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PDF file - 65K, Empirical P-values generated from patient/LCL enrichment analyses using a range of P-value inclusion thresholds for SNP overlap.

1000 SNPs with greatest statistical association with cumulative docetaxel dose at grade 3+ neuropathy in CALGB 90401 discovery GWAS.

PDF file - 409K, SNP call plots from the CALGB 40101 patient genotyping on the Illumina 610-Quad platform for the patient/LCL overlap SNPs in genes. R is the combined SNP intensity and theta is the allelic intensity ratio.

PDF file - 1866K, The 11 overlap SNPs within genes associated with both patient paclitaxel-induced sensory peripheral neuropathy (P < 0.05) and LCL paclitaxel-induced cytotoxicity (P < 0.001). The Kaplan Meier plots show the probability of the first instance of Grade 2 or greater neuropathy (event) as a function of cumulative paclitaxel dose. The boxplots show the survival of LCLs treated with 12.5 nM paclitaxel (adjusted for percent CEU ancestry) versus each genotype.

Purpose: We sought to show the relevance of a lymphoblastoid cell line (LCL) model in the discovery of clinically relevant genetic variants affecting chemotherapeutic response by comparing LCL genome-wide association study (GWAS) results to clinical GWAS results.Experimental Design: A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMap Project and compared with a GWAS of sensory peripheral neuropathy in patients with breast cancer (n = 855) treated with paclitaxel in the Cancer and Leukemia Group B (CALGB) 40101 trial. Significant enrichment was assessed by permutation resampling analysis.Results: We observed an enrichment of LCL cytotoxicity-associated single-nucleotide polymorphisms (SNP) in the sensory peripheral neuropathy-associated SNPs from the clinical trial with concordant allelic directions of effect (empirical P = 0.007). Of the 24 SNPs that overlap between the clinical trial (P < 0.05) and the preclinical cytotoxicity study (P < 0.001), 19 of them are expression quantitative trait loci (eQTL), which is a significant enrichment of this functional class (empirical P = 0.0447). One of these eQTLs is located in RFX2, which encodes a member of the DNA-binding regulatory factor X family. Decreased expression of this gene by siRNA resulted in increased sensitivity of Neuroscreen-1(NS-1; rat pheochromocytoma) cells to paclitaxel as measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of RFX2 in nerve cell response to paclitaxel.Conclusions: The enrichment results and functional example imply that cellular models of chemotherapeutic toxicity may capture components of the underlying polygenic architecture of related traits in patients. Clin Cancer Res; 19(2); 491–9. ©2012 AACR.

Number of patients who experienced neuropathy, completed treatment without neuropathy and discontinued treatment early without having neuropathy while on study and within each range of cumulative treatment.

Peripheral neuronal cells (Peri.4U) treated with docetaxel were found to have a significant decrease in sensitivity for A) mean process lengths but not for B) mean outgrowth intensity or C) relative straightness as measured after 24 hours post-drug treatment. For paclitaxel treatment at the same time point, the cells were also found to have significantly decreased sensitivity for D) relative mean process length and E) mean outgrowth intensity but not for F) relative straightness. Neurite parameters measured with MetaXPress® software were averaged from 3 independent experiments. Error bars represent the standard error of the mean from three independent transfection experiments. NTC = non-targeting control, UT= untransfected control.

PDF file - 68K, Expression and eQTL status of the patient/LCL overlap genes and SNPs.

Sensitivity to mechanical stimuli with Von Frey filaments for C57BL/6J mice and litter-mates heterozygous for VAC14 prior to docetaxel treatment. The figure displays the estimate of the proportion of mice without a hind-paw withdrawal response to stimulation by each Von Frey fiber weight, e.g., no mice respond to fibers {less than or equal to}0.2 g and all mice respond to fibers{greater than or equal to}1.4 g. The VAC14 heterozygous mice (hatched line) are more likely than wild-type mice (solid line) to respond, meaning they are more sensitive to nociceptive stimuli (p=0.0012). Gray lines denote 95% confidence intervals.

