EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy.

The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

A Need for a Novel Survival Risk Scoring System for Intensive Care Admissions Due to Sepsis in Pediatric Hematology/Oncology Patients.

Background: Children with hemato-oncological diseases or following stem cell transplantation (SCT) are at high risk for life-threatening infections; sepsis in this population constitutes a substantial proportion of pediatric intensive care unit (PICU) admissions. The current pediatric prognostic scoring tools to evaluate illness severity and mortality risk are designed for the general pediatric population and may not be adequate for this vulnerable subpopulation. Methods: Retrospective analysis was performed on all PICU admissions for sepsis in children with hemato-oncological diseases or post-SCT, in a single tertiary pediatric hospital between 2008 and 2021 (n = 233). We collected and analyzed demographic, clinical, and laboratory data and outcomes for all patients, and evaluated the accuracy of two major prognostic scoring tools, the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) and the Pediatric Risk of Mortality III (PRISM III). Furthermore, we created a new risk-assessment model that contains additional parameters uniquely relevant to this population. Results: The survival rate for the cohort was 83%. The predictive accuracies of PELOD-2 and PRISM III, as determined by the area under the curve (AUC), were 83% and 78%, respectively. Nine new parameters were identified as clinically significant: age, SCT, viral infection, fungal infection, central venous line removal, vasoactive inotropic score, bilirubin level, C-reactive protein level, and prolonged neutropenia. Unique scoring systems were established by the integration of these new parameters into the algorithm; the new systems significantly improved their predictive accuracy to 91% (p = 0.01) and 89% (p < 0.001), respectively. Conclusions: The predictive accuracies (AUC) of the PELOD-2 and PRISM III scores are limited in children with hemato-oncological diseases admitted to PICU with sepsis. These results highlight the need to develop a risk-assessment tool adjusted to this special population. Such new scoring should represent their unique characteristics including their degree of immunosuppression and be validated in a large multi-center prospective study.

Elevated intraocular pressure in children with acute lymphoblastic leukaemia: A prospective study.

Most childhood acute lymphoblastic leukaemia (ALL) protocols include high-dose steroid therapy. However, the known potential of high-dose steroids to significantly elevate intraocular pressure (IOP) and lead to glaucomatous optic neuropathy has not been intensively investigated in children with ALL. Moreover, as children with ALL do not routinely undergo IOP measurements, the need for IOP monitoring and therapy is unknown. We prospectively measured IOP in 90 children with newly diagnosed ALL attending a tertiary paediatric haematology/oncology centre, at diagnosis and at the middle and end of induction therapy. Ocular hypertension (IOP > 21 mm Hg) at any time point was documented in 64 children (71%), and the prevalence increased during induction. Thirty-six children (40%) had elevated IOP at ALL diagnosis before therapy initiation, and stratification to non-standard ALL was a risk factor. IOP reduction therapy was administered to 13 children (14%); none required surgery. Values normalised in all cases. On multivariate logistic regression analysis, dexamethasone therapy was a significant risk factor for ocular hypertension. High body mass index was an additional risk factor in children with elevated IOP at ALL diagnosis. Routine evaluation of IOP during steroid therapy is very important in children with ALL to ensure early intervention which may prevent permanent ocular damage.

Mother-level random effect in the association between PM2.5 and fetal growth: A population-based pregnancy cohort.

BACKGROUND: A growing body of literature reports associations between exposure to particulate matter with diameter ≤2.5 µm (PM2.5) during pregnancy and birth outcomes. However, findings are inconsistent across studies. OBJECTIVES: To assess the association between PM2.5 and birth outcomes of fetal growth in a cohort with high prevalence of siblings by multilevel models accounting for geographical- and mother-level correlations. METHODS: In Israel, we used Maccabi Healthcare Services data to establish a population-based cohort of 381,265 singleton births reaching 24-42 weeks' gestation and birth weight of 500-5000 g (2004-2015). Daily PM2.5 predictions from a satellite-based spatiotemporal model were linked to the date of birth and maternal residence. We generated mean PM2.5 values for the entire pregnancy and for exposure periods during pregnancy. Associations between exposure and birth outcomes were modeled by using multilevel logistic regression with random effects for maternal locality of residence, administrative census area (ACA) and mother. RESULTS: In fully adjusted models with a mother-level random intercept only, a 10-µg/m3 increase in PM2.5 over the entire pregnancy was positively associated with term low birth weight (TLBW) (Odds ratio, OR = 1.25, 95% confidence interval, CI: 1.09,1.43) and small for gestational age (SGA) (OR = 1.15, 95% CI: 1.06,1.26). Locality- and ACA-level effects accounted for <0.4% of the variance while mother-level effects explained ∼50% of the variability. Associations varied by exposure period, infants' sex, birth order, and maternal pre-pregnancy BMI. CONCLUSIONS: Consideration of mother-level variability in a region with high fertility rates provides new insights on the strength of associations between PM2.5 and birth outcomes.

