Hun-Mo Ryoo

RandomizEd phase II trial of Sunitinib four weeks on and two weeks off versus Two weeks on and One week off in metastatic clear-cell type REnal cell carcinoma: RESTORE trial

BACKGROUND The standard sunitinib schedule, 4 weeks on, followed by 2 weeks off (4/2 schedule), is associated with troublesome toxicities, and maintenance of adequate sunitinib dosing and drug levels, which are essential for achieving an optimal treatment outcome, is challenging. The objective of this study was to investigate the efficacy and safety of an alternative sunitinib dosing schedule of 2 weeks on and 1 week off (2/1 schedule) compared with the standard sunitinib schedule of 4 weeks on and 2 weeks off (4/2 schedule). PATIENTS AND METHODS In this multicenter, randomized, open-label, phase II trial, treatment-naïve patients with clear-cell type metastatic renal cell carcinoma (mRCC) were randomly assigned to 4/2 or 2/1 schedules after stratification by Memorial Sloan Kettering Cancer Center risk group and the presence or absence of measurable lesions. The primary end point was the 6-month failure-free survival (FFS) rate, determined by intention-to-treat analysis. RESULTS From November 2007 to February 2014, 76 patients were accrued, and 74 were eligible. FFS rates at 6 months were 44% with the 4/2 schedule (N = 36) and 63% with the 2/1 schedule (N = 38). Neutropenia (all grades, 61% versus 37%; grade 3-4, 28% versus 11%) and fatigue (all grades, 83% versus 58%) were more frequently observed with schedule 4/2. There was a strong tendency toward a lower incidence of stomatitis, hand-foot syndrome, and rash with schedule 2/1. Objective response rates (ORRs) were 47% in schedule 2/1 and 36% in schedule 4/2. With a median follow-up of 30.0 months, the median time to progression (TTP) was 12.1 months in schedule 2/1 and 10.1 months in schedule 4/2. CONCLUSION Sunitinib administered with a 2/1 schedule is associated with less toxicity and higher FFS at 6 months than a 4/2 schedule, without compromising the efficacy in terms of ORR and TTP (NCT00570882).

The efficacy of docetaxel and cisplatin combination chemotherapy for the treatment of advanced gastric cancer after failing to 5-fluorouracil based chemotherapy.

PURPOSE This study was conducted to confirm the efficacy and toxicity of docetaxel and cisplatin combination chemotherapy (DP) in patients with advanced gastric cancer. MATERIALS AND METHODS Patients with measurable gastric adenocarcinoma received intravenous docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) with premedication on day 1, which was repeated every 3 weeks. All patients received DP as a second-line treatment after failing to 5-FU based chemotherapy. RESULTS 34 patients were enrolled in this study between January 1998 and August 2003. A total of 112 cycles (median 3 cycles) were administered. Responses were evaluable in 30 patients. The objective response rate was 16.7% (95% CI: 3.5 approximately 30.3), with a stable disease in 56.7% (95% CI: 40.0 approximately 74.4) and a progressive disease in 26.7% (95% CI: 10.9 approximately 42.5) of patients, with a median follow up duration of 20 months for all the patients, The median duration of response, time to progression and overall survival were 2.1 months (95% CI: 0.4 approximately 3.9), 4.2 months (95% CI: 2.3 approximately 6.1) and 6.8 months (95% CI: 1.3 approximately 12.3), respectively, with a 1-year survival rate of 32%. The toxicity was evaluated in 30 patients, with neutropenia being most common. Renal impairment was seen in two patients with grade 3 creatinine elevation and liver enzyme elevation in four with grades 3 and 4. CONCLUSION Although DP was an active combination regimen, with a tumor control rate of about 73% and with moderate tolerance, adjustment of the administration schedule, with further evaluation of other combination chemotherapies of docetaxel with new agents, other than cisplatin, seem warranted.

