Longitudinal clinical outcomes in a real-world population of patients with idiopathic pulmonary fibrosis: the PROOF registry.

BACKGROUND: The PROOF registry is an observational study initiated in October 2013 with the aim to monitor disease progression in a real-world population of patients with idiopathic pulmonary fibrosis (IPF). Here, we present longitudinal clinical outcomes from the PROOF registry. METHODS: Patients with IPF were enrolled across eight centers in Belgium and Luxembourg. For all patients, clinical outcomes data were collected, including mortality, lung transplant, acute exacerbations, and pulmonary hypertension. For patients treated with pirfenidone at any time during follow-up (2013-2017), for any duration of treatment (the pirfenidone-treated population): pirfenidone treatment patterns were collected; changes in pulmonary function (forced vital capacity [FVC] and carbon monoxide diffusing capacity [DLco]) were reviewed up to 24 months post-inclusion; and time-to-event analyses from the time of registry inclusion were performed. RESULTS: The PROOF registry enrolled a total of 277 patients. During follow-up, 23.1% of patients died, 5.1% received a lung transplant, 5.4% experienced an acute exacerbation, and 6.1% had comorbid pulmonary hypertension. In the pirfenidone-treated population (N = 233, 84.1%), 12.9% of patients had a temporary dose discontinuation and 31.8% had a temporary dose reduction; 4.3% of patients permanently discontinued pirfenidone due to an adverse drug reaction. Mean percent predicted FVC was 81.2% (standard deviation [SD] 19.0) at Month 0 and 78.3% (SD 25.0) at Month 24, and mean percent predicted DLco was 47.0% (SD 13.2) and 45.0% (SD 16.5), respectively. Rates of ≥ 10% absolute decline in percent predicted FVC and ≥ 15% absolute decline in percent predicted DLco over 24 months were 31.0% and 23.2%, respectively. Mean times from registry inclusion to categorical absolute decline in percent predicted FVC and percent predicted DLco were 20.1 (standard error [SE] 0.6) months and 23.4 (SE 0.5) months, respectively; mean time from registry inclusion to death was 31.0 (SE 0.9) months. CONCLUSIONS: The PROOF registry is a source of European data characterizing longitudinal clinical outcomes of patients with IPF. Over 12 months of follow-up, pulmonary function remained largely stable in patients with IPF who received pirfenidone for any duration of treatment. Pulmonary function remained similar at 24 months of follow-up, although patient numbers were lower. TRIAL REGISTRATION: PROOF is registered with the relevant authorities in Belgium and Luxembourg, with registration to Comité National d'Éthique et de Recherche (CNER) N201309/03-12 September 2013 and a notification to Comité National de Protection des Données (CNDP) for Luxembourg.

Health-related quality of life impact of cobimetinib in combination with vemurafenib in patients with advanced or metastatic BRAFV600 mutation-positive melanoma.

BACKGROUND: In the coBRIM study, cobimetinib plus vemurafenib (C+V) significantly improved survival outcomes vs placebo and vemurafenib (P+V) in patients with advanced/metastatic BRAFV600-mutated melanoma. An analysis of health-related quality of life (HRQOL) from coBRIM is reported. METHODS: Patients completing the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline and ⩾1 time point thereafter constituted the analysis population. Change from baseline ⩾10 points was considered clinically meaningful. RESULTS: Mean baseline scores for all QLQ-C30 domains were similar between arms. Most on-treatment scores for QLQ-C30 domains were also comparable between arms. A transient deterioration in role function in cycle 1 day 15 (C1D15; -14.7 points) in the P+V arm and improvement in insomnia in the C+V arm at C2D15 (-12.4 points) was observed. Among patients who experienced a ⩾10-point change from baseline (responders), between-group differences were greatest for insomnia (16%), social functioning (10%), fatigue (9%) and pain (7%), all favouring C+V. Diarrhoea, photosensitivity reaction, pyrexia, and rash did not meaningfully affect global health status (GHS). Serous retinopathy was associated with a transient decrease in GHS at C1D15 assessment. CONCLUSIONS: In patients with advanced/metastatic BRAFV600-mutated melanoma, treatment with C+V maintained HRQOL compared with P+V, with superior efficacy.

