Impact of clinical, cytogenetic, and molecular profiles on long-term survival after transplantation in patients with chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a heterogeneous group of clonal hematopoietic malignancies with variable clinical and molecular features. We analyzed long-term results of allogeneic hematopoietic cell transplantation in patients with CMML and determined clinical and molecular risk factors associated with outcomes. Data from 129 patients, aged 7-74 (median 55) years, at various stages of the disease and transplanted from related or unrelated donors were analyzed. Using a panel of 75 genes somatic mutations present before hematopoietic cell transplantation were identified In 52 patients. The progression-free survival rate at 10 years was 29%. The major cause of death was relapse (32%), which was significantly associated with adverse cytogenetics (hazard ratio, 3.77; P=0.0002), CMML Prognostic Scoring System (hazard ratio, 14.3, P=0.01), and MD Anderson prognostic scores (hazard ratio, 9.4; P=0.005). Mortality was associated with high-risk cytogenetics (hazard ratio, 1.88; P=0.01) and high Hematopoietic Cell Transplantation Comorbidity Index (score ≥4: hazard ratio, 1.99; P=0.01). High overall mutation burden (≥10 mutations: hazard ratio, 3.4; P=0.02), and ≥4 mutated epigenetic regulatory genes (hazard ratio 5.4; P=0.003) were linked to relapse. Unsupervised clustering of the correlation matrix revealed distinct high-risk groups with unique associations of mutations and clinical features. CMML with a high mutation burden appeared to be distinct from high-risk groups defined by complex cytogenetics. New transplant strategies must be developed to target specific disease subgroups, stratified by molecular profiling and clinical risk factors.

Correlation of Thyroid Transcription Factor-1 Expression with EGFR Mutations in Non-Small-Cell Lung Cancer: A Meta-Analysis.

OBJECTIVES: This meta-analysis investigated the relationship between thyroid transcription factor-1 (TTF-1) expression and epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) to clarify whether TTF-1 can be a potential surrogate marker for EGFR mutation status in advanced NSLCL. METHODS: A systematic searching of databases, including PubMed, EMBASE, Cochrane Library, and Google Scholar, was performed to identify studies assessing the correlation of TTF-1 expression with EGFR mutations. From 17 studies, 9764 patients were included in the combined analysis of odds ratio (OR) for the correlation between TTF-1 expression and EGFR mutations. RESULTS: Compared with NSCLCs showing negative TTF-1 expression, tumors harboring TTF-1 overexpression showed a significantly higher rate of EGFR mutations (OR = 5.19, 95% confidence interval: 3.60⁻7.47, p < 0.00001). This correlation was observed in both subgroups of East Asian (OR = 4.33, 95% CI: 3.46⁻5.41, p < 0.00001) and European patients (OR = 4.64, 95% CI: 1.41⁻15.28, p < 0.01). In addition, TTF-1 expression was significantly associated with EGFR mutations in exon 19 (OR = 4.63, 95% CI: 2.89⁻7.41, p < 0.00001) as well as exon 21 (OR = 3.16, 95% CI: 1.04⁻9.60, p = 0.04). CONCLUSIONS: This meta-analysis demonstrates a significant correlation between TTF-1 expression and EGFR mutations in patients with NSCLC. The status of TTF-1 expression may be a biomarker to guide anticancer treatment in patients with NSCLC and unknown EGFR mutation status.

Phase II study of oxaliplatin, irinotecan and S-1 therapy in patients with advanced gastric cancer: the Korean Cancer Study Group ST14-11.