Efficacy and safety of deferasirox estimated by serum ferritin and labile plasma iron levels in patients with aplastic anemia, myelodysplastic syndrome, or acute myeloid leukemia with transfusional iron overload

Patients receiving red blood cell (RBC) transfusions are at risk of iron overload, which can cause significant organ damage and is an important cause of morbidity and mortality.

Prospective, multicenter, phase II study on reducing the dosage of idarubicin and FLAG for patients younger than 65 years with resistant acute myeloid leukemia: a comparison with a higher dosage trial.

We previously assessed continuous infusion (CI) of fludarabine and cytarabine plus idarubicin (CI-FLAG1) for patients under 65 years of age with resistant acute myeloid leukemia. Induction chemotherapy consisted of idarubicin (IDA) plus fludarabine and cytarabine (ARAC) as a 24-hour CI. In response to induction, 31.6% of patients achieved complete remission (CR) and in 68.4% the treatment failed. We concluded that CI-FLAG1 carried a high risk of toxicity and reduced CI-FLAG doses were recommended. Therefore, we revised the protocol (CI-FLAG2) by reducing the dose of IDA and ARAC. In total, 38 and 68 patients were enrolled into CI-FLAG1 and CI-FLAG2, respectively. When comparing outcomes between CI-FLAG1 and CI-FLAG2, there were no differences in terms of the CR rate (p = 0.306) and the overall response rate (ORR; p = 0.206). The treatment failure patterns were different between CI-FLAG1 and CI-FLAG2. The median overall survival showed only a trend towards longer survival in CI-FLAG2 (p = 0.074). Among intermediate-risk patients, there were high response rates favoring CI-FLAG2 in terms of the CR rate (p = 0.108), the ORR (p = 0.031), and overall survival (p = 0.033). This represented a relatively improved response rate compared to our previous study. There was decreased aplasia with dose reductions at the expense of increased resistance. A reduced dose of CI-FLAG might be most beneficial for intermediate-risk groups.

Abstract 3113: Knockdown of cell division cycle-associated 8 (CDCA8) suppresses hepatocellular carcinoma growth via the upregulation of tumor suppressor ATF3

Background: Hepatocellular carcinoma (HCC) is the third most lethal cancer worldwide which remains a major challenge due to poor prognosis and limited treatment options. Cell division cycle associated 8 (CDCA8) is known as a component of a chromosomal passenger complex required for stability of the bipolar mitotic spindle and it is commonly overexpressed in human HCC. However, the functional role of CDCA8 in HCC progression remains to be clarified. In this study, we hypothesized if targeting of CDCA8 with small interfering (si) RNA could alter the course of HCC progression. We also investigated the molecular mechanism that mediates HCC cell death caused by CDCA8 silencing. Methods: Human HCC cell lines, Huh1 and Huh7, were transfected with CDCA8 siRNA and tested for growth inhibition and apoptotic induction using MTS, FACS and microscopic analysis. To obtain insights into the molecular changes in response to CDCA8 knockdown, global changes in gene expression were examined using RNA sequencing. Results: siRNA silencing of CDCA8 inhibited HCC cell growth and long-term colony formation by blocking cell cycle progression and by inducing apoptotic cell death. RNA sequencing data showed that, representatively, the anti-proliferative effects were driven by a subset of molecular alterations including the upregulation of tumor suppressive ATF3 and GADD34 genes and the downregulation of BGLAP, a key regulator of cell growth and invasiveness. Subsequent Western blot analysis affirmed that CDCA8 silencing induces the increase in the levels of ATF3 and GADD34 and the decrease in phosphorylated Akt in both Huh1 and Huh7 cells. Also, the same condition decreased the levels of PARP-1 and pro-caspase 3, accelerating apoptosis. Of importance, silencing of CDCA8 expression effectively suppressed HCC tumor growth in a murine xenograft model. Conclusion: These findings suggest that targeting CDCA8 could be an attractive option for molecular therapy of HCC. Citation Format: Tae-Won Jeon, Min Ji Ko, Yu-Ri Seo, In Hye Baik, Ilseon Hwang, Hun-Mo Ryoo, Jin Young Kim, Keon Uk Park, Yun-Han Lee. Knockdown of cell division cycle-associated 8 (CDCA8) suppresses hepatocellular carcinoma growth via the upregulation of tumor suppressor ATF3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3113. doi:10.1158/1538-7445.AM2017-3113

