Epigenetic priming by EHMT1/EHMT2 in acute lymphoblastic leukemia induces TP53 and TP73 overexpression and promotes cell death.

Euchromatic histone-lysine N-methyltransferase 1 (EHMT1) and EHMT2 are upregulated in various human cancers, and their deregulation is associated with tumor development and progression. In this paper, we investigated the expression level of EHMT1/EHMT2 in acute lymphoblastic leukemia (ALL) and whether the modulation of these enzymes could have any cellular or molecular impact on ALL cells. For this, we used UNC0646 as a priming strategy to target EHMT1/EHMT2 and investigated its effect on proliferation and cell viability of Jurkat cells by MTT assay. Then, considering the IC50 and IC75, cellular death was determined by Annexin V/PI staining using flow cytometry. Finally, we investigated by RT-PCR the molecular bases that could be involved in the observed effects. Interestingly, accessing the International Microarray Innovations in Leukemia (MILE) study group, we detected that both EHMT1 and EHMT2 are overexpressed in ALL. More important, we determined that inhibition of EHMT1/EHMT2 significantly decreased Jurkat cell viability in a dose-dependent manner. Accordingly, we observed that inhibition of EHMT1/EHMT2 promoted Jurkat cell death, which was accompanied by increased expression of P53, TP73, BAX, and MDM4. These results clearly indicate that inhibition of EHMT1/EHMT2 induces pro-apoptotic gene expression in ALL and promotes cell death. More importantly, the modulation of these histone methyltransferases may be a promising epigenetic target for ALL treatment.

Genomic characterization and prognostication applied to a Brazilian cohort of patients with myelofibrosis.

Genomic characterization of patients with myeloproliferative neoplasms (MPN) may lead to better diagnostic classification, prognostic assessment, and treatment decisions. These goals are particularly important in myelofibrosis (MF). We performed target Next Generation Sequencing for a panel of 255 genes and Chromosome Microarray Analysis (CMA) in 27 patients with MF. Patients were classified according to genomic findings and we compared the performance of a personalized prognostication system with IPSS, MIPSS70 and MIPSS70 + v2. Twenty-six patients presented mutations: 11.1% had single driver mutations in either JAK2, CALR or MPL; 85.2% had mutations in non-restricted genes (median: 2 per patient). CMA was abnormal in 91.7% of the 24 cases with available data. Copy-Number-Neutral Loss-of-Heterozygosity was the most common finding (66.7%). Del13q was the most frequent copy number variation, and we could define a 2.4 Mb minimally affected region encompassing RB1, SUCLA2 and CLLS2 loci. The largest genomic subgroup consisted of patients with mutations in genes involved with chromatin organization and splicing control (40.7%) and the personalized system showed better concordance and accuracy than the other prognostic systems. Comprehensive genomic characterization reveals the striking genetic complexity of MF and, when combined with clinical data, led, in our cohort, to better prognostication performance.

High Frequency of Copy-Neutral Loss of Heterozygosity in Patients with Myelofibrosis.

Myelofibrosis is the rarest and most severe type of Philadelphia-negative classical myeloproliferative neoplasms. Although mutually exclusive driver mutations in JAK2, MPL, or CALR that activate JAK-STAT pathway have been related to the pathogenesis of the disease, chromosome abnormalities have also been associated with the phenotype and prognosis of the disease. Here, we report the use of a chromosomal microarray platform consisting of both oligo and SNP probes to improve the detection of chromosome abnormalities in patients with myelofibrosis. Sixteen patients with myelofibrosis were tested, and the results were compared to karyotype analysis. Driver mutations in JAK2, MPL, or CALR were investigated by PCR and MLPA. Conventional cytogenetics revealed chromosome abnormalities in 3 out of 16 cases (18.7%), while chromosomal microarray analysis detected copy-number variations (CNV) or copy-neutral loss of heterozygosity (CN-LOH) alterations in 11 out of 16 (68.7%) patients. These included 43 CN-LOH, 14 deletions, 1 trisomy, and 1 duplication. Ten patients showed multiple chromosomal abnormalities, varying from 2 to 13 CNVs or CN-LOHs. Mutational status for JAK2, CALR, and MPL by MLPA revealed a total of 3/16 (18.7%) patients positive for the JAK2 V617F mutation, 9 with CALR deletion or insertion and 1 positive for MPL mutation. Considering that most of the CNVs identified were smaller than the karyotype resolution and the high frequency of CN-LOHs in our study, we propose that chromosomal microarray platforms that combine oligos and SNP should be used as a first-tier genetic test in patients with myelofibrosis.

