Gyeong-Won Lee

A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia

We conducted a phase 3 randomized trial comparing 2 different doses of daunorubicin as induction chemotherapy in young adults (60 years of age or younger) with acute myeloid leukemia (AML). Of 383 patients who were analyzed, 189 received standard-dose daunorubicin (SD-DN, 45 mg/m² per day times 3 days) and 194 received high-dose daunorubicin (HD-DN, 90 mg/m² per day times 3 days) in addition to cytarabine (200 mg/m² per day times 7 days) to induce complete remission (CR). The CR rates were 72.0% in the SD-DN arm and 82.5% in the HD-DN arm (P = .014). At a median follow-up of 52.6 months, overall (OS) and event-free (EFS) survival were higher in the HD-DN arm than in the SD-DN arm (OS, 46.8% vs 34.6%, P = .030; EFS, 40.8% vs 28.4%, P = .030). Differences in CR rate and both OS and EFS remained significant after adjusting for other variables (CR, hazard ratio [HR], 1.802, P = .024; OS, HR, 0.739, P = .032; EFS, HR, 0.774, P = .048). The survival benefits of HD-DN therapy were evident principally in patients with intermediate-risk cytogenetic features. The toxicity profiles were similar in the 2 arms. In conclusion, HD-DN improved both the CR rate and survival duration compared with SD-DN in young adults with AML. This study is registered at www.clinicaltrials.gov as #NCT00474006.

The prognostic impact of the neutrophil-to-lymphocyte ratio in patients with small-cell lung cancer.

Background:The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are prognostic factors for various types of cancer. In this study, we assessed the association of NLR and PLR with the prognosis of small-cell lung cancer (SCLC) in patients who received the standard treatment.Methods:We retrospectively reviewed patients who were diagnosed with SCLC and treated with platinum-based chemotherapy between July 2006 and October 2013 in Gyeongsang National University Hospital Regional Cancer Center and Changwon Samsung Hospital.Results:In total, 187 patients were evaluated. Compared with low NLR (<4), high NLR (⩾4) at diagnosis was associated with poor performance status, advanced stage, and lower response rate. Median overall survival (OS) and progression-free survival (PFS) were worse in the high-NLR group (high vs low, 11.17 vs 9.20 months, P=0.019 and 6.90 vs 5.49 months, P=0.005, respectively). In contrast, PLR at diagnosis was not associated with OS or PFS (P=0.467 and P=0.205, respectively). In multivariate analysis, stage, lactate dehydrogenase, and NLR at diagnosis were independent prognostic factors for OS and PFS.Conclusions:NLR is easily measurable and reflects the SCLC prognosis. A future prospective study is warranted to confirm our results.

Combination chemotherapy with gemcitabine and cisplatin as first-line treatment for immunohistochemically proven cholangiocarcinoma.

Objectives:The aim of this study was to determine the efficacy and safety profile of gemcitabine plus cisplatin in patients with immunohistochemically proven unresectable cholangiocarcinoma. Patients and Methods:Between March 2002 and December 2004, a total of 24 patients with immunohistochemically proven cholangiocarcinoma were entered in this study. Treatment consisted of gemcitabine 1000 mg/m2 intravenous infusion on day 1 and 8 and cisplatin 70 mg/m2 intravenously on day 1 every 3 weeks. Results:Seventy-one cycles of treatment were given, with a median of 3 cycles (range, 2–6 cycles). Five patients had a partial response (PR), 12 patients had stable disease (SD), and 7 patients progressed during treatment. A median survival of 9.30 months (range, 6.43–12.17) was obtained hematologic and nonhematologic toxicities were generally acceptable. However, there was one treatment-related mortality caused by thrombotic thrombocytopenia purpura (TTP) associated with gemcitabine and cisplatin. Conclusions:The combination chemotherapy of gemcitabine and cisplatin had a modest effect and was a well tolerated treatment of patients with immunohistochemically proven metastatic or unresectable cholangiocarcinoma.

Human adipose tissue-derived mesenchymal stem cells protect kidneys from cisplatin nephrotoxicity in rats

