This study examines the quality of street heroin seized in Vienna in 1999 and whether there was a relationship between the purity of street heroin and the number of heroin-related emergencies as well as the number of heroin-related deaths. Street heroin confiscated by the Viennese police, run-sheets of drug-related emergencies, and postmortem reports of drug-related deaths in Vienna in 1999 were analyzed. A total of 415 retail samples with a total weight of 128.02 g contained a median percentage of 6.5% diacetylmorphine (range: 0.0-47.0%). All the samples contained a diluent, mainly lactose, as well as adulterants, such as caffeine and/or paracetamol. During the study period, 75 heroin-related deaths and 387 heroin-related emergencies were registered in Vienna. Time-series analysis revealed no statistically significant relationship between the rate of heroin-related incidents and the diacetylmorphine concentration of street heroin samples confiscated in Vienna in 1999. The widely held belief that the number of heroin-related deaths could be explained simply through fluctuations in the purity of street heroin could not be substantiated, even though the results of this study do not rule out an association between the purity of heroin and heroin-related deaths/emergencies.

<div>AbstractPurpose:<p>Human malignant pleural mesothelioma (MPM) is characterized by dismal prognosis. Consequently, dissection of molecular mechanisms driving malignancy is of key importance. Here we investigate whether activating mutations in the telomerase reverse transcriptase (<i>TERT</i>) gene promoter are present in MPM and associated with disease progression, cell immortalization, and genomic alteration patterns.</p>Experimental Design:<p><i>TERT</i> promoters were sequenced in 182 MPM samples and compared with clinicopathologic characteristics. Surgical specimens from 45 patients with MPM were tested for <i>in vitro</i> immortalization. The respective MPM cell models (<i>N</i> = 22) were analyzed by array comparative genomic hybridization, gene expression profiling, exome sequencing as well as TRAP, telomere length, and luciferase promoter assays.</p>Results:<p><i>TERT</i> promoter mutations were detected in 19 of 182 (10.4%) MPM cases and significantly associated with advanced disease and nonepithelioid histology. Mutations independently predicted shorter overall survival in both histologic MPM subtypes. Moreover, 9 of 9 (100%) mutated but only 13 of 36 (36.1%) wild-type samples formed immortalized cell lines<i>. TERT</i> promoter mutations were associated with enforced promoter activity and <i>TERT</i> mRNA expression, while neither telomerase activity nor telomere lengths were significantly altered. <i>TERT</i> promoter–mutated MPM cases exhibited distinctly reduced chromosomal alterations and specific mutation patterns. While <i>BAP1</i> mutations/deletions were exclusive with <i>TERT</i> promoter mutations, homozygous deletions at the <i>RBFOX1</i> and the <i>GSTT1</i> loci were clearly enriched in mutated cases.</p>Conclusions:<p><i>TERT</i> promoter mutations independently predict a dismal course of disease in human MPM. The altered genomic aberration pattern indicates that <i>TERT</i> promoter mutations identify a novel, highly aggressive MPM subtype presumably based on a specific malignant transformation process.</p></div>

<div>AbstractPurpose:<p>Human malignant pleural mesothelioma (MPM) is characterized by dismal prognosis. Consequently, dissection of molecular mechanisms driving malignancy is of key importance. Here we investigate whether activating mutations in the telomerase reverse transcriptase (<i>TERT</i>) gene promoter are present in MPM and associated with disease progression, cell immortalization, and genomic alteration patterns.</p>Experimental Design:<p><i>TERT</i> promoters were sequenced in 182 MPM samples and compared with clinicopathologic characteristics. Surgical specimens from 45 patients with MPM were tested for <i>in vitro</i> immortalization. The respective MPM cell models (<i>N</i> = 22) were analyzed by array comparative genomic hybridization, gene expression profiling, exome sequencing as well as TRAP, telomere length, and luciferase promoter assays.</p>Results:<p><i>TERT</i> promoter mutations were detected in 19 of 182 (10.4%) MPM cases and significantly associated with advanced disease and nonepithelioid histology. Mutations independently predicted shorter overall survival in both histologic MPM subtypes. Moreover, 9 of 9 (100%) mutated but only 13 of 36 (36.1%) wild-type samples formed immortalized cell lines<i>. TERT</i> promoter mutations were associated with enforced promoter activity and <i>TERT</i> mRNA expression, while neither telomerase activity nor telomere lengths were significantly altered. <i>TERT</i> promoter–mutated MPM cases exhibited distinctly reduced chromosomal alterations and specific mutation patterns. While <i>BAP1</i> mutations/deletions were exclusive with <i>TERT</i> promoter mutations, homozygous deletions at the <i>RBFOX1</i> and the <i>GSTT1</i> loci were clearly enriched in mutated cases.</p>Conclusions:<p><i>TERT</i> promoter mutations independently predict a dismal course of disease in human MPM. The altered genomic aberration pattern indicates that <i>TERT</i> promoter mutations identify a novel, highly aggressive MPM subtype presumably based on a specific malignant transformation process.</p></div>

<p>Supplementary Figure S6. Relation between TERT mRNA expression and MPM patient survival in the TCGA dataset.</p>

<p>Supplementary Tables S1 to S9 with the exception of Supplementary Table S6</p>