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Objectives The purpose of this prospective observational study is to evaluate the relation of the comprehensive geriatric assessment (CGA) to tolerability and survival of multi-agent chemotherapy for curative intent in elderly patients with aggressive non-Hodgkin lymphoma (NHL). Materials and Methods Patients who were 1) age ≥ 65 years, 2) newly diagnosed aggressive NHL, and 3) treated with multi-agent chemotherapy within 2 weeks from the time of diagnosis were enrolled from January 2011 to June 2014. Baseline clinical, laboratory, and CGA data being composed of Mini Nutritional Assessment-Short Form (MNA-SF), Korean version of Mini Mental Status Exam, Korean-Geriatric Depression Scale, and Groningen Frailty Index (GFI), were collected and analyzed for the relation to the outcome factors. Results Seventy patients were included; the median age was 73.5 years, 27 (38.6%) patients were Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or more, and half of the patients were high or high-intermediate risk by age-adjusted international prognostic index (aaIPI). Most patients received CHOP or CHOP-like chemotherapy. Factors affecting discontinuation of chemotherapy within 12 weeks were poor MNA-SF, poor GFI, poor PS, and presence of B symptom. Among those, poor MNA-SF was independent of other variables in multivariate analysis. Poor MNA-SF, bone marrow involvement, and baseline anemia of hemoglobin < 10 g/dL were found to be independent factors associated with inferior overall survival whereas aaIPI factors were not. Conclusion MNA-SF predicted tolerability to multi-agents chemotherapy and overall survival in elderly patients with aggressive NHL who were treated with multi-agent chemotherapy. [ABSTRACT FROM AUTHOR]

We report a phase II study to evaluate the survival rate, response rate and toxicity of concurrent chemoradiation therapy (CCRT) followed by consolidation chemotherapy (CT) with oral etoposide and cisplatin for patients with locally advanced inoperable non-small cell lung cancer (NSCLC). Fifty-four patients with locally advanced inoperable NSCLC who had received no prior therapy were enrolled into this trial between May 1995 and December 2000. Treatment consisted of two cycles of concurrent CT and four cycles of consolidation CT with oral etoposide (50 mg/m2) on days 1–14 during the CCRT courses and on days 1–21 during the consolidation CT courses, plus cisplatin (75 mg/m2 i.v.) on day 1 of a 28-day cycle. Conventional radiotherapy (1.8 Gy/fraction, 63 Gy over 7 weeks) was delivered from day 1 of the CT. Fifty-two patients were evaluable for response. Twelve patients (22%) achieved complete responses, and 32 patients (60%) achieved partial responses, for an overall response rate of 82% with a median duration of response of 9.1 months. Forty-three per cent developed grade 4 haematological toxicity, 11% grade 3 or 4 oesophagitis and 7% grade 3 or 4 lung toxicity. There were two treatment-related deaths, one from radiation pneumonitis and the other from sepsis. After a median follow-up duration of 50 months (range 20–85), the median overall survival time was 15.3 months (95% CI, 9.7–20.8), and the 1-, 2-, 3-, and 5 year overall survival rates were 62, 40, 30 and 16%, respectively. The duration of median progression-free survival was 12.3 months (95% CI, 7.4–17.3), and the 1-, 2-, 3-, and 5-year progression-free survival rates were 47, 40, 29 and 23%, respectively. Thus, concurrent conventional chest radiotherapy with oral etoposide plus cisplatin followed by consolidation CT led to an encouraging survival rate and prolongation of the time to progression, with moderate toxicity in patients with locally advanced inoperable NSCLC. [Copyright &y& Elsevier]

Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy (TMA), characterized by micro-angiopathic hemolytic anemia, thrombocytopenia, and renal failure. In more than half of cases, genetic defects leading to overactivation of the alternative complement system have been identified. In this study, we investigated genetic defects in Korean adult patients with aHUS. Sixty-six Korean adult patients with aHUS were ascertained from the Korean TMA Registry. Genetic variants of 15 aHUS-related genes (eight core genes [ CFH , CFB , CFI , CD46 , C3 , THBD , PLG , and DGKE ] and seven candidate genes [ CFP , C4BPA , and CHFR1 - 5 ]) were analyzed from exome sequencing data. Multiplex ligation-dependent probe amplification of CFH and related genes was performed to detect hybrid genes or large deletions. Thirty patients (45%) had at least one aHUS-related variant (s) in eight core genes (total 40 variant alleles). The most frequently affected gene was CFH (13/40, 32%), followed by THBD (8/40, 20%) and CD46 (7/40, 18%). The two most common variants were Asp486Tyr of THBD (N = 7) and Tyr1058His-Val1060Leu of CFH (N = 5, linked on the same allele), accounting for 30% (12/40). In seven candidate genes, 19 variants were detected. When combined, 40 patients (61%) had at least one variant in 15 core or candidate genes. No patients had anti-CFH Ab or hybrid gene/ CFHR1 homozygous deletions. The genetic profile of Korean adult aHUS was unique with recurrent missense variants, demonstrating ethnicity- and age-dependent differences in the genetic background of aHUS. • Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy. • About half of aHUS patients have genetic defects. • The genetic profile of Korean adult aHUS was distinct from Korean pediatric aHUS. • The genetic profile of Korean adult aHUS was distinct from other ethnicities. [ABSTRACT FROM AUTHOR]

Abstract: Although autologous and allogeneic hematopoietic stem cell transplantation (HSCT) are fundamentally different procedures, a tailored approach to bacterial bloodstream infection (BSI) according to the type of HSCT has not yet been suggested. We evaluated the characteristics of BSI after HSCT, with a focus on comparison of BSIs between recipients of autologous HSCT (auto-HSCT) and allogeneic HSCT (allo-HSCT). Among 134 patients (59 received allo-HSCT and 75 received auto-HSCT) who underwent HSCT, BSIs were reported earlier in patients who underwent auto-HSCT, compared with those who underwent allo-HSCT (mean 12.1 ± 3.4 days versus 32.8 ± 27.1 days, P = .006). Among patients receiving allo-HSCT, postneutrophil-engraftment bacterial BSI showed an association with grade ≥2 acute graft-versus-host disease (GVHD). In patients who underwent auto-HSCT, results of multivariate analysis showed that not receiving prophylactic antibiotics (P = .004) and having elevated serum C-reactive protein (P = .034) were risk factors of BSI. Elevated CRP (P = .01) and acute GVHD ≥ grade 2 (P = .002) were independent risk factors in patients who underwent allo-HSCT. Those differences originated mainly from the impact of acute GVHD-related postengraftment BSIs of patients who underwent allo-HSCT. To establish the best defense strategy against BSI, the distinctive natures of bacterial BSI after HSCT between auto-HSCT and allo-HSCT should be considered. [Copyright &y& Elsevier]

Abstract: Previous studies have shown that the ginseng saponin metabolite, Compound K (20-O-d-glucopyranosyl-20(S)-protopanaxadiol, IH901), suppresses proliferation of various cancers and induces apoptosis. AMP-activated protein kinase (AMPK) is a sensor of cellular energy states and is involved in apoptosis of cancer cells. We hypothesized that Compound K may exert cytotoxicity in MCF-7 human breast cancer cells through modulation of AMPK, followed by a decrease in cyclooxygenase-2 (COX-2) expression. Compound K inhibited cell growth, induced apoptosis via generation of reactive oxygen species (ROS), as well as decreasing COX-2 expression and prostaglandin E2 (PGE2) levels. These effects of Compound K were induced via an AMPK-dependent pathway and were abrogated by a specific AMPK inhibitor. These results suggest that Compound K induced apoptosis by modulating AMPK–COX-2 signaling in MCF-7 human breast cancer cells. [ABSTRACT FROM AUTHOR]

• Ultra-deep sequencing is a sensitive method for genetic-based treatment decisions. • Specific mutations could have a prognostic application in predicting response. • Based on mutational analyses, nilotinib is a promising option for Korean patients. Ultra-deep sequencing detects low-frequency genetic mutations with high sensitivity. We used this approach to prospectively examine mutations in the BCR/ABL1 tyrosine kinase from patients with newly diagnosed, chronic-phase chronic myeloid leukemia (CML) treated with the tyrosine kinase inhibitor nilotinib. Between May 2013 and November 2014, 50 patients from 18 institutions were enrolled in the study. We screened 103 somatic mutations and found that mutations in the P-loop domain were the most frequent (173/454 mutations in the P-loop) and noted the presence of the V299 L mutation (dasatinib-resistant/nilotinib-sensitive) in 98 % of patients (49/50). No patients had Y253H, E255 V, or F359 V/C/I mutations, which would recommend dasatinib rather than nilotinib treatment. The S417Y mutation was associated with lower achievement of a major molecular response (MMR) at 6 months, and the V371A mutation was associated with reduced MMR and MR4.5 durations (MMR for 2 years: 100 % for no mutation vs. 75 % for mutation, P= 0.039; MR4.5 for 15 months: 94.1 % vs. 25 %, P= 0.002). Patients with known nilotinib-resistant mutations had lower rates of MR4.5 achievement. In conclusion, ultra-deep sequencing is a sensitive method for genetic-based treatment decisions. Based on the results of these mutational analyses, nilotinib treatment is a promising option for Korean patients with CML. [ABSTRACT FROM AUTHOR]

Summary: Docetaxel and gemcitabine combination chemotherapy has been reported to be active against non-small cell lung cancer (NSCLC) and myelosuppression is the most common dose-limiting toxicity. This prospective phase II study was designed to test the hypothesis that better tolerance and increased dose intensity might be achieved if patients are treated with weekly administration schedule. Thirty-five patients with stage IIIB/IV NSCLC and a performance status 0–2 received first-line chemotherapy with docetaxel 35mg/m2 and gemcitabine 600mg/m2 on days 1, 8 and 15. Treatment was repeated every 4 weeks, for up to 4 cycles. In total, 85 chemotherapy cycles were given (median, 2; range, 1–4). Other than the completion of all 4 planned cycles (n =6), the main reasons for treatment discontinuation were toxicity (n =15) and progressive disease (n =14). The most frequently encountered toxic effects were anemia (52% of patients), nausea and vomiting (60%), fatigue (71%) and anorexia (57%). One patient died of bilateral pneumonitis, which developed shortly after the administration of second cycle. Disease control (objective response and stable disease) in the intent-to-treat (ITT) population was achieved in 60% of patients and the overall response rate was 29% (95% CI, 14–44%). With a median follow-up duration of 13 months, the median progression-free survival and overall survival were 2.8 (95% CI, 0.7–4.8) months and 10.6 (95% CI, 7.0–14.3) months, respectively. In conclusion, weekly schedule of docetaxel and gemcitabine has modest activity with acceptable toxicity profile in advanced NSCLC, but as high frequency of early discontinuation occurred does not merit further study with the present regimen. [Copyright &y& Elsevier]

Purpose: With the improvement concurrent chemoradiotherapy (CCRT) in the management of patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC), distant failures have become a more relevant problem in terms of survival. The primary objective of this Phase II study is to assess the feasibility of docetaxel and cisplatin consolidation after primary CCRT for patients with HNSCC. Methods and Materials: Patients with locoregionally advanced HNSCC received chemotherapy with three cycles of cisplatin, 100 mg/m2, on Days 1, 22, and 43. Concurrent radiotherapy to the primary tumor and neck was given in a daily dose of 2 Gy to a total dose of 70–70.2 Gy over 7 weeks. After completion of CCRT, patients without evidence of disease progression received an additional four cycles of consolidation chemotherapy with docetaxel, 75 mg/m2, and cisplatin, 75 mg/m2, every 3 weeks. Results: Of 33 patients, 27 (81%) completed CCRT. After CCRT, three complete and 19 partial responses were recorded, giving an overall response rate of 67%. Of 19 patients who went to the consolidation phase, only 4 (21%) received all four cycles of docetaxel and cisplatin. Causes of failure of consolidation chemotherapy were toxicity in 11 patients, including three treatment-related deaths, and progression in 4 patients. Three patients died of sepsis during the consolidation phase. Median survival was 11 months for all patients and 8 months for those treated with consolidation chemotherapy. Conclusion: The poor compliance and high incidence of severe toxicities prompted no further evaluation of this consolidation chemotherapy after CCRT. [Copyright &y& Elsevier]

Abstract: The International Prognostic Index (IPI) and Follicular Lymphoma Prognostic Index (FLIPI) are used as prognostic indices for NHL and indolent lymphoma. However, marginal zone B-cell lymphoma (MZL) evidences a distinctive clinical presentation and a natural course; thus, in this study, we attempted to devise an adequate prognostic index for MZL. Two-hundred and five patients diagnosed with MZL were retrospectively reviewed. After analysis of the prognostic factors, progression-free survival (PFS), and overall survival (OS), we constructed a prognostic index of MZL (MZLPI) via the summation of each factor. We then compared PFS and OS with IPI, FLIPI, and MZLPI. According to our multivariate analysis, nodal MZL, ECOG performance ⩾2, and advanced stage were composed of MZLPI. MZLPI was grouped as follows: score 0 as a low-risk group, score 1 as an intermediate risk group, and score ⩾2 as a high-risk group. The PFS curve, according to MZLPI results, evidenced a more discriminated pattern than IPI and FLIPI, and this was especially true in the intermediate risk group. In OS, MZLPI (P =0.0007) evidenced a more discriminated pattern than IPI (P =NS) or FLIPI (P =0.0044). MZLPI, which is constructed of relatively simple factors, may represent a useful prognostic index for the prediction of PFS and OS in MZL, and may also be used as a substitute for IPI or FLIPI. [Copyright &y& Elsevier]