Real-world patient characteristics, treatment patterns, and clinical outcomes associated with tucatinib therapy in HER2-positive metastatic breast cancer.

Background: Tucatinib is an oral human epidermal growth factor receptor 2 (HER2)-directed therapy approved in combination with trastuzumab and capecitabine for use in patients with previously treated HER2+ metastatic breast cancer (MBC) with/without brain metastases (BM). To inform clinical decision-making, it is important to understand tucatinib use in real-world clinical practice. We describe patient characteristics, treatment patterns, and clinical outcomes for tucatinib treatment in the real-world setting. Methods: This retrospective cohort study included patients diagnosed with HER2+ MBC (January 2017-December 2022) who received tucatinib treatment in a nationwide, de-identified electronic health record-derived metastatic breast cancer database. Patient demographics and clinical characteristics were described at baseline (prior to tucatinib initiation). Key outcomes included real-world time to treatment discontinuation (rwTTD), time to next treatment (rwTTNT), and overall survival (rwOS). Results: Of 3,449 patients with HER2+ MBC, 216 received tucatinib treatment (n=153 with BM; n=63 without BM) and met inclusion criteria. Median (range) age of patients was 56 (28-84) years, 57.9% were White, and 68.5% had Eastern Cooperative Oncology Group performance status ≤1. Median (IQR) follow-up from start of tucatinib treatment was 12 (6-18) months. Among all patients who received tucatinib treatment, median (95% CI) rwTTD was 6.5 (5.4-8.8) months with 39.8% and 21.4% remaining on treatment at 12 and 24 months, respectively. Median (95% CI) rwTTNT was 8.7 (6.8-10.7) months. Patients who received the approved tucatinib triplet combination after ≥1 HER2-directed regimen in the metastatic setting had a similar median (95% CI) rwTTD (any line: 8.1 [5.7-9.5] months; second-line (2L) and third-line (3L): 9.4 [6.3-14.1] months) and rwTTNT (any line: 8.8 [7.1-11.8] months; 2L and 3L: 9.8 [6.8-14.1] months) to the overall population. Overall, median (95% CI) rwOS was 26.6 (20.2-not reached [NR]) months, with similar findings for patients who received the tucatinib triplet (26.1 [18.8-NR] months) and was NR in the subgroup limited to the 2L/3L population. Conclusion: Tucatinib treatment in the real-world setting was associated with a similar median rwTTD, rwTTNT, and rwOS as in the pivotal HER2CLIMB trial, with particular effectiveness in patients in the 2L/3L setting. These results highlight the importance of earlier use of tucatinib in HER2+ MBC.

Economic and health care resource utilization burden of central nervous system metastases in patients with metastatic melanoma.