BACKGROUND: Doublet chemotherapy of platinum and 5-fluorouracil is a standard first-line treatment for patients with unresectable gastric cancer. Although the addition of taxane or irinotecan to this regimen has yielded promising efficacy, its use has been limited due to severe toxicities. To overcome this limitation, we evaluated the efficacy and safety of the combination of irinotecan, oxaliplatin, and S-1 (OIS) for the treatment of advanced gastric cancer. METHODS: Chemotherapy-naïve patients with pathologically proven advanced gastric adenocarcinoma were assessed for eligibility. Irinotecan (135 mg/m2) and oxaliplatin (65 mg/m2) were administered intravenously on day 1, and S-1 (80 mg/m2/day) was administered orally on days 1-7 of every 2-week cycle. RESULTS: Forty-four patients (median age 57 years) were enrolled and all but one patient had a good performance status (ECOG 0 or 1). A total of 529 cycles were administered, with a median of 9.5 (range 1-31) cycles per patient. The overall response rate was 61.4% (95% confidence interval [CI] 46.6-74.3). The median progression-free survival and overall survival were 10.8 months (95% CI 7.6-14.0) and 15.4 months (95% CI 12.6-18.2), respectively. Major toxicities included grade 3/4 neutropenia (38.6%), febrile neutropenia (13.6%), abdominal pain (9.1%), and diarrhea (9.1%). CONCLUSION: These data suggest that the OIS regimen is effective and relatively well tolerated in patients with advanced gastric cancer. Given that all the patients treated, but one, had a good performance status, these results must be confirmed in a patient population more representative of regular clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02527785.

Efficacy and tolerability of ramucirumab monotherapy or in combination with paclitaxel in gastric cancer patients from the Expanded Access Program Cohort by the Korean Cancer Study Group (KCSG).

BACKGROUND: Ramucirumab improves survival in gastric cancer patients. The efficacy and safety of ramucirumab outside of a clinical trial were evaluated using an expanded access program (EAP). METHODS: Advanced gastric cancer patients treated with ramucirumab in combination with paclitaxel or with ramucirumab monotherapy in a Korean EAP were evaluated. Baseline characteristics were assessed for progression-free survival (PFS) and overall survival (OS), and adverse events were evaluated according to the treatment regimen. RESULTS: Of 265 patients, 228 received ramucirumab plus paclitaxel, and 37 received ramucirumab monotherapy. Grade 3 or 4 neutropenia was more common with ramucirumab plus paclitaxel than with ramucirumab monotherapy (46.7 vs. 8.1%). Gastrointestinal (GI) perforation developed in seven patients (3.1%) in the ramucirumab plus paclitaxel group. The overall response and disease control rates were 16.6 and 66.3% in the ramucirumab plus paclitaxel group, and 5.4 and 37.8% in the ramucirumab monotherapy group, respectively. PFS and OS were 3.8 and 8.6 months in the ramucirumab plus paclitaxel group, and 1.8 and 6.4 months in the ramucirumab monotherapy group, respectively. In multivariate analysis, alkaline phosphatase, albumin, and neutrophil-to-lymphocyte ratio (NLR) were the independent prognostic factors for PFS, while albumin, NLR, number of metastatic sites, and large amount of ascites were independent prognostic factors for OS. CONCLUSION: In the Korean EAP cohort, ramucirumab showed similar efficacy to the results of the previous trials for gastric cancer. However, the level of GI perforation was slightly increased in the ramucirumab plus paclitaxel group.

Multicenter, cross-sectional observational study of the impact of neuropathic pain on quality of life in cancer patients.

PURPOSE: Neuropathic cancer pain (NCP) is a common and potentially debilitating symptom in cancer patients. We investigated the prevalence of NCP, as well as its management and association with QOL. METHODS: Cancer patients with pain ≥1 on the visual analogue scale (VAS) were surveyed with the Douleur Neuropathique (DN4) questionnaire, the Brief Pain Inventory-Short Form (BPI-SF), and the EuroQOL five dimensions (EQ-5D) questionnaire. The associations between NCP and pain severity or NCP and QOL, while controlling for variables relevant to QOL, were then analyzed. RESULTS: A total of 2003 patients were enrolled in this survey; the prevalence of NCP was 36.0% (n = 722, 95% CI, 32.5-39.5). We found that NCP in cancer patients was closely correlated to a higher pain severity (BPI-SF; 4.96 ± 1.94 versus 4.24 ± 2.02, p < 0.001), and in patients with NCP, pain more severely interfered with daily living, as compared to those without NCP (BPI-SF; 4.86 ± 2.71 versus 4.41 ± 2.87, p < 0.001). Patients with NCP also had worse QOL than those without NCP, as measured by EQ-5D index score (0.47 ± 0.30 vs. 0.51 ± 0.30, p = 0.005), and this was confirmed using multivariate analysis (p < 0.001), even after controlling for other variables such as age, sex, disease stage, cancer duration, radiotherapy, chemotherapy, and comorbidities. Importantly, adjuvant analgesics were used in less than half of patients with NCP (n = 358, 46.4%). CONCLUSIONS: We found that NCP in cancer patients was significantly associated with a worsened QOL, and current management is inadequate. Therefore, future research aimed at developing improved strategies for management of NCP is required.