Mucormycosis in children with haematological malignancies is a salvageable disease: a report from the Israeli Study Group of Childhood Leukemia.

Mucormycosis has emerged as an increasingly important cause of morbidity and mortality in immunocompromised patients, but contemporary data in children are lacking. We conducted a nationwide multicentre study to investigate the characteristics of mucormycosis in children with haematological malignancies. The cohort included 39 children with mucormycosis: 25 of 1136 children (incidence 2·2%) with acute leukaemias prospectively enrolled in a centralized clinical registry in 2004-2017, and an additional 14 children with haematological malignancies identified by retrospective search of the databases of seven paediatric haematology centres. Ninety-two percent of mucormycosis cases occurred in patients with acute leukaemias. Mucormycosis was significantly associated with high-risk acute lymphoblastic leukaemia (OR 3·75; 95% CI 1·51-9·37; P = 0·004) and with increasing age (OR 3·58; 95% CI 1·24-9·77; P = 0·01). Fifteen patients (38%) died of mucormycosis. Rhinocerebral pattern was independently associated with improved 12-week survival (OR 9·43; 95% CI 1·47-60·66; P = 0·02) and relapsed underlying malignancy was associated with increased 12-week mortality (OR 6·42; 95% CI, 1·01-40·94; P = 0·05). In patients receiving frontline therapy for their malignancy (n = 24), one-year cumulative mucormycosis-related mortality was 21 ± 8% and five-year overall survival was 70 ± 8%. This largest paediatric population-based study of mucormycosis demonstrates that children receiving frontline therapy for their haematological malignancy are often salvageable.

Poorer outcome of childhood acute lymphoblastic leukemia in the Bedouin population: A report from the Berlin-Frankfurt-Muenster-based Israeli national protocols.

BACKGROUND: Therapy outcomes for childhood acute lymphoblastic leukemia (ALL) had substantially improved in the last decades, but variability across racial and ethnic groups was identified in some clinical studies. In this study, we aimed to investigate whether such a difference in outcome is found in the diverse ethnicities in Israel as well. METHODS: A retrospective study was conducted among 1154 patients (855 Jews, 195 Muslims, 52 Bedouins, 26 Druze, and 26 others) aged 1 to 21 years, who were diagnosed with ALL between 1989 and 2011 and were treated according to the same Berlin-Frankfurt-Muenster-based Israel National Study protocols. RESULTS: Bedouins had a higher incidence of t(1;19) (16% vs 3% for non-Bedouins) and a lower incidence of high-hyperdiploidy (10% vs 25% for non-Bedouins) (P = 0.01). Five-year event-free survival (EFS) and overall survival (OS) were poorer for the Bedouins (60.3% ± 7.2% and 63.1% ± 7.2%, respectively) compared with the Jews, Muslims, and Druze (80.4% ± 1.4%, 77.3% ± 3.2%, and 84% ± 7.3%, respectively, for EFS [P = 0.02], and 86.3% ± 1.2%, 82.3% ± 2.9%, and 88.3% ± 6.4%, respectively, for OS [P = 0.002]). Adherence to intensive chemotherapy was similar between the Muslims and the Bedouins. CONCLUSIONS: Our findings suggest that the Bedouins, a highly inbred ethnic Arab people, may be considered a higher risk group that may need more intensive chemotherapy and/or supportive care in order to improve their outcome.

Thrombophilia screening and thromboprophylaxis may benefit specific ethnic subgroups with paediatric acute lymphoblastic leukaemia.