CONSORT diagram illustrating patient flow from enrollment on parent study to population included in pharmacogenetic discovery analysis and quality control filtering of SNPs from the Illumina HumanHap610-Quad into the pharmacogenetic analysis.

Most Highly Enriched Canonical Pathways

PDF file - 73K

Purpose: Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy.Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy.Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10−8, adjusted P = 5.88 × 10−7). siRNA knockdown of VAC14 in stem cell–derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001).Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890–900. ©2016 AACR.

PDF file - 68K, Positional information and effect sizes of the 24 patient/LCL overlap SNPs.

The information provided here gives a sense of the value of comparing population studies between the Republic and Northern Ireland, albeit incomplete comparisons in this case since the studies were conducted independently. We share enough that is both common and unique in our attitudes, health profiles and health systems to enable fruitful comparisons for both sides. Future opportunities for comparison should be more explicitly incorporated into the planning stages of such studies. We hope that this report will provide a catalyst for joint survey planning, such that information forthcoming can inform and benefit policy and practice in the pursuit of good health and well-being in the coming years in both the Republic of Ireland and Northern Ireland.

First published online: 21 May 2021 This paper investigates changes over the period 2005 to 2014 in material deprivation dynamics of social risk groups in 11 European countries covering a range of welfare regimes. The period covered experienced dramatic economic change, encompassing periods of boom, the Great Recession and early recovery. Social risk groups are defined as groups which differ in the challenges that they face in converting resources into desired outcomes. The comparative element of the paper allows us to assess whether certain welfare regimes were better at protecting more vulnerable groups. Results, based on the longitudinal component of the European Union Statistics on Income and Living Conditions and on analysis of deprivation dynamics between pairs of years, showed large inequality between groups in the risk of persistent deprivation – with lone parents and people with disability most at risk in all countries. Variation across welfare regimes was restricted to the contrast between the liberal and the remaining regimes. Countries belonging to the former regime (UK and Ireland) were distinctive in showing the largest social risk gap in persistent deprivation and were the only ones which experienced substantial polarisation between groups with the Great Recession. This article received funding from the University Association for Contemporary European Studies (UACES), Grant European Nonviolence Network. This article was published Open Access with the support from the EUI Library through the CRUI - CUP Transformative Agreement (2020-2022)

A new ESRI study commissioned by the Department of Social Protection found that tied cash and non-cash transfers are associated with lower deprivation, especially among vulnerable families. The authors considered benefits tied to housing, childcare, and medical services using 2017 data.

In this paper, we draw on Irish SILC data to examine the roles of social class, non-class risk groups and state policies in influencing enforced material deprivation as Ireland moved from a period of economic boom through deep recession and on to early recovery. We also employ Sen’s capability approach to explore the extent to which certain social risk groups differ in their capacity to convert social class-differentiated resources into increased capability in relation to avoiding material deprivation. The findings refute the notion of polarization either across time as a result of recession or as a result of more vulnerable social risk groups experiencing more pronounced social class differences. Instead, the impact of recession on social class and social risk group operated mainly in an additive manner with each having a relatively independent impact on deprivation. The exception was lone parents who were less able to convert the benefits of higher social class position into reduced deprivation levels.

