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1.
Nat Commun ; 11(1): 27, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911640

RESUMO

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.

2.
Support Care Cancer ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974768

RESUMO

PURPOSE: Adolescents and young adults (AYA) with cancer are increasingly using the internet and social media (SM) for cancer-related information. AYA face specific challenges and thus require tailored resources that meet their needs. We describe the internet and SM preferences of AYA related to their cancer information seeking behaviors and their preferences for a future resource compared to middle-aged adults (MAA). METHODS: Cancer patients completed a cross-sectional survey related to their internet and SM usage, cancer information, and preferences for future resources. Chi-square tests were used to compare AYA and MAA. RESULTS: The mean (±SD) age in the AYA group was 30±6.1 years (n = 129); in MAA 55±6.7 years (n = 157). In general, AYA preferred internet sites over SM platforms for cancer-related information and prefer a website platform over a SM platform for a new resource. Few AYA were aware of hospital-based AYA-specific resources. MAA were less likely to use SM compared with AYA (13% vs 4%, p = 0.01); however, websites and SM platforms that were used were similar between the 2 groups. Participants endorsed having already researched certain topics - yet, these were also those desired in a new resource. Compared to MAA, AYA sought more information on diet/nutrition, physical activity, exercise/fitness, fertility, sexual health, and body image (all p values < 0.05). CONCLUSION: AYA and MAA use similar resources on the internet and SM, but AYA sought information related to specific needs. Development of future resources should focus on an internet-based platform rather than a SM platform, coupled with promoting awareness of the resource.

3.
Clin Trials ; : 1740774519895966, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31894702

RESUMO

BACKGROUND: Recruitment to clinical trials is suboptimal, increasing costs, and delaying the potential implementation of clinical advances. Among other barriers, the lack of marketing experience among trialists may limit recruitment. In this observational study, in the context of the Pan-Canadian Early Detection of Lung Cancer Trial, we assessed the value of a motivational survey of study participants in planning a tailored advertising campaign and analysed the value of individual components of advertising in generating telephone calls to the study and recruited subjects. METHODS: The Pan-Canadian Early Detection of Lung Cancer Trial was a single arm study assessing risk modelling for lung cancer screening by low-dose computed tomography scan and autofluorescence bronchoscopy. Individuals were recruited to eight sites across Canada without a central marketing plan. On contact with the study, individuals reported how they heard about the study according to a predefined list. One site, the Juravinski Cancer Centre, worked with a marketing expert to develop a survey to assess participant motivations, source of study awareness, and personal habits. The survey was used to develop a media campaign for recruitment. Media events were collected from all sites. The primary analysis assessed the number of telephone contacts and recruited subjects associated with various media factors. Individual print media characteristics were assessed for their effect on recruitment. RESULTS: At all sites, 7059 individuals contacted the study, and 2537 were eligible and recruited. Among 52 individuals completing the Juravinski Cancer Centre survey, motivation included concern for personal risk of lung cancer (71%), followed by desire to contribute to a cure (67%), followed by personal knowledge of a person with lung cancer (50%). Most reported hearing of the study from the newspaper (58%) despite no print ad yet being distributed. With survey input, a newsprint campaign was executed. The number of media events varied by site (median: 13, range: 3-28). Among all recruits, 56.4% reported referral by newspaper followed by family/friend (14%). Telephone contacts and recruited subjects per event varied significantly by site, while unpaid media events appeared superior to paid events. Print media characteristics associated with increased telephone contacts and recruitment included use of a rational appeal (vs a mixed rational-emotional), less use of white space, and larger headline font. CONCLUSION: A survey of trial candidates provides useful information regarding personal motivation, media use, and lifestyle. Unpaid media events appear superior in generating recruitment, while print media may be superior to radio and television in selecting eligible recruits. The utility of individual print media characteristics appears to differ from the commercial advertising literature. Further research on marketing in clinical trials is encouraged to improve recruitment ( ClinicalTrials.gov registration: NCT00751660, https://clinicaltrials.gov/ct2/show/NCT00751660 ).

4.
Int J Cancer ; 146(7): 1862-1878, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31696517

RESUMO

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.

