National Hospital Organization Kyushu Cancer Center

Fukuoka-shi, Japan

National Hospital Organization Kyushu Cancer Center

Fukuoka-shi, Japan
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PubMed | National Hospital Organization, Okayama Rousai Hospital, Kumamoto University, Nanpuh Hospital and 7 more.
Type: Clinical Trial, Phase II | Journal: International journal of clinical oncology | Year: 2016

Combination chemotherapy with S-1 and irinotecan is one of the standard treatments for metastatic colorectal cancer (mCRC) in Japan. However, there are few alternative practical second-line therapies. We conducted a phase II trial to evaluate the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab as a second-line treatment for oxaliplatin-refractory mCRC.Patients with mCRC who were previously treated with oxaliplatin-containing regimens were enrolled. Oral S-1 at a dose of 80mg/m(2) was administered twice daily for 2weeks, followed by a 1-week drug-free interval. Irinotecan at a dose of 150mg/m(2) and bevacizumab at a dose of 7.5mg/kg were administered on day 1. The primary endpoint was progression-free survival (PFS).Thirty-seven patients were enrolled, and 34 and 36 patients were assessed for response and safety, respectively. The overall response rate was 20.6% (95% confidenceinterval [CI] 8.7-37.9), and thedisease control rate was 76.5% (95% CI 58.8-89.3). The median PFS was 5.6months (95% CI 3.8-7.0).The median overall survival was 16.4months (95% CI 8.1-20.0). The most common grade 3/4 adverse events included neutropenia (25.0%), anorexia (22.2%), anemia (16.7%), and fatigue/malaise (16.7%). The most common grade 3/4 adverse event of special interest forbevacizumabwas hypertension (30.6%). One treatment-related death caused by gastrointestinal bleeding occurred.The findings suggest that the combination of S-1 and irinotecan plus bevacizumab is effective and tolerable as second-line chemotherapy for patients with oxaliplatin-refractory mCRC.


Nakashima K.,St Lukes International Hospital | Nakashima K.,National Hospital Organization Kyushu Cancer Center | Kusakawa I.,St Lukes International Hospital | Yamamoto T.,St Lukes International Hospital | And 4 more authors.
Heart and Vessels | Year: 2013

A 5-year-old girl developed cardiopulmonary arrest after crying. From the electrocardiogram and echocardiography, a left ventricular noncompaction (LVNC) with long QT syndrome (LQT) was suspected as the cause of the cardiopulmonary arrest, and treatment with a β-blocker and a calcium antagonist was then begun. A genetic screening of LQT-related genes revealed a previously reported heterozygous KCNQ1 mutation. The association of LVNC and LQT is an extremely rare condition, and long-term treatment based on the characteristics of both disorders is required. Also, the association of cardiomyopathy and LQT could become a new clinical entity in the future. © 2012 Springer.


Hironaka S.,Chiba Cancer Center | Sugimoto N.,Japan National Cardiovascular Center Research Institute | Yamaguchi K.,Saitama Cancer Center | Moriwaki T.,University of Tsukuba | And 15 more authors.
The Lancet Oncology | Year: 2016