One of the standard of care regimens for advanced pancreatic cancer is gemcitabine-based chemotherapy. The efficacy of gemcitabine is limited by dose-limiting hematologic toxicities especially neutropenia. Uncovering the variability of these toxicities attributed to germline DNA variation is of great importance.CALGB 80303 was a randomized study in advanced pancreatic cancer patients treated with gemcitabine with or without bevacizumab. The study protocol included genotyping of genes of gemcitabine disposition (CDA, DCTD, SLC29A1, SLC28A1, and SLC29A2), as well as a genome-wide analysis. The clinical phenotype was time to early high-grade neutropenia event accounting for progression or death or other treatment-terminating adverse events as competing for informative events. The inference was carried out on the basis of the association between genotype and cause-specific hazard of a neutropenic event.The primary analyses were carried out on the basis of 294 genetically estimated European pancreatic cancer patients. For CDA rs2072671 (AC), AC and CC patients had a lower risk of neutropenia than AA patients (P=0.01, hazard ratio: 0.61, 95% confidence interval: 0.41-0.89). For SLC28A1 rs3825876 (GA), AA patients have a higher risk of neutropenia than GA and GG patients (P=0.02, hazard ratio: 1.51, 95% confidence interval: 1.06-2.16). CDA rs2072671 was associated with increased mRNA expression in whole blood in three studies (P=2.7e-14, 6.61e-62, and 9.70e-65). In the genome-wide analysis, variants in TGFB2 were among the top hits (lowest P=1.62e-06) but had no effect in luciferase assays.This is the first genetic analysis of gemcitabine-induced neutropenia using a competing risk model in a prospective randomized clinical study has proposed a potentially novel mechanism of the protective effect of the CDA rs2072671 variant. Further confirmation is needed.

The SLÁN 2007 survey contained a series of questions relating to alcohol use. These included questions about frequency (how often) an quantity (how much) of alcohol consumed, as well as questions about alcohol-related harm. Quantity of alcohol consumed was assessed by asking respondents how many standard drinks were taken, a ‘standard’ drink being defined as a half pint or a glass of beer, lager or cider; a single measure of spirits; a single glass of wine, sherry or port; or a bottle of alcopop (long neck). This report forms part of a series of reports which seek to contextualise the SLÁN 2007 findings (see p. iv for full list of SLÁN 2007 reports).

The issue of multidimensionality is well established in poverty research, and it is generally recognised that income alone is inadequate as a measure of social inclusion or quality of life (QoL). However, social policy still tends to address the different dimensions of QoL—such as poverty, health, housing and social cohesion—in isolation. This raises the question of the variation across dimensions or groups in the extent of multidimensionality. For instance, are housing or health problems experienced by people with a range of other QoL problems, or do they tend to occur in isolation? Does this differ between social risk groups, such as lone parents, older adults or children? The answers have implications for the service needs of people with health problems or with inadequate housing. We address these issues in this paper, analysing the 2013 quality of life module on the EU-SILC data for Ireland and adapting the adjusted headcount ratio methodology of Alkire and Foster to address the issue of multidimensionality.

This paper draws on longitudinal data to examine the extent to which parents’ educational expectations shape academic development and changes in self-concept among young people with different types of disability. The analysis is based on the Growing Up in Ireland longitudinal study, which tracked 7423 children between the primary to secondary school years, 21% of whom were identified with one of four main disability types. Our conceptual framework assumes that parental expectations at age 9 will be influenced by both the child’s disability and child’s academic achievement at that stage, as well as being influenced by other factors such as parent’s own education, family economic vulnerability, family relationships and family structure. Therefore, we take these factors into account in tracing the consequences of parental expectations at age 9, on academic and social outcomes at age 13 after the transition to secondary education. Among young people with a disability, poorer self-concept at age 13 is ...

Introduction In Ireland between 2002–2013, Musculoskeletal Disorders (MSD) accounted for 50% of self-reported work-related illnesses. Moreover the average number of days absent (15.9 days) was higher than the average of 12.8 days for all other illnesses (except stress, anxiety and depression). Methods This paper examines trends and determinants for work-related MSD between 2002 and 2013, using annual cross-sectional data from the Quarterly National Household Survey (QNHS). Results Rates of MSD were strongly linked to the economic cycle. Rates per 1000 workers ranged from 11 in 2002 to 19 during the economic boom before falling to 7 during the recession (2009). The 2013 rate in a recovering economy was 14 per 1000 workers. This pro-cyclical pattern remained when characteristics of workers and their workplace were held constant using logistic regression. Furthermore, within sectors, rates were higher when the annual percentage change in employment was positive. We also found that certain worker and workplace factors influenced the risk of MSD independently. Workers aged 35–64 had the highest risk of MSD (2.5 times more than workers Discussion These findings show that some groups of workers face a higher risk of work-related MSD and that further monitoring and targeted measures are needed to support employers and employees especially at a time of economic recovery. Full results and description of the methodology can be found at http://www.esri.ie/publications/work-related-illness/