This study investigated the prevalence of inherited thrombophilia, risk of venous thromboembolism (VTE) and benefit of low molecular weight heparin prophylaxis in 476 Israeli children with acute lymphoblastic leukaemia (ALL) treated between 2004 and 2016. Thrombophilia was found in 15·5%. Arab children had a higher prevalence of F5 R506Q (factor V Leiden) than Jewish children (19·4% vs. 2·9%, P < 0·01). Patients with thrombophilia had higher VTE rates VTE (26·5% vs. 5·6%, P < 0·001). None of the thrombophilic children given prophylaxis had severe VTE. Routine evaluation for inherited thrombophilia followed by thromboprophylaxis when findings are positive may benefit at-risk patients with ALL.

Traffic-related Air Pollution and Pregnancy Loss.

BACKGROUND: Traffic-related air pollution has been linked to multiple adverse pregnancy outcomes. However, few studies have examined pregnancy loss, targeting losses identified by hospital records, a large limitation as it does not capture events not reported to the medical system. METHODS: We used a novel variation of the time-series design to determine the association, and identify the critical window of vulnerability, between week-to-week traffic-related air pollution and conceptions resulting in live births, using nitrogen dioxide (NO2) as a traffic emissions tracer. We used information from all live births recorded at Beth Israel Deaconess Medical Center in Boston, MA (2000-2013) and all live births in Tel Aviv District, Israel (2010-2013). RESULTS: In Boston (68,969 live births), the strongest association was during the 15th week of gestation; for every 10 ppb of NO2 increase during that week, we observed a lower rate of live births (rate ratio [RR] = 0.87; 95% confidence interval [CI], 0.78, 0.97), using live birth-identified conceptions to infer pregnancy losses. In the Tel Aviv District (95,053 live births), the strongest estimate was during the 16th gestational week gestation (RR = 0.82; 95% CI, 0.76, 0.90 per 10 ppb of NO2). CONCLUSIONS: Using weekly conceptions ending in live birth rather than identified pregnancy losses, we comprehensively analyzed the relationship between air pollution and all pregnancy loss throughout gestation. The observed results, with remarkable similarity in two independent locations, suggest that higher traffic-related air pollution levels are associated with pregnancy loss, with strongest estimates between the 10th and 20th gestational weeks.

Blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric B-cell precursor acute lymphoblastic leukemia: Report from the Israeli Study Group of Childhood Leukemia.

Tremendous progress in the therapy of pediatric acute lymphoblastic leukemia (ALL) has been achieved through combination cytotoxic chemotherapy, leading to high cure rates, at the cost of significant life-threatening toxicity. The bispecific T-cell engager blinatumomab, recently approved for relapsed/refractory ALL, has a unique nonmyelotoxic toxicity profile. As blinatumomab causes B-cell depletion, the safety of its use during severe chemotherapy-induced toxicity is unclear. We report 11 pediatric patients with ALL, treated with blinatumomab following overwhelming chemotherapy-associated toxicity, with recovery of all patients and successful bridging to further antileukemia therapy. Blinatumomab can be considered for rare patients who cannot tolerate cytotoxic therapy.

Meta-analysis of fine particulate matter exposure during pregnancy and birth weight: Exploring sources of heterogeneity.

BACKGROUND: Several meta-analyses assessed the relationship between exposure to PM with aerodynamic diameter ≤ 2.5 µm (PM2.5) during pregnancy and birth weight (BW), but results were inconsistent and substantial unexplained heterogeneity was reported. We aimed to investigate the above association and to explore sources of heterogeneity across studies. METHODS: We systematically reviewed the current worldwide evidence examining the association between PM2.5 and BW. The review protocol was registered on the PROSPERO website (CRD42020188996) and followed PRISMA guidelines. We extracted association measures for BW and low birth weight (LBW, BW < 2500 g) from each study to evaluate pooled summary measures and to explore sources of between-study heterogeneity. FINDINGS: Of the 2677 articles identified, 84 met the inclusion criteria (~42 M births). Our random effects meta-analyses revealed substantial heterogeneity among included studies (I2 = 98.4 % and I2 = 77.7 %, for BW and LBW respectively). For LBW, the heterogeneity decreased (I2 = 59.7 %) after excluding four outlying studies, with a pooled odds ratio 1.07 (95 % confidence interval, CI: 1.05, 1.09) per a 10-µg/m3 increase in mean PM2.5 exposure over the entire pregnancy. Further subgroup analysis revealed geographic heterogeneity with higher association in Europe (1.34, (1.16, 1.55)) compared to Asia (1.06, (1.03, 1.10)) and US (1.07, (1.04, 1.10)). CONCLUSION: The association between PM2.5 and birth weight varied depending on several factors. The sources of heterogeneity between studies included modifiers such as study region and period. Hence, it is advisable not to pool summary measures of PM2.5-BW associations and that policy would be informed by local evidence.

