In vivo dosimetry for lung radiotherapy including SBRT

SBRT for lung cancer is being rapidly adopted as a treatment option in modern radiotherapy centres. This treatment is one of the most complex in common clinical use, requiring significant expertise and resources. It delivers a high dose per fraction (typically ∼6–30 Gy/fraction) over few fractions. The complexity and high dose delivered in only a few fractions make powerful arguments for the application of in vivo dosimetry methods for these treatments to enhance patient safety. In vivo dosimetry is a group of techniques with a common objective – to estimate the dose delivered to the patient through a direct measurement of the treatment beam(s). In particular, methods employing an electronic portal imaging device have been intensely investigated over the past two decades. Treatment verification using in vivo dosimetry approaches has been shown to identify errors that would have been missed with other common quality assurance methods. With the addition of in vivo dosimetry to verify treatments, medical physicists and clinicians have a higher degree of confidence that the dose has been delivered to the patient as intended.In this review, the technical aspects and challenges of in vivo dosimetry for lung SBRT will be presented, focusing on transit dosimetry applications using electronic portal imaging devices (EPIDs). Currently available solutions will be discussed and published clinical experiences, which are very limited to date, will be highlighted.     

Megakaryocytic Potentiating Factor and Mature Mesothelin Stimulate the Growth of a Lung Cancer Cell Line in the Peritoneal Cavity of Mice

The mesothelin (MSLN) gene encodes a 71 kilodalton (kDa) precursor protein that is processed into megakaryocytic potentiating factor (MPF), a 31 kDa protein that is secreted from the cell, and mature mesothelin (mMSLN), a 40 kDa cell surface protein. The mMSLN binds to CA125, an interaction that has been implicated in the intra-cavitary spread of mesothelioma and ovarian cancer. To better define the role of MPF and mMSLN, growth of the lung cancer cell line A549 was evaluated in immuno-deficient mice with inactivation of the Msln gene. We observed that Msln–/– mice xenografted with intraperitoneal A549 tumors survive significantly long than tumor-bearing Msln+/+ mice. When tumor-bearing Msln–/– mice are supplemented with recombinant MPF (and to a lesser extent mMSLN), most of this survival advantage is lost. These studies demonstrate that MPF and mMSLN have an important role in the growth of lung cancer cells in vivo and raise the possibility that inactivation of MPF may be a useful treatment for lung and other MSLN expressing cancers.     

Bidirectional epithelial–mesenchymal crosstalk provides self-sustaining profibrotic signals in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2 to 4 years. Injury to and/or dysfunction of the alveolar epithelium is strongly implicated in IPF disease initiation, but the factors that determine whether fibrosis progresses rather than normal tissue repair occurs remain poorly understood. We previously demonstrated that zinc finger E-box-binding homeobox 1–mediated epithelial–mesenchymal transition in human alveolar epithelial type II (ATII) cells augments transforming growth factor-β–induced profibrogenic responses in underlying lung fibroblasts via paracrine signaling. Here, we investigated bidirectional epithelial–mesenchymal crosstalk and its potential to drive fibrosis progression. RNA-Seq of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced epithelial–mesenchymal transition identified many differentially expressed genes including those involved in cell migration and extracellular matrix regulation. We confirmed that paracrine signaling between RAS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a zinc finger E-box-binding homeobox 1–tissue plasminogen activator axis. In a reciprocal fashion, paracrine signaling from transforming growth factor-β–activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially through the secreted protein acidic and rich in cysteine, which may signal via the epithelial growth factor receptor via epithelial growth factor–like repeats. Together, these data identify that aberrant bidirectional epithelial–mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining profibrotic signals.     