Our previous study showed that a less toxic regimen comprising reduced cyclophosphamide (Cy), fludarabine and anti-thymocyte globulin (ATG) (Cy-Flu-ATG), was less toxic for allogeneic hematopoietic cell transplantation (alloHCT) compared with standard Cy-ATG in patients with adult severe aplastic anemia (AA). We postulated that replacing Cy with Flu (Flu-ATG) would be more beneficial. Therefore, we performed a randomized phase III study to compare the regimen-related toxicities (RRTs) of two different conditioning regimens: Cy-ATG vs. Flu-ATG. Pre-defined RRTs were defined as pulmonary complications, hepatic sinusoidal obstruction syndrome (SOS), hemorrhagic cystitis and death of any causes. We present the final analysis. Patients in the Cy-ATG arm received Cy at 200 mg/kg. Those in the Flu-ATG arm received fludarabine (Flu) at 180 mg/m2. Bone marrow (BM) as allowed when the donor was matched sibling donor and otherwise stem cell source was mobilized peripheral blood (PB). Regimen for graft-versus-host disease (GvHD) was cyclosporine and short-course methotrexate. A total of 63 patients (31 patients in Cy-ATG and 32 patients in Flu-ATG) were enrolled. The basic patients'characteristics were similar between both arms in terms of gender, age, prior immune suppression therapy history, stem cell source, stem cell dose, donor type and HLA-matching. There were 36 unrelated donors in each arm (p=1.000). All predefined RRTs were similar between Cy-ATG and Flu-ATG (33.3% vs. 21.9%; p = 0.691). There was no difference between Cy-ATG and Flu-ATG in terms of pulmonary complications (12.9% vs. 3.1%; p = 1.000), SOS (0% vs. 3.1%; p = 1.000), hemorrhagic cystitis (6.5% vs. 3.1%; p = 0.607) and death of any causes (23.3% vs. 15.6%; p = 0.443). Primary engraftment failure was not found in Flu-ATG arm but 2 patients in Cy-ATG (p = 0.230), one of which died of treatment-related hepatic toxicity before engraftment. However, there was higher secondary engraftment failure inFlu-ATG arms compared with Cy-ATG (2nd GF; 21.9% vs. 6.9%; p = 0.098). Therefore, any engraftment failure was not different between Cy-ATG vs. Flu-ATG (13.3% vs. 21.9%; p = 0.379). The incidence of all grades acute GvHD was significantly higher in Cy-ATG arm (35.7% vs. 9.4%; p = 0.013). The incidence of chronic GvHD was lower in Cy-ATG arm but was not statistically significant (11.5% vs. 23.1%; p = 0.271). Any significant treatment-related toxicities including RRTs were similar between Cy-ATG and Flu-ATG arms (43.3% vs. 43.8%; p = 0.974). The 3-year survival rate did not differ between Cy-ATG and Flu-ATG (72.9% vs. 79.3%; p = 0.329). In conclusion, Flu-ATG can be comparable with Cy-ATG in terms of RRT and survival. [ABSTRACT FROM AUTHOR]

Abstract: Dimethylsulfoxide (DMSO) has been known to differentiate HL60 cells into neutrophil like cells. Here, we provide an evidence for the involvement of tumor suppressor PTEN, an antagonist of phosphatidylinositol 3-kinase (PI3K) in the DMSO-induced differentiation of HL60 cells. DMSO upregulated PTEN with unaffecting the expression of PI3K. The upregulation of PTEN by DMSO lead to the decrease of Akt phosphorylation, a downstream of PI3K. The DMSO-induced upregulation of PTEN might be mediated by NF-κB activation, which was evidenced by the blockage of DMSO-induced PTEN upregulation with an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC). [Copyright &y& Elsevier]