Cytogenetics in the management of clonal chromosomal abnormalities of undetermined significance and persistent polyclonal B-cell lymphocytosis: Guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH).

Acquired clonal chromosomal abnormalities (CAs) are usually considered to be disease-related. However, when a CA of this type is the only abnormality present (and especially in small clones), the clinical significance is unclear. Here, we review the literature on recurrent CAs whose significance is regularly subject to debate. Our objective was to help with their interpretation and develop guidelines for sex chromosome loss, trisomy 15, trisomy 8, deletion 20q and other isolated non-myelodysplastic neoplasm (MDS)-defining CAs. We suggest that non-MDS-defining CAs correspond to clonal hematopoiesis of indeterminate potential (CHIP) in the absence of cytopenia and clonal cytopenia of undetermined significance (CCUS) in the presence of cytopenia. Lastly, we review the literature on persistent polyclonal binucleated B-cell lymphocytosis; although usually benign, this condition may correspond to a premalignant state.

Hospitalization and hospital mortality rates during the first and second waves of the COVID-19 pandemic in Quebec: interrupted time series and decomposition analysis.

OBJECTIVES: We investigated hospitalization and hospital mortality rates by cause during the first year of the COVID-19 pandemic in Quebec, Canada. STUDY DESIGN: Interrupted time series and decomposition analysis. METHODS: We analyzed hospital mortality during the first (February 25-August 22, 2020) and second waves (August 23, 2020-March 31, 2021), compared with 2019. We identified the cause of death and examined trends using: 1) interrupted time series analysis; 2) log-binomial regression; and 3) decomposition of cause-specific mortality. RESULTS: Hospitalization rates decreased; however, the proportion of deaths increased from 27.0 per 1000 in 2019 to 35.0 per 1000 in the first wave, for an excess of 8.0 deaths per 1000 admissions. COVID-19 was the cause of a third of excess deaths (2.6 per 1000). Other drivers of excess deaths included respiratory conditions (1.6 deaths per 1000), circulatory disorders (0.6 deaths per 1000), and cancer (0.9 deaths per 1000). COVID-19 was the cause of 58% of excess deaths in the second wave. Interrupted time series regression indicated that the proportion of deaths increased at the outset of the first wave but returned to prepandemic levels before increasing again in the second wave. Compared with 2019, the first wave was associated with 1.31 times (95% confidence interval [CI] 1.28-1.33) and the second wave with 1.17 times (95% CI 1.15-1.19) the risk of death during hospitalization. CONCLUSIONS: The pandemic was associated with a greater risk of hospital mortality. Excess deaths were driven by COVID-19 but also other causes, including respiratory conditions, circulatory disorders, and cancer.

Clinical utility of circulating tumor DNA sequencing with a large panel: a National Center for Precision Medicine (PRISM) study.

BACKGROUND: Circulating tumor DNA (ctDNA) sequencing is a promising approach for tailoring therapy in patients with cancer. We report hereby the results from a prospective study where we investigated the impact of comprehensive molecular profiling of ctDNA in patients with advanced solid tumors. PATIENTS AND METHODS: Genomic analysis was performed using the FoundationOne Liquid CDx Assay [324 genes, tumor mutational burden (TMB), microsatellite instability status]. Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB). Actionable targets were classified by ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) tier leading to molecular-based treatment suggestions wherever it was possible. RESULTS: Between December 2020 and November 2021, 1772 patients with metastatic solid tumors underwent molecular profiling. Median time to assay results was 12 days. Results were contributive for 1658 patients (94%). At least one actionable target was detected in 1059 patients (64%) with a total of 1825 actionable alterations including alteration of the DNA damage repair response pathway (n = 336, 18%), high TMB (>16 mutations/Mb; n = 243, 13%), PIK3CA mutations (n = 150, 8%), ERBB family pathway alterations (n = 127, 7%), PTEN alterations (n = 95, 5%), FGFR alterations (n = 67, 4%) and MET activations (n = 13, 0.7%). The MTB recommended a matched therapy for 597 patients (56%) with a total of 819 therapeutic orientations: clinical trials (n = 639, 78%), off-label/compassionate use (n = 81, 10%), approved drug (n = 51, 6%), and early access program (n = 48, 6%). In total, 122 patients (21%) were treated. Among the assessable patients (n = 107), 4 (4%) had complete response, 35 (33%) had partial response, 27 (25%) had stable disease, and 41 (38%) a progressive disease as best response. The median progression-free survival and median overall survival were 4.7 months (95% confidence interval 2.7-6.7 months) and 8.3 months (95% confidence interval 4.7-11.9 months) respectively. CONCLUSIONS: ctDNA sequencing with a large panel is an efficient approach to match patients with advanced cancer with targeted therapies.

