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The New England Journal of Medicine Jun 2024
Topics: Adult; Female; Humans; Male; Administration, Oral; Complement Factor B; Hematologic Agents; Hemoglobinuria, Paroxysmal
PubMed: 38838319
DOI: 10.1056/NEJMc2404445 -
Cancer Research Jun 2024DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the...
DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the hypothesis that cytosine demethylation will lead to re-expression of tumor suppressor genes. 5-Aza-4'-thio-2'-deoxycytidine (Aza TdCyd or ATC) is a recently described thiol substituted DNMTi that has been shown to have anti-tumor activity in solid tumor models. Here, we investigated the therapeutic potential of ATC in a murine transplantation model of myelodysplastic syndrome. ATC treatment led to transformation of transplanted wild-type bone marrow nucleated cells into lymphoid leukemia, and healthy mice treated with ATC also developed lymphoid leukemia. Whole exome sequencing revealed thousands of acquired mutations, almost all of which were C>G transversions in a specific 5'-NCG-3' context. These mutations involved dozens of genes involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Human cells treated in vitro with ATC showed thousands of acquired C>G transversions in a similar context. Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C>G transversions. Taken together, these findings demonstrate a highly penetrant mutagenic and leukemogenic phenotype associated with ATC.
PubMed: 38832931
DOI: 10.1158/0008-5472.CAN-23-2785 -
JAMA Network Open Jun 2024Published research suggests that patient-reported outcomes (PROs) are neither commonly collected nor reported in randomized clinical trials (RCTs) for solid tumors....
IMPORTANCE
Published research suggests that patient-reported outcomes (PROs) are neither commonly collected nor reported in randomized clinical trials (RCTs) for solid tumors. Little is known about these practices in RCTs for hematological malignant neoplasms.
OBJECTIVE
To evaluate the prevalence of PROs as prespecified end points in RCTs of hematological malignant neoplasms, and to assess reporting of PROs in associated trial publications.
EVIDENCE REVIEW
All issues of 8 journals known for publishing high-impact RCTs (NEJM, Lancet, Lancet Hematology, Lancet Oncology, Journal of Clinical Oncology, Blood, JAMA, and JAMA Oncology) between January 1, 2018, and December 13, 2022, were searched for primary publications of therapeutic phase 3 trials for adults with hematological malignant neoplasms. Studies that evaluated pretransplant conditioning regimens, graft-vs-host disease treatment, or radiotherapy as experimental treatment were excluded. Data regarding trial characteristics and PROs were extracted from manuscripts and trial protocols. Univariable analyses assessed associations between trial characteristics and PRO collection or reporting.
FINDINGS
Ninety RCTs were eligible for analysis. PROs were an end point in 66 (73%) trials: in 1 trial (1%) as a primary end point, in 50 (56%) as a secondary end point, and in 15 (17%) as an exploratory end point. PRO data were reported in 26 of 66 primary publications (39%): outcomes were unchanged in 18 and improved in 8, with none reporting worse PROs with experimental treatment. Trials sponsored by for-profit entities were more likely to include PROs as an end point (49 of 55 [89%] vs 17 of 35 [49%]; P < .001) but were not significantly more likely to report PRO data (20 of 49 [41%] vs 6 of 17 [35%]; P = .69). Compared with trials involving lymphoma (18 of 29 [62%]) or leukemia or myelodysplastic syndrome (18 of 28 [64%]), those involving plasma cell disorders or multiple myeloma (27 of 30 [90%]) or myeloproliferative neoplasms (3 of 3 [100%]) were more likely to include PROs as an end point (P = .03). Similarly, compared with trials involving lymphoma (3 of 18 [17%]) or leukemia or myelodysplastic syndrome (5 of 18 [28%]), those involving plasma cell disorders or multiple myeloma (16 of 27 [59%]) or myeloproliferative neoplasms (2 of 3 [67%]) were more likely to report PROs in the primary publication (P = .01).
CONCLUSIONS AND RELEVANCE
In this systematic review, almost 3 of every 4 therapeutic RCTs for blood cancers collected PRO data; however, only 1 RCT included PROs as a primary end point. Moreover, most did not report resulting PRO data in the primary publication and when reported, PROs were either better or unchanged, raising concern for publication bias. This analysis suggests a critical gap in dissemination of data on the lived experiences of patients enrolled in RCTs for hematological malignant neoplasms.
Topics: Humans; Patient Reported Outcome Measures; Hematologic Neoplasms; Clinical Trials, Phase III as Topic; Randomized Controlled Trials as Topic
PubMed: 38829615
DOI: 10.1001/jamanetworkopen.2024.14425 -
[Rinsho Ketsueki] the Japanese Journal... 2024The epigenome regulates transcription of target genes through DNA methylation- or histone methylation/acetylation/phosphorylation/ubiquitination-mediated alteration of... (Review)
Review
The epigenome regulates transcription of target genes through DNA methylation- or histone methylation/acetylation/phosphorylation/ubiquitination-mediated alteration of genomic function or chromatin conformation. Recent genomic studies have shown that multiple genes encoding epigenetic regulators are frequently and recurrently mutated in MDS, suggesting that epigenetic dysregulation is significantly associated with the molecular pathogenesis and clinical features of MDS. In this review, we will present our recent findings together with others, focusing on physiological molecular functions of epigenetic regulators recurrently mutated in MDS and on functional correlation between dysregulated epigenomic regulators and molecular pathogenesis/clinical features of MDS.
