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Background: Cardiovascular diseases (CVD) stand out as the leading cause of mortality, and the mortality rate attributed to this disease is notably elevated in Iran. Consequently, dedicated studies on CVD become imperative., Methods: This cross-sectional study utilized data from the death registration system of the Ministry of Health, Treatment and Medical Education of Iran. In this study, the statistical population of all people who died due to CVD in Iran were18,146, 21,945, and 24,352 individuals in the years 2017, 2018, and 2019, respectively. The primary objective is to conduct a spatiotemporal analysis of CVD mortality spatiotemporally using GIS-based methodologies. To achieve this, CVD mortality data at the township level for the years 2017, 2018, and 2019 in Iran are subjected to spatial statistical tests, including Anselin Local Moran's I and Hot Spot Analysis (Getis-Ord Gi*), as well as analytical techniques such as Mean Center (MC), (SD), and (GIS)., Results: The study identified a rising trend in cardiovascular disease-related deaths in Iran, reaching (46.36% females and 53.64 males), (45.39% females and 54.61% males) and (45.67% females and 54.33% males) individuals in the years 2017, 2018, and 2019, respectively. Throughout this period, the mortality rate was higher among men, with the elderly showing the highest mortality. Notably, distinct hotspots of cardiovascular disease mortality emerged in the western, southern, and eastern regions of Iran. These findings emphasize the importance of targeted interventions and further investigation into the contributing factors in these specific geographic areas., Conclusion: Geographic factors are identified as significant contributors to an elevated risk of cardiovascular disease mortality. Our study, shedding light on the spatial dynamics of the disease, offers valuable insights for decision-makers. The findings can contribute to the formulation of effective strategies and policies, aligning with a Holistic Cardiovascular Health Strategy, Gender-Based Healthcare Policies, and Spatial Planning and Environmental Policies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders, characterized by specific cognitive and behavioral symptoms. A fronto-cerebellar circuit is implicated in ADHD, and despite its role in cognitive/behavioral aspects, the neurochemical alterations in this circuit are not well understood. The present study aimed to compare neurometabolite ratios of the fronto-cerebellar circuit between ADHD and control participants, using proton magnetic resonance spectroscopy ( 1 H MRS), and investigate whether neurometabolites related to cognitive/behavioral characteristics. Fifteen children and adolescents with ADHD and 19 healthy control participants were enrolled in this study. Two single voxel spectra localized in the right dorsolateral prefrontal cortex (DLPFC) and left Crus 1 were taken using PRESS sequence. Also, neuropsychological performance and behavioral characteristics were evaluated. Results revealed that ADHD group had different choline/creatine and glutamate/creatine ratios in the fronto-cerebellar circuit, compared to healthy controls. The current study also found significant correlations between neurometabolite ratios in the both region of interests (ROIs) and cognitive/behavioral characteristics. These results suggest that alterations in fronto-cerebellar metabolites may be related to cognitive and behavioral deficits in ADHD, and also, our findings highlight that the cerebellum may be involved in the pathophysiology of ADHD., Competing Interests: Declaration of competing interest The authors have nothing to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Despite a number of treatment options, patients with diffuse large B-cell lymphoma (DLBCL) whose disease has become refractory to treatment have a poor prognosis. Selinexor is a novel, oral drug that is approved to treat patients with relapsed/refractory DLBCL. In this post hoc analysis of the SADAL study, a multinational, open-label study, we evaluated subpopulations to determine if response to single agent selinexor is impacted by number of lines of prior treatment, autologous stem cell transplant (ASCT), response to first and most recent therapies, and time to progressive disease., Patients: Patients (n = 134) with DLBCL after 2-5 prior therapies were enrolled in SADAL and received 60mg selinexor twice weekly., Results: The median overall survival was 9.0 months and median progression free survival was 2.6 months. Patients who had the best overall response rate (ORR) and disease control rate were those who had prior ASCT (42.5% and 50.0%) or responded to last line of therapy (35.9% and 43.5%). Patients with primary refractory DLBCL also showed responses (ORR 21.8%). Adverse events between subgroups were similar to the overall study population, the most common being thrombocytopenia (29.1%), fatigue (7.5%), and nausea (6.0%)., Conclusion: Regardless of prior therapy and disease refractory status, selinexor treatment demonstrated results consistent with its novel mechanism of action and lack of cross-resistance. Thus, single agent oral selinexor can induce deep, durable, and tolerable responses in patients with DLBCL who have recurrent disease after several chemoimmunotherapy combination regimens., (Copyright © 2021. Published by Elsevier Inc.)