Background: Although leucovorin enhances the efficacy of fluorouracil, the anti-tumour activity of S-1 and leucovorin and their combination with oxaliplatin for patients with advanced gastric cancer is unknown. We compared the activity and safety of S-1 plus leucovorin, S-1 plus leucovorin and oxaliplatin, and S-1 plus cisplatin as first-line chemotherapy for advanced gastric cancer. Methods: In this multicentre, randomised, open-label, phase 2 trial, we recruited chemotherapy-naive patients with unresectable or recurrent gastric cancer with measurable lesions aged 20 years or older from 25 general hospitals and specialist centres in Japan. Patients were randomly assigned (1:1:1) centrally to receive S-1 plus leucovorin (S-1 40-60 mg orally plus oral leucovorin 25 mg twice a day for 1 week, every 2 weeks), S-1 plus leucovorin and oxaliplatin (S-1 plus leucovorin and intravenous oxaliplatin 85 mg/m2 on day 1, every 2 weeks), or S-1 plus cisplatin (S-1 40-60 mg orally twice a day for 3 weeks, plus intravenous cisplatin 60 mg/m2 on day 8, every 5 weeks). Randomisation was done with the minimisation method using performance status (0 vs 1) and tumour stage (stage IV vs recurrent) as stratification factors. The primary endpoint was independently reviewed overall response in the full analysis set. This trial is registered with Japic CTI, number 111635. Findings: Between Oct 20, 2011, and Dec 17, 2012, we enrolled and randomly assigned 145 patients: 49 patients were assigned to S-1 plus leucovorin, 47 to S-1 plus leucovorin and oxaliplatin, and 49 to S-1 plus cisplatin. An objective response assessed by the independent review committee was achieved in 20 (43% [95% CI 28·3-57·8]) of the 47 patients in the S-1 plus leucovorin group, 31 (66% [50·7-79·1]) of the 47 patients in the S-1 plus leucovorin and oxaliplatin group, and 22 (46% [31·4-60·8]) of the 48 patients in the S-1 plus cisplatin group (Fisher's exact test, p=0·84 for S-1 plus leucovorin vs S-1 plus cisplatin, p=0·063 for S-1 plus leucovorin and oxaliplatin vs S-1 plus cisplatin, and p=0·038 for S-1 plus leucovorin and oxaliplatin vs S-1 plus leucovorin). The most common grade 3-4 adverse events were neutropenia (three [6%] of 48 patients in the S-1 plus leucovorin group vs 12 [26%] of 47 patients in the S-1 plus leucovorin and oxaliplatin group vs 17 [35%] of 49 patients in the S-1 plus cisplatin group), decreased appetite (six [13%] vs 14 [30%] vs 12 [24%]), anaemia (five [10%] vs seven [15%] vs 13 [27%]), and hyponatraemia (two [4%] vs two [4%] vs nine [18%]). Interpretation: S-1 plus leucovorin and oxaliplatin was more active than S-1 plus leucovorin or S-1 plus cisplatin with acceptable toxic effects for patients with advanced gastric cancer. A phase 3 trial comparing S-1 plus leucovorin and oxaliplatin with S-1 plus cisplatin is underway. Funding: Taiho Pharmaceutical. © 2016 Elsevier Ltd.


Yumimoto K.,Kyushu University | Akiyoshi S.,Kyushu University | Ueo H.,Kyushu University | Sagara Y.,Sagara Hospital | And 6 more authors.
Journal of Clinical Investigation | Year: 2015

The gene encoding F-box protein FBXW7 is frequently mutated in many human cancers. Although most previous studies have focused on the tumor-suppressive capacity of FBXW7 in tumor cells themselves, we determined that FBXW7 in the host microenvironment also suppresses cancer metastasis. Deletion of Fbxw7 in murine BM-derived stromal cells induced accumulation of NOTCH and consequent transcriptional activation of Ccl2. FBXW7-deficient mice exhibited increased serum levels of the chemokine CCL2, which resulted in the recruitment of both monocytic myeloid-derived suppressor cells and macrophages, thereby promoting metastatic tumor growth. Administration of a CCL2 receptor antagonist blocked the enhancement of metastasis in FBXW7-deficient mice. Furthermore, in human breast cancer patients, FBXW7 expression in peripheral blood was associated with serum CCL2 concentration and disease prognosis. Together, these results suggest that FBXW7 antagonizes cancer development in not only a cell-autonomous manner, but also a non-cell-autonomous manner, and that modulation of the FBXW7/NOTCH/CCL2 axis may provide a potential approach to suppression of cancer metastasis.


