Saiura A.,Cancer Institute Hospital |
Yamamoto J.,National Defense Medical College |
Hasegawa K.,University of Tokyo |
Oba M.,University of Tokyo |
And 9 more authors.
Drug Discoveries and Therapeutics | Year: 2014
The use of adjuvant systemic chemotherapy for resectable liver metastases from colorectal cancer (CRC) is controversial because no trial demonstrated its benefit. We conducted the phase III trial to evaluate UFT/leucovorin (LV) for colorectal liver metastases (CRLM). The primary endpoint has not been available until 2014, we first report the feasibility and safety data of UFT/LV arm. In this multicenter trial, patients who underwent curative resection of liver metastases from colorectal cancer were randomly assigned to receive surgery alone or surgery followed by adjuvant chemotherapy with UFT/LV. The primary endpoint was relapse-free survival. Secondary endpoints included overall survival and safety. A total of 180 patients were enrolled, 90 were randomly assigned to receive UFT/LV therapy. Eighty two of whom were included in safety analyses. In the UFT/LV group, the completion rate of UFT/LV was 54.9%, the relative dose intensity was 70.8% and grade 3 or higher adverse events occurred in 12.2% of the patients. Elevated bilirubin levels, decreased hemoglobin levels, elevated alanine aminotransferase levels, diarrhea, anorexia were common. Most other adverse events were grade 2 or lower and tolerable. In conclusions, UFT/LV is a safe regimen for postoperative adjuvant chemotherapy in patients who have undergone resection of liver metastases from colorectal cancer. Further studies are warranted to improve completion rate, but UFT/LV is found to be a promising treatment in this setting.
Murata S.,University of Tsukuba |
Mukai H.Y.,Janssen Pharmaceutical |
Kojima H.,Ibaraki Prefectural Central Hospital and Cancer Center
Journal of Thrombosis and Haemostasis | Year: 2010
Background: The pro-apoptotic BH3-only protein Bim is recognized as a pivotal regulator of apoptosis induced by the depletion of cytokines. In the present study, we examined the role of Bim in megakaryopoiesis. Methods: Megakaryocyte (MK) progenitors obtained from bim knockout (KO) mice were analyzed in vitro for liability to apoptosis after the depletion of cytokines, ability to differentiate into MKs and proliferation/cell cycle progression in response to thrombopoietin (TPO). The production of platelets in vitro was evaluated by assaying the formation of proplatelets in MKs. Megakaryopoiesis in vivo was observed in a mouse model of thrombocytopenia induced by injecting fluorouracil (5-FU). Results: Bim-deficient CD34-/c-kit+/Sca-1+/Lineage- stem cells and MKs were highly resistant to apoptosis induced by cytokine depletion, suggesting that Bim is involved in the apoptotic process in both stem cells and MKs. As bim KO mice exhibited splenomegaly and thrombocytopenia, splenectomized mice were used for experiments in vivo. Platelet recovery after 5-FU-induced thrombocytopenia was significantly delayed in bim KO mice. Corresponding with this, numbers of MKs in the recovery phase bone marrow were significantly reduced in bim KO mice. Culture of c-kit+/Lineage- progenitors with TPO revealed that Bim-deficient cells poorly proliferate and differentiate into CD41+ cells in comparison with wild-type (WT) cells. However, once differentiated into MKs, these cells matured normally. Furthermore, cell cycle analyses demonstrated that transition from the G1 to the S phase was delayed in Bim-deficient stem cells. Conclusions: In the present study, we demonstrated that Bim plays a pivotal role in the regulation of cell cycle progression in hepatopoietic progenitors during megakaryopiesis. © 2010 International Society on Thrombosis and Haemostasis.
Higuchi K.,Kitasato University |
Tanabe S.,Kitasato University |
Shimada K.,Showa University |
Hosaka H.,Gunma Prefectural Cancer Center |
And 13 more authors.