BACKGROUND: In patients with metastatic melanoma, central nervous system (CNS) involvement is associated with poor prognosis, increased costs, and higher health care resource utilization (HCRU); however, previous cost-estimate studies were conducted before widespread use of targeted therapies and immunotherapies. OBJECTIVE: To estimate costs and HCRU in patients with metastatic melanoma with and without CNS metastases in the current treatment era following introduction of targeted therapies and immunotherapies. METHODS: This real-world retrospective cohort study used data from the IQVIA PharMetrics Plus claims database to estimate and compare costs and HCRU in patients with metastatic melanoma by presence or absence of CNS metastases between January 2011 and June 2019. Patients with at least 2 melanoma claims, at least 2 metastatic claims, and continuous enrollment at least 6 months before and at least 1 month after first metastatic diagnosis were included. Mean per-patient-per-month (PPPM) costs are reported in 2019 US dollars. Analyses were also conducted by time period of first metastatic diagnosis: 2011-2014 (reflecting BRAF inhibitor monotherapy and anti-CTLA-4 therapy) and 2015-2019 (reflecting availability of BRAF and MEK inhibitor combinations and anti-PD-1/PD-L1 therapies). RESULTS: Of 4,078 patients, 1,253 (30.7%) had CNS metastases. Patients with CNS metastases were more likely to receive any treatment (89.1% vs 58.9%; P < 0.001), including systemic treatment (73.3% vs 55.4%; P < 0.001) and radiation (65.8% vs 11.8%; P < 0.001), and to have brain imaging any time after metastatic diagnosis (98.3% vs 67.2%; P < 0.001). In patients with CNS metastases, 40.0% had dexamethasone 4 mg within 30 days of CNS metastatic diagnosis. Patients with CNS metastases incurred higher total mean PPPM costs ($29,953 vs $14,996; P < 0.001). The largest contributors were total radiology ($2,351 vs $1,110), targeted therapies ($2,499 vs $638), and immunotherapies ($7,398 vs $5,036). HCRU and costs were higher in patients with vs without CNS metastases regardless of time period of first metastatic diagnosis. In patients with CNS metastases, use of any systemic treatment was increased in 2015-2019 vs 2011-2014 (81.2% vs 64.5%; P < 0.001), including chemotherapy (68.1% vs 50.0%; P < 0.001), immunotherapy (60.9% vs 30.1%; P < 0.001), and/or targeted therapies (32.7% vs 27.4%; P = 0.05). Mean total PPPM costs for patients with CNS metastases increased from $28,183 in 2011-2014 to $31,569 in 2015-2019 (P < 0.001); main drivers were immunotherapies and targeted therapies. CONCLUSIONS: CNS metastases occur frequently in patients with metastatic melanoma and are associated with significantly increased economic burden compared with patients without CNS metastases; the largest contributors to total costs in the current treatment era are radiology, targeted therapies, and immunotherapies. Brain imaging remains underused, and there is an opportunity to improve outcomes through early detection of CNS metastases, potentially reducing the high HCRU and costs associated with CNS metastases. DISCLOSURES: This study was funded by F. Hoffmann-La Roche Ltd. The sponsor was involved in the study design, data collection, data analysis, manuscript preparation, and publication decisions. Seetasith and Lee are employed by and report stock ownership in Genentech, Inc. Bartley and McKenna were employed by Genentech, Inc., at the time of this study and report stock ownership. Tawbi reports grants and personal fees from Genentech/Roche, Novartis, BMS, and Merck; grants from GSK and Celgene; and personal fees from Eisai, outside the submitted work. Kent, Burton, and Haydu have nothing to disclose. The results of this study were presented in part at the AMCP Nexus 2020 Virtual Meeting, October 19-23, 2020.

Treatment patterns and clinical outcomes for patients with melanoma and central nervous system metastases: A real-world study.

BACKGROUND: Patients with melanoma and central nervous system (CNS) metastases have poor survival outcomes. We investigated real-world treatment patterns and overall survival (OS) of patients with melanoma and CNS metastases. METHODS: A retrospective analysis utilizing a nationwide de-identified electronic health record-derived database was undertaken in patients diagnosed with advanced melanoma between January 2011 and September 2018. Patients with any visit ≤90 days of metastatic diagnosis and with confirmed CNS metastases were included. RESULTS: Of 3473 patients diagnosed with advanced melanoma, 791 patients with confirmed CNS metastases were identified and included in this analysis. Synchronous CNS metastasis (≤30 days of metastatic diagnosis) was associated with longer median OS than metachronous CNS metastasis (>30 days after metastatic diagnosis, 0.58 vs 0.42 years). Stereotactic radiosurgery (SRS) was the most common treatment (40.5%) alone or in combination with other local or systemic therapies, being more frequent in patients diagnosed in 2015+ versus 2011-2014 (44.1% vs 35.5%, respectively). The most common systemic treatment was immune checkpoint inhibitors (ICIs; 30.5%), predominantly anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) alone (2011-2014) and anti-programmed death-1 alone or in combination with anti-CTLA-4 (2015+). Median OS was longest in SRS-treated patients (1.17 years) regardless of number of CNS metastases. Median OS for SRS-treated patients increased from 0.83 years (2011-2014) to 1.75 years (2015+). In multivariable analysis, the effect of SRS remained significant after adjustment for sex, race, intracranial and extracranial disease burden, and timing of CNS metastases. Interaction testing to examine potential synergy between SRS/whole-brain radiation therapy and ICIs found no significant interaction. CONCLUSIONS: Despite advances in treatment, patients with melanoma and CNS metastases have poor survival outcomes. Prevalence of SRS increased over time and was associated with improved outcomes.

Healthcare Resource Utilization and Cost of Care in Patients With Periocular Basal Cell Carcinoma: A Real-World Study.