Background & Aims: Impact of micronutrient deficiency on childhood malignancy is unexplored. We estimated the prevalence of baseline micronutrient deficiency in children with cancer and its impact on event-free survival (EFS) and overall survival (OS)., Methods: A longitudinal cohort study was conducted at a tertiary cancer centre in India. Children (≤18 years) with de novo malignancy were enrolled between October 2012 and May 2014. Baseline levels of vitamin B 12 , folate, zinc, selenium, copper, and iron were measured and values below 150 pmol/L, 6 ng/mL, International Zinc Nutrition Collaborative Group cut-off, 0.5 μmol/L, 10 μmol/L, and 50 μg/dL, respectively, indicated deficiency., Results: Total 535 children [326 (60.9%) haematological and 209 (39.1%) solid malignancies] were enrolled with median follow-up of 66 months. Vitamin B 12 , folate, zinc, selenium, copper and iron deficiencies were found in 209 (39.1%), 89 (16.6%), 173 (32.3%), 39 (7.3%), 12 (2.2%), and 231 (43.2%) children, respectively. Selenium deficiency independently predicted poor EFS (hazard ratio [HR] = 1.56; p = 0.038) and OS (HR = 1.65; p = 0.027) in the cohort. In haematological malignancies, selenium deficiency predicted poor EFS (HR = 1.81; p = 0.023) and OS (HR = 2.12; p = 0.004). In solid malignancies, vitamin B 12 (HR = 1.55; p = 0.028) and zinc (HR = 1.74; p = 0.009) deficiencies predicted poor EFS, and zinc deficiency predicted poor OS (HR = 1.77; p = 0.009). Multiple micronutrient (≥3) deficiencies also predicted poor EFS (HR = 1.69; p = 0.001) and OS (HR = 1.83; p < 0.001) in the whole cohort., Conclusions: Selenium deficiency was independently predictive of adverse outcomes in childhood cancer, particularly in haematological malignancies. Zinc deficiency adversely affected solid tumours. The adjunct use of micronutrient supplementation in paediatric malignancies should be explored., Competing Interests: Conflict of interest The authors declare no potential conflicts of interest., (Copyright © 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objective: To develop and test a brief Composite Intervention Module for Pre-adolescents with Acute Lymphoblastic Leukemia (CIMPALL)., Design: Single-center randomized controlled design., Setting: A tertiary care center of national importance PARTICIPANTS: A total of 36 children with acute lymphoblastic leukemia in the maintenance phase of the treatment., Intervention: A five-session (540 min) brief, multidomain, audiovisually aided, therapist-facilitated conjoint intervention module for children with cancer and their parents., Main Outcome Measures: Standardized psychological tools for children including CBCL, CPSS (Child Posttraumatic Stress Disorder Symptoms Scale), PedsQol (Pediatric Quality of Life), and NIMHANS (National Institute of Mental Health and Neurosciences) neuropsychological battery and parents including PTSD CC (Posttraumatic Stress Disorder Civilian Checklist), CHIP (Coping Health Inventory for Parents), CBS (Caregiver Burden Scale), and SRQ (Self-Reporting Questionnaire)., Results: A total of 36 patients were randomized to an experimental or a control group. Over 80% agreement was observed on indices of expert evaluation; 100% of participants found the sessions to be helpful, useful, appropriate in terms of time, duration, and place, and interventionist. The participation rate in the sessions was 94% and the study flow was smooth; 97.3% eligible candidates agreed to participate. Furthermore, 100% agreement on performance of activities was observed and the attrition rate was 5.26%., Conclusion: This pilot study presents the CIMPALL, which to the best of our knowledge is the first of its kind in India. The data suggest that the CIMPALL intervention is feasibly delivered by a clinical psychologist and that the CIMPALL intervention has an impact on important