Type II Transmembrane Serine Protease Gene Variants Associate with Breast Cancer

Type II transmembrane serine proteases (TTSPs) are related to tumor growth, invasion, and metastasis in cancer. Genetic variants in these genes may alter their function, leading to cancer onset and progression, and affect patient outcome. Here, 464 breast cancer cases and 370 controls were genotyped for 82 single-nucleotide polymorphisms covering eight genes. Association of the genotypes was estimated against breast cancer risk, breast cancer–specific survival, and survival in different treatment groups, and clinicopathological variables. SNPs in TMPRSS3 (rs3814903 and rs11203200), TMPRSS7 (rs1844925), and HGF (rs5745752) associated significantly with breast cancer risk (P _trend = 0.008–0.042). SNPs in TMPRSS1 (rs12151195 and rs12461158), TMPRSS2 (rs2276205), TMPRSS3 (rs3814903), and TMPRSS7 (rs2399403) associated with prognosis (P = 0.004–0.046). When estimating the combined effect of the variants, the risk of breast cancer was higher with 4–5 alleles present compared to 0–2 alleles (P = 0.0001; OR, 2.34; 95% CI, 1.39–3.94). Women with 6–8 survival-associating alleles had a 3.3 times higher risk of dying of breast cancer compared to women with 1–3 alleles (P = 0.001; HR, 3.30; 95% CI, 1.58–6.88). The results demonstrate the combined effect of variants in TTSPs and their related genes in breast cancer risk and patient outcome. Functional analysis of these variants will lead to further understanding of this gene family, which may improve individualized risk estimation and development of new strategies for treatment of breast cancer.     

Resveratrol Induces Premature Senescence in Lung Cancer Cells via ROS-Mediated DNA Damage

Resveratrol (RV) is a natural component of red wine and grapes that has been shown to be a potential chemopreventive and anticancer agent. However, the molecular mechanisms underlying RV''s anticancer and chemopreventive effects are incompletely understood. Here we show that RV treatment inhibits the clonogenic growth of non-small cell lung cancer (NSCLC) cells in a dose-dependent manner. Interestingly, the tumor-suppressive effect of low dose RV was not associated with any significant changes in the expression of cleaved PARP and activated caspase-3, suggesting that low dose RV treatment may suppress tumor cell growth via an apoptosis-independent mechanism. Subsequent studies reveal that low dose RV treatment induces a significant increase in senescence-associated β–galactosidase (SA-β-gal) staining and elevated expression of p53 and p21 in NSCLC cells. Furthermore, we show that RV-induced suppression of lung cancer cell growth is associated with a decrease in the expression of EF1A. These results suggest that RV may exert its anticancer and chemopreventive effects through the induction of premature senescence. Mechanistically, RV-induced premature senescence correlates with increased DNA double strand breaks (DSBs) and reactive oxygen species (ROS) production in lung cancer cells. Inhibition of ROS production by N-acetylcysteine (NAC) attenuates RV-induced DNA DSBs and premature senescence. Furthermore, we show that RV treatment markedly induces NAPDH oxidase-5 (Nox5) expression in both A549 and H460 cells, suggesting that RV may increase ROS generation in lung cancer cells through upregulating Nox5 expression. Together, these findings demonstrate that low dose RV treatment inhibits lung cancer cell growth via a previously unappreciated mechanism, namely the induction of premature senescence through ROS-mediated DNA damage.     

Body size and composition and risk of site-specific cancers in the UK Biobank and large international consortia: A mendelian randomisation study