Cisplatin has multiple cellular targets and modes of action that lead to nephrotoxicity. This suggests novel therapies that act at multiple cisplatin target sites may be effective. We tested whether human adipose tissue-derived mesenchymal stem cells (Ad-MSCs) can affect multiple target sites and protect against cisplatin-induced kidney damage. Rats were divided into four groups: control, infused with Ad-MSCs, injected with cisplatin, and cisplatin followed by infusion of Ad-MSCs. Animal survival and renal function were decreased and histological damage was increased in cisplatin-treated rats at day 3. Infusion of Ad-MSCs ameliorated renal dysfunction and tissue injury caused by cisplatin, leading to increased survival. Apoptotic cell death in the kidney was significantly reduced by infusion of Ad-MSCs. Activation of p53, JNK, and ERK and the expression of inflammation-related molecules were also decreased in the kidney that received Ad-MSCs. Very few Ad-MSCs were detected in the kidney. Conditioned medium from cultured Ad-MSCs had renal-protective functions in vivo and in vitro. Renal dysfunction and tissue damage caused by cisplatin were significantly reduced in rats treated with Ad-MSCs-conditioned medium. The viability of cultured renal proximal tubular cells exposed to cisplatin was also improved by coculture with Ad-MSCs or with conditioned medium. Release of proinflammatory mediators induced by cisplatin was inhibited in coculture with Ad-MSCs. Our results show that human Ad-MSCs exert a paracrine-protective effect on cisplatin nephrotoxicity at multiple target sites and suggest that human Ad-MSCs might be a new therapeutic approach for patients with acute kidney injury.

Prognostic value of metabolic tumor volume on PET / CT in primary gastrointestinal diffuse large B cell lymphoma

Primary gastrointestinal (PGI) diffuse large B cell lymphoma (DLBCL) is a relatively common disease. Recent studies indicate that measurement of maximum standardized uptake value (SUVmax) on pretreatment for 18F‐fluorodeoxyglucose PET is an important prognostic factor in PGI DLBCL. However, there is still an association between initial tumor burden and prognosis. Thus, in the present study, we investigated whether tumor volume by PET could have a potential prognostic value to predict the outcome. From 2006 to 2009, 165 Stage I E/II E PGI DLBCL patients were enrolled in the study. One hundred and five patients received cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R‐CHOP) only, whereas 60 patients underwent surgery plus R‐CHOP. Metabolic tumor volume (MTV) was defined initial tumor burden as target GI lesion above SUV, 2.5 by PET as a contouring border. Over a median follow‐up period of 36.6 months, receiver operating characteristic (ROC) analysis indicated that the best cut‐off values for MTV and SUVmax were 160.1 cm3 and 12.0, respectively. The estimated area under the ROC curve was higher for MTV than SUVmax. Thus, MTV was a better predictor for survival than SUVmax. In patients with a low MTV (<160.1 cm3), there were no significant differences in survival between patients undergoing R‐CHOP alone and surgery plus R‐CHOP (P = 0.347 for progression‐free survival [PFS]; P = 0.148 for overall survival [OS]). Conversely, in patients with a high MTV (>160.1 cm3), survival was longer in those who underwent surgery plus R‐CHOP than in those treated with R‐CHOP alone (P < 0.001 for PFS; P < 0.001 for OS). Multivariate analysis revealed that high MTV is an independent factor for predicting survival. Even in the era of rituximab, treatment of PGI DLBCL is not easy in patients with a high MTV. (Cancer Sci 2012; 103: 477–482)

Reduction of breast cancer cell migration via up‐regulation of TASK‐3 two‐pore domain K+ channel

Aim:  Many kinds of K+ channels are expressed in a variety of cells, including cancer cells. However, only a small amount of research has explored the relationship between voltage‐independent K+ channels and breast cancer. This study was performed to investigate whether changes in two‐pore domain K+ (K2P) channel expression levels are related to the migration of human breast cancer cells.

Angiography, Scintigraphy, Intraosseous Pressure, and Histologic Findings in High-Risk Osteonecrotic Femoral Heads With Negative Magnetic Resonance Images

One hundred twenty-six hips of 68 patients who were suspected of having osteonecrosis or being at risk for osteonecrosis were studied with magnetic resonance (MR) imaging. Abnormal patterns on MR imaging characteristic of osteonecrosis were observed in 98 hips. The remaining 28 hips (22 patients) with negative MR images underwent superselective angiography of the medial femoral circumflex artery. Angiography showed interruption of the superior retinacular arteries in 13 hips (12 patients), including 6 of 7 symptomatic hips. Bone scans were performed on 8 of 13 hips angiographically positive for osteonecrosis. Decrease of radionuclide uptake (cold lesions) was observed in all 8 of these femoral heads. Thirteen femoral heads with interruption of superior retinacular arteries underwent intraosseous pressure measurement and core biopsy. Intraosseous pressure was elevated in 11 hips. The results of histologic study showed evidence of early necrosis in 10 femoral heads. This study indicates that there are a considerable number of femoral heads at high risk, even when they have negative MR images. They do, however, show positive findings on angiography, scintigraphy (cold lesions), intraosseous pressure measurement, and histologic study.

Glutamine protects against cisplatin-induced nephrotoxicity by decreasing cisplatin accumulation.

