Low-Dose Computed Tomography Screening in Relatives With a Family History of Lung Cancer.

INTRODUCTION: The role of a family history of lung cancer (LCFH) in screening using low-dose computed tomography (LDCT) has not been prospectively investigated with long-term follow-up. METHODS: A multicenter prospective study with up to three rounds of annual LDCT screening was conducted to determine the detection rate of lung cancer (LC) in asymptomatic first- or second-degree relatives of LCFH. RESULTS: From 2007 to 2011, there were 1102 participants enrolled, including 805 and 297 from simplex and multiplex families (MFs), respectively (54.2% women and 70.0% never-smokers). The last follow-up date was May 5, 2021. The overall LC detection rate was 4.5% (50 of 1102). The detection rate in MF was 9.4% (19 of 202) and 4.4% (4 of 91) in never-smokers and in those who smoked, respectively. The corresponding rates for simplex families were 3.7% (21 of 569) and 2.7% (6 of 223), respectively. Of these, 68.0% and 22.0% of cases with stage I and IV diseases, respectively. LC diagnoses within a 3-year interval from the initial screening tend to be younger, have a higher detection rate, and have stage I disease; thereafter, more stage III-IV disease and 66.7% (16 of 24) with negative or semipositive nodules in initial computed tomography scans. Within the 6-year interval, only maternal (modified rate ratio = 4.46, 95% confidence interval: 2.32-8.56) or maternal relative history of LC (modified rate ratio = 5.41, 95% confidence interval: 2.84-10.30) increased the risk of LC. CONCLUSIONS: LCFH is a risk factor for LC and is increased with MF history, among never-smokers, younger adults, and those with maternal relatives with LC. Randomized controlled trials are needed to confirm the mortality benefit of LDCT screening in those with LCFH.

Cultural Adaptation and Validation of Mullen Scales of Early Learning in Taiwanese children with Autism Spectrum Disorder, Global Developmental Delay, and Typically Developing Children.

BACKGROUND: The Mullen Scales of Early Learning (MSEL) is a standardized comprehensive developmental assessment tool for children aged 0-68 months. However, few Asia-based studies have explored cultural and linguistic adaptations of the MSEL or investigated its psychometric properties in populations with autism spectrum disorder (ASD). AIMS: This study evaluated the reliability and validity of the MSEL-Taiwan version (MSEL-T) for Taiwanese children with ASD, global developmental delay (GDD), and typical development (TD). METHODS AND PROCEDURES: The MSEL items were translated and modified according to the language and culture in Taiwan. In total, 191 children (ASD, 69; GDD, 36; and TD, 86) aged 19-68 months were assessed using the MSEL-T and Peabody Developmental Motor Scales 2 (PDMS-2) at enrollment, followed by the assessments of Vineland Adaptive Behavior Scale-Chinese version (VABS-C) at the age of 36 months or later. OUTCOMES AND RESULTS: All subscales were verified to have good interrater reliability and internal consistency, and subscale scores indicated moderate to high correlations with PDMS-2 and VABS-C scores. Significant differences in MSEL-T scores were observed between same-aged pairs of children with TD and GDD and between pairs of children with TD and ASD. CONCLUSIONS AND IMPLICATIONS: The findings provide evidence of validity and reliability of the MSEL-T. And it is suggested that the culturally and linguistically adapted MSEL-T is a good tool for the clinical assessment of children with and without ASD.

Relationship Between Motor Skills and Language Abilities in Children With Autism Spectrum Disorder.

OBJECTIVES: Few studies have examined the relationship between language abilities and specific motor skills in toddlers with autism spectrum disorder (ASD). The aim of this study was to compare the relationship of receptive language (RL) and expressive language (EL) abilities with motor functioning in toddlers with ASD aged 24 to 36 months and their peers with typical development (TD). Furthermore, the study compared multidimensional motor functioning in toddlers with ASD with delayed RL and EL development and toddlers with ASD and typical RL and EL development. The predictive powers of the motor skills were examined for the group with delayed RL and EL development. METHODS: The language abilities of 38 toddlers with ASD and 38 age-matched toddlers with TD were evaluated using the Receptive and Expressive Language Subscales of the Mullen Scale of Early Learning, and their motor skills were assessed using the Peabody Developmental Motor Scales, Second Edition. RESULTS: Significant correlations between language ability and motor functioning were observed in the ASD and TD groups. The ASD group with delayed RL and EL development had lower scores for multidimensional motor functioning than the ASD group with typical RL and EL development and the TD group. Moreover, the risks of delayed EL and RL development could be predicted by the lower motor scores in toddlers with ASD. CONCLUSIONS: The positive correlation between language abilities and motor functioning in toddlers with ASD indicated potential connections between the early onsets of motor and speech-language impairments in these toddlers. IMPACT: The results may have implications for the development of motor-based interventions targeting language development in young children with ASD.