psychosocial variables for children with acute lymphoblastic leukemia and their parents., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Background: The SADAL study evaluated oral selinexor in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior lines of systemic therapy. In this post-hoc analysis, we analyzed the outcomes of the SADAL study by DLBCL subtype to determine the effects of DLBCL subtypes on efficacy and tolerability of selinexor., Patients and Methods: Data from 134 patients in SADAL were analyzed by DLBCL subtypes for overall response rate (ORR), overall survival (OS), duration of treatment response, progression-free survival, and adverse events rate., Results: ORR in the entire cohort was 29.1%, and similar in patients with germinal center (GCB) versus non-GCB DLBCL (31.7% vs. 24.2%, P = 0.45); transformed DLBCL showed a trend towards higher ORR than de novo DLBCL: 38.7% vs. 26.2% (P = 0.23). Despite similar prior treatment regimens and baseline characteristics, patients with DLBCL and normal C-MYC/BCL-2 protein expression levels had a significantly higher ORR (46.2% vs.14.8%, P = 0.012) and significantly longer OS (medians 13.7 vs. 5.1 months, hazard ratio 0.43 [95% CI, 0.23-0.77], P = 0.004) as compared with those whose DLBCL had C-MYC and BCL-2 overexpression. Among patients who had normal expression levels of either C-MYC or BCL-2 and baseline hemoglobin levels ≥ 10g/dL, ORR was 51.5% (n = 47), with median OS of 15.5 months and median PFS of 4.6 months. Similar rates of adverse events were noted in all subgroups., Conclusions: Overall, single agent oral selinexor showed strong responses in patients with limited treatment alternatives regardless of germinal center B-cell type or disease origin., (Copyright © 2021. Published by Elsevier Inc.)

Background: IKZF1 deletions are associated with adverse outcomes in B-cell acute lymphoblastic leukemia (B-ALL). We assessed the prevalence and clinical impact of functional subtypes of IKZF1 deletions in pediatric BCR-ABL1-negative B-ALL., Patients and Methods: This retrospective study of IKZF1 deletions was done in cases of pediatric BCR-ABL1-negative B-ALL. The genomic DNA of cases, over a 53-month period, was analyzed using multiplex ligation-dependent probe amplification and multiplex fluorescent polymerase chain reaction. The deletions were divided into functional subgroups: (1) loss-of-function/haploinsufficiency, (2) dominant-negative, and (3) a combination of both types of deletion. The post-induction remission status, event-free survival (EFS), and overall survival (OS) were noted., Results: Out of 320 cases, 47 (14.7%) had IKZF1 deletions. Thirty-six of the 47 (77%) had loss-of-function deletions, 10 (21%) had dominant-negative deletions, and one (2%) had a combination of both types. The post-induction remission rates in cases with loss-of-function deletions (22/30, 73%; P = .060) and dominant-negative deletions (4/5, 80%; P = .517) were lower compared with those without deletions (215/248, 86.7%). These cases also had worse median EFS: 21.1 months (P = .006) for loss-of-function and 15.4 months (P = .156) for dominant-negative deletions, compared with 46.4 months in cases without IKZF1 deletions. They also had worse median OS: 23.4 months (P = .012) for loss-of-function deletions and 15.7 months (P = .233) for dominant-negative deletions, compared with median not reached in cases without IKZF1 deletions., Conclusion: The IKZF1 deletions were seen in 14.7% of BCR-ABL1-negative pediatric B-ALL. Most of these deletions (77%) were loss-of-function type. The cases with loss-of-function deletions had lower remission rates and poor EFS and OS compared with cases without IKZF1 deletions. A similar trend of poor outcome was seen in the few cases with dominant-negative IKZF1 deletions., (Copyright © 2021. Published by Elsevier Inc.)

