Hyeon Seok Eom

Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin

Nuclear factor erythroid‐related factor 2 (NRF2) encodes a transcription factor that induces expression of cytoprotective proteins upon oxidative stress and oncogenic NRF2 mutations have been found in lung and head/neck cancers that inactivate KEAP1‐mediated degradation of NRF2. The aim of this study was to catalogue NRF2 mutations in other human cancers. For this, we analysed 1145 cancer tissues from carcinomas from oesophagus, skin, uterine cervix, lung, larynx, breast, colon, stomach, liver, prostate, urinary bladder, ovary, uterine cervix, and kidney, and meningiomas, multiple myelomas, and acute leukaemias by single‐strand conformation polymorphism (SSCP) assay. We detected NRF2 mutations in oesophagus (8/70; 11.4%), skin (1/17; 6.3%), lung (10/125; 8.0%), and larynx (3/23; 13.0%) cancers. Of note, all of the 22 mutations except one were found in squamous cell carcinomas (SCCs) (95.5%). The mutations were observed within or near DLG and ETGE motifs that are important in NRF2 and KEAP1 interaction. All of the oesophageal SCCs and skin SCCs with the NRF2 mutations showed increased NRF2 expression in the nuclei. However, none of the SCCs from oesophagus and skin harboured KEAP1 mutation. Our study demonstrated here that NRF2 mutation occurs not only in lung and head/neck cancers, but also in oesophageal and skin cancers. Our data suggest that the NRF2 mutation plays a role in the development of SCC and is a feature of SCC. Copyright

Phase II Trial of Concurrent Radiation and Weekly Cisplatin Followed by VIPD Chemotherapy in Newly Diagnosed, Stage IE to IIE, Nasal, Extranodal NK/T-Cell Lymphoma: Consortium for Improving Survival of Lymphoma Study

PURPOSE On the basis of the benefits of frontline radiation in early-stage, extranodal, natural killer (NK)/T-cell lymphoma (ENKTL), we conducted a phase II trial of concurrent chemoradiotherapy (CCRT) followed by three cycles of etoposide, ifosfamide, cisplatin, and dexamethasone (VIPD). PATIENTS AND METHODS Thirty patients with newly diagnosed, stages IE to IIE, nasal ENKTL received CCRT (ie radiation 40 to 52.8 Gy and cisplatin 30 mg/m(2) weekly). Three cycles of VIPD (etoposide 100 mg/m(2) days 1 through 3, ifosfamide 1,200 mg/m(2) days 1 through 3, cisplatin 33 mg/m(2) days 1 through 3, and dexamethasone 40 mg days 1 through 4) were scheduled after CCRT. RESULTS All patients completed CCRT, which resulted in 100% response that included 22 complete responses (CRs) and eight partial responses (PRs). The CR rate after CCRT was 73.3% (ie, 22 of 30 responses; 95% CI, 57.46 to 89.13). Twenty-six of 30 patients completed the planned three cycles of VIPD, whereas four patients did not because they withdrew (n = 2) or because they had an infection (n = 2). The overall response rate and the CR rate were 83.3% (ie; 25 of 30 responses; 95% CI, 65.28 to 94.36) and 80.0% (ie, 24 of 30 responses; 95% CI, 65.69 to 94.31), respectively. Only one patient experienced grade 3 toxicity during CCRT (nausea), whereas 12 of 29 patients experienced grade 4 neutropenia. The estimated 3-year, progression-free and overall survival rates were 85.19% (95% CI, 72.48 to 97.90) and 86.28% (95% CI, 73.97 to 98.59), respectively. CONCLUSION Patients with newly diagnosed, stages IE to IIE, nasal ENKTL are best treated with frontline CCRT.

