Systematic literature review for the association of biomarkers with efficacy of anti-PD-1 inhibitors in advanced melanoma.

Aim: Summarize the literature assessing biomarkers in predicting efficacy of anti-PD-1 therapy for patients with high-risk unresectable or metastatic melanoma. Materials & methods: Relevant studies were identified via a systematic literature review. Results: About 334 unique biomarkers or biomarker combinations were identified from 121 citations. Neutrophil-to-lymphocyte ratio was the most frequently studied biomarker, followed by C-reactive protein. Fifty-nine biomarkers were significantly associated with overall survival (OS), 51 with progression-free survival (PFS) and 44 with response. Twenty biomarkers were associated with both OS and PFS; two were associated with OS, PFS and response (MHC-II and tumor mutational burden). Conclusion: Numerous biomarkers could potentially predict the efficacy of anti-PD-1-based therapy for melanoma patients. However, confirmatory studies are needed as well as determination of implications for clinical decision-making.

A review of telomere length in sarcopenia and frailty.

Sarcopenia and frailty are associated with several important health-related adverse events, including disability, loss of independence, institutionalization and mortality. Sarcopenia can be considered a biological substrate of frailty, and the prevalence of both these conditions progressively increases with age. Telomeres are nucleoprotein structures located at the end of linear chromosomes and implicated in cellular ageing, shorten with age, and are associated with various age-related diseases. In addition, telomere length (TL) is widely considered a molecular/cellular hallmark of the ageing process. This narrative review summarizes the knowledge about telomeres and analyzes for the first time a possible association of TL with sarcopenia and frailty. The overview provided by the present review suggests that leukocyte TL as single measurement, calculated by quantitative real-time polymerase chain reaction (qRT-PCR), cannot be considered a meaningful biological marker for complex, multidimensional age-related conditions, such as sarcopenia and frailty. Panels of biomarkers, including TL, may provide more accurate assessment and prediction of outcomes in these geriatric syndromes in elderly people.

Non-oncology physician visits after diagnosis of cancer in children.

BACKGROUND: Children diagnosed with cancer often require extensive care for medical, psychosocial and educational problems during and after therapy. Part of this care is provided by family physicians and non-cancer specialists, but their involvement in the first years after diagnosis has barely been studied. Studying non-oncology physician visits may provide insight into the roles of different health care providers. METHODS: We included 757 children diagnosed with cancer under age 15 between 1991 and 2001 from a Canadian provincial registry, and matched each to 10 controls of the same birth year and sex. We determined the number of family physician and non-cancer specialist visits in the 5 years after diagnosis (for patients) or inclusion (for controls) using data from the provincial health insurance plan. RESULTS: In the first year after diagnosis, almost all patients visited both a family physician and non-cancer specialist. Although after 5 years percentages decreased to 85 and 76 %, respectively, these were still significantly higher than in controls. In the first year after diagnosis, both family physicians and non-cancer specialists were often consulted for neoplasms (62 and 90 %, respectively) and to discuss results of lab tests. In addition, family physicians were often consulted for general symptoms and non-cancer specialists for nervous system problems and complications of medical care. CONCLUSIONS: Family physicians and non-cancer specialists are highly involved in the care for children with cancer in the first years after diagnosis, including for health problems related to cancer or its treatment. This necessitates good communication among all physicians.

Population diversity in cuticular hydrocarbons and mtDNA in a mountain social wasp.

Nestmate recognition is a common phenomenon in social insects that typically is mediated by cuticular hydrocarbons. Geographical variation in cuticular hydrocarbons has been observed, although the pattern of variation is not consistent across species and is usually related to the biology and ecology of the different species. Polistes biglumis (Hymenoptera: Vespidae) is a social wasp that lives in high mountains where populations are separated by significant geographical barriers. Here we investigated the level of chemical variation among populations of P. biglumis in the Alps, and shed light on the phylogeography of this species. Populations could be discriminated by means of their cuticular hydrocarbon profiles, which showed a pattern consistent with the isolation-by-distance hypothesis. Molecular data highlighted two areas with different levels of haplotype diversity, although all wasps belonged to the same species. These results suggest that the populations of P. biglumis in the Alps are geographically isolated from one another, favoring their genetic and chemical differentiation.

Late morbidity leading to hospitalization among 5-year survivors of young adult cancer: a report of the childhood, adolescent and young adult cancer survivors research program.

