Molecular response patterns in relapsed/refractory AML patients treated with selinexor and chemotherapy.

Relapse in patients with acute myeloid leukemia (AML) is common and is associated with a dismal prognosis. Treatment options are limited and the understanding of molecular response patterns is still challenging. We analyzed the clonal response patterns of 15 patients with relapsed/refractory AML treated with selinexor in a phase II trial (SAIL). DNA was analyzed at three time points and showed a decline of mutated alleles in FLT3, SF3B1, and TP53 under SAIL treatment. Overall survival (OS) was similar between patients with declining versus persisting clones. We show an interesting long-term course of a patient who relapsed after allogeneic stem cell transplantation (alloHCT) with SF3B1- and SRSF2-mutated AML and received selinexor as maintenance treatment for 4 years. Measurable residual disease (MRD) remained detectable for 2 weeks after donor lymphocyte infusion (DLI) in this patient and then remained negative under selinexor maintenance treatment. Selinexor was tolerated well and was stopped after 4 years of SAIL treatment. We present an exploratory study and identify subclonal patterns of patients treated with selinexor.

Synergistic activity of IDH1 inhibitor BAY1436032 with azacitidine in IDH1 mutant acute myeloid leukemia.

Mutant IDH1 (mIDH1) inhibitors have shown single-agent activity in relapsed/refractory AML, though most patients eventually relapse. We evaluated the efficacy and molecular mechanism of the combination treatment with azacitidine, which is currently the standard of care in older AML patients, and mIDH1 inhibitor BAY1436032. Both compounds were evaluated in vivo as single agents and in combination with sequential (azacitidine, followed by BAY1436032) or simultaneous application in two human IDH1 mutated AML xenograft models. Combination treatment significantly prolonged survival compared to single agent or control treatment (P<.005). The sequential combination treatment depleted leukemia stem cells (LSC) by 470-fold. Interestingly, the simultaneous combination treatment depleted LSCs by 33,150-fold compared to control mice. This strong synergy is mediated through inhibition of MAPK/ERK and RB/E2F signaling. Our data strongly argues for the concurrent application of mIDH1 inhibitors and azacitidine and predicts improved outcome of this regimen in IDH1 mutated AML patients.

Three-Dimensional Multi-detector Computed Tomography (3D-MDCT) Gastric Volumetry in Patients with obesity and Normal-Weight Individuals.

BACKGROUND: Obesity is a widely prevalent medical and socioeconomic problem. Bariatric surgery is indicated for patients with clinically severe obesity. Reduction of gastric volume is an important factor that contributes to weight loss after laparscopic sleeve gastrectomy (LSG). The impact of the gastric volume on weight after LSG has been studied. AIM OF THE STUDY: This study was designed to assess the gastric volume in patients with obesity prior to LSG and in the normal-weight patients, using three-dimensional multi-detector computer tomography (3D-MDCT), and to evaluate the potential correlation of the gastric volume with body mass index (BMI). PATIENTS AND METHODS: A total of 100 patients were equally enrolled in two groups: one group for patients with obesity scheduled for LSG and another one for normal-weight patients scheduled for non-bariatric surgery. The study patients underwent 3D-MDCT gastric volumetry. RESULTS: The gastric volume ranged from 525 to 1170 mL in patients with obesity and from 312 to 676 mL in the normal-weight group. Statistically significant difference was found between the two groups. Age, weight, and BMI were found to be predictors for the gastric volume in normal-weight patients only. CONCLUSION: MDCT gastric volumetry is a feasible method to assess the stomach volume. Higher volumes were evident in patients with obesity. Age, weight, and BMI are predictors for the gastric volume in normal-weight patients with linear regression equations that could help during the preoperative planning of bariatric surgeries.

Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia.

NUP98-NSD1-positive acute myeloid leukemia (AML) is a poor prognostic subgroup that is frequently diagnosed in pediatric cytogenetically normal AML. NUP98-NSD1-positive AML often carries additional mutations in genes including FLT3, NRAS, WT1, and MYC. The purpose of our study was to characterize the cooperative potential of the fusion and its associated Neuroblastoma rat sarcoma (NRAS) mutation. By constitutively expressing NUP98-NSD1 and NRASG12D in a syngeneic mouse model and using a patient-derived xenograft (PDX) model from a NUP98-NSD1-positive AML patient, we evaluated the functional role of these genes and tested a novel siRNA formulation that inhibits the oncogenic driver NUP98-NSD1. NUP98-NSD1 transformed murine bone marrow (BM) cells in vitro and induced AML in vivo. While NRASG12D expression was insufficient to transform cells alone, co-expression of NUP98-NSD1 and NRASG12D enhanced the leukemogenicity of NUP98-NSD1. We developed a NUP98-NSD1-targeting siRNA/lipid nanoparticle formulation that significantly prolonged the survival of the PDX mice. Our study demonstrates that mutated NRAS cooperates with NUP98-NSD1 and shows that direct targeting of the fusion can be exploited as a novel treatment strategy in NUP98-NSD1-positive AML patients.