Topics: Humans; Epigenesis, Genetic; Myelodysplastic Syndromes; DNA Methylation; Mutation; Histones
PubMed: 38825515
DOI: 10.11406/rinketsu.65.362 -
The Journal of Veterinary Medical... Jun 2024Non-neoplastic bone marrow disorders are main causes of non-regenerative anemia in dogs. Despite the high incidence of the diseases, their molecular pathophysiology has...
Non-neoplastic bone marrow disorders are main causes of non-regenerative anemia in dogs. Despite the high incidence of the diseases, their molecular pathophysiology has not been elucidated. We previously reported that Miniature Dachshund (MD) was a predisposed breed to be diagnosed with non-neoplastic bone marrow disorders in Japan, and immunosuppressive treatment-resistant MDs showed higher number of platelets and morphological abnormalities in peripheral blood cells. These data implied that treatment-resistant MDs might possess distinct pathophysiological features from treatment-responsive MDs. Therefore, we conducted transcriptomic analysis of bone marrow specimens to investigate the pathophysiology of treatment-resistant MDs. Transcriptomic analysis comparing treatment-resistant MDs and healthy control dogs identified 179 differentially expressed genes (DEGs). Pathway analysis using these DEGs showed that "Wnt signaling pathway" was a significantly enriched pathway. We further examined the expression levels of DEGs associated with Wnt signaling pathway and confirmed the upregulation of AXIN2 and CCND2 and the downregulation of SFRP2 in treatment-resistant MDs compared with treatment-responsive MDs and healthy control dogs. This alteration implied the activation of Wnt signaling pathway in treatment-resistant MDs. The activation of Wnt signaling pathway has been reported in human patients with myelodysplastic syndrome (MDS), which is characterized by dysplastic features of blood cells. Therefore, the results of this study implied that treatment-resistant MDs have distinct molecular pathological features from treatment-responsive MDs and the pathophysiology of treatment-resistant MDs might be similar to that of human MDS patients.
PubMed: 38825482
DOI: 10.1292/jvms.23-0371 -
Clinical Chemistry Jun 2024
Topics: Humans; Myelodysplastic Syndromes
PubMed: 38825341
DOI: 10.1093/clinchem/hvae016 -
Journal of the Association of Genetic... 2024The Fanconi anemia (FA) genes are a family of at least 23 known genes that are spread across many chromosomes and participate in interstrand crosslink (ICLs) DNA repair....
The Fanconi anemia (FA) genes are a family of at least 23 known genes that are spread across many chromosomes and participate in interstrand crosslink (ICLs) DNA repair. In this pathway, FA proteins are involved in sensing sites of ICLs, translocating repair enzymes from the cytoplasm to the nucleus, excising the area of damage, and facilitating repair of the fractured DNA. Mutations in these genes lead to Fanconi anemia, a syndrome characterized primarily by pancytopenia but with associated symptoms involving nearly every organ system; the majority of patients present with dermatological symptoms and growth deficits. Additionally, individuals with Fanconi anemia are known to be predisposed individuals to an increased risk of malignancies, particularly acute myeloid dystrophy and myelodysplastic syndrome, but also in the head, neck, esophagus, reproductive organs, brain, skin, liver, and kidneys. In fact, the cytogenetic aberrations seen in those with FA-associated AML differ from those in typical AML. In contrast, the cytogenetic changes seen in FA-associated MDS are similar to those in typical MDS.
PubMed: 38824651
DOI: No ID Found -
Journal of Managed Care & Specialty... Jun 2024
Topics: Humans; Hemoglobinuria, Paroxysmal
PubMed: 38824627
DOI: 10.18553/jmcp.2024.30.6.618 -
Clinics in Laboratory Medicine Jun 2024Despite the apparent complexity of the molecular genetic underpinnings of myeloid neoplasms, most myeloid mutational profiles can be understood within a simple... (Review)
Review
Despite the apparent complexity of the molecular genetic underpinnings of myeloid neoplasms, most myeloid mutational profiles can be understood within a simple framework. Somatic mutations accumulate in hematopoietic stem cells with aging and toxic insults, termed clonal hematopoiesis. These "old stem cells" mutations, predominantly in the epigenetic and RNA spliceosome pathways, act as "founding" driver mutations leading to a clonal myeloid neoplasm when sufficient in number and clone size. Subsequent mutations can create the genetic flavor of the myeloid neoplasm ("backseat" drivers) due to their enrichment in certain entities or act as progression events ("aggressive" drivers) during clonal evolution.
Topics: Humans; Mutation; Myelodysplastic Syndromes; Myeloproliferative Disorders
PubMed: 38821648
DOI: 10.1016/j.cll.2023.08.007