Inhibition of DNMT3B and PI3K/AKT/mTOR and ERK Pathways as a Novel Mechanism of Volasertib on Hypomethylating Agent-Resistant Cells

Resistance to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is a concerning problem. Polo-like kinase 1 (PLK1) is a key cell cycle modulator and is known to be associated with an activation of the PI3K pathway, which is related to the stabilization of DNA methyltransferase 1 (DNMT1), a target of HMAs. We investigated the effects of volasertib on HMA-resistant cell lines (MOLM/AZA-1 and MOLM/DEC-5) derived from MOLM-13, and bone marrow (BM) samples obtained from patients with MDS (BM blasts >5%) or AML evolved from MDS (MDS/AML). Volasertib effectively inhibited the proliferation of HMA-resistant cells with suppression of DNMTs and PI3K/AKT/mTOR and ERK pathways. Volasertib also showed significant inhibitory effects against primary BM cells from patients with MDS or MDS/AML, and the effects of volasertib inversely correlated with DNMT3B expression. The DNMT3B-overexpressed AML cells showed primary resistance to volasertib treatment. Our data suggest that volasertib has a potential role in overcoming HMA resistance in patients with MDS and MDS/ AML by suppressing the expression of DNMT3 enzymes and PI3K/AKT/mTOR and ERK pathways. We also found that DNMT3B overexpression might be associated with resistance to volasertib.

Treatment outcome and prognostic factors of Korean patients with chronic lymphocytic leukemia: a multicenter retrospective study

Background/Aims@#Compared with Western countries, chronic lymphocytic leukemia (CLL) rarely occurs in Asia and has different clinical characteristics. Thus, we aimed to evaluate the clinical characteristics, treatment outcomes, and prognostic significance of Korean patients with CLL. @*Methods@#We retrospectively analyzed 90 patients with CLL who had received chemotherapy at 6 centers in Korea between 2000 and 2012. @*Results@#Compared with Western patients with CLL, Korean patients with CLL express lambda (42.0%) and atypical markers such as CD22 and FMC7 (76.7% and 40.0%, respectively) more frequently. First-line chemotherapy regimens included chlorambucil (n = 43), fludarabine and cyclophosphamide (FC) (n = 20), fludarabine (n = 13), rituximab-FC (n = 4). The remaining patients were treated with other various regimens (n = 10). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 79.3% and 28.1%, respectively. Multivariate analyses showed that hyperleukocytosis (≥ 100 × 103/μL), extranodal involvement, and the Binet C stage were significant negative prognostic factors for OS (hazard ratio [HR] 4.75, p = 0.039; HR 21.6, p = 0.002; and HR 4.35, p = 0.034, respectively). Cytogenetic abnormalities including complex karyotypes (≥ 3), del(11q), and del(17) had a significantly adverse impact on both OS and PFS (p < 0.001 and p = 0.010, respectively). @*Conclusions@#Initial hyperleukocytosis, extranodal involvement, complex karyotype, del(17) and del(11q) need to be considered in the risk stratification system for CLL.

Pediatric-inspired regimen with late intensification and increased dose of L-asparaginase for adult acute lymphoblastic leukemia: the KALLA 1406/1407 study