Introduction Given the changing nature of employment, including the long term shift from manufacturing and agriculture to the service sector, an increasing proportion of the workforce is engaged in employment which is less physically demanding but which brings with it a range of stress-related and psycho-social risks. Eurofound (2006) estimated that in 2005, 20% of EU-15 workers reported health related risk due to work-related stress and the EU OSHA (2007) has identified high emotional demands and work intensification as key emerging psychosocial risks for the occupational health and safety of workers. Methods This paper draws on the 2015 European Working Conditions Survey to examine differences in the exposure of workers across Europe to (a) work stressors (physical risks, chemical/biological hazards, physically demanding work, psychosocial risks and work pressure); (b) the mediating role of work organised to enhance autonomy, supportiveness of management and colleagues and (b) the response of workers in terms of the subjective experience of stress, anxiety and depression. Results Results to include the following: Country differences in exposure to workplace hazards and stressors Extent to which these are linked to country differences in the composition of jobs by sector The role played by the organisation of work (autonomy, supportiveness) in mediating the impact on workers Country differences in the extent to which they adopt forms of work organisation that ameliorate the impact of stressors on workers. Discussion The organisation of work has an important role to play in ameliorating the impact of workplace risks on outcomes for workers.

Post-Leaving Certificate (PLC) courses represent the largest component of full-time further education and training (FET) provision in Ireland, with over 32,000 learners enrolled in such courses in 2015-2016. Recent research on the FET sector as a whole highlighted concerns around its structures and responsiveness to labour market conditions, among other issues (McGuinness et al., 2014). The SOLAS FET Strategy (2014) subsequently pointed to the need for a stronger evidence base in order to inform future policy development in the sector. This study, commissioned by SOLAS, provides a more detailed evaluation of PLC provision. In order to undertake a comprehensive evaluation, our approach has been to combine a variety of research modes in order to examine the underlying processes, experiences and outcomes of PLC provision. This involved three complementary research strands. Firstly, a desk-based analysis of administrative data was used to document the type of provision in terms of field of study and the distribution of PLC places across the country. Secondly, a survey of PLC principals was carried out in order to explore their perceptions of goals, adequacy of existing facilities and the benefits and challenges of PLC provision. Thirdly, a survey of PLC and Leaving Certificate leavers was conducted to assess their labour market outcomes as well as their experiences while taking PLC and higher education courses. Together, these strands provide comprehensive evidence to inform the future development of the sector.

This study, commissioned by the GAA and the GPA, uses data from a survey of 2016 players to examine the commitments required to play senior inter-county Gaelic games, and the impact that this has on players' personal and professional lives, and their club involvement.

A new ESRI study, funded by the Health and Safety Authority (HSA), finds that job stress among employees in Ireland doubled from 8 per cent in 2010 to 17 per cent in 2015. However, the level of job stress in Ireland was still below the average for ten Western European countries in 2015 (19 per cent). The report uses two waves of a European-wide dataset, the European Working Conditions Survey, carried out in 2010 and 2015, to examine the working conditions that are associated with job stress.

A core assumption in conventional poverty measurement is that household members share equally in total household income. This paper focuses on heterosexual couple households and asks to what extent male and female partners may derive different benefits from total couple resources. Drawing on the 2010 Irish Survey on Income and Living Conditions module, we examined the couple financial regime, by which we mean which partners received income, whether the income was from work, the extent to which income was contributed for the benefit of other household members and responsibility for decision-making. We explored whether the couple’s financial regime was associated with different living standard outcomes for the partners. Among the findings was the beneficial impact of having income from work and of shared responsibility for decision-making. The paper concludes by pointing to some implications for our understanding of power and bargaining in couples.

