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Somatic genetic abnormalities are initiators and drivers of disease and have proven clinical utility at initial diagnosis. However, the genetic landscape and its clinical utility at relapse are less well understood and have not been studied comprehensively. We analyzed cytogenetic data from 427 children with relapsed B-cell precursor ALL treated on the international trial, ALLR3. Also we screened 238 patients with a marrow relapse for selected copy number alterations (CNAs) and mutations. Cytogenetic risk groups were predictive of outcome postrelapse and survival rates at 5 years for patients with good, intermediate-, and high-risk cytogenetics were 68%, 47%, and 26%, respectively ( < .001). P TP53 alterations and / deletions were associated with a higher risk NR3C1 BTG1 of progression: hazard ratio 2.36 (95% confidence interval, 1.51-3.70, < .001) and P 2.15 (1.32-3.48, 5 .002). mutations were associated with an increased risk of P NRAS progression among standard-risk patients with high hyperdiploidy: 3.17 (1.15-8.71, P 5 .026). Patients classified clinically as standard and high risk had distinct genetic profiles. The outcome of clinical standard-risk patients with high-risk cytogenetics was equivalent to clinical high-risk patients. Screening patients at relapse for key genetic abnormalities will enable the integration of genetic and clinical risk factors to improve patient stratification and outcome. This study is registered at www.clinicaltrials.org as #ISCRTN45724312. [ABSTRACT FROM AUTHOR]

Dexamethasone is a key component in the treatment of childhood acute lymphoblastic leukaemia ( ALL). Despite playing a key role in the improved survival of ALL over several decades, intensification of dexamethasone therapy has also contributed to the increased toxicity associated with treatment, which is now seen to be at unacceptable levels given the favourable disease prognosis. Therefore the focus for treatment is now shifting towards reducing toxicity whilst maintaining current survival rates. As approximately 50% of patients were successfully treated on less intensive protocols of the 1980s, it has been questioned whether therapy intensification is necessary in all patients. Furthermore, there remains a subset of children who are still not cured of their disease. New strategies are therefore needed to identify patients who could benefit from dose reduction or intensification. However, adjusting a potentially life threatening therapy is a challenging task, particularly given the heterogeneous nature of ALL. This review focuses on the potential for patient stratification based on our current knowledge of dexamethasone pharmacokinetics, pharmacogenetics and the action of dexamethasone at the cellular level. A carefully designed, combined approach is needed if we are to achieve the aim of improved personalization of dexamethasone therapy for future patients. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukaemia is the most common childhood cancer and for those children who relapse, prognosis is poor and new therapeutic strategies are needed. Recurrent pathways implicated in relapse include RAS, JAK STAT, cell cycle, epigenetic regulation, B cell development, glucocorticoid response, nucleotide metabolism and DNA repair. Targeting these pathways is a rational therapeutic strategy and may deliver novel, targeted therapies into the clinic. Relapse often stems from a minor clone present at diagnosis and thus analysis of persisting leukaemia during upfront therapy may allow targeted drug intervention to prevent relapse. [ABSTRACT FROM AUTHOR]

The substantial health burden associated with major depressive disorder (MDD) is a product of both its high prevalence and the significant risk of relapse, recurrence, and chronicity. Establishing recurrence vulnerability factors (VFs) could improve the long-term management of MDD by identifying the need for further intervention in seemingly recovered patients. We present a model of sensitization in depression vulnerability, with an emphasis on the integration of behavioral and neural systems accounts. Evidence suggests that VFs fall into 2 categories: dysphoric attention and dysphoric elaboration. Dysphoric attention is driven by fixation on negative life events, and is characterized behaviorally by reduced executive control, and neurally by elevated activity in the brain's salience network. Dysphoric elaboration is driven by rumination that promotes overgeneral self- and contextual appraisals, and is characterized behaviorally by dysfunctional attitudes, and neurally by elevated connectivity within normally distinct prefrontal brain networks. Although few prospective VF studies exist from which to catalogue a definitive neurobehavioral account, extant data support the value of the proposed 2-factor model. Measuring the continued presence of these 2 VFs during recovery may more accurately identify remitted patients who would benefit from targeted prophylactic intervention. [ABSTRACT FROM AUTHOR]

For most children who relapse with acute lymphoblastic leukemia (ALL), the prognosis is poor, and there is a need for novel therapies to improve outcome. We screened samples from children with B-lineage ALL entered into the ALL-REZ BFM 2002 clinical trial (www.clinicaltrials.gov, #NCT00114348) for somatic mutations activating the Ras pathway (KRAS, NRAS, FLT3, and PTPN11) and showed mutation to be highly prevalent (76 from 206). Clinically, they were associated with high-risk features including early relapse, central nervous system (CNS) involvement, and specifically for NRAS/KRAS mutations, chemoresistance. KRAS mutations were associated with a reduced overall survival. Mutation screening of the matched diagnostic samples found many to be wild type (WT); however, by using more sensitive allelic-specific assays, low-level mutated subpopulations were found in many cases, suggesting that they survived up-front therapy and subsequently emerged at relapse. Preclinical evaluation of the mitogen-activated protein kinase kinase 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) showed significant differential sensitivity in Ras pathway-mutated ALL compared with WT cells both in vitro and in an orthotopic xenograft model engrafted with primary ALL; in the latter, reduced RAS-mutated CNS leukemia. Given these data, clinical evaluation of selumetinib may be warranted for Ras pathway-mutated relapsed ALL. [ABSTRACT FROM AUTHOR]

Abstract: Objectives. : Amplification of the 11q13 locus is commonly observed in a number of human cancers including both breast and ovarian cancer. Cyclin D1 and EMS1 have been implicated as candidate oncogenes involved in the emergence of amplification at this locus. Detailed analysis of the 11q13 amplicon in breast cancer led to the discovery of four regions of amplification suggesting the involvement of other genes. Here, we investigate the role of EMSY, a recently described BRCA2 interacting protein, as a key element of the 11q13 amplicon in ovarian cancer. EMSY maps to 11q13.5 and is amplified in 13% of breast and 17% of ovarian carcinomas. Methods. : EMSY amplification was assessed by fluorescent in-situ hybridization (FISH) in 674 ovarian cancers in a tissue microarray and correlated with histopathological subtype and tumor grade. A detailed map of the 11q13 amplicon in 51 cases of ovarian cancer was obtained using cDNA-array-based comparative genomic hybridization (aCGH). To further characterize the role of EMSY within this amplicon, we evaluated both the amplification profiles and RNA expression levels of EMSY and two other genes from the 11q13 amplicon in an additional series of 22 ovarian carcinomas. Results. : EMSY amplification was seen in 52/285 (18%) high grade papillary serous carcinomas, 4/27 (15%) high grade endometrioid carcinomas, 3/38 (8%) clear cell carcinomas, and 3/10 (30%) undifferentiated carcinomas. aCGH mapping of 11q13 in ovarian cancer showed that EMSY localized to the region with the highest frequency of copy number gain. Cyclin D1 and EMS1 showed a lower frequency of copy number gain. A highly significant correlation between EMSY gene amplification and RNA expression was also observed (P = 0.0001). This was a stronger correlation than for other genes at 11q13 including Cyclin D1 and PAK1. Conclusions. : These findings support the role of EMSY as a key oncogene within the 11q13 amplicon in ovarian cancer. [Copyright &y& Elsevier]

