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1.  Genetic alterations of JAK/STAT cascade and histone modification in extranodal NK/T-cell lymphoma nasal type 
Oncotarget  2015;6(19):17764-17776.
Extranodal NK/T-cell lymphoma nasal type (ENKL) is a rare type of non-Hodgkin lymphoma that more frequently occurs in East Asia and Latin America. Even though its molecular background has been discussed in the last few years, the current knowledge does not explain the disease pathogenesis in most cases of ENKL. Here, we performed multiple types of next-generation sequencing on 34 ENKL samples, including whole-exome sequencing (9 cancer tissues and 4 cancer cell lines), targeted sequencing (21 cancer tissues), and RNA sequencing (3 cancer tissues and 4 cancer cell lines). Mutations were found most frequently in 3 genes, STAT3, BCOR, and MLL2 (which were present in 9, 7, and 6 cancer samples, respectively), whereas there were only 2 cases of JAK3 mutation. In total, JAK/STAT pathway- and histone modification-related genes accounted for 55.9% and 38.2% of cancer samples, respectively, and their involvement in ENKL pathogenesis was also supported by gene expression analysis. In addition, we provided 177 genes upregulated only in cancer tissues, which appear to be linked with angiocentric and angiodestructive growth of ENKL. In this study, we propose several novel driver genes of ENKL, and show that these genes and their functional groups may be future therapeutic targets of this disease.
PMCID: PMC4627344  PMID: 25980440
extranodal NK/T-cell lymphoma nasal type; next-generation sequencing; JAK-STAT pathway; chromatin modification; somatic mutation
2.  Brentuximab vedotin for relapsed or refractory CD30+ Hodgkin lymphoma: a multicenter analysis from Asia 
OncoTargets and therapy  2014;7:1717-1722.
Introduction
Brentuximab vedotin (SGN-35), an anti-cluster of differentiation (CD)-30 antibody conjugated to the anti-tubulin agent monomethyl auristatin E, has demonstrated promising efficacy and tolerability in relapsed and heavily treated Hodgkin lymphoma (HL). In this study, we report the Asian experience with brentuximab vedotin in patients with relapsed or refractory CD30-positive (CD30+) HL.
Methods
This is an observational, multicenter, retrospective study. Between October 2011 and June 2013, a total of 22 patients were treated with brentuximab vedotin under a named patient program in Asia. Patients received a 30 min infusion of brentuximab vedotin at a dose of 1.8 mg/kg of body weight every 3 weeks.
Results
Four patients (18.2%) showed a complete response, and the overall response rate was 72.7%. The median duration of response was 4.4 months (range 1.0–17.4). The median progression-free survival was 5.7 months, and the median overall survival has not yet been reached. The 1-year expected survival rate was 67.2%. The most common grade 3/4 adverse events were neutropenia (n=7; 31.8%). No patients experienced grade 3/4 sensory neuropathy.
Conclusions
These results confirm that brentuximab vedotin as a single agent is also effective and well tolerated when used in Asian patients with relapsed and refractory CD30+ HL.
doi:10.2147/OTT.S67380
PMCID: PMC4196794  PMID: 25328405
Asian; efficacy; safety
3.  Clinical outcomes of radiation therapy for early-stage gastric mucosa-associated lymphoid tissue lymphoma 
AIM: To evaluate the clinical outcomes of radiation therapy (RT) for early-stage gastric mucosa-associated lymphoid tissue lymphoma (MALToma).
METHODS: The records of 64 patients treated between 1998 and 2011 were analyzed retrospectively. For Helicobacter pylori (H. pylori)-positive patients (n = 31), chemotherapy or H. pylori eradication therapy was the initial treatment. In patients with failure after H. pylori eradication, RT was performed. For H. pylori-negative patients (n = 33), chemotherapy or RT was the first-line treatment. The median RT dose was 36 Gy. The target volume included the entire stomach and the perigastric lymph node area.
RESULTS: All of the patients completed RT without interruption and showed complete remission on endoscopic biopsy after treatment. Over a median follow-up period of 39 mo, the 5-year local control rate was 89%. Salvage therapy was successful in all relapsed patients. Secondary malignancies developed in three patients. The 5-year overall survival rate was 94%. No patient presented symptoms of moderate-to-severe treatment-related toxicities during or after RT.