Women make up the majority of those employed in the civil service but are underrepresented at the most senior grades, where key policy and operational decisions are taken. Action 8 of the Civil Service Renewal Plan commits to improving gender balance at each level, including senior grades. The present study was commissioned by a high-level steering group set up to oversee implementation of this action. It draws on a combination of administrative data, reanalysis of the Civil Service Employee Engagement Survey conducted in 2015, and in-depth work history interviews with 50 senior civil servants across four departments. In addition, in-depth interviews were conducted with staff involved in recruitment and promotion within the public service. This rich combination of data yields new insights into the processes shaping gender differences in representation at the most senior grades of the civil service and thus provides a strong evidence base to inform future policy and practice.

This report provides annual projections of demand for public and private health and social care services in Ireland for the years 2015–2030. These projections are based on new ESRI projections for population growth, the first projections to be published based on the 2016 Census. The report contains the most comprehensive mapping of public and private activity in the Irish healthcare system to have been published.

A new report published by the ESRI finds that education is key to improving the employment and living circumstances of Travellers. The authors of A Social Portrait of Travellers in Ireland draw on the full 2011 Census of Population to explore whether certain groups of Travellers (in terms of gender, age and region) experience particularly high levels of disadvantage in four areas: education, employment, housing and health.

XK469 (NSC 697887) is a selective topoisomerase II β inhibitor eliminated mainly via aldehyde oxidase I (AOX1). We performed a candidate gene study to investigate whether AOX1 genetic variation contributes to interindividual variability in XK469 clearance. Forty-one AOX1 single nucleotide polymorphisms (SNPs) and seven liver expression quantitative trait loci were genotyped in Caucasian patients with advanced refractory solid tumors (n=59) and leukemia (n=33). We found a significant decrease in clearance (τ = −0.32, P = 0.003) in solid tumor patients with rs10931910, although it failed to replicate in the leukemia cohort (τ = 0.18, P = 0.20). Four other AOX1 SNPs were associated with clearance (P = 0.01-0.02) in only one of the two cohorts. Our study provides a starting point for future investigations on the functionality of AOX1 SNPs. However, variability in XK469 clearance cannot be attributed to polymorphisms in AOX1.

Background and objective In this era of increasing options for treatment of ‘surgical’ lung cancer patients, preoperative physiologic assessment of accurate patient selection is becoming more important. The variability in an objective measure of cardiorespiratory fitness (peak oxygen consumption (VO2peak)) across performance in operable non-small-cell lung cancer (NSCLC) patients enrolled in the Cancer and Leukemia Group B trial was compared. Methods Using a cross-sectional design, 392 NSCLC patients underwent an incremental cardiopulmonary cycling exercise test to symptom limitation with expired gas analysis to determine VO2peak. Performance status (PS) was assessed using the Eastern Cooperative Oncology Group (ECOG) tool. Results There was a significant decrease in VO2peak across increasing ECOG categories (P

Allogeneic stem cell transplantation is the standard approach to Philadelphia chromosome positive acute lymphoblastic leukemia. We hypothesized that imatinib plus sequential chemotherapy will result in significant leukemia cell cytoreduction in patients with Philadelphia chromosome positive acute lymphoblastic leukemia, allowing collection of normal hematopoietic stem cells uncontaminated by residual BCR/ABL1(+) lymphoblasts and thus reduce the likelihood of relapse after autologous stem cell transplantation for patients under 60 years of age without sibling donors. We enrolled 58 patients; 19 underwent autologous and 15 underwent allogeneic stem cell transplantation on study. Imatinib plus sequential chemotherapy resulted in reverse-transcriptase polymerase chain reaction-negative stem cells in 9 patients and remained minimally positive in 4 (6 were not evaluable). Overall survival (median 6.0 years vs. not reached) and disease-free survival (median 3.5 vs. 4.1 years) were similar between those who underwent autologous and those who underwent allogeneic stem cell transplantation. We conclude that autologous stem cell transplantation represents a safe and effective alternative for allogeneic stem cell transplantation in Philadelphia chromosome positive acute lymphoblastic leukemia patients without sibling donors (clinicaltrials.gov identifier:00039377).