The article highlights the findings of a study regarding the occurrence of glucocorticoid (GC) resistance in two key models of acute lymphoblastic leukemia at the level of the glucocorticoid receptor. It mentions that a model of GC-resistance development from both a T cell acute lymphoblastic leukemia (ALL) cell line and a B-ALL cell line was generated in the study.

ZINC IS A COMMON SUPPLEMENT AND IS WIDELY AVAILABLE as a standard component of many over-the-counter products. A number of reports have identified an association between excessive zinc intake and severe cytopenia. We report a case of zinc-induced copper deficiency in a young adult to illustrate this under-recognized cause of anemia and neutropenia. [ABSTRACT FROM AUTHOR]

Background: Outcomes for patients with relapsed acute lymphoblastic leukemia (ALL) are poor and there is a need for novel therapies to improve outcomes. Targeted inhibition of WEE1 with small-molecule inhibitor adavosertib (AZD1775) has emerged as a therapeutic strategy to sensitize cancer cells to DNA-damaging chemotherapeutics, particularly in the context of TP53-mutated tumors. However, WEE1 inhibition as a potential therapeutic strategy for patients with high-risk and relapsed ALL, including those with TP53 mutations, has not been definitively evaluated. Methods: Anti-leukemic effects of adavosertib were investigated using a relapsed TP53 isogenic cell model system, primary patient, and patient-derived ALL samples (n = 27) in an ex vivo co-culture model system with bone marrow-derived mesenchymal stem cells. Combination effects with drugs currently used for relapsed ALL were quantified by Excess over Bliss analyses. Investigations for alterations of cell cycle and apoptosis as well as related proteins were examined by flow cytometry and Western blot, respectively. Results: Our study demonstrates the potent anti-leukemic activity of the clinically advanced WEE1 inhibitor adavosertib in a large majority (n = 18/27) of high-risk and relapsed ALL specimens at lower than clinically attainable concentrations, independent of TP53 mutation status. We show that treatment with adavosertib results in S-phase disruption even in the absence of DNA-damaging agents and that premature mitotic entry is not a prerequisite for its anti-leukemic effects. We further demonstrate that WEE1 inhibition additively and synergistically enhances the anti-leukemic effects of multiple conventional chemotherapeutics used in the relapsed ALL treatment setting. Particularly, we demonstrate the highly synergistic and cytotoxic combination of adavosertib with the nucleoside analog cytarabine and provide mechanistic insights into the combinational activity, showing preferential engagement of apoptotic cell death over cell cycle arrest. Our findings strongly support in vivo interrogation of adavosertib with cytarabine in xenograft models of relapsed and high-risk ALL. Conclusions: Together, our data emphasize the functional importance of WEE1 in relapsed ALL cells and show WEE1 as a promising p53-independent therapeutic target for the improved treatment of high-risk and relapsed ALL. [ABSTRACT FROM AUTHOR]

Abstract: Haematopoietic stem cell transplantation (HSCT) remains the only cure for most haematological malignancies, however, the mortality rate remains high. Complications after HSCT include relapse, graft versus host disease (GvHD), graft rejection and infection. Over the last few years several groups, have demonstrated that non‐HLA gene polymorphisms can be predictive of outcome after HSCT. Since the glucocorticoid cortisol is pivotal in the regulation of the immune system, we decided to examine single nucleotide polymorphisms (SNPs; rs6198, rs33388 and rs33389) within the glucocorticoid receptor (GR) and correlate with HSCT outcome. The training set consisted of patients (n = 458) who underwent HSCT for acute leukaemia between 1983 and 2005. In the recipients, the absence of the ACT haplotype and absence of the T allele of rs33388 were associated with decreased OS and the absence of the ACT haplotype, the absence of the T allele of rs33388 and the presence of the ATA haplotype were associated with increased risk of relapse. In addition, the presence of the ACT haplotype in the recipient showed a trend to be associated with increased risk of chronic graft versus host disease (cGvHD). The patients in this cohort received mainly myeloablative conditioning (n = 327). The SNPs in the glucocorticoid receptor were then investigated in a validation set (n = 251) of HSCT patients transplanted for acute leukaemia from 2006. This cohort contained significantly more patients that had received reduced intensity conditioning (RIC). Some of the results could be validated in these patients. However, contrary to the training set, the absence of the haplotype ACT in the donor in this cohort was associated with increased risk of cGvHD. Differences in the conditioning were shown to influence the results. These results are the first to associate GR SNPs with HSCT outcome and demonstrate the inherent problems of replicating SNP association studies in HSCT, due to different pre‐transplant regimens. [ABSTRACT FROM AUTHOR]

Recent data support the predictive implications of molecular subtype assignment in endometrial cancer (EC). Our objective was to retrospectively assess clinical outcomes according to adjuvant treatment received within EC molecular subtypes. Clinical outcomes (disease-specific and progression-free survival DSS/PFS) of EC patients from a single institution and population-based cohorts that had undergone molecular classification were assessed with respect to adjuvant therapy received and 2016 ESMO risk group. 2472 ECs were assessed; 184 (7.4%) POLE mut, 638 (25.8%) MMRd, 1223 (49.5%) NSMP and 427 (17.3%) p53abn. N = 774 (34.6%) of the cohort were ESMO 2016 high risk and 109 (4.8%) were advanced or metastatic. In patients with MMRd EC, assessed across and within stage, there was no observed benefit in DSS or PFS with the addition of chemotherapy +/− radiation compared to radiation alone in ESMO high risk (p = 0.694) or ESMO high, advanced, metastatic risk groups combined (p = 0.852). In patients with p53abn EC, adjuvant chemotherapy given with radiation was associated with significantly longer DSS compared to radiation alone in ESMO high risk (p = 0.007) and ESMO high, advanced and metastatic risk groups combined (p = 0.015), even when restricted to stage I disease (p < 0.001) and when compared in serous vs. non-serous histotypes (p = 0.009). Adjuvant chemotherapy is associated with more favorable outcomes for patients with p53abn EC, including stage I disease and non-serous histotypes, but does not appear to add benefit within MMRd ECs for any stage of disease, consistent with PORTEC-3 molecular subanalysis. Prospective trials, assessing treatment efficacy within molecular subtype are needed, however these 'real-world' data should be considered when discussing adjuvant treatment with patients. • Greater precision is needed in making adjuvant treatment decisions for chemotherapy (chemo) and radiation (RT) in endometrial cancer (EC). • Retrospective data from 2500 ECs assessed the associations of chemo and RT on clinical outcomes within molecular subtype. • Adjuvant chemo and RT was associated with longer DSS for patients with p53abn EC, including stage I and non-serous ECs. • Chemo was not associated with improved outcomes in MMRd EC patients, even in stage III disease. • Molecular subtype should be considered when making adjuvant therapy decisions in EC. [ABSTRACT FROM AUTHOR]