6.
Support Care Cancer ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31781945

RESUMO

BACKGROUND: Smoking cessation is an integral part of cancer survivorship. To help improve survivorship education, clinicians need an understanding of patient awareness of the harms of continued smoking. METHODS: Cancer survivors from Princess Margaret Cancer Centre (Toronto, ON) were surveyed on their awareness of the harms of continued smoking on cancer-related outcomes. Multivariable logistic regression models assessed factors associated with awareness and whether awareness was associated with subsequent cessation among smokers at diagnosis. RESULTS: Among 1118 patients, 23% were current smokers pre-diagnosis and 54% subsequently quit; 25% had lung and 30% head and neck cancers. Many patients reported being unaware that continued smoking results in greater cancer surgical complications (53%), increased radiation side effects (62%), decreased quality of life during chemotherapy (51%), decreased chemotherapy or radiation efficacy (57%), increased risk of death (40%), and increased development of second primaries (38%). Being a current smoker was associated with greater lack of awareness of some of these smoking harms (aORs = 1.53-2.20, P < 0.001-0.02), as was exposure to any second-hand smoke (aORs = 1.45-1.53, P = 0.006-0.04) and being diagnosed with early stage cancer (aORs = 1.38-2.31, P < 0.001-0.06). Among current smokers, those with fewer pack-years, being treated for cure, or had a non-tobacco-related cancer were more likely unaware. Awareness that continued tobacco use worsen quality of life after chemotherapy was associated with subsequent cessation (aOR = 2.26, P = 0.006). CONCLUSIONS: Many cancer survivors are unaware that continued smoking can negatively impact cancer-related outcomes. The impact of educating patients about the potential harms of continued smoking when discussing treatment plans should be further evaluated.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31756444

RESUMO

BACKGROUND & AIMS: Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones are associated with risk of EAC or Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization analysis using data from patients with EAC (n = 2488) or BE (n = 3247) and control participants (n = 2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single-nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. RESULTS: Higher genetically predicted levels of follicle-stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01-1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per SD increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulfate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. CONCLUSIONS: In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle-stimulating and luteinizing hormones and risk of BE and EAC.

8.
Clin Cancer Res ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694835

RESUMO

PURPOSE: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide. There is an unmet need to develop novel clinically relevant models of NSCLC to accelerate identification of drug targets and our understanding of the disease. EXPERIMENTAL DESIGN: Thirty surgically resected NSCLC primary patient tissue and 35 previously established patient-derived xenograft (PDX) models were processed for organoid culture establishment. Organoids were histologically and molecularly characterized by cytology and histology, exome sequencing, and RNA-sequencing analysis. Tumorigenicity was assessed through subcutaneous injection of organoids in NOD/SCID mice. Organoids were subjected to drug testing using EGFR, FGFR, and MEK-targeted therapies. RESULTS: We have identified cell culture conditions favoring the establishment of short-term and long-term expansion of NSCLC organoids derived from primary lung patient and PDX tumor tissue. The NSCLC organoids recapitulated the histology of the patient and PDX tumor. They also retained tumorigenicity, as evidenced by cytologic features of malignancy, xenograft formation, preservation of mutations, copy number aberrations, and gene expression profiles between the organoid and matched parental tumor tissue by whole-exome and RNA sequencing. NSCLC organoid models also preserved the sensitivity of the matched parental tumor to targeted therapeutics, and could be used to validate or discover biomarker-drug combinations. CONCLUSIONS: Our panel of NSCLC organoids closely recapitulates the genomics and biology of patient tumors, and is a potential platform for drug testing and biomarker validation.

9.
J Thorac Oncol ; 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31634667

RESUMO

INTRODUCTION: Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients. METHODS: In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal. RESULTS: In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9-99.6) in the 450-mg cohort and 60% (95% CI: 26.2-87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7-84.3) in the 450-mg cohort and 25% (95% CI: 5.5-57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1-87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0-58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported. CONCLUSION: Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.

