Byung-Ock Choi

Feasibility of the TNM-based staging system of ocular adnexal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma).

The American Joint Committee on Cancer has proposed the tumor, node, metastasis (TNM) staging system to overcome the limitations of the Ann Arbor staging system for ocular adnexal lymphoma. We performed this study to evaluate the feasibility of the TNM staging system for ocular adnexal extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue (OAML). The data form 66 total eyes from 54 patients with biopsy‐confirmed OAML according to World Health Organization classification were retrospectively analyzed. Using the TNM staging system, we reclassified all patients into two categories: (1) T1N0M0 stage group (n = 26), for patients with lymphoma involving only the conjunctiva; and (2) above T1N0M0 or bT1N0M0 stage group (n = 28), for patients with lymphoma extending to the orbit, eyelid, or adjacent structures, and/or bilateral OAML. After a 24‐month median follow‐up period for all patients, the T1N0M0 group revealed higher progression‐free survival (PFS) than the above T1N0M0 or the bT1N0M0 group (P = 0.041). In a separate analysis of only 50 patients categorized as Ann Arbor stage IE, the T1N0M0 group demonstrated higher PFS (100%) than the above T1N0M0 or the bT1N0M0 group (84.7%; P = 0.067). Our data show that the poor prognostic group classified as Ann Arbor stage IE can be further distinguished by using the TNM staging system. Thus, further studies to develop treatment strategies for reducing relapse after treatment for OAML should use the TNM staging system. Am. J. Hematol. 2011.

The relevance of serum carcinoembryonic antigen as an indicator of brain metastasis detection in advanced non-small cell lung cancer

Although many biomarkers have emerged in non-small cell lung cancer (NSCLC), the predictive value of site-specific spread is not fully defined. We designed this study to determine if there is an association between serum biomarkers and brain metastasis in advanced NSCLC. We evaluated 227 eligible advanced NSCLC patients between May 2005 and March 2010. Patients who had been newly diagnosed with stage IV NSCLC but had not received treatment previously, and had available information on at least one of the following pretreatment serum biomarkers were enrolled: carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA 21-1), cancer antigen 125 (CA 125), cancer antigen 19-9, and squamous cancer cell antigen. Whole body imaging studies and magnetic resonance imaging of the brain were reviewed, and the total number of metastatic regions was scored. Brain metastasis was detected in 66 (29.1%) patients. Although serum CEA, CYFRA 21-1, and CA 125 levels were significantly different between low total metastatic score group (score 1–3) and high total metastatic score group (score 4–7), only CEA level was significantly different between patients with brain metastasis and those without brain metastasis (pu2009<u20090.0001). The area under the receiver operating curve of serum CEA for the prediction of brain metastasis was 0.724 (pu2009=u20090.0001). The present study demonstrated that the pretreatment serum CEA level was significantly correlated with brain metastasis in advanced NSCLC. These findings suggested the possible role of CEA in the pathogenesis of brain invasion. More vigilant surveillance would be warranted in the high-risk group of patients with high serum CEA level and multiple synchronous metastasis.

Ophthalmologic outcomes after chemotherapy and/or radiotherapy in non-conjunctival ocular adnexal MALT lymphoma

In the present study, we evaluated the ophthalmologic outcomes of 24 patients who received chemotherapy and/or radiotherapy for the treatment of non-conjunctival ocular adnexal mucosa-associated lymphoid tissue-type (MALT) lymphoma. Ophthalmologic outcomes were assessed in patients who received chemotherapy and/or radiotherapy from March 2004 until May 2010. Outcomes were determined according to common symptoms following chemotherapy and/or radiotherapy, which consisted of decreased visual acuity, dry eye symptoms, retinopathy, optic neuropathy, increased intraocular pressure, and blepharitis. Nine patients received chemotherapy alone, eight patients received radiotherapy alone, and seven patients received chemotherapy with additional radiotherapy (chemoradiation therapy). Patients treated by chemotherapy alone showed better ophthalmologic outcome scores (mean score, 1.56) than those treated by radiation alone or chemoradiation therapy (mean score, 4.01). In conclusion, the treatment of ocular adnexal lymphoma including radiotherapy showed poor ophthalmologic outcomes due to radiation-induced complications. Recently, many new treatment options have emerged, such as immunotherapy or radioimmunotherapy. In the future study, to select a better treatment modality with fewer complications, well-designed prospective trials with ophthalmologic outcomes are needed.

Hepatocellular carcinoma with portal vein tumor thrombosis: Improved treatment outcomes with external beam radiation therapy

The treatment of advanced hepatocellular carcinoma (HCC) associated with portal vein tumor thrombosis (PVTT) is very challenging because of HCCs grave prognosis. Despite many efforts to improve the treatment results, patient survival has been limited to several months. In this situation, radiotherapy has been considered as an alternative treatment modality because of the growth of knowledge about the radiotolerance of normal tissue and the advances of radiotherapy techniques such as three dimensional conformal radiotherapy, intensity modulated radiotherapy, stereotactic body radiotherapy and proton therapy. More restoration of the liver function and longer survival of the patients can be achieved by the better response after radiotherapy. However, considering the high risk of intrahepatic advanced tumor or extrahepatic dissemination by PVTT at disease presentation, a combination of radiation therapy and systemic agents will be desirable. Therefore, performing prospective randomized clinical trials is important to assess the benefits of radiotherapy and to develop combination treatment strategies.

