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1.  Blockade of TGF- by Catheter-based Local Intravascular Gene Delivery Does Not Alter The In-Stent Neointimal Response, But Enhances Inflammation in Pig Coronary Arteries 
International journal of cardiology  2010;145(3):468-475.
Extracellular matrix (ECM) accumulation significantly contributes to in-stent restenosis. In this regard, transforming growth factor (TGF)-β, a positive regulator of ECM deposition, may be implicated in in-stent restenosis. The goal of this study was to assess the effect of blockade of TGF-β on stent-induced restenosis in porcine coronary arteries.
An adenovirus expressing the ectodomain of the TGF-β type II receptor (AdTβ-ExR) was applied onto a coronary arterial segment of a pig (n=10) using an Infiltrator™, followed by stent deployment. Controls consisted of adenoviruses expressing β-galactosidase (AdLacZ) or phosphate-buffered saline (PBS) applied onto the other segment (n=10) of the same pig.
Computer-based pathological morphometric analysis of stented coronary arteries, performed 4 weeks after stenting, demonstrated no significant difference in morphometric parameters such as in-stent neointimal area and % area stenosis between the AdTβ-ExR group and control (n=7 for each). However the AdTβ-ExR group had increased neointimal cell density, infiltration of inflammatory cells mostly consisting of CD3+ T cell, accumulation of hyaluronan, cell proliferation rate, and adventitial matrix metalloproteinase-1 (MMP-1) expression compared with control. The expression of connective tissue growth factor mRNA, measured by reverse transcription PCR, in cultured rat arterial smooth muscle cells was inhibited by AdTβ-ExR at moi 60.
Blockade of TGF-β by catheter based local intravascular gene delivery does not reduce stent-induced neointima formation 4 weeks after stenting in spite of modest inhibition of ECM accumulation, but it induces vascular inflammation and associated pathological changes that may potentially aggravate lesion progression.
PMCID: PMC4100469  PMID: 20053468
hyaluronan; inflammation; restenosis; stents; transforming growth factor-β
2.  Expression of CD99 in Multiple Myeloma: A Clinicopathologic and Immunohistochemical Study of 170 Cases 
Korean Journal of Pathology  2014;48(3):209-216.
Multiple myeloma (MM) is a heterogeneous and ultimately fatal disease. Risk stratification using prognostic biomarkers is crucial to individualize treatments. We sought to investigate the role of CD99, a transmembrane protein highly expressed in many hematopoietic cells including subpopulations of normal and neoplastic plasma cells, for MM risk stratification.
CD99 expression was measured in paraffin samples of bone marrow and extramedullary biopsies of 170 patients with MM. Patients were divided into those with high score (moderately and strongly positive) and low score (negative and weakly positive), with all staining being cytoplasmic and/or membranous.
High anti-CD99 immunostaining was observed in 72 of 136 (52.9%) bone marrow biopsies and 24 of 87 (27.6%) extramedullary biopsies in MM. High CD99 expression of extramedullary specimens was associated with significantly longer overall survival (OS; p=.016). High CD99 expression of extramedullary specimens was also associated with better prognosis in the nonautologous stem cell transplantation group of MM patients (p=.044). In multivariate analysis, International Staging System stage was an independent prognostic factor, whereas CD99 expression was no longer statistically significant.
Expression of CD99 in extramedullary specimens was correlated with longer OS, suggesting that CD99 may be a helpful immunohistochemical marker for risk stratification.
PMCID: PMC4087134  PMID: 25013419
CD99; Multiple myeloma; Immunostaining; Autologous stem cell transplantation
3.  Abbreviated chemotherapy for limited-stage diffuse large B-cell lymphoma after complete resection 
Blood research  2014;49(2):115-119.
Abbreviated chemotherapy followed by radiotherapy or full cycles of chemotherapy is recommended as a standard treatment for limited-stage (LS) diffuse large B-cell lymphoma (DLBCL). After complete resection of tumors, however, Burkitt and childhood B-cell Non-Hodgkin lymphoma show favorable outcomes, even after abbreviated chemotherapy of only 2 or 3 cycles. We investigated the effectiveness of abbreviated chemotherapy in patients with LS DLBCL after complete tumor resection.
We retrospectively reviewed 18 patients with LS DLBCL who underwent complete tumor resection followed by either 3 or 4 cycles of chemotherapy between March 2002 and May 2010.
With a median follow-up period of 57.9 months (range, 31.8-130.2 months), no patients experienced disease relapse or progression; however, 1 patient experienced secondary acute myeloid leukemia during follow-up. The 5-year progression-free survival rate and overall survival rate were 93.3% and 94.1%, respectively.