10.
Cancer Med ; 8(18): 7542-7555, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31650705

RESUMO

BACKGROUND: As the treatment landscape in patients with non-small cell lung cancer (NSCLC) harboring mutations in the epidermal growth factor receptor (EGFRm) continues to evolve, real-world health utility scores (HUS) become increasingly important for economic analyses. METHODS: In an observational cohort study, questionnaires were completed in EGFRm NSCLC outpatients, to include demographics, EQ-5D-based HUS and patient-reported toxicity and symptoms. Clinical and radiologic characteristics together with outcomes were extracted from chart review. The impact of health states, treatment type, toxicities, and clinical variables on HUS were evaluated. RESULTS: Between 2014 and 2018, a total of 260 patients completed 994 encounters. Across treatment groups, patients with disease progression had lower HUS compared to controlled disease (0.771 vs 0.803; P = .01). Patients predominantly received gefitinib as the first-line EGFR tyrosine kinase inhibitor (TKI) (n = 157, mean-HUS = 0.798), whereas osimertinib (n = 62, mean-HUS = 0.806) and chemotherapy (n = 38, mean-HUS = 0.721) were more likely used in subsequent treatment lines. In longitudinal analysis, TKIs retained high HUS (>0.78) compared to chemotherapy (HUS < 0.74). There were no differences between the frequency or severity of toxicity scores in patients receiving gefitinib compared to osimertinib; however, TKI therapy resulted in fewer toxicities than chemotherapy (P < .05), with the exception of worse diarrhea and skin rash (P < .001). Severity in toxicities inversely correlated with HUS (P < .001). Clinico-demographic factors significantly affecting HUS included age, Eastern Cooperative Oncology Group Performance Score (ECOG PS), disease state, treatment group, and metastatic burden. CONCLUSIONS: In a real-world EGFRm population, patients treated with gefitinib or osimertinib had similar HUS and toxicities, scores which were superior to chemotherapy. Health utility scores inversely correlated with patient-reported toxicity scores. In the era of targeted therapies, future economic analyses should incorporate real-world HUS.

12.
Int J Cancer ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31577861

RESUMO

Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large-scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta-analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10 × 10-8 ; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25 × 10-7 ; 12p13.31: rs71450133, Deletion, OR = 1.09, p = 8.83 × 10-7 ; and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64 × 10-8 ). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis.

13.
Cancer ; 125(23): 4210-4223, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31490550

RESUMO

BACKGROUND: Diabetes is positively associated with various cancers, but its relationship with tumors of the esophagus/esophagogastric junction remains unclear. METHODS: Data were harmonized across 13 studies in the International Barrett's and Esophageal Adenocarcinoma Consortium, comprising 2309 esophageal adenocarcinoma (EA) cases, 1938 esophagogastric junction adenocarcinoma (EGJA) cases, 1728 Barrett's esophagus (BE) cases, and 16,354 controls. Logistic regression was used to estimate study-specific odds ratios (ORs) and 95% CIs for self-reported diabetes in association with EA, EGJA, and BE. Adjusted ORs were then combined using random-effects meta-analysis. RESULTS: Diabetes was associated with a 34% increased risk of EA (OR, 1.34; 95% CI, 1.00-1.80; I2  = 48.8% [where 0% indicates no heterogeneity, and larger values indicate increasing heterogeneity between studies]), 27% for EGJA (OR, 1.27; 95% CI, 1.05-1.55; I2  = 0.0%), and 30% for EA/EGJA combined (OR, 1.30; 95% CI, 1.06-1.58; I2  = 34.9%). Regurgitation symptoms modified the diabetes-EA/EGJA association (P for interaction = .04) with a 63% increased risk among participants with regurgitation (OR, 1.63; 95% CI, 1.19-2.22), but not among those without regurgitation (OR, 1.03; 95% CI, 0.74-1.43). No consistent association was found between diabetes and BE. CONCLUSIONS: Diabetes was associated with increased EA and EGJA risk, which was confined to individuals with regurgitation symptoms. Lack of an association between diabetes and BE suggests that diabetes may influence progression of BE to cancer.