Long-term Outcome of Extranodal NK/T Cell Lymphoma Patients Treated With Postremission Therapy Using EBV LMP1 and LMP2a-specific CTLs

Extranodal NK/T-cell lymphoma (ENKTCL) is associated with latent Epstein-Barr virus (EBV) infection and frequent relapse even after complete response (CR) to intensive chemotherapy and radiotherapy. The expression of EBV proteins in the tumor provides targets for adoptive immunotherapy with antigen-specific cytotoxic T cells (CTL). To evaluate the efficacy and safety of EBV latent membrane protein (LMP)-1 and LMP-2a-specific CTLs (LMP1/2a CTLs) stimulated with LMP1/2a RNA-transferred dendritic cells, we treated 10 ENKTCL patients who showed complete response to induction therapy. Patients who completed and responded to chemotherapy, radiotherapy, and/or high-dose therapy followed by stem cell transplantation (HDT/SCT) were eligible to receive eight doses of 2u2009×u2009107 LMP1/2a CTLs/m2. Following infusion, there were no immediate or delayed toxicities. The 4-year overall survival (OS) and progression-free survival (PFS) were 100%, and 90% (95% CI: 71.4 to 100%) respectively with a median follow-up of 55·5 months. Circulating IFN-γ secreting LMP1 and LMP2a-specific T cells within the peripheral blood corresponded with decline in plasma EBV DNA levels in patients. Adoptive transfer of LMP1/2a CTLs in ENKTCL patients is a safe and effective postremission therapeutic approach. Further randomized studies will be needed to define the role of EBV-CTLs in preventing relapse of ENKTCL.

Retrospective analysis of treatment outcomes for extranodal NK/T-cell lymphoma (ENKL), nasal type, stage I-IIE: single institute experience of combined modality treatment for early localized nasal extranodal NK/T-cell lymphoma (ENKL)

Extranodal natural killer/T-cell lymphoma (ENKL) is a very aggressive disease frequently involving the nasal cavity and upper aerodigestive tract. We retrospectively reviewed the treatment outcomes and treatment-associated complications of the patients with stage I–II early localized ENKL. A total of 24 patients were included. All patients were treated with combined chemoradiotherapy. Three, sixteen, and five patients were initially treated with radiation therapy, chemotherapy, and surgical procedures, respectively. Nine patients underwent hematopoietic stem cell transplantation (HSCT), and four patients administered immunotherapy with pegylated-interferon alpha. The mean observation time was 71.6xa0months (range, 29.7–183.6xa0months). Twenty patients achieved complete remission; thus, the overall response rate was 83.3xa0%. The 5-year overall survival (OS) and relapse-free survival (RFS) rates were 70.3xa0% and 62.2xa0%, respectively. In univariate analysis, HSCT was a significant prognostic indicator for OS and RFS. By combining HSCT, the 5-year OS and RFS rates were 100.0xa0% vs. 52.5xa0% (pu2009=u20090.018) and 88.9xa0% vs. 45.7xa0% (pu2009=u20090.045), respectively. Also, absence of B symptoms was a good prognostic factor for RFS, the 5-year RFS rate, 75.0xa0% vs. 25.0xa0% (pu2009=u20090.010), and B symptoms were significant for RFS in multivariate analysis (odds ratiou2009=u20097.4, confidence intervalu2009=u20091.6~34.1, pu2009=u20090.011). However, a total of four cases of grade 3 toxicities were reported. Radiation dose range (≤4,500 vs. >4,500xa0cGy) was significantly correlated with late complications, as more severe complications occurred more frequently with a radiation dose >4,500xa0cGy (pu2009=u20090.026, in multivariate analysis). For more efficient treatment of ENKL, chemotherapy, HSCT, and/or immunotherapy can be combined with radiation therapy to prolong long-term survival and achieve good local control. Also, lower radiation dose could be administered to avoid severe late complications.

Supine linac treatment versus tomotherapy in craniospinal irradiation: planning comparison and dosimetric evaluation.