Multicenter Phase II Study of Bendamustine Plus Rituximab in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

PURPOSE Effective and less aggressive therapies are required for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for or have undergone autologous stem-cell transplantation (ASCT). The present phase II study assessed the efficacy and safety of bendamustine plus rituximab (BR) in this population. PATIENTS AND METHODS Patients with relapsed or refractory DLBCL treated with one to three prior chemotherapy regimens received rituximab 375 mg/m(2) intravenous (IV) infusion on day 1 and bendamustine 120 mg/m(2) by IV infusion on days 2 and 3 of each 21-day cycle for up to six cycles. The primary end point was overall response rate (ORR), and the secondary end points were complete response (CR) rate, progression-free survival (PFS), and safety. RESULTS Sixty-three patients were enrolled, and 59 received BR. The median age was 67 years (range, 36 to 75 years), and 62.7% of patients were 65 years of age or older. Fifty-seven patients (96.6%) were previously treated with rituximab-containing chemotherapy. The ORR was 62.7% (95% CI, 49.1% to 75.0%), with a CR rate of 37.3% (95% CI, 25.0% to 50.9%). The ORRs were comparable between patients ≥ 65 years of age and less than 65 years (62.2% and 63.6%, respectively). The median PFS was 6.7 months (95% CI, 3.6 to 13.7 months). The most frequently observed grade 3 or 4 adverse events were hematologic: lymphopenia (78.0%), neutropenia (76.3%), leukopenia (72.9%), CD4 lymphopenia (66.1%), and thrombocytopenia (22.0%). CONCLUSION BR is a promising salvage regimen for patients with relapsed or refractory DLBCL after rituximab-containing chemotherapy, warranting further investigation.

Positive conversion of negative signaling of CTLA4 potentiates antitumor efficacy of adoptive T-cell therapy in murine tumor models

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been known to be a strong tolerance-inducing inhibitory receptor on T-cell surface. Systemic blocking of CTLA4 function with blocking antibodies has been regarded as an attractive strategy to enhance antitumor immunity. However, this strategy accompanies systemic autoimmune side effects that are sometimes problematic. Therefore, we developed a novel CTLA4 mutant that could be expressed in tumor antigen-specific T cells to enhance antitumor effect without systemic autoimmunity. This mutant, named CTLA4-CD28 chimera, consists of extracellular and transmembrane domains of CTLA4, linked with cytoplasmic CD28 domain. Overexpression of CTLA4-CD28 chimera in T cells delivered stimulatory signals rather than inhibitory signals of CTLA4 and significantly enhanced T-cell reactivity. Although this effect was observed in both CD4 and CD8 T cells, the effect on CD4 T cells was predominant. CTLA4-CD28 chimera gene modification of CD4 T cells significantly enhanced antitumor effect of unmodified CD8 T cells. Nonetheless, the gene modification of CD8 T cells along with CD4 T cells further maximized antitumor effect of T cells in 2 different murine tumor models. Thus, CTLA4-CD28 chimera gene modification of both tumor antigen-specific CD4 and CD8 T cells would be an ideal way of modulating CTLA4 function to enhance tumor-specific T-cell reactivity.

Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: analysis from the Asia Lymphoma Study Group.

BACKGROUND Hepatitis B virus (HBV) reactivation is increasing, as rituximab has become widely used for B-cell lymphoma. Thus, prevention and management of HBV reactivation are important in HBV-endemic areas. METHODS Hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)-positive patients and HBsAg-negative/HBV core antibody (HBcAb)-positive patients who received rituximab-containing chemotherapy was investigated by the Asia Lymphoma Study Group via retrospective (n=340), and the results were compared to cross-sectional analysis with patients who were prospectively monitored in a single institute (n=127). The goal of the study was to define the frequency of HBV reactivation and the efficacy of antiviral prophylaxis. RESULTS HBV reactivation was found in 27.8% of HBsAg-positive patients (45/162) in the retrospective analysis, being significantly less frequent in patients receiving antiviral prophylaxis than those not (22.9%, 32/140 versus 59.1%, 13/22; p<0.001). Lamivudine was most commonly used (96/162, 59.3%), but more than 20% of HBsAg-positive patients showed breakthrough HBV reactivation. In the cross-sectional analysis, a reduced rate of HBV reactivation occurred for entecavir as compared with lamivudine prophylaxis (6.3% versus 39.3%; p<0.05). HBV DNA monitoring of HBsAg-negative/HBcAb-positive patients in the cross-sectional analysis showed HBV reactivation in only 2.4% of cases. CONCLUSIONS This is the largest study of HBV reactivation in patients receiving rituximab-containing chemotherapy to date, and we defined the probability of HBV reactivation in an HBV-endemic region.

