Vacuolization of hematopoietic precursors: an enigma with multiple etiologies

Cytoplasmic vacuoles in precursors can be seen in a number of clinical settings, including copper deficiency, zinc toxicity, alcohol abuse, antibiotic treatment, myelodysplasia, and VEXAS syndrome. Gurnari et al asked how common VEXAS syndrome is in patients whose bone marrow aspirates show this distinctive feature, finding 2 diagnoses of VEXAS among 24 cases with vacuoles

Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation

TCR repertoire diversification constitutes a foundation for successful immune reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). Deep TCR V beta sequencing of 135 serial specimens from a cohort of 35 allo-HCT recipients/donors was performed to dissect posttransplant TCR architecture and dynamics. Paired analysis of clonotypic repertoires showed a minimal overlap with donor expansions. Rarefied and hyperexpanded clonotypic patterns were hallmarks of T cell reconstitution and influenced clinical outcomes. Donor and pretransplant TCR diversity as well as divergence of class I human leukocyte antigen genotypes were major predictors of recipient TCR repertoire recovery. Complementary determining region 3-based specificity spectrum analysis indicated a predominant expansion of pathogen- and tumor-associated clonotypes in the late post-allo-HCT phase, while autoreactive clones were more expanded in the case of graft-versus-host disease occurrence. These findings shed light on post-allo-HCT adaptive immune reconstitution processes and possibly help in tracking alloreactive responses

Использование барий-стронциевого карбонатита при изготовлении сварочных флюсов на основе техногенных отходов металлургического производства

В данной работе рассмотрена возможность использования барий-стронциевого карбонатита при изготовлении сварочных флюсов на основе шлака производства силикомарганца, а так же на основе ковшевых электросталеплавильных шлаков, образованных при производстве рельсовых марок стали. В серии опытов в лабораторных условиях изготавливали и исследовали различные составы сварочных флюсов, были определены химические составы наплавленного металла, проведен металлографический анализ.In this paper the possibility of using barium-strontium carbonatite in the manufacture of welding fluxes on the basis of slag from the production of silicomanganese, and based on ladle steelmaking slags formed in the production of rail steel grades. In a series of experiments in the laboratory have produced and investigated different compositions of welding fluxes, were determined the chemical compositions of the weld metal metallographic analysis

Machine learning integrates genomic signatures for subclassification beyond primary and secondary acute myeloid leukemia

Although genomic alterations drive the pathogenesis of acute myeloid leukemia (AML), traditional classifications are largely based on morphology, and prototypic genetic founder lesions define only a small proportion of AML patients. The historical subdivision of primary/de novo AML and secondary AML has shown to variably correlate with genetic patterns. The combinatorial complexity and heterogeneity of AML genomic architecture may have thus far precluded genomic-based subclassification to identify distinct molecularly defined subtypes more reflective of shared pathogenesis. We integrated cytogenetic and gene sequencing data from a multicenter cohort of 6788 AML patients that were analyzed using standard and machine learning methods to generate a novel AML molecular subclassification with biologic correlates corresponding to underlying pathogenesis. Standard supervised analyses resulted in modest cross-validation accuracy when attempting to use molecular patterns to predict traditional pathomorphologic AML classifications. We performed unsupervised analysis by applying the Bayesian latent class method that identified 4 unique genomic clusters of distinct prognoses. Invariant genomic features driving each cluster were extracted and resulted in 97% cross-validation accuracy when used for genomic subclassification. Subclasses of AML defined by molecular signatures overlapped current pathomorphologic and clinically defined AML subtypes. We internally and externally validated our results and share an open-access molecular classification scheme for AML patients. Although the heterogeneity inherent in the genomic changes across nearly 7000 AML patients was too vast for traditional prediction methods, machine learning methods allowed for the definition of novel genomic AML subclasses, indicating that traditional pathomorphologic definitions may be less reflective of overlapping pathogenesis

New targets for therapy in breast cancer: Mammalian target of rapamycin (mTOR) antagonists

Mammalian target of rapamycin (mTOR) is a serine-threonine kinase member of the cellular phosphatidylinositol 3-kinase (PI3K) pathway, which is involved in multiple biologic functions such as transcriptional and translational control. mTOR is a downstream mediator in the PI3K/Akt signaling pathway and plays a critical role in cell survival. In breast cancer this pathway can be activated by membrane receptors, including the HER (or ErbB) family of growth factor receptors, the insulin-like growth factor receptor, and the estrogen receptor. There is evidence suggesting that Akt promotes breast cancer cell survival and resistance to chemotherapy, trastuzumab, and tamoxifen. Rapamycin is a specific mTOR antagonist that targets this pathway and blocks the downstream signaling elements, resulting in cell cycle arrest in the G(1 )phase. Targeting the Akt/PI3K pathway with mTOR antagonists may increase the therapeutic efficacy of breast cancer therapy

