Exposure to benzene in a pooled analysis of petroleum industry case-control studies.

Cases of lymphohematopoietic cancer from three petroleum industry cohorts, matched to controls from the respective cohort, were pooled into single study. Average benzene exposure was quantitatively estimated in ppm for each job based on measured data from the relevant country, adjusted for the specific time period, site and job exposure characteristics and the certainty of the exposure estimate scored. The probability of dermal exposure and of peak exposure was also assessed. Before risk was examined, an exposure estimate comparison and rationalisation exercise was performed across the studies to ensure accuracy and consistency of approach. This article evaluates the final exposure estimates and their use in the risk assessments. Overall benzene exposure estimates were low: 90% of participants accumulated less than 20 ppm-years. Mean cumulative exposure was estimated as 5.15 ppm-years, mean duration was 22 years, and mean exposure intensity was 0.2 ppm. 46% of participants were allocated a peak exposure (>3 ppm at least weekly). 40% of participants had a high probability of dermal exposure (based on the relative probability of at least weekly exposure). There were differences in mean intensity of exposure, probability of peak, and/or dermal exposure associated with job category, job site, and decade of exposure. Terminal Operators handling benzene-containing products were the most highly exposed group, followed by Tanker Drivers carrying gasoline. Exposures were higher around 1940-1950 and lower in more recent decades. Overall confidence in the exposure estimates was highest for recently held jobs and for white-collar jobs. We used sensitivity analyses, which included and excluded case-sets on the basis of exposure certainty scores, to inform the risk assessment. The above analyses demonstrated that the different patterns of exposure across the three studies are largely attributable to differences in jobs, site types, and time frames rather than study. This provides reassurance that the previous rationalisation of exposures achieved inter-study consistency and that the data could be confidently pooled.

Temozolomide-induced severe myelosuppression: analysis of clinically associated polymorphisms in two patients.

Genotyping of putative determinants of temozolomide (TMZ)-induced life-threatening bone marrow suppression was performed in two patients with glioma treated with adjuvant TMZ and radiation therapy. DNA was extracted from the patients' mononuclear cells and genotyping of O-methylguanine-DNA-methyltransferase (MGMT), multidrug resistance (MDR1; also known as ABCB1), NQO1, and GSTP1 genes and analysis for the epigenetic silencing of specific MGMT gene promoters were carried out to evaluate the possible genetic determinants of increased risk of severe TMZ-induced myelosuppression. Although both patients were heterozygous for all ABCB1 single nucleotide polymorphisms and for rs12917 and rs1803965 in the MGMT gene, patient 1 was heterozygous for rs1695 in GSTP1 and rs2308327 in the MGMT gene. This patient also exhibited GG genotype for the MGMT single nucleotide polymorphisms, rs2308321, which is noteworthy for its 0.7% frequency globally. Epigenetic silencing of MGMT gene was not detected in either patient. Two single nucleotide polymorphisms identified in patient 1 (missense I143V and K178R polymorphisms; rs2308321 and rs2308327, respectively) have recently been shown to correlate with an increased risk of severe TMZ-induced myelosuppression. The polymorphisms identified in patient 2 have not been associated with an increased risk of severe TMZ-induced myelosuppression. Genotyping analyses of larger patient populations administered TMZ are required to validate the genetic determinants of severe TMZ-induced myelosuppression.

Autonomous growth of committed hematopoietic progenitors from peripheral blood of workers exposed to low levels of benzene.

We investigated whether exposure to low levels of benzene (geometric mean of exposures = 0.28-0.41 parts per million) results in perturbations of the hemopoietic system found in patients with myeloproliferative diseases. Erythroid (BFU-E) and granulocyte-monocyte (CFU-GM) colonies from peripheral blood were grown in methylcellulose with and without the addition of cytokines (erythropoietin and granulocyte-stimulating factor). Colony growth from 17 workers exposed to low levels of benzene was compared with 20 healthy control subjects. Exposed workers had significantly increased growth of autonomous BFU-E and unstimulated CFU-GM when compared with the control subjects. Unexposed smokers had increased colony growth without the addition of cytokines. Colony growth was not significantly different between the groups after the addition of cytokines. Workers exposed to low concentrations of benzene and unexposed smokers have increased cytokine-independent hematopoiesis.

Randomized study of combination chemotherapy in unresectable gastric cancer. The Gastrointestinal Tumor Study Group.

Two hundred forty-one patients with unresectable gastric adenocarcinoma were entered, between December 1978 and March 1981, into a prospectively randomized comparison of three chemotherapy regimens to identify therapeutic activity and determine patient tolerability: (1) 5-fluorouracil plus Adriamycin (FA); (2) FA plus methyl-CCNU (FAMe); and (3) FA plus mitomycin C (FAMi). Patients were stratified by stage and performance status prior to randomization. Treatment groups were well balanced with respect to known prognostic discriminants. The primary endpoint to evaluate treatment effect was patient survival. Pair-wise comparisons using a proportional hazards model adjusted for stage and performance status documented a significant survival advantage for FAMe compared with FA (P less than 0.03). Toxicity was primarily hematologic and was seen more frequently in patients receiving FAMe. Further investigations of the FAMe regimen in the surgical adjuvant setting and combined with radiotherapy for patients with locally unresectable gastric cancer are under development.

Increased therapeutic index using moderate dose methotrexate and leucovorin twice weekly vs. weekly high dose methotrexate-leucovorin in patients with advanced squamous carcinoma of the head and neck: a safe new effective regimen.

A new intensive methotrexate regimen for the treatment of advanced squamous carcinoma of the head and neck is presented, employing twice-weekly parenteral low-moderate doses of methotrexate and a single parenteral dose of leucovorin 24 hours following methotrexate. Toxicity and therapeutic results in 20 patients treated with this regimen favorably with results of weekly high-dose methotrexate-leucovorin in 36 patients treated immediately before initiation of the new regimen. Moderate nephrotoxicity and mild gastrointestinal/mucosal toxicity were common to both, while myelotoxicity was rarely seen with the low dose regimen and was more frequent with the high-dose regimen. Partial response was observed in 60% of patients treated on the intensive low-moderate dose schedule, and 50% of patients previously untreated with methotrexate on the weekly high-dose schedule. None of 12 patients previously failing low-moderate doses of methotrexate responded to high doses administered in this trial. The characteristics of antitumor response with low-moderate and high-dose schedules were similar except for the median dose required to attain response (50 mg/m2 vs. 3 g/m2) and the lesser toxicity of intensive lower dose therapy with leucovorin.