Acquired pure megakaryocytic aplasia successfully treated with cyclosporine

Acquired pure megakaryocytic aplasia is a rare hematological disorder characterized by thrombocytopenia with absent or markedly reduced megakaryocytes in the bone marrow. We report a case of a 25-year-old male diagnosed as acquired pure megakaryocytic aplasia. Treatment with prednisone and intravenous immunoglobulin failed, but he was successfully treated with cyclosporine, with complete remission after 90 days and normal platelet count maintained thereafter

Sanguinarine Induces Apoptosis Pathway in Multiple Myeloma Cell Lines via Inhibition of the JaK2/STAT3 Signaling.

Sanguinarine (SNG), a benzophenanthridine alkaloid, has displayed various anticancer abilities in several vivo and studies. However, the anticancer potential of SNG is yet to be established in multiple myeloma (MM), a mostly incurable malignancy of plasma cells. In this study, we aimed to investigate the potential anti-proliferative and pro-apoptotic activities of SNG in a panel of MM cell lines (U266, IM9, MM1S, and RPMI-8226). SNG treatment of MM cells resulted in a dose-dependent decrease in cell viability through mitochondrial membrane potential loss and activation of caspase 3, 9, and cleavage of PARP. Pre-treatment of MM cells with a universal caspase inhibitor, Z-VAD-FMK, prevented SNG mediated loss of cell viability, apoptosis, and caspase activation, confirming that SNG-mediated apoptosis is caspase-dependent. The SNG-mediated apoptosis appears to be resulted from suppression of the constitutively active STAT3 with a concomitant increase in expression of protein tyrosine phosphatase (SHP-1). SNG treatment of MM cells leads to down-regulation of the anti-apoptotic proteins including cyclin D, Bcl-2, Bclxl, and XIAP. In addition, it also upregulates pro-apoptotic protein, Bax. SNG mediated cellular DNA damage in MM cell lines by induction of oxidative stress through the generation of reactive oxygen species and depletion of glutathione. Finally, the subtoxic concentration of SNG enhanced the cytotoxic effects of anticancer drugs bortezomib (BTZ) by suppressing the viability of MM cells via induction of caspase-mediated apoptosis. Altogether our findings demonstrate that SNG induces mitochondrial and caspase-dependent apoptosis, generates oxidative stress, and suppresses MM cell lines proliferation. In addition, co-treatment of MM cell lines with sub-toxic doses of SNG and BTZ potentiated the cytotoxic activity. These results would suggest that SNG could be developed into therapeutic agent either alone or in combination with other anticancer drugs in MM

Circulating tumor cells for comprehensive and multiregional non-invasive genetic characterization of multiple myeloma

Multiple myeloma (MM) patients undergo repetitive bone marrow (BM) aspirates for genetic characterization. Circulating tumor cells (CTCs) are detectable in peripheral blood (PB) of virtually all MM cases and are prognostic, but their applicability for noninvasive screening has been poorly investigated. Here, we used next-generation flow (NGF) cytometry to isolate matched CTCs and BM tumor cells from 53 patients and compared their genetic profile. In eight cases, tumor cells from extramedullary (EM) plasmacytomas were also sorted and whole-exome sequencing was performed in the three spatially distributed tumor samples. CTCs were detectable by NGF in the PB of all patients with MM. Based on the cancer cell fraction of clonal and subclonal mutations, we found that ~22% of CTCs egressed from a BM (or EM) site distant from the matched BM aspirate. Concordance between BM tumor cells and CTCs was high for chromosome arm-level copy number alterations (≥95%) though not for translocations (39%). All high-risk genetic abnormalities except one t(4;14) were detected in CTCs whenever present in BM tumor cells. Noteworthy, ≥82% mutations present in BM and EM clones were detectable in CTCs. Altogether, these results support CTCs for noninvasive risk-stratification of MM patients based on their numbers and genetic profile.This study was supported by the Centro de Investigación Biomédica en Red—Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/00236, CB16/12/00369, CB16/12/00489, and CB16/12/00400); by Cancer Research UK [C355/A26819] and FC AECC and AIRC under the Accelerator Award Program; by the Instituto de Salud Carlos III, FCAECC and co-financed by FEDER (ERANET-TRANSCAN-2 iMMunocell AC17/00101); the Spanish Ministry of Science and Innovation and co-financed by FSE (Torres Quevedo fellowship, PTQ-16-08623); the Black Swan Research Initiative of the International Myeloma Foundation; European Research Council (ERC) under the European Commission’s H2020 Framework Programme (MYELOMANEXT, 680200); the Qatar National Research Fund (QNRF) Award No. 7-916-3-237; the AACR-Millennium Fellowship in Multiple Myeloma Research (15-40-38-PAIV); the Leukemia Research Foundation; and the Multiple Myeloma Research Foundation (MMRF) under the 2019 Research Fellowship Award