BackgroundEvidence for the impact of body size and composition on cancer risk is limited. This mendelian randomisation (MR) study investigates evidence supporting causal relationships of body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and height with cancer risk.Methods and findingsSingle nucleotide polymorphisms (SNPs) were used as instrumental variables for BMI (312 SNPs), FMI (577 SNPs), FFMI (577 SNPs), and height (293 SNPs). Associations of the genetic variants with 22 site-specific cancers and overall cancer were estimated in 367,561 individuals from the UK Biobank (UKBB) and with lung, breast, ovarian, uterine, and prostate cancer in large international consortia. In the UKBB, genetically predicted BMI was positively associated with overall cancer (odds ratio [OR] per 1 kg/m² increase 1.01, 95% confidence interval [CI] 1.00–1.02; p = 0.043); several digestive system cancers: stomach (OR 1.13, 95% CI 1.06–1.21; p < 0.001), esophagus (OR 1.10, 95% CI 1.03, 1.17; p = 0.003), liver (OR 1.13, 95% CI 1.03–1.25; p = 0.012), and pancreas (OR 1.06, 95% CI 1.01–1.12; p = 0.016); and lung cancer (OR 1.08, 95% CI 1.04–1.12; p < 0.001). For sex-specific cancers, genetically predicted elevated BMI was associated with an increased risk of uterine cancer (OR 1.10, 95% CI 1.05–1.15; p < 0.001) and with a lower risk of prostate cancer (OR 0.97, 95% CI 0.94–0.99; p = 0.009). When dividing cancers into digestive system versus non-digestive system, genetically predicted BMI was positively associated with digestive system cancers (OR 1.04, 95% CI 1.02–1.06; p < 0.001) but not with non-digestive system cancers (OR 1.01, 95% CI 0.99–1.02; p = 0.369). Genetically predicted FMI was positively associated with liver, pancreatic, and lung cancer and inversely associated with melanoma and prostate cancer. Genetically predicted FFMI was positively associated with non-Hodgkin lymphoma and melanoma. Genetically predicted height was associated with increased risk of overall cancer (OR per 1 standard deviation increase 1.09; 95% CI 1.05–1.12; p < 0.001) and multiple site-specific cancers. Similar results were observed in analyses using the weighted median and MR–Egger methods. Results based on consortium data confirmed the positive associations between BMI and lung and uterine cancer risk as well as the inverse association between BMI and prostate cancer, and, additionally, showed an inverse association between genetically predicted BMI and breast cancer. The main limitations are the assumption that genetic associations with cancer outcomes are mediated via the proposed risk factors and that estimates for some lower frequency cancer types are subject to low precision.ConclusionsOur results show that the evidence for BMI as a causal risk factor for cancer is mixed. We find that BMI has a consistent causal role in increasing risk of digestive system cancers and a role for sex-specific cancers with inconsistent directions of effect. In contrast, increased height appears to have a consistent risk-increasing effect on overall and site-specific cancers.

Mathew Vithayathil and colleagues study associations of body mass index and other measures with incidence of specific cancers.     

Evaluation of the ability of three commercially available dosimeters to detect systematic delivery errors in step-and-shoot IMRT plans

BackgroundThere is limited data on error detectability for step-and-shoot intensity modulated radiotherapy (sIMRT) plans, despite significant work on dynamic methods. However, sIMRT treatments have an ongoing role in clinical practice. This study aimed to evaluate variations in the sensitivity of three patient-specific quality assurance (QA) devices to systematic delivery errors in sIMRT plans.Materials and methodsFour clinical sIMRT plans (prostate and head and neck) were edited to introduce errors in: Multi-Leaf Collimator (MLC) position (increasing field size, leaf pairs offset (1–3 mm) in opposite directions; and field shift, all leaves offset (1–3 mm) in one direction); collimator rotation (1–3 degrees) and gantry rotation (0.5–2 degrees). The total dose for each plan was measured using an ArcCHECK diode array. Each field, excluding those with gantry offsets, was also measured using an Electronic Portal Imager and a MatriXX Evolution 2D ionisation chamber array. 132 plans (858 fields) were delivered, producing 572 measured dose distributions. Measured doses were compared to calculated doses for the no-error plan using Gamma analysis with 3%/3 mm, 3%/2 mm, and 2%/2 mm criteria (1716 analyses).ResultsGenerally, pass rates decreased with increasing errors and/or stricter gamma criteria. Pass rate variations with detector and plan type were also observed. For a 3%/3 mm gamma criteria, none of the devices could reliably detect 1 mm MLC position errors or 1 degree collimator rotation errors.ConclusionsThis work has highlighted the need to adapt QA based on treatment plan type and the need for detector specific assessment criteria to detect clinically significant errors.     