In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site.

Mutations in isocitrate dehydrogenase 1 (IDH1) are found in 6% of AML patients. Mutant IDH produces R-2-hydroxyglutarate (R-2HG), which induces histone- and DNA-hypermethylation through the inhibition of epigenetic regulators, thus linking metabolism to tumorigenesis. Here we report the biochemical characterization, in vivo antileukemic effects, structural binding, and molecular mechanism of the inhibitor HMS-101, which inhibits the enzymatic activity of mutant IDH1 (IDH1mut). Treatment of IDH1mut primary AML cells reduced 2-hydroxyglutarate levels (2HG) and induced myeloid differentiation in vitro. Co-crystallization of HMS-101 and mutant IDH1 revealed that HMS-101 binds to the active site of IDH1mut in close proximity to the regulatory segment of the enzyme in contrast to other IDH1 inhibitors. HMS-101 also suppressed 2HG production, induced cellular differentiation and prolonged survival in a syngeneic mutant IDH1 mouse model and a patient-derived human AML xenograft model in vivo. Cells treated with HMS-101 showed a marked upregulation of the differentiation-associated transcription factors CEBPA and PU.1, and a decrease in cell cycle regulator cyclin A2. In addition, the compound attenuated histone hypermethylation. Together, HMS-101 is a unique inhibitor that binds to the active site of IDH1mut directly and is active in IDH1mut preclinical models.

Prevalence of hepatitis C virus antibodies among intravenous drug abusers and prostitutes in Damascus, Syria.

OBJECTIVE: In studies of risk factors among patients presenting with acute and chronic hepatitis C, a history of intravenous drug use is the most common finding, accounting for 40% or more of subjects. The prevalence of anti-hepatitis C virus antibodies among intravenous drug users is considered one of the highest numbers among high risk groups. Whether hepatitis C virus is transmitted efficiently or at all via sexual contact remains controversial. Therefore, the prevalence of hepatitis C virus antibodies among a group of Syrian intravenous drug users, prostitutes, and blood donors was studied. METHODS: The prevalence of anti-hepatitis C virus in a population of 38 Syrian intravenous drug abusers, 102 Syrian prostitutes, and 2100 blood donors, was carried out in the laboratory of Al-Assad University Hospital, Damascus, Syria. Antibodies of hepatitis C virus were studied by 3rd generation enzyme immunoassay. Hepatitis B surface antigen and antibodies to hepatitis B core were carried out using enzyme immunoassays. Liver enzymes (alanine aminotransferase, aspartate aminotransferase) and total bilirubin were measured using reagents on chemistry autoanalyzer (Hitachi 911). Intravenous drug users group (38) was aged 31 5.6 years, 33 males and 5 females. Prostitutes group (102) were aged 25.1 7 years. Blood donors group (2100) aged were 26.3 10.3 years, 1960 males and 140 females. RESULTS: The prevalence of hepatitis C virus antibodies was 60.5% among intravenous drug abusers, 1.96% among the prostitutes group, and 0.95% among blood donors group. Whereas, the positivity of hepatitis B surface antigen was 5.3% among the intravenous drug abusers, 10.8% among the prostitutes group, and 3.8% among blood donors group. Biochemical parameter results were compared to the results of these parameters that were determined in a group of healthy members (blood donors) during our study. CONCLUSION: The prevalence of hepatitis C virus antibodies among intravenous drug abusers is considered the highest number among high risk groups, however, it is comparable to that reported in other countries. The impact of hepatitis C among drug users is profound, amplifying the spread of hepatits C virus infection and sustaining it in the general population. The prevalence of anti-hepatitis C virus among the prostitutes group was a little higher than that determined among the general population. The transmission of hepatitis C virus via a sexual route is still common and important. The control of the sexual behavior may have a role in minimizing the spread of this pathogen among the general population.