India has made significant improvement in childhood cancer services in last few decades. However, the outcome still remains modest as compared to global standards due to significant barriers in recognition, diagnosis and cure. Data regarding comprehensive childhood cancer burden in country is lacking due to low and urban predominant coverage of population-based cancer registry programs. The available data shows lower incidence of childhood cancer incidence especially in leukaemia and CNS tumours which may suggest poor awareness of caregivers and delayed diagnosis with many "missed cases". Incidence data are also skewed towards male preponderance which suggests gender bias in seeking healthcare. The childhood cancer services in India are predominantly restricted to few tertiary care centres in major cities. The outcome in major groups of cancer is complicated by delayed and more advanced stage of presentation and poor supportive care during intensive treatment. Treatment refusal and abandonment remains major hurdles. Last few decades saw development of dedicated paediatric oncology services and training programs in the country. The development of InPOG (Indian Paediatric Oncology group) for conducting collaborative trials will lead to adoption of uniform treatment protocols suited for the country. Financial support through the government promoted health insurance and holistic support through philanthropic organizations have improved treatment adherence and outcome. Moving forward, the focus should be on strengthening the cancer registries for capturing nationwide data, improving awareness of childhood cancer among caregivers and healthcare workers for early recognition and improving accessibility of childhood cancer care services beyond major cities., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: CD123 is overexpressed in many hematologic malignancies and found to be useful in characterizing leukemic blasts of both acute myeloid leukemia (AML) and B-acute lymphoblastic leukemia (B-ALL). CD123 has been recently found to be a marker of leukemic stem cells, and its utility to measure residual disease and potential role in disease relapse is under evaluation., Materials and Methods: Herein, we have evaluated the expression of CD123 in 757 samples of acute leukemia including 479 treatment-naive and 278 follow-up samples and compared with post-induction morphologic complete remission and measurable residual disease (MRD) status. Multiparametric flow cytometry was used for assessment of CD123 expression and immunophenotypic characterization of leukemic blasts at diagnostic and MRD assessment time points., Results: Using variable cutoffs of 5%, 10%, and 20% to define a case as CD123-positive, expression of CD123 was observed in 75.6%, 66.2%, and 50% of AML and 88.6%, 81.8%, and 75% of B-ALL, respectively. Of 11 patients, 7 (63.63%) had mixed phenotype acute leukemia, but none of the 12 patients with T-acute lymphoblastic leukemia showed positivity for CD123. CD123 expression at diagnosis was associated with post-induction MRD-positive status in both B-ALL (P < .001) and AML (P = .001). We also evaluated the utility of CD123 as a leukemia-associated aberrant immunophenotype and found it to be useful in both patients with AML (baseline, 50.6%; follow-up, 53%) and B-ALL (baseline, 75%; follow-up, 73.07%)., Conclusions: In conclusion, CD123 may be considered as a cardinal marker for residual disease assessment and response evaluation in AML and B-ALL., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Chronic myeloid leukemia (CML) is an uncommon malignancy in children in which tyrosine kinase inhibitors (TKIs) have significantly improved outcome in recent years., Patients and Methods: We performed a retrospective analysis of CML patients (≤ 18 years old) presenting to our center between January 2005 and December 2018 with respect to baseline demographics, response to imatinib, and real-world management of those with a suboptimal response., Results: A total of 124 patients were diagnosed with CML with 99 (80%) in the chronic phase. There was a male preponderance (males:females = 3.1:1) with a median age of 13 years. The common presenting clinical features were splenomegaly (90.9%) and fever (51.5%) with a median leukocyte count of 165 × 10 3 /μL. The proportion of patients attaining a complete hematologic response (CHR) at 3 months, a complete cytogenetic response (CCyR) at 12 months, and a major molecular response at 12 months were 79.7%, 54.1%, and 50.9%, respectively. At a median follow-up of 67.4 months, the 5-year overall survival rate and the event-free survival (EFS) rate were 92% ± 3% and 64% ± 6%, respectively. Failure to achieve CCyR at 12 months was associated with poor EFS beyond 1 year (hazard ratio = 2.865, P = .044). Among 15 patients not achieving CHR at 3 months, dose escalation of imatinib resulted in the attainment of CHR in 13 (87%) patients. Seven patients in the cohort had a loss of the established response to imatinib because of documented poor compliance., Conclusion: Imatinib remains the frontline treatment of choice in CML with a reasonable outcome in children, especially when financial