Statistics of hematologic malignancies in Korea: incidence, prevalence and survival rates from 1999 to 2008

Background The nationwide statistical analysis of hematologic malignancies in Korea has not been reported yet. Methods The Korea Central Cancer Registry and the Korean Society of Hematology jointly investigated domestic incidence rates and prevalence of hematologic malignancies occurred between 1999 and 2008, and analyzed survival rates of patients who were diagnosed between 1993 and 2008. Data of hematologic malignancies from 1993 to 2008 were obtained from the Korean National Cancer Incidence Data base. The crude incidence rates, age-specific incidence rates, age-standardized incidence rates, annual percentage change of incidence, and prevalence from 1999-2008 were calculated. Survival rates for patients diagnosed in 1993-2008 were estimated. Results In 2008, a total of 8,006 cases of hematologic malignancies were occurred, which comprised 4.5% of all malignancies. In all genders, non-Hodgkin lymphoma, myeloid leukemia, and multiple myeloma were most frequent diseases. In terms of age, ages between 60 and 69 were most prevalent. From 1999 to 2008, the age-standardized incidence rates increased from 10.2 to 13.7, and the annual percentage change was 3.9%. The 5-year survival rate increased from 38.2% during 1993-1995 to 55.2% during 2004-2008. As of January 2009, number of patients with 10-year prevalence was 33,130, and with 5- to 10-year prevalence was 10,515. Conclusion This is the first nationwide statistical report of hematologic malignancies in Korea. It could be used as the basic information to help investigate epidemiologic characteristics, evaluate progress during the past years, and establish future strategies for hematologic malignancies. Periodic statistical analysis of hematologic malignancies in Korea should be continued.

Clinical outcomes and prognostic factors in patients with breast diffuse large B cell lymphoma; Consortium for Improving Survival of Lymphoma (CISL) study

BackgroundThe breast is a rare extranodal site of non-Hodgkin lymphoma, and primary breast lymphoma (PBL) has been arbitrarily defined as disease localized to one or both breasts with or without regional lymph nodes involvement. The aim of this study was to evaluate the clinical outcomes in patients with diffuse large B cell lymphoma (DLBCL) and breast involvement, and to find the criteria of PBL reflecting the outcome and prognosis.MethodsWe retrospectively analyzed data from 68 patients, newly diagnosed with DLBCL and breast involvement at 16 Korean institutions between January 1994 and June 2009.ResultsMedian age at diagnosis was 48 years (range, 20-83 years). Forty-three (63.2%) patients were PBL according to previous arbitrary criteria, sixteen (23.5%) patients were high-intermediate to high risk of international prognostic index. The patients with one extranodal disease in the breast (OED) with or without nodal disease were 49 (72.1%), and those with multiple extranodal disease (MED) were 19 (27.9%). During median follow-up of 41.5 months (range, 2.4-186.0 months), estimated 5-year progression-free survival (PFS) was 53.7 ± 7.6%, and overall survival (OS) was 60.3 ± 7.2%. The 5-year PFS and OS was significantly higher for patients with the OED group than those with the MED group (5-year PFS, 64.9 ± 8.9% vs. 27.5 ± 11.4%, p = 0.001; 5-year OS, 74.3 ± 7.6% vs. 24.5 ± 13.0%, p < 0.001). In multivariate analysis, MED (hazard ratio [HR], 3.61; 95% confidence interval [CI], 1.07-12.2) and fewer than four cycles of systemic chemotherapy with or without local treatments (HR, 4.47; 95% CI, 1.54-12.96) were independent prognostic factors for worse OS. Twenty-five (36.8%) patients experienced progression, and the cumulative incidence of progression in multiple extranodal sites or other than breasts and central nervous system was significantly different between the OED group and the MED group (5-year cumulative incidence, 9.7 ± 5.4% vs. 49.0 ± 15.1%, p = 0.001).ConclusionsOur results show that the patients included in OED group, reflecting different treatment outcome, prognosis and pattern of progression, should be considered as PBL in the future trial. Further studies are warranted to validate our suggested criteria.