Background/Aims@#The objective of this study was to evaluate the efficacy and feasibility of the pediatric-inspired regimen of the adult acute lymphoblastic leukemia (ALL) Working Party, the Korean Society of Hematology. @*Methods@#Data of 99 patients with newly diagnosed ALL, who were treated with the KALLA 1406/1407 protocol, were retrospectively analyzed. All patients equally received age-adjusted daunorubicin, vincristine, and prednisolone. L-asparaginase was additionally administered to Philadelphia (Ph)-negative patients according to age, whereas Ph-positive patients received 600 mg/day of imatinib. @*Results@#A total of 99 patients were enrolled in this study, of whom 62 (62.6%) were diagnosed with Ph-negative ALL and 37 (37.3%) were diagnosed with Ph-positive ALL. The median age of patients in the Ph-negative ALL group was 46 years, and that of patients in the Ph-positive ALL group was 49 years. In patients with Ph-negative ALL, 57 (92%) patients achieved complete remission (CR) and CR with incomplete hematologic recovery (CRi). Disease-free survival (DFS) and overall survival (OS) rates at 2 years were estimated to be 42% and 63%, respectively. In patients with Ph-positive ALL, 32 (86%) patients achieved CR/CRi, and 2-year DFS and OS were 31.2% and 49.1%, respectively. Patients who were able to proceed to the allogeneic hematopoietic cell transplantation and younger patients showed significantly superior survival in both Ph-negative ALL and Ph-positive ALL. Neutropenic fever and bacterial infection were the most common and severe adverse events. @*Conclusions@#The KALLA 1406/1407 protocol showed tolerable toxicities in adult ALL patients. Especially, younger patients had more survival benefits with KALLA 1406/1407 protocol.

Reduced-Intensity Conditioning with Busulfan and Fludarabine for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Lymphoblastic Leukemia

Purpose@#Allogeneic hematopoietic stem cell transplantation (HSCT) with optimal conditioning has helped better long-term survival in acute lymphoblastic leukemia (ALL). This study investigated the efficacy and safety of reduced-intensity conditioning (RIC) with busulfan and fludarabine in adult ALL patients unfit for myeloablation. @*Materials and Methods@#Records of 78 patients who underwent HSCT with RIC consisting of 3.2 mg/kg/day of busulfan for 2 or 3 days and 30 mg/m2/day of fludarabine for 5 or 6 days were analyzed. @*Results@#The median age at diagnosis was 49 years. Over a median follow-up of 22 months, 2-year estimates of relapse-free survival (RFS) and overall survival were 57.4% and 68.7%, respectively. Multivariate analysis showed a trend of improved RFS in patients with chronic graft-versus-host disease (GVHD) (hazard ratio, 0.53; 95% confidence interval, 0.26–1.08; p=0.080). The cumulative incidences of relapse and non-relapse mortality were 42.9% and 19.6%, respectively and one case of central nervous system relapse was noted. No hepatic veno-occlusive disease was reported. Grade II–IV acute GVHD and any grade chronic GVHD occurred in 21.1% and 41.7%, respectively. @*Conclusion@#RIC with busulfan and fludarabine is an effective and safe conditioning regimen for adult ALL patients unfit for myeloablation.

Clinical impact of anti-thymocyte globulin on survival and graft-versus-host disease in patients undergoing human leukocyte antigen mismatched allogeneic stem cell transplantation

Background/Aims@#Rabbit anti-thymocyte globulin (ATG) is usually incorporated in hematopoietic stem cell transplantation (HSCT) to reduce the incidence of graft-versus-host disease (GVHD). This study aimed to find optimal ATG doses in patients undergoing human leukocyte antigen (HLA)-mismatched allogeneic HSCT. @*Methods@#We retrospectively collected medical records from 352 consecutive patients with acute myeloid leukemia (n = 214), acute lymphoblastic leukemia (n = 62), or myelodysplastic syndrome (n = 76) in eight centers of Korea between 2005 and 2015. All patients received busulfan-based conditioning without total body irradiation (TBI) and received stem cells from HLA-mismatched donors. @*Results@#In the current study, 5-year overall survival rates of patients receiving low to medium doses of ATG (2.5 to 7.5 mg/kg) were higher than those receiving other doses of ATG (hazard ratio [HR], 0.528; 95% confidence interval [CI], 0.311 to 0.897; p = 0.018). The incidence rates of extensive chronic GVHD (ecGVHD) after administration of low to medium doses of ATG were lower than those after other doses of ATG (HR, 0.447; 95% CI, 0.224 ton 0.889; p = 0.022). @*Conclusions@#The low to medium doses of ATG may be associated with improving survival outcomes and reducing incidence of ecGVHD without enhancing the chances of relapse in patients with acute leukemia or myelodysplastic syndrome undergoing non-TBI-based HLA-mismatched allogeneic HSCT.