Aims Sex cord stromal tumours ( SCSTs) of the ovary encompass several histological tumour subtypes that are defined by characteristic histological features. Some can show morphological overlap with other subtypes of SCSTs, as well as with non- SCSTs. The E-cadherin/catenin complex constitutes the adherens junction, which is well developed in epithelial tissue, but the constituent molecules are also expressed in several non-epithelial tumours. The aim of this study was to determine whether the expression patterns of E-cadherin and catenins in ovarian SCSTs can be of diagnostic utility. Methods and results We studied the expression of E-cadherin, α-, β- and γ-catenin in 55 tumours using immunohistochemistry. We found that all tumour subtypes showed nuclear expression of E-cadherin, while only microcystic stromal tumours ( MCSTs) displayed a distinct profile, with nuclear localization of all three catenins in almost all cases. Conclusions We conclude that the E-cadherin expression profile in SCSTs can assist in distinguishing between SCSTs and non- SCSTs in which there is no nuclear expression of E-cadherin. The nuclear localization of catenins may be of potential use in distinguishing MCST from other subtypes of SCST. [ABSTRACT FROM AUTHOR]

A previous literature review found at least 4/9 (>=44.4%) CMMRD-associated ALL were T-ALL [[1]], and 8/88 (9.1%, 95% CI: 0.4-17.1%) childhood T-LBL patients were diagnosed with CMMRD in a consecutive series between 2007 and 2020 [[15]], suggesting an association of CMMRD with T cell lineage malignancies. For example, PCR-fragment length analysis has been shown to be insensitive to MSH6 deficiency in ALL relapse samples [[3]], and detected increased MSI in only 27% of CMMRD haematological malignancies and in 0% of non-neoplastic CMMRD tissues [[9]]. Here, 1/17 (5.9%, 95% CI: 0.2-28.7%) ALL patients with SMN had CMMRD, which is similar to the 14/189 (7.4%, 95% CI: 4.1-12.1%) pediatric non-Hodgkin lymphoma patients with SMN who had CMMRD in another recent study [[16]]. Constitutional mismatch repair deficiency (CMMRD, MIM #276300) is a rare, recessive pediatric and adolescent cancer syndrome, caused by pathogenic variants in a mismatch repair (MMR) gene: I MLH1 i , I MSH2 i , I MSH6 i , or I PMS2 i . [Extracted from the article]

We measured the variation in practice across all aspects of endometrial cancer (EC) management and assessed the potential impact of implementation of molecular classification. Centers from across Canada provided representative tumor samples and clinical data, including preoperative workup, operative management, hereditary cancer program (HCP) referrals, adjuvant therapy, surveillance and outcomes, for all EC patients diagnosed in 2016. Tumors were classified into the four ProMisE molecular subtypes. A total of 1336 fully evaluable EC patients were identified from 10 tertiary cancer centers (TC; n = 1022) and 19 community centers (CC; n = 314). Variation of surgical practice across TCs was profound (14–100%) for lymphadenectomy (LND) (mean 57% Gr1/2, 82% Gr3) and omental sampling (20% Gr1/2, 79% Gr3). Preoperative CT scans were inconsistently obtained (mean 32% Gr1/2, 51% Gr3) and use of adjuvant chemo or chemoRT in high risk EC ranged from 0–55% and 64–100%, respectively. Molecular subtyping was performed retrospectively and identified 6% POLE mut, 28% MMRd, 48% NSMP and 18% p53abn ECs, and was significantly associated with survival. Within patients retrospectively diagnosed with MMRd EC only 22% had been referred to HCP. Of patients with p53abn EC, LND and omental sampling was not performed in 21% and 23% respectively, and 41% received no chemotherapy. Comparison of management in 2016 with current 2020 ESGO/ESTRO/ESP guidelines identified at least 26 and 95 patients that would have been directed to less or more adjuvant therapy, respectively (10% of cohort). Molecular classification has the potential to mitigate the profound variation in practice demonstrated in current EC care, enabling reproducible risk assessment, guiding treatment and reducing health care disparities. • Characterization of National practice in EC reveals profound variation in workup, surgery, treatment, and genetic testing. • Molecular classification identified missed opportunities for EC patients managed by traditional risk stratification. • Both overtreatment (POLE mut given adjuvant therapy) and undertreatment (p53abn not given chemo or any therapy) were exposed. • Only 22% retrospectively identified MMRd ECs had been referred for genetic testing with <4% confirmed to have Lynch Syndrome. • Molecular classification can objectively categorize ECs, direct treatment, and has the potential to reduce practice variation and disparities. [ABSTRACT FROM AUTHOR]

Keywords: ambiguous lineage leukaemia; bilineal; monocytic; paediatric EN ambiguous lineage leukaemia bilineal monocytic paediatric e34 e39 6 01/28/22 20220201 NES 220201 Ambiguous lineage leukaemia (ALAL) is a rare sub-type of paediatric acute leukaemia. There are four main subgroups according to the lineage of differentiation, namely: (i) mixed phenotype acute leukaemia (MPAL), (ii) bilineal acute leukaemia, (iii) undifferentiated acute leukaemia, and (iv) acute leukaemia with early switch to a different lineage.1-4 MPAL accounts for 1-2% of paediatric leukaemia.3 The World Health Organization (WHO) classifications (2008 and 2016) have established strict criteria for diagnosis of MPAL, emphasising myeloperoxidase for myeloid lineage, cytoplasmic cluster of differentiation 3 (CD3) for T lineage, and CD19 and other B markers for B lineage.1,4 Flow cytometry has been pivotal in diagnosis, treatment response and minimal residual disease (MRD) assessment in MPAL. Acute lymphoblastic leukemia-like treatment regimen provides better response in mixed phenotype acute leukemia: a comparative study between adults and pediatric MPAL patients. A provisional diagnosis of AML with monocytic differentiation was considered and commenced on AML treatment as per UK national guidelines due to rising white blood cell counts (Table I). [Extracted from the article]