Phase II study of docetaxel, oxaliplatin, and S-1 therapy in patients with metastatic gastric cancer.

BACKGROUND: Although the docetaxel, 5-fluorouracil, and cisplatin triplet has yielded significant improvements in time to progression, overall survival, and overall response rate, the high incidence of severe adverse events limits the use of the docetaxel, 5-fluorouracil, and cisplatin triplet. To overcome this limitation, we evaluated the efficacy and safety of the combination of docetaxel, oxaliplatin, and S-1 for the treatment of metastatic gastric cancer. METHODS: Chemotherapy-naive patients with pathologically proven unresectable recurrent or metastatic gastric adenocarcinoma were assessed for eligibility. Docetaxel at 52.5 mg/m(2) and oxaliplatin at 105 mg/m(2) were administered intravenously on day 1, and S-1 was administered orally at 80 mg/m(2) on days 1-14 of every 21-day cycle. RESULTS: Forty-four patients (median age 54.5 years) were enrolled. All patients had metastatic disease. A total of 340 cycles of chemotherapy were administered (median of eight cycles per patient; range 1-36 cycles). Toxicities were evaluated in 43 patients, and the responses were evaluated in 40 patients. Major toxicities included grade 3/4 neutropenia (37.2 %) and leukopenia (27.9 %). The overall response rate was 54.5 % [95 % confidence interval (CI) 40.1-68.3 %] in the intention-to-treat population. The median progression-free survival and overall survival were 7.6 months (95 % CI 6.2-9.0 months) and 12.0 months (95 % CI 6.9-17.2 months), respectively. CONCLUSION: These data suggest that the docetaxel, oxaliplatin, and S-1 combination regimen is effective and relatively well tolerable, and it seems to have potential to be a reasonable therapeutic strategy in patients with metastatic or recurrent gastric cancer.

Single-lesion measurement per organ for assessing tumor response in advanced gastric cancer.

OBJECTIVE: The criterion of two target lesions per organ in the revised Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) is an arbitrary decision. We assumed that measuring the single largest lesion per organ (modified RECIST 1.1, hereafter referred to as mRECIST 1.1) instead of two (RECIST 1.1) might be enough to assess tumor responses. METHODS: We compared tumor response using computed tomography according to the RECIST 1.1 and mRECIST 1.1 in patients with advanced gastric cancer (AGC) who received first-line chemotherapy. RESULTS: A total of 51 patients who had at least two target lesions in any organ according to the RECIST 1.1 were included in the study. The level of concordance in the tumor response between the RECIST 1.1 and mRECIST 1.1 was excellent (k = 0.904). Only 3 patients (5.9%) showed a disagreement of tumor responses between the two criteria. The overall response rate was not significantly different between the two criteria (45.1% by RECIST 1.1 vs. 49.0% by mRECIST 1.1, p = 0.692). CONCLUSION: The mRECIST 1.1 showed a high concordance with the original RECIST 1.1 in the assessment of tumor response for patients with AGC. Our result suggests that it may be possible to measure the single largest target lesion per organ for assessing tumor response in clinical practice.

Predictors of high score patient-reported barriers to controlling cancer pain: a preliminary report.