Association between ambient particulate matter and preterm birth stratified by temperature: A population-based pregnancy cohort study.

A growing body of literature reports associations between exposure to particulate matter with aerodynamic diameters ≤2.5 µm (PM2.5) and 2.5-10 µm (PM10-2.5) during pregnancy and preterm birth (PTB). However, the role of ambient temperature in PM-PTB associations was rarely investigated. In Israel, we used Maccabi Healthcare Services data to establish a population-based cohort of 381,265 singleton births reaching 24-42 weeks' gestation and birth weight of 500-5000 g (2004-2015). Daily PM and ambient temperature predictions from a satellite-based spatiotemporal model, at a 1 × 1 km spatial resolution, were linked to the date of birth and maternal residence. Mixed effects Cox regression models, adjusted for covariates, with a random intercept at the mother level were used to assess associations between mean exposure during pregnancy and PTB. We found that exposure to PM2.5 was positively associated with PTB when the average exposure during pregnancy was either low (first quintile) or high (fifth quintile), compared to exposure in the 2nd-4th quintiles, with hazard ratios (HRs) 1.18 (95% confidence interval [CI], 1.13-1.24) and 1.07 (95% CI, 1.02-1.12), respectively. The results revealed effect modification of temperature. For mothers exposed to low (below median) average temperature during pregnancy, HRs of PTB were 0.93 (95% CI, 0.87-1.00) and 1.21 (95% CI, 1.14-1.29) for the first and fifth PM2.5 quintiles, respectively, when compared to the 2nd-4th quintiles. However, a reverse trend was indicated for high-temperature pregnancies, where the corresponding HRs were 1.48 (95% CI, 1.39-1.58) and 0.92, (95% CI, 0.96-0.98). In conclusion, consideration of climatic factors can provide new insights into the risk of PTB as a result of exposure to PM2.5 during pregnancy.

Maternal exposure to particulate matter early in pregnancy and congenital anomalies in offspring: Analysis of concentration-response relationships in a population-based cohort with follow-up throughout childhood.

Studies have suggested an association between particulate matter (PM) air pollution and certain congenital anomalies (CAs). However, most studies assumed a linear concentration-response relation and were based on anomalies that were ascertained at birth or up to 1 year of age. We investigated associations between exposures to PM during the first trimester of pregnancy and CAs in 9 organ systems using birth and childhood follow-up data from a leading health care provider in Israel. We conducted a retrospective population-based cohort study among 396,334 births, 2004-2015. Daily PM data at a 1 × 1 km spatial grid were obtained from a satellite-derived prediction models and were linked to the mothers' residential addresses at birth. Adjusted odds ratios (ORs) were estimated with logistic regression models using exposure levels as either continuous or categorical variables. We captured 57,638 isolated CAs with estimated prevalence of 96 and 136 anomalies per 1000 births in the first year of life and by age 6 years, respectively. Analysis of continuous PM with diameter < 2.5 µm (PM2.5) indicated a supra-linear relation with anomalies in the circulatory, respiratory, digestive, genital and integument systems (79 % of CAs). The slope of the concentration-response function was positive and steepest for PM2.5 lower than the median concentration (21.5 µg/m3) and had a less steep or negative slope at higher levels. Similar trends were observed for PM2.5 quartiles. For example, for cardiac anomalies, the ORs were 1.09 (95 % confidence interval: 1.02, 1.15), 1.04 (0.98, 1.10) and 1.00 (0.94, 1.07) for births in the second, third and fourth quartiles, respectively, when compared to the first quartile. In sum, this study adds new evidence for adverse effects of air pollution on neonatal health even with low-level air pollution. Information on late diagnosis of children with anomalies is important in evaluating the burden of disease.

The regression-based discrepancy definition of learning disability: a critical appraisal.