Objective Clinical similarities between the metabolic syndrome and Cushing's syndrome have led to speculation of genetic association between them. The Bcl1 polymorphism in intron 2 of the glucocorticoid receptor (GR) gene has been associated with insulin resistance/hyperinsulinaemia. Our objective was to test the association of rs2918419, a T→C single nucleotide change in intron 2 downstream of the Bcl1 locus, with components of the metabolic syndrome and its interaction with the Bcl1 locus. Design and methods We genotyped a subsample of 325 White subjects (116 men) in the Newcastle Heart Project (NHP), a population-based study in north-east England. Gender-specific statistical analysis by stepwise backward multiple regression was performed to test the association of allele status with adiposity, glucose and insulin responses to oral glucose tolerance test (OGTT), fasting lipids and blood pressure. Results Minor allele frequency was 0·14 for rs2918419 and 0·39 for the Bcl1 polymorphism. rs2918419 was associated with higher fasting insulin concentration and insulin resistance in men but not in women. Contrary to earlier studies, the Bcl1 polymorphism on its own was not associated with insulin resistance/hyperinsulinaemia in either gender. Subjects carrying variant rs2918419 alleles also had variant alleles at the Bcl1 locus. In men, but not women, Bcl1 variant alleles on a background of rs2918419 wild-type alleles associated with lower fasting insulin compared to wild-type alleles at both loci or variant alleles at both loci. Conclusions We report that rs2918419 was linked with hyperinsulinaemia and insulin resistance in men. Carrying Bcl1 variant alleles without rs2918419 was not associated with hyperinsulinaemia/insulin resistance. Previous reports of the association of Bcl1 polymorphism with obesity-related characteristics may reflect linkage disequilibrium with rs2918419. [ABSTRACT FROM AUTHOR]

Background: Treatment on risk adapted intensive pediatric protocols has improved outcome for teenagers and young adults (TYA) with T‐cell acute lymphoblastic leukemia (T‐ALL). Understanding the biology of disease in this age group and the genetic basis of relapse is a key goal as patients with relapsed/refractory disease have poor outcomes with conventional chemotherapy and novel molecular targets are required. This study examines the question of whether TYA T‐ALL has a specific biological‐molecular profile distinct from pediatric or adult T‐ALL. Methods: Genomic characterization was undertaken of a retrospective discovery cohort of 80 patients aged 15–26 years with primary or relapsed T‐ALL, using a combination of Genome‐Wide Human SNP Array 6.0, targeted gene mutation and promoter methylation analyses. Findings were confirmed by MLPA, real‐time quantitative PCR, and FISH. Whole Exome Sequencing was performed in 4 patients with matched presentation and relapse to model clonal evolution. A prevalence analysis was performed on a final data set of 1,792 individual cases to identify genetic lesions with age specific frequency patterns, including 972 pediatric (1–14 years), 439 TYA (15–24 years) and 381 adult (≥25 years) cases. These cases were extracted from 19 publications with comparable genomic data identified through a PubMed search. Results: Genomic characterization of this large cohort of TYA T‐ALL patients identified recurrent isochromosome 7q i(7q) in our discovery cohort (n = 3). Prevalence analysis did not identify any age specific genetic abnormalities. Genomic analysis of 6 pairs of matched presentation – relapsed T‐ALL established that all relapses were clonally related to the initial leukemia. Whole exome sequencing analysis revealed recurrent, targetable, mutations disrupting NOTCH, PI3K/AKT/mTOR, FLT3, NRAS as well as drug metabolism pathways. Conclusions: All genetic aberrations in TYA T‐ALL occurred with an incidence similar or intermediate to that reported in the pediatric and adult literature, demonstrating that overall TYA T‐ALL exhibits a transitional genomic profile. Analysis of matched presentation – relapse supported the hypothesis that relapse is driven by the Darwinian evolution of sub‐clones associated with drug resistance (NT5C2 and TP53 mutations) and re‐iterative mutation of known key T‐ALL drivers, including NOTCH1. [ABSTRACT FROM AUTHOR]

Outcomes of children with high-risk (HR) relapsed acute lymphoblastic leukaemia (ALL) (N = 393), recruited to ALLR3 and ALL-REZ BFM 2002 trials, were analysed. Minimal residual disease (MRD) was assessed after induction and at predetermined time points until haematopoietic stem cell transplantation (SCT). Genetic analyses included karyotype, copy-number alterations and mutation analyses. Ten-year survivals were analysed using Kaplan-Meier and Cox models for multivariable analyses. Outcomes of patients were comparable in ALLR3 and ALL-REZ BFM 2002. The event-free survival of B-cell precursor (BCP) and T-cell ALL (T-ALL) was 22.6% and 26.2% (P = 0. 94), respectively, and the overall survival (OS) was 32.6% and 28.2% (P = 0.11), respectively. Induction failures (38%) were associated with deletions of NR3C1 (P = 0.002) and BTG1 (P = 0. 03) in BCP-ALL. The disease-free survival (DFS) and OS in patients with good vs poor MRD responses were 57.4% vs 22.6% (P < 0.0001) and 57.8% vs 32.0% (P = 0. 0004), respectively. For BCP- and T-ALL, the post-SCT DFS and OS were 42.1% and 56.8% (P = 0. 26) and 51.6% and 55.4% (P = 0. 67), respectively. The cumulative incidences of post-SCT relapse for BCP- and T-ALL were 36.9% and 17.8% (P = 0. 012) and of death were 10.7% and 25.5% (P = 0. 013), respectively. Determinants of outcomes after SCT were acute graft versus host disease, pre-SCT MRD (≥10−3), HR cytogenetics and TP53 alterations in BCP-ALL. Improvements in outcomes for HR ALL relapses require novel compounds in induction therapy to improve remission rates and immune targeted therapy after induction to maintain remission after SCT. ALLR3: NCT00967057 ; ALL REZ-BFM 2002: NCT00114348 • Paediatric high-risk relapsed B- and T-cell leukaemias have comparably poor outcomes. • Determinants of induction failure in high-risk B-cell relapses were identified. • Molecular good responders had better outcomes after stem cell transplantation. • Benchmarks for evaluation of novel immune or targeted therapies were provided. [ABSTRACT FROM AUTHOR]