These results warrant further investigation into abbreviated chemotherapy as an alternative treatment for patients who have undergone complete resection of LS DLBCL.
PMCID: PMC4090332  PMID: 25025013
Diffuse large B-cell lymphoma; Limited Stage; Resection; Abbreviated chemotherapy
4.  Current Concepts in Primary Effusion Lymphoma and Other Effusion-Based Lymphomas 
Korean Journal of Pathology  2014;48(2):81-90.
Primary effusion lymphoma (PEL) is a human herpes virus 8 (HHV8)-positive large B-cell neoplasm that presents as an effusion with no detectable tumor in individuals with human immunodeficiency virus infection or other immune deficiencies. PEL is an aggressive neoplasm with a poor prognosis. PEL cells show diverse morphologies, ranging from immunoblastic or plasmablastic to anaplastic. The immunophenotype of PEL is distinct, but its lineage can be misdiagnosed if not assessed thoroughly. PEL cells usually express CD45, lack B- and T-cell-associated antigens, and characteristically express lymphocyte activation antigens and plasma cell-associated antigens. Diagnosis of PEL often requires the demonstration of a B-cell genotype. HHV8 must be detected in cells to diagnose PEL. In most cases, PEL cells also harbor the Epstein-Barr virus (EBV) genome. Similar conditions associated with HHV8 but not effusion-based are called "extracavitary PELs." PELs should be differentiated from HHV8-negative, EBV-positive, body cavity-based lymphomas in patients with long-standing chronic inflammation; the latter can occur in tuberculous pleuritis, artificial pneumothorax, chronic liver disease and various other conditions. Despite their morphological similarity, these various lymphomas require different therapeutic strategies and have different prognostic implications. Correct diagnosis is essential to manage and predict the outcome of patients with PEL and related disorders.
PMCID: PMC4026813  PMID: 24868220
Lymphoma, primary effusion; Human herpes virus 8
5.  Primary mediastinal large B-cell lymphoma: a single-center experience in Korea 
Blood research  2014;49(1):36-41.
Primary mediastinal large B-cell lymphoma (PMBL) is a distinct subtype of non-Hodgkin lymphoma, which has no consensus for its ideal treatment or prognosis.
We reviewed the clinicopathologic features and clinical outcomes of 25 PMBL cases diagnosed at a single institution between 1993 and 2009 and compared them with 588 cases of non-mediastinal, diffuse large B-cell lymphoma (DLBCL, control group) diagnosed during the same period.
Thirteen (52.0%) PMBL patients had Ann Arbor stage III or IV disease, and 10 (40.0%) had B symptoms. Thirteen (52%) PMBL patients were classified as high-intermediate/high-risk according to the International Prognostic Index. There was a significant prevalence of young (median: 31 years; range, 15-78 years; P<0.001), female (68%; P=0.014) patients in the PMBL group compared to the control group (median: 56 years; range, 15-85 years; 43.2% female). Bulky disease and elevated levels of lactate dehydrogenase (LDH) were more frequent in the PMBL group (P<0.001 and P=0.003, respectively). Nineteen (76%) PBML patients achieved complete remission, and 18 were alive at the last follow-up (median: 43 months; range, 1-92 months). There was no difference in the 3-year, overall survival rate (72%, 95% confidence interval [CI]: 54.0-83.0 versus 70.1%, 95% CI, 109.0-126.0; P=0.686) between PMBL and control patients, respectively.
Compared to patients with non-mediastinal DLBCL, Korean patients with PMBL are predominantly young women with bulky disease and high LDH levels but with no significant difference in survival.
PMCID: PMC3974955  PMID: 24724065
Lymphoma; B cell; PMBL; Prognosis; Treatment
6.  CD163 Expression Was Associated with Angiogenesis and Shortened Survival in Patients with Uniformly Treated Classical Hodgkin Lymphoma 
PLoS ONE  2014;9(1):e87066.
Recent studies have reported the prognostic value of tissue-associated magrophages (TAMs) in classical Hodgkin lymphoma (cHL). In addition, TAMs are implicated in the tumor angiogenesis. In this study, we examined the prognostic relevance of TAMs in relation to vascular endothelial growth factor (VEGF) expression and angiogenesis in uniformly treated cases of cHL.
Diagnostic tissue from 116 patients with ABVD-treated cHL was evaluated retrospectively by immunohistochemical analysis for CD68, CD163 and VEGF expression and for CD31 expression as a measure of microvessel density (MVD).