Recurrent Genomic Gains in Preinvasive Lesions as a Biomarker of Risk for Lung Cancer

Lung carcinoma development is accompanied by field changes that may have diagnostic significance. We have previously shown the importance of chromosomal aneusomy in lung cancer progression. Here, we tested whether genomic gains in six specific loci, TP63 on 3q28, EGFR on 7p12, MYC on 8q24, 5p15.2, and centromeric regions for chromosomes 3 (CEP3) and 6 (CEP6), may provide further value in the prediction of lung cancer. Bronchial biopsy specimens were obtained by LIFE bronchoscopy from 70 subjects (27 with prevalent lung cancers and 43 individuals without lung cancer). Twenty six biopsies were read as moderate dysplasia, 21 as severe dysplasia and 23 as carcinoma in situ (CIS). Four-micron paraffin sections were submitted to a 4-target FISH assay (LAVysion, Abbott Molecular) and reprobed for TP63 and CEP 3 sequences. Spot counts were obtained in 30–50 nuclei per specimen for each probe. Increased gene copy number in 4 of the 6 probes was associated with increased risk of being diagnosed with lung cancer both in unadjusted analyses (odds ratio = 11, p<0.05) and adjusted for histology grade (odds ratio = 17, p<0.05). The most informative 4 probes were TP63, MYC, CEP3 and CEP6. The combination of these 4 probes offered a sensitivity of 82% for lung cancer and a specificity of 58%. These results indicate that specific cytogenetic alterations present in preinvasive lung lesions are closely associated with the diagnosis of lung cancer and may therefore have value in assessing lung cancer risk.     

MicroRNA-21 as a diagnostic and prognostic biomarker of lung cancer: a systematic review and meta-analysis

Background: The relationship between microRNA-21 (miRNA-21) and pathogenesis of lung cancer is a considerable focus of research interest. However, to our knowledge, no in-depth meta-analyses based on existing evidence to ascertain the value of miRNA-21 in diagnosis and clinical prognosis of lung cancer have been documented.Methods: We comprehensively searched all the literature pertaining to ‘miRNA-21’ and ‘lung cancer’ from four databases from the period of inception of each database until May 2020. Using specific inclusion and exclusion criteria, the literature for inclusion was identified and the necessary data extracted.Results: In total, 46 articles were included in the meta-analysis, among which 31 focused on diagnostic value and 15 on prognostic value. Combined sensitivity (SEN) of miRNA-21 in diagnosis of lung cancer was 0.77 (95% confidence interval (CI): 0.72–0.81), specificity (SPE) was 0.86 (95% CI: 0.80–0.90), diagnostic odds ratio (DOR) was (95% CI: 12–33), and area under the SROC curve (AUC) was 0.87 (95% CI: 0.84–0.90). No significant correlations were observed between abnormal expression of miRNA-21 and gender, smoking habits, pathological type and clinical stage of lung cancer (P>0.05). In terms of overall survival (OS), univariate analysis (hazards ratio (HR) = 1.49, 95% CI: 1.22–1.82) revealed high expression of miRNA-21 as an influencing factor for lung cancer. MiRNA-21 was confirmed as an independent risk factor for poor prognosis in multivariate analysis (HR = 1.65, 95% CI: 1.24–2.19).Conclusion: MiRNA-21 has potential clinical value in the diagnosis and prognosis of lung cancer and may serve as an effective diagnostic marker and therapeutic target in the future.     

How Have We Diagnosed Early-Stage Lung Cancer without Radiographic Screening? A Contemporary Single-Center Experience

Background

The National Lung Screening Trial (NLST), which demonstrated a reduction in lung cancer mortality, may result in widespread computed tomography (CT)-based screening of select populations. How early-stage lung cancer has been diagnosed without screening, and what proportion of these cases would be captured by a screening program modeled on the NLST, is not currently known. We therefore evaluated current patterns of early-stage lung cancer presentation.

