Ik Chan Song

A Multicenter Retrospective Analysis of the Clinical Features of Pernicious Anemia in a Korean Population

To determine the approximate incidence and clinical features of pernicious anemia in a Korean population, we retrospectively analyzed clinical data for patients with pernicious anemia who were diagnosed between 1995 and 2010 at five hospitals in Chungnam province. Ninety-seven patients were enrolled, who accounted for 24% of patients with vitamin B12 deficiency anemia. The approximate annual incidence of pernicious anemia was 0.3 per 100,000. The median age was 66 (range, 32-98) yr, and the male/female ratio was 1.25. Anemia-associated discomfort was the most common symptom (79.4%), followed by gastrointestinal and neurological symptoms (78.4% and 38.1%, respectively). Pancytopenia was found in 36 patients (37.1%), and autoimmune disorders were found in 15 patients (15.5%). Antibody to intrinsic factor was detected in 62 (77.5%) of 80 patients examined, and antibody to parietal cells was detected in 35 (43.2%) of 81 patients examined. Of the 34 patients who underwent tests for Helicobacter pylori, 7 (12.5%) were positive. The anemia-associated and gastrointestinal symptoms resolved completely in all patients after intramuscular injection of cobalamin, whereas neurological symptoms remained in some. In conclusion, pernicious anemia is less frequent in Koreans than in Western populations; however, the clinical features of this disorder in Koreans do not differ from those of Western cases.

Loss of NDRG2 promotes epithelial-mesenchymal transition of gallbladder carcinoma cells through MMP-19-mediated Slug expression

BACKGROUND & AIMS Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract and one of the most lethal forms of human cancer. However, there is limited information about the molecular pathogenesis of GBC. Here, we examined the functional role of the tumor suppressor N-myc downstream-regulated gene 2 (NDRG2) and the underlying molecular mechanisms of disease progression in GBC. METHODS Clinical correlations between NDRG2 expression and clinicopathological factors were determined by immunohistochemical analysis of tumor tissues from 86 GBC patients. Biological functions of NDRG2 and NDRG2-mediated signaling pathways were determined in GBC cell lines with NDRG2 knockdown or overexpression. RESULTS Loss of NDRG2 expression was an independent predictor of decreased survival and was significantly associated with a more advanced T stage, higher cellular grade, and lymphatic invasion in patients with GBC. GBC cells with loss of NDRG2 expression showed significantly enhanced proliferation, migration, and invasiveness in vitro, and tumor growth and metastasis in vivo. Loss of NDRG2 induced the expression of matrix metalloproteinase-19 (MMP-19), which regulated the expression of Slug at the transcriptional level. In addition, MMP-19-induced Slug, increased the expression of a receptor tyrosine kinase, Axl, which maintained Slug expression through a positive feedback loop, and stabilized epithelial-mesenchymal transition of GBC cells. CONCLUSIONS The results of our study help to explain why the loss of NDRG2 expression is closely correlated with malignancy of GBC. These results strongly suggest that NDRG2 could be a favorable prognostic indicator and promising target for therapeutic agents against GBC.

Diagnostic and Prognostic Implications of Spine Magnetic Resonance Imaging at Diagnosis in Patients with Multiple Myeloma

Purpose The aim of this study is to determine the diagnostic and prognostic role of baseline spinal magnetic resonance imaging (MRI) in patients with multiple myeloma. Materials and Methods We enrolled patients newly diagnosed with multiple myeloma from 2004-2011 at a single center. Abnormal MRI findings that were not detected in radiographs have been analyzed and categorized as malignant compression fractures or extramedullary plasmacytoma. The bone marrow (BM) infiltration patterns on MRI have been classified into five categories. Results A total of 113 patients with a median age of 65 years (range, 40 to 89 years) were enrolled in the study. Malignant compression fractures not detected in the bone survey were found in 26 patients (23.0%), including three patients (2.6%) with no related symptoms or signs. Extramedullary plasmacytoma was detected in 22 patients (19.5%), including 15 (13.3%) with epidural extension of the tumor. Of these 22 patients, 11 (50.0%) had no relevant symptoms or signs. The presence of malignant compression fractures did not influence overall survival; whereas non-epidural extramedullary plasmacytoma was associated with poor overall survival in the multivariate analysis (hazard ratio, 3.205; 95% confidence interval [CI], 1.430 to 9.845; p=0.042). During the follow-up for a median of 21 months (range, 1 to 91 months), overall survival with the mixed BM infiltrative pattern (median, 24.0 months; 95% CI, 22.9 to 25.1 months) was shorter than those with other patterns (median 56 months; 95% CI, 48.9 to 63.1 months; p=0.030). Conclusion These results indicate that spine MRI at the time of diagnosis is useful for detecting skeletal lesions and predicting the prognosis in patients with multiple myeloma.