Abstract 3927: Programmed cell death ligand 1 expression in resected colorectal adenocarcinomas: association with micrometastasis

Background: Programmed cell death 1 (PD-1) and its ligand (PD-L1) are key suppressors of the cytotoxic immune response. PD-L1 expression on tumor cells may be induced by the immune microenvironment, resulting in immune escape, and an adverse prognosis in many malignancies. In colorectal carcinoma the response to PD-1/PD-L1 inhibition is correlated with microsatellite instability. However, little is known about the clinicopathologic, molecular, and prognostic characteristics of colorectal carcinoma with PD-L1 expression. In surgically resected colorectal adenocarcinoma, micrometastasis should be crucial for recurrence, and micrometastasis may be related to PD-L1. The aim of this study is to assess the PD-L1 expression and its association with clinicopathologic manifestations. Methods: PD-L1 expression was evaluated in 176 resected colorectal adenocarcinomas using tissue microarrays. Immunohistochemical staining was performed to evaluate the expression of PD-L1. The relationship of clinicopathologic manifestations and PD-L1 expression in colorectal cancer were evaluated by chi-squared test, Kaplan-Meier survival and Cox regression test. Results: High PD-L1 expression was present in 52.8% colorectal adenocarcinoma and was not related pathologic T or N stage. High PD-L1 expression was associated with decreased recurrence rate (p Conclusion: High PD-L1 expression is an independent prognostic factor, such as pathologic stage in colorectal adenocarcinoma. PD-L1 expression is independent prognostic factor, relating immune response to micrometastasis and immune suppression by PD-L1 may not be effective in micrometastasis of colorectal adenocarcinoma. Key words: PD-L1, colon, cancer, immunology, micrometastasis Citation Format: Ilseon Hwang, Keon Uk Park, Jin Young Kim, Hun-Mo Ryoo, Yun-Han Lee. Programmed cell death ligand 1 expression in resected colorectal adenocarcinomas: association with micrometastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3927. doi:10.1158/1538-7445.AM2017-3927

Abstract 4769: Inhibition of ribosomal protein L9 expression suppresses colorectal carcinoma cell growth in vitro and in vivo

Background: Ribosomal protein L9 (RPL9), a component of the 60S subunit, is upregulated in human colorectal cancer (CRC). We thus hypothesized if targeting of RPL9 with small interfering (si) RNA could inhibit CRC progression. We also investigated molecular mechanism to mediate CRC cell death caused by RPL9 silencing. Methods: HCT116 and HT29 human CRC cells were transfected with RPL9 siRNA and tested for growth inhibition and apoptotic induction using MTS, FACS and microscopic analysis. To obtain insights into the molecular changes in response to RPL9 knockdown, global changes in gene expression were examined using RNA sequencing. Results: RPL9 silencing caused inhibition of CRC cell growth through induction of apoptotic cell death. RNA sequencing revealed that RPL9-specific knockdown led to dysregulation of 622 genes in HCT116 and 2882 genes in HT29 cells. Among those, 256 genes showed the same directional regulation (128 up- and 168 down-regulated genes), including up-regulation of tumor suppressors such as KLF6 and ATF3, and were considered as a common RPL9 knockdown signature. Western blotting proved that downregulation of RPL9 was accompanied with the decrease in the levels of PARP-1 and pro-caspase 3 delaying cell cycle progression and accelerating apoptotic signaling. Of importance, targeting RPL9 significantly inhibited CRC growth in a murine xenograft model. Conclusion: These results suggest that inhibition of RPL9 expression could be an attractive option for molecular targeted therapy of colorectal cancer. Citation Format: In Hye Baik, Keon Uk Park, Ilseon Hwang, Hun-Mo Ryoo, Yun-Han Lee. Inhibition of ribosomal protein L9 expression suppresses colorectal carcinoma cell growth in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4769.