PURPOSE: To date, there are no studies on healthcare resource utilization (HRU) and costs for treating periocular basal cell carcinoma (pBCC). We investigated real-world HRU and costs of patients with limited versus extensive pBCC. DESIGN: This was a retrospective cost analysis. METHODS: Administrative claims database was mined for basal cell carcinoma (BCC)-related claims from January 2011 to December 2018. Patients had ≥1 inpatient or ≥2 outpatient nondiagnostic claims for pBCC ≥30 days apart, ≥6 months of continuous enrollment in a health plan before the index date, and ≥18 months of continuous enrollment after the index date. Patients were categorized by disease severity (limited or extensive) using Current Procedural Terminology codes. A total of 1368 patients were propensity matched 1:1 for limited and extensive pBCC (n = 684 each). Outcomes were cost and HRU measures during the 18-month follow-up period. RESULTS: Patients with extensive disease had a higher number of outpatient visits (32.47 vs 28.81; P < .0001), radiation therapies (0.53 vs 0.17; P = .001), surgeries (1.82 vs 1.24; P < .001), days between first and last surgery (40.82 vs 16.51 days; P < .001), outpatient pBCC claims (3.89 vs 3.38; P < .001), and days between pBCC claims (170.43 vs 144.01 days; P < .001). Patients with extensive disease incurred higher total all-cause costs ($36,986.10 vs $31,893.13; P = .02), outpatient costs ($20,450.26 vs $16,885.87; P = .005), radiation therapy costs ($314.28 vs $89.81; P = .01), and surgery costs ($3,697.08 vs $2,585.80; P < .001) than patients with limited disease. CONCLUSIONS: Patients with extensive pBCC incurred higher costs, greater HRU, and longer time between first and last surgery versus patients with limited pBCC. Early diagnosis and early treatment of pBCC have economic benefits.

Quality of Life and Healthcare Resource Use in a Real-world Patient Population with Idiopathic Pulmonary Fibrosis: The PROOF Registry.

INTRODUCTION: The PROOF registry is a prospective, observational study that aimed to monitor disease progression in a real-world cohort of patients with idiopathic pulmonary fibrosis (IPF). Here, longitudinal quality-of-life (QoL) outcomes, healthcare resource use (HCRU), and the association between QoL and mortality in patients enrolled in the PROOF registry are presented. METHODS: QoL outcomes (St. George's Respiratory Questionnaire [SGRQ], EuroQoL-5 dimensions-5 levels Health Questionnaire [EQ-5D-5L], EuroQoL-5 dimensions Health Questionnaire [EQ-5D] visual analogue scale [VAS] and cough VAS) and HCRU were collected for all patients. Associations between baseline QoL and mortality were assessed using univariate and multivariate analyses. During multivariate analyses, individual QoL measures were adjusted for the following covariates: age, sex, percent predicted forced vital capacity, percent predicted diffusing capacity of the lungs for carbon monoxide, smoking status, and supplementary oxygen use at registry inclusion. RESULTS: In total, 277 patients were enrolled in the PROOF registry. During the follow-up period, worsening in cough VAS score, SGRQ symptom score, and SGRQ activity score was observed, while EQ-5D VAS, SGRQ total score, and SGRQ impact score remained stable. During univariate analyses, EQ-5D VAS and all SGRQ sub-scores and total score at baseline were associated with mortality; however, during multivariate analyses, only the SGRQ total score, SGRQ impact score, and SGRQ symptom score at baseline were associated with mortality. During the follow-up period, 261 (94.2%) patients required an outpatient consultation (IPF- or non-IPF-related) and there were 182 hospitalizations in total, most of which were respiratory related (66.5%). CONCLUSIONS: The PROOF registry provided valuable, real-world data on the association between baseline QoL and mortality, and longitudinal HCRU and QoL outcomes in patients with IPF over 24 months and identified that SGRQ may be an independent prognostic factor in IPF.

Haplotypes of DNA repair and cell cycle control genes, X-ray exposure, and risk of childhood acute lymphoblastic leukemia.