Metabolic characterization of imatinib-resistant BCR-ABL T315I chronic myeloid leukemia cells indicates down-regulation of glycolytic pathway and low ROS production

Abstract Long-term imatinib treatment induces drug-resistant chronic myeloid leukemia (CML) cells harboring T315I gate keeper mutation of breakpoint cluster region (BCR)-ABL oncogenic kinase. However, although cell proliferation is coupled with cellular energy status in CML carcinogenesis, the metabolic characteristics of T315I-mutant CML cells have never been investigated. Here, we analyzed cell proliferation activities and metabolic phenotypes, including cell proliferation, oxygen consumption, lactate production, and redox state in the KBM5 (imatinib-sensitive) and KBM5-T315I (imatinib-resistant) CML cell lines. Interestingly, KBM5-T315I cells showed decreased cell proliferation, lactate production, fatty acid synthesis, ROS production, and down regulation of mRNA expression related to ROS scavengers, such as SOD2, catalase, GCLm, and GPx1. Taken together, our data demonstrate that the lower growth ability of KBM5-T315I CML cells might be related to the decreased expression of glycolysis-related genes and ROS levels, and this will be used to identify therapeutic targets for imatinib resistance in CML.

A case of acute promyelocytic leukemia concomitant with plasma cell myeloma.