Once- versus twice-daily dosing of eliglustat in adults with Gaucher disease type 1: The Phase 3, randomized, double-blind EDGE trial.

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) with compatible CYP2D6-metabolizer phenotypes (>90% of patients). The randomized, double-blind EDGE trial (NCT01074944, Sanofi Genzyme) evaluated once-daily eliglustat dosing compared with the approved twice-daily regimen at the same total daily dose in adults with GD1. Subjects received twice-daily dosing during a 6- to 18-month lead-in period. Only subjects who attained prespecified treatment goals for hemoglobin, platelet count, spleen and liver volumes, and bone symptoms during the lead-in period were randomized to once- or twice-daily dosing. Of 170 enrolled patients, 156 completed the lead-in period and 131 met all requirements to enter the double-blind treatment period. To achieve the composite primary endpoint in the double-blind period, patients had to maintain clinical stability relative to baseline on all five endpoints (hemoglobin, platelet count, spleen and liver volumes, and bone symptoms) and meet pharmacokinetic and other tolerability requirements as determined by the investigator after 1year of eliglustat treatment. After 1year, 80.4% (95% CI: 67.6, 89.8) of once-daily patients were stable compared with 83.1% (95% CI: 71.0, 91.6) of twice-daily patients. The 95% CI for the mean difference of -2.7% between groups was -17.7, 11.9. Because the lower bound of the CI exceeded the pre-defined non-inferiority margin of -15%, once-daily dosing could not be declared non-inferior to twice-daily dosing. Both once-daily and twice-daily patients maintained mean values for hematologic and visceral measures within established therapeutic goals during the double-blind treatment and long-term extension periods. Eliglustat was generally well-tolerated during this long-term trial (mean treatment duration: 3.3years), with just four withdrawals (2%) for related adverse events (AE), and similar AE profiles for both dosing regimens. Patients on twice-daily eliglustat showed more stability overall, and this dose regimen was better tolerated, confirming the dosing regimen for most patients specified in the drug label.

Development and implementation of a comprehensive psychosocial screening program in a Brazilian cancer center.

OBJECTIVE: International guidelines recommend routine screening for distress as part of care practices. Accordingly, a Brazilian cancer center developed and implemented a distress screening program (DS) in 2007, which was enhanced in 2009 through the inclusion of a psychosocial care meeting group (DS + PCM) regarding patients' psychosocial needs. The current paper will provide an overview of the development and pilot implementation of this program and initial analyses to assess patient outcomes and report initial results to extend international research on this key aspect of cancer care. METHOD: Patients were assessed for distress, anxiety and depression, and in the DS+PCM phase for quality of life at the first day of chemotherapy infusion, at midpoint, and at treatment end. We compared data from program phases (DS vs DS + PCM), with a sequential cohort design and mixed effects modeling. RESULTS: Clinical and demographic characteristics were similar between groups. Patients receiving DS + PCM showed significantly lower distress and depression/anxiety upon chemotherapy initiation (Ps < .001). While both groups reported significantly lowered distress and total depression/anxiety scores across time (Ps < .003), patients receiving DS + PCM maintained the lowest distress and total anxiety/depression at all assessments. Patients from DS + PCM group also reported improvements in quality of life over time. CONCLUSIONS: The current study provides preliminary evidence that a multidisciplinary structured screening program utilizing validated measures and team meetings is associated with reduced impairment in patients' psychological well being. This program provided more opportunities for collaboration among providers with increased multidisciplinary meetings, enabled patients to more easily report problems, and ensured rapid access to relevant resources.