Abstract 2027: Carbamylated albumin increase MMP9 activity via ERK MAPK pathway

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Objective: Carbamylation, the binding of cyanate to amino acid lysine residues, is a post-translational modification. Pathophysiological consequences of carbamylation and adverse effects of carbamylated proteins remain poorly understood. This study was designed to influence of carbamylated albumin on matrix metalloproteinase(MMP) expressions in rat mesangial cells (RMC). Methods and Results: The effect of carbamylated albumin was evaluated using zymography, Western blot analysis, MMP-9 promoter luciferase assay, and ELISA. We found that carbamylated albumin significantly increased MMP-9 productions in RMCs via stimulating MMP-9 promoter activity and ERK1/2 MAPK phosphorylation. DecreasedTIMP-1 activity by carbamylated albumin was not observed. Conclusion: We demonstrated that carbamylated albumin increased MMP-9 activity via ERK1/2MAPK mediated pathway and further studies as to the functions of carbamylated albumin will be of merit. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2027. doi:1538-7445.AM2012-2027

Abstract 3705: Multicenter phase II clinical trial of gemcitabine and liposomal paclitaxel combination chemotherapy in patients with advanced biliary cancer

OBJECTIVE: Advanced biliary tract cancer is associated with a poor prognosis due to wide resistance to chemotherapeutic agents. This phase II clinical trial was conducted to determine the safety and efficacy of weekly gemcitabine and liposomal paclitaxel (Genexol-PM®) in patients with unrectable or metastatic biliary cancer. METHODS: The eligibility criteria were patients 1) with pathologically proven unresectable or metastatic biliary cancer, 2) with an ECOG performance status 0 to 2, 3) aged more than 18, 4) with measurable lesions, 5) with adequate hematologic, renal and liver functions, and 6) who provided written informed consent. Each treatment cycle was consisted of gemcitabine 1000 mg/m*2 and liposomal paclitaxel 100 mg/m*2 on days 1, 8 followed by rest perioid of 14 days. It was repeated until the appearance of disease progression or unacceptable toxicity up to maximal 9 cycles. The primary end point of this study was reponse rate, and secondary end points included toxicity, progression free survival and overall survival. RESULTS: Thirty five patients were enrolled; median age was 63 years; male (n=30) and female (n-10). The median number of cycles administered was 3.5 (range, 1-10). Thirty patients were assessable for efficacy. Nine partial responses and 16 stable diseases were confirmed. Giving an overall response rate was 35.6% and disease control rate was 55.6% in per-protocol population. Median overall survival was 12.3 months (95% CI: 5.79-18.74) and median progression free survival was 4.07 months(95% CI: 3.12-5.01). The most frequent adverse events (AE) of all grades were anemia and neutropenia (n=17) followed by leucopenia (13). Grade 3/4 hematologic AEs: anemia (n=6), neutropenia (n=11), thrombocytopenia (n=1). Grade 3/4 non-hematologic AEs: elevated liver function tests (n=3), hyperbilirubinemia (n=1) hyponatremia (n=1). CONCLUSION: Weekly gemcitabine combined with liposomal paclitaxel appears to be effective against advanced biliary cancers. Further randomized trials are needed to confirm this finding. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3705. doi:1538-7445.AM2012-3705

Cancer pain management with hydromorphone OROS in Korean cancer patients: Evaluation of its clinical usefulness in reduction of breakthrough pain medication frequency: Multicenter, prospective, open-label study.

e19566 Background: A majority of patients with cancer experience cancer pain of higher than moderate severity during the progression of cancer. Of these, 2/3 of patients with cancer have been repor...