To estimate the risk of late morbidity leading to hospitalization among young adult cancer 5-year survivors compared to the general population and to examine the long-term effects of demographic and disease-related factors on late morbidity, a retrospective cohort of 902 five-year survivors of young adult cancer diagnosed between 1981 and 1999 was identified from British Columbia (BC) Cancer Registry. A matched comparison group (N = 9020) was randomly selected from the provincial health insurance plan. All hospitalizations until the end of 2006 were determined from the BC health insurance plan hospitalization records. The Poisson regression model was used to estimate the rate ratios for late morbidity leading to hospitalization except pregnancy after adjusting for sociodemographic and clinical risk factors. Overall, 455 (50.4%) survivors and 3,419 (37.9%) individuals in the comparison group had at least one type of late morbidity leading to hospitalization. The adjusted risk of this morbidity for survivors was 1.4 times higher than for the comparison group (95% CI = 1.22-1.54). The highest risks were found for hospitalization due to blood disease (RR = 4.2; 95% CI = 1.98-8.78) and neoplasm (RR = 4.3; 95% CI = 3.41-5.33). Survivors with three treatment modalities had three-fold higher risk of having any type of late morbidity (RR = 3.22; 95% CI = 2.09-4.94) than the comparators. These findings emphasize that young adult cancer survivors still have high risks of a wide range of late morbidities.

Gastric cancer does not affect the expression of atrophy-related genes in human skeletal muscle.

INTRODUCTION: We evaluated the gene expression levels of atrogin-1, MuRF1, myostatin, follistatin, activin A, and inhibin alpha in skeletal muscle samples of patients with gastric cancer and controls. METHODS: We studied 38 cancer patients and 12 controls who underwent surgery for gastric adenocarcinoma and benign abdominal diseases, respectively. A biopsy specimen was obtained from the rectus abdominis muscle from all participants. The relative gene expression of atrogin-1, MuRF1, myostatin, follistatin, activin A, and inhibin alpha was determined by quantitative real-time polymerase chain reaction analysis. RESULTS: Atrogin-1 and MuRF1 mRNA expression was similar between cancer patients and controls and was unaffected by the disease stage or the severity of body weight loss. Transcript levels of myostatin and follistatin did not differ between cases and controls and were similar across disease stages and categories of weight loss. Finally, no differences were detected in activin A and inhibin alpha gene expression between cancer patients and controls. CONCLUSIONS: In skeletal muscle, the gene expression of atrogin-1, MuRF1, myostatin, follistatin, activin A, and inhibin alpha is not affected by the presence of cancer. The expression of atrophy-related genes is unaffected by the disease stage and the degree of weight loss.

HtrA1 in human urothelial bladder cancer: a secreted protein and a potential novel biomarker.

Our aim was to analyze the expression of the serine protease HtrA1 in human bladder tissue and urine in order to point out its possible association with the presence of urothelial bladder cancer. Bladder tissue and urine specimens from cancer patients with different tumor grades and stages (n = 68) and from individuals with cystitis (n = 16) were collected along with biopsy specimens and urine from healthy individuals (n = 68). For the first time, we demonstrated by immunohistochemistry that HtrA1 protein is produced by bladder urothelium in both physiological and inflammatory conditions, whereas it is not detectable in urothelial cancer cells regardless of tumor grade and stage. A different HtrA1 expression between normal-looking and neoplastic bladder tissue, despite similar HtrA1 mRNA levels, was also found by western blotting, which disclosed the presence of two forms of HtrA1, a native form of ∼50 kDa and an autocatalytic form of ∼38 kDa. Our investigations documented the presence of the two forms of HtrA1 also in urine. The ∼38 kDa form was significantly down-regulated in neoplastic tissue, whereas significantly higher amounts of both HtrA1 forms were found in urine from cancer patients compared with both healthy subjects and patients with cystitis. Our findings suggest that HtrA1 is a downexpressed molecule since an early stage of bladder urothelial carcinoma development and that urinary HtrA1 protein may be considered, if successfully validated, as an early and highly sensitive and specific biomarker for this neoplasia (the sensitivity and specificity of HtrA1 are 92.65% and 95.59%, respectively).

Antidepressant use among survivors of childhood, adolescent and young adult cancer: a report of the Childhood, Adolescent and Young Adult Cancer Survivor (CAYACS) Research Program.

BACKGROUND: Although survivors of childhood, adolescent, and young adult (AYA) cancer are at risk for late psychological sequelae, it is unclear if they are more likely to be prescription antidepressant users than their peers. PROCEDURE: All 5-year survivors of childhood or AYA cancer diagnosed before age 25 years in British Columbia from 1970 to 1995 were identified. Those with complete follow-up in the provincial health insurance registry from 2001 to 2004 were included (n = 2,389). A birth-cohort and gender-matched set of population controls 10 times the size of the survivor group was randomly selected (n = 23,890). All prescriptions filled between 2001 and 2004 were identified through linkage to the provincial prescription drug administrative database. Logistic regression analyses determined the impact of cancer survivorship on the likelihood of ever filling an antidepressant prescription. RESULTS: After adjusting for sociodemographic factors, survivors of childhood and AYA cancer were more likely to have filled an antidepressant prescription compared to controls (OR 1.21, 95% CI 1.09-1.35). Cancer survivors had an increased likelihood of using all categories of antidepressants, and of using drugs from two or more antidepressant categories, compared to peers (OR 1.31, 95% CI 1.11-1.55 [≥2 antidepressant categories]). Treatment was not a significant predictor of antidepressant use. Female survivors, those in young adulthood and those more than 20 years post-treatment had increased antidepressant use. CONCLUSIONS: Survivors of childhood and AYA cancer are more likely to fill antidepressant prescriptions compared to peer controls. This may indirectly reflect an increased underlying prevalence of mental health conditions among survivors.

Social regulation of reproduction: control or signal?

Traditionally, dominant breeders have been considered to be able to control the reproduction of other individuals in multimember groups that have high variance in reproductive success/reproductive skew (e.g., forced sterility/coercion of conspecifics in eusocial animals; sex-change suppression in sequential hermaphrodites). These actions are typically presented as active impositions by reproductively dominant individuals. However, how can individuals regulate the reproductive physiology of others? Alternatively, all contestants make reproductive decisions, and less successful individuals self-downregulate reproduction in the presence of dominant breeders. Shifting perspective from a top-down manipulation to a broader view, which includes all contenders, and using a multitaxon approach, we propose a unifying framework for the resolution of reproductive skew conflicts based on signalling rather than control, along a continuum of levels of strategic regulation of reproduction.

The oxidative cost of competing for egg fertilization exceeds the cost of egg production.

Measuring reproductive costs is crucial to understanding sexual conflict and its evolutionary outcomes. Sexual conflict is thought to originate from anisogamy-the size difference between male and female gametes; if sperm are tiny and not produced in vastly greater numbers than eggs, at any mating females' gametic investment is larger than that of males. Testing this prediction has proven difficult, especially because males and females differ in many more traits than just gamete size. We overcame this difficulty by exposing simultaneously hermaphroditic polychaete worms Ophryotrocha diadema (two sexual functions in the same body) to two social conditions, pairs, and groups >2, where hermaphrodites invest either relatively more in the female function or relatively more in the male function, respectively. Then we measured four markers of cellular oxidative status, a physiological mediator of life-history strategies. Less female-biased hermaphrodites produced fewer eggs but, unexpectedly, had lower levels of antioxidant protection than more female-biased hermaphrodites, which produced more eggs. Male-biased hermaphrodites compete for mating as males (hermaphrodites in pairs do not) suggesting that in the short-term male competition might be costlier than egg production in terms of regulation of oxidative status. These results highlight the need of including behavioral traits, namely competition over egg fertilization, in the measures of reproductive costs.

Genome and cuticular hydrocarbon-based species delimitation shed light on potential drivers of speciation in a Neotropical ant species complex.

Geographic separation that leads to the evolution of reproductive isolation between populations generally is considered the most common form of speciation. However, speciation may also occur in the absence of geographic barriers due to phenotypic and genotypic factors such as chemical cue divergence, mating signal divergence, and mitonuclear conflict. Here, we performed an integrative study based on two genome-wide techniques (3RAD and ultraconserved elements) coupled with cuticular hydrocarbon (CHC) and mitochondrial (mt) DNA sequence data, to assess the species limits within the Ectatomma ruidum species complex, a widespread and conspicuous group of Neotropical ants for which heteroplasmy (i.e., presence of multiple mtDNA variants in an individual) has been recently discovered in some populations from southeast Mexico. Our analyses indicate the existence of at least five distinct species in this complex: two widely distributed across the Neotropics, and three that are restricted to southeast Mexico and that apparently have high levels of heteroplasmy. We found that species boundaries in the complex did not coincide with geographic barriers. We therefore consider possible roles of alternative drivers that may have promoted the observed patterns of speciation, including mitonuclear incompatibility, CHC differentiation, and colony structure. Our study highlights the importance of simultaneously assessing different sources of evidence to disentangle the species limits of taxa with complicated evolutionary histories.