Methodology/Principal Findings

We performed a single-institution retrospective analysis of patients diagnosed with stage I–II non-small cell lung cancer (NSCLC) from 2000–2009. Associations between patient and imaging characteristics were assessed using univariate and multivariate analyses. A total of 412 patients met criteria for analysis. Among those with available reason for initial imaging, the reason was symptoms in 51%, follow-up of other conditions in 43%, and screening in 6%. Reason for imaging was associated with race (P<0.001), insurance type (P = 0.005), and disease stage (P<0.001). Type of initial imaging was associated with reason for imaging (P<0.001), year (chest x-ray 67% in 2000–2004 vs. 49% in 2005–2009; P<0.001), and disease stage (P = 0.005). Among patients with available quantified smoking history, 48% were age 55–74 years and smoked 30-plus pack-years, therefore meeting NLST entry criteria.

Conclusions/Significance

Symptoms remain a dominant but declining reason for detection of early-stage NSCLC. The proportion of cases detected initially by CT scan without antecedent chest x-ray has increased considerably. Because as few as half of cases meet NLST eligibility criteria, clinicians should remain aware of the diverse circumstances of early-stage lung cancer presentation to expedite therapy.     

Evaluation of volumetric modulated arc therapy (VMAT) — based total body irradiation (TBI) in pediatric patients

BackgroundThe dosimetric characterization of volumetric modulated arc therapy (VMAT)-based total-body irradiation (TBI) in pediatric patients is evaluated.Materials and methodsTwenty-two patients between the ages of 2 and 12 years were enrolled for VMAT-based TBI from 2018 to 2020. Three isocenters were irradiated over three overlapping arcs. While prescribing 90% of the TBI dose to the planning treatment volume (PTV), two fractions (2 Gy each) were delivered each day; hence 12 Gy was delivered in six fractions. During treatment optimization, the mean lung and kidney doses were set not to exceed 7 Gy and 7.5 Gy, respectively. The maximum lens dose was also set to less than 4 Gy. Patient quality assurance was carried out by comparing treatment planning system doses to the 3-dimensional measured doses by the ArcCHECK^® detector. The electronic portal imaging device (EPID) gamma indices were also obtained.ResultsThe average mean lung dose was 7.75 ± 0.18 Gy, mean kidney dose 7.63 ± 0.26 Gy, maximum lens dose 4.41 ± 0.39 Gy, and the mean PTV dose 12.69 ± 0.16 Gy. The average PTV heterogeneity index was 1.15 ± 0.03. Average differences in mean kidney dose, mean lung dose, and mean target dose were 2.79% ± 0.88, 0.84% ± 0.45 and 0.93% ± 0.47, respectively; when comparing planned and ArcCHECK^® measured doses. Only grade 1–2 radiation toxicities were recorded, based on CTCAE v5.0 scoring criteria.ConclusionsVMAT-TBI was characterized with good PTV coverage, homogeneous dose distribution, planned and measured dose agreement, and low toxicity.     

Functional Polymorphisms of CHRNA3 Predict Risks of Chronic Obstructive Pulmonary Disease and Lung Cancer in Chinese