Dear Editor AML is a myeloid clonal malignancy characterized by the accumulation of abnormal immature myeloid cells in the bone marrow. The occurrence of therapy-related AML as a late complication of cytotoxic therapy is well documented [1], and several regimens for the treatment of plasma cell myeloma (PCM) have been associated with the development of myeloid neoplasms, such as AML, myelodysplastic syndrome, and myeloproliferative neoplasm [2]. The simultaneous occurrence of AML with various plasma cell dyscrasias without prior exposure to chemotherapy or radiotherapy is extremely rare, and most reported cases are of the myelomonocytic or monocytic subtype [3-6]. Herein, we report the first case of simultaneous acute promyelocytic leukemia (APL) and PCM presentation without previous exposure to chemotherapy or radiotherapy. A 60-yr-old man with a history of diabetic nephropathy, hypertension, and acute myocardial infarction with subsequent congestive heart failure presented to the emergency department with a 1-week history of general weakness, poor oral intake, and nausea. Neither hepatomegaly nor splenomegaly was detected on physical examination. The initial complete blood counts were the following: hemoglobin (11.5 g/dL, reference range: 13.5-17.4 g/dL), white blood cell count (2.7×109/L, reference range: 3.8-10.0×109/L), platelet count (378×109/L, reference range: 130-400×109/L), and white blood cell differential indicated 1% band neutrophils; 29% neutrophils; 62% lymphocytes; 2% monocytes; 4% eosinophils; and 2% basophils. Initial biochemical tests determined levels of total protein, (7.1 g/dL, reference range: 6.5-8.0 g/dL), albumin (2.9 g/dL, reference range: 4.0-5.0 g/dL), creatinine (5.1 mg/dL, reference range: 0.8-1.2 mg/dL), total calcium (6.6 mg/dL, reference range: 8.7-10.6 mg/dL), phosphorus (4.8 mg/dL, reference range: 2.5-4.7 mg/dL), β2 microglobulin (9.29 mg/L, reference range: 0-3.0 mg/L), and serum IgG (3,018 mg/dL, reference range: 680-1,620 mg/dL). Capillary electrophoresis (Sebia, Norcross, GA, USA) of serum and urine proteins showed a monoclonal peak (1.41 g/dL, 21.1% in serum; 0.22 g/dL, 8.3% in urine) in the gamma-globulin region, and immunofixation electrophoresis confirmed monoclonal gammopathy of IgG, kappa type. The ratios of serum and urine kappa/lambda light chains were 1.69 (reference range: 0.26-1.65) and 5.33 (reference range: 0.26-1.65), respectively. Radiologically, no osteolytic lesions were detected, but spinal magnetic resonance imaging (MRI) showed abnormal bone marrow signal intensity related to PCM. A bone marrow aspirate was composed of 10% myeloblasts, 23% abnormal hypergranular promyelocytes containing Auer rods, and 16% plasma cells. Myeloblasts and abnormal promyelocytes stained strongly positive for myeloperoxidase (MPO). The cellularity of biopsy was 70% and diffuse infiltration of two distinct populations consisting of leukemic myeloid cells (myeloblasts and abnormal promyelocytes) and plasma cells was observed. Immunohistochemical staining of the marrow biopsy showed significant positivity for CD138 and kappa light chain (Fig. 1). Flow cytometric analysis demonstrated blastic cells expressing CD13, CD33, and cytoplasmic MPO, but not HLA-DR, CD34, or CD15, consistent with the characteristics of APL. Cytogenetic analysis revealed a karyotype of 46,XY,t(15;17)(q22;q21)[4]/46,XY[16], and FISH confirmed nuc ish (PML,RARA)x3(PML con RARAx2)[64/200]. Nested reverse transcriptase-polymerase chain reaction (Seegene, Seoul, Korea) determined rearrangement of the PML/RARA gene. On the basis of these findings, we diagnosed the patient with APL concomitant with PCM, and the patient was initially treated with all-trans retinoic acid (ATRA) for 1 week. The patient refused additional chemotherapy because of his deteriorating physical condition after administration of ATRA and was discharged after 4 months of supportive care. Fig. 1 (A) Bone marrow aspiration showing abnormal promyelocytes (yellow arrow), Faggot cells (black arrow), and plasma cells (red arrow) (Wright stain, ×1,000) and (B) Immunohistochemical stain with CD138, (left, ×100), kappa light chain (middle, ... AML and PCM are different disease entities, and most concomitant cases result from leukemia that develops because of chemotherapy for preceding myeloma. Undiagnosed or untreated PCM co-presenting with AML is rare, with only 13 reports in the literature to date [7-9]. To our knowledge, this is the first reported case of APL concomitant with PCM worldwide. In this case, the diagnosis of APL was evident because of the presence of abnormal promyelocytes, Faggot cells, and the PML/RARA gene rearrangement. Before concluding that plasmacytosis is associated with clonal hematologic malignancy or PCM, reactive plasmacytosis should be ruled out because plasmacytosis can co-occur with AML [10], in which interleukin-6 production by leukemic blasts may stimulate plasma cell growth [11]. The patients various chronic conditions confounded the assessment of CRAB (hypercalcemia, renal insufficiency, anemia, and bony lesion) to prove end-organ damage by PCM. In this case, anemia could be attributed to the underlying chronic diseases, and the decrease of albumin and elevation of creatinine levels usually accompanied by PCM were masked by diabetic nephropathy. Elevation of total protein levels was not prominent, and hypercalcemia was also not observed because of the patients nephropathy. As MRI is more sensitive than a skeletal survey, the increased signal intensity detected by MRI determined bony lesions in PCM [12]. The creatinine level in this patient was stable (3 mg/dL), but was aggravated on presentation possibly because of PCM, and urgent hemodialysis was needed. In addition, bone marrow with 16% plasma cells was noted, which is not usually seen in reactive plasmacytosis, where plasma cells typically do not exceed 10% [13]. The presence of >10% plasma cells, monoclonal gammopathy by electrophoresis, kappa restriction by immunohistochemical stain, aggravation of kidney function, and bony lesions in MRI lead to the conclusion of clonal plasmacytosis, and a final diagnosis of APL concomitant with PCM was made. The proposed reasons for concurrent presentation of 2 different hematologic malignancies are abnormal multipotent stem cells, environmental risk factors, repeated infections that result in the development of a leukemic clone, and decreased immune surveillance, which may result in failure to eliminate leukemic clones [6, 11, 14]. In cases of APL followed by chemotherapy for PCM, a regimen of ATRA or allogeneic stem cell transplantation can be considered treatment options [1, 15], but treatment regimens for concomitant malignancies are not fully established because the co-occurrence of APL and PCM is rare. In this case, treatment with ATRA was begun with the intent to add idarubicine; however, additional chemotherapy was discontinued because the patient developed sepsis with aggravated general weakness. Aside from 1 patient who received stem cell transplantation [9], there have been no reports on survival of patients with concomitant AML and PCM who received chemotherapy, and the time interval from diagnosis to death in most cases was <5 months. The prognosis of this patient was poor because of his deteriorating condition despite appropriate supportive care. In conclusion, we described the first case of concomitant APL and PCM, suggesting that 2 distinct diseases can present coin cidentally without previous chemotherapy. Although rare, plasmacytosis can occur in AML, and clonality should be ruled out because of the simultaneous presentation of these 2 different hematological malignancies.