Sub-multiplicative interaction between polygenic risk score and household coal use in relation to lung adenocarcinoma among never-smoking women in Asia.

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10-26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10-3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.

Multidimensional Developments and Free-Play Movement Tracking in 30- to 36-Month-Old Toddlers With Autism Spectrum Disorder Who Were Full Term.

BACKGROUND: Few studies have investigated multidimensional developments and free-play movement performance in toddlers with an early diagnosis of autism spectrum disorder (ASD). OBJECTIVE: This study compared cognitive, motor, and behavioral developments and free-play movement performance in toddlers with ASD who were full term (FT-ASD), toddlers who were full term and are typically developing (FT-TD), and toddlers who were born preterm and had a very low birth weight (VLBW-PT). DESIGN: This was a prospective cross-sectional study. METHODS: Forty-five 30- to 36-month-old age-matched toddlers were recruited and divided into FT-ASD, FT-TD, and VLBW-PT groups. Their developments were examined using the Mullen Scales of Early Learning; the Peabody Developmental Motor Scales, Second Edition; the Child Behavior Checklist for Ages 1.5 to 5; and the Repetitive Behavior Scale-Revised. In addition, the toddlers' free-play movements were tracked in laboratory settings using an automatic movement tracking system. RESULTS: Toddlers with FT-ASD exhibited lower cognitive and motor scores and a higher degree of behavioral problems compared with toddlers with FT-TD or VLBW-PT. Furthermore, the movement tracking data in a free-play setting revealed that toddlers with FT-ASD displayed a higher degree of turning velocity, a higher moving time, and a higher frequency of moving toward the peripheral region compared with toddlers with FT-TD or VLBW-PT. Moreover, several motor developmental and movement-tracking indicators were found to correlate with behavioral problems and cognitive scores in toddlers with FT-ASD. LIMITATIONS: The study results may have been affected by the small sample size, the cross-sectional design, and tracking only the whole body without subtle movements or segmental motions. CONCLUSIONS: The findings suggest varied aspects of co-occurring developmental conditions and movement-based problems in toddlers with FT-ASD. Using standardized and sensitive measures for the early assessment of perceptuo-motor impairments is necessary for timely early intervention for such toddlers.

The Size of Spontaneous Pneumothorax is a Predictor of Unsuccessful Catheter Drainage.

Small-bore thoracic catheter drainage is recommended for a first large or symptomatic episode of primary spontaneous pneumothorax (PSP). However, one-third of these patients require a second procedure because of treatment failure. We investigated the factors associated with unsuccessful pigtail catheter drainage in the management of PSP. In this retrospective study, using a prospectively collected database, we enrolled 253 consecutive patients with PSP who underwent pigtail catheter drainage as initial treatment, from December 2006 to June 2011. The chest radiograph was reviewed in each case and pneumothorax size was estimated according to Light's index. Other demographic factors and laboratory data were collected via chart review. Pigtail catheter drainage was successful in 71.9% (182/253) of cases. Treatment failure rates were 42.9%, 25.9%, and 15.5% in patients with pneumothorax sizes of >62.6%, 38-62.6%, and <38%, respectively (tertiles). An alternative cut-off point of 92.5% lung collapse was defined using a classification and regression tree method. According to the multivariate analysis, a large-size pneumothorax (p = 0.009) was the only significant predictor of initial pigtail catheter drainage treatment failure in patients with PSP. Early surgical treatment could be considered for those patients with a large-sized pneumothorax.

Fanconi anemia genes in lung adenocarcinoma- a pathway-wide study on cancer susceptibility.