High CD163 expression (≥35% of cellularity) correlated with VEGF expression (Pearson’s Chi-square test, P = 0.008) and MVD (Spearman correlation coefficient 0.310, P<0.001). High CD163 expression was associated with inferior event-free survival (EFS, P = 0.005) and overall survival (OS, P<0.001) in univariate analysis. In multivariate analysis, high CD163 expression was strongly associated with inferior EFS (P = 0.043) and OS (P = 0.008). Patients with high MVD had a lower OS than those with low MVD, but the difference was not significant (P = 0.071, respectively). While high expression of CD68 was also associated with inferior EFS (P = 0.007), it showed no correlation with VEGF or MVD.
Our data confirms that CD163 expression provides independent prognostic information in cHL. The correlation of CD163 with VEGF expression and MVD suggests the role of CD163-positive cells in tumor angiogenesis of cHL.
PMCID: PMC3906082  PMID: 24489836
7.  Intestinal Diffuse Large B-Cell Lymphoma: An Evaluation of Different Staging Systems 
The gastrointestinal tract is the most common primary extranodal site for diffuse large B-cell lymphoma (DLBCL). However, there is no consensus on the most appropriate staging system for intestinal DLBCL. We evaluated the utility of the modified Ann Arbor system, the Lugano system, and the Paris staging system (a modification of the Tumor, Node, Metastases [TNM] staging for epithelial tumors) in 66 cases of resected intestinal DLBCL. The cases were treated with surgery, plus either cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy alone (n=26) or with the addition of rituximab immunotherapy (n=40). Median follow-up time was 40.4 months (range, 2.1-171.6 months). Fifty-six patients (84.8%) achieved complete remission. The overall 5-yr survival rate was 86.4% (57/66). Of the stage categories defined for each staging system, only the T stage of the Paris classification showed prognostic significance for overall survival by univariate analysis. However, none of the stage parameters was significantly correlated with patient survival on multivariate analysis. In conclusion, the results suggest that the T stage of the Paris classification system may be a prognostic indicator in intestinal DLBCL. The results also imply that in surgically resected intestinal DLBCL, the addition of rituximab to the CHOP regimen does not confer significant survival advantage.
PMCID: PMC3890477  PMID: 24431906
Lymphoma, Large B-Cell, Diffuse; Intestines; Stage; Rituximab
8.  Prognostic Significance of Absolute Lymphocyte Count/Absolute Monocyte Count Ratio at Diagnosis in Patients with Multiple Myeloma 
Korean Journal of Pathology  2013;47(6):526-533.
Absolute lymphocyte count (ALC) in peripheral blood has recently been reported to be an independent prognostic factor in multiple myeloma (MM). Previous studies indicated that the absolute monocyte count (AMC) in peripheral blood reflects the state of the tumor microenvironment in lymphomas. Neither the utility of the AMC nor its relationship with ALC has been studied in MM.
The prognostic value of ALC, AMC, and the ALC/AMC ratio at the time of diagnosis was retrospectively examined in 189 patients with MM.
On univariate analysis, low ALC (<1,400 cells/µL), high AMC (≥490 cells/µL), and low ALC/AMC ratio (<2.9) were correlated with worse overall survival (OS) (p=.002, p=.038, and p=.001, respectively). On multivariate analysis, the ALC/AMC ratio was an independent prognostic factor (p=.047), whereas ALC and AMC were no longer statistical significant. Low ALC, high AMC, and low ALC/AMC ratio were associated with poor prognostic factors such as high International Staging System stage, plasmablastic morphology, hypoalbuminemia, and high β2-microglobulin.
Univariate analysis demonstrated that changes in ALC, AMC, and the ALC/AMC ratio are associated with patient survival in MM. Multivariate analysis showed that, of these factors, the ALC/AMC ratio was an independent prognostic factor for OS.
PMCID: PMC3887154  PMID: 24421845
Multiple myeloma; Lymphocytes; Monocytes; Lymphocyte/monocyte ratio; Prognosis
9.  Prognostic value of immunohistochemical algorithms in gastrointestinal diffuse large B-cell lymphoma 
Blood research  2013;48(4):266-273.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous clinicopathological entity, and its molecular classification into germinal center B cell-like (GCB) and activated B cell-like (ABC) subtypes using gene expression profile analysis has been shown to have prognostic significance. Recent attempts have been made to find an association between immunohistochemical findings and molecular subgroup, although the clinical utility of immunohistochemical classification remains uncertain.
The clinicopathological features and follow-up data of 68 cases of surgically resected gastrointestinal DLBCL were analyzed. Using the immunohistochemical findings on tissue microarray, the cases were categorized into GCB and non-GCB subtypes according to the algorithms proposed by Hans, Muris, Choi, and Tally.