Prevalence and Anatomy of Aberrant Right Subclavian Artery Evaluated by Computed Tomographic Angiography at a Single Institution in Korea

OBJECTIVE: Aberrant right subclavian artery (ARSA) is a rare anatomical variant of the origin of the right subclavian artery. ARSA is defined as the right subclavian artery originating as the final branch of the aortic arch. The purpose of this study is to determine the prevalence and the anatomy of ARSA evaluated with computed tomography (CT) angiography.METHODS: CT angiography was performed in 3460 patients between March 1, 2014 and November 30, 2015 and the results were analyzed. The origin of the ARSA, course of the vessel, possible inadvertent ARSA puncture site during subclavian vein catheterization, Kommerell diverticula, and associated vascular anomalies were evaluated. We used the literature to review the clinical importance of ARSA.RESULTS: Seventeen in 3460 patients had ARSA. All ARSAs in 17 patients originated from the posterior aspect of the aortic arch and traveled along a retroesophageal course to the right thoracic outlet. All 17 ARSAs were located in the anterior portion from first to fourth thoracic vertebral bodies and were located near the right subclavian vein at the medial third of the clavicle. Only one of 17 patients presented with dysphagia.CONCLUSION: It is important to be aware ARSA before surgical approaches to upper thoracic vertebrae in order to avoid complications and effect proper treatment. In patients with a known ARSA, a right transradial approach for aortography or cerebral angiography should be changed to a left radial artery or transfemoral approach.

Prevalence and Anatomy of Aberrant Right Subclavian Artery Evaluated by Computed Tomographic Angiography at a Single Institution in Korea

OBJECTIVE: Aberrant right subclavian artery (ARSA) is a rare anatomical variant of the origin of the right subclavian artery. ARSA is defined as the right subclavian artery originating as the final branch of the aortic arch. The purpose of this study is to determine the prevalence and the anatomy of ARSA evaluated with computed tomography (CT) angiography. METHODS: CT angiography was performed in 3460 patients between March 1, 2014 and November 30, 2015 and the results were analyzed. The origin of the ARSA, course of the vessel, possible inadvertent ARSA puncture site during subclavian vein catheterization, Kommerell diverticula, and associated vascular anomalies were evaluated. We used the literature to review the clinical importance of ARSA. RESULTS: Seventeen in 3460 patients had ARSA. All ARSAs in 17 patients originated from the posterior aspect of the aortic arch and traveled along a retroesophageal course to the right thoracic outlet. All 17 ARSAs were located in the anterior portion from first to fourth thoracic vertebral bodies and were located near the right subclavian vein at the medial third of the clavicle. Only one of 17 patients presented with dysphagia. CONCLUSION: It is important to be aware ARSA before surgical approaches to upper thoracic vertebrae in order to avoid complications and effect proper treatment. In patients with a known ARSA, a right transradial approach for aortography or cerebral angiography should be changed to a left radial artery or transfemoral approach.

High-grade nodal marginal zone lymphoma with diffuse bone marrow involvement and IgM-type monoclonal paraproteinemia: a case report and review of the literature

No abstract available.

Bone marrow metastasis of small cell lung carcinoma with spontaneous tumor lysis syndrome without hepatic metastasis at diagnosis: first case report in Korea and review of literature

No abstract available.

Expression and prognostic significance of microRNAs in Korean patients with myelodysplastic syndrome

BACKGROUND/AIMS@#Various alterations of microRNA (miRNA) expression have been reported in myelodysplastic syndrome (MDS). We aimed to investigate the unique patterns and prognostic significance of miRNA expression in Korean patients with MDS.@*METHODS@#Bone marrow mononuclear cells were collected from eight healthy controls and 26 patients with MDS, and miRNAs were isolated and assessed via quantitative real-time polymerase chain reaction for selected miRNAs, including miR-21, miR-124a, miR-126, miR-146b-5p, miR-155, miR-182, miR-200c, miR-342-5p, miR-708, and Let-7a.@*RESULTS@#MiR-124a, miR-155, miR-182, miR-200c, miR-342-5p, and Let-7a were significantly underexpressed in patients with MDS, compared to healthy controls. MiR-21, miR-126, 146b-5p, and miR-155 transcript levels were significantly lower in international prognostic scoring system lower (low and intermediate-1) risk MDS than in higher (intermediate-2 and high) risk MDS. Higher expression levels of miR-126 and miR-155 correlated with significantly shorter overall survival and leukemia-free survival. Higher miR-124a expression also tended to be related to shorter survivals.@*CONCLUSIONS@#Although our study was limited by the relatively small number of patients included, we identified several miRNAs associated with pathogenesis, leukemic transformation, and prognosis in MDS.