European Journal of Cancer | Year: 2014
Purpose We compared biweekly irinotecan plus cisplatin (BIRIP) with irinotecan alone as the second-line chemotherapy (SLC) for advanced gastric cancer (AGC). Methods Patients with metastatic or recurrent gastric cancer refractory to S-1-based first-line chemotherapy were randomly assigned to receive BIRIP (irinotecan 60 mg/m2 plus cisplatin 30 mg/m 2, every 2 weeks) or irinotecan alone (irinotecan 150 mg/m 2, every 2 weeks). The primary end-point was to show the superiority of BIRIP to irinotecan in terms of progression free survival (PFS). Results 130 patients were enrolled. PFS was significantly longer in the BIRIP group (3.8 months [95% confidence interval (CI) 3.0-4.7]) than in the irinotecan group (2.8 months [2.1-3.3]; hazard ratio 0.68, 95% CI 0.47-0.98; P = 0.0398). Median overall survival was 10.7 months in the BIRIP group and 10.1 months in the irinotecan group (HR 1.00, 95% CI 0.69-1.44, P = 0.9823). The objective response rate was 22% in the BIRIP group and 16% in the irinotecan group (P = 0.4975). However, the disease control rate was significantly better in the BIRIP group (75%) than in the irinotecan group (54%, P = 0.0162). The incidences of grade 3 or worse adverse events did not differ between the two groups. Any grade elevation of serum creatinine was more common in the BIRIP group (25% versus 8%, P = 0.009), but any grade diarrhoea (17% versus 42%, P = 0.002) was more common in the irinotecan group. Conclusion BIRIP significantly prolonged PFS as compared with irinotecan alone and was tolerated as SLC, but did not demonstrate the survival benefit in this trial. © 2014 Elsevier Ltd. All rights reserved.
PubMed | Ibaraki Prefectural Central Hospital and Cancer Center, Gunma Prefectural Cancer Center, Showa General Hospital, Showa University and 6 more.
Type: Clinical Trial, Phase III | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2014
We compared biweekly irinotecan plus cisplatin (BIRIP) with irinotecan alone as the second-line chemotherapy (SLC) for advanced gastric cancer (AGC).Patients with metastatic or recurrent gastric cancer refractory to S-1-based first-line chemotherapy were randomly assigned to receive BIRIP (irinotecan 60mg/m(2) plus cisplatin 30mg/m(2), every 2weeks) or irinotecan alone (irinotecan 150mg/m(2), every 2weeks). The primary end-point was to show the superiority of BIRIP to irinotecan in terms of progression free survival (PFS).130 patients were enrolled. PFS was significantly longer in the BIRIP group (3.8months [95% confidence interval (CI) 3.0-4.7]) than in the irinotecan group (2.8months [2.1-3.3]; hazard ratio 0.68, 95% CI 0.47-0.98; P=0.0398). Median overall survival was 10.7months in the BIRIP group and 10.1months in the irinotecan group (HR 1.00, 95% CI 0.69-1.44, P=0.9823). The objective response rate was 22% in the BIRIP group and 16% in the irinotecan group (P=0.4975). However, the disease control rate was significantly better in the BIRIP group (75%) than in the irinotecan group (54%, P=0.0162). The incidences of grade 3 or worse adverse events did not differ between the two groups. Any grade elevation of serum creatinine was more common in the BIRIP group (25% versus 8%, P=0.009), but any grade diarrhoea (17% versus 42%, P=0.002) was more common in the irinotecan group.BIRIP significantly prolonged PFS as compared with irinotecan alone and was tolerated as SLC, but did not demonstrate the survival benefit in this trial.
PubMed | National Hospital Organization Osaka National Hospital, Aichi Cancer Center Hospital, Prefectural Aichi Hospital, Japan National Cardiovascular Center Research Institute and 7 more.
Type: Journal Article | Journal: Cancer science | Year: 2016
The prognostic and predictive value of KRAS gene mutations in stage III colorectal cancer is controversial because many recent clinical trials have not involved a surgery-alone arm. Additionally, data on the significance of extended RAS (KRAS/NRAS) mutations in stage III cancer are not available. Hence, we undertook a combined analysis of two phase III randomized trials, in which the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) was evaluated, as compared with surgery alone. We determined the association of extended RAS and mismatch repair (MMR) status with the effectiveness of adjuvant chemotherapy. Mutations in KRAS exons 2, 3, and 4 and NRAS exons 2 and 3 were detected by direct DNA sequencing. Tumor MMR status was determined by immunohistochemistry. Total RAS mutations were detected in 134/304 (44%) patients. In patients with RAS mutations, a significant benefit was associated with adjuvant UFT in relapse-free survival (RