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PubMed1998

Behavioral risk factors in emergency department patients: a multisite survey.

BACKGROUND: Many people rely on EDs for routine health care. Often, however, screening and counseling for health risks are not provided. OBJECTIVE: To determine prevalence rates of chronic disease and injury risk factors and access to routine health care in a random sample of ED patients in 3 cities. METHODS: A prospective survey was conducted at 3 hospital EDs in Akron, OH, Boston, MA, and Denver, CO. A modified version of the national Behavioral Risk Factor Surveillance Survey was administered by trained researchers to a convenience sample of non-critically ill patients during randomly selected shifts. RESULTS: Of 1,143 eligible patients, 923 (81%) agreed to participate. Their mean age was 39 (range = 17-96) years. Most were female (58%), white (60%), and unmarried (68%). Thirty-eight percent had no access to primary care. Injury-prone behaviors were prevalent: 53% of the respondents did not wear seat belts regularly; 15% had no working smoke detector; 3% kept loaded, unlocked handguns in their homes; 11% had attempted suicide; 23% had a positive CAGE screen for alcoholism; 3% had operated a motor vehicle in the preceding month while alcohol-intoxicated; and 11% had ridden in an automobile with an intoxicated driver. Cancer and chronic disease risks were also common: 48% smoked; 16% had not received a blood pressure check in the preceding year; and 4% reported unsafe sexual practices. Among women aged > 50 years, 42% had not received a Pap test in the prior 2 years and 14% had never had mammography. Many prevalence rates and access to care varied among the 3 sites. However, for most risk factors, prevalence rates did not differ in patients with and without access to primary health care. CONCLUSIONS: ED patients have high rates of injury and chronic disease risks, and many have no other source of routine health care. Research is needed to determine whether ED-based programs, designed to reduce injury and chronic disease risks, are feasible and cost-effective.

Adolescent↗
PubMed2026

Origin and evolution of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN).

Colorectal neuroendocrine carcinoma (NEC) is a rare and aggressive cancer and in a subset of patients associated with an adenocarcinoma (AC) component. When both components exceed 30% of the tumour, it is classified as mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), although there is an ongoing debate about whether any presence of two distinct components should be sufficient for a MiNEN diagnosis. This study aimed to investigate the origin and subsequent genetic changes of these two components. Ten colorectal cases suitable for sampling of an AC and a poorly differentiated NEC component were identified from the NORDIC NEC 2 study and sequenced across a 360-cancer gene panel. Mock phylogenetic trees were constructed from the molecular profiles of each sample within a patient. All ten cases revealed a common trunk of shared somatic mutations, including well-known colorectal cancer driver mutations such as BRAF, KRAS, APC, and TP53. In all cases, a single branching point separated the AC and NEC components. Private AC and NEC mutations generally had low variant allele frequencies, indicating that most AC and NEC cells were genetically similar. NEC, when compared with AC samples, demonstrated a higher frequency of private mutations (P = 0.009), indicating a higher mutation rate and greater ploidy (P = 0.012), suggesting an association between genomic duplication and AC-to-NEC transition. Shared mutations indicate a common clonal origin, underscoring the role of established colorectal driver mutations in the early development of these tumours, while the mechanisms underlying NEC differentiation remain poorly understood and may involve non-genetic factors.

Humans↗
PubMed2026

Whole genome and exome sequencing of pancreatic neuroendocrine tumour to investigate PRRT response.

Patients with pancreatic neuroendocrine tumours (PNETs) often have similar baseline clinical characteristics, including grade and molecular imaging phenotype, yet have highly variable responses to peptide receptor radionuclide therapy (PRRT). To identify genomic alterations and mutational patterns associated with PRRT treatment response and acquired somatic changes following PRRT exposure, whole genome or exome sequencing was applied to 40 PNET samples from 32 patients, including eight paired pre- or post-PRRT samples. The genomic profile of tumours reflected the known mutational landscape of PNET with MEN1 (34%), ATRX/DAXX (47%) alterations and a recurrent pattern of aneuploidy (38%) detected. A recurrent PSIP1::TBL1X fusion of unknown function was also identified in four tumours. The disease control rate following PRRT using RECIST1.1 and molecular imaging criteria was 88% (28/32). No mutational features were found to be statistically associated with progression-free survival. There was no significant increase in tumour mutational burden in the post-PRRT tumours, nor recurrent emergent mutational changes in cancer driver genes to explain progression to higher-grade disease, when observed. However, a small indel signature (ID8) previously associated with DNA damage repair by non-homologous end joining (NHEJ) was higher in PRRT-exposed compared with PRRT-naive samples (23.8 vs 4.8%, respectively; P < 0.001). Thus, comprehensive DNA analysis of pancreatic NETs did not identify biomarkers predictive of PRRT response nor evidence for high-level PRRT-induced genomic instability or hypermutation, yet mutation signature analysis supports NHEJ as being important for DNA repair and survival of neuroendocrine cells following exposure to beta-particle radiation.

Humans↗
PubMed1987

The Copenhagen case-referent study on bladder cancer. Risks among drivers, painters and certain other occupations.

Occupational risk of bladder cancer (including papilloma) was investigated as part of a case-referent study in Copenhagen. Occupational histories were obtained on 389 cases and 790 referents drawn at random from the general population of the study area. When persons with missing information were excluded, a total of 371 cases (280 men, 91 women) and 771 referents (577 men, 194 women) were left for analysis. After adjustment for tobacco smoking, age, and sex, significantly increased relative risks were observed for occupation in land transport, in particular bus, taxi, or truck driving. A statistically significant trend was seen with duration of employment in these trades. Based on a logistic regression analysis, a relative risk (RR) of 1.3 was determined for 10 years of employment in the trade. An association was also found for employment in trades undertaking painting (RR = 1.4 for 10 years' employment), and a significant trend emerged for duration of employment. A positive association with employment in the textile and leather industry disappeared after adjustment for tobacco smoking, and no association with duration of employment emerged. No association was found with employment in the chemical, rubber, iron and metal industries or in health services.

Automobile Driving↗
PubMed2026

Multi-cohort integration and machine learning identify CPVL as a novel oncogenic driver in gastric cancer.

BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, and the prognosis of advanced GC remains poor. Systematic identification of robust biomarkers through multi-cohort integration and computational prioritization may facilitate the discovery of novel therapeutic targets. AIM: To identify key genes associated with gastric cancer progression through integrative multi-omics analysis and to elucidate the biological functions and molecular mechanisms of the top-prioritized candidate gene. METHODS: Comprehensive bioinformatics analyses integrating The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) datasets were performed using differential expression analysis, weighted gene co-expression network analysis (WGCNA), Cox regression, and eight machine-learning algorithms to systematically identify and prioritize GC-associated hub genes. Among the identified candidates, CPVL was selected for further validation based on its diagnostic and prognostic performance. CPVL expression and clinical relevance were validated by independent datasets and immunohistochemistry. Lentiviral constructs were used to overexpress or silence CPVL in GC cell lines. Functional assays were performed, including CCK-8, colony formation, EdU incorporation, and flow cytometry, to assess cell proliferation and cell-cycle distribution. Western blotting and JAK2 inhibitor (AZD1480) rescue experiments were performed to elucidate the underlying mechanisms, and a nude mouse xenograft model was used to evaluate tumorigenicity in vivo. RESULTS: Multi-cohort screening identified five hub genes (CPVL, AADAC, BCAT1, CPXM1, and FBN1). Among them, CPVL exhibited the highest diagnostic accuracy (AUC&#x2009;=&#x2009;0.895) and the strongest correlation with poor overall survival, and was therefore selected for mechanistic investigation. CPVL expression was markedly upregulated in GC tissues and cell lines. Functional assays demonstrated that CPVL promotes GC cell proliferation and accelerates G1/S-phase transition. Mechanistically, CPVL activated the JAK2/STAT3 signaling pathway, upregulating Cyclin D1 and CDK4 while downregulating p27. Treatment with the JAK2 inhibitor AZD1480 partially reversed these effects. In vivo, CPVL knockdown significantly inhibited tumor growth. CONCLUSION: Through systematic multi-cohort integration and machine-learning prioritization, CPVL was identified as a novel oncogenic driver in gastric cancer. CPVL promotes tumor growth via activation of the JAK2/STAT3 pathway and regulation of the Cyclin D1/CDK4/p27 axis, highlighting its potential as a diagnostic biomarker and therapeutic target.

Biomarker↗
PubMed2006

Cyclin D1 in non-small cell lung cancer: a key driver of malignant transformation.

PURPOSE: To review the evidence implicating the deregulation of cyclin D1 in the pathogenesis of non-small cell lung cancer (NSCLC), and to discuss the opportunities for targeted clinical intervention. METHODS: Data published until June 2006 are summarized, and previously unpublished results from our own research are included. RESULTS: In normal cells, cyclin D1 complexes with and activates cyclin-dependent kinases (CDK) and acts as a transcriptional regulator. The protein is frequently overexpressed in a wide range of cancers, sometimes coincident with CCND1 (cyclin D1) gene amplification (5-20% of tumours). A low level of somatic mutations have been seen in certain tumours. CCND1 is amplified in NSCLC and cyclin D1 is frequently overexpressed in tumours and pre-invasive bronchial lesions, generally from one parental allele. Mutation analyses revealed a frequent CCND1 gene polymorphism (A870G) that modulates alternative splicing and allows expression of an alternative cyclin D1 transcript (transcript cyclin D1b). The encoded cyclin D1b protein lacks a specific phosphorylation site required for nuclear export. Genotype has been correlated with the risk and/or severity of disease or drug response across a range of malignancies, including lung cancer. Together, these findings suggest a strong pathological role for cyclin D1 deregulation in bronchial neoplasia. CONCLUSION: Current data indicate that cyclin D1 overexpression is not a consequence of, but rather a pivotal element in the process of malignant transformation in the lung and other tissues. This understanding may open new avenues for lung cancer diagnosis, treatment and prevention.

Adenoma↗
PubMed2024

Co-expression in tissue-specific gene networks links genes in cancer-susceptibility loci to known somatic driver genes.

BACKGROUND: The genetic background of cancer remains complex and challenging to integrate. Many somatic mutations within genes are known to cause and drive cancer, while genome-wide association studies (GWAS) of cancer have revealed many germline risk factors associated with cancer. However, the overlap between known somatic driver genes and positional candidate genes from GWAS loci is surprisingly small. We hypothesised that genes from multiple independent cancer GWAS loci should show tissue-specific co-regulation patterns that converge on cancer-specific driver genes. RESULTS: We studied recent well-powered GWAS of breast, prostate, colorectal and skin cancer by estimating co-expression between genes and subsequently prioritising genes that show significant co-expression with genes mapping within susceptibility loci from cancer GWAS. We observed that the prioritised genes were strongly enriched for cancer drivers defined by COSMIC, IntOGen and Dietlein et al. The enrichment of known cancer driver genes was most significant when using co-expression networks derived from non-cancer samples of the relevant tissue of origin. CONCLUSION: We show how genes within risk loci identified by cancer GWAS can be linked to known cancer driver genes through tissue-specific co-expression networks. This provides an important explanation for why seemingly unrelated sets of genes that harbour either germline risk factors or somatic mutations can eventually cause the same type of disease.

Humans↗
PubMed2025

ProgModule: A novel computational framework to identify mutation driver modules for predicting cancer prognosis and immunotherapy response.

BACKGROUND: Cancer originates from dysregulated cell proliferation driven by driver gene mutations. Despite numerous algorithms developed to identify genomic mutational signatures, they often suffer from high computational complexity and limited clinical applicability. METHODS: Here, we presented ProgModule, an advanced computational framework designed to identify mutation driver modules for cancer prognosis and immunotherapy response prediction. In ProgModule, we introduced the Prognosis-Related Mutually Exclusive Mutation (PRMEM) score, which optimizes the balance between exclusive mutation coverage and the incorporation of mutation combination mechanisms critical for cancer prognosis. RESULTS: Applying to BLCA and HNSC cohorts, ProgModule successfully identified driver modules that stratify patients into distinct prognostic subgroups, and the combination of these modules could serve as an effective prognostic biomarker. Extending our method to diverse cancers, ProgModule presented robust prognostic performance and stability across model parameters, including stopping criteria and network topology. Moreover, our analysis suggested that driver modules can predict immunotherapeutic benefit more effectively than existing signatures. Further analyses based on published CRISPR data indicated that genes within these modules may serve as potential therapeutic targets. CONCLUSIONS: Altogether, ProgModule emerges as a powerful tool for identifying mutation driver modules as prognostic and immunotherapy response biomarkers, and genes within these modules may be used as potential therapeutic targets for cancer, offering new insights into precision oncology.

Humans↗
PubMed1997

Increased risk of lung cancer among male professional drivers in urban but not rural areas of Sweden.

OBJECTIVES: To study the risk of lung cancer in different subgroups of professional drivers in urban and rural areas of Sweden. METHODS: Information on occupation and geographical region was obtained from the Swedish census of 1970 and data on the incidence of lung cancer between 1971 and 1984 from the National Swedish Cancer Registry. Professional drivers were separated into bus, taxi, and long and short distance lorry drivers. Comparisons of cumulative incidence of lung cancer were made between each particular group of drivers and gainfully employed men in the same region. RESULTS: Taxi drivers, and long and short distance lorry drivers in Stockholm County showed increased relative risks (RRs) of lung cancer with the highest risk among the short distance lorry drivers (RR 2.0, 95% confidence interval (95% CI) 1.5 to 2.6). These categories of drivers also showed increased risks in the other two large conurbations in Sweden. In the rest of the country (mainly rural areas) there were no increased RRs for any category of driver. The RR for bus drivers was not increased in any region. After adjustment for assumed differences in smoking habits the RRs remained significantly increased for lorry drivers in Stockholm but not for other groups of drivers in other areas. However, the RRs remained numerically higher in large conurbations than in rural regions for all groups of drivers. CONCLUSIONS: These findings suggest that some factors present in the urban environment play a substantial part in the excess of lung cancer among short distance lorry drivers in urban areas of Sweden. Exposure to motor exhaust fumes may have contributed to this excess.

Adult↗
PubMed2002

Outpatient cancer drug costs: changes, drivers, and the future.

BACKGROUND: To the authors' knowledge, no analysis has examined the specific components of drug spending for overall cancer care. The authors' objective was to quantify and characterize trends in outpatient drug expenditures for cancer patients. METHODS: The authors retrospectively analyzed pharmacy and outpatient professional claims data from commercial and Medicare health maintenance organization enrollees with a solid tumor diagnosis in 1995 and 1998. Charges were subdivided by type of drug (antineoplastic drugs, chemotherapy adjuncts, supportive drugs, and drugs unrelated to cancer treatment). RESULTS: In 1995, 14,663 cancer patients received outpatient drug treatment and 13,829 patients in 1998. Total charges increased from $17.9 million (mean charge of $1218 per patient) to $27.9 million (mean charge of $2003 per patient), an average annual increase of 16%. Antineoplastic therapy constituted the largest component of cancer-related drug costs (67%) and represented 76% of the increase from 1995 to 1998. Most charges were incurred in the professional setting for agents administered by injection. The primary explanation for the increases appeared to be a shift in treatment patterns toward newer, more expensive antineoplastic agents. Supportive therapy represented 17% of the increase in cancer drug costs, followed by chemotherapy adjuncts (7%). Charges for drugs unrelated to cancer therapy increased by 21% per year. CONCLUSIONS: Antineoplastic therapy administered in an office or clinic was the single most important cost driver, with newer more expensive agents replacing older, less expensive drugs. Attempts to understand and control outpatient drug cost increases for cancer patients should focus primarily on antineoplastic therapy, especially the appropriate substitution of newer agents for older, less expensive alternatives. Some non-chemotherapy cancer drugs may offer an opportunity to improve quality of life with a relatively small effect on overall cancer drug costs.

Adolescent↗
PubMed1994

A mortality study of lung cancer among swiss professional drivers: accounting for the smoking related fraction by a multivariate approach.

The mortality due to lung cancer among 'chauffeurs', who have a presumably long-term exposure to diesel exhaust fumes, was analysed. As controls, men in industrial occupations of similar socio-economic status were selected. Cases were drawn from the Swiss mortality register for the years 1979-1983. Person-years were obtained using data from the 1980 census records. These two data files were combined by occupation, age class and socio-economic status. Age adjusted incidence rates were calculated applying Poisson regression. To control for tobacco related lung cancer mortality an indirect adjustment was undertaken. Using information about the smoking habits of the people in the occupations under study, smoking-attributable lung cancer mortality was accounted for by incorporating Axelson's technique into multivariate regression modeling. The mortality ratio for lung cancer for chauffeurs with respect to the controls was 2.27, which is significantly in excess of 1:95% CI (1.99, 2.58). Other tobacco related diagnoses such as bladder cancer, esophageal cancer and ischemic heart diseases showed excess risks as well. After accounting for smoking, a slight but significant increase in lung cancer mortality remained among chauffeurs (mortality ratio 1.48, 95% CI: 1.30, 1.68). In summary, the present results do support the hypothesis that diesel exhaust is a significant cause of lung cancer.

Adult↗
PubMed1988

Cancer incidence among urban bus drivers in Denmark.

During the period from 1978-1984 the incidence of cancer among 2,465 male urban bus drivers in three major cities in Denmark was studied. The information with regard to cancer diagnosis was obtained from the Danish Cancer Registry. Danish men in 1981 were used as reference. Standardized Morbidity Ratio (SMR) for bladder- and skin cancer was significantly elevated among the bus drivers with values of 206 and 202, respectively. As to other cancers, no significant deviations from the expected were found. The same result was found when only drivers with more than ten years' seniority were included in the calculations. The incidence of skin cancer remained significantly elevated when corrected for degree of urbanization. Traffic density and whether the drivers worked in Copenhagen or in the province were not related to cancer incidence.