Seto T.,National Hospital Organization Kyushu Cancer Center | Kiura K.,Okayama University | Nishio M.,Cancer Institute Hospital | Nakagawa K.,Kinki University | And 12 more authors.
The Lancet Oncology | Year: 2013

Background: Currently, crizotinib is the only drug that has been approved for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). We aimed to study the activity and safety of CH5424802, a potent, selective, and orally available ALK inhibitor. Methods: In this multicentre, single-arm, open-label, phase 1-2 study of CH5424802, we recruited ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC from 13 hospitals in Japan. In the phase 1 portion of the study, patients received CH5424802 orally twice daily by dose escalation. The primary endpoints of the phase 1 were dose limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetic parameters. In the phase 2 portion of the study, patients received CH5424802 at the recommended dose identified in the phase 1 portion of the study orally twice a day. The primary endpoint of the phase 2 was the proportion of patients who had an objective response. Treatment was continued in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. The analysis was done by intent to treat. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-101264. Findings: Patients were enrolled between Sept 10, 2010, and April 18, 2012. The data cutoff date was July 31, 2012. In the phase 1 portion, 24 patients were treated at doses of 20-300 mg twice daily. No DLTs or adverse events of grade 4 were noted up to the highest dose; thus 300 mg twice daily was the recommended phase 2 dose. In the phase 2 portion of the study, 46 patients were treated with the recommended dose, of whom 43 achieved an objective response (93·5%, 95% CI 82·1-98·6) including two complete responses (4·3%, 0·5-14·8) and 41 partial responses (89·1%, 76·4-96·4). Treatment-related adverse events of grade 3 were recorded in 12 (26%) of 46 patients, including two patients each experiencing decreased neutrophil count and increased blood creatine phosphokinase. Serious adverse events occurred in five patients (11%). No grade 4 adverse events or deaths were reported. The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment. Interpretation: CH5424802 is well tolerated and highly active in patients with advanced ALK-rearranged NSCLC. © 2013 Elsevier Ltd.


PubMed | Red Cross, Kobe City Medical Center General Hospital, Aichi Cancer Center Hospital, Tohoku University and 8 more.
Type: Journal Article | Journal: Cancer science | Year: 2016

In this multicenter, single-arm, phase II study, the efficacy and safety of ibrutinib were examined in Japanese patients with relapsed or refractory mantle cell lymphoma (MCL). Patients (age 20 years) with relapsed or refractory MCL who had progressed after receiving at least one prior treatment regimen, were enrolled. Patients were treated with oral ibrutinib (560 mg once daily; 28-day cycle) until disease progression (or relapse), unacceptable toxicity, or study end. The primary end-point was overall response rate. Secondary end-points included duration of response (DOR), time to response, progression-free survival (PFS), overall survival, and safety. Of the 16 patients who received treatment, 5 patients discontinued the study (progressive disease, 4; sepsis, 1). Median duration of ibrutinib exposure was 6.5 months (range, 2.8-8.3 months). The overall response rate was 87.5% (90% confidence interval, 65.6-97.7; complete response = 2 [12.5%]; partial response = 12 [75.0%]). Median time to response for all responders (n = 14) was 1.8 months (range, 0.7-5.3 months). The median DOR and PFS were not estimable due to censoring (range: DOR, 1.1-6.4+ months; PFS, 2.8-8.0+ months). Overall survival data were immature due to the limited observation period. A total of 8/16 patients (50%) had at least one grade 3 adverse event (AE), and 5 (31.3%) patients reported serious AEs. The most commonly reported AEs were diarrhea and stomatitis (37.5% each), platelet count decrease (31.3%), and anemia (25%). Overall, orally administered single agent ibrutinib was efficacious with an acceptable safety profile in Japanese patients with relapsed or refractory MCL. Clinical trial registration NCT02169180 (ClinicalTrials.gov).


PubMed | Juntendo University, National Defence Medical College Hospital, Saitama Cancer Center, National Cancer Center Hospital East and 5 more.
Type: Journal Article | Journal: Surgical endoscopy | Year: 2016