CONCLUSION: Radiotherapy results in favorable clinical outcomes in patients with early-stage gastric MALToma who experience failure of H. pylori eradication therapy and those who are H. pylori negative.
doi:10.3748/wjg.v19.i36.6062
PMCID: PMC3785628  PMID: 24106407
Gastric mucosa-associated lymphoid tissue lymphoma; Radiation therapy; Treatment response
4.  Extranodal natural killer/T-cell lymphoma with long-term survival and repeated relapses: does it indicate the presence of indolent subtype? 
The Korean Journal of Hematology  2012;47(3):202-206.
Background
Extranodal natural killer (NK)/T-cell lymphoma is a subtype of lymphoma that is derived from NK cells. It is considered as an aggressive form of non-Hodgkin's lymphoma because of frequent relapses and resistance to treatment. Relapsed NK/T-cell lymphoma often follows a fulminant course that is refractory to conventional chemotherapy treatment.
Methods
Several patients with extranodal NK/T-cell lymphoma showed long-term survival in spite of frequent relapses. Thus, the medical records of patients diagnosed with extranodal NK/T-cell lymphoma from 1995 to 2007 were reviewed and assessed.
Results
Of the 140 cases reviewed, 6 were selected (4.29%). Each of these patients had a minimum of 3 relapses or disease progression during the follow-up period, and their median overall survival was 66 months (range, 42-89 months). They were grouped according to the atypical clinical behavior observed: (1) repeated relapses or progression (≥3 times) during follow-up; and (2) long-term survival of more than 40 months, as the longest overall survival median was previously considered at approximately 40 months. The clinicopathological and laboratory characteristics of these patients were similar to those of other extranodal NK/T-cell lymphoma patients. However, 5 of the studied cases involved relatively lower expression of the proliferation-related antigen Ki-67 (<40-50%), indicating less proliferative activity. Clinically, they showed delayed relapse for at least 20 months after the initial complete remission.
Conclusion
Our observations suggest that the clinical behavior of some extranodal NK/T-cell lymphoma patients differs from the typical clinical course.
doi:10.5045/kjh.2012.47.3.202
PMCID: PMC3464337  PMID: 23071475
Extranodal NK/T-cell lymphoma; Relapse; Survival; Indolent
5.  Schedule-dependent synergistic effect of rituximab on methotrexate chemotherapy against lymphoma of the central nervous system 
We hypothesized that methotrexate (MTX) normalizes the increased permeability of the blood-tumor barrier and thus reduces the accessibility of rituximab (RTX) to central nervous system (CNS) lymphoma. Here, we evaluated the combinational treatment capability of RTX and MTX using an alternative treatment schedule against CNS lymphoma. We developed a CNS lymphoma animal model that closely mimics the morphological and molecular characteristics of human CNS lymphoma by injecting Raji human Burkitt lymphoma cells into the brains of immune-compromised mice and tested a novel combinational treatment schedule by which penetration of RTX was not influenced by MTX administration. RTX was conjugated with Alexa Fluor 680, and its distribution in the brain was analyzed by in vivo imaging. When MTX treatment was followed by a 3-day post RTX administration, RTX was scarcely distributed in the brain, and there were only modest statistically insignificant therapeutic effects compared with the control mice which received sham injections. In contrast, RTX administration followed by a 3-day post MTX treatment showed significantly increased distribution of RTX and significantly reduced tumor volume in the brain. Collectively, our data demonstrate that RTX can be successfully combined with MTX using an alternative treatment schedule that allows increased distribution of RTX in CNS lymphoma.
doi:10.3892/etm.2010.143
PMCID: PMC3445961  PMID: 22993623
central nervous system lymphoma; methotrexate; rituximab; combination therapy; mouse model
6.  Orbital Infiltration as the First Site of Relapse of Primary Testicular T-cell Lymphoma 
A 43-year-old male presented with a painless left testicular mass. The pathologic diagnosis of the radical orchiectomy specimen was peripheral T-cell lymphoma, unspecified (PTCL-u). According to the Ann Arbor staging system, his initial stage was III because of the right nasopharyngeal involvement. After first-line chemotherapy with four courses of the CHOP regimen and this was followed by involved-field radiotherapy, he achieved complete remission. Two months later, disease recurred to the left ciliary body of the left eye without evidence of involvement at other sites. Although the patient received intensive chemotherapy with autologous hematopoietic stem cell transplantation, he ultimately died of leptomeningeal seeding. Because both the central nervous system (CNS) and the orbit are sanctuary sites for chemotherapy, orbital infiltration of lymphoma should prompt physicians to evaluate involvement of the CNS and to consider performing prophylactic intrathecal chemotherapy as a treatment option.
doi:10.4143/crt.2007.39.1.40
PMCID: PMC2739356  PMID: 19746228
Non-Hodgkin's lymphoma; T cell lymphoma; Testes; Eye neoplasm
7.  Detection of MYD88 L265P in patients with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia and other B-cell non-Hodgkin lymphomas 
Blood research  2016;51(3):181-186.