Craniospinal irradiation (CSI) is the standard treatment of primary intracranial tumour with risk of leptomeningeal dissemination. However, supine setup field-in-field technique does not need inter-fractional junction shift. Recently, the studies of CSI with tomotherapy showed excellent target coverage and tolerable normal organ dose in paediatric patients. The planning comparison and dosimetric difference between conventional radiotherapy and tomotherapy are presented. Three patients with central nervous system germinoma received supine CSI treatment. Normal tissue complication probability calculation was performed for parotid gland, kidney, lens, small bowel, ovary and testis. Homogenous vertebral body coverage for tomotherapy compared with conformal radiotherapy was found. The mean dose to each parotid gland decreased by 7.3 and 10 Gy, respectively, with tomotherapy. The volume of oesophagus and small bowel receiving >10 Gy was significantly lower. The V2, V5, V10 and V20 of the lungs are 81.6, 12.4, 2.3 and 0 % with tomotherapy. Tomotherapy showed excellent homogenous dose distribution through the craniospinal axis (PTV) and higher conformity index.

Clinical outcomes of post-remission therapy using 90yttrium ibritumomab tiuxetan (Zevalin®) for high-risk patients with diffuse large B-cell lymphoma

This phase II trial evaluated the efficacy and safety of tandem consolidation using 90yttrium ibritumomab tiuxetan (90Y-IT) and high-dose therapy (HDT) with autologous peripheral blood stem cell transplantation (PBSCT) in high-risk patients with diffuse large B-cell lymphoma (DLBCL) who were in primary remission. Eleven patients with high-risk DLBCL were enrolled. All patients had achieved complete or partial response after six to eight cycles of rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as a frontline chemotherapy. Subsequently, the patients received one to two courses of ifosfamide-containing regimen for peripheral blood stem cell mobilization and harvesting. First consolidation with 90Y-IT was performed, followed by second consolidation using HDT with PBSCT. All patients received 90Y-IT therapy, but three patients did not undergo PBSCT. During the median follow-up period of 18.1xa0months, 9 of 11 patients exhibited disease progression, and 8 patients died. The estimated 2-year progression-free survival was 18.2%, and overall survival was 36.4%. Adverse events following 90Y-IT consolidation were primarily transient hematologic toxicities. The present pilot study suggests that tandem consolidation therapy using 90Y-IT followed by HDT with autologous PBSCT is not feasible for treatment of high-risk patients with DLBCL in remission after R-CHOP. In addition, this treatment failed to provide beneficial effects for the clinical outcome of subsequent PBSCT.

Differential expression of MicroRNAs in patients with glioblastoma after concomitant chemoradiotherapy.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, and notorious for resistance to chemoradiotherapy. MicroRNAs (miRNAs) are significantly involved in the initiation and progression of numerous cancers; however, the role of miRNAs in recurrence of tumors remains unknown. Here we tried to identify novel miRNAs that are differentially expressed in recurrent GBM. Tissue samples were obtained from patients with primary and recurrent GBM treated with chemoradiotherapy, and the expression changes of miRNAs were measured by microarray. A total of 318 miRNAs were expressed in the GBM patients. The expression of 43 miRNAs were significantly altered at least 2-fold in primary and recurrent GBMs. Bioinformatic analysis revealed that the differentially expressed miRNAs and their putative target genes were mainly involved in cell death, cellular development, and cellular growth and proliferation, which are the key regulators for stem cells. Pathway analysis supported that the miRNAs may regulate signaling associated with induction and maintenance of cancer and stem cell, such as p53, ErbB1, Notch, Wnt, and TGF-β signaling pathways. These data suggest that, in recurrent GBM, growth factor and anti-apoptotic signalings for cancer cell growth and proliferation are regulated by miRNAs. Our findings will aid future research in understanding the pathophysiology of recurrent GBM and identifying diagnostic markers and/or therapeutic targets for recurrence of GBM.

Total lymphoid irradiation based conditioning for hematopoietic stem cell transplantation in severe aplastic anemia

PURPOSEnTo retrospectively evaluate the outcome and toxicity of total lymphoid irradiation (TLI) based conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) patients who experienced an engraftment failure from prior HSCT or were heavily transfused.nnnMATERIALS AND METHODSnBetween 1995 and 2006, 20 SAA patients received TLI for conditioning of HSCT. All patients were multi-transfused or had long duration of disease. Fifteen (75%) patients had graft failure from prior HSCT. In 18 (90%) patients, the donors were human leukocyte antigen identical siblings. The stem cell source was the peripheral blood stem cell in 15 (75%) patients. The conditioning regimen was composed of antithymocyte globulin plus TLI with a median dose of 750 cGy in 1 fraction. The graft-versus-host disease (GVHD) prophylaxis used cyclosporine with methotrexate.nnnRESULTSnWith a median follow-up of 10.8 years, graft failures developed in 6 patients. Among them, 3 patients received their third HSCT to be engrafted finally. The Kaplan-Meier overall survival rate was 85.0% and 83.1% at 5 and 10 years, respectively. The incidence of acute and chronic GVHD was 20% and 20%, respectively. None of the patients have developed a malignancy after HSCT.nnnCONCLUSIONnIn our study, TLI based conditioning in allogeneic HSCT was feasible with acceptable rates of GVHD in SAA patients who experienced graft failure from prior HSCT or was at a high risk of graft rejection. We achieved relatively better results of engraftment and survival with a long term follow-up.