PURPOSE: Pain is one of the most common and devastating symptoms in cancer patients, and misunderstandings on the patient's part can cause major obstacles in pain management. METHOD: We evaluated factors associated with patient's high barrier score to managing cancer-associated pain by having 201 patients complete the Korean Barriers Questionnaire II, the Brief Pain Inventory--Korean, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, and the Korean Beck Depression Inventory. The Pain Management Index (PMI) was also assessed. RESULTS: The patients were from nine oncology clinics in university hospitals and a veterans' hospital in South Korea. The median pain score (0-10 scale) was 4, with a median percentage of pain improvement during the last 24 h of 70 %. A total of 150 patients (75 %) received strong opioids, and 177 (88 %) achieved adequate analgesia (positive PMI). Mean scores ± SD for the Barriers Questionnaire II ranged from 1.5 ± 1 to 2.8 ± 1.1, with the harmful effects subscale the highest. In the multiple regression model, depression was significantly associated with total barrier score to pain management (p < 0.0001). Pain reduction was significantly associated with the fatalism subscale. CONCLUSIONS: Depression was associated with high barrier score in patients with cancer pain. Management of cancer pain should include screening for depression, and management of depression could reduce patient-reported barriers to pain management.

Sunitinib as a second-line therapy for advanced GISTs after failure of imatinib: relationship between efficacy and tumor genotype in Korean patients.

BACKGROUND: To assess the efficacy and safety of sunitinib with regards to primary genotypes of tumor in Korean patients with advanced gastrointestinal stromal tumors (GISTs) who failed an initial therapy of imatinib. METHODS: Clinical data were collected from 88 consecutive patients with metastatic/unresectable GISTs treated with sunitinib at the Asan Medical Center. RESULTS: The median time-to-progression (TTP) and overall survival (OS) times were 7.1 months and 17.6 months, respectively. Of the 74 patients tested for KIT (exons 9, 11, 13, 17) and PDGFRA (exons 12 and 18), patients with KIT exon 9 mutant GIST (n = 11, 14.9%) showed numerically better clinical benefit (objective response or stable disease ≥ 24 weeks) rate (63.6% vs 46.8%, p = 0.504) and TTP (median 13.6 mo vs 6.9 mo, p = 0.631) than those with KIT exon 11 mutant GIST (n = 47, 63.5%). The most common grade 3/4 adverse events included neutropenia (34.1%), thrombocytopenia (33.0%) and hand-foot skin reaction (25.0%). CONCLUSIONS: Sunitinib is an effective and safe second-line therapy for Korean patients with advanced GIST. The superior efficacy of sunitinib against GISTs with KIT exon 9 mutations appears to be similar in Korean patients to Western experience although statistical significance was not secured.

A phase II study of chemotherapy in combination with telomerase peptide vaccine (GV1001) as second-line treatment in patients with metastatic colorectal cancer.

Background: GV1001 is a human telomerase peptide vaccine that induces a CD4/CD8 T-cell response against cancer cells, thereby affording an immunological anti-tumor effect. Here, we evaluated the efficacy and safety of GV1001 in combination with chemotherapy in patients with metastatic colorectal cancer who had failed first-line chemotherapy. Methods: This multicenter, non-randomized, single-arm phase II study recruited recurrent or metastatic colorectal cancer patients with measurable disease who had failed first-line chemotherapy. Patients received GV1001 and chemotherapy concomitantly based on a pre-established schedule. Cytotoxic chemotherapy and targeted agents (bevacizumab, cetuximab, or aflibercept) were allowed to be used at the discretion of the investigator. The primary endpoint was the disease control rate; secondary endpoints were the objective response rate, progression-free survival, overall survival, and safety outcomes. The baseline serum eotaxin level (a potential predictive biomarker of GV1001) was analyzed. To determine whether an adequate immune response had been induced, a delayed-type hypersensitivity test and a T-cell proliferation test were performed. Results: From May 13, 2015 to October 13, 2020, 56 patients with recurrent or metastatic colorectal cancer treated in seven hospitals of South Korea were enrolled. The median patient age was 64 years (range, 29-82 years); 67.9% were men. Of all patients, 66.1% had left-side colorectal cancer and the RAS mutation was present in 25%. The disease control rate and the objective response rates were 90.9% (95% confidence interval [CI]: 82.4-99.4%) and 34.1% (95% CI, 20.1-48.1%), respectively. The median progression-free survival was 7.1 months (95% CI, 5.2-9.1 months) and the median overall survival was 12.8 months (95% CI, 9.9-15.8 months). The most common all-grade adverse events were neutropenia (48.2%), nausea (26.8%), neuropathy (25.0%), stomatitis (21.4%), and diarrhea (21.4%). Immune response analysis showed that no patient had positive delayed-type hypersensitivity test results; antigen-specific T-cell proliferation was observed in only 28% of patients. The baseline eotaxin level was not associated with any efficacy outcome. Conclusion: Although no clear GV1001-specific immune response was observed, the addition of GV1001 vaccination to chemotherapy was tolerable and associated with modest efficacy outcomes.