Recently, several genome-wide association studies (GWAS) have identified many susceptible single nucleotide polymorphisms (SNPs) for chronic obstructive pulmonary disease (COPD) and lung cancer which are two closely related diseases. Among those SNPs, some of them are shared by both the diseases, reflecting there is possible genetic similarity between the diseases. Here we tested the hypothesis that whether those shared SNPs are common predictor for risks or prognosis of COPD and lung cancer. Two SNPs (rs6495309 and rs1051730) located in nicotinic acetylcholine receptor alpha 3 (CHRNA3) gene were genotyped in 1511 patients with COPD, 1559 lung cancer cases and 1677 controls in southern and eastern Chinese populations. We found that the rs6495309CC and rs6495309CT/CC variant genotypes were associated with increased risks of COPD (OR = 1.32, 95% C.I. = 1.14–1.54) and lung cancer (OR = 1.57; 95% CI = 1.31–1.87), respectively. The rs6495309CC genotype contributed to more rapid decline of annual Forced expiratory volume in one second (FEV1) in both COPD cases and controls (P<0.05), and it was associated with advanced stages of COPD (P = 0.033); the rs6495309CT/CC genotypes conferred a poor survival for lung cancer (HR = 1.41, 95%CI = 1.13–1.75). The luciferase assays further showed that nicotine and other tobacco chemicals had diverse effects on the luciferase activity of the rs6495309C or T alleles. However, none of these effects were found for another SNP, rs1051730G>A. The data show a statistical association and suggest biological plausibility that the rs6495309T>C polymorphism contributed to increased risks and poor prognosis of both COPD and lung cancer.     

Radiation Effects on Mortality from Solid Cancers Other than Lung,Liver, and Bone Cancer in the Mayak Worker Cohort: 1948–2008

Radiation effects on mortality from solid cancers other than lung, liver, and bone cancer in the Mayak worker cohort: 1948–2008. The cohort of Mayak Production Association (PA) workers in Russia offers a unique opportunity to study the effects of prolonged low dose rate external gamma exposures and exposure to plutonium in a working age population. We examined radiation effects on the risk of mortality from solid cancers excluding sites of primary plutonium deposition (lung, liver, and bone surface) among 25,757 workers who were first employed in 1948–1982. During the period 1948–2008, there were 1,825 deaths from cancers other than lung, liver and bone. Using colon dose as a representative external dose, a linear dose response model described the data well. The excess relative risk per Gray for external gamma exposure was 0.16 (95% CI: 0.07 – 0.26) when unadjusted for plutonium exposure and 0.12 (95% CI 0.03 – 0.21) when adjusted for plutonium dose and monitoring status. There was no significant effect modification by sex or attained age. Plutonium exposure was not significantly associated with the group of cancers analyzed after adjusting for monitoring status. Site-specific risks were uncertainly estimated but positive for 13 of the 15 sites evaluated with a statistically significant estimate only for esophageal cancer. Comparison with estimates based on the acute exposures in atomic bomb survivors suggests that the excess relative risk per Gray for prolonged external exposure in Mayak workers may be lower than that for acute exposure but, given the uncertainties, the possibility of equal effects cannot be dismissed.     

Curcumin Inhibits Non-Small Cell Lung Cancer Cells Metastasis through the Adiponectin/NF-κb/MMPs Signaling Pathway

Adipose tissue is now considered as an endocrine organ involved in metabolic and inflammatory reactions. Adiponectin, a 244–amino acid peptide hormone, is associated with insulin resistance and carcinogenesis. Curcumin (diferuloylmethane) is the principal curcuminoid of the popular Indian spice, turmeric. Curcumin possesses antitumor effects, including the inhibition of neovascularization and regulation of cell cycle and apoptosis. However, the effects of adiponectin and curcumin on non-small cell lung cancer (NSCLC) remain unclear. In this study, we evaluated the expression of adiponectin in paired tumors and normal lung tissues from 77 patients with NSCLC using real-time polymerase chain reaction, western blotting, and immunohistochemistry. Kaplan–Meier survival analysis showed that patients with low adiponectin expression ratio (<1) had significantly longer survival time than those with high expression ratio (>1) (p = 0.015). Curcumin inhibited the migratory and invasive ability of A549 cells via the inhibition of adiponectin expression by blocking the adiponectin receptor 1. Curcumin treatment also inhibited the in vivo tumor growth of A549 cells and adiponectin expression. These results suggest that adiponectin can be a prognostic indicator of NSCLC. The effect of curcumin in decreasing the migratory and invasive ability of A549 cells by inhibiting adiponectin expression is probably mediated through NF-κB/MMP pathways. Curcumin could be an important potential adjuvant therapeutic agent for lung cancer in the future.     