Sanguinarine Induces Apoptosis Pathway in Multiple Myeloma Cell Lines via Inhibition of the JaK2/STAT3 Signaling

Sanguinarine (SNG), a benzophenanthridine alkaloid, has displayed various anticancer abilities in several vivo and in vitro studies. However, the anticancer potential of SNG is yet to be established in multiple myeloma (MM), a mostly incurable malignancy of plasma cells. In this study, we aimed to investigate the potential anti-proliferative and pro-apoptotic activities of SNG in a panel of MM cell lines (U266, IM9, MM1S, and RPMI-8226). SNG treatment of MM cells resulted in a dose-dependent decrease in cell viability through mitochondrial membrane potential loss and activation of caspase 3, 9, and cleavage of PARP. Pre-treatment of MM cells with a universal caspase inhibitor, Z-VAD-FMK, prevented SNG mediated loss of cell viability, apoptosis, and caspase activation, confirming that SNG-mediated apoptosis is caspase-dependent. The SNG-mediated apoptosis appears to be resulted from suppression of the constitutively active STAT3 with a concomitant increase in expression of protein tyrosine phosphatase (SHP-1). SNG treatment of MM cells leads to down-regulation of the anti-apoptotic proteins including cyclin D, Bcl-2, Bclxl, and XIAP. In addition, it also upregulates pro-apoptotic protein, Bax. SNG mediated cellular DNA damage in MM cell lines by induction of oxidative stress through the generation of reactive oxygen species and depletion of glutathione. Finally, the subtoxic concentration of SNG enhanced the cytotoxic effects of anticancer drugs bortezomib (BTZ) by suppressing the viability of MM cells via induction of caspase-mediated apoptosis. Altogether our findings demonstrate that SNG induces mitochondrial and caspase-dependent apoptosis, generates oxidative stress, and suppresses MM cell lines proliferation. In addition, co-treatment of MM cell lines with sub-toxic doses of SNG and BTZ potentiated the cytotoxic activity. These results would suggest that SNG could be developed into therapeutic agent either alone or in combination with other anticancer drugs in MM

Molecular study of the perforin gene in familial hematological malignancies

Perforin gene (PRF1) mutations have been identified in some patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH) and in patients with lymphoma. The aim of the present study was to determine whether patients with a familial aggregation of hematological malignancies harbor germline perforin gene mutations. For this purpose, 81 unrelated families from Tunisia and France with aggregated hematological malignancies were investigated. The variants detected in the PRF1 coding region amounted to 3.7% (3/81). Two of the three variants identified were previously described: the p.Ala91Val pathogenic mutation and the p.Asn252Ser polymorphism. A new p.Ala 211Val missense substitution was identified in two related Tunisian patients. In order to assess the pathogenicity of this new variation, bioinformatic tools were used to predict its effects on the perforin protein structure and at the mRNA level. The segregation of the mutant allele was studied in the family of interest and a control population was screened. The fact that this variant was not found to occur in 200 control chromosomes suggests that it may be pathogenic. However, overexpression of mutated PRF1 in rat basophilic leukemia cells did not affect the lytic function of perforin differently from the wild type protein

Prediction of Multiple Clinical Complications in Cancer Patients to Ensure Hospital Preparedness and Improved Cancer Care