Course of distress, anxiety, and depression in hematological cancer patients: Association between gender and grade of neoplasm.

OBJECTIVE: The aim of our study was to explore the impact of gender and hematological cancer grade on distress, anxiety, and depression in patients receiving chemotherapy. METHODS: A prospective study was done in a cohort of 104 patients with hematological cancer. We employed the (1) Distress Thermometer (DT) and the Problem List (PL) and (2) the Hospital Anxiety and Depression Scale (HADS) for assessments at baseline (T1), the halfway timepoint (T2), and completion of chemotherapy (T3). RESULTS: The proportion of patients experiencing significant distress (DT ≥ 4) decreased from the first to the last timepoint; the proportion experiencing anxiety and depression (as assessed by HADS) also decreased. Specifically, 50% of participants reported significant distress levels, 47.1% anxiety, and 26% depression at T1. At T2, the proportion of patients experiencing distress was reduced by 60.8%, by 76% for anxiety, and by 48.5% for depression; at T3, the reduction was close to 80% for all assessments compared with T1. Emotional and physical problems were most commonly reported. Significant reductions were discovered for distress and problem-related distress levels over time, and a significant interaction was found between gender and practical and physical problems (p < 0.05). SIGNIFICANCE OF RESULTS: Our findings suggest that female patients reported more distress, anxiety, and depression than male patients. Gender differences were related to problem-related distress but not to grade of neoplasm. We observed that, over the course of chemotherapy, the distress levels of patients with hematological cancer decrease over time.

Treinamento médico para comunicação de más notícias: revisão da literatura / Medical training for breaking bad news: review of the literature

Nos últimos anos, diretrizes para a comunicação médica de más notícias aos pacientes foram publicadas. Treinamentos para esta tarefa passaram a ser incluídos nos currículos de graduação, especialização e educação médica continuada. O objetivo desta revisão foi avaliar as evidências existentes na literatura sobre a eficácia destes treinamentos. Apenas sete estudos controlados, quatro dos quais randomizados, foram encontrados. Quatro deles indicam melhora dos aprendizes que foram treinados. Estes achados mostram que o treinamento em comunicação de más notícias pode ser eficaz para médicos e estudantes, mas há importantes limitações que impedem conclusões definitivas. Estas limitações são discutidas.

Guidelines for communicating bad news to patients have been published and training programs for this task have been included in graduate and post-graduate medical courses. The aim of this review was to evaluate evidence_ of the efficacy of these trainings in the medical literature. Only seven controlled trials, four of them randomized, were found. Four for them showed improvement in communication skills in the trained apprentices. These findings suggest that training undergraduate and post-graduate doctors in the skills for communicating bad news may be beneficial but there are important limitations to reach a definitive conclusion. These limitations are discussed.

Problemas e perspectivas do tratamento da Leucemia Mielóide Crônica no Brasil / Problems and perspectives for the treatment of Chronic Myeloid Leukemia in Brazil

O autor discute as limitações enfrentadas pelos centros de onco-hematologia nacionais na condução de pacientes com Leucemia Mielóide Crônica e os problemas relacionados à implementação, custeio e avaliação de resultados dos programas de tratamento para esta enfermidade.

This article discusses the limitations which Brazilian hematology-oncology centers face when conducting treatment programs for Chronic Myeloid Leukemia and the problems concerning their implementation, funding and quality assessment by National Health Organization.

Reagudizaçäo de cardite chagásica provocando insuficiência ventricular direita exclusiva / Reactivation of Myocarditis in Chagas' Disease Inducing Isolated Right Ventricular Failure

Woman, 42 years-old, receiving immunosuppressive therapy for a lymphoma, presented reagudization of Chagas' disease, from its indeterminate phase. Intense inflammatory visceral aggression, due to extensive intracellular proliferation of the Trypanosoma cruzi, was the likely mechanism for acute myocarditis leading to severe right ventricular failure. Antiparasite chemotherapy was effective in the control of visceral involvement and for the remission of cardiac failure. The clinical course in this case is compatible with the hypothesis of early right ventricular damage in Chagas' disease