Background
Recent studies have identified a high prevalence of the MYD88 L265P mutation in lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM) cases, whereas low frequencies have been observed in other B cell non-Hodgkin lymphomas (NHLs).
Methods
We evaluated the sensitivity of the mutant enrichment 3'-modified oligonucleotide (MEMO)-PCR technique, a new detection method. We examined the MYD88 L265P mutation in a series of Korean patients with LPL/WM and other B cell NHLs in bone marrow aspirates, using the MEMO-PCR technique.
Results
The sensitivity of MEMO-PCR was estimated to be approximately 10-16.7%. MYD88 L265P was detected in 21 of 28 LPL cases (75%) and only three of 69 B cell NHL cases (4.3%).
Conclusion
Although MEMO-PCR had relatively low sensitivity, we confirmed the high prevalence of the MYD88 L265P mutation in Korean LPL patients. Our study suggests the diagnostic value of MYD88 L265P for differentiating B-cell NHLs.
doi:10.5045/br.2016.51.3.181
PMCID: PMC5054250  PMID: 27722129
Lymphoplasmacytic lymphoma; MYD88 L265P; Aspirate; MEMO-PCR
8.  Evolution of frontline treatment of diffuse large B-cell lymphoma: a brief review and recent update 
F1000Research  2016;5:F1000 Faculty Rev-1933.
Various strategies have been implemented to improve the outcomes of diffuse large B-cell lymphoma (DLBCL). In recent years, remarkable advances have been achieved, based on the discovery of cell-of-origin in DLBCL and on more effective targeted agents. This commentary will summarize recent updates on the evolution of frontline therapies for DLBCL, focusing on the upcoming promising frontline chemotherapy platforms and on activated B-cell subtype DLBCL and double-hit DLBCL.
doi:10.12688/f1000research.8790.1
PMCID: PMC4979644  PMID: 27606052
9.  Usefulness of Flow Cytometric Analysis for Detecting Leptomeningeal Diseases in Non-Hodgkin Lymphoma 
Annals of Laboratory Medicine  2016;36(3):209-214.
Background
The clinical usefulness of flow cytometry (FCM) for the diagnosis of leptomeningeal diseases (LMD) in non-Hodgkin lymphomas has been suggested in previous studies but needs to be further validated. With this regards, we evaluated the use of FCM for LMD in a series of Korean patients with non-Hodgkin lymphoma.
Methods
FCM and cytomorphology were conducted using samples obtained from clinically suspected LMD patients, follow-up LMD patients, and those with high risk of developing tumorigenic diseases. We then compared results of FCM and cytomorphology. In total, 55 and 47 CSF samples were analyzed by FCM and cytomorphology, respectively.
Results
Of the samples analyzed, 25.5% (14/55) and 12.8% (6/47) were positive by FCM and cytomorphology, respectively. No samples were determined as negative by FCM but positive by cytomorphology. Seven patients were positive only by FCM and negative by cytomorphology, and six among them were clinically confirmed to have LMD either by follow-up cytomorphology or imaging study.
Conclusions
We observed a high detection rate of tumor cells by FCM compared with cytomorphology. FCM study can be useful in early sensitive detection of LMD.
doi:10.3343/alm.2016.36.3.209
PMCID: PMC4773260  PMID: 26915608
Flow cytometry; CSF; Leptomeningeal diseases
10.  Treatment outcomes and clinical relevance of the Follicular Lymphoma International Prognostic Index in Korean follicular lymphoma patients treated with chemotherapy 
Background/Aims:
The Follicular Lymphoma International Prognostic Index (FLIPI) and FLIPI2 are well-known prognostic models for patients with follicular lymphoma (FL). However, their prognostic relevance has not been examined before in Korean patients with FL.