Adult↗
PubMed2025

Comparison of actionable alterations in cancers with kinase fusion, mutation, and copy number alteration.

Kinase-related gene fusion and point mutations play pivotal roles as drivers in cancer, necessitating optimized, targeted therapy against these alterations. The efficacy of molecularly targeted therapeutics varies depending on the specific alteration, with great success reported for such therapeutics in the treatment of cancer with kinase fusion proteins. However, the involvement of actionable alterations in solid tumors, especially regarding kinase fusions, remains unclear. Therefore, in this study, we aimed to compare the number of actionable alterations in patients with tyrosine or serine/threonine kinase domain fusions, mutations, and copy number alterations (CNAs). We analyzed 613 patients with 40 solid cancer types who visited our division between June 2020 and April 2024. Furthermore, to detect alterations involving multiple-fusion calling, we performed comprehensive genomic sequencing using FoundationOne&#xae; companion diagnostic (F1CDx) and FoundationOne&#xae; Liquid companion diagnostic (F1LCDx). Patient characteristics and genomic profiles were analyzed to assess the frequency and distribution of actionable alterations across different cancer types. Notably, 44 of the 613 patients had fusions involving kinases, transcriptional regulators, or tumor suppressors. F1CDx and F1LCDx detected 13 cases with kinase-domain fusions. We identified 117 patients with kinase-domain mutations and 58 with kinase-domain CNAs. The number of actionable alterations in patients with kinase-domain fusion, mutation, or CNA (median [interquartile range; IQR]) was 2 (1-3), 5 (3-7), and 6 (4-8), respectively. Patients with kinase fusion had significantly fewer actionable alterations than those with kinase-domain mutations and CNAs. However, those with fusion involving tumor suppressors tended to have more actionable alterations (median [IQR]; 4 [2-9]). Cancers with kinase fusions exhibited fewer actionable alterations than those with kinase mutations and CNAs. These findings underscore the importance of detecting kinase alterations and indicate the pivotal role of kinase fusions as strong drivers of cancer development, highlighting their potential as prime targets for molecular therapeutics.

Humans↗
PubMed1994

Past exposure to asbestos and combustion products and incidence of cancer among Finnish locomotive drivers.

Locomotive drivers in the steam engine era were exposed to asbestos during their vocational training for two years while training in workshops. Later in their career they had exposure to coal and diesel combustion products. To assess the level of earlier exposure historical working conditions were reconstructed and hygienic conditions were measured. The average exposure to asbestos (mainly anthophylline) fibres > 5 microns was 5.0 fibres/cm3. Incidence of cancer in a cohort of 8391 members of the Finnish Locomotive Drivers' Association, 1953-91, was analysed. The incidence of lung cancer and also total cancer was below the national average, probably due to the low prevalence of smoking among the drivers in the steam engine era. A four-fold risk of mesothelioma was found, most likely caused by exposure to asbestos. Also the observed 1.5-fold incidence of non-melanoma skin cancer and 1.7-fold risk of cancer of the oral cavity and pharynx may be related to occupation.

Asbestos↗
PubMed1998

Increased risk of lung cancer among different types of professional drivers in Denmark.

OBJECTIVES: To study risk of lung cancer among groups of professional drivers probably exposed to different levels of traffic exhaust fumes. METHODS: A nationwide case-control study (1970-89) based on employees comprising 28,744 men with primary lung cancer and incidence density sampled matched controls (1:1). Employment histories were reconstructed back to 1964 for each study subject from the records of a nationwide pension scheme with compulsory membership. Socioeconomic status was derived from the individual job title taken from the national population registry. Information on tobacco smoking habits was available from historical surveys. Relative risks were estimated by odds ratios (ORs) based on conditional logistic regression analyses. RESULTS: In total 2251 of the male lung cancer cases had been employed as bus, lorry, taxi, or unspecified drivers. No significant difference in tobacco smoking habits was found among professional male Danish drivers and the total employed population. The OR for lung cancer adjusted for socioeconomic status was 1.6 (95% confidence interval (95% CI) 1.2 to 2.2) among taxi drivers, who were considered to be exposed to the highest concentrations of vehicle exhaust fumes, and 1.3 (1.2 to 1.5) for bus and lorry drivers. The OR was 1.4 (1.3 to 1.5) for unspecified drivers. The adjusted risk of lung cancer increased significantly with increasing duration of employment as a driver, and the risk was highest for long term taxi drivers with 10 years of lag time (OR 3.0; 1.2 to 6.8). CONCLUSION: Occupational factors, probably exposure to vehicle exhaust, seems to play an important part in the development of lung cancer among drivers.

Adolescent↗