Purpose: We sought to show the relevance of a lymphoblastoid cell line (LCL) model in the discovery of clinically relevant genetic variants affecting chemotherapeutic response by comparing LCL genome-wide association study (GWAS) results to clinical GWAS results. Experimental Design: A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMap Project and compared with a GWAS of sensory peripheral neuropathy in patients with breast cancer (n = 855) treated with paclitaxel in the Cancer and Leukemia Group B (CALGB) 40101 trial. Significant enrichment was assessed by permutation resampling analysis. Results: We observed an enrichment of LCL cytotoxicity-associated single-nucleotide polymorphisms (SNP) in the sensory peripheral neuropathy-associated SNPs from the clinical trial with concordant allelic directions of effect (empirical P = 0.007). Of the 24 SNPs that overlap between the clinical trial (P < 0.05) and the preclinical cytotoxicity study (P < 0.001), 19 of them are expression quantitative trait loci (eQTL), which is a significant enrichment of this functional class (empirical P = 0.0447). One of these eQTLs is located in RFX2, which encodes a member of the DNA-binding regulatory factor X family. Decreased expression of this gene by siRNA resulted in increased sensitivity of Neuroscreen-1(NS-1; rat pheochromocytoma) cells to paclitaxel as measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of RFX2 in nerve cell response to paclitaxel. Conclusions: The enrichment results and functional example imply that cellular models of chemotherapeutic toxicity may capture components of the underlying polygenic architecture of related traits in patients. Clin Cancer Res; 19(2); 491–9. ©2012 AACR.

Purpose: Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy. Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy. Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10−8, adjusted P = 5.88 × 10−7). siRNA knockdown of VAC14 in stem cell–derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001). Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890–900. ©2016 AACR.

Identifying strong markers of prognosis is critical to optimize treatment and survival outcomes in patients with nonsmall cell lung cancer (NSCLC). The authors investigated the prognostic significance of preoperative cardiorespiratory fitness (peak oxygen consumption [VO(2peak)]) among operable candidates with NSCLC.By using a prospective design, 398 patients with potentially resectable NSCLC enrolled in Cancer and Leukemia Group B 9238 were recruited between 1993 and 1998. Participants performed a cardiopulmonary exercise test to assess VO(2peak) and were observed until death or June 2008. Cox proportional models were used to estimate the risk of all-cause mortality according to cardiorespiratory fitness category defined by VO(2peak) tertiles (0.96 of 0.96-1.29/1.29 L/min⁻¹) with adjustment for age, sex, and performance status.Median follow-up was 30.8 months; 294 deaths were reported during this period. Compared with patients achieving a VO(2peak)0.96 L/min⁻¹, the adjusted hazard ratio (HR) for all-cause mortality was 0.64 (95% confidence interval [CI], 0.46-0.88) for a VO(2peak) of 0.96 to 1.29 L/min⁻¹, and 0.56 (95% CI, 0.39-0.80) for a VO(2peak) of1.29 L/min⁻¹) (P(trend) = .0037). The corresponding HRs for resected patients were 0.66 (95% CI, 0.46-0.95) and 0.59 (95% CI, 0.40-0.89) relative to the lowest VO(2peak) category (P(trend) = .0247), respectively. For nonresected patients, the HRs were 0.78 (95% CI, 0.34-1.79) and 0.39 (95% CI, 0.16-0.94) relative to the lowest category (P(trend) = .0278).VO(2peak) is a strong independent predictor of survival in NSCLC that may complement traditional markers of prognosis to improve risk stratification and prognostication.

