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in situ hybridization assay, whereas all non--YWHAE-FAM22 tumors were confirmed to lack YWHAE rearrangement by fluorescence in situ hybridization assay. The reverse transcription--polymerase chain reaction assay optimized for formalin-fixed and paraffin-embedded samples detected YWHAE-FAM22 fusion transcripts in all 6 YWHAE-FAM22 endometrial stromal sarcomas and none of the 24 non-- YWHAE-FAM22 uterine sarcomas. These findings show that this reverse transcription-polymerase chain reaction assay is sensitive and specific for detection of YWHAE-FAM22 fusion transcript and can serve as a useful adjunct diagnostic assay to confirm the diagnosis of YWHAE-FAM22 endometrial stromal sarcoma in formalin-fixed and paraffin-embedded tumor samples. [ABSTRACT FROM AUTHOR]

Abstract: Demands faced by health care professionals include heavy caseloads, limited control over the work environment, long hours, as well as organizational structures and systems in transition. Such conditions have been directly linked to increased stress and symptoms of burnout, which in turn, have adverse consequences for clinicians and the quality of care that is provided to patients. Consequently, there exists an impetus for the development of curriculum aimed at fostering wellness and the necessary self-care skills for clinicians. This review will examine the potential benefits of mindfulness-based stress reduction (MBSR) programs aimed at enhancing well-being and coping with stress in this population. Empirical evidence indicates that participation in MBSR yields benefits for clinicians in the domains of physical and mental health. Conceptual and methodological limitations of the existing studies and suggestions for future research are discussed. [Copyright &y& Elsevier]

Summary: Ovarian surface epithelial carcinomas are routinely subclassified by pathologists based on tumor cell type and grade. It is controversial whether cell type or grade is superior in predicting patient response to treatment or survival, in patients stratified by stage of disease. The aim of this study was to uniformly apply updated criteria for cell-type and grade assignment to a series of 575 cases of ovarian surface epithelial carcinoma. All patients were optimally surgically debulked, with no macroscopic residual disease after primary surgery. Slides from these cases were reviewed by a single pathologist, who was blinded to patient outcomes. In 50 cases, 2 additional pathologists reviewed the slides independently to determine interobserver variation in assessment of cell type and grade. The distribution of tumor stage was as follows: stage I—233 cases, stage II—246 cases, stage III—96 cases. The most common cell type encountered was serous carcinoma (229/575, 40%), followed by clear cell (149/575, 26%), endometrioid (139/575, 24%), and mucinous (36/575, 6%). Serous carcinomas were significantly more likely to present with advanced stage disease (76/229 [33.2%] were stage III, and 82% of all stage III tumors were serous), whereas all nonserous cell types were stage I or II at diagnosis in greater than 90% of cases. Both FIGO grade and Silverberg grade stratified patients into groups with significantly different risks of relapse and survival, but the Silverberg grading system was a more powerful prognosticator. In multivariate analysis, stage was the most powerful prognostic indicator (P < .0001), followed by tumor cell type (P = .015), but grade was not of independent significance. Interobserver variation in assignment of cell type was very good (κ = 0.77) with moderate reproducibility in assignment of Silverberg grade (κ = 0.40) and minimal reproducibility in assignment of FIGO grade (κ = 0.27). Thus, in this series of cases of ovarian surface epithelial carcinomas with no macroscopic residual disease after primary debulking surgery, assignment of tumor cell type was both more reproducible and provided superior prognostic information compared with assignment of tumor grade. As tumor cell type also correlates with underlying molecular abnormalities and may predict response to chemotherapy, this suggests that tumor cell type could be used to guide treatment decisions for patients with ovarian surface epithelial carcinoma. [Copyright &y& Elsevier]

Summary: Diagnosis of synchronous endometrioid carcinomas of the uterine corpus and ovary as either separate independent primary or as metastatic tumors requires careful consideration of a number of gross and histological features. Although such assessment is often sufficient, recent evidence has suggested that molecular analysis may facilitate the diagnosis in problematic cases. Furthermore, as independent synchronous tumors limited to the uterus and ovary are generally associated with favorable outcome, determination of genetic alterations associated with this group of neoplasms may indicate molecular markers of less aggressive behavior. We examined 12 cases of synchronous carcinomas of the uterus and ovary, correlating conventional gross and histological parameters with molecular genetic alterations common to single endometrioid carcinomas occurring in these sites. We identified a frequency of molecular alterations in both independent and metastatic tumors, including microsatellite instability (uterine tumors, 50% and 67%, respectively; ovarian tumors, 33% and 67%) and PTEN mutations (uterine tumors, 38% and 100%; ovarian tumors, 33% and 83%) that is higher than that observed in single sporadic tumors. Loss of heterozygosity for chromosome 17p and 10q was also frequently observed. Nuclear immunoreactivities for β-catenin and CTNNB1 mutations were restricted to independent uterine and ovarian tumors and were absent in all of the metastatic tumors, providing direct evidence for a divergence of molecular oncogenetic mechanisms in the subset of synchronous endometrioid carcinomas. Furthermore, our data show that molecular genetic classification of synchronous independent versus metastatic tumors based on β-catenin expression/mutation correlates with clinical outcome. [Copyright &y& Elsevier]

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]

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]

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]

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]

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]