The median patient age was 56 years (range, 26-77 years). Of the 68 cases included, 39.7% (27/68) involved the stomach, and 60.3% (41/68) involved the intestines. The GCB and non-GCB groups sorted according to Hans, Choi, and Tally algorithms, but not the Muris algorithm, were closely concordant (Hans vs. Choi, κ=0.775, P<0.001; Hans vs. Tally, κ=0.724, P<0.001; Choi vs. Tally, κ=0.528, P<0.001). However, there was no prognostic difference between the GCB and non-GCB subtypes, regardless of the algorithm used. On univariate survival analyses, international prognostic index risk group and depth of tumor invasion both had prognostic significance.
The Hans, Choi, and Tally algorithms might represent identical DLBCL subgroups, but this grouping did not correlate with prognosis. Further studies may delineate the association between immunohistochemical subgroups and prognosis.
PMCID: PMC3894385  PMID: 24466551
Diffuse large B-cell lymphoma; Gastrointestinal tract; Immunohistochemistry; Prognosis
10.  The Ratio of the Absolute Lymphocyte Count to the Absolute Monocyte Count Is Associated with Prognosis in Hodgkin's Lymphoma: Correlation with Tumor-Associated Macrophages 
The Oncologist  2012;17(6):871-880.
The prognostic value of the peripheral blood absolute lymphocyte count (ALC), absolute monocyte count (AMC), and ALC/AMC ratio at diagnosis in patients with classic Hodgkin's lymphoma was evaluated, and relationships with tumor-associated macrophages were examined.
Although most patients with classical Hodgkin's lymphoma (cHL) have a long survival duration, the current risk stratification is imperfect. A recent study suggested a prognostic role for the peripheral blood absolute lymphocyte count/absolute monocyte count (ALC/AMC) ratio at diagnosis in cHL. It is intriguing to investigate the significance of the ALC/AMC ratio in relation to tumor-associated macrophages (TAMs), yet another prognostic factor for cHL.
We examined the prognostic impact of the ALC, AMC, and ALC/AMC ratio in 312 cHL patients (median age, 37 years) using receiver operating characteristic curve analysis for optimal cutoff values, and compared these with TAM content.
The median follow-up was 65 months (range, 0.1–245 months). On univariate analysis, a low ALC/AMC ratio (<2.9) was correlated with a poorer overall survival (OS) outcome. A subgroup analysis of patients with limited-stage disease showed that the ALC/AMC ratio was significantly correlated with the OS time. Multivariate analysis showed the ALC/AMC ratio to be an independent prognostic factor for OS outcome. A Spearman correlation test of TAM content showed a negative correlation with the ALC/AMC ratio and a positive correlation with the peripheral blood macrophage percentage.
This study suggests that the ALC/AMC ratio may be a simple, inexpensive, and independent prognostic factor for OS outcome in patients with cHL and may have a role in the stratification of cHL patients in addition to the International Prognostic Score and TAM content.
PMCID: PMC3380887  PMID: 22588324
Hodgkin's lymphoma; Monocytes; Lymphocytes; Lymphocyte/monocyte ratio; Prognosis
13.  Rosai-Dorfman Disease: Report of a Case Associated with IgG4-Related Sclerotic Lesions 
Korean Journal of Pathology  2012;46(6):583-586.
We describe a rare case of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) associated with a six-year history of autoimmune pancreatitis, which was controlled by steroid treatment. The patient presented with multiple, cervical and thoracic lymphadenopathy and abnormal, nodular opacities in the lung. Histologically, Rosai-Dorfman disease with numerous IgG4-positive cells was identified in a subcutaneous lymph node in the patient's left forearm. The patient recovered uneventfully with steroid treatment.
PMCID: PMC3540337  PMID: 23323110
Rosai-Dorfman disease; Histiocytosis, sinus; Immunoglobulin G4
14.  Yttrium-90 ibritumomab tiuxetan plus busulfan, cyclophosphamide, and etoposide (BuCyE) versus BuCyE alone as a conditioning regimen for non-Hodgkin lymphoma 
The Korean Journal of Hematology  2012;47(2):119-125.
Radioimmunotherapy agents have a highly significant role in autologous stem cell transplantation as they improve tolerability and increase the efficacy of the conditioning regimen.
We retrospectively analyzed the efficacy and toxicity of yttrium-90 ibritumomab tiuxetan (Zevalin) combined with intravenous busulfan, cyclophosphamide, and etoposide (Z-BuCyE) compared with those of BuCyE alone followed by autologous stem cell transplantation in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL). The efficacy, toxicity, and engraftment characteristics were compared between 19 patients who received Z-BuCyE and 19 historical controls who received BuCyE.