The regression-based discrepancy definition of learning disabilities has been suggested by Rutter and Yule as an improvement of the well-known and much criticized achievement-intelligence discrepancy definition, whereby the examinee's predicted reading attainment is substituted for the intelligence score in the discrepancy expression. Even though the regression-based discrepancy definition has been with us for more than 30 years, critical examination of this approach is scarce. This article fills this lacuna by examining the implications of two variables in the model on the diagnosis of learning disabilities: (a) the effect of predictive validity on the proportion of examinees identified as learning disabled, and (b) the effect of the predictor's identity on the identity of the examinees diagnosed with learning disabilities. Implications of these effects concerning the validity of the regression-based discrepancy model and of the results of its implementation are discussed.

Invasive Fusariosis in Pediatric Hematology/Oncology and Stem Cell Transplant Patients: A Report from the Israeli Society of Pediatric Hematology-Oncology.

Invasive Fusarium species infections in immunocompromised patients occur predominantly in those with hematological malignancies. Survival rates of 20−40% were reported in adults, but data in children are limited. Our retrospective, nationwide multicenter study of invasive fusariosis in pediatric hematology/oncology and stem cell transplant (SCT) patients identified twenty-two cases. Underlying conditions included hematological malignancies (n = 16; 73%), solid tumors (n = 2), and non-malignant hematological conditions (n = 4). Nineteen patients (86%) were neutropenic, nine (41%) were SCT recipients, and seven (32%) received corticosteroids. Sixteen patients (73%) had disseminated fusariosis, five had local infection, and one had isolated fungemia. Fifteen patients (68%) had skin involvement and eight (36%) had a bloodstream infection. Four patients (18%) presented with osteoarticular involvement and four with pulmonary involvement. Nineteen patients (86%) received combination antifungal therapy upfront and three (14%) received single-agent treatment. Ninety-day probability of survival was 77%: four of the five deaths were attributed to fusariosis, all in patients with relapsed/refractory acute leukemias. Ninety-day probability of survival for patients with relapsed/refractory underlying malignancy was 33% vs. 94% in others (p < 0.001). Survival rates in this largest pediatric population-based study were strikingly higher than those reported in adults, demonstrating that invasive fusariosis is a life-threatening but salvageable condition in immunosuppressed children.

Concentration-response relationships between hourly particulate matter and ischemic events: A case-crossover analysis of effect modification by season and air-mass origin.

Most studies linking cardiovascular disease with particulate matter (PM) exposures have focused on total mass concentrations, regardless of their origin. However, the origin of an air mass is inherently linked to particle composition and possible toxicity. We examine how the concentration-response relation between hourly PM exposure and ischemic events is modified by air-mass origin and season. Using telemedicine data, we conducted a case-crossover study of 1855 confirmed ischemic cardiac events in Israel (2005-2013). Based on measurements at three fixed-sites in Tel Aviv and Haifa, ambient PM with diameter < 2.5 µm (PM2.5) and 2.5-10 µm (PM10-2.5) concentrations during the hours before event onset were compared with matched control periods using conditional logistic regression that allowed for non-linearity. We also examined effect modification of these associations based on the geographical origin of each air mass by season. Independent of the geographical origin of the air mass, we observed concentration-response curves that were supralinear. For example, the overall odds ratios (ORs) of ischemic events for an increase of 10-µg/m3 in the 2-h average of PM10-2.5 were 1.08 (95% confidence interval (CI): 1.03-1.14) and 1.00 (0.99-1.01) at the median (17.8 µg/m3) and 95th percentile (82.3 µg/m3) values, respectively. Associations were strongest at low levels of PM10-2.5 when air comes from central Europe in the summer (OR: 1.27; 95% CI: 1.06, 1.52). Our study demonstrates that hourly associations between PM2.5 and PM10-2.5 and ischemic cardiac events are supralinear during diverse pollution conditions in a single population that experiences a wide range of exposure levels.

The "Sick immigrant" and "Healthy immigrant" phenomenon among Jews migrating from the USSR to Israel.