BACKGROUND: Carcinogens in cigarette smoke can induce the formation of DNA-DNA cross-links, which are repaired by the Fanconi anemia (FA) pathway, and it is tempting to speculate that this pathway is involved in lung tumorigenesis. This study is to determine whether genetic polymorphism of the FA genes is associated with an elevated risk of lung adenocarcinoma, and whether the association between genotypes and risk is modified by exposure to cigarette smoke. METHODS: This case-control study genotyped 53 single-nucleotide polymorphisms (SNPs) in FA genes in 709 patients (354 males and 355 females) with lung adenocarcinoma and in 726 cancer-free individuals (339 males and 387 females). Genotypic frequencies of SNPs were compared between cases and controls to identify important FA genes associated with cancer susceptibility. Joint effects in determining cancer risk contributed by genes and smoking-related risk factors and by multiple genes involved in different FA subpathways were evaluated by multivariate regression analysis and stratified analysis. All analyses were performed on males and females separately, and the comparison of results was considered a way of examining the validity of study findings. RESULTS: Lung adenocarcinomas in both male and female patients were associated with (a) genotypic polymorphisms of FANCC and FANCD1; (b) a combined effect of harboring a higher number of high-risk genotypes and smoking/passive smoking; (c) specific interactions of multiple genes, proteins encoded by which have been known to work jointly within the FA pathway. CONCLUSIONS: Genetic polymorphism of the FA genes is associated with inter-individual susceptibility to lung adenocarcinoma.

Interactions between household air pollution and GWAS-identified lung cancer susceptibility markers in the Female Lung Cancer Consortium in Asia (FLCCA).

We previously carried out a multi-stage genome-wide association study (GWAS) on lung cancer among never smokers in the Female Lung Cancer Consortium in Asia (FLCCA) (6,609 cases, 7,457 controls) that identified novel susceptibility loci at 10q25.2, 6q22.2, and 6p21.32, and confirmed two previously identified loci at 5p15.33 and 3q28. Household air pollution (HAP) attributed to solid fuel burning for heating and cooking, is the leading cause of the overall disease burden in Southeast Asia, and is known to contain lung carcinogens. To evaluate the gene-HAP interactions associated with lung cancer in loci independent of smoking, we analyzed data from studies participating in FLCCA with fuel use information available (n = 3; 1,731 cases; 1,349 controls). Coal use was associated with a 30% increased risk of lung cancer (OR 1.3, 95% CI 1.0-1.6). Among the five a priori SNPs identified by our GWAS, two showed a significant interaction with coal use (HLA Class II rs2395185, p = 0.02; TP63 rs4488809 (rs4600802), p = 0.04). The risk of lung cancer associated with coal exposure varied with the respective alleles for these two SNPs. Our observations provide evidence that genetic variation in HLA Class II and TP63 may modify the association between HAP and lung cancer risk. The roles played in the cell cycle and inflammation pathways by the proteins encoded by these two genes provide biological plausibility for these interactions; however, additional replication studies are needed in other non-smoking populations.

Circulating interleukin-6 level is a prognostic marker for survival in advanced nonsmall cell lung cancer patients treated with chemotherapy.

Lung cancer is the leading cause of cancer death worldwide as well as in Taiwan. Interleukin-6 (IL-6) is a multifunctional cytokine and has been implicated in tumor progression. This study recruited 245 patients with advanced (Stage 3B/4) nonsmall cell lung cancer (NSCLC) that had received chemotherapy, to evaluate associations between IL-6 and lung cancer-specific survival. Among these subjects, 112 gave blood samples before and 133 after the start of chemotherapy. Plasma IL-6 was measured using an enzyme linked-immunosorbent assay. The 33rd and 66th percentiles of IL-6 concentrations were 2.01 and 25.16 for the 245 patients and were defined as the cutoff points for dividing the patients into low, intermediate and high groups. Kaplan-Meier and Cox proportional-hazard models were used to evaluate the relationship between the IL-6 level and survival time. Results after adjusting for age, sex, smoking history, histologic type and stage of lung cancer revealed a significant relationship. For all patients, the hazard ratio with high IL-6 levels for lung cancer-specific survival was 2.10 [95% confidence interval (CI) = 1.49 - 2.96] compared with low IL-6 levels. The hazard ratio for patients who were recruited before and after the start of chemotherapy was1.25 (95% CI = 0.73 - 2.13) and 3.66 (95% CI = 2.18 - 6.15), respectively. Patients with high circulating IL-6 also responded poorly to chemotherapy. Therefore, a high level of circulating IL-6 was associated with an inferior response and survival outcome in NSCLC patients treated with chemotherapy.

EGFR exon 19 in-frame deletion and polymorphisms of DNA repair genes in never-smoking female lung adenocarcinoma patients.