This observational study was conducted to compare the rate of symptomatic anastomotic leakage (AL), as defined by precise criteria, between laparoscopic and open surgery in patients with mid-to-low rectal cancer using a relatively novel statistical technique.A total of 1014 consecutive low anterior resection (LAR) patients were registered, of whom 936 were included in this prospective, multicenter, and cohort study (UMIN-CTR, Number 000004017). Patients with rectal cancer within 10cm from the anal verge underwent either open or laparoscopic LAR at one of the 40 institutions in Japan from June 2010 to February 2013. The primary endpoint of this study was to compare the rate of symptomatic AL between the two groups before and after propensity score matching (PSM). The secondary endpoint was to analyze the risk factors for symptomatic AL in open and laparoscopic surgery.After PSM, the incidence of symptomatic AL in open and laparoscopic surgery was 12.4 and 15.3%, respectively (p=0.48). AL requiring relaparotomy occurred after 3.8% of open surgeries and 6.2% of laparoscopic surgeries (p=0.37). Multivariate analysis identified male gender as an independent risk factor for symptomatic AL following laparoscopic surgery (p=0.001; odds ratio 5.2; 95% CI 2.0-13.8), and male gender (p=0.004; odds ratio 2.6; 95% CI 1.3-5.6), tumor size (p=0.002; odds ratio 1.2; 95% CI 0.7-0.9), and number of stapler firing (p=0.04; odds ratio 4.1; 95% CI 1.0-15.0) following open surgery.The rate of symptomatic AL was comparable following laparoscopic and open LAR in this large, multicenter, cohort study after PSM. Male gender was associated with an increased risk of symptomatic AL after laparoscopic LAR.


Murata A.,Kumamoto University | Baba Y.,Kumamoto University | Ishimoto T.,Kumamoto University | Miyake K.,Kumamoto University | And 12 more authors.
Oncotarget | Year: 2015

Mammalian DNA is epigenetically marked by 5'-cytosine methylation (5-methylcytosine [5-mC]). The Ten-eleven translocation (TET) enzymes (TET1, TET2, and TET3) are implicated in DNA demethylation, through dioxygenase activity that converts 5-mC to 5-hydroxymethylcytosine (5-hmC). Although decreased TET is reportedly associated with decreased 5-hmC levels in various cancers, functions of 5-hmC and TET expression in esophageal squamous cell carcinoma (ESCC) are unclear. We used ELISA and immunohistochemistry tests to analyze 5-hmC status in ESCC tissues, RT-qPCR to analyze TET family mRNA expression in normal and tumor tissues, and pyrosequencing to quantify LINE-1 (i.e., global DNA methylation) levels. ELISA and immunohistochemical testing showed 5-hmC levels were significantly lower in ESCC than in paired normal tissues (P < 0.0001). TET2 expression was significantly lower in ESCCs than paired normal tissues (P < 0.0001), and significantly associated with 5-hmC levels in ESCCs (P = 0.003, r = 0.33). 5-hmC levels were also significantly associated with LINE-1 methylation level (P = 0.0002, r = 0.39). Patients with low 5-hmC levels had shorter overall survival than those with higher levels, although not significantly so (P = 0.084). In conclusion, 5-hmC expression was decreased in ESCC tissues, and was associated with TET2 expression level. TET2 reduction and subsequent 5-hmC loss might affect ESCC development.


Driskell I.,University of Cambridge | Oda H.,Howard Hughes Medical Institute | Oda H.,National Hospital Organization Kyushu Cancer Center | Blanco S.,University of Cambridge | And 3 more authors.
EMBO Journal | Year: 2012

Setd8/PR-Set7/KMT5a-dependent mono-methylation of histone H4 at lysine 20 is essential for mitosis of cultured cells; yet, the functional roles of Setd8 in complex mammalian tissues are unknown. We use skin as a model system to explore how Setd8 may regulate cell division in vivo. Deletion of Setd8 in undifferentiated layers of the mouse epidermis impaired both proliferation and differentiation processes. Long-lived epidermal progenitor cells are lost in the absence of Setd8, leading to an irreversible loss of sebaceous glands and interfollicular epidermis. We show that Setd8 is a transcriptional target of c-Myc and an essential mediator of Myc-induced epidermal differentiation. Deletion of Setd8 in c-Myc-overexpressing skin blocks proliferation and differentiation and causes apoptosis. Increased apoptosis may be explained by our discovery that p63, an essential transcription factor for epidermal commitment is lost, while p53 is gained upon removal of Setd8. Both overexpression of p63 and deletion of p53 rescue Setd8-induced apoptosis. Thus, Setd8 is a crucial inhibitor of apoptosis in skin and its activity is essential for epidermal stem cell survival, proliferation and differentiation. © 2012 European Molecular Biology Organization | All Rights Reserved.

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