Emerging therapies for acute myeloid leukemia

Abstract Acute myeloid leukemia (AML) is characterized by clinical and biological heterogeneity. Despite the advances in our understanding of its pathobiology, the chemotherapy-directed management has remained largely unchanged in the past 40 years. However, various novel agents have demonstrated clinical activity, either as single agents (e.g., isocitrate dehydrogenase (IDH) inhibitors, vadastuximab) or in combination with standard induction/consolidation at diagnosis and with salvage regimens at relapse. The classes of agents described in this review include novel cytotoxic chemotherapies (CPX-351 and vosaroxin), epigenetic modifiers (guadecitabine, IDH inhibitors, histone deacetylase (HDAC) inhibitors, bromodomain and extraterminal (BET) inhibitors), FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors, and antibody-drug conjugates (vadastuximab), as well as cell cycle inhibitors (volasertib), B-cell lymphoma 2 (BCL-2) inhibitors, and aminopeptidase inhibitors. These agents are actively undergoing clinical investigation alone or in combination with available chemotherapy

A Multi-Center Open-Labeled Phase II Study of Intensive Salvage Therapy Followed By Enasidenib Maintenance for Patients with Relapsed/Refractory IDH2mutant AML

Introduction: Patients with relapsed/refractory acute myeloid leukemia (R/R AML) have limited therapeutic options and effective management remains clinical challenge. For medically fit patients, salvage therapy with an intensive chemotherapy regimen is the standard of care with remission rates of about 40-50%. Long-term survival is achievable only with disease control followed by allogeneic hematopoietic stem cell transplantation (HCT). A majority of patients with R/R AML who achieve a morphologic clinical remission with salvage chemotherapy frequently harbor detectable clonal events that act as a reservoir for disease relapse. Relapsed/refractory isocitrate dehydrogenase 2 (IDH2) mutant AML patients who undergo cytarabine based salvage chemotherapy will largely retain detectable IDH2 mutations and enasidenib maintenance therapy offers an attractive and tolerable approach to maintenance for such patients. Enasidenib (AG221) is a first-in-class, selective, potent inhibitor of the neomorphic activity of mutant IDH2 enzyme. It is FDA approved as monotherapy for R/R AML with a time to response of approximately 2 months, but there is limited data on the use of this agent following salvage chemotherapy. In the upfront setting, the combination of enasidenib with induction chemotherapy has demonstrated high response rates, providing rationale for this approach (and tolerability with the combination) in the R/R population. Methods: To understand the impact of tailored consolidation following salvage chemotherapy in fit R/R AML we designed a multi-center, phase II trial with 2 cohorts. Cohort assignment is based upon the investigators assignment of patients eligibility (cohort 1.) for allogeneic HCT or (cohort 2) no allogeneic HCT. The main inclusion criteria are, (a.) age over 18 years (b.) received salvage cytarabine based chemotherapy or venetoclax combined with hypomethylating agents (HMA) or 2 or more cycles of HMA for confirmed R/R AML (c.) achieved at least >50% reduction in blast percentage in a nadir marrow from salvage chemotherapy and (d.) adequate organ function and lack of acute life threatening illness. Patients will have received the investigator's choice of salvage therapy and subsequently undergo bone marrow assessment with protocol sampling. Patients confirmed to have obtained a remission will then begin enasidenib 100mg once a day starting between 14 and 60 days after starting salvage therapy. Patients in cohort 1 will receive 1-4 cycles of enasidenib and proceed with HCT; enasidenib can be re-initiated between D30-100 following HCT for a planned total of 24 cycles. Cohort 2 will continue enasidenib maintenance until progression/death or relapse (Schema: Fig 1). Study Endpoints: The primary endpoint of the study to determine the effect of enasidenib maintenance therapy following salvage induction therapy for IDH2 R/R AML, we will evaluate EFS at 12 months separately in the two cohorts of the study. Secondary endpoints include (1) Rate of successful HCT of the subjects enrolled on the study (2) Median duration of maintenance therapy in both the study arms & (3) Overall survival at 12 and 24 months in each cohort. The efficacy of the treatment will be assessed using Simon (1989) optimal two-stage, single arm, unblinded Phase II trials allowing for early termination for futility. This design has a 90% power to detect a 20% improvement rate compared to historical data, while controlling to 10% probability of erroneously findings. A total of 39 (C1) + 25 (C2) = 64 evaluable patients will be enrolled. Interim safety analysis will be done after enrollment of the first 28 patient in C1 and 17 patients in C2. Conclusion: This study is currently is open and enrolling patients at multiple collaborative institutions to answer the key question of efficacy of enasidenib maintenance following salvage chemotherapy. Correlative studies are being performed to understand minimal residual disease in IDH2 mutant AML and its clonal architecture. Disclosures Carraway: BMS: Consultancy, Other: Research support, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; ASTEX: Other: Independent Advisory Committe (IRC); Abbvie: Other: Independent Advisory Committe (IRC); Takeda: Other: Independent Advisory Committe (IRC); Stemline: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Griffiths:Novartis: Honoraria, Research Funding; Boston Biomedical: Honoraria; Genentech Inc: Research Funding; Astex Pharmceuticals: Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; AbbVie Inc: Honoraria; Persimmune: Research Funding