A phase II study of gemcitabine, erlotinib and S-1 in patients with advanced pancreatic cancer.

Background: We evaluated the efficacy and safety of gemcitabine in combination with erlotinib and S-1 for the treatment of advanced pancreatic cancer. Methods: Chemotherapy-naïve patients with pathologically-proven locally advanced, recurrent, or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine was administered at 1,000 mg/m2 intravenously on days 1 and 8, erlotinib was administered at 100 mg/day on days 1-21, and S-1 was administered at 60 mg/m2 on days 1-14 every 21 days and continued to a maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2 was permitted from the second cycle for pre-defined tolerable patients. Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1-8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The confirmed overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and the disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. Conclusion: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer.

Ki-67 expression as a prognostic factor in diffuse large B-cell lymphoma patients treated with rituximab plus CHOP.

BACKGROUND: Assessment of tumor cell proliferation based on Ki-67 expression yielded conflicting prognostic predictions of patients with diffuse large B-cell lymphoma (DLBCL). The introduction of rituximab to the DLBCL treatment regime has led to alterations in the significance of previous prognostic factors. METHODS: We analyzed Ki-67 expression and its correlation with prognosis in 144 patients with DLBCL treated with rituximab plus CHOP (R-CHOP) between July 2003 and January 2008. RESULTS: The complete response (CR) rates following R-CHOP administration were not significantly different, based on Ki-67 expression status (P = 0.104). However, higher rates of relapse were observed in the high Ki-67 expression group (Ki-67 >or= 85%, n = 46) with 25.0%, compared to 10.0% in the low Ki-67 expression group (Ki-67 < 85%, n = 88) (P = 0.040). The 2-yr event-free survival (EFS) rates were 44.3% and 74.1% in the high and low Ki-67 expression groups, respectively (P = 0.011). The 2-yr overall survival (OS) rate was 66.4% in the high Ki-67 expression group and 82.2% in the low Ki-67 expression group (P = 0.016). In multivariate analysis, Ki-67 expression was a significant prognostic factor for EFS [hazard ratio (HR) = 2.909; 95% confidence interval (CI) 1.261-6.708; P = 0.012]. Ki-67 was associated with OS but with borderline significance (HR = 2.876; 95% CI, 0.972-8.508; P = 0.056). CONCLUSION: Elevated Ki-67 expression seems to be associated with higher relapse after CR and inferior EFS in patients with DLBCL treated with R-CHOP.

Bilateral subdural hemorrhage as a possible adverse event of gefitinib in a patient with non-small cell lung cancer.

Gefitinib, a selective inhibitor of epidermal growth factor receptor tyrosine kinase is an effective agent used in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Adverse drug reactions were frequently observed in the skin, gastrointestinal tract, and liver, but they were generally mild in severity and reversible. Therefore, gefitinib has been regarded as a relatively safe agent. As a serious adverse effect, however, acute lung injury has been reported. The present report describes a patient with NSCLC who developed bilateral subdural hemorrhage as a possible adverse drug reaction after gefitinib therapy. We expect that this case may provide a reference for clinicians being involved in the treatment with gefitinib.

Expression and prognostic significance of microRNAs in Korean patients with myelodysplastic syndrome.