Methods:
We reviewed clinical and laboratory information from our database of patients between 1995 and 2012. In total, 125 patients were stratified in three categories according to FLIPI or FLIPI2 scores: low-, intermediate-, and high-risk groups. We compared FLIPI and FLIPI2 in terms of progression-free survival (PFS) and overall survival (OS).
Results:
Among the 125 patients, the prognostic value of FLIPI and FLIPI2 was evaluated in 73 patients who fulfilled the criteria of both prognostic models. Risk stratification by FLIPI and FLIPI2 showed significant differences in unfavorable parameters among each risk group, particularly between low- and intermediate-risk groups. The high-risk group b was significantly associated with poor PFS on both FLIPI and FLIPI2 (p < 0.05). However, the OS was significantly different only in the risk groups determined by FLIPI2 (p = 0.042). In a subgroup analysis of patients who received rituximab-containing chemotherapy, the risk stratification of both prognostic models showed a significant impact on PFS, especially in the low-risk group.
Conclusions:
FLIPI and FLIPI2 are appropriate prognostic models in Korean FL patients, especially for discriminating low-risk patients from intermediate- and high-risk groups.
doi:10.3904/kjim.2014.222
PMCID: PMC4855088  PMID: 26898595
Follicular lymphoma; Prognosis; Index
11.  l-asparaginase-based regimens followed by allogeneic hematopoietic stem cell transplantation improve outcomes in aggressive natural killer cell leukemia 
Aggressive nature killer cell leukemia (ANKL) is a mature NK-T cell lymphoma with worse prognosis, but optimal treatment is unclear. Therefore, we analyzed the efficacy of l-asparaginase-based regimens for ANKL patients. Twenty-one patients who received dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide (SMILE) or etoposide, ifosfamide, dexamethasone, and l-asparaginase (VIDL) chemotherapy at Samsung Medical Center were selected. The overall response rate for all patients was 33 % (7/21); 38 % (5/13) in SMILE and 40 % (2/5) in VIDL, respectively. The median progression-free survival was 3.9 months (95 % CI 0.0–8.1 months) and median overall survival was 7.0 months (95 % CI 2.3–11.7 months). Treatment response (P = 0.001), hematopoietic stem cell transplantation (HSCT) (P = 0.007) and negative conversion of Epstein-Barr virus (EBV) DNA titer after treatment (P = 0.004) were significantly associated with survival. Thus, l-asparaginase-based regimens followed by allogeneic HSCT seem to improve the outcome for ANKL patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-016-0271-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13045-016-0271-4
PMCID: PMC4835915  PMID: 27091029
ANKL; l-asparaginase; Allogeneic HSCT; Response; Survival
12.  Clonal relationships in recurrent B-cell lymphomas 
Oncotarget  2016;7(11):12359-12371.
Immunoglobulin (Ig) gene rearrangements remain largely unmodified during the clonal expansion of neoplastic cells. We investigated the clonal relationships between lymphoma components at diagnosis and at relapse by analyzing Ig gene rearrangements. A BIOMED-2 multiplex polymerase chain reaction (PCR) assay was performed in 27 patients using formalin-fixed paraffin embedded tissues, with subsequent cloning and sequencing of the amplified Ig genes in 17 patients. All 27 cases of primary and corresponding relapsed tumors showed monoclonal rearrangements of the Ig genes by BIOMED-2 PCR. Whereas IgVH or IgVK fragment lengths were identical in 8/27 pairs (30%), fragment lengths differed in 19/27 pairs (70%). In 17 cases analyzed by sequencing, an identical VDJ gene rearrangement was confirmed in 4/4 pairs (100%) with the same fragment lengths and in 10/13 pairs (77%) with different fragment lengths. Four of 17 primary lymphomas had multiple VDJ rearrangements, and three of them showed an unrelated relapse. Unrelated relapse was observed in 1/8 mantle cell lymphomas, 1/5 diffuse large B-cell lymphomas, and a large B cell lymphoma developed in a patient with a small lymphocytic lymphoma. Unrelated relapses developed after a longer disease-free interval and tended to show poorer outcome compared with related relapse. In summary, relapse of a lymphoma from an unrelated clone is uncommon, but can occur in B-cell lymphomas. Clonal relationships should be determined by sequencing of the Ig genes, and not just by comparing the PCR product size.
doi:10.18632/oncotarget.7132
PMCID: PMC4914290  PMID: 26848863
recurrent B-cell lymphomas; clonality; immunoglobulin gene rearrangements; BIOMED-2 multiplex polymerase chain reaction
13.  Cross-sectional Study of Patients with Diffuse Large B-Cell Lymphoma: Assessing the Effect of Host Status, Tumor Burden, and Inflammatory Activity on Venous Thromboembolism 
Purpose
The risk factors for venous thromboembolism (VTE) in diffuse large B-cell lymphoma (DLBCL) are not clear although thrombosis can be associated with host status, tumor burden, and inflammatory activity. We assessed the effect of those factors on VTE in a cross-sectional study of patients enrolled in a prospective cohort study.