Retrospective data suggests prolonging the time to complete thoracic radiotherapy (TRT) may negatively impact tumor control and survival in limited stage small cell lung cancer (LSCLC). We examined the association between TRT duration and outcomes on a prospective phase III study.This review included 267 patients who received protocol TRT on a phase III CALGB LSCLC study assessing the addition of tamoxifen to standard chemo-radiotherapy. TRT, to a planned dose of 50Gy in 2Gy daily fractions, was initiated with the fourth chemotherapy cycle. TRT interruptions were mandated for hematologic toxicity (granulocytes1000/mm3 or platelets75,000/mm3) and esophageal toxicity (dysphagia necessitating intravenous hydration).TRT interruptionsor =3 days occurred in 115 patients (43%), most frequently during the 4th week of TRT, and did not differ between treatment arms. Hematologic toxicity and esophageal toxicity were the most frequent indications for interrupting TRT. Variables including advanced age (70 years), gender, race, or radiotherapy treatment volume did not predict for TRT interruptions. Overall survival (OS) and local tumor control did not correlate with the administration of TRT interruptions or with TRT duration.Toxicity mandated interruptions of conventional dose, once-daily, TRT may not adversely affect outcomes for patients receiving TRT concurrent with chemotherapy (cycle 4) for LSCLC. The implications for accelerated or high dose TRT regimens are not clear.

IntroductionA stepwise approach to the functional assessment of lung resection candidates is widely accepted, and this approach incorporates the measurement of exercise peak Vo2 when spirometry and radionuclear studies suggest medical inoperability. A new functional operability (FO) algorithm incorporates peak exercise Vo2 earlier in the preoperative assessment to determine which patients require preoperative radionuclear studies. This algorithm has not been studied in a multicenter study.MethodsThe CALGB (Cancer and Leukemia Group B) performed a prospective multi-institutional study to investigate the use of primary exercise Vo2 measurement for the prediction of surgical risk. Patients with known or suspected resectable non-small cell lung cancer (NSCLC) were eligible. Exercise testing including measurement of peak oxygen uptake (Vo2), spirometry, and single breath diffusion capacity (DLCO) was performed on each patient. Nuclear perfusion scans were obtained on selected high-risk patients. After surgery, morbidity and mortality data were collected and correlated with preoperative data. Mortality and morbidity were retrospectively compared by algorithm-based risk groups.ResultsThree hundred forty-six patients with suspected lung cancer from nine institutions underwent thoracotomy with or without resection; 57 study patients did not undergo thoracotomy. Patients who underwent surgery had a median survival time of 30.9 months, whereas patients who did not undergo surgery had a median survival time of 15.6 months. Among the 346 patients who underwent thoracotomy, 15 patients died postoperatively (4%), and 138 patients (39%) exhibited at least one cardiorespiratory complication postoperatively. We found that patients who had a peak exercise Vo2 of

Purpose Standard therapy for unresectable stage III non–small-cell lung cancer includes concomitant chemoradiotherapy. In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival. Patients and Methods Between July 1998 and May 2002, 366 patients were randomly assigned to arm A, which involved immediate concurrent chemoradiotherapy with carboplatin area under the concentration-time curve (AUC) of 2 and paclitaxel 50 mg/m2 given weekly during 66 Gy of chest radiotherapy, or arm B, which involved two cycles of carboplatin AUC 6 and paclitaxel 200 mg/m2 administered every 21 days followed by identical chemoradiotherapy. The accrual goal was 360 patients. Results Thirty-four percent of patients were female, 66% were male, and the median age was 63 years. Grade 3 or 4 toxicities during induction chemotherapy on arm B consisted mainly of neutropenia (18% and 20%, respectively). During concurrent chemoradiotherapy, there was no difference in severity of in-field toxicities of esophagitis (grade 3 and 4 were, respectively, 30% and 2% for arm A v 28% and 8% for arm B) and dyspnea (grade 3 and 4 were, respectively, 11% and 3% for arm A v 15% and 4% for arm B). Survival differences were not statistically significant (P = .3), with a median survival on arm A of 12 months (95% CI, 10 to 16 months) versus 14 months (95% CI, 11 to 16 months) on arm B and a 2-year survival of 29% (95% CI, 22% to 35%) and 31% (95% CI, 25% to 38%). Age, weight loss before therapy, and performance status were statistically significant predictive factors. Conclusion The addition of induction chemotherapy to concurrent chemoradiotherapy added toxicity and provided no survival benefit over concurrent chemoradiotherapy alone. The median survival achieved in each of the treatment groups is low, and the routine use of weekly carboplatin and paclitaxel with simultaneous radiotherapy should be re-examined.