BACKGROUND: Acute leukemias of childhood are a heterogeneous group of malignancies characterized by cytogenetic abnormalities, such as translocations and changes in ploidy. These abnormalities may be influenced by altered DNA repair and cell cycle control processes. METHODS: We examined the association between childhood acute lymphoblastic leukemia (ALL) and 32 genes in DNA repair and cell cycle pathways using a haplotype-based approach, among 377 childhood ALL cases and 448 controls enrolled during 1995-2002. RESULTS: We found that haplotypes in APEX1, BRCA2, ERCC2, and RAD51 were significantly associated with total ALL, while haplotypes in NBN and XRCC4, and CDKN2A were associated with structural and numerical change subtypes, respectively. In addition, we observed statistically significant interaction between exposure to 3 or more diagnostic X-rays and haplotypes of XRCC4 on risk of structural abnormality-positive childhood ALL. CONCLUSIONS: These results support a role of altered DNA repair and cell cycle processes in the risk of childhood ALL, and show that this genetic susceptibility can differ by cytogenetic subtype and may be modified by exposure to ionizing radiation. To our knowledge, our study is the first to broadly examine the DNA repair and cell cycle pathways using a haplotype approach in conjunction with X-ray exposures in childhood ALL risk. If confirmed, future studies are needed to identify specific functional SNPs in the regions of interest identified in this analysis.

Patient journey and treatment patterns in adults with IPF based on health care data in Sweden from 2001 to 2015.

BACKGROUND: For patients with idiopathic pulmonary fibrosis (IPF), there is limited real-world data on patient journey and treatment patterns. AIM: To explore predictors of early diagnosis and treatment initiation, and treatment patterns in IPF patients using linked data from Swedish registers and electronic medical records (EMRs). POPULATION: A national cohort (C1) of 17,247 pulmonary fibrosis patients (ICD-10 code J84.1; no competing diagnosis) diagnosed between 2001 and 2015, and an EMR-based regional subset (C2) comprising 1755 IPF patients diagnosed between 2004 and 2017. The time from early disease symptoms to diagnosis, use of anti-fibrotic medications, time from diagnosis to initiation of anti-fibrotic treatment, and adherence, persistence and treatment length with pirfenidone were explored in these patients. RESULTS: In C1, the median time to diagnosis from the first symptoms dyspnoea, cough and fatigue were 307, 563 and 639 days, respectively. Glucocorticoids were the most frequently prescribed medication. Less than 10% of patients undergoing or initiating treatment, used pirfenidone or nintedanib. Males had a higher probability of initiating anti-fibrotic treatment than females within a year of diagnosis. One-year persistence in pirfenidone patients was 42% in C1 and 25% in C2. CONCLUSION: Diagnosis of pulmonary fibrosis was delayed in patients with cough and fatigue, which are early symptoms of IPF. This, and lower than expected utilisation of anti-fibrotic medications, suggests missed opportunities for early disease diagnosis and treatment. The high rate of treatment discontinuation underscores the importance of supporting and guiding patients to persist with their medications to ensure an accrual benefit of treatment.

Epidemiology of Pulmonary Fibrosis: A Cohort Study Using Healthcare Data in Sweden.

INTRODUCTION: Data on the epidemiology of idiopathic pulmonary fibrosis (IPF) in Sweden are lacking. This study estimates the incidence and prevalence of IPF in Sweden, and describes the demographic and clinical characteristics and the overall survival of patients with IPF. METHODS: Two cohorts were studied: a national cohort of 17,247 patients with pulmonary fibrosis (ICD-10 code J84.1 with no competing diagnosis) from the Swedish National Patient Register (cohort 1 [C1]); and an electronic medical record-based regional subset of C1 comprising 1755 patients having pulmonary fibrosis and a radiology procedure (C2). RESULTS: The incidence of pulmonary fibrosis in C1 ranged from 10.4 to 15.4 cases per 100,000 population per year between 2001 and 2015. The prevalence increased from 15.4 to 68.0 cases per 100,000 population per year. Patients ≥ 70 years and men had a higher incidence and prevalence of pulmonary fibrosis. Common comorbidities included respiratory infections and cardiovascular disorders. Approximately one-third of patients in each cohort were hospitalised with pulmonary fibrosis within a year of diagnosis. The median survival time from disease diagnosis was 2.6 years in C1 and 5.2 years in C2. Older patients had a higher risk of hospitalisation and mortality. Women had a better prognosis than men. CONCLUSION: This study underscores the importance of pulmonary fibrosis as a cause of respiratory-related morbidity and mortality in Sweden. The stable incidence and increasing prevalence over time suggests longer survival. The higher morbidity and mortality in older patients highlights the importance of early case detection, diagnosis and management for better prognosis. FUNDING: F. Hoffmann-La Roche, Ltd./Genentech, Inc.