Materials and Methods
We analyzed the occurrence of VTE in 322 patients with newly diagnosed DLBCL who received rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) between 2008 and 2011. Serum levels of inflammatory cytokines were measured from serum samples archived at diagnosis.
Results
With a median follow-up duration of 41.9 months, VTE was documented in 34 patients (10.6%). A comparison of baseline characteristics indicated the group with VTE had higher percentage of old age, stage III/IV and extranodal involvements than the group without VTE (p < 0.05). Thus, the International Prognostic Index was significantly associated with VTE, but the Khorana score was not. A univariate competing risk factor analysis for VTE revealed that increased levels of inflammatory cytokines such as interleukin (IL)-6 and IL-10 were also associated with VTE (p < 0.05) in addition to host and tumor burden. However, a multivariate analysis showed that two host factors including age (≥ 60 years) and poor performance were independent risk factors for VTE.
Conclusion
Among potential risk factors for VTE including tumor burden and inflammatory activity, age and performance status had a strong impact on the occurrence of VTE in patients with DLBCL who received R-CHOP.
doi:10.4143/crt.2014.266
PMCID: PMC4720058  PMID: 25761485
Diffuse large B-cell lymphoma; Venous thromboembolism; Risk factors; Chemotherapy
14.  Iron deficient erythropoiesis might play key role in development of anemia in cancer patients 
Oncotarget  2015;6(40):42803-42812.
Introduction
Multifactorial pathogenesis is involved in anemia of cancer patients and defining the causes of anemia is not always simple.
Methods
The incidence of anemia among 4 major cancers (gastric, colorectal, lung cancer and hepatocellular carcinoma), and biochemical features of anemia using ferritin, CRP, hepcidin and soluble transferrin receptor (sTfR) were assessed. Anemia was defined either by hemoglobin (Hb) ≤11 g/dL or a drop of Hb 2 g/dL or more during anticancer treatment.
Results
Among the 345 patients including 152 lung cancer, 101 gastric cancer, 69 colorectal cancer and 23 hepatocellular carcinoma, 49 patients (14.2%) had anemia at their initial diagnosis of cancer. During treatment, 129 (37.4%) experienced anemia, and 34 (26.4%) were treated mostly by transfusion. Biochemical feature of anemia was examined with 39 patients' samples. When comparing to the reference value from general population, cancer patients showed numerically higher ferritin, sTfR, CRP and hepcidin level. Among the cancer patients, anemic patients had significantly higher ferritin (p = 0.050) and sTfR (p = 0.009) level compared to non-anemic patients.
Conclusion
Anemia is a common issue in cancer patients and is largely undertreated with sub-optimal diagnoses of cause. The rates of anemia increase significantly during anti-cancer treatment and appear to be largely associated with iron deficiency.
PMCID: PMC4767472  PMID: 26517509
cancer; anemia; soluble transferrin receptor; hepcidin
15.  Intraocular lymphoma in Korea: the Consortium for Improving Survival of Lymphoma (CISL) study 
Blood research  2015;50(4):242-247.
Background
Intraocular lymphoma (IOL) is a rare malignant lymphoma that most closely resembles a diffuse large B-cell lymphoma, and it is a subtype of primary central nervous system lymphoma (PCNSL). IOL is located inside the eye in the retina, uvea, and/or optic nerve. We retrospectively analyzed IOL patient data to identify treatment patterns and survival rates in Korea.
Methods
Cytological confirmation for a diagnosis of IOL was performed for all patients. The clinical data collected from medical records included Ann Arbor stage, International Prognostic Index, performance status, date of diagnosis, treatment modality and response, date of relapse, and date of last follow-up.