In this paper we make use of the first and second waves of the 2008 and 1998 cohorts of the Growing Up in Ireland study, to develop a multidimensional and dynamic approach to understanding the impact on families and children in Ireland of the Great Recession. Economic vulnerability is operationalised as involving a distinctive risk profile in relation to relative income, household joblessness and economic stress. We find that the recession was associated with a significant increase in levels of economic vulnerability and changing risk profiles involving a more prominent role for economic stress for both the 2008 and 1998 cohorts. The factors affecting vulnerability outcomes were broadly similar for both cohorts. Persistent economic vulnerability was significantly associated with lone parenthood, particularly for those with more than one child, lower levels of primary care giver (PCG) education and, to a lesser extent, younger age of PCG at child’s birth, number of children and a parent leaving or dying. Similar factors were associated with transient vulnerability in the first wave but the magnitude of the effects was significantly weaker particularly in relation to lone parenthood and level of education of the PCG. For entry into vulnerability the impact of these factors was again substantially weaker than for persistent and transient vulnerability indicating a significantly greater degree of socioeconomic heterogeneity among the group that became vulnerable during the recession. The findings raise policy and political problems that go beyond those associated with catering for groups that have tended to be characterized by high dependence on social welfare.

BACKGROUND The overexpression of HER-2 occurs in a minority of patients with nonsmall cell lung carcinoma. Trastuzumab, which is a monoclonal antibody to HER-2, is an effective treatment in some women with breast carcinomas that overexpress HER-2, as demonstrated by immunohistochemistry. The objective of this Phase II study was to determine whether trastuzumab would effect responses in patients with nonsmall cell lung carcinoma who had tumors that overexpressed HER-2. METHODS Patients were required to have Stage IIIB or Stage IV nonsmall cell lung carcinoma and tumors with 2+ or 3+ expression of HER-2, as determined with immunohistochemistry, and they may have received up to 1 prior chemotherapy regimen. Trastuzumab at a dose of 4 mg/kg was given intravenously on Week 1; then, weekly doses of 2 mg/kg were given. Response revaluation was performed every 8 weeks. RESULTS Among 209 screened patients, 24 patients (11%) had tumors with 2+ or 3+ expression of HER-2. One patient achieved a partial response, and one patient experienced a treatment-related death due to pulmonary toxicity. CONCLUSIONS Single-agent trastuzumab did not exhibit significant clinical activity against nonsmall cell lung carcinoma when HER-2 expression levels were measured by immunohistochemistry. Cancer 2005. © 2005 American Cancer Society.

Attrition in the first five waves of the European Community Household Panel is examined. Although overall attrition rates are high in several countries, multivariate analysis revealed that only a small proportion of the total variation in attrition is accounted for by a comprehensive set of substantive variables of the kind likely to be of interest in research on poverty and social exclusion The loss of respondents is greatest among those adults who did not complete a personal interview in the initial wave (indicating reluctant participation in the survey), and individuals who are geographically mobile. There are also smaller, but statistically significant, differences between countries in the tendency to lose individuals either from the top (the Southern countries and Ireland) or the bottom (the remaining countries) of the income distribution. Nevertheless, even in the absence of compensating attrition weights, attrition has only a minor impact on the estimates of two key social exclusion indicators: the poverty rate and the quintile income share ratio (S80/20). The results indicate that fears that attrition has undermined the representativeness of the ECHP samples in later waves of the survey are largely unfounded