Obstetric haemorrhage and risk of cardiovascular disease after three decades: a population-based cohort study.

OBJECTIVE: To investigate the association between obstetric haemorrhage and cardiovascular disease up to three decades after pregnancy. DESIGN: Population-based cohort study. SETTING AND POPULATION: All women who delivered between 1989 and 2016 in Quebec, Canada. METHODS: Using hospital admissions data, 1 224 975 women were followed from their first delivery until March 2018. The main exposure measures were antenatal (placenta praevia, placental abruption, peripartum haemorrhage) or postpartum haemorrhage, with or without transfusion. Adjusted Cox regression models were used to assess the association between obstetric haemorrhage and future cardiovascular disease. MAIN OUTCOME MEASURE: Cardiovascular hospitalisation. RESULTS: Among 104 291 (8.5%) women with haemorrhage, 4612 (4.4%) required transfusion. Women with haemorrhage had a higher incidence of cardiovascular hospitalisation than women without haemorrhage (15.5 versus 14.1 per 10 000 person-years; 2437 versus 28 432 events). Risk of cardiovascular hospitalisation was higher for obstetric haemorrhage, with or without transfusion, compared with no haemorrhage (adjusted hazard ratio [aHR] 1.06, 95% CI 1.02-1.10). Women with haemorrhage and transfusion had a substantially greater risk of cardiovascular hospitalisation (aHR 1.47, 95% CI 1.23-1.76). Among transfused women, placental abruption (aHR 1.79, 95% CI 1.06-3.00) and postpartum haemorrhage (aHR 1.38, 95% CI 1.13-1.68) were both associated with risk of cardiovascular hospitalisation. Antenatal haemorrhage with transfusion was associated with 2.46 times the risk of cardiovascular hospitalisation at 5 years (95% CI 1.59-3.80) and 2.14 times the risk at 10 years (95% CI 1.47-3.12). CONCLUSIONS: Obstetric haemorrhage requiring transfusion is associated with maternal cardiovascular disease. The benefit of cardiovascular risk prevention in pregnant women with obstetric haemorrhage requires further investigation. TWEETABLE ABSTRACT: Risk of future cardiovascular disease is increased for women with obstetric haemorrhage who require transfusion.

Prenatal Substance Use Disorders and Dental Caries in Children.

Substance use is common in women of reproductive age, but limited data exist on the dental health of their children, including risk of caries. We conducted a longitudinal cohort study of 790,758 infants born between 2006 and 2016 in Quebec, Canada. We identified women with substance use disorders before or during pregnancy. The main outcome measure was hospitalization for dental caries in offspring up to 12 y after birth. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of maternal substance use with pediatric dental caries, adjusted for potential confounders. Children exposed to maternal substance use had a higher incidence of hospitalization for dental caries than unexposed children (105.2 vs. 27.0 per 10,000 person-years). Maternal substance use was associated with 1.96 times the risk of childhood dental caries (95% CI, 1.80-2.14), including a greater risk of caries of enamel, dentin, or cementum (HR, 2.00; 95% CI, 1.82-2.19) and dental pulp (HR, 2.36; 95% CI, 2.07-2.70), relative to no substance use. Associations were elevated for alcohol (HR, 2.31; 95% CI, 2.03-2.64) but were also present for cocaine, cannabis, opioids, and other substances. Substance use during pregnancy was more strongly associated with dental caries hospitalization than prepregnancy substance use. Associations were stronger in early childhood. Maternal substance use is associated with the future risk of dental caries hospitalization in children. Targeting substance use early in the lives of women may contribute to dental caries prevention in offspring.

