***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Patients with malignant endocrine pancreatic tumors ( EPTs ) are responsive to combinations of chemotherapy with streptozotocin and 5‐fluorouracil/doxorubicin , whereas patients with malignant carcinoids are not . For both categories of patients , α‐interferon and /or somatostatin analogs can produce long‐lasting responses . Cisplatin in combination with etoposide has been suggested to be effective in patients with malignant neuroendocrine carcinomas . The authors used this therapy as second‐line or third‐line treatment in patients with poorly differentiated and /or rapidly progressing disease BACKGROUND Mutational inactivation in cancer of key apoptotic pathway components , such as TP53/p53 , undermines cytotoxic therapies that aim to increase apoptosis . Accordingly , TP53 mutations are reproducibly associated with poor treatment outcomes . Moreover , cytotoxic treatments destroy normal stem cells with intact p53 systems , a problem especially for myeloid neoplasms , as these cells reverse the low blood counts that cause morbidity and death . Pre clinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 ( DNMT1 ) inhibitor decitabine produce p53-independent cell-cycle exits by reversing aberrant epigenetic repression of proliferation-terminating ( MYC-antagonizing ) differentiation genes in cancer cells . METHODS In this clinical trial , patients with myelodysplastic syndrome ( n=25 ) received reduced decitabine dosages ( 0.1 - 0.2 mg/kg/day compared with the FDA -approved 20 - 45 mg/m2/day dosage , a 75%-90 % reduction ) to avoid cytotoxicity . These well-tolerated doses were frequently administered 1 - 3 days per week , instead of pulse cycled for 3 to 5 days over a 4- to 6-week period , to increase the probability that cancer S-phase entries would coincide with drug exposure , which is required for S-phase-dependent DNMT1 depletion . RESULTS The median subject age was 73 years ( range , 46 - 85 years ) , 9 subjects had relapsed disease or were refractory to 5-azacytidine and /or lenalidomide , and 3 had received intensive chemoradiation to treat other cancers .  Adverse events were related to neutropenia present at baseline : neutropenic fever ( 13 of 25 subjects ) and septic death ( 1 of 25 subjects ) . Blood count improvements meeting the International Working Group criteria for response occurred in 11 of 25 ( 44 % ) subjects and were highly durable . Treatment-induced freedom from transfusion lasted a median of 1,025 days ( range , 186 - 1,152 days ; 3 ongoing ) , and 20 % of subjects were treated for more than 3 years . Mutations and /or deletions of key apoptosis genes were frequent ( present in 55 % of responders and in 36 % of nonresponders ) . Noncytotoxic DNMT1 depletion was confirmed by serial BM γ-H2AX ( DNA repair/damage marker ) and DNMT1 analyses . MYC master oncoprotein levels were markedly decreased . CONCLUSION Decitabine regimens can be re design ed to minimize cytotoxicity and increase exposure time for DNMT1 depletion , to safely and effectively circumvent mutational apoptotic defects . TRIAL REGISTRATION Clinical trials.gov NCT01165996 . FUNDING NIH ( R01CA138858 , CA043703 ) ; Department of Defense ( PR081404 ) ; Clinical and Translational Science Award ( CTSA ) ( UL1RR024989 ) ; and the Leukemia and Lymphoma Society ( Translational Research Program ) BACKGROUND The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia ( AML ) or myelodysplastic syndromes ( MDS ) are unclear . METHODS We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine  to identify somatic mutations and their relationships to clinical responses . Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles . We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients . An extension cohort included 32 additional patients who received decitabine in different protocol s. RESULTS Of the 116 patients , 53 ( 46 % ) had bone marrow blast clearance ( < 5 % blasts ) . Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile ( 29 of 43 patients [ 67 % ] vs. 24 of 71 patients [ 34 % ] , P<0.001 ) and among patients with TP53 mutations than among patients with wild-type TP53 ( 21 of 21 [ 100 % ] vs. 32 of 78 [ 41 % ] , P<0.001 ) . Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes . However , in this study of 10-day courses of decitabine , neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles . CONCLUSIONS Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk , TP53 mutations , or both had favorable clinical responses and robust ( but incomplete ) mutation clearance after receiving serial 10-day courses of decitabine . Although these responses were not durable , they result ed in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine . ( Funded by the National Cancer Institute and others ; Clinical Trials.gov number , NCT01687400 . ) This report investigated in vivo turnover kinetics of marrow hematopoietic progenitors and precursors using a recently developed stable isotope-mass spectrometric technique ( SIMST ) . Human subjects were administered a 2-day infusion of 6,6-[2H2]-glucose , a nontoxic stable isotope-labeled form of glucose , which becomes incorporated into DNA of all S-phase cells . The percent [2H2]-glucose incorporated into DNA in the form of [2H2]-deoxyadenosine ( % [2H2]-dA enrichment ) was determined by gas chromatography-mass spectrometry . The rate constant of replacement of unlabeled by labeled DNA str and s ( labeling kinetics ) was used to calculate population turnover kinetics of CD34 + cells , CD133 + cells , and CD133-CD34 + cells . The observed mean replacement half-life ( t1/2 ) was 2.6 days for CD34 + cells , 2.5 days for