affordability, availability of second-generation TKIs, and poor compliance still remain major challenges in management. Dose escalation of imatinib remains an option in patients with a suboptimal response., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To analyze the activation of NFκB1/p50 in the inflammatory and non-inflammatory environment of uveal melanoma and its association with clinicopathological factors and patient outcome., Methods: Activation of NFκB1/p50 was evaluated in 75 cases of uveal melanoma by immunohistochemistry. mRNA expression in 58 fresh UM specimen was measured by quantitative reverse-transcriptase PCR (qRT-PCR). Western blotting was performed to validate the immunohistochemistry results in representative cases., Results: Forty-five cases showed both cytoplasmic and nuclear immunoreactivity of NFκB1/p50. Increased level of NFκB1/p50 activation was more frequent in the inflammatory environment group as compared to non-inflammatory environment group at both transcriptional and translational level. In multivariate analysis, infiltrating macrophages and nuclear immunoreactivity of NFκB1/p50 (p < .05) in tumor cells were found to be an independent prognostic factor for poor survival., Conclusion: Our results suggest that nuclear immunoreactivity NFκB1/p50 may serve as a useful marker in assessing the prognosis of uveal melanoma patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: There is a lack of clinical predictors for prognosticating lymphoblastic lymphoma (LBL). In view of this lacuna, we evaluated outcomes and prognostic factors for LBL treated with a uniform protocol at our center., Patients and Methods: This study included consecutive patients of pediatric LBL aged ≤18 years from January 2003 to January 2017. Patients were staged using the St Jude staging system. All patients were treated with acute lymphoblastic leukemia like BFM90 protocol. The Kaplan-Meier method was used for survival analysis. A statistical model was made using stepwise regression and forward selection of the factors predicting event-free survival (EFS) and overall survival (OS)., Results: Sixty-five patients were evaluated with a median age of 12 years (range, 1-18 years) and male:female ratio of 2.25:1. Fifty-four patients presented with mediastinal disease. Median follow-up was 54.57 months (range, 0.6-140.5 months). EFS at 10 years was 62 ± 6% (95% confidence interval [CI], 0.49-0.73) and OS 71 ± 5% (95% CI, 0.57-0.81). In multivariate analysis, symptom duration ≤30 days, white blood cell (WBC) count >12000/µL and serum albumin ≤3.5 g/dL predicted inferior EFS and OS. A prognostic model with these 3 factors suggested that those without any of these risk factors had an OS of 92 ± 5% whereas those with 2 or 3 factors had an OS of 37 ± 14%., Conclusion: Our outcomes are 15% to 20% lower than in the published literature. Low albumin level, high WBC count at baseline, and symptom duration <30 days emerged as adverse predictors for EFS and OS. These clinical predictors and prognostic model for pediatric LBL should be validated in prospective cohorts., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Role of mitochondrial DNA variations, particularly in D loop region, remains investigational in acute myeloid leukaemia (AML). Consecutive 151 pediatric AML patients were prospectively enrolled from June 2013 to August 2016, for evaluating pattern of variations in mitochondrial D-loop region and to determine their association, if any, with expression of mitochondrial-encoded genes. For each patient, D-loop region was sequenced on baseline bone marrow, buccal swab and mother's blood sample. Real time PCR was used for relative gene expression of four mitochondrial DNA encoded genes viz. Nicotinamide-adenine-dineucleotide-dehydrogenase subunit 3 (ND3), Cytochrome-B (Cyt-B), Cytochrome c oxidase-I (COX1) and ATP-synthetase F 0 subunit-6 (ATP6). Total 1490 variations were found at 237 positions in D-Loop; 1206 (80.9%) were germline and 284 (19.1%) were somatic. Positions 73-263 were identified as a probable hotspot region. G bases appeared to be most stable nucleotide (least number of single base substitutions) whereas T appeared to be most susceptible to variations with germline T-C being the commonest. Gene expression of Cyt-B was found to be significantly higher for any variation (somatic or germline) at positions 16,192 and 16,327 while it was significantly lower for variations at positions 16,051 and 207. Any variation at positions 152, 207 and 513 significantly decreased COX1 expression while those at positions 16,051 and 152 attenuated ATP6 expression. This first study evaluated type and overall pattern of D-loop variations in AML, and also showed that some of these variations in D loop region might have an effect on the mitochondrial-encoded genes which is new and valuable information in AML genomics., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The purpose of our study was to evaluate the clinical, cytogenetic, and molecular features, and survival outcomes in patients with acute myeloid leukemia (AML) with myeloid sarcoma (MS) and compare them with patients with AML without MS., Patients and Methods: This was a retrospective analysis of de novo pediatric AML patients with or without MS diagnosed at our cancer center between June 2003 and June 2016., Results: MS was present in 121 of 570 (21.2%), the most frequent site being the orbit. Patients with MS had a younger median age (6 years vs. 10 years) and presented with higher hemoglobin and platelet but lower white blood cell count compared with patients without MS. Further, t (8; 21) (P < .01), loss of Y chromosome (P < .01), and deletion 9q (P = .03) were significantly higher in patients with AML with MS. Event-free survival (EFS; P = .003) and overall survival (OS; P = .001) were better among patients with AML with MS (median EFS 21.0 months and median OS 37.1 months) compared with those with AML without MS (median EFS 11.2 months and median OS 16.2 months). The t (8; 21) was significantly associated with MS (odds ratio, 3.92). In a comparison of the 4 groups divided according to the presence or absence of MS and t (8; 21), the subgroup of patients having MS without concomitant t (8; 21) was the only group to have a significantly better OS (hazard ratio, 0.53; 95% confidence interval, 0.34-0.82; P = .005)., Conclusion: Although t (8; 21) was more frequently associated with MS, it did not appear to be the reason for better outcome., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Polymorphisms in genes coding for imatinib transporters and metabolizing enzymes may affect imatinib pharmacokinetics and clinical response. Aim of this study was to assess the influence of polymorphisms in MDR1 and CYP3A5 genes on imatinib trough levels, cytogenetic and molecular response in patients with CML. Newly diagnosed patients with chronic-phase CML started on imatinib therapy were enrolled and followed up prospectively for 24 months. The following single nucleotide polymorphisms were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene. Genotyping was done using PCR-RFLP method and validated by direct gene sequencing. Trough levels of imatinib were measured using LC-MS/MS. Cytogenetic response was assessed by conventional bone-marrow cytogenetics. Molecular response was assessed by qRTPCR using international scale. A total of 173 patients were included, out of which 71 patients were imatinib responders, while 102 were non-responders. Marked inter-individual variability in trough levels of imatinib was seen. Patients with GG genotype for CYP3A5-A6986G (P=0.016) and TT genotype for MDR1-C3435T (P=0.013) polymorphisms had significantly higher trough levels of imatinib. Patients with AA genotype for CYP3A5-A6986G [RR=1.448, 95% CI (1.126, 1.860), P=0.029] and CC genotype for MDR1-C1236T [RR=1.397, 95% CI (1.066, 1.831), P=0.06] &MDR1-C3435T [RR=1.508, 95% CI (1.186, 1.917), P=0.018] polymorphisms were at high risk for failure of imatinib therapy. Patients with CGC haplotype for MDR1 polymorphisms had significantly lower imatinib trough levels and were at a higher risk of imatinib failure [RR=1.547, 95% CI (1.324, 1.808), P<0.001]. GG vs. non-GG genotype for CYP3A5-A6986G [adjusted OR: 0.246; 95% CI (0.116, 0.519); P<0.001] and TT vs. non-TT genotype for MDR1-C1236T [adjusted OR: 0.270; 95% CI (0.110, 0.659); P=0.004] &MDR1-C3435T [adjusted OR: 0.289; 95% CI (0.135, 0.615); P=0.001] polymorphisms were independent factors predicting imatinib response in multivariate analysis. To conclude, MDR1 and CYP3A5 genetic polymorphisms significantly influence plasma trough levels and therapeutic response of imatinib in patients with CML. Genotyping of these polymorphisms could be of value to individualize the therapy and optimize the clinical outcomes., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Oral mucositis is a common inflammatory complication in patients undergoing high-dose chemotherapy and radiation followed by haematopoietic stem cell transplantation (HSCT). Lactobacillus brevis CD2 has been proven efficacious in preventing chemoradiotherapy-induced oral mucositis in squamous cell carcinoma of head and neck., Methods: This phase II study aimed to evaluate the safety and efficacy of L. brevis CD2 lozenges in preventing oral mucositis in patients undergoing HSCT. Eligible patients received four to six lozenges of L. brevis CD2 per day, beginning from 4 to 7 days before initiation of chemotherapy and continuing until resolution of mucositis or till day +24., Results: Of 31 patients enrolled, 7 (22.6%) patients did not develop any mucositis, 6 (19.4%) patients developed grade 1, 12 (38.7%) patients developed grade 2, 4 (12.9%) and 2 (6.5%) patients developed grade 3 and grade 4 mucositis, respectively. Median time to onset and for resolution of mucositis were 6 days and 8 days, respectively. No adverse events were reported with usage of study drug. However, one patient died of Klebsiella sepsis., Conclusion: Promising results from the study encourage the use of L. brevis CD2 lozenges as a supportive care treatment option; however, a randomised, double-blind, multicentric trial in a larger population is warranted., Trials Registration Number: NCT01480011 at https://www.clinicaltrials.gov/ (Registered on Nov 04, 2011)., Competing Interests: Competing interests: None declared.