Use of 5-azacitidine for therapy-related myeloid neoplasms in patients with concomitant active neoplastic disease.

BACKGROUND: Patients diagnosed with therapy-related myeloid neoplasms (TRMN) with concomitant active neoplastic disorder (CAND) are usually proposed for best supportive care (BSC). We evaluated the feasibility of using 5-azacytidine (AZA) in this setting. METHODS: All patients referred to Gustave Roussy between 2010 and 2015 for TRMN diagnosis (less than 30% blast) and eligible for AZA treatment were included. Patients with CAND proposed for BSC were also described. Patient's outcomes were analyzed based on the presence or not of a CAND. RESULTS: Fifty-two patients with TRMN were analyzed, including 19 patients with CAND (14 eligible for AZA) and 33 without CAND eligible for AZA. The 5 patients with CAND ineligible for AZA had a worst performance status (p=0.016) at diagnosis and a shorter overall survival (OS) (0.62 months). Baseline characteristics of patients eligible for AZA were similar in the 2 groups except a trend for best performance status in patients with CAND (p=0.06). Overall response rate (71.4% vs 60.3%), transfusion independence (50.0% vs 45.5%) and OS (12.7 months vs 10.8 months) were similar between patients with and without CAND respectively (p=ns). CONCLUSION: Here we report the feasibility and efficacy of AZA for selected patients with TRMN and a CAND.

Pre-eclampsia and risk of infantile haemangioma.

BACKGROUND: Infantile haemangioma is the most common tumour of infancy, but the association with pre-eclampsia is poorly understood. OBJECTIVES: We determined the relationship between variants of pre-eclampsia and risk of infantile haemangioma. METHODS: We carried out a retrospective cohort study of hospital data for all live births between 1989 and 2013 in Quebec, Canada. We identified 14 240 neonates with, and 1 930 564 without haemangioma before discharge, and determined whether early- or late-onset pre-eclampsia was documented on the maternal chart. We used log-binomial regression to compute prevalence ratios (PRs) and 95% confidence intervals (CIs) for the association between pre-eclampsia and infantile haemangioma, adjusted for maternal characteristics. RESULTS: The prevalence of any haemangioma was higher for pre-eclampsia than for no pre-eclampsia (81·3 vs. 72·9 per 10 000), with a PR of 1·15 (95% CI 1·06-1·25) after adjustment for maternal characteristics. Pre-eclampsia with onset before 34 weeks' gestation was associated with cutaneous (PR 2·32, 95% CI 1·68-3·21), noncutaneous (PR 3·66, 95% CI 2·49-5·37) and unspecified haemangioma (PR 2·49, 95% CI 1·77-3·49). However, the association between early-onset pre-eclampsia and haemangioma was attenuated once long neonatal length of hospital stays was accounted for. There was no association with late-onset pre-eclampsia after 34 weeks, and associations were weaker for other variants including severe pre-eclampsia and pre-eclampsia with low birthweight. CONCLUSIONS: Early-onset pre-eclampsia is associated with increased risk of haemangioma at birth, but detection bias due to longer hospital stays and closer follow-up may be part of the reason.

Language and infant mortality in a large Canadian province.