The "healthy immigrant" phenomenon finds that immigrants are in better health than natives, while the "sick immigrant" phenomenon finds the opposite. We examined this phenomenon using the relationship between immigration and mortality, stratified by income level, among Soviet immigrants to Israel in the 1990s, compared to veteran immigrants with similar ethnic origin. A retrospective cohort study of mortality during 1990-2016 was conducted among 63,847 immigrants born during 1940-1950 in the USSR or Eastern Europe, and who immigrated to Israel during 1990-1995. They were compared to a control group of 75,347 Israeli Jews born during the same period in the same countries or second-generation immigrants with parents from these countries and who immigrated by 1960. After adjusting for sex, age, income, and marital status, we found higher mortality rates among immigrants than non-immigrants for the total study population (adjusted hazard ratio (AHR) = 1.399, 99% confidence intervals (CI) = 1.341, 1.459) and among 19,033 men (AHR = 2.852, 99%CI = 2.619, 3.107) and 24,355 women (AHR = 1.705, 99%CI = 1.566, 1.857) with low incomes. The opposite relationship was found for 25,436 men (AHR = 0.710,99%CI = 0.617, 0.0.816) and for 12,922 women (AHR = 0.693,99%CI = 0.534, 0.900) with high incomes. When examining the total study population, we found evidence to support the "sick immigrant" phenomenon. However, both men and women in the high-income subgroup, and women in the middle-income subgroup, demonstrated the "healthy immigrant" phenomenon. Decision-makers in Israel should pay particular attention to immigrants from a low socioeconomic level. Our results emphasize the need for social stratification when examining the relationships between immigration and health outcomes.

Venous Thromboembolism and Its Risk Factors in Children with Acute Lymphoblastic Leukemia in Israel: A Population-Based Study.

Venous thromboembolism (VTE) is a serious complication of acute lymphoblastic leukemia (ALL) therapy. The aim of this population-based study was to evaluate the rate, risk factors, and long-term sequelae of VTE in children treated for ALL. The cohort included 1191 children aged 1-19 years diagnosed with ALL between 2003-2018, prospectively enrolled in two consecutive protocols: ALL-IC BFM 2002 and AIEOP-BFM ALL 2009. VTEs occurred in 89 patients (7.5%). Long-term sequelae were uncommon. By univariate analysis, we identified four significant risk factors for VTEs: Severe hypertriglyceridemia (p = 0.005), inherited thrombophilia (p < 0.001), age >10 years (p = 0.015), and high-risk ALL group (p = 0.039). In addition, the incidence of VTE was significantly higher in patients enrolled in AIEOP-BFM ALL 2009 than in those enrolled in ALL-IC BFM 2002 (p = 0.001). Severe VTE occurred in 24 children (2%), all of whom had at least one risk factor. Elevated triglyceride levels at diagnosis did not predict hypertriglyceridemia during therapy. In a multivariate analysis of 388 children, severe hypertriglyceridemia and inherited thrombophilia were independent risk factors for VTE. Routine evaluation for these risk factors in children treated for ALL may help identify candidates for intervention.

Extended triple intrathecal therapy in children with T-cell acute lymphoblastic leukaemia: a report from the Israeli National ALL-Studies.

Owing to the increased central nervous system (CNS) relapse risk in T-cell acute lymphoblastic leukaemia (ALL), it is unclear whether preventive cranial radiation (pCRT) can be safely omitted. In this study, pCRT was replaced by extended triple intrathecal therapy (TIT) in prednisone good early responders - medium-risk (MR) group, accounting for 76% of T-ALL patients. From 1989 to 2003, 143 T-ALL patients aged 1-18 years were enrolled in the Israel National Studies (INS) 89 (n = 84) and INS 98 (n = 59) trials, based on ALL-Berlin-Frankfurt-Munster (BFM) 86/90 and ALL-BFM 95 protocols, respectively. Five-year event-free survival (EFS) of the MR group in the INS 89 (n = 60) was 70 +/- 5.9% and the INS 98 (n = 43), 83.7 +/- 5.6% (P = 0.12); the cumulative incidence (CI) of any CNS relapse was 5.0 +/- 2.8% and 2.3 +/- 2.3% (P = 0.50), respectively. There was no difference in outcome between MR patients with a white blood cell count (WBC) >or=100 x 10(9)/l treated with extended TIT (n = 17) or pCRT (n = 10). For all T-ALL patients, 5-year EFS was 61.9 +/- 5.3% in INS 89 and 72.9 +/- 5.8% in INS 98, (P = 0.21); the CI of any CNS relapse was 7.1 +/- 2.8% and 1.7 +/- 1.7% (P = 0.142), respectively. Outcome of T-ALL MR patients given extended TIT in the context of BFM-based protocols with long-term follow-up appeared to be comparable to studies in which a larger proportion of patients was irradiated, and was associated with low risk of CNS relapse, regardless of the WBC.