Introduction: Acute myeloid leukemia is characterized by accumulation of immature cells because of imbalance between proliferation and apoptosis. In AML, simultaneous expression of proliferative (FLT-3, c-KIT) and antiapoptotic genes (BCL-2), are unknown., Patients and Methods: We prospectively assessed proliferative and antiapoptotic gene transcripts using Taqman probe chemistry in 48 adult AML patients. A stepwise Cox regression model was applied for independent prognostic factors., Results: Thirty-two of 48 (75%) patients achieved complete remission. At follow-up ranging from 0.5 to 57.3 months, event-free survival (EFS) was 26.9 ± 6.3% (range, 15.5%-39.6%) and OS 34.5 ± 7.46% (range, 20.5%-48.9%). High white blood cell count correlated with an inferior complete remission rate (P = .021). Cytogenetics and FLT-3 internal tandem duplication did not predict EFS or OS. The transcripts of FLT-3, c-KIT, and BCL-2 showed a significant linear association with each other in Pearson correlation (FLT-3 vs. c-KIT: R = 0.8234; P < .001; c-KIT vs. BCL-2: R = 0.3377; P = .01; FLT-3 vs. BCL-2: R = 0.3815; P = .007). In a validation cohort (Microarray Data Set GSE1159) of adult AML patients, the global gene expression profile depicted a similar interrelationship. Patients with a greater platelet count were associated with increased transcript levels of BCL-2 (P = .034). In univariate analysis, a high transcript level of FLT-3 and high transcript ratio of FLT-3/BCL-2 and FLT-3 and c-KIT/BCL-2 significantly predicted OS (P = .043, .028, and .028, respectively). In a stepwise Cox regression model, high FLT-3 and c-KIT/BCL-2 ratio predicted OS (HR, 2.29)., Conclusion: To our knowledge, this is the first study that evaluated proliferative and antiapoptotic transcripts simultaneously, and results have shown that it is the relative levels of these transcripts that determine outcome in AML patients rather than their expression in isolation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Data on thoracic primitive neuroectodermal tumor (PNET) treated with a uniform chemotherapy protocol are minimal in the literature. We analyzed patients with thoracic PNET for outcome and prognostic factors., Methods: This is a single-institutional data review of patients treated between June 2003 and November 2011 with uniform neoadjuvant chemotherapy, surgical intervention, or radiotherapy (RT), or a combination of these treatments as local therapy followed by adjuvant chemotherapy., Results: Thoracic PNET was found in 84 of 374 (22%) patients with PNET with a median age of 15 years (range, 3-40 years); 27 (32%) of these patients had metastases. Thirty patients underwent surgical resection; 27 patients received radical RT after neoadjuvant chemotherapy. The radical RT group did not have adverse tumor characteristics or poor response to neoadjuvant chemotherapy. At median follow-up of 20.8 months (range, 2-104.6 months), 5-year event-free survival (EFS), overall survival (OS), and local control rate (LCR) were 24.4% ± 5.9%, 47.9% ± 8.4%, and 59.3% ± 9%, respectively, for the entire cohort, and 31% ± 7.7%, 59% ± 10.4%, and 67% ± 9.7%, respectively, for the group with localized tumors. In multivariate analysis, symptom duration longer than 4 months (p = 0.03), primary tumor of skeletal origin (p = 0.03), and radical RT (p = 0.006) predicted inferior EFS in the entire cohort and those with localized disease; metastatic disease (p = 0.002) predicted inferior OS. Radical RT predicted inferior LCR in the entire cohort and the group with localized tumor; tumor diameter larger than 8 cm (p = 0.02) and symptom duration longer than 4 months (p = 0.02) predicted inferior LCR in the group with localized tumor., Conclusions: This is a single-institutional experience of 84 patients with thoracic PNETs who underwent a uniform chemotherapy protocol. Novel prognostic factors were identified for thoracic PNET. All efforts should be made to resect primary tumor after neoadjuvant chemotherapy because radical RT results in inferior EFS and LCR despite good response to neoadjuvant chemotherapy., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: The present study prospectively evaluated outcome, pathologic findings, and compliance in orbital retinoblastoma patients (International Retinoblastoma Staging System [IRSS] stage III)., Design: Prospective study and case series., Participants: Twenty-eight consecutive IRSS stage III retinoblastoma patients were enrolled prospectively in the study after ethics committee approval and written informed consent., Methods: Planned therapy for patients included treatment with a uniform protocol consisting of neoadjuvant chemotherapy followed by enucleation, adjuvant radiotherapy, and chemotherapy. Prospective computerized data entry and telephone contact were undertaken to improve