Additive Synergism between Asbestos and Smoking in Lung Cancer Risk: A Systematic Review and Meta-Analysis

Smoking and asbestos exposure are important risks for lung cancer. Several epidemiological studies have linked asbestos exposure and smoking to lung cancer. To reconcile and unify these results, we conducted a systematic review and meta-analysis to provide a quantitative estimate of the increased risk of lung cancer associated with asbestos exposure and cigarette smoking and to classify their interaction. Five electronic databases were searched from inception to May, 2015 for observational studies on lung cancer. All case-control (N = 10) and cohort (N = 7) studies were included in the analysis. We calculated pooled odds ratios (ORs), relative risks (RRs) and 95% confidence intervals (CIs) using a random-effects model for the association of asbestos exposure and smoking with lung cancer. Lung cancer patients who were not exposed to asbestos and non-smoking (A-S-) were compared with; (i) asbestos-exposed and non-smoking (A+S-), (ii) non-exposure to asbestos and smoking (A-S+), and (iii) asbestos-exposed and smoking (A+S+). Our meta-analysis showed a significant difference in risk of developing lung cancer among asbestos exposed and/or smoking workers compared to controls (A-S-), odds ratios for the disease (95% CI) were (i) 1.70 (A+S-, 1.31–2.21), (ii) 5.65; (A-S+, 3.38–9.42), (iii) 8.70 (A+S+, 5.8–13.10). The additive interaction index of synergy was 1.44 (95% CI = 1.26–1.77) and the multiplicative index = 0.91 (95% CI = 0.63–1.30). Corresponding values for cohort studies were 1.11 (95% CI = 1.00–1.28) and 0.51 (95% CI = 0.31–0.85). Our results point to an additive synergism for lung cancer with co-exposure of asbestos and cigarette smoking. Assessments of industrial health risks should take smoking and other airborne health risks when setting occupational asbestos exposure limits.     

Evaluation of LiF:Mg,Ti (TLD-100) for Intraoperative Electron Radiation Therapy Quality Assurance

Background

Purpose of the present work was to investigate thermoluminescent dosimeters (TLDs) response to intraoperative electron radiation therapy (IOERT) beams. In an IOERT treatment, a large single radiation dose is delivered with a high dose-per-pulse electron beam (2–12 cGy/pulse) during surgery. To verify and to record the delivered dose, in vivo dosimetry is a mandatory procedure for quality assurance. The TLDs feature many advantages such as a small detector size and close tissue equivalence that make them attractive for IOERT as in vivo dosimeters.

Methods

LiF:Mg,Ti dosimeters (TLD-100) were irradiated with different IOERT electron beam energies (5, 7 and 9 MeV) and with a 6 MV conventional photon beam. For each energy, the TLDs were irradiated in the dose range of 0–10 Gy in step of 2Gy. Regression analysis was performed to establish the response variation of thermoluminescent signals with dose and energy.

Results

The TLD-100 dose-response curves were obtained. In the dose range of 0–10 Gy, the calibration curve was confirmed to be linear for the conventional photon beam. In the same dose region, the quadratic model performs better than the linear model when high dose-per-pulse electron beams were used (F test; p<0.05).

Conclusions

This study demonstrates that the TLD dose response, for doses ≤10Gy, has a parabolic behavior in high dose-per-pulse electron beams. TLD-100 can be useful detectors for IOERT patient dosimetry if a proper calibration is provided.     