Hospital-related morbidity among childhood cancer survivors in British Columbia, Canada: report of the childhood, adolescent, young adult cancer survivors (CAYACS) program.

Our study examines inpatient, hospital-related morbidity in a geographically-defined cohort of long-term cancer survivors diagnosed before age 20 years in the province of British Columbia (BC), Canada. A total of 1374 survivors diagnosed from 1981 to 1995 surviving at least 5-years postdiagnosis, and a matched sample of 13,740 BC residents, were identified from population registers, and linked to provincial hospitalization records from 1986 to 2000. Logistic regression was used to assess relative risk and effect of sociodemographic, clinical, and temporal factors on risk. Approximately 41% of survivors vs. 17% of the population sample had at least one type of hospitalization-related late morbidity in the observation period (adjusted RR 4.1, 95% CI 3.7-4.5). Those at highest risk were survivors of leukemia (RR 4.8, 95% CI 4.0-5.8), central nervous system tumors (RR 4.8, 95% CI 4.0-5.8), bone and soft tissue sarcomas (RR 4.9, 95% CI 3.8-6.2), and kidney cancer (RR 4.9, 95% CI 3.4-7.0). Adjusted relative risk was elevated for all types of morbidity except pregnancy and birth complications, and highest for neoplasms (including second primary cancers) (RR 21.7, 95% CI 16.3-28.7). Morbidity was elevated for all combinations of primary treatment and highest for those with previous radiation, chemotherapy, and surgery (RR 7.1, 95% CI 5.5-9.0). Over time, morbidity for late effects other than neoplasms became more prevalent. These results suggest that survivors are at increased ongoing risk of many types of hospital-related late morbidity, implying that long-term monitoring for multiple health problems is warranted.

Patterns of physician follow-up among young cancer survivors: report of the Childhood, Adolescent, and Young Adult Cancer Survivors (CAYACS) research program.

OBJECTIVE: To describe the frequency and pattern of physician visits in 1998 to 2000 among childhood and adolescent cancer survivors in British Columbia (BC), to compare their use of physician services with use in the general population, and to examine the effects of clinical and sociodemographic factors on care. DESIGN: Retrospective, observational, population-based cohort study, with a comparison group. Cohort records from population registries were linked to physician claim data and oncology visit records for 1998 to 2000. SETTING: Outpatient physician care in BC. PARTICIPANTS: All (N = 1157) survivors of cancer diagnosed before age 20 years in BC between 1970 and 1992 who survived at least 5 years after diagnosis, and an age-sex frequency-matched population sample of 11 570 individuals. MAIN OUTCOME MEASURES: Probability of a physician visit and frequency of physician visits. RESULTS: Approximately 97% of survivors saw at least 1 physician in the 3-year period, compared with 50% of the general population sample. The probability of a GP visit was 96% higher (adjusted 95% confidence interval [CI] 1.8 to 2.1), and the likelihood of a specialist visit was 157% higher (adjusted 95% CI 2.4 to 2.8) than for the general population. Survivors were more than twice as likely to see GPs at least 10 times (adjusted relative risk 2.23, 95% CI 2.0 to 2.4) and had 49% more visits than the general population. Cancer diagnosis and treatment affected visit patterns, but socioeconomic status and rural residency did not significantly affect the probability of a visit. CONCLUSION: Demand for physician care among childhood and adolescent cancer survivors is considerably greater than for the general population, and this need persists many years after diagnosis. Physicians need information on the unique health care requirements of this patient group in order to provide appropriate care.

Analysis of recurrent events with non-negligible event duration, with application to assessing hospital utilization.

In an attempt to provide tools for assessing hospital utilization, this paper extends well-known models for recurrent events to address non-negligible event duration and presents a procedure for estimating the model parameters. The model extension is natural and easy to understand. Asymptotic properties of the associated inferences are derived adapting the well-developed methods based on the counting process formulation. Several specifications of the proposed modeling are illustrated with the hospitalization records of childhood cancer survivors from a health care insurance system that motivated this research. The usefulness and robustness of the proposed approach is demonstrated numerically via simulation.

Chemically Insignificant Social Parasites Exhibit More Anti-Dehydration Behaviors than Their Hosts.

Social parasites have evolved adaptations to overcome host resistance as they infiltrate host colonies and establish there. Among the chemical adaptations, a few species are chemically "insignificant"; they are poor in recognition cues (cuticular hydrocarbons) and evade host detection. As cuticular hydrocarbons also serve a waterproofing function, chemical insignificance is beneficial as it protects parasites from being detected but is potentially harmful because it exposes parasites to desiccation stress. Here I tested whether the social parasites Polistes atrimandibularis employ behavioral water-saving strategies when they live at Polistes biglumis colonies. Observations in the field showed that parasites were less active than their cohabiting host foundresses, spent more time at the nest, and rested in the shadowy, back face of the nest, rather than at the front face, which contradicted expectations for the use of space for dominant females-typically, dominants rest at the nest front-face. These data suggest that behavioral adaptations might promote resistance to desiccation stress in chemical insignificant social parasites.

A Stresipteran parasite extends the lifespan of workers in a social wasp.

In social wasps, female lifespan depends on caste and colony tasks: workers usually live a few weeks while queens as long as 1 year. Polistes dominula paper wasps infected by the strepsipteran parasite Xenos vesparum avoid all colony tasks, cluster on vegetation where parasite dispersal and mating occur, hibernate and infect the next generation of wasp larvae. Here, we compared the survival rate of infected and uninfected wasp workers. Workers' survival was significantly affected by parasite sex: two-third of workers parasitized by a X. vesparum female survived and overwintered like future queens did, while all workers infected by a X. vesparum male died during the summer, like uninfected workers that we used as controls. We measured a set of host and parasite traits possibly associated with the observed lifespan extension. Infected overwintering workers had larger fat bodies than infected workers that died in the summer, but they had similar body size and ovary development. Furthermore, we recorded a positive correlation between parasite and host body sizes. We hypothesize that the manipulation of worker's longevity operated by X. vesparum enhances parasite's fitness: if workers infected by a female overwinter, they can spread infective parasite larvae in the spring like parasitized gynes do, thus contributing to parasite transmission.

Matching-adjusted indirect treatment comparison of onasemnogene abeparvovec and nusinersen for the treatment of symptomatic patients with spinal muscular atrophy type 1.

OBJECTIVE: Onasemnogene abeparvovec, a one-time intravenous gene replacement therapy, and nusinersen, an antisense oligonucleotide that requires ongoing intrathecal administration, have been evaluated as treatments for spinal muscular atrophy (SMA) type 1 in separate Phase III trials, but no head-to-head comparison studies have been conducted. Onasemnogene abeparvovec was compared with nusinersen using a matching-adjusted indirect comparison (MAIC) to estimate the treatment effect of onasemnogene abeparvovec relative to nusinersen for the treatment of symptomatic patients with SMA type 1 for up to 24 months of follow-up. METHODS: In the absence of studies for both onasemnogene abeparvovec and nusinersen with a common comparator, a Bayesian naïve indirect treatment comparison (ITC) and MAIC between onasemnogene abeparvovec and nusinersen were conducted to compare efficacy and safety of onasemnogene abeparvovec with nusinersen. Outcomes of interest were event-free survival (EFS), overall survival (OS), and motor milestone achievements (independent sitting and independent walking). Relative treatment effects were expressed as relative risk (RR) and risk difference. RESULTS: Pooled and weighted patient-level data illustrated a favorable effect toward onasemnogene abeparvovec, suggesting longer EFS for patients compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.19 [95% CI: 0.07-0.54; 99% CI: 0.05-0.74]). At 24 months of follow-up, patients receiving onasemnogene abeparvovec were statistically significantly more likely to achieve the motor milestone of sitting independently compared with patients treated with nusinersen. Although statistically significant differences were not observed at 6 to 18 months between treatment options, the likelihood of sitting independently at 12 and 18 months numerically favored onasemnogene abeparvovec. A numerically greater likelihood of walking by 18 and 24 months was also observed for patients treated with onasemnogene abeparvovec compared with nusinersen. Onasemnogene abeparvovec therapy was also associated with a favorable (but statistically nonsignificant) outcome for OS and may be associated with prolonged survival compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.35 [95% CI: 0.09-1.32; 99% CI: 0.06-2.01]). Bayesian naïve ITC results were similar to the MAIC analysis for EFS, OS, and motor milestone achievements. Small sample size limited covariate matching to baseline CHOP INTEND and nutritional support requirement, leading to wider CIs and statistically inconclusive outcomes for some of the results. CONCLUSIONS: Despite limitations of the current MAIC analysis (mainly a small sample size for statistical testing, even for the pooled onasemnogene abeparvovec trials, and potential differences in prognostic and predictive factors between studies), the relative treatment effects in EFS, OS, and motor milestone achievement indicate that onasemnogene abeparvovec may offer continued benefit compared with nusinersen through 24 months of follow-up.