The 2 treatment groups shared similar baseline characteristics. The median time to platelet engraftment (>20×109/L) and neutrophil engraftment (>0.5×109/L) did not significantly differ between the Z-BuCyE group (12 days and 10 days, respectively) and the BuCyE group (12 days and 10 days, respectively). No significant differences were observed between the groups with respect to toxicities and treatment-related mortality. The median follow-up period was 30.4 months, and median event-free survival was generally better in the Z-BuCyE group (12.5 months) vs. the BuCyE group (6.2 months, P=0.236). No significant difference in overall survival between the groups was noted.
Adding ibritumomab tiuxetan to BuCyE high-dose chemotherapy may benefit patients with relapsed or refractory B-cell NHL with no risk of additional toxicity.
PMCID: PMC3389060  PMID: 22783358
Yttrium-90 ibritumomab tiuxetan; BuCyE; Autologous stem cell transplantation; Non-Hodgkin lymphoma
15.  Epidemiologic overview of malignant lymphoma 
The Korean Journal of Hematology  2012;47(2):92-104.
Malignant lymphoma encompasses a wide variety of distinct disease entities. It is generally more common in developed countries and less common in developing countries. The East Asia region has one of the lowest incidence rates of malignant lymphoma. The incidence of malignant lymphoma around the world has been increasing at a rate of 3-4% over the last 4 decades, while some stabilization has been observed in developed countries in recent years. The reasons behind this lymphoma epidemic are poorly understood, although improving diagnostic accuracy, the recent AIDS epidemic, an aging world population and the increasing adoption of cancer-causing behaviors are suggested as contributing factors. Etiologies of malignant lymphoma include infectious agents, immunodeficiency, autoimmune disease, exposure to certain organic chemicals, and pharmaceuticals. The distribution of many subtypes exhibit marked geographic variations. Compared to the West, T/natural killer (NK) cell lymphomas (T/NK-cell lymphoma) and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) are relatively more common, whereas other B-cell lymphomas, particularly follicular lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, are less common in Asia. Some subtypes of T/NK-cell lymphomas defined by Epstein-Barr virus association are predominantly Asian diseases, if not exclusively so. Both ethnic and environmental factors play roles in such diversity. In this review, we discuss the geographic distribution and etiology of malignant lymphoma, as well as the trend.
PMCID: PMC3389073  PMID: 22783355
Malignant lymphoma; Epidemiology; Asia
16.  A phase I/II study of bortezomib plus CHOP every 2 weeks (CHOP-14) in patients with advanced-stage diffuse large B-cell lymphomas 
Bortezomib targets molecular dysregulation of nuclear factor-κB activation and cell cycle control, which are characteristic features of diffuse large B-cell lymphoma (DLBCL). We evaluated the safety and efficacy of bortezomib treatment with dose-dense cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) every 2 weeks (CHOP-14).
Untreated DLBCL patients were enrolled. A phase I dose-escalation study with 1.0, 1.3, and 1.6 mg/m2 bortezomib administration on day 1 and 4 in addition to the CHOP-14 regimen was performed to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT). Lenograstim 5 µg/kg/d was administered on day 4-13. The bortezomib dose from the phase I study was used in the phase II study.
Nine and 37 patients were enrolled in the phase I and phase II studies, respectively. The analysis of the phase II results (40 patients) included data of the 3 patients in the last MTD dose cohort of the phase I trial. During the phase I trial, no DLT was observed at any bortezomib dose; therefore, the recommended dose was 1.6 mg/m2. In phase II, the overall response rate was 95% (complete response: 80%; partial response: 15%). Nine out of the 40 patients showed grade 3 sensory neuropathy, and 22 required at least 1 dose reduction. Three patients could not complete the intended 6 cycles of treatment because of severe neuropathy.
Bortezomib plus CHOP-14 was highly effective for the treatment of untreated DLBCL patients, but in many cases, dose or schedule modification was required to reduce neurotoxicity.
PMCID: PMC3317471  PMID: 22479278
Bortezomib; CHOP-14; Diffuse large B-cell lymphoma
17.  Relapse pattern and prognostic factors for patients with primary central nervous system lymphoma 
Primary central nervous system lymphoma (PCNSL) rarely relapses in extracranial sites, and no specialized guidelines for follow-up evaluation have been proposed.
We analyzed 65 patients with newly diagnosed PNCSL to evaluate the pattern of relapse and prognostic factors.