Impact of Uncertainties in Exposure Assessment on Thyroid Cancer Risk among Persons in Belarus Exposed as Children or Adolescents Due to the Chernobyl Accident

BackgroundThe excess incidence of thyroid cancer in Ukraine and Belarus observed a few years after the Chernobyl accident is considered to be largely the result of ¹³¹I released from the reactor. Although the Belarus thyroid cancer prevalence data has been previously analyzed, no account was taken of dose measurement error.MethodsWe examined dose-response patterns in a thyroid screening prevalence cohort of 11,732 persons aged under 18 at the time of the accident, diagnosed during 1996–2004, who had direct thyroid ¹³¹I activity measurement, and were resident in the most radio-actively contaminated regions of Belarus. Three methods of dose-error correction (regression calibration, Monte Carlo maximum likelihood, Bayesian Markov Chain Monte Carlo) were applied.ResultsThere was a statistically significant (p<0.001) increasing dose-response for prevalent thyroid cancer, irrespective of regression-adjustment method used. Without adjustment for dose errors the excess odds ratio was 1.51 Gy⁻ (95% CI 0.53, 3.86), which was reduced by 13% when regression-calibration adjustment was used, 1.31 Gy⁻ (95% CI 0.47, 3.31). A Monte Carlo maximum likelihood method yielded an excess odds ratio of 1.48 Gy⁻ (95% CI 0.53, 3.87), about 2% lower than the unadjusted analysis. The Bayesian method yielded a maximum posterior excess odds ratio of 1.16 Gy⁻ (95% BCI 0.20, 4.32), 23% lower than the unadjusted analysis. There were borderline significant (p = 0.053–0.078) indications of downward curvature in the dose response, depending on the adjustment methods used. There were also borderline significant (p = 0.102) modifying effects of gender on the radiation dose trend, but no significant modifying effects of age at time of accident, or age at screening as modifiers of dose response (p>0.2).ConclusionsIn summary, the relatively small contribution of unshared classical dose error in the current study results in comparatively modest effects on the regression parameters.     

Association Studies of ERCC1 Polymorphisms with Lung Cancer Susceptibility: A Systematic Review and Meta-Analysis

Background

Excision repair cross-complimentary group 1 (ERCC1) is an essential component of the nucleotide excision repair system that is responsible for repairing damaged DNA. Functional genetic variations in the ERCC1 gene may alter DNA repair capacity and modulate cancer risk. The putative roles of ERCC1 gene polymorphisms in lung cancer susceptibility have been widely investigated. However, the results remain controversial.

Objectives

An updated meta-analysis was conducted to explore whether lung cancer risk could be attributed to the following ERCC1 polymorphisms: rs11615 (T>C), rs3212986 (C>A), rs3212961 (A>C), rs3212948 (G>C), rs2298881 (C>A).

Methods

Several major databases (MEDLINE, EMBASE and Scopus) and the Chinese Biomedical database were searched for eligible studies. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to measure the strength of associations.

Results

Sixteen studies with 10,106 cases and 13,238 controls were included in this meta-analysis. Pooled ORs from 11 eligible studies (8,215 cases vs. 11,402 controls) suggested a significant association of ERCC1 rs11615 with increased risk for lung cancer (homozygous: CC versus TT, OR = 1.24, 95% CI: 1.04–1.48, P = 0.02). However, such an association was disproportionately driven by a single study. Removal of that study led to null association. Moreover, initial analyses suggested that ERCC1 rs11615 exerts a more profound effect on the susceptibility of non-smokers to lung cancer than that of smokers. Moreover, no statistically significant association was found between remaining ERCC1 polymorphisms of interest and lung cancer risk, except for rs3212948 variation (heterozygous: CG vs.GG, OR = 0.78, 95% CI: 0.67–0.90, P = 0.001; dominant: CG/CC vs.GG, OR = 0.79, 95% CI: 0.69–0.91, P = 0.001).

Conclusion

Overall, this meta-analysis suggests that ERCC1 rs3212948 G>C, but not others, is a lung cancer risk-associated polymorphism. Carefully designed studies with large sample size involving different ethnicity, smoking status, and cancer types are needed to validate these findings.