Results
Twenty patients who were diagnosed with IOL, between December 2007 and June 2014 at multiple centers in Korea, were included in the analysis. Four patients were diagnosed with IOL alone, not involving the CNS. Two patients with isolated IOL later developed PCNSL. Nine patients developed CNS lesions before the onset of ocular lymphoma. Five patients had simultaneous onset in the eye and CNS. Twelve patients were treated by intravitreal injection of methotrexate for IOL. The median progression-free survival (PFS) for patients was 19.7 months (95% CI, 8.7-30.7 mo). The estimated 3-year overall survival (OS) for all patients was 75.1%.
Conclusion
Treatment for IOL patients included radiotherapy and intraocular chemotherapy. IOL patients showed favorable PFS and OS. These patients would require long-term follow-up to identify relapse and adverse effects of radiotherapy or intraocular chemotherapy.
doi:10.5045/br.2015.50.4.242
PMCID: PMC4705050  PMID: 26770952
Intraocular; Lymphoma; Chemotherapy; Radiotherapy
18.  Clinical Significance of Non-neutropenic Fever in the Management of Diffuse Large B-Cell Lymphoma Patients Treated with Rituximab-CHOP: Comparison with Febrile Neutropenia and Risk Factor Analysis 
Purpose
Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard chemotherapy in diffuse large B-cell lymphoma (DLBCL) patients. Although febrile neutropenia (FN) is the major toxicity of this regimen, non-neutropenic fever (NNF) becomes an emerging issue.
Materials and Methods
We analyzed clinical features and outcomes of febrile complications from 397 patients with newly diagnosed DLBCL who were registered in the prospective cohort study. They had completed R-CHOP between September 2008 and January 2013.
Results
Thirty-nine patients (9.8%) had NNF whereas 160 patients (40.3%) had FN. Among them, 24 patients (6.0%) had both during their treatment. Compared to frequent occurrence of initial FN after the first cycle (> 50% of total events), more than 80% of NNF cases occurred after the third cycle. Interstitial pneumonitis comprised the highest proportion of NNF cases (54.8%), although the causative organism was not identified in the majority of cases. Thus, pathogen was identified in a limited number of patients (n=9), and Pneumocystis jiroveci pneumonia (PJP) was the most common. Considering that interstitial pneumonitis without documented pathogen could be clinically diagnosed with PJP, the overall rate of PJP including probable cases was 4.5% (18 cases from 397 patients). The NNF-related mortality rate was 10.3% (four deaths from 39 patients with NNF) while the FN-related mortality rate was only 1.3%.
Conclusion
NNF was observed with incidence of 10% during R-CHOP treatment, and showed different clinical manifestations with respect to the time of initial episode and causes.
doi:10.4143/crt.2014.034
PMCID: PMC4506109  PMID: 25648098
Fever; Lymphoma; Rituximab
19.  The serum CXCL13 level is associated with the Glasgow Prognostic Score in extranodal NK/T-cell lymphoma patients 
Background
The Glasgow Prognostic Score (GPS) measures inflammation and proves its prognostic value in patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTL) which is commonly combined with inflammatory lesion. Given inflammatory chemokines play an important role in tumor progression, we hypothesized that chemokines might influence ENKTL aggressiveness through interaction with their receptors in the tumor tissue.
Methods
We measured the serum levels of C-X-C motif ligand 13 (CXCL13) in 69 patients with ENKTL who received non-anthracycline-based chemotherapy and/or concurrent chemoradiotherapy because CXCL13 is thought to have a pro-tumor effect through interaction with its receptor, the C-X-C chemokine receptor 5 (CXCR5). We analyzed the association of serum CXCL13 with the GPS, and their prognostic relevance. The levels of CXCL13 were measured using a multiplex chemokine assay on archived frozen serum samples.
Results
Patients were categorized into high and low CXCL13 groups if they had CXCL13 levels above or below the median value of 29.1 pg/mL, respectively. The high CXCL13 group and grouping by the GPS showed a significant association with poor progression-free survival. The elevated serum levels of CXCL13 were also significantly associated with a high score of the GPS. High CXCL13 levels and GPS were significantly associated with high tumor burden predicting poor prognosis including stages III/IV, extranasal presentation, bone marrow invasion, and presence of Epstein-Barr virus (EBV) DNA in blood. Furthermore, serum CXCL13 and GPS discriminated patients at risk of treatment failure among patients with low tumor burden (stage I/II) and non-detectable EBV DNA.