The use of dexamethasone in acute lymphoblastic leukaemia therapy contributes to short- and long-term toxicities. The UKALL 2011 randomised trial investigated whether a more intense dexamethasone dose (10 mg/m2/d x 14d, short vs 6 mg/m2/d x 28d, standard) would lead to a more rapid cytoreduction and reduced adverse effects associated with longer durations of steroids in induction. The impact of dose and duration on dexamethasone pharmacokinetics was investigated. Blood samples were obtained on one of the first three and last three days of induction dexamethasone dosing at time points up to 8 h after oral administration. Plasma dexamethasone levels were quantified in 1084 plasma samples obtained from 174 children and a population pharmacokinetic model developed. Drug exposure varied significantly between patients, with a >12-fold variation in AUC 0–12h values and a marked overlap in dexamethasone exposures between dose levels. Intuitively, AUC 0–12h was significantly higher with short dosing (10 mg/m2/d), but cumulative exposure was significantly higher with standard dosing over 28 days, after a higher cumulative dose. Concomitant rasburicase administration was associated with a 60% higher dexamethasone clearance. Day 8 bone marrow response was comparable between dosing arms, but those with <5% blast count exhibited a greater mean dexamethasone exposure than those with >5%. No statistical differences were observed between arms in terms of steroid-related toxicity or minimal residual disease at the end of induction. The potential significance of dexamethasone AUC 0–12h on early response and higher cumulative exposure on the standard arm suggest that duration of therapy and exposure may be more important factors than absolute dose from a clinical pharmacology perspective. • The impact of dose and duration on dexamethasone pharmacokinetics has been investigated in ALL patients. • Dexamethasone levels were quantified in 1084 plasma samples obtained from 174 children. • Marked interpatient pharmacokinetic variability was observed between patients on different dose levels. • Patients with a day 8 blast count <5% had significantly higher dexamethasone exposures than those with a blast count >5%. • Duration of dexamethasone therapy may be more important than absolute dose from a clinical pharmacology perspective. [ABSTRACT FROM AUTHOR]

Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Münster Study of Leukemias of Ambiguous Lineage [iBFM-AMBI2012]) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)- type primary therapy (80% ± 4%) was superior to that of children who received acute myeloid leukemia (AML)-type or combined-type treatment (36% ± 7.2% and 50% ± 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19+ leukemia was 83% ± 5.3% on ALL-type primary treatment compared with 0% ± 0% and 28% ± 14% on AML-type and combined-type primary treatment, respectively. Superiority of ALL-type treatment was documented in single-population mixed phenotype ALAL (using World Health Organization and/or European Group for Immunophenotyping of Leukemia definitions) and bilineal ALAL. Treatment with ALL-type protocols is recommended for the majority of pediatric patients with ALAL, including cases with CD19+ ALAL. AMLtype treatment is preferred in a minority of ALAL cases with CD19- and no other lymphoid features. No overall benefit of transplantation was documented, and it could be introduced in some patients with a poor response to treatment. As no clear indicator was found for a change in treatment type, this is to be considered only in cases with ≥5% blasts after remission induction. The results provide a basis for a prospective trial. [ABSTRACT FROM AUTHOR]

Objective: Both Mindfulness Based Cognitive Therapy (MBCT) and Cognitive Therapy (CT) enhance self-management of prodromal symptoms associated with depressive relapse, albeit through divergent therapeutic procedures. We evaluated rates of relapse in remitted depressed patients receiving MBCT and CT. Decentering and dysfunctional attitudes were assessed as treatment-specific process markers. Method: Participants in remission from Major Depressive Disorder (MDD; N = 166) were randomized to 8 weeks of either MBCT (N = 82) or CT (N = 84) and were followed for 24 months, with process markers measured every 3 months. Attendance in both treatments was high (6.3/8 session) and treatment fidelity and competence were evaluated. Relapse was defined as a return of symptoms meeting the criteria for major depression on Module A of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID). Results: Intention-to-treat analyses indicated no differences between MBCT and CT in either rates of relapse to MDD or time to relapse across 24 months of follow up. Both groups experienced significant increases in decentering and participants in CT reported greater reductions in dysfunctional attitudes. Within both treatments, participants who relapsed evidenced lower decentering scores than those who stayed well over the follow up. Conclusions: This is the first study to directly compare relapse prophylaxis following MBCT and CT directly. The lack of group differences in time to relapse supports the view that both interventions are equally effective and that increases in decentering achieved via either treatment are associated with greater protection. These findings lend credence to Teasdale et al.’s (2002) contention that, even though they may be taught through dissimilar methods, CT and MBCT help participants develop similar metacognitive skills for the regulation of distressing thoughts and emotions. [ABSTRACT FROM AUTHOR]

Background Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD) are highly prevalent, comorbid, and have significant impact on morbidity, mortality, and socioeconomic burden in Canada. Combined psycho- and pharmacotherapies for both conditions promise better outcomes than treatment as usual (TAU). At the Centre for Addiction and Mental Health, Toronto, Canada, we developed and implemented an Integrated Care Pathway (ICP) specifically for treatment of concurrent MDD and AUD. The goal of the study is to assess the clinical effectiveness of the ICP approach in comparison to TAU. Materials and Methods Non-randomized design, clinical chart review, Chi-square and t-tests, Cohen's d, Linear Mixed Effects Models, Kaplan-Meier, and log-rank analyses. Results Eighty-one ICP patients were included, matched to 81 controls by age, sex, severity of depressive symptoms, and patterns of drinking. ICP cohort had a significantly lower dropout rate (18.5% vs 69.1%, p < .001; at 16 weeks of treatment, respectively), both cohorts demonstrated significant reduction in the number of heavy drinking days ( β = .01, p < .001) and standard drinks per week ( β = .15, p < .001) with a significantly higher reduction of both indicators over time in the ICP cohort. Significant reduction in depressive symptoms severity (QIDS: 14.6 vs 10.0, p < .001; BDI: 26.3 vs 16.2, p < .001) was observed in ICP cohort (no data for TAU cohort). Conclusions The ICP patients demonstrated improvements on several levels including depressive symptoms, and changes in alcohol drinking patterns. The study demonstrated the overall effectiveness of the ICP and apparent advantage over TAU, which must be corroborated through a randomized clinical trial. (Am J Addict 2017;26:602-609) Scientific Significance This study is one of the first works showing the outcomes of an ICP developed in the mental health area and for co-occurring disorders. Despite the limitations, the relative advantage of the ICP methodology warrants future research in this area. [ABSTRACT FROM AUTHOR]