Of the 65 patients analyzed, 55 had only parenchymal brain disease, and 10 had both intracranial and extracranial lesions. As a first-line treatment, 29 patients received chemotherapy only (CTx), 13 received chemotherapy followed by whole brain radiotherapy (CTx-WBRT), 18 received chemotherapy followed by autologous stem cell transplantation (CTx-ASCT), 2 received palliative WBRT, and 3 received best supportive care. The overall response rate to the initial treatment was 75.8%, with specific response rates of 62.1% to CTx, 84.6% to CTx-WBRT, and 100% to CTx-ASCT. The complete response (CR) rate was higher with CTx-ASCT than in the absence of ASCT (77.8% vs. 43.2%; P=0.025). After a median follow-up of 18.8 months, the median failure-free survival (FFS) and overall survival (OS) were 13.0 and 36.1 months, respectively. No systemic relapse without a CNS lesion was noted. Multivariate analysis showed that ASCT was predictive of better FFS but not of OS. Age and the Memorial-Sloan Kettering Cancer Center prognostic score were predictive of survival.
We observed no systemic relapse without a CNS lesion, suggesting that regular systematic evaluation of extracranial sites may not always be necessary. Age was prognostic of survival irrespective of treatment scheme. ASCT may improve CR rate and FFS.
PMCID: PMC3317473  PMID: 22479279
Primary CNS lymphoma; Relapse; Prognostic factor
18.  Prognostic Value of Immunohistochemical Biomarkers at Different Cut-off Values in Patients with Diffuse Large B-cell Lymphoma Treated with CHOP Chemotherapy 
Journal of Korean Medical Science  2011;26(12):1556-1562.
Many predictive models have been proposed for better stratification of diffuse large B-cell lymphoma (DLBCL). Hans' algorithm has been widely used as standard to sub-classify DLBCL into germinal center B-cell (GCB) and non-GCB origins. However, there have been disagreements in the literature regarding its prognostic significance. Here, we retrospectively analyzed Hans' algorithm and the individual immunohistochemical biomarkers at different cut-off values (5%, 30%, 50% or 75%) in 94 Korean patients with DLBCL treated with combination chemotherapy with cyclophosphamide, daunorubicin, vincristine, and prednisone. No significant differences were observed between the GCB (18 patients, 19.1%) and non-GCB (76, 80.9%) groups. Among individual biomarkers, CD10 negativity (cut point: 30%) and bcl-6 positivity (cut point: 5%) were independent good prognostic markers in progression-free survival (PFS), whereas bcl-6 (cut point: 5%) positivity was an independent good prognostic marker in overall survival irrelevant of international prognostic index. The present study showed the lack of predictability of Hans' algorithm in DLBCL patients, and that CD10, Bcl-6 may have diverse prognostic significance at different cut-off values. Our results suggest that the proposed cut-off value may not be applied universally, and that the optimal cut-off value may need to be optimized for individual laboratory.
PMCID: PMC3230014  PMID: 22147991
Diffuse Large B-cell Lymphoma (DLBCL); Hans' Algorithm; Germinal Center B-cell (GCB); Non-germinal Center B-cell (Non-GCB); CHOP Chemotherapy; CD10; Bcl-6
19.  Treatment outcome of nasal natural killer/T-cell lymphoma 
Radiation Oncology Journal  2011;29(3):174-180.
To evaluate the radiotherapy treatment outcome of patients in stage IE and IIE nasal natural killer/T-cell lymphoma.
Materials and Methods
From August 1999 to August 2009, 46 patients with stage IE and IIE nasal natural killer/T-cell lymphoma were treated by definitive radiotherapy and chemotherapy. 33 patients were treated with chemotherapy followed by radiotherapy (CT + RT) and they received 50.4 Gy in 28 fractions. 13 patients were treated with concurrent chemoradiotherapy (CCRT) and they received 40 Gy in 20 fractions.
The median follow-up period was 4.6-137.6 months (median, 50.2 months) for all patients. The 4-year overall survival was 68.6% and 4-year disease free survival (DFS) was 61.9%. The 4-year locoregional recurrence free survival was 65.0%, and 4-year distant metastasis free survival (DMFS) was 66.2%. For patients treated with CT + RT, 15 patients (45.5%) achieved complete response after chemotherapy, and 13 patients (39.4%) achieved partial response. 13 patients (81.8%) achieved complete response after radiotherapy, and 6 patients (18.2%) achieved partial response. For patients treated with CCRT, 11 patients (84.6%) achieved complete response, and one patient (7.7%) achieved partial response. In univariate analysis, presence of cervical lymph node metastasis was only significant prognostic factor for DFS and DMFS.
This study did not show satisfactory overall survival rate and disease free survival rate of definitive radiotherapy and chemotherapy for stage IE and IIE nasal natural killer/T-cell lymphoma. For patients with cervical lymph node metastasis, further investigation of new chemotherapy regimens is necessary to reduce the distant metastasis.