Reliable and rapid medical diagnosis is the cornerstone for improving the survival rate and quality of life of cancer patients. The problem of clinical decision-making pertaining to the management of patients with hematologic cancer is multifaceted and intricate due to the risk of therapy-induced myelosuppression, multiple infections, and febrile neutropenia (FN). Myelosuppression due to treatment increases the risk of sepsis and mortality in hematological cancer patients with febrile neutropenia. A high prevalence of multidrug-resistant organisms is also noted in such patients, which implies that these patients are left with limited or no-treatment options amidst severe health complications. Hence, early screening of patients for such organisms in their bodies is vital to enable hospital preparedness, curtail the spread to other weak patients in hospitals, and limit community outbreaks. Even though predictive models for sepsis and mortality exist, no model has been suggested for the prediction of multidrug-resistant organisms in hematological cancer patients with febrile neutropenia. Hence, for predicting three critical clinical complications, such as sepsis, the presence of multidrug-resistant organisms, and mortality, from the data available from medical records, we used 1166 febrile neutropenia episodes reported in 513 patients. The XGboost algorithm is suggested from 10-fold cross-validation on 6 candidate models. Other highlights are (1) a novel set of easily available features for the prediction of the aforementioned clinical complications and (2) the use of data augmentation methods and model-scoring-based hyperparameter tuning to address the problem of class disproportionality, a common challenge in medical datasets and often the reason behind poor event prediction rate of various predictive models reported so far. The proposed model depicts improved recall and AUC (area under the curve) for sepsis (recall = 98%, AUC = 0.85), multidrug-resistant organism (recall = 96%, AUC = 0.91), and mortality (recall = 86%, AUC = 0.88) prediction. Our results encourage the need to popularize artificial intelligence-based devices to support clinical decision-making

Refractory cold agglutinin disease successfully treated with daratumumab. A case report and review of literature

ABSTRACTBackground: Cold agglutinin disease (CAD) is immune-mediated hemolytic anemia. The disease is caused by cold reactive autoantibodies that induce hemolysis through the activation of the complement pathway. Most patients with CAD are elderly, and half may have refractory CAD that may not respond to the first-line treatment option (i.e. rituximab). Some cases are refractory to multiple lines of therapy, including chemotherapeutic agents, which might be toxic, especially for elderly patients. Daratumumab is a human monoclonal antibody targeting CD 38 glycoprotein, a transmembrane protein highly expressed in lymphoid and plasma cells. Daratumumab is currently approved for treating multiple myeloma and is used mainly as a combination therapy with other agents.Case presentation: Our patient is a 69-year-old female diagnosed with CAD after presenting with severe anemia and significant circulatory symptoms. Rituximab was not effective in controlling her disease, and she refused other available chemotherapeutic agents due to their side effects profile. We used daratumumab combined with erythropoietin, which led to a dramatic response measured by stabilizing her hemoglobin levels and transfusion independence.Conclusion: Our case is the third reported case of refractory CAD successfully treated with daratumumab, which suggests that daratumumab might be a potential agent for the treatment and control of refractory Cold Agglutinin Disease

Erythema nodosum following treatment with dasatinib plus chemotherapy in a patient with myeloid blast phase of chronic myeloid leukemia

Key Clinical Message Erythema nodosum (EN) is a type of panniculitis occurring due to various conditions. It can be associated with certain malignancies or manifest as a side effect of drugs. This article presents a unique case of EN in a patient with chronic myeloid leukemia (CML‐blast phase) following dasatinib and chemotherapy. Timely recognition and appropriate management are crucial to alleviate symptoms and consider potential drug‐induced etiology

Dasatinib‐induced chylothorax: An unusual presentation of a common adverse event—A case report with literature review

Abstract Tyrosine kinase inhibitors (TKIs) are the key agents for treating CML and BCR–ABL+ B‐ALL. Dasatinib is a potent second‐generation TKI. Here, we have discussed the case of a 51‐year‐old gentleman diagnosed with B‐myeloid mixed‐phenotype acute leukemia with t(9;22)(q34.1;q11.2); BCR–ABL1p210, in complete hematological, cytogenetic, and molecular remission, who developed chylothorax. Though pleural effusion is a commonly observed adverse effect of dasatinib therapy, chylothorax is rare. The ability of Dasatinib to inhibit multiple families of tyrosine kinases could be considered the etiology. Discontinuation of the drug resolved the symptom, but pleural effusion recurred once Dasatinib was resumed. Chylothorax induced by Dasatinib is a differential to be kept in mind, owing to the limited number of cases being reported