A Type 1 Persistent Proatlantal Artery Originating from the External Carotid Artery Detected by Computed Tomographic Angiography

A persistent proatlantal artery (PA) is rare. We report a type 1 persistent PA originating from the right external carotid artery (ECA). A 78-year-old woman presented with dizziness. Computed tomographic (CT) angiography showed a persistent PA originating from the right ECA. This persistent PA did not pass through the atlas transverse foramen. The extracranial segment of this artery in the atlas transverse process level had a more lateral position than a normal left vertebral artery. CT angiography well demonstrated the relationship with bony structures and the course of this persistent PA. This anomalous artery in our patient presented as an incidental finding. Surgeon should recognize a persistent PA when performing carotid endarterectomy or ligation of the ECA for avoidance of complication.

Pancreatic Metastasis from Invasive Ductal Carcinoma of the Breast / 대한내과학회지

Pancreatic metastases from primary breast cancer are very rare. We report a case of pancreatic metastasis from invasive ductal carcinoma 13 years after the initial diagnosis of breast cancer. When the pancreatic mass was discovered, it was believed to be a primary pancreatic cancer due to the long interval from the initial diagnosis of breast cancer to metastasis. However, it was confirmed as metastatic breast cancer based on the pathology after surgical removal. Follow-up imaging has shown no recurrence.

JAK2 V617F, MPL, and CALR Mutations in Korean Patients with Essential Thrombocythemia and Primary Myelofibrosis

Mutations in the calreticulin gene, CALR, have recently been discovered in subsets of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). We investigated Korean patients with ET and PMF to determine the prevalence, and clinical and laboratory correlations of CALR/JAK2/MPL mutations. Among 84 ET patients, CALR mutations were detected in 23 (27.4%) and were associated with higher platelet counts (P=0.006) and lower leukocyte counts (P=0.035) than the JAK2 V617F mutation. Among 50 PMF patients, CALR mutations were detected in 11 (22.0%) and were also associated with higher platelet counts (P=0.035) and trended to a lower rate of cytogenetic abnormalities (P=0.059) than the JAK2 V617F mutation. By multivariate analysis, triple-negative status was associated with shorter overall survival (HR, 7.0; 95% CI, 1.6-31.1, P=0.01) and leukemia-free survival (HR, 6.3; 95% CI, 1.8-22.0, P=0.004) in patients with PMF. The type 1 mutation was the most common (61.1%) type among all patients with CALR mutations, and tended toward statistical predominance in PMF patients. All 3 mutations were mutually exclusive and were never detected in patients with other myeloid neoplasms showing thrombocytosis. CALR mutations characterize a distinct group of Korean ET and PMF patients. Triple-negative PMF patients in particular have an unfavorable prognosis, which supports the idea that triple-negative PMF is a molecularly high-risk disease.

R-CHOP chemoimmunotherapy followed by autologous transplantation for the treatment of diffuse large B-cell lymphoma