Conclusions
Serum levels of CXCL13 were associated with the prognostic value of GPS. Grouping by the serum CXCL13 might predict survival outcomes in patients with ENKTL, suggesting that it is a potential therapeutic target.
doi:10.1186/s13045-015-0142-4
PMCID: PMC4437674  PMID: 25966773
Extranodal NK/T-cell lymphoma; Inflammation; Chemokine; CXCL13; GPS
20.  Treatment Outcomes of Rituximab Plus Hyper-CVAD in Korean Patients with Sporadic Burkitt or Burkitt-like Lymphoma: Results of a Multicenter Analysis 
Purpose
This study was conducted to evaluate outcomes in adult patients with Burkitt lymphoma (BL) or Burkitt-like lymphoma treated with an rituximab plus hyper-CVAD (R-hyper-CVAD) regimen by focusing on tolerability and actual delivered relative dose intensity (RDI).
Materials and Methods
Patients ≥ 20 years of age and pathologically diagnosed with BL or Burkitt-like lymphoma were treated with at least one cycle of R-hyper-CVAD as the first-line treatment in this study. Eligible patients’ case report forms were requested from their physicians to obtain clinical and laboratory data for this retrospective study.
Results
Forty-three patients (median age, 51 years) from 14 medical centers in Korea were analyzed, none of which were infected with human immunodeficiency virus. The majority of patients had advanced diseases, and 24 patients achieved a complete response (75.0%). After a median follow-up period of 20.0 months, 2-year event-free and overall survival rates were 70.9% and 81.4%, respectively. Eleven patients (25.6%) were unable to complete the R-hyper-CVAD regimen, including six patients due to early death. The RDIs of adriamycin, vincristine, methotrexate, and cytarabine were between 60% and 65%, which means less than 25% of patients received greater than 80% of the planned dose of each drug. Poor performance status was related to the lower RDIs of doxorubicin and methotrexate.
Conclusion
R-hyper-CVAD showed excellent treatment outcomes in patients who were suitable for dose-intense chemotherapy. However, management of patients who are intolerant to a dose-intense regimen remains problematic due to the frequent occurrence of treatmentrelated complications.
doi:10.4143/crt.2014.055
PMCID: PMC4398112  PMID: 25544581
Burkitt lymphoma; Rituximab; CVAD protocol
21.  Prognostic significance of metabolic tumor burden by positron emission tomography/computed tomography in patients with relapsed/refractory diffuse large B-cell lymphoma 
Cancer Science  2015;106(2):186-193.
The aim of the present study was to investigate the feasibility of measuring metabolic tumor burden using [F-18] fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with bendamustine–rituximab. Because the standardized uptake value is a critical parameter of tumor characterization, we carried out a phantom study of 18F-FDG PET/CT to ensure quality control for 28 machines in the 24 institutions (Japan, 17 institutions; Korea, 7 institutions) participating in our clinical study. Fifty-five patients with relapsed or refractory DLBCL were enrolled. The 18F-FDG PET/CT was acquired before treatment, after two cycles, and after the last treatment cycle. Treatment response was assessed after two cycles and after the last cycle using the Lugano classification. Using this classification, remission was complete in 15 patients (27%) and incomplete in 40 patients (73%) after two cycles of therapy, and remission was complete in 32 patients (58%) and incomplete in 23 patients (42%) after the last treatment cycle. The percentage change in all PET/CT parameters except for the area under the curve of the cumulative standardized uptake value–volume histogram was significantly greater in complete response patients than in non-complete response patients after two cycles and the last cycle. The Cox proportional hazard model and best subset selection method revealed that the percentage change of the sum of total lesion glycolysis after the last cycle (relative risk, 5.24; P = 0.003) was an independent predictor of progression-free survival. The percent change of sum of total lesion glycolysis, calculated from PET/CT, can be used to quantify the response to treatment and can predict progression-free survival after the last treatment cycle in patients with relapsed or refractory DLBCL treated with bendamustine–rituximab.
doi:10.1111/cas.12588
PMCID: PMC4399031  PMID: 25495273
[F-18] fluorodeoxyglucose; diffuse large B-cell lymphoma; lymphoma; metabolic tumor burden; positron emission tomography/computed tomography
23.  Comparison of the Freiburg and Charlson Comorbidity Indices in Predicting Overall Survival in Elderly Patients with Newly Diagnosed Multiple Myeloma 
BioMed Research International  2014;2014:437852.