PMCID: PMC3429900  PMID: 22984668
Nasal natural killer/T-cell lymphoma; Radiotherapy; Concurrent chemoradiotherapy
20.  Addition of rituximab to the CHOP regimen has no benefit in patients with primary extranodal diffuse large B-cell lymphoma 
The Korean Journal of Hematology  2011;46(2):103-110.
The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy (R-CHOP) has significantly improved clinical outcomes for patients with diffuse large B-cell lymphoma (DLBCL). However, new predictors of patient response to R-CHOP have not been established. We aimed to evaluate the impact of R-CHOP compared with CHOP in patients with DLBCL and to establish clinical predictors of better outcomes in these patients.
We retrospectively identified 177 patients diagnosed with CD20-positive DLBCL and treated with CHOP (N=82) or R-CHOP (N=95). The response rate, event-free survival (EFS), and overall survival (OS) rates were compared between the 2 treatment groups. All patients were classified into primary extranodal lymphoma (PENL) or nodal lymphoma (NL) subgroups, and the clinical parameters of each subgroup were analyzed.
The overall response rate was higher in R-CHOP group (95% vs. 84%, P=0.07). The 3-year EFS rate was significantly higher in R-CHOP group (71% vs. 52%, P=0.013), but the OS rate was comparable between the 2 groups (79% vs. 69%, P=0.23). A significant survival benefit was seen with R-CHOP compared to CHOP therapy in NL patients (P=0.002 for EFS and 0.04 for OS). Multivariate analyses confirmed that R-CHOP therapy is an independent prognostic factor for EFS (hazard ratio of 0.32 [0.17-0.62], P=0.001) and OS (hazard ratio of 0.4 [0.18-0.87], P=0.02) in NL patients.
Patients in the PENL group did not benefit from R-CHOP chemotherapy.
PMCID: PMC3128890  PMID: 21747882
CHOP; Diffuse large B-cell lymphoma; Rituximab; Primary extranodal lymphoma
21.  Modified Number of Extranodal Involved Sites as a Prognosticator in R-CHOP-Treated Patients with Disseminated Diffuse Large B-Cell Lymphoma 
Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (R-CHOP) has improved survival in patients with diffuse large B-cell lymphoma (DLBCL) and weakened the prognostic power of the international prognostic index (IPI). We evaluated the efficacy of the IPI and revised IPI (R-IPI) in patients with DLBCL who were treated with R-CHOP, focusing on extranodal site number (ENS) because extranodal involvement occurs frequently in Koreans.
A total of 126 R-CHOP-treated patients with stage III/IV DLBCL were analyzed. We performed a retrospective analysis of the clinicopathologic factors and verified the predictive power of the standard IPI and R-IPI. Various numbers of extranodal sites were analyzed for further stratification, and we set the extranodal site-modified IPI (E-IPI) as the IPI when the number of extranodal sites was stratified as < 3 vs. ≥ 3.
A univariate analysis showed that ENS was associated with complete response (CR, p = 0.04), event-free survival (EFS, p = 0.01), and overall survival (OS, p < 0.001) when the ENS cut-off was set at ≥ 3. A multivariate analysis revealed that an ENS ≥ 3 remained associated with EFS (p < 0.01; hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.29 to 5.26) and OS (p < 0.01; HR, 3.52; 95% CI, 1.68 to 7.35). The IPI was effective for determining prognosis in terms of OS (p = 0.04) but not EFS (p = 0.17). The R-IPI was effective in terms of both variables (p = 0.02 and 0.04, respectively), as was the E-IPI (p = 0.01 and 0.001, respectively).
An ENS < 3 vs. ≥ 3, rather than the original < 2 vs. ≥ 2, was the most significant prognostic factor for EFS and OS. All three indices were predictive, but only the E-IPI identified the high-risk group of R-CHOP-treated Korean patients with disseminated DLBCL.
PMCID: PMC2932944  PMID: 20830228
Prognosis; Lymphoma, large B-cell, diffuse; Rituximab; Extranodal
22.  Image analytic study of nuclear area in mantle cell lymphoma 
The Korean Journal of Hematology  2010;45(3):193-196.
Malignant lymphomas are classified on the basis of morphology, immunohistochemistry, and genetic and molecular biological features. Morphology is considered the most important and basic feature. Lymphomas can be classified as small, medium, or large depending on the cell size, but this criterion tends to be rather subjective. The aim of this study was to investigate the usefulness of an objective approach based on quantitative measurements.
Twenty specimens of mantle cell lymphoma and 2 specimens of the tonsil were examined. The nuclear area of 6,401 tumor cells of mantle cell lymphoma and 743 normal mantle cells of reactive tonsils were measured by 3 authors by using a user-controlled image-analyzer. The images of the nuclei were outlined using the spline method and the i-solution software, and the data were assessed using ANOVA and Student's t-test.