We explored potential associations between genetic polymorphisms in genes related to DNA repair and detoxification metabolism and epidermal growth factor receptor (EGFR) mutations in a cohort of 410 never-smoking patients with lung adenocarcinoma. Multivariate-adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CI) of EGFR mutation status in association with the genotypes of DNA repair and detoxification metabolism genes were evaluated using logistic regression analysis. We found an association between in-frame deletion in EGFR exon 19 and a single nucleotide polymorphism (SNP) rs1800566C/T located in NQO1 (aOR, 2.2 with 95% CI, 1.0-4.8) in female never-smokers. The SNP rs744154C/G in ERCC4 was also associated with the EGFR exon 19 in-frame deletion both in never-smokers (aOR, 1.7 with 95% CI, 1.0-3.0) and female never-smokers (aOR, 1.9 with 95% CI, 1.0-3.6). Although the association was marginally significant in multivariate logistic regression analysis, the A/A genotype of rs1047840 in EXO1 was associated with a 7.6-fold increase in the occurrence of the EGFR exon 19 in-frame deletion in female never-smokers. Moreover, risk alleles in NQO1, ERCC4 and EXO1 were associated with an increasing aOR of the EGFR exon 19 in-frame deletion both in never-smokers (p = 0.007 for trend) and female never-smokers (p = 0.002 for trend). Our findings suggest that the in-frame deletion in EGFR exon 19 is associated with polymorphisms in DNA repair and detoxification metabolism genes in never-smoking lung adenocarcinoma patients, especially in females.

EGFR L858R mutation and polymorphisms of genes related to estrogen biosynthesis and metabolism in never-smoking female lung adenocarcinoma patients.

PURPOSE: To assess whether polymorphisms of genes related to estrogen biosynthesis and metabolism are associated with EGFR mutations. EXPERIMENTAL DESIGN: We studied 617 patients with lung adenocarcinoma, including 302 never-smoking women. On the basis of multiple candidate genes approach, the effects of polymorphisms of CYP17, CYP19A1, ERα, and COMT in association with the occurrence of EGFR mutations were evaluated using logistic regression analysis. RESULTS: In female never-smokers, significant associations with EGFR L858R mutation were found for the tetranucleotide (TTTA)(n) repeats in CYP19A1 (odds ratio, 2.6; 95%CI, 1.2-5.7 for 1 or 2 alleles with (TTTA)(n) repeats >7 compared with both alleles with (TTTA)(n) repeats ≤ 7), and the rs2234693 in ERα (OR, 2.1; 95% CI, 1.1-4.0 for C/T and C/C genotypes compared with T/T genotype). The C/C genotype (vs. T/T genotype) of ERα was significantly associated with EGFR L858R mutation (OR, 3.0; 95% CI, 1.1-8.1), in-frame deletion (OR, 2.9; 95% CI, 1.1-7.6) and other mutations (OR, 4.3; 95% CI, 1.3-14.0). The genotype of COMT rs4680 was significantly associated with EGFR L858R mutation in female and male never-smokers showing OR's (95% CI) of 1.8 (1.0-3.2) and 3.6 (1.1-11.3), respectively, for genotypes G/A and G/G compared with genotype A/A. The number of risk alleles of CYP17, CYP19A1, ERα, and COMT was associated with an increasing OR of EGFR L858R mutation in female never-smokers (P = 0.0002 for trend). CONCLUSIONS: The L858R mutation of EGFR is associated with polymorphisms of genes related to estrogen biosynthesis and metabolism in never-smoking female lung adenocarcinoma patients.

Human papilloma virus and female lung adenocarcinoma.

Lung cancer is the leading cause of cancer among women worldwide, and adenocarcinoma is the most common histological subtype among non-smoking women. Previous studies showed that human papillomavirus (HPV) infection may relate to the tumorigenesis of pulmonary adenocarcinoma. Women with anogenital malignancy have a higher risk of lung cancer, which raises the possibility of HPV transmission from the cervix to the lung. Two postulated pathways are discussed in this work. First, HPV may infect the female cervix and then move to the lung by blood circulation. The second transmission route is the HPV infection of oral cavity resulting from dangerous sexual contacts, and subsequently transmitted to the lung. This chapter also reviews the techniques for detecting the existence, subtypes, and viral load of HPV. Future studies are needed to demonstrate the causal inference between HPV infection and the risk of female lung adenocarcinoma.