Biochemical and Pathological Response of Prostate Cancer in a Patient with Metastatic Renal Cell Carcinoma on Sunitinib Treatment

Abstract Sunitinib is a small molecular inhibitor of tyrosine kinases and is used to treat advanced renal cell carcinoma and gastrointestinal stromal tumour after disease progression or intolerance to imatinib therapy. Here, we describe biochemical and pathological response of prostate cancer in a patient with metastatic renal cell carcinoma during sunitinib treatment. A 62-year-old man was referred to our hospital because of a mass in the scalp. He was diagnosed with left renal cell carcinoma with right renal and scalp metastases. In addition, synchronous prostate cancer involving less than one-half of the right lobe was found with a prostate-specific antigen (PSA) value of 23.4 ng/ml. Treatment was begun with sunitinib (50 mg daily, 4 weeks on and 2 weeks off). Regarding the prostate cancer, active monitoring was planned considering the far advanced renal cell carcinoma. Surprisingly, the PSA level was 3.4 ng/ml at week 6 and 0.2 ng/ml at week 12, and it subsequently remained normal. At the time of writing (cycle 6 of sunitinib therapy), the prostate nodule significantly decreased in size. Furthermore, a 12-core re-biopsy revealed pathological evidence of regression with sunitinib treatment, with control of his renal cell carcinoma.

L‑Deprenyl exerts cytotoxicity towards acute myeloid leukemia through inhibition of mitochondrial respiration

The identification of large numbers of genetic mutations in immature myeloid cells has made it difficult to identify specific targets for acute myeloid leukemia (AML) therapy. Although current pharmacological targets for controlling cancer are focused on identifying genetic mutations, it is hard to develop the specific drugs to achieve complete remission due to complex and variable genetic mutations. To overcome the failure of the genetic mutation theory, the present study targeted mitochondrial metabolism as a strategy for inducing anti‑leukemic activity, based on evidence that AML cells have an abnormally high amount of mitochondria and that somatic mutations can alter metabolic flux in cancer. It was found that L‑deprenyl, which is clinically available for the treatment of Parkinsons disease, exerts anti‑mitochondria activity in KG‑1α cells, as assessed by detection of oxygen consumption rate (OCR) and extracellular acidification (ECAR) using XF analyzer, respectively. Using a luciferase assay for detecting adenosine triphosphate (ATP) content, it was found that suppression of mitochondrial activity led to ATP depletion and was associated with potent cytotoxic activity. L‑deprenyl is known to target monoamine oxidase‑B (MAO‑B) on the outer membrane of mitochondria, therefore, the activity of MAO‑A and ‑B was measured based on the fluorometric detection of H2O2 produced by the enzyme reaction. Notably, MAO‑A and -B activity was low in AML cells and the present findings suggested that the anticancer effect of L‑deprenyl was independent of MAO‑B. Change of mitochondrial respiration‑ and glycolysis‑related gene expression levels were measured by reverse transcription‑quantitative polymerase chain reaction. Consistent with the aforementioned results, treatment with L‑deprenyl reduced the mRNA level of mitochondrial respiration‑ and glycolysis‑related genes. Collectively, the present results identify L‑deprenyl as a novel candidate for the treatment of AML through inhibition of mitochondrial respiration.

No benefit of hypomethylating agents compared to supportive care for higher risk myelodysplastic syndrome

Background/Aims This study evaluated the role of hypomethylating agents (HMA) compared to best supportive care (BSC) for patients with high or very-high (H/VH) risk myelodysplastic syndrome (MDS) according to the Revised International Prognostic Scoring System. Methods A total of 279 H/VH risk MDS patients registered in the Korean MDS Working Party database were retrospectively analyzed. Results HMA therapy was administered to 205 patients (73.5%), including 31 patients (11.1%) who then received allogeneic hematopoietic cell transplantation (allo-HCT), while 74 patients (26.5%) received BSC or allo-HCT without HMA. The 3-year overall survival (OS) rates were 53.1% ± 10.7% for allo-HCT with HMA, 75% ± 21.7% for allo-HCT without HMA, 17.3% ± 3.6% for HMA, and 20.8% ± 6.9% for BSC groups (p < 0.001). In the multivariate analysis, only allo-HCT was related with favorable OS (hazard ratio [HR], 0.356; p = 0.002), while very poor cytogenetic risk (HR, 5.696; p = 0.042), age ≥ 65 years (HR, 1.578; p = 0.022), Eastern Cooperative Oncology Group performance status (ECOG PS) 2 to 4 (HR, 2.837; p < 0.001), and transformation to acute myeloid leukemia (AML) (HR, 1.901; p = 0.001) all had an adverse effect on OS. Conclusions For the H/VH risk group, very poor cytogenetic risk, age ≥ 65 years, ECOG PS 2 to 4, and AML transformation were poor prognostic factors. HMA showed no benefit in terms of OS when compared to BSC. Allo-HCT was the only factor predicting a favorable long-term outcome. The use of HMA therapy did not seem to have an adverse effect on the transplantation outcomes. However, the conclusion of this study should be carefully interpreted and proven by large scale research in the future.