BACKGROUND/AIMS: Various alterations of microRNA (miRNA) expression have been reported in myelodysplastic syndrome (MDS). We aimed to investigate the unique patterns and prognostic significance of miRNA expression in Korean patients with MDS. METHODS: Bone marrow mononuclear cells were collected from eight healthy controls and 26 patients with MDS, and miRNAs were isolated and assessed via quantitative real-time polymerase chain reaction for selected miRNAs, including miR-21, miR-124a, miR-126, miR-146b-5p, miR-155, miR-182, miR-200c, miR-342-5p, miR-708, and Let-7a. RESULTS: MiR-124a, miR-155, miR-182, miR-200c, miR-342-5p, and Let-7a were significantly underexpressed in patients with MDS, compared to healthy controls. MiR-21, miR-126, 146b-5p, and miR-155 transcript levels were significantly lower in international prognostic scoring system lower (low and intermediate-1) risk MDS than in higher (intermediate-2 and high) risk MDS. Higher expression levels of miR-126 and miR-155 correlated with significantly shorter overall survival and leukemia-free survival. Higher miR-124a expression also tended to be related to shorter survivals. CONCLUSION: Although our study was limited by the relatively small number of patients included, we identified several miRNAs associated with pathogenesis, leukemic transformation, and prognosis in MDS.

Prognostic Impact of TTF-1 Expression in Non-Squamous Non-Small-Cell Lung Cancer: A Meta-Analysis.

Thyroid transcription factor-1 (TTF-1) is overexpressed in up to 95% of primary lung adenocarcinoma while negative for almost all squamous cell carcinomas. TTF-1 expression has been investigated as a prognostic factor in non-small-cell lung cancer (NSCLC) with conflicting results. We conducted this meta-analysis to gain a better insight into the prognostic role of TTF-1 in patients only with non-squamous (non-SQ) NSCLC. A systematic computerized search of the electronic databases including PubMed, PMC, EMBASE, Web of Science, and Cochrane Library was performed. From 21 studies, 6,451 patients were included in the combined analysis of hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival. Compared with patients with non-SQ NSCLC showing negative TTF-1 expression, those with tumors harboring TTF-1 overexpression had significantly better survival (HR = 0.49, 95% CI: 0.42-0.57, p < 0.00001). Subgroup analyses revealed that TTF-1 expression significantly correlated with a better prognosis in stage I (HR = 0.65, 95% CI: 0.50-0.84, p = 0.0008) as well as stage III-IV non-SQ NSCLC (HR = 0.38, 95% CI: 0.29-0.49, p < 0.00001). In conclusion, this meta-analysis demonstrates that TTF-1 overexpression is a favorable prognostic factor in patients with non-SQ NSCLC. The subgroup analyses indicate that TTF-1 is a good prognostic marker for survival not only in early-stage but also in advanced non-SQ NSCLC.

Multicenter Phase II Study of Oxaliplatin, Irinotecan, and S-1 as First-line Treatment for Patients with Recurrent or Metastatic Biliary Tract Cancer.

PURPOSE: Although gemcitabine plus cisplatin has been established as the standard first-line chemotherapy for patients with advanced biliary tract cancer (BTC), overall prognosis remains poor. We investigated the efficacy of a novel triplet combination of oxaliplatin, irinotecan, and S-1 (OIS) for advanced BTC. MATERIALS AND METHODS: Chemotherapy-naive patientswith histologically documented unresectable or metastatic BTC were eligible for this multicenter, single-arm phase II study. Patients received 65 mg/m2 oxaliplatin (day 1), 135 mg/m2 irinotecan (day 1), and 40 mg/m2 S-1 (twice a day, days 1-7) every 2 weeks. Primary endpoint was objective response rate. Targeted exome sequencing for biomarker analysis was performed using archival tissue. RESULTS: In total, 32 patients were enrolled between October 2015 and June 2016. Median age was 64 years (range, 40 to 76 years), with 24 (75%) male patients; 97% patients had metastatic or recurrent disease. Response rate was 50%, and median progression-free survival and overall survival (OS) were 6.8 months (95% confidence interval [CI], 4.8 to 8.8) and 12.5 months (95% CI, 7.0 to 18.0), respectively. The most common grade 3-4 adverse events were neutropenia (32%), diarrhea (6%), and peripheral neuropathy (6%). TP53 and KRAS mutations were the most frequent genomic alterations (42% and 32%, respectively), and KRAS mutations showed a marginal relationship with worse OS (p=0.07). CONCLUSION: OIS combination chemotherapy was feasible and associated with favorable efficacy outcomes as a first-line treatment in patients with advanced BTC. Randomized studies are needed to compare OIS with gemcitabine plus cisplatin.