The mean nuclear areas of mantle cell lymphoma cells measured by the 3 authors were 37.9 [7.9] µm2, 37.9 [7.2] µm2, and 38.2 [7.7] µm2 and those of normal mantle cells in reactive tonsil were 28.6 [2.3] µm2, 28.8 [2.0] µm2, and 27.0 [3.0] µm2. There was no statistical difference between the 3 observations of mantle cell lymphoma (P=0.580) and normal tonsils.
For morphology, nuclear area is considered an important feature in the classification schemes of lymphoma. We showed that nuclear area measurement by using image analyzer can be used as an objective quantitative method. We think that nuclear morphometry may play a significant role in the diagnosis of lymphoma.
PMCID: PMC2983036  PMID: 21120209
Image analysis; Morphometry; Nuclear area; Mantle cell lymphoma
23.  Simultaneous Occurrence of Hodgkin's Lymphoma and Langerhans Cell Histiocytosis of the Spine : A Rare Combination 
Hodgkin's disease presenting with spinal cord compression owing to extradural and bone involvement is extremely unusual. A 48-year-old man presented with progressive lower extremity weakness resulting from spinal cord compression attributable to an epidural mass in the thoracic vertebrae. The patient underwent decompressive surgery, and was then treated with chemotherapy for Langerhans cell histiocytosis. However, the disease progressed, and we performed second decompressive surgery with stabilization. Subsequent histopathological investigations revealed Hodgkin's lymphoma of the bone. Here, we describe an unusual case of spinal Hodgkin's lymphoma and Langerhans cell histiocytosis to draw attention to this combination as a possible diagnosis in patients with mixed inflammatory cell infiltrate lesions in the spine.
PMCID: PMC2864826  PMID: 20461174
Hodgkin's disease; Lymphoma; Langerhans cell histiocytosis; Spinal cord compression
24.  A Case of Histiocytic Sarcoma Presenting with Primary Bone Marrow Involvement 
Journal of Korean Medical Science  2010;25(2):313-316.
Histiocytic sarcoma (HS) is a very rare neoplasm that often shows an aggressive clinical course and systemic symptoms, such as fever, weight loss, adenopathy, hepatosplenomegaly and pancytopenia. It may present as localized or disseminated disease. We describe here a 63-yr-old male who manifested systemic symptoms, including fever, weight loss and generalized weakness. Abdominal and chest computed tomography failed to show specific findings, but there was suspicion of multiple bony changes at the lumbar spine. Fusion whole body positron emission tomography, bone scan and lumbar spine magnetic resonance imaging showed multiple bone lesions, suggesting a malignancy involving the bone marrow (BM). Several BM and bone biopsies were inconclusive for diagnosis. Necropsy showed replacement of the BM by a diffuse proliferation of neoplastic cells with markedly increased cellularity (95%). The neoplastic cells were positive for lysozyme and CD68, but negative for T- and B-cell lineage markers, and megakaryocytic, epithelial, muscular and melanocytic markers. Morphologic findings also distinguished it from other dendritic cell neoplasms.
PMCID: PMC2811304  PMID: 20119590
Histiocytic Sarcoma; Bone Marrow
25.  Clinicopathologic Characteristics of T-cell Non-Hodgkin's Lymphoma: A Single Institution Experience 
Although the incidence of T-cell non-Hodgkin's lymphoma (NHL) is higher in Far East Asia than in Western countries, its incidence and clinical course in Korea are not well-defined. Therefore, we assessed the relative frequency and clinical features of T-cell NHL in Korea.
We performed a retrospetcive analysis of 586 patients with NHL.
101 (17.2%) had T-cell NHL. The most frequent subtypes of T-cell NHL were extranodal NK/T-cell lymphoma, nasal type (NASAL), peripheral T-cell lymphoma, unspecified type (PTCL-U), and anaplastic large cell lymphoma, T/null cell, primary systemic type (ALCL). The seven pathological subtypes could be classified into three prognostic subgroups. When patients with the three most frequent subtypes were grouped together, their survival was reflected in the International Prognostic Index (IPI) scores. Univariate analysis of IPI elements and other clinical features showed that clinical stage and extranodal sites were significant predictors of survival. Cox multivariate analysis showed that the number of extranodal sites was the only independent prognostic indicator.
The relative frequency of T-cell NHL seems to be decreasing in Korea, although NASAL remains frequent. Korean patients with ALCL appear to have an unfavorable prognosis. Large-scale studies are warranted for Korean patients with T-cell NHL.
PMCID: PMC2698621  PMID: 19543491
Lymphoma; T-cell; Peripheral

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