CD133-CD34 + cells , and 6.2 days for CD133 + cells . Results from the estimated rate constant of replacement of labeled by unlabeled DNA ( delabeling kinetics ) also demonstrated slower turnover rates for CD133 + cells than for CD133-CD34 + cells . Although there was a relatively rapid initial decrease in the % [2H2]-dA enrichment , low levels of labeled DNA persisted in CD34 + cells for at least 4 weeks . The results indicate the presence of sub population s of CD34 + cells with relatively rapid turnover rates and sub population s with a slower t1/2 of 28 days . Results also demonstrate that in vivo [2H2]-glucose-SIMST is sensitive enough to detect differences in turnover kinetics between erythroid and megakaryocyte lineage cells . These studies are the first to demonstrate the use of in vivo [2H2]-glucose-SIMST to measure in vivo turnover kinetics of sub population s of CD34 + cells and precursors in healthy human subjects Primary myelofibrosis ( PMF ) and overlap myelodysplastic/myeloproliferative neoplasms ( MDS/MPN ) are clonal hematopoietic disorders that share similar clinical features and molecular abnormalities , such as the Janus kinase 2 ( JAK2 ) valine to phenylalanine mutation at codon 617 ( V617F ) and the tet methylcytosine dioxygenase 2 ( TET2 ) mutation . There are limited therapeutic options available for these diseases , and single agents have only modest efficacy . In this phase 2 study , the authors combined multiple active agents ( thalidomide , arsenic trioxide , dexamethasone , and ascorbic acid [ TADA ] ) to treat patients with these disorders PURPOSE This study was design ed to assess the effectiveness of vinblastine , ifosfamide , and cisplatin ( VeIP ) as second-line therapy in patients with recurrent germ cell tumors with previous treatment with cisplatin plus etoposide , usually in combination with bleomycin .  PATIENTS AND METHODS From July 1984 through December 1989 , 135 patients with progressive , disseminated germ cell tumors after cisplatin-etoposide-based combination therapy induction chemotherapy were treated with VeIP .  Patients who progressed within 3 weeks of previous cisplatin therapy were not eligible . Progression was documented by biopsy or increasing serum markers . No exclusion was made on the basis of metastatic site or performance status . The dosages were vinblastine 0.11 mg/kg/d ( days 1 and 2 ) , ifosfamide 1.2 gm/m2/d ( days 1 through 5 ) , and cisplatin 20 mg/m2/d ( days 1 through 5 ) , with courses repeated every 21 days for four cycles . RESULTS Sixty-seven ( 49.6 % ) patients achieved a disease-free status after chemotherapy with or without surgical resection of residual carcinoma or teratoma . Overall , 42 ( 32 % ) patients are alive and 32 ( 23.7 % ) are continuously free of disease . None of the 32 patients with nonseminomatous extragonadal tumors are disease-free compared with 30 of 100 patients with gonadal primaries . Two of three extragonadal seminomas are continuously disease-free . CONCLUSION VeIP is capable of producing durable complete remissions in patients with disseminated germ cell cancer who relapse after cisplatin-etoposide-based induction therapy . Long-term disease-free survival is not seen in those patients with extragonadal nonseminomatous germ cell tumors BACKGROUND All-trans retinoic acid ( ATRA ) with chemotherapy is the st and ard of care for acute promyelocytic leukemia ( APL ) , result ing in cure rates exceeding 80 % . Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity . METHODS We conducted a phase 3 , multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk ( white-cell count , ≤10 × 10(9 ) per liter ) . Patients were r and omly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or st and ard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA . The study was design ed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5 % . RESULTS Complete remission was achieved in all 77 patients in the ATRA-arsenic  trioxide group who could be evaluated ( 100 % ) and in 75 of 79 patients in the ATRA-chemotherapy group ( 95 % ) ( P=0.12 ) . The median follow-up was 34.4 months . Two-year event-free survival rates were 97 % in the ATRA-arsenic trioxide group and 86 % in the ATRA-chemotherapy group ( 95 % confidence interval for the difference , 2 to 22 percentage points ; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide ) . Overall survival was also better with ATRA-arsenic trioxide ( P=0.02 ) . As compared with ATRA-chemotherapy , ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity . CONCLUSIONS ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL . ( Funded by Associazione Italiana contro le Leucemie and others ; Clinical Trials.gov number , NCT00482833 . ) 
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Our analyses suggested loss-of-function events to master TF drivers of lineage-fates and their cofactors as being linked to differentiation-failure : genomic data in TCGA and ICGC data bases demonstrated frequent haploinsufficiency of lineage master TFs ( e.g. , GATA4/6 ) in poorly differentiated tumors ; the coactivators that these TFs use to activate genes ( e.g. ARID1A , PBRM1 ) were also frequently inactivated by genetic mutation and /or deletion .
By contrast , corepressor components ( e.g. , DNMT1 , EED , UHRF1 , and BAZ1A/B ) , that oppose coactivators to repress or turn off genes , were frequently amplified instead , and the level of amplification was highest in poorly differentiated lesions .
This selection by neoplastic evolution towards unbalanced activity of transcriptional corepressors suggests these enzymes as c and i date targets for inhibition aim ing to re-engage forward-differentiation .