Methylprednisolone versus intravenous immune globulin as an initial therapy in adult primary immune thrombocytopenia

Background/Aims Few studies have addressed whether there are differences in clinical efficacy between intravenous methylprednisolone (methyl-Pd) and intravenous immunoglobulin (IVIg) use. Methods We retrospectively compared platelet responses and toxicities associated with these two treatments in adult patients with immune thrombocytopenia. Patients received intravenous methyl-Pd therapy followed by oral prednisolone (Pd) from 1993 to 2002 and IVIg together with oral Pd from 2003 to 2008. Results Early response and maintenance of the response were assessed at 7 days and 6 months after treatment, respectively. Of the 87 patients enrolled, 77 (88.5%) were eligible for analysis. Early responses occurred in 30 of 39 patients (76.9%) receiving methyl-Pd versus 33 of 38 patients (86.6%) receiving IVIg (p = 0.187). The response was maintained in 28 patients (71.8%) in the methyl-Pd arm and in 23 patients (60.5%) in the IVIg arm (p = 0.187). The time to a complete response in the IVIg arm (6 days; range, 1 to 35) was shorter than that in the methyl-Pd arm (13.5 days; range, 2 to 29) (p = 0.002). Side effects were mild and tolerable in both arms. Five years after initiating treatment, 7 of 18 patients (38.9%) and five of 14 patients (35.7%) were still maintaining a response in the methyl-Pd and IVIg arms, respectively. Conclusions These results indicate that neither the early response rate nor the long-term outcome differed between the methyl-Pd and IVIg treatments. However, IVIg induced a complete response more rapidly than did methyl-Pd.

Two Cases of Intravascular Lymphoma Presenting with Pulmonary Involvement

Intravascular lymphoma (IVL) is a rare type of extranodal non-Hodgkins lymphoma. It is characterized by the proliferation of malignant lymphocytes within the lumen of small vessels and sparing of surrounding tissue (1,2,3,5). Pulmonary presentation of IVL is rare in Asian population and shows poor prognosis (4,5). It can be also a cause of unexplained interstitial lung disease. Because the prognosis is poor, the need of more intensive treatment should be considered. Two women, 56 years old (patient 1) and 59 years old (patient 2), commonly had a one month history of fever, weight loss, and upper respiratory symptoms. They did not show skin lesions and hepatosplenomegaly. Chest computed tomography (CT) scans also commonly showed ground-glass opacities and consolidations in both lungs (Fig. 1). In the bone marrow study, secondary hemophagocytosis (patient 1) and lymphoma involvement (patient 2) were observed, respectively. A positron emission tomography (PET) scan with 2 patients revealed diffuse increased glucose uptake in both of the lungs. These findings of CT scan and PET scan considered atypical bacterial or viral pneumonia, and acute hypersensitivity pneumonitis as possible diagnosis. An open lung biopsy for a confirmative diagnosis showed that CD20, CD79a, bcl-2, and MUM-1 were positive in the intravascular atypical cells (Fig. 1). Patient 1 was given best supportive care because of poor general condition due to delayed diagnosis. It was much delayed (2 months [patient 1], 1 month [patient 2], respectively) to diagnose finally from the initial hospital visit. On several reports, the prognosis of IVL is very poor, early introduction of systemic chemotherapy may be important to improve prognosis (4,6). The previous reports recommended an anthracycline-based chemotherapy regimen including CHOP. Rituximab is added in cases of B-cell lineage (2,3,6). Therefore we decided to use intensive chemotherapy for patient 2, who was given 3 cycles of R-hyper CVAD regimen. After 2 cycles of R-hyper CVAD, partial remission was observed. However, disease rapidly progressed and the patients eventually expired at three (patient 1) and four months (patient 2) after initial presentation, respectively. For early diagnosis of IVL with lung involvement, the early suspect based on symptoms, chest CT scan and PET scan are important because of no specific findings for IVL of lung involvement, and early aggressive diagnostic procedures (such as trans-bronchial biopsy, open lung biopsy) are required. Because the prognosis of IVL is poor, the more intensive treatment including front-line autologous transplantation should be explored. Here, we reported two cases of intravascular large B-cell lymphoma involving the lungs with their images and histopathology findings. Fig. 1 Findings of 56-year-old (A, B) and 59-year-old (C, D) women with pulmonary intravascular lymphoma. (A) Chest CT scan shows patchy GGOs and consolidations in both lungs, mainly located in the central portion. (B) Open lung biopsy specimen shows that many ...