OBJECTIVES: Infant mortality in minority populations of Canada is poorly understood, despite evidence of ethnic inequality in other countries. We studied infant mortality in different linguistic groups of Quebec, and assessed how language and deprivation impacted rates over time. STUDY DESIGN: Population-level study of vital statistics data for 1,985,287 live births and 10,283 infant deaths reported in Quebec from 1989 through 2012. METHODS: We computed infant mortality rates for French, English, and foreign languages according to level of material deprivation. Using Kitagawa's method, we evaluated the impact of changes in mortality rates, and population distribution of language groups, on infant mortality in the province. RESULTS: Infant mortality declined from 6.05 to 4.61 per 1000 between 1989-1994 and 2007-2012. Most of the decline was driven by Francophones who contributed 1.39 fewer deaths per 1000 births over time, and Anglophones of wealthy and middle socio-economic status who contributed 0.13 fewer deaths per 1000 births. The foreign language population and poor Anglophones contributed more births over time, including 0.08 and 0.02 more deaths per 1000 births, respectively. Mortality decreased for Francophones and Anglophones in each level of deprivation. Rates were lower for foreign languages, but increased over time, especially for the poor. CONCLUSIONS: Infant mortality rates decreased for Francophones and Anglophones in Quebec, but increased for foreign languages. Poor Anglophones and individuals of foreign languages contributed more births over time, and slowed the decrease in infant mortality. Language may be useful for identifying inequality in infant mortality in multicultural nations.

Dangers of death on the first day of life by the minute.

OBJECTIVE: To evaluate mortality on the first day of life by minute and hour, and examine changes in major causes of death in the past three decades. STUDY DESIGN: We evaluated mortality on the first day of life by the hour (0, 1, …, 23 h), and in the first hour by 5-min block (0-4, 5-9, …, 55-59 min) using data on cause of death for 15,690 infants in Canada from 1981 to 2012. RESULTS: Infant mortality on the first day declined from 2.60 per 1000 in the 1980s to 1.26 in the 2000s. The decline was greater at 6-23 h than at 0-5 h of life, and among infants with congenital anomalies compared with prematurity and birth asphyxia. CONCLUSION: Infant mortality is highest on the first day of life. More focus on prematurity and birth asphyxia in the first 5 h of life is needed to improve infant mortality.

EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients.

BACKGROUND: AZD9291 is an oral, irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI), which specifically targets both sensitizing and resistant T790M mutations. This compound has shown outstanding activity, in a phase I/II (AURA) trial. However, despite impressive tumor responses in T790M-positive patients, acquired resistance to this drug limits the benefit of this compound. Mutations at the EGFR C797 codon, located within the kinase-binding site, were very recently reported to be a potential mechanism of resistance to AZD9291 in T790M-positive patients. PATIENTS AND METHODS: To identify potential mechanisms of resistance to AZD9291, we report here on two patients with resistant biopsy specimens that had been treated with AZD9291. RESULTS: We identified in two distinct cases, HER2 and MET amplification by FISH and CGH as a potential mechanism of acquired resistance to third-generation EGFR-TKI. Interestingly, this event occurred with complete loss of the T790M mutation. In one case, we observed a different molecular status at two biopsy sites (the T790M mutation at the primary site and wild-type T790M at the metastatic site with different pathways of acquired resistance to AZD9291). CONCLUSION: Our observations suggest that T790M-positive and wild-type T790M clones may coexist at baseline. AZD9291 efficiently suppresses the growth of T790M-positive cells, but a population of wild-type T790M cells at baseline will mediate the development of resistance, here via a by-pass pathway activating either HER2 or MET.

High level of chromosomal instability in circulating tumor cells of ROS1-rearranged non-small-cell lung cancer.