Baseline clinical characteristics, comorbidities and prescribed medication in a real-world population of patients with idiopathic pulmonary fibrosis: the PROOF registry.

INTRODUCTION: PROOF (a Prospective Observational Registry to Describe the Disease Course and Outcomes of Idiopathic Pulmonary Fibrosis) is an ongoing, observational registry initiated in 2013 with the aim of collecting real-world data from patients with idiopathic pulmonary fibrosis (IPF). Here, we present comprehensive baseline data, which were collected from patients on registry inclusion. METHODS: Patients with IPF were enrolled across eight centres in Belgium and Luxembourg. Baseline data collected included demographics, diagnostic information and clinical characteristics, including lung function and health-related quality of life. Data on comorbidities and prescribed medication were also collected. RESULTS: A total of 277 patients were enrolled in the PROOF registry. At inclusion, 92.8% and 6.5% of patients had a definite or probable diagnosis of IPF, respectively. Mean per cent predicted forced vital capacity and carbon monoxide diffusing capacity were 80.6% and 46.9%, respectively. Mean St. George's Respiratory Questionnaire total score was 47.0, and mean Cough-Visual Analogue Scale score was 30.5 mm. The most prevalent comorbidities reported at inclusion were gastrointestinal disorders (50.2%), including gastro-oesophageal reflux disease (47.3%) and metabolism and nutrition disorders (39.7%). At inclusion, 67.2% and 2.2% of patients were prescribed pirfenidone and nintedanib, respectively, with treatment initiated either prior to, or at the time of, inclusion. Medication prescribed concomitantly with pirfenidone included antihypertensives (54.8%), statins (37.1%) and prophylactic antithrombotics/anticoagulants (36.6%). CONCLUSION: The PROOF registry provides valuable demographic and clinical data from a real-world population of patients with IPF in Belgium and Luxembourg, demonstrating the high burden of comorbidities and prescribed medication in these patients. Longitudinal data from this patient population will be investigated in future analyses. TRIAL REGISTRATION: PROOF is registered with the relevant authorities in Belgium and Luxembourg, with registration to Comité National d'Éthique et de Recherché (CNER) N201309/03 - 12 September 2013 and a notification to Comité National de Protection des Données (CNDP).

Assessment of quality of life using Skindex-16 in patients with advanced basal cell carcinoma treated with vismodegib in the STEVIE study.

Health-related quality of life (HRQoL) data are limited in patients with advanced basal cell carcinoma. To report HRQoL outcomes based on STEVIE (NCT01367665), a phase 2 study of vismodegib safety in patients with metastatic BCC or locally advanced BCC that is unsuitable for surgery or radiotherapy. Skindex-16 and MD Anderson Symptom Inventory (MDASI) questionnaires were completed at baseline and at three subsequent visits. Clinically meaningful improvement was defined as a ≥10-point decrease from baseline (Skindex-16) or improvement of at least 3 points from baseline (MDASI). HRQoL-evaluable patients with locally advanced BCC (n = 730) had ≥10-point improvements in Skindex-16 emotion domain scores at all time points. Changes in symptom and function scores in these patients or in any domain scores at any time point in patients with metastatic BCC (n = 10) were not clinically meaningful. Of 10 patients with symptomatic metastatic BCC at baseline, six had ≥3-point improvements in MDASI symptom severity. Skindex-16 and MDASI showed improvement in HRQoL in vismodegib-treated patients with locally advanced or metastatic BCC or BCC.

Tobacco smoke exposure and the risk of childhood acute lymphoblastic and myeloid leukemias by cytogenetic subtype.

