the CDC, are corroborated by the additional data. Possible explanations for these discrepancies are given, and suggestions are made for improving the utility of the approach.