14.
Oncologist ; 24(11): e1219-e1227, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31409744

RESUMO

BACKGROUND: Recent studies have demonstrated improved outcomes with real-time patient-reported outcome questionnaires (PRO questionnaires) using questions adapted for patient use from the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). Outside of the clinical trial setting, limited information exists on factors affecting the completion of PRO questionnaires in routine practice. The primary aim of this prospective cross-sectional study was to evaluate patient willingness to complete PRO questionnaires on a regular basis and to better understand responder biases to improve patient feedback. MATERIALS AND METHODS: Patients performing PRO-CTCAE toxicity and symptom PRO questionnaires in oncology clinics at Princess Margaret Cancer Centre from 2013 to 2016 were assessed for their willingness to complete PRO questionnaires using a nine-item, tablet-based acceptability survey. Patient-reported characteristics (i.e., age, sex, language, marital status, education, occupation, etc.), cancer type, treatment modalities, and health metrics (i.e., Eastern Cooperative Oncology Group) were also collected. Characteristics were evaluated by logistic regression (odds ratios [OR]) using the primary outcome with prespecified levels of significance for univariate (p ≤ .10), and additional multivariate (p ≤ .05) testing. RESULTS: A total of 1,792 patients (median age 60 years; range 18-97) with various cancer diagnoses were assessed. A greater proportion of female (56%) and white (74%) respondents with an annual household income of <$100,000 (69%) participated. More than half (58%) of respondents were willing to complete PRO questionnaires at every clinic visit, and a high proportion (77%) found utility in reporting physical and emotional feelings to clinicians using PRO questionnaires. In general, patients did not find that PRO questionnaires made clinic visits more difficult (93%). In uni- and multivariable testing, patients were more willing to complete sleep- and fatigue-related PRO questionnaires relative to chemotoxicity-based PRO questionnaires (OR 1.52; p = .012). Patients aged 40-65 versus 18-40 years were also more likely to report high PRO questionnaire acceptability (OR 1.49; p = .025). Additional patient characteristics such as white ethnicity (OR 1.76), Canada as country of birth (OR 1.66), and English language (OR 2.15) relative to other had higher acceptability on uni- (p < .001) and multivariable (p < .001) analyses. Patients reporting treatment intent as palliative (OR 0.69; p = .0013) or hematological (OR 0.73; p = .027) were less likely to report high PRO questionnaire acceptability on univariable analysis; however, only palliative patients (OR 0.72) maintained this effect on multivariable testing (p = .012). Patients reporting higher health utility scores (per change in .05) also had significantly increased PRO questionnaire acceptability in uni- (OR 1.06; p < .001) and multivariable (OR 1.05; p = .008) analyses. No significant differences in PRO questionnaire acceptability were seen between cancer types, education level, household income, employment status, or treatment modality. CONCLUSION: Routine assessment using PRO questionnaires is associated with moderate acceptability by patients with cancer. Specific patient characteristics are associated with higher completion willingness. Additional research is necessary to identify factors associated with low acceptability of PRO questionnaires and to develop site-, ethnicity-, and treatment-specific instruments to assess the value of PRO questionnaires for symptom monitoring in clinical practice. IMPLICATIONS FOR PRACTICE: This study will help to identify the clinical, demographic, and survey characteristics associated with willingness to complete patient-reported outcome questionnaires regularly in the cancer outpatient setting.

15.
J Otolaryngol Head Neck Surg ; 48(1): 34, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345259

RESUMO

OBJECTIVE: A number of in vitro and clinical studies have suggested potential antineoplastic effects of metformin. The impact of this medication on outcomes in head and neck cancer is less clear. Our aim was to determine the effect of metformin on outcomes within our large cohort of head and neck cancer patients with Type II Diabetes (T2DM). STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary Cancer Centre. SUBJECTS AND METHODS: A retrospective review of individuals with head and neck squamous carcinoma (HNSCC) and T2DM between January 2005 and December 2011 at Princess Margaret Cancer Centre was conducted. Medication history was obtained from surveys at initial presentation and electronic medical record review. Using Cox regression analyses, the association between metformin use and local, regional and distant failures was explored. Subgroup analyses were conducted for oral cavity, oropharynx and larynx. RESULTS: A total of 329 HNSCC patients with T2DM were identified, including 195 metformin users and 134 non-metformin users. Patients were well-matched in terms of clinical, pathologic, and treatment factors. No difference in local, regional, or distant failure was observed between diabetic metformin users and diabetic non-metformin users for the entire cohort or within subgroup analysis for subsite. No difference between the two groups was observed for overall survival, recurrence-free survival, and disease-specific survival at 5 years. CONCLUSION: No association between metformin use and oncologic outcomes were observed in this large cohort of HNSCC patients. Multicenter, prospective studies may be needed to verify previous studies identifying a potential anti-neoplastic effect of this medication.

16.
Cancers (Basel) ; 11(7)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31330989

RESUMO

The burden of somatic mutations and neoantigens has been associated with improved survival in cancer treated with immunotherapies, especially non-small cell lung cancer (NSCLC). However, there is uncertainty about their effect on outcome in early-stage untreated cases. We posited that the burden of mutations in a specific set of genes may also contribute to the prognosis of early NSCLC patients. From a small cohort of 36 NSCLC cases, we were able to identify somatic mutations and copy number alterations in 865 genes that contributed to patient overall survival. Simply, the number of altered genes (NAG) among these 865 genes was associated with longer disease-free survival (hazard ratio (HR) = 0.153, p = 1.48 × 10-4). The gene expression signature distinguishing patients with high/low NAG was also prognostic in three independent datasets. Patients with a high NAG could be further stratified based on the presence of immunogenic mutations, revealing a further subgroup of stage I NSCLC with even better prognosis (85% with >5 years survival), and associated with cytotoxic T-cell expression. Importantly, 95% of the highly-altered genes lacked direct relation to cancer, but were implicated in pathways regulating cell proliferation, motility and immune response.

17.
Int J Cancer ; 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269236

RESUMO

In cancer epidemiological studies, determination of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) typically depends on the availability of tumor tissue testing, and/or tumor tissue access. Identifying alternative methods for estimating HPV status can improve the quality of such studies when tissue is unavailable. We developed multiple predictive models for tumor HPV status and prognosis by combining both clinico-epidemiological variables and either serological multiplex assays of HPV or multiple imputation of HPV status (HPVmi ). Sensitivity, specificity and accuracy of these methods compared to either p16 immunostaining (p16 IHC) or survival were assessed. When compared to a reference of tumor tissue p16 IHC in 783 OPSCC patients, the clinic-HPVsero model incorporating a composite of 20 HPV serological antibodies (HPVsero ) and 4 clinical factors (c-index: 0.96) performed better than using HPVsero (c-index: 0.92) or HPVmi (c-index: 0.76) alone. However, the model that contained a single HPV16 E6 antibody combined with four clinical variables, performed extremely well (clinic-s1-16E6; c-index: 0.95). When defining HPV status by HPVsero , s1-16E6, HPVmi or through p16 IHC, each of these definitions demonstrated improved overall and disease-free survival in HPV-positive OPSCC patients, when compared to HPV-negative patients (adjusted hazard ratios between 0.25 and 0.63). Our study demonstrates that when blood samples are available, a model that utilizes a single s1-16E6 antibody combined with several clinical features has excellent test performance characteristics to estimate HPV status and prognosis. When neither blood nor tumor tissue is available, multiple imputation, calibrated on local population characteristics, remains a viable, but suboptimal option.

18.
J Thorac Oncol ; 14(10): 1704-1717, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31260832

RESUMO

The accurate diagnosis of mesothelioma is critical for the appropriate clinical management of this cancer. Many issues complicate making the diagnosis of mesothelioma including the presence of reactive mesothelial cells in benign pleural effusions, the heterogeneity of mesothelioma histopathology, the relatively high incidence of other epithelial malignancies that metastasize to the pleura, and primary sarcomas that arise within the pleura. Given the rapidly evolving field of molecular profiling and the need for translational correlates in mesothelioma clinical trials, the National Cancer Institute (NCI)-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Clinical Trials Planning Meeting was convened in March 2017 to develop a consensus on standard pathology guidelines for future NCI-sponsored clinical trials in mesothelioma. This consensus statement covers recommendations for specimen handling, pathologic classification and diagnosis, biobanking, and tissue correlative studies.

19.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1228-1237, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31263055

RESUMO

BACKGROUND: Lung cancer remains the leading cause of cancer mortality with relatively few prognostic biomarkers. We investigated associations with overall survival for telomere length (TL) and genetic variation in chromosome 5p15.33, an established telomere maintenance locus. METHODS: Leukocyte TL was measured after diagnosis in 807 patients with non-small cell lung cancer (NSCLC) from the Princess Margaret Cancer Center in Toronto and assessed prospectively in 767 NSCLC cases from the Copenhagen City Heart Study and the Copenhagen General Population Study. Associations with all-cause mortality were tested for 723 variants in 5p15.33, genotyped in 4,672 NSCLC cases. RESULTS: Short telomeres (≤10th percentile) were associated with poor prognosis for adenocarcinoma in both populations: TL measured 6 months after diagnosis [HR = 1.65; 95% confidence intervals (CI), 1.04-2.64] and for those diagnosed within 5 years after blood sampling (HR = 2.42; 95% CI, 1.37-4.28). Short TL was associated with mortality in never smokers with NSCLC (HR = 10.29; 95% CI, 1.86-56.86) and adenocarcinoma (HR = 11.31; 95% CI, 1.96-65.24). Analyses in 5p15.33 identified statistically significant prognostic associations for rs56266421-G in LPCAT1 (HR = 1.86; 95% CI, 1.38-2.52; P = 4.5 × 10-5) in stage I-IIIA NSCLC, and for the SLC6A3 gene with OS in females with NSCLC (P = 1.6 × 10-3). CONCLUSIONS: Our findings support the potential clinical utility of TL, particularly for adenocarcinoma patients, while associations in chromosome 5p15.33 warrant further exploration. IMPACT: This is the largest lung cancer study of leukocyte TL and OS, and the first to examine the impact of the timing of TL measurement. Our findings suggest that extremely short telomeres are indicative of poor prognosis in NSCLC.

20.
Mol Carcinog ; 58(11): 1960-1973, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31355511

RESUMO

Brahma (BRM), of the SWI/SNF complex, has two 6 to 7 bp insertion promoter polymorphisms (BRM-741/BRM-1321) that cause epigenetic BRM suppression, and are associated with risk of multiple cancers. BRM polymorphisms were genotyped in malignant pleural mesothelioma (MPM) cases and asbestos-exposed controls. Multivariable logistic regression (risk) and Cox regression (prognosis) were performed, including stratified analyses by smoking status to investigate the effect of polymorphisms on MPM risk and prognosis. Although there was no significant association overall between BRM-741/BRM-1321 and risk in patients with MPM, a differential effect by smoking status was observed (P-interaction < .001), where homozygous variants were protective (aOR of 0.18-0.28) in ever smokers, while never smokers had increased risk when carrying homozygous variants (aOR of 2.7-4.4). While there was no association between BRM polymorphisms and OS in ever-smokers, the aHR of carrying homozygous-variants of BRM-741, BRM-1321 or both were 4.0 to 8.6 in never-smokers when compared to wild-type carriers. Mechanistically, lower mRNA expression of BRM was associated with poorer general cancer prognosis. Electrophoretic mobility shift assays and chromatin immunoprecipitation experiments (ChIP) revealed high BRM insertion variant homology to MEF2 regulatory binding sites. ChIP experimentation confirmed MEF2 binding only occurs in the presence of insertion variants. DNA-affinity purification assays revealed YWHA scaffold proteins as vital to BRM mRNA expression. Never-smokers who carry BRM homozygous variants have an increased chance of developing MPM, which results in worse prognosis. In contrast, in ever-smokers, there may be a protective effect, with no difference in overall survival. Mechanisms for the interaction between BRM and smoking require further study.


Assuntos
Neoplasias Pulmonares/genética , Mesotelioma/genética , Neoplasias Pleurais/genética , Fumar/efeitos adversos , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Pessoa de Meia-Idade , Neoplasias Pleurais/patologia , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Regiões Promotoras Genéticas , Fatores de Risco , Fumar/genética
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