Egg-trading worms start reciprocation with caution, respond with confidence and care about partners' quality.

Conditional reciprocity (help someone who helped you before) explains the evolution of cooperation among unrelated individuals who take turns helping each other. Reciprocity is vulnerable to exploitations, and players are expected to identify uncooperative partners who do not return the help they received. We tested this prediction in the simultaneously hermaphroditic worm, Ophryotrocha diadema, which engages in mutual egg donations by alternating sexual roles (one worm releases' eggs and the other fertilizes them). We set up dyads with different cooperativeness expectations; partners were either the same or a different body size (body size predicts clutch size). Large worms offered larger clutches and did so sooner when paired with large rather than small partners. They also released smaller egg clutches when they started egg donations than when they responded to a partners' donation, fulfilling the prediction that a players' first move will be prudent. Finally, behavioral bodily interactions were more frequent between more size-dissimilar worms, suggesting that worms engaged in low-cost behavioral exchanges before investing in such costly moves as egg donations. These results support the hypothesis that simultaneously hermaphroditic worms follow a conditional reciprocity paradigm and solve the conflict over sexual roles by sharing the costs of reproduction via the male and the female functions.

An integrated approach for experimental target identification of hypoxia-induced miR-210.

miR-210 is a key player of cell response to hypoxia, modulating cell survival, VEGF-driven endothelial cell migration, and the ability of endothelial cells to form capillary-like structures. A crucial step in understanding microRNA (miRNA) function is the identification of their targets. However, only few miR-210 targets have been identified to date. Here, we describe an integrated strategy for large-scale identification of new miR-210 targets by combining transcriptomics and proteomics with bioinformatic approaches. To experimentally validate candidate targets, the RNA-induced silencing complex (RISC) loaded with miR-210 was purified by immunoprecipitation along with its mRNA targets. The complex was significantly enriched in mRNAs of 31 candidate targets, such as BDNF, GPD1L, ISCU, NCAM, and the non-coding RNA Xist. A subset of the newly identified targets was further confirmed by 3'-untranslated region (UTR) reporter assays, and hypoxia induced down-modulation of their expression was rescued blocking miR-210, providing support for the approach validity. In the case of 9 targets, such as PTPN1 and P4HB, miR-210 seed-pairing sequences localized in the coding sequence or in the 5'-UTR, in line with recent data extending miRNA targeting beyond the "classic" 3'-UTR recognition. Finally, Gene Ontology analysis of the targets highlights known miR-210 impact on cell cycle regulation and differentiation, and predicts a new role of this miRNA in RNA processing, DNA binding, development, membrane trafficking, and amino acid catabolism. Given the complexity of miRNA actions, we view such a multiprong approach as useful to adequately describe the multiple pathways regulated by miR-210 during physiopathological processes.

Chronic and acute effects of coal tar pitch exposure and cardiopulmonary mortality among aluminum smelter workers.

Air pollution causes several adverse cardiovascular and respiratory effects. In occupational studies, where levels of particulate matter and polycyclic aromatic hydrocarbons (PAHs) are higher, the evidence is inconsistent. The effects of acute and chronic PAH exposure on cardiopulmonary mortality were examined within a Kitimat, Canada, aluminum smelter cohort (n = 7,026) linked to a national mortality database (1957-1999). No standardized mortality ratio was significantly elevated compared with the province's population. Smoking-adjusted internal comparisons were conducted using Cox regression for male subjects (n = 6,423). Ischemic heart disease (IHD) mortality (n = 281) was associated with cumulative benzo[a]pyrene (B(a)P) exposure (hazard ratio = 1.62, 95% confidence interval: 1.06, 2.46) in the highest category. A monotonic but nonsignificant trend was observed with chronic B(a)P exposure and acute myocardial infarction (n = 184). When follow-up was restricted to active employment, the hazard ratio for IHD was 2.39 (95% confidence interval: 0.95, 6.05) in the highest cumulative B(a)P category. The stronger associations observed during employment suggest that risk may not persist after exposure cessation. No associations with recent or current exposure were observed. IHD was associated with chronic (but not current) PAH exposure in a high-exposure occupational setting. Given the widespread workplace exposure to PAHs and heart disease's high prevalence, even modest associations produce a high burden.