BACKGROUND: Genetic aberrations affecting the c-ros oncogene 1 (ROS1) tyrosine kinase gene have been reported in a small subset of patients with non-small-cell lung cancer (NSCLC). We evaluated whether ROS1-chromosomal rearrangements could be detected in circulating tumor cells (CTCs) and examined tumor heterogeneity of CTCs and tumor biopsies in ROS1-rearranged NSCLC patients. PATIENTS AND METHODS: Using isolation by size of epithelial tumor cells (ISET) filtration and filter-adapted-fluorescence in situ hybridization (FA-FISH), ROS1 rearrangement was examined in CTCs from four ROS1-rearranged patients treated with the ROS1-inhibitor, crizotinib, and four ROS1-negative patients. ROS1-gene alterations observed in CTCs at baseline from ROS1-rearranged patients were compared with those present in tumor biopsies and in CTCs during crizotinib treatment. Numerical chromosomal instability (CIN) of CTCs was assessed by DNA content quantification and chromosome enumeration. RESULTS: ROS1 rearrangement was detected in the CTCs of all four patients with ROS1 rearrangement previously confirmed by tumor biopsy. In ROS1-rearranged patients, median number of ROS1-rearranged CTCs at baseline was 34.5 per 3 ml blood (range, 24-55). In ROS1-negative patients, median background hybridization of ROS1-rearranged CTCs was 7.5 per 3 ml blood (range, 7-11). Tumor heterogeneity, assessed by ROS1 copy number, was significantly higher in baseline CTCs compared with paired tumor biopsies in the three patients experiencing PR or SD (P < 0.0001). Copy number in ROS1-rearranged CTCs increased significantly in two patients who progressed during crizotinib treatment (P < 0.02). CTCs from ROS1-rearranged patients had a high DNA content and gain of chromosomes, indicating high levels of aneuploidy and numerical CIN. CONCLUSION: We provide the first proof-of-concept that CTCs can be used for noninvasive and sensitive detection of ROS1 rearrangement in NSCLC patients. CTCs from ROS1-rearranged patients show considerable heterogeneity of ROS1-gene abnormalities and elevated numerical CIN, a potential mechanism to escape ROS1-inhibitor therapy in ROS1-rearranged NSCLC tumors.

Segmental chromosomal alterations lead to a higher risk of relapse in infants with MYCN-non-amplified localised unresectable/disseminated neuroblastoma (a SIOPEN collaborative study).

BACKGROUND: In neuroblastoma (NB), the presence of segmental chromosome alterations (SCAs) is associated with a higher risk of relapse. METHODS: In order to analyse the role of SCAs in infants with localised unresectable/disseminated NB without MYCN amplification, we have performed an array CGH analysis of tumours from infants enrolled in the prospective European INES trials. RESULTS: Tumour samples from 218 out of 300 enroled patients could be analysed. Segmental chromosome alterations were observed in 11%, 20% and 59% of infants enroled in trials INES99.1 (localised unresectable NB), INES99.2 (stage 4s) and INES99.3 (stage 4) (P<0.0001). Progression-free survival was poorer in patients whose tumours harboured SCA, in the whole population and in trials INES99.1 and INES99.2, in the absence of clinical symptoms (log-rank test, P=0.0001, P=0.04 and P=0.0003, respectively). In multivariate analysis, a SCA genomic profile was the strongest predictor of poorer progression-free survival. CONCLUSION: In infants with stage 4s MYCN-non-amplified NB, a SCA genomic profile identifies patients who will require upfront treatment even in the absence of other clinical indication for therapy, whereas in infants with localised unresectable NB, a genomic profile characterised by the absence of SCA identifies patients in whom treatment reduction might be possible. These findings will be implemented in a future international trial.

Socio-economic inequalities in suicide attempts and suicide mortality in Québec, Canada, 1990-2005.