Cisplatin is a chemotherapeutic drug but induces acute kidney injury (AKI). Cisplatin-induced AKI depends on several signaling pathways leading to apoptosis in tubular epithelial cells. Glutamine is a substrate for the synthesis of glutathione, the most abundant intracellular thiol and antioxidant, and plays an important role in protecting cells from apoptosis induced by different stimuli. In the present study, we investigated the protective effect of glutamine on cisplatin-induced AKI. Rats were divided into control, glutamine, cisplatin, and cisplatin plus glutamine groups. Glutamine ameliorated renal dysfunction, tissue injury, and cisplatin-induced apoptosis. Cisplatin increased cell death, caspase-3 cleavage, activation of MAPKs and p53, oxidative stress, and mRNA expression of TNF-α and TNFR1 in HK-2 cells. Glutamine treatment reduced cisplatin-induced these changes in HK-2 cells. Notably, glutamine reduced the cisplatin-induced expression of organic cation transporter 2 (OCT2) and cisplatin accumulation. Our results suggest that the protective effect of glutamine on cisplatin is specific for proximal tubular cells and the initial effects may be related to attenuation of cisplatin uptake. Thus, glutamine administration might represent a new strategy for the treatment of cisplatin-induced AKI.

A Phase II Study of Irinotecan, Continuous 5-Fluorouracil, and Leucovorin (FOLFIRI) Combination Chemotherapy for Patients With Recurrent or Metastatic Gastric Cancer Previously Treated With a Fluoropyrimidine-Based Regimen

Objectives:A phase II study was carried out to assess the efficacy and toxicity of combination chemotherapy with irinotecan, 5-fluorouracil (5-FU), and leucovorin (FOLFIRI) for the treatment of patients with metastatic or recurring gastric cancer previously treated with fluoropyrimidine-based chemotherapy. Methods:Eligible patients were those who had metastatic gastric cancer previously treated with a fluoropyrimidine-based chemotherapy regimen or had disease recurrence within 6 months of completing adjuvant fluoropyrimidine-containing chemotherapy. Participants received irinotecan (150 mg/m2 on day 1) and leucovorin (LV; 20 mg/m2 on days 1–2) followed by continuous infusion of 5-FU (1500 mg/m2 on days 1–2), every 2 weeks. Results:Between April 2006 and March 2008, 33 patients were enrolled in the study. FOLFIRI served as a second-line treatment in 27 patients, third-line treatment in 4 patients, and fourth-line treatment in 2 patients. The patients had a median age of 60 years (range, 40–75) and underwent 132 cycles of chemotherapy, with a median of 3 cycles (range, 1–15) per patient. The response rate was 18.2%, and the disease control rate was 36%. Median overall survival was 5.1 months (95% confidence interval, 3.74–6.45), and median time to progression was 2.3 months (95% confidence interval, 1.81–2.78). The major grade 3–4 toxicity was neutropenia (45.4%). Conclusion:Combination chemotherapy with irinotecan, 5-FU, and LV is feasible in gastric cancer patients previously treated with fluoropyrimidine-based chemotherapy.

ABCG2 Q141K polymorphism is associated with chemotherapy-induced diarrhea in patients with diffuse large B-cell lymphoma who received frontline rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone chemotherapy.

ATP‐binding cassette transporter G2 (ABCG2) is the most recently described transporter of the multidrug‐resistance pump and it promotes resistance to anticancer drugs such as doxorubicin, mitoxantrone, topotecan, and SN‐38. Of the ABCG2 polymorphisms, V12M and Q141K alter the functional activity of the ABCG2 transporter and influence the drug response and various toxicities to chemotherapeutic agents. We therefore evaluated the impact of the ABCG2 V12M and Q141K polymorphisms on the therapeutic outcomes and toxicities of primary rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R‐CHOP) therapy in 145 Korean patients with diffuse large B‐cell lymphoma (DLBCL). ABCG2 V12M and Q141K genotyping was carried out by pyrosequencing of polymerase chain reaction products. The clinical characteristics, treatment outcomes, toxicities of the patients, and the predictive value of the polymorphisms on response, survival, and adverse events to R‐CHOP for 145 patients were analyzed according to the ABCG2 V12M and Q141K polymorphisms. No differences were observed according to ABCG2 Q141K and V12M genotype in patient characteristics, disease characteristics, response, survival, or hematology toxicity profiles in patients with DLBCL who received frontline R‐CHOP chemotherapy. On multivariate analysis, grade I–IV diarrhea was statistically significant according to ABCG2 Q141K polymorphism (the QQ genotype vs the QK or KK genotypes; hazard ratio 2.835; 95% confidence interval 1.432–5.613; P = 0.003). This study demonstrates that the ABCG2 Q141K polymorphism may correlate with chemotherapy‐induced diarrhea in patients with DLBCL who have received frontline R‐CHOP chemotherapy, and this has implications for optimizing treatment with such agents. (Cancer Sci 2008; 99: 2496–2501)