Multiple myeloma occurs primarily in elderly patients. Considering the high prevalence of comorbidities, comorbidity is an important issue for the management of myeloma. However, the impact of comorbidity on clinical outcomes has not been fully investigated. We retrospectively analyzed patients with newly diagnosed myeloma. Comorbidities were assessed based on the Charlson comorbidity index (CCI) and the Freiburg comorbidity index (FCI). The CCI is a summary measure of 19 comorbid conditions. FCI is determined by performance status, renal impairment, and lung disease. This study included 127 patients with a median age of 71 years. Approximately half of the patients had additional disorders at the time of diagnosis, and diabetes mellitus was the most frequent diagnosis (18.9%). The most significant factors for prognosis among patient-related conditions were a history of solid cancer and performance status (ECOG ≥ 2). The FCI score was divided into 3 groups (0, 1, and 2-3), and the CCI score was divided into 2 groups (2-3 and ≥4). FCI was a strong prognostic tool for OS (P > 0.001) and predicted clinical outcome better than CCI (P = 0.059). In conclusion, FCI was more useful than CCI in predicting overall survival in elderly patients with myeloma.
doi:10.1155/2014/437852
PMCID: PMC4119725  PMID: 25114902
24.  Unusual Manifestation of Intravascular Large B-Cell Lymphoma: Severe Hypercalcemia with Parathyroid Hormone-Related Protein 
Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma. It usually presents with nonspecific symptoms, such as fever, rather than with overt lymphadenopathy. Reports of hypercalcemia, as the initial presentation of IVLBCL, are limited in the literature, despite it being a well-known complication of various solid cancers. We present a 68-year-old male with severe hypercalcemia and increased levels of serum parathyroid hormone-related protein. He was diagnosed with IVLBCL, involving the bone marrow and spleen, and was successfully treated with rituximab-containing chemotherapy. A few previous case reports have shown hypercalcemia in patients with IVLBCL. Much like our case, previous cases with hypercalcemia had advanced diseases, including bone marrow invasion. Although it was an extremely rare manifestation of IVLBCL, we suggest that IVLBCL should be a part of the differential diagnosis in patients with unexplained hypercalcemia. Therefore, an active work-up might be recommended, including positron emission tomography/ computed tomography scan and bone marrow examination, which may be useful for early diagnosis.
doi:10.4143/crt.2014.46.3.307
PMCID: PMC4132453  PMID: 25038766
Intravascular lymphoma; Hypercalcemia; Parathyroid hormone-related protein
25.  Clinical characteristics, pathological distribution, and prognostic factors in non-Hodgkin lymphoma of Waldeyer's ring: nationwide Korean study 
Background/Aims
In Asia, the incidence of non-Hodgkin lymphoma (NHL) has increased in recent decades. Waldeyer's ring (WR) is the most common site of NHL involving the head and neck. In this study, the pathological distribution of WR-NHL and its clinical features were analyzed retrospectively.
Methods
From January 2000 through December 2010, we analyzed the medical records of 328 patients from nine Korean institutions who were diagnosed with WR-NHL.
Results
The study group comprised 197 male and 131 female patients with a median age of 58 years (range, 14 to 89). The rate of localized disease (stage I/II) was 64.9%, and that of low-risk disease (low/low-intermediate, as defined by the International Prognostic Index) was 76.8%. Diffuse large B-cell lymphoma (DLBCL; 240 patients, 73.2%) was the most common pathologic subtype, followed by peripheral T-cell lymphoma (14 patients, 4.3%) and nasal NK/T-cell lymphoma (14 patients, 4.3%). WR-NHL occurred most frequently in the tonsils (199 patients, 60.6%). Extranodal involvement was greater with the T-cell subtype (20 patients, 42.5%) compared with the B-cell subtype (69 patients, 24.5%). Multivariate analyses showed that age ≥ 62 years, T-cell subtype, and failure to achieve complete remission were significant risk factors for overall survival.
Conclusions
DLBCL was found to have a higher incidence in Korea than those incidences reported by other WR-NHL studies. T-cell lymphoma occurred more frequently than did follicular lymphoma. T-cell subtype, age ≥ 62 years, and complete remission failure after first-line treatment were significant poor prognostic factors for overall survival according to the multivariate analysis.
doi:10.3904/kjim.2014.29.3.352
PMCID: PMC4028525  PMID: 24851070
Head and neck; Non-Hodgkin lymphoma; Diffuse large B-cell lymphoma; T-cell lymphoma

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