OBJECTIVES: Little research has evaluated changes in the association between area deprivation and suicidal behaviour over time. This study investigated patterns in suicide attempts and suicide mortality according to material deprivation in the province of Québec, Canada between 1990 and 2005. STUDY DESIGN: Ecological analysis. METHODS: Data on suicide attempts were extracted from the hospital discharge summary database (n=47,516) and data on suicides were extracted from the Québec death file (n=20,851). Gender- and age-specific (10-24, 25-44, 45-64 and > or = 65 years) suicide attempt and mortality rates were calculated for four time periods (1990-1993, 1994-1997, 1998-2001 and 2002-2005) for the entire Québec population aged 10 years and older residing in 162 communities ranked by decile of material deprivation. Absolute and relative measures of inequality were calculated to summarize differences between the most and least materially deprived areas. Commonly used methods of suicidal behaviour were examined. RESULTS: Differentials in suicide attempt hospitalization between the most and least deprived areas were present for all age groups, and these decreased slightly among males and increased among females over time. Inequalities in suicide attempts were greatest among young adults (age 25-44 years) for both genders, and were smallest among the elderly (> or = 65 years). For suicide mortality, differentials increased among females but not males; these differentials were greatest among males and 25-44 year olds, and smallest among the elderly. Differentials in commonly used methods were evident for poisoning hospitalizations in both genders and for hanging deaths among males. CONCLUSIONS: In Québec, differences in suicide attempts and mortality between the most and least materially deprived areas persisted or even increased over time. Inequalities were more pronounced for suicide attempts than for suicide mortality, and were greatest among adults of working age. Strategies to reduce socio-economic differences in suicidal behaviour may be important.

Community-level income inequality and mortality in Québec, Canada.

OBJECTIVES: Evidence of the association between income inequality and mortality for small rather than large areas is conflicting. This study evaluated community-level income inequality in relation to age- and cause-specific mortality. STUDY DESIGN: Ecological analysis. METHODS: Mortality data were extracted from the Québec, Canada registry for 1999-2003. For Québec communities (n=143), directly standardized mortality rates were calculated for all-cause (overall, working-age and post-working-age), suicide, alcohol, tobacco and cardiovascular mortality. Using 2001 Canada Census data, the tertiles of income inequality measured as the decile ratio, coefficient of variation and median share were calculated. The relative risk (RR) of death was determined using Poisson regression, accounting for median community income, family structure and rural-urban area. RESULTS: Income inequality was most strongly associated with alcohol-related mortality (RR(CoefficientVariation) 0.85, 95% confidence interval 0.77-0.94), followed by statistically significant but weaker inverse associations with tobacco-related and age-specific all-cause mortality. CONCLUSIONS: Income inequality in Québec communities is inversely associated with mortality outcomes, particularly alcohol-related mortality. These associations contrast with positive or null associations observed in studies of larger US and Canadian metropolitan areas, respectively. Community-level studies accounting for individual-level covariates are necessary to clarify the relationship between income inequality and mortality.

Neighbourhood socioeconomic status, maternal education and adverse birth outcomes among mothers living near highways.

BACKGROUND: Residential proximity to highways is a potential proxy for exposure to traffic-related pollution that has been linked to adverse birth outcomes. We evaluated whether proximity to highway interacts with individual and neighbourhood socioeconomic status (SES) to influence birth outcomes. METHODS: The study population consisted of all live singleton births in Montréal, Canada, from 1997 to 2001 (n = 99,819). Proximity was defined as residing within 200 m of a highway. Neighbourhood SES was measured for census tracts as the proportion of families below the low-income threshold. Individual SES was represented by maternal education. Using multilevel logistic regression, the odds of preterm birth (PTB), low birthweight (LBW) and small-for-gestational-age (SGA) birth were calculated for mothers residing in proximity to highways, accounting for individual and neighbourhood SES. Effect modification between SES and proximity to highway was tested for each outcome. RESULTS: In wealthy neighbourhoods, proximity to highway was associated with an elevated odds of PTB (OR 1.58, 95% CI 1.23 to 2.04), LBW (OR 1.81, 95% CI 1.36 to 2.41) and SGA birth (OR 1.32, 95% CI 1.05 to 1.66). For highly educated mothers, proximity to highway was associated with PTB (OR 1.25, 95% CI 1.07 to 1.46) and LBW (OR 1.24, 95% CI 1.03 to 1.49), but the association was borderline for SGA birth (OR 1.15, 95% CI 1.00 to 1.32). Proximity to highway was not associated with birth outcomes in other maternal and neighbourhood SES categories. CONCLUSION: Counterintuitively, high SES mothers may be more likely than low SES mothers to experience adverse births associated with residential proximity to highway.