Establishment and characterization of hypomethylating agent-resistant cell lines, MOLM/AZA-1 and MOLM/DEC-5.

Two hypomethylating agents (HMAs), azacitidine and decitabine, have demonstrated clinical activities in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML); however, potential problems include development of acquired resistance. HMA-resistant patients have very poor prognosis and this cohort of patients constitutes an important area of research. To understand the mechanisms underlying HMA-resistance and to overcome it, we established an azacitidine-resistant cell line, MOLM/AZA-1 and a decitabine-resistant cell line, MOLM/DEC-5 using MOLM-13. For cytogenetic characterization, we performed microarray-based comparative genomic hybridization (array-CGH), which identified a total of 15 copy number alterations (CNAs). Among these CNAs, eight regions in HMA-resistant cell lines showed CNA patterns distinct from the parental MOLM-13 genome. Single nucleotide polymorphism (SNP) microarray was also performed to obtain a more reliable interpretation of the identified CNAs, and all HMA-resistance-specific CNAs except one detected by array-CGH were successfully validated. In addition to CNAs, copy neutral loss of heterozygosity and mosaic loss events were identified in HMA-resistant cell lines. In our resistant cell lines, MDR-1 was not overexpressed, while DNMT3b was upregulated. Azacitidine and decitabine did not inhibit DNMT1, DNMT3a, or DNMT3b in both HMA-resistant cell lines, while they inhibited the enzymes in parental MOLM-13. We also developed mouse xenograft models using MOLM/AZA-1 and MOLM/DEC-5. Our in vitro and in vivo models of HMA-resistant cell lines will provide clues for the elucidation of molecular mechanisms related to the development of resistance to HMA and tools for the application of novel therapeutics for AML and MDS.

A dose-finding study for oxaliplatin, irinotecan, and S-1 (OIS) in patients with metastatic or recurrent gastrointestinal cancer.

PURPOSES: To determine the maximum tolerated dose (MTD), recommended dose (RD), and activity of combined oxaliplatin, irinotecan, and S-1 chemotherapy for metastatic or recurrent gastrointestinal (GI) cancer. METHODS: Oxaliplatin and irinotecan were administered intravenously on day 1, and S-1 was administered orally on days 1-7, every 2 weeks. This phase I study used the following dose levels for oxaliplatin/irinotecan/S-1: level 1, 85/120/60 mg/m2; level 2, 85/120/80 mg/m2; level 3, 85/120/100 mg/m2; level 4, 85/150/100 mg/m2; and level 5, 85/180/100 mg/m2. Treatment was repeated for a maximum of 12 cycles, until disease progression, or until unacceptable toxicity. RESULTS: Twenty-four patients were enrolled between October 2012 and February 2014 (median age 59 years). During the first cycle, one of the six patients in levels 1, 3, and 4 developed a dose-limiting toxicity (grade 3 febrile neutropenia), and none of the three patients in level 5 developed a dose-limiting toxicity. As the planned maximum dose did not reach the MTD, the level 5 dose was defined as the RD. Twenty-one patients were evaluated for response, which included 2 cases of complete response and 8 cases of partial response, with an overall response rate of 47.6 %. CONCLUSIONS: The combination of oxaliplatin, irinotecan, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced GI cancer. The RD was 85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan, and 100 mg/m2 of S-1 every 2 weeks.