Prevention of central nervous system (CNS) relapse is critical for cure of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Despite this, mechanisms of CNS infiltration are poorly understood, and the timing, frequency, and properties of BCP-ALL blasts entering the CNS compartment are unknown. We investigated the CNS-engrafting potential of BCP-ALL cells xenotransplanted into immunodeficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJmice. CNS engraftmentwas seen in 23 of 29 diagnostic samples (79%): 2 of 2 from patients with overt CNS disease and 21 of 27 from patients thought to be CNS negative by diagnostic lumbar puncture. Histologic findings mimic human pathology and demonstrate that leukemic cells transit the blood-cerebrospinal fluid barrier situated close to the dural sinuses, the site of recently discovered CNS lymphatics. Retrieval of blasts from the CNS showed no evidence for chemokine receptor-mediated selective trafficking. The high frequency of infiltration and lack of selective trafficking led us to postulate that CNS tropism is a generic property of leukemic cells. To test this, we performed serial dilution experiments which showed CNS engraftment in 5 of 6mice after transplant of as few as 10 leukemic cells. Clonal tracking techniques confirmed the polyclonal nature of CNS-infiltrating cells, with multiple clones engrafting in both the CNS and periphery. Overall, these findings suggest that subclinical seeding of the CNS is likely to be present in most BCP-ALL patients at original diagnosis, and efforts to prevent CNS relapse should concentrate on effective eradication of disease from this site rather than targeting entry mechanisms. [ABSTRACT FROM AUTHOR]

Noonan syndrome is associated with a range of malignancies including acute lymphoblastic leukemia (ALL). However, little information is available regarding the frequency, natural history, characteristics and prognosis of ALL in Noonan syndrome or RASopathies in general. Cross-referencing data from a large prospective cohort of 1176 patients having a molecularly confirmed RASopathy with data from the French childhood cancer registry allowed us to identify ALL in 6 (0.5%) patients including 4/778 (0.5%) with a germline PTPN11 mutation and 2/94 (2.1%) with a germline SOS1 mutation. None of the patients of our series with CFC syndrome (with germline BRAF or MAP2K1 / MAP2K2 mutation – n = 121) or Costello syndrome (with HRAS mutation – n = 35) had an ALL. A total of 19 Noonan-ALL were gathered by adding our patients to those of the International Berlin-Munster-Frankfurt (I-BFM) study group and previously reported patients. Strikingly, all Noonan-associated ALL were B-cell precursor ALL, and high hyperdiploidy with more than 50 chromosomes was found in the leukemia cells of 13/17 (76%) patients with available genetics data. Our data suggest that children with Noonan syndrome are at higher risk to develop ALL. Like what is observed for somatic PTPN11 mutations, NS is preferentially associated with the development of hyperdiploid ALL that will usually respond well to chemotherapy. However, Noonan syndrome patients seem to have a propensity to develop post therapy myelodysplasia that can eventually be fatal. Hence, one should be particularly cautious when treating these patients. [ABSTRACT FROM AUTHOR]

Glucocorticoid ( GC) resistance is a continuing clinical problem in childhood acute lymphoblastic leukaemia ( ALL) but the underlying mechanisms remain unclear. A proteomic approach was used to compare profiles of the B-lineage ALL GC-sensitive cell line, PreB 697, and its GC-resistant sub-line, R3F9, pre- and post-dexamethasone exposure. PAX5, a transcription factor critical to B-cell development was differentially regulated in the PreB 697 compared to the R3F9 cell line in response to GC. PAX5 basal protein expression was less in R3F9 compared to its GC-sensitive parent and confirmed to be lower in other GC-resistant sub-lines of Pre B 697 and was associated with a decreased expression of the PAX5 transcriptional target, CD19. Gene set enrichment analysis showed that increasing GC-resistance was associated with differentiation from preB- II to an immature B-lymphocyte stage. GC-resistant sub-lines were shown to have higher levels of phosphorylated JNK compared to the parent line and JNK inhibition caused re-sensitization to GC. Exploiting this maturation may be key to overcoming GC resistance and targeting signalling pathways linked to the maturation state, such as JNK, may be a novel approach. [ABSTRACT FROM AUTHOR]

Mindfulness-based cognitive therapy (MBCT) and mindfulness-based stress reduction (MBSR) are particularly effective treatment approaches in terms of alleviating depressive symptoms and preventing relapse once remission has been achieved. Although engaging in mindfulness practice is an essential element of both treatments; it is unclear whether informal or formal practices differentially impact on symptom alleviation. The current study utilizes a correlational design to examine data provided by thirty-two previously depressed, remitted outpatients who received either MBCT or MBSR treatment. Outpatients in the MBCT group received treatment as part of a previously published randomized efficacy trial (Segal et al. in Arch Gen Psychiatry 67:1256-1264, ), while those in the MBSR group received treatment as part of a separate, unpublished randomized clinical trial. Throughout treatment, clients reported on their use of formal and informal mindfulness practices. Results indicate that engaging in formal (but not informal) mindfulness practice was associated with decreased rumination, which was associated with symptom alleviation. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is the major pediatric cancer diagnosed in economically developed countries with B-cell precursor (BCP)-ALL, accounting for approximately 70% of ALL. Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence for common inherited susceptibility to BCP-ALL, identifying susceptibility loci at 7p12.2, 9p21.3,10q21.2, and 14q11.2. To identify additional BCP-ALL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1658 cases and 4723 controls, with validation in 1449 cases and 1488 controls. Combined analysis identified novel loci mapping to 10p12.2 (rs10828317, odds ratio [OR] = 1.23; P = 2.30 × 10-9) and 10p14 marked by rs3824662 (OR = 1.31; P = 8.62 × 10-12). The single nucleotide polymorphism rs10828317 is responsible for the N215S polymorphism in exon 7 of PIP4K2A, and rs3824662 localizes to intron 3 of the transcription factor and putative tumor suppressor gene GATA3. The rs10828317 association was shown to be specifically associated with hyperdiploid ALL, whereas the rs3824662-associated risk was confined to nonhyperdiploid non-TEL-AML1 + ALL. The risk allele of rs3824662 was correlated with older age at diagnosis (P< .001) and significantly worse event-free survivorship (P < .0001). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to BCP-ALL and the influence of constitutional genotype on disease development. [ABSTRACT FROM AUTHOR]

To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 × 10−14), 6p21.33 (rs2285803, PSORS1C2, P = 9.67 × 10−11), 17p11.2 (rs4273077, TNFRSF13B, P = 7.67 × 10−9) and 22q13.1 (rs877529, CBX7, P = 7.63 × 10−16). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition. [ABSTRACT FROM AUTHOR]

Abstract: Background: Fibroblast growth factor receptor 3 (FGFR3) is up-regulated as a result of the t(4;14)(p16;q32) translocation that occurs in up to 20% of multiple myeloma (MM) patients. Recent studies have demonstrated that up-regulation of FGFR3 promotes cell survival, growth and drug resistance in malignant plasma cells, both in vitro and in vivo. Therefore, inhibition of FGFR3 signalling is potential target for the chemotherapeutic intervention in t(4;14) MM. Methods: Small molecule receptor tyrosine kinase inhibitors (PD173074, sunitinib (SU-11248), vandetanib (ZD6474) and vatalanib (PTK-787)) with varying degrees of inhibitory activity and selectivity against FGFR, were assessed in Ba/f3 cells expressing ZNF198-FGFR1 and MM cell lines. Cell viability, FGFR3 and ZNF198-FGFR1 phosphorylation and apoptosis were evaluated by growth inhibition assays, immunoblotting and fluorescence-activated cell sorting analysis, respectively. An in vivo study was performed with sunitinib in t(4;14)-positive and t(4;14)-negative human MM tumour xenograft models. Results: PD173074 and sunitinib differentially inhibited the growth of Ba/f3 cells expressing ZNF198-FGFR1 (GI50 =10nM and 730nM, versus GI50 >1μM and 2.7μM for parental cells; p <0.0001) and t(4;14) positive MM cell lines (GI50 =4–10μM and 1–3μM, versus GI50 =14–15μM and 4–5μM for t(4;14) negative MM cells; p ≤0.002). In addition, both PD173074 and sunitinib inhibited the activation of FGFR3 in t(4;14)-positive MM cells. PD173074 and sunitinib induced an apoptotic response in a concentration and time-dependent manner in a t(4;14)-positive (PD174073 and sunitinib) but not a t(4;14)-negative MM cell line (sunitinib only); however, in in vivo tumours derived from the same cell lines, sunitinib was only active in the t(4;14)-negative model. Conclusions: These data demonstrate that PD173074 and sunitinib are inhibitors of FGFR3 in MM cell lines, and that sunitinib has in vivo activity in a human MM tumour xenograft model. However, caution should be exercised in using the t(4;14) translocation as a predictive biomarker for patient selection in clinical trials with sunitinib. [Copyright &y& Elsevier]

Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) that has a dismal outcome when treated with standard therapy. For improved diagnosis and risk stratification, the initiating genetic events need to be elucidated. To investigate the genetic basis of BCP-ALL, genomes of 94 iAMP21 patients were interrogated by arrays, FISH, and multiplex ligation-dependent probe amplification. Most copy number alterations targeted chromosome 21, reinforcing the complexity of this chromosome. The common region of amplification on chromosome 21 was refined to a 5.1-mb region that included RUNX1, miR-802, and genes mapping to the Down syndrome critical region. Recurrent abnormalities affecting genes in key pathways were identified: IKZF1 (22%), CDKN2A/B (17%), PAX5 (8%), ETV6 (19%), and RB1 (37%). Investigation of clonal architecture provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to chromosome 21 rearrangements. Patient outcome was uniformly poor with standard therapy irrespective of the presence or absence of these changes. This study has provided evidence that chromosome 21 instability is the only anomaly among those so far investigated that is common to all iAMP21 patients, and therefore the initiating event is likely to be found among the complex structural rearrangements of this abnormal chromosome. [ABSTRACT FROM AUTHOR]

Abstract: Glucocorticoids (GCs) are pivotal agents in the treatment of childhood acute lymphoblastic leukaemia (ALL) but the molecular basis of GC-resistance remains unclear. Expression-array studies have shown that commonly upregulated genes associated with GC-sensitivity include GR, glucocorticoid-induced leucine zipper (GILZ) and IκBα, which all negatively interact with components of the pro-survival NFκB pathway and therefore may be critical determinants of GC-sensitivity. We have investigated these regulators and their effect on NFκB activity in GC-resistant descendents of the B-lineage ALL cell line, PreB 697. We show that while differential up regulation of the modulators (GILZ, GR and IκBα) was demonstrated in GC-sensitive compared to GC-resistant sub-lines, this was not coupled with altered nuclear translocation or functionality of the RelA, p50 or c-Rel subunits of NFκB. Thus, GC-resistance in the PreB 697 cell line model is not mediated by NFκB, however further investigation of the impact of these GC-sensitive associated proteins on other survival pathways, such as the RAS-RAF-MEK-ERK pathway, is warranted. [ABSTRACT FROM AUTHOR]

Abstract: The mismatch repair (MMR) pathway is a post-replicative DNA repair process and MMR deficiency is a common feature of ALL cell lines. In this study we have investigated MMR deficiency in a large cohort of primary relapsed ALL (n =40) and investigated coding microsatellites (MS) of the lymphoid transcription factors, PAX5 and IKZF1 as downstream target genes. Only one patient showed MMR deficiency, as evidenced by microsatellite instability, which was acquired at relapse and was associated with reduced expression of both MLH1 and MSH2. Coding MS in candidate target genes including PAX5, IKZF1, BAX and TGFBRII were all wild type in this patient but the MMR-deficient cell line REH, was confirmed to have a coding MS in both PAX5 and TGFBRII. Whilst MMR deficiency is not highly prevalent in primary ALL, optimisation of the drug regimen to omit/replace thioguanines should be considered for children with MMR deficiency and/or reduced expression of key pathway components. [Copyright &y& Elsevier]

Abstract: Mismatch repair (MMR) deficiency is a common feature of acute lymphoblastic leukaemia (ALL) cell lines and in some cases is due to the mutations of hMLH1 which affect mRNA splicing. Therefore, we have analysed alternative splicing of hMLH1 in a cohort of children with ALL. We show that alternative splicing of hMLH1 is highly variable in normal and leukaemic cells and can occur by exon skipping or by the use of an alternative splice site, both serving to down-regulate the amount of full-length hMLH1 mRNA/protein produced. Aberrant splicing was found in one child with an aggressive leukaemia in which there was a predominant hMLH1Δ6 form and an associated loss of wild-type hMLH1 protein but this was not accompanied by microsatellite instability. Functional analysis of one of the most abundant spliced forms, hMLH1Δ9/10, was shown to have a significant dominant negative effect on the functionality of the MMR pathway but again was similarly expressed in ALL and normal cells. [Copyright &y& Elsevier]

To identify risk variants for childhood acute lymphoblastic leukemia (ALL), we conducted a genome-wide association study of two case-control series, analyzing the genotypes with respect to 291,423 tagging SNPs in a total of 907 ALL cases and 2,398 controls. We identified risk loci for ALL at 7p12.2 (IKZF1, rs4132601, odds ratio (OR) = 1.69, P = 1.20 × 10−19), 10q21.2 (ARID5B, rs7089424, OR = 1.65, P = 6.69 × 10−19) and 14q11.2 (CEBPE, rs2239633, OR = 1.34, P = 2.88 × 10−7). The 10q21.2 (ARID5B) risk association appears to be selective for the subset of B-cell precursor ALL with hyperdiploidy. These data show that common low-penetrance susceptibility alleles contribute to the risk of developing childhood ALL and provide new insight into disease causation of this specific hematological cancer. Notably, all three risk variants map to genes involved in transcriptional regulation and differentiation of B-cell progenitors. [ABSTRACT FROM AUTHOR]

Promoter methylation is a common phenomenon in tumours, including haematological malignancies. In the present study, we investigated 36 cases of high hyperdiploid (>50 chromosomes) acute lymphoblastic leukaemia (ALL) with methylation-specific multiplex ligase-dependent probe amplification to determine the extent of aberrant methylation in this subgroup. The analysis, which comprised the promoters of 35 known tumour suppressor genes, showed that 16 genes displayed abnormal methylation in at least one case each. The highest number of methylated gene promoters seen in a single case was thirteen, with all but one case displaying methylation for at least one gene. The most common targets were ESR1 (29/36 cases; 81%), CADM1 ( IGSF4, TSLC1; 25/36 cases; 69%), FHIT (24/36 cases; 67%) and RARB (22/36 cases; 61%). Interestingly, quantitative reverse transcription-polymerase chain reaction showed that although methylation of the CADM1 and RARB promoters resulted in the expected pattern of downregulation of the respective genes, no difference could be detected in FHIT expression between methylation-positive and -negative cases. Furthermore, TIMP3 was not expressed regardless of methylation status, showing that aberrant methylation does not always lead to gene expression changes. Taken together, our findings suggest that aberrant methylation of tumour suppressor gene promoters is a common phenomenon in high hyperdiploid ALL. [ABSTRACT FROM AUTHOR]

Summary: We examined the leukemic stem cell potential of blasts at different stages of maturation in childhood acute lymphoblastic leukemia (ALL). Human leukemic bone marrow was transplanted intrafemorally into NOD/scid mice. Cells sorted using the B precursor differentiation markers CD19, CD20, and CD34 were isolated from patient samples and engrafted mice before serial transplantation into primary or subsequent (up to quaternary) recipients. Surprisingly, blasts representative of all of the different maturational stages were able to reconstitute and reestablish the complete leukemic phenotype in vivo. Sorted blast populations mirrored normal B precursor cells with transcription of a number of stage-appropriate genes. These observations inform a model for leukemia-propagating stem cells in childhood ALL. [Copyright &y& Elsevier]

A letter to the editor is presented related to the impact of pathogenesis in chronic lymphocytic leukaemia and Hodgkin lymphoma on multiple myeloma.

Using data from a genome-wide association study of 907 individuals with childhood acute lymphoblastic leukemia (cases) and 2,398 controls and with validation in samples totaling 2,386 cases and 2,419 controls, we have shown that common variation at 9p21.3 (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk (odds ratio = 0.71, P = 3.01 × 10−11), irrespective of cell lineage. [ABSTRACT FROM AUTHOR]

Background: Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD) are highly prevalent, comorbid, and have significant impact on morbidity, mortality, and socioeconomic burden in Canada. Combined psycho- and pharmacotherapies for both conditions promise better outcomes than treatment as usual (TAU). At the Centre for Addiction and Mental Health, Toronto, Canada, we developed and implemented an Integrated Care Pathway (ICP) specifically for treatment of concurrent MDD and AUD. The goal of the study is to assess the clinical effectiveness of the ICP approach in comparison to TAU.Materials and Methods: Non-randomized design, clinical chart review, Chi-square and t-tests, Cohen's d, Linear Mixed Effects Models, Kaplan-Meier, and log-rank analyses.Results: Eighty-one ICP patients were included, matched to 81 controls by age, sex, severity of depressive symptoms, and patterns of drinking. ICP cohort had a significantly lower dropout rate (18.5% vs 69.1%, p < .001; at 16 weeks of treatment, respectively), both cohorts demonstrated significant reduction in the number of heavy drinking days (β = .01, p < .001) and standard drinks per week (β = .15, p < .001) with a significantly higher reduction of both indicators over time in the ICP cohort. Significant reduction in depressive symptoms severity (QIDS: 14.6 vs 10.0, p < .001; BDI: 26.3 vs 16.2, p < .001) was observed in ICP cohort (no data for TAU cohort).Conclusions: The ICP patients demonstrated improvements on several levels including depressive symptoms, and changes in alcohol drinking patterns. The study demonstrated the overall effectiveness of the ICP and apparent advantage over TAU, which must be corroborated through a randomized clinical trial. (Am J Addict 2017;26:602-609) SCIENTIFIC SIGNIFICANCE: This study is one of the first works showing the outcomes of an ICP developed in the mental health area and for co-occurring disorders. Despite the limitations, the relative advantage of the ICP methodology warrants future research in this area. [ABSTRACT FROM AUTHOR]

Presents a letter about V617F mutation in Jak2 kinase in childhood acute lymphoblastic leukemia

In silico analyses have established that transcripts from some genes can be processed into RNAs with rearranged exon order relative to genomic structure (post-transcriptional exon shuffling, or PTES). Although known to contribute to transcriptome diversity in some species, to date the structure, distribution, abundance, and functional significance of human PTES transcripts remains largely unknown. Here, using high-throughput transcriptome sequencing, we identify 205 putative human PTES products from 176 genes. We validate 72 out of 112 products analyzed using RT-PCR, and identify additional PTES products structurally related to 61% of validated targets. Sequencing of these additional products reveals GT-AG dinucleotides at >95% of the splice junctions, confirming that they are processed by the spliceosome. We show that most PTES transcripts are expressed in a wide variety of human tissues, that they can be polyadenylated, and that some are conserved in mouse. We also show that they can extend into 5' and 3' UTRs, consistent with formation via trans-splicing of independent pre-mRNA molecules. Finally, we use real-time PCR to compare the abundance of PTES exon junctions relative to canonical exon junctions within the transcripts from seven genes. PTES exon junctions are present at <0.01% to >90% of the levels of canonical junctions, with transcripts from MAN1A2, PHC3, TLE4, and CDK13 exhibiting the highest levels. This is the first systematic experimental analysis of PTES in human, and it suggests both that the phenomenon is much more widespread than previously thought and that some PTES transcripts could be functional. [ABSTRACT FROM AUTHOR]