Do mother's education and foreign born status interact to influence birth outcomes? Clarifying the epidemiological paradox and the healthy migrant effect.

INTRODUCTION: The unresolved "epidemiological paradox" concerns the association between low socioeconomic status and unexpectedly favourable birth outcomes in foreign born mothers. The "healthy migrant" effect concerns the association between foreign born status per se and birth outcomes. The epidemiological paradox and healthy migrant effect were analysed for newborns in a favourable sociopolitical environment. METHODS: 98,330 live births to mothers in Montreal, Canada from 1997 to 2001 were analysed. Mothers were categorised as foreign born versus Canadian born. Outcomes were: small for gestational age (SGA) birth; low birth weight (LBW) and preterm birth (PTB). Multilevel logistic regression was used to examine the interaction between maternal education and foreign born status, adjusting for covariates. RESULTS: Not having a high school diploma was associated with LBW in Canadian (odds ratio (OR) 3.20; 95% CI 2.61 to 3.91) but not foreign born (OR 1.14; 95% CI 0.99 to 2.10) mothers and was more strongly associated with SGA birth in Canadian (OR 2.03; 95% CI 1.84 to 2.22) than in foreign born (OR 1.26; 95% CI 1.07 to 1.49) mothers. Foreign born status was associated with SGA birth (OR 1.37; 95% CI 1.28 to 1.47), LBW (OR 1.51; 95% CI 1.27 to 1.79) and PTB (OR 1.12; 95% CI 1.03 to 1.22) in university-educated mothers only. CONCLUSIONS: The epidemiological paradox associated with low educational attainment was present for SGA birth and LBW but not PTB. Foreign born status was associated with adverse birth outcomes in university-educated mothers, the opposite of the healthy migrant effect.

Polymorphism in Sp1 recognition site of the EGF receptor gene promoter and risk of glioblastoma.

We investigated two polymorphisms of the epidermal growth factor receptor promoter as potential risk factors and prognostic markers for glioblastoma. The -216T allele (which results in a 30% higher activity) was more frequent in the patients compared with the control population (224/376 = 59.6% vs 165/352 = 46.8%; p = 0.0006) corresponding to an odd ratio of 1.67 (1.24; 2.25). A modest difference in median survival was also associated with the TT genotype.

Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia.

Imatinib mesylate (Gleevec), an inhibitor of the BCR-ABL tyrosine kinase, was introduced recently into the therapy of chronic myeloid leukemia (CML). Several cases of emergence of clonal chromosomal abnormalities after therapy with imatinib have been reported, but their incidence, etiology and prognosis remain to be clarified. We report here a large series of 34 CML patients treated with imatinib who developed Philadelphia (Ph)-negative clones. Among 1001 patients with Ph-positive CML treated with imatinib, 34 (3.4%) developed clonal chromosomal abnormalities in Ph-negative cells. Three patients were treated with imatinib up-front. The most common cytogenetic abnormalities were trisomy 8 and monosomy 7 in twelve and seven patients, respectively. In 15 patients, fluorescent in situ hybridization with specific probes was performed in materials archived before the initiation of imatinib. The Ph-negative clone was related to previous therapy in three patients, and represented a minor pre-existing clone that expanded after the eradication of Ph-positive cells with imatinib in two others. However, in 11 patients, the new clonal chromosomal abnormalities were not detected and imatinib may have had a direct effect. No myelodysplasia was found in our cohort. With a median follow-up of 24 months, one patient showed CML acceleration and two relapsed.