BACKGROUND: We investigated factors that influence outcomes in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab combined with the CHOP regimen (R-CHOP) followed by upfront autologous stem cell transplantation (Auto-SCT). METHODS: We retrospectively evaluated survival differences between subgroups based on the age-adjusted International Prognostic Index (aaIPI) and revised-IPI (R-IPI) at diagnosis, disease status, and positron emission tomographic/computerized tomographic (PET/CT) status at transplantation in 51 CD20-positive DLBCL patients treated with R-CHOP followed by upfront Auto-SCT. RESULTS: Patients had either stage I/II bulky disease (5.9%) or stage III/IV disease (94.1%). The median patient age at diagnosis was 47 years (range, 22-66 years); 53.3% and 26.7% had high-intermediate and high risks according to aaIPI, respectively. At the time of Auto-SCT, 72.5% and 27.5% experienced complete (CR) and partial remission (PR) after R-CHOP, respectively. The median time from diagnosis to Auto-SCT was 7.27 months (range, 3.4-13.4 months). The 5-year overall (OS) and progression-free survival (PFS) were 77.3% and 72.4%, respectively. The 5-year OS and PFS rates according to aaIPI, R-IPI, and PET/CT status did not differ between the subgroups. More importantly, the 5-year OS and PFS rates of the patients who achieved PR at the time of Auto-SCT were not inferior to those of the patients who achieved CR (P=0.223 and 0.292, respectively). CONCLUSION: Survival was not influenced by the aaIPI and R-IPI at diagnosis, disease status, or PET/CT status at transplantation, suggesting that upfront Auto-SCT might overcome unfavorable outcomes attributed to PR after induction chemoimmunotherapy.

Healthcare-Associated Pneumonia among Hospitalized Patients: Is It Different from Community Acquired Pneumonia? / 결핵및호흡기질환

BACKGROUND: The increasing number of outpatients with multidrug-resistant (MDR) pathogens has led to a new category of pneumonia, termed healthcare-associated pneumonia (HCAP). We determined the differences in etiology and outcomes between patients with HCAP and those with community-acquired pneumonia (CAP) to clarify the risk factors for HCAP mortality. METHODS: A retrospective study comparing patients with HCAP and CAP at Jeju National University Hospital. The primary outcome was 30-day mortality. RESULTS: A total of 483 patients (208 patients HCAP, 275 patients with CAP) were evaluated. Patients with HCAP were older than those with CAP (median, 74 years; interquartile range [IQR], 65-81 vs. median, 69 years; IQR, 52-78; p<0.0001). Streptococcus pneumoniae was the major pathogen in both groups, and MDR pathogens were isolated more frequently from patients with HCAP than with CAP (18.8% vs. 4.9%, p<0.0001). Initial pneumonia severity was greater in patients with HCAP than with CAP. The total 30-day mortality rate was 9.9% and was higher in patients with HCAP based on univariate analysis (16.3% vs. 5.1%; odds ratio (OR), 3.64; 95% confidence interval (CI), 1.90-6.99; p<0.0001). After adjusting for age, sex, comorbidities, and initial severity, the association between HCAP and 30-day mortality became non-significant (OR, 1.98; 95% CI, 0.94-4.18; p=0.167). CONCLUSION: HCAP was a common cause of hospital admissions and was associated with a high mortality rate. This increased mortality was related primarily to age and initial clinical vital signs, rather than combination antibiotic therapy or type of pneumonia.

A Case Report of Rituximab Therapy for Recurrent Thrombotic Thrombocytopenia Purpura / 대한혈액학회지

Thrombotic thrombocytopenic purpura (TTP) is a rare medical condition characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurologic manifestations, and infrequently, renal involvement. In many cases, TTP is associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13, and treatment with plasma exchange is effective in the majority of patients. We report a patient with acute TTP in whom remission was not achieved by initial treatment consisting of plasma exchange and corticosteroids. In view of the severe autoantibody-mediated ADAMTS-13 deficiency, treatment was initiated with rituximab, a chimeric monoclonal antibody directed against the CD 20 antigen present on B lymphocytes. The patient received 4 weekly infusions of rituximab (375 mg/m2). Four weeks after the last infusion of rituximab, a complete clinical and laboratory remission was documented. We conclude that rituximab should be considered in patients with TTP with acquired ADAMTS-13 deficiency, who fail to respond to standard treatment with plasma exchange and corticosteroids. Rituximab may result in a lowered requirement for plasmapheresis and avoid the complications of salvage immunosuppressive therapy.