compliance, a major issue in treatment of orbital retinoblastoma., Main Outcome Measures: Event-free survival (EFS) and overall survival (OS) were calculated using Kaplan-Meier survival analysis. The difference between groups was analyzed using the log-rank test., Results: Median follow-up was 14.75 months (range, 2.23-26.3 months). The OS for all patients was 40.4% and the EFS was 33.33% at a follow-up of 26.3 months. The median EFS and OS were 10.37 months and 15.73 months, respectively. At baseline, bilateral retinoblastoma predicted inferior EFS (P = 0.0006) and OS (P = 0.0081). Twenty-two of 28 patients underwent enucleation, and viable tumor was present in 21 of 22 enucleated specimens (95%). Neoadjuvant chemotherapy prevented orbital exenterations. Presence of tumor in the cut end of the optic nerve significantly correlated with inferior EFS (P = 0.012) and OS (P = 0.0098). Central nervous system metastasis was the most common site of relapse and death. The overall rate of compliance with treatment was 67.8% (19/28), which was twice the compliance rate at the authors' center before initiation of the present study., Conclusions: There is a paucity of information in the literature on outcomes and pathologic findings after neoadjuvant chemotherapy in IRSS stage III retinoblastoma treated with a uniform treatment protocol, and as far as the authors are aware, there has been no prospective study. Neoadjuvant chemotherapy was able to avoid exenteration in all operated patients; however, residual viable tumor was present in 95% of enucleated specimens. Bilaterality and tumor in the optic nerve cut end after neoadjuvant chemotherapy were associated with inferior outcome. Compliance could be improved with computerized data entry and regular telephone contact., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

National surveys reveal that the public has lost confidence in the safety of food. There is lack of co-ordination and failure to overcome institutional barriers at many levels throughout the food chain. The abolition of the post of medical officer of health and the public health departments of local government over which it presided, in view of many, including members of parliament, has been the most damaging of all changes to the public health and many have asked for the restoration of this post. Health departments have no overall statutory responsibility for food safety. The medical expertise of medical officers of health provided the executive authority with the necessary support in managing and controlling outbreaks of food poisoning, a point emphasised in the recommendations made by an inquiry set up by the government following the worst ever outbreak of food poisoning in Lanarkshire, Scotland, UK. Only such an appointment at local level will restore public confidence in food safety.

This is a retrospective descriptive study examining medical records of notified cases of tuberculosis in Birmingham, UK, who died before completion of treatment, plus notified cases identified at postmortem. During the study period, 1989-1995, there were a total of 2088 notifications of tuberculosis of which 75 (3.6%) died. This case-fatality rate is lower than that reported from earlier studies, a finding which may be due to improved ascertainment, earlier diagnosis and improved treatment in recent years. Forty-five deaths (60%) were in males and 30 (40%) in females. The median age at death was 66 y. Forty-five deaths (60%) were among the white ethnic group, 21 (28%) among persons of Indian sub-continent origin, 4 (5.3%) among Black Caribbeans and 5 (6.6%) among the other ethnic groups. Case-fatality rates were significantly higher (P < 0.01) in caucasians (9.4%) than in Asians (1.5%) and only half of this difference was explained by the age of those affected. Twenty-two (29%) cases were confirmed by a positive sputum smear and a further 23 (31%) by a positive sputum culture. Eighteen (24%) cases also had histological confirmation. Twelve (16%) cases were identified on autopsy. The case fatality rate in respiratory disease was significantly higher (RR = 1.19, P > 0.05) than in non-respiratory disease. As delay in diagnosis is likely to be the main contributing factor leading to death, a high index of suspicion of tuberculosis is needed when investigating elderly patients with general chronic illness, especially if there are prolonged respiratory symptoms. Early diagnosis will reduce mortality as the disease rapidly responds to treatment.

A family with olivopontocerebellar atrophy is presented. Out of 7 siblings two male and one female were involved at a similar age of 5 years. Early onset of the disease is striking. The index case presented with progressively increasing choreiform movements and cerebellar signs. Magnetic resonance imaging morphology revealed the diagnosis.