BACKGROUND: Tobacco smoke contains carcinogens known to damage somatic and germ cells. We investigated the effect of tobacco smoke on the risk of childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML), especially subtypes of prenatal origin such as ALL with translocation t(12;21) or high-hyperdiploidy (51-67 chromosomes). METHODS: We collected information on exposures to tobacco smoking before conception, during pregnancy, and after birth in 767 ALL cases, 135 AML cases, and 1,139 controls (1996-2008). Among cases, chromosome translocations, deletions, or aneuploidy were identified by conventional karyotype and fluorescence in situ hybridization. RESULTS: Multivariable regression analyses for ALL and AML overall showed no definite evidence of associations with self-reported (yes/no) parental prenatal active smoking and child's passive smoking. However, children with history of paternal prenatal smoking combined with postnatal passive smoking had a 1.5-fold increased risk of ALL [95% confidence interval (CI), 1.01-2.23], compared to those without smoking history (ORs for pre- or postnatal smoking only were close to one). This joint effect was seen for B-cell precursor ALL with t(12;21) (OR = 2.08; 95% CI, 1.04-4.16), but not high hyperdiploid B-cell ALL. Similarly, child's passive smoking was associated with an elevated risk of AML with chromosome structural changes (OR = 2.76; 95% CI, 1.01-7.58), but not aneuploidy. CONCLUSIONS: Our data suggest that exposure to tobacco smoking was associated with increased risks of childhood ALL and AML; and risks varied by timing of exposure (before and/or after birth) and cytogenetic subtype, based on imprecise estimates. IMPACT: Parents should limit exposures to tobacco smoke before and after the child's birth.

Matching on Race and Ethnicity in Case-Control Studies as a Means of Control for Population Stratification.

Some investigators argue that controlling for self-reported race or ethnicity, either in statistical analysis or in study design, is sufficient to mitigate unwanted influence from population stratification. In this report, we evaluated the effectiveness of a study design involving matching on self-reported ethnicity and race in minimizing bias due to population stratification within an ethnically admixed population in California. We estimated individual genetic ancestry using structured association methods and a panel of ancestry informative markers, and observed no statistically significant difference in distribution of genetic ancestry between cases and controls (P=0.46). Stratification by Hispanic ethnicity showed similar results. We evaluated potential confounding by genetic ancestry after adjustment for race and ethnicity for 1260 candidate gene SNPs, and found no major impact (>10%) on risk estimates. In conclusion, we found no evidence of confounding of genetic risk estimates by population substructure using this matched design. Our study provides strong evidence supporting the race- and ethnicity-matched case-control study design as an effective approach to minimizing systematic bias due to differences in genetic ancestry between cases and controls.

Diagnostic X-rays and risk of childhood leukaemia.

BACKGROUND: The association between diagnostic X-ray exposures early in life and increased risk of childhood leukaemia remains unclear. METHODS: This case-control study included children aged 0-14 years diagnosed with acute lymphoid leukaemia (ALL, n = 711) or acute myeloid leukaemia (AML, n = 116) from 1995 to 2008. Controls were randomly selected from the California birth registry and individually matched to cases with respect to date of birth, sex, Hispanic ethnicity and maternal race. Conditional logistic regression analyses were performed to assess whether ALL or AML was associated with self-reported child's X-rays after birth (post-natal), including number of X-rays, region of the body X-rayed and age at first X-ray, as well as maternal X-rays before and during pregnancy (preconception and prenatal). RESULTS: After excluding X-rays in the year prior to diagnosis (reference date for matched controls), risk of ALL was elevated in children exposed to three or more post-natal X-rays [odds ratio (OR) = 1.85, 95% confidence interval (CI) 1.12-2.79]. For B-cell ALL specifically, any exposure (one or more X-rays) conferred increased risk (OR = 1.40, 95% CI 1.06-1.86). Region of the body exposed was not an independent risk factor in multivariable analyses. No associations were observed between number of post-natal X-rays and AML (OR = 1.05, 95% CI 0.90-1.22) or T-cell ALL (OR = 0.84, 95% CI 0.59-1.19). Prevalence of exposure to prenatal and preconception X-rays was low, and no associations with ALL or AML were observed. CONCLUSIONS: The results suggest that exposure to post-natal diagnostic X-rays is associated with increased risk of childhood ALL, specifically B-cell ALL, but not AML or T-cell ALL. Given the imprecise measures of self-reported X-ray exposure, the results of this analysis should be interpreted with caution and warrant further investigation.