Lymphopenia is an important prognostic factor in peripheral T-cell lymphoma (NOS) treated with anthracycline-containing chemotherapy

BackgroundPeripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of aggressive T-cell lymphomas with poor treatment outcomes. The aim of this study was to evaluate whether lymphopenia at diagnosis would have an adverse effect on survival in patients with PTCL-NOS treated with anthracycline-containing chemotherapy.MethodsA total of 118 patients with PTCL-NOS treated with anthracycline-containing chemotherapy from 4 Korean institutions were included.ResultsThirty-six patients (30.5%) had a low absolute lymphocyte count (ALC, < 1.0 × 109/L) at diagnosis. Patients with lymphopenia had shorter overall survival (OS) and progression-free survival (PFS) rates compared with patients with high ALCs (P = 0.003, P = 0.012, respectively). In multivariate analysis, high-intermediate/high-risk International Prognostic Index (IPI) scores and lymphopenia were both associated with shorter OS and PFS. Treatment-related mortality was 25.0% in the low ALC group and 4.8% in the high ALC group (P = 0.003). In patients considered high-intermediate/high-risk based on IPI scores, lymphopenia was also associated with shorter OS and PFS (P = 0.002, P = 0.001, respectively).ConclusionThis study suggests that lymphopenia could be an independent prognostic marker to predict unfavorable OS and PFS in patients with PTCL-NOS treated with anthracycline-containing chemotherapy and can be used to further stratify high-risk patients using IPI scores.

Matched-pair analysis comparing the outcomes of primary breast and nodal diffuse large B-cell lymphoma in patients treated with rituximab plus chemotherapy†

Primary breast diffuse large B‐cell lymphoma (DLBCL) is an extremely rare presentation of non‐Hodgkins lymphoma that has been associated with poorer clinical outcomes compared with nodal DLBCL in the pre‐rituximab era. The aim of this study was to investigate the impact of rituximab on clinical outcomes in patients with primary breast DLBCL. Data from 25 female patients with primary breast DLBCL receiving rituximab plus chemotherapy were matched to 75 female patients (1:3) with nodal DLBCL by following five established prognostic factors (age, Ann Arbor stage, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase level and B symptoms). Overall survival (OS) was similar between primary breast and nodal DLBCL groups (3‐year OS rate, 82.2% vs. 90.7%, respectively; p = 0.345). In the analysis of immunohistochemically defined prognostic subgroups, 19 of 20 available cases in the primary breast DLBCL group displayed a non‐germinal center (GC) phenotype. Compared with patterns of recurrence, extranodal progression in the breast or central nervous system (CNS) was significantly higher in the primary breast DLBCL group than in the nodal DLBCL group (p < 0.001). Additionally, the stage‐modified International Prognostic Index was the only independent prognostic factor for OS in this population. This suggests that clinical outcomes of primary breast DLBCL might no longer be inferior to those of nodal DLBCL in the rituximab era, which might be associated with the intrinsic biologic characteristics of the non‐GC phenotype. However, despite including rituximab, extranodal progression in the breast or CNS was problematic. This study was registered at www.clinicaltrials.gov as no. NCT01266668.

Multiple myeloma in Korea: past, present, and future perspectives. Experience of the Korean Multiple Myeloma Working Party.

The incidence of multiple myeloma suggests an ethnic difference. Compared to Caucasians, who have an incidence rate of 3–5/100,000, Asians show much lower incidence rate compared to them, in the range of 0.5–3/100,000. In Korea, The very first case report of multiple myeloma was published in 1959 [1], and was followed by a few case reports until the 1970s. Since that time, the number of cases of multiple myeloma in Korea increased steadily, reaching 100 cases/year in 1990 [2] and 500 cases/year in 2000 [3], and it is still going up. Currently in Korea, 1,000 patients are estimated to be diagnosed with multiple myeloma, and 700 patients are assumed to die of this disease every year, and 4,000–5,000 patients are suffering from this disease [4]. The most updated, age-standardized, incidence rate of multiple myeloma in Korea is 1.4/100,000, and ranked as the third most common among the hematologic malignancies, only surpassed by non-Hodgkin’s lymphoma and acute myeloid leukemia [5]. Besides, the mortality from multiple myeloma