Fine and Coarse Particulate Matter Exposures and Associations with Acute Cardiac Events among Participants in a Telemedicine Service: A Case-Crossover Study.

BACKGROUND: Subclinical cardiovascular changes have been associated with ambient particulate matter (PM) exposures within hours. Although the U.S. Environmental Protection Agency continues to look for additional evidence of effects associated with sub-daily PM exposure, this information is still limited because most studies of clinical events have lacked data on the onset time of symptoms to assess rapid increased risk. OBJECTIVE: Our objective was to investigate associations between sub-daily exposures to PM and acute cardiac events using telemedicine data. METHODS: We conducted a case-crossover study among telemedicine participants [Formula: see text] of age who called a service center for cardiac-related symptoms and were transferred to a hospital in Tel Aviv and Haifa, Israel (2002-2013). Ambient [Formula: see text] and [Formula: see text] measured by monitors located in each city during the hours before the patient called with symptoms were compared with matched control periods. We investigated the sensitivity of these associations to more accurate symptom onset time and greater certainty of diagnosis. RESULTS: We captured 12,661 calls from 7,617 subscribers experiencing ischemic (19%), arrhythmic (31%), or nonspecific (49%) cardiac events. PM concentrations were associated with small increases in the odds of cardiac events. For example, odds ratios for any cardiac event in association with a [Formula: see text] increase in 6-h and 24-h average [Formula: see text] were 1.008 [95% confidence interval (CI): 0.998, 1.018] and 1.006 (95% CI: 0.995, 1.018), respectively, and for [Formula: see text] were 1.003 (95% CI: 1.001, 1.006) and 1.003 (95% CI: 1.000, 1.007), respectively. Associations were stronger when using exposures matched to the call time rather than calendar date and for events with higher certainty of the diagnosis. CONCLUSIONS: Our analysis of telemedicine data suggests that risks of cardiac events in telemedicine participants [Formula: see text] of age may increase within hours of PM exposures. https://doi.org/10.1289/EHP2596.

Ethnic variation in medical and lifestyle risk factors for B cell non-Hodgkin lymphoma: A case-control study among Israelis and Palestinians.

BACKGROUND: Risk factors for B-cell non-Hodgkin lymphoma (B-NHL) have not been assessed among Palestinian Arabs (PA) and Israeli Jews (IJ). METHODS: In a case-control study we investigated self-reported medical and lifestyle exposures, reporting odds ratios (ORs) and 95% confidence intervals [CIs], by ethnicity, for overall B-NHL and subtypes. RESULTS: We recruited 823 cases and 808 healthy controls. Among 307 PA/516 IJ B-NHL cases (mean age at diagnosis = 51 [±17] versus 60 [±15] years, respectively) subtype distributions differed, with diffuse large B-cell lymphoma (DLBCL) being prominent among PA (71%) compared to IJ (41%); follicular lymphoma (FL), was observed in 14% versus 28%, and marginal zone lymphoma, in 2% versus 14%, respectively. Overall B-NHL in both populations was associated with recreational sun exposure OR = 1.43 [CI:1.07-1.91], black hair-dye use OR = 1.70 [CI:1.00-2.87], hospitalization for infection OR = 1.68 [CI:1.34-2.11], and first-degree relative with hematopoietic cancer, OR = 1.69 [CI:1.16-2.48]. An inverse association was noted with alcohol use, OR = 0.46 [CI:0.34-0.62]. Subtype-specific exposures included smoking (FL, OR = 1.46 [CI:1.01-2.11]) and >monthly indoor pesticide use (DLBCL, OR = 2.01 [CI:1.35-3.00]). Associations observed for overall B-NHL in PA only included: gardening OR = 1.93 [CI:1.39-2.70]; history of herpes, mononucleosis, rubella, blood transfusion (OR>2.5, P<0.01 for all); while for IJ risk factors included growing fruits and vegetables, OR = 1.87 [CI:1.11-3.15]; and self-reported autoimmune diseases, OR = 1.99 [CI:1.34-2.95]. CONCLUSIONS: In these geographically proximate populations we found some unique risk factors for B-NHL. Heterogeneity in the observed associations by ethnicity could reflect differences in lifestyle, medical systems, and reporting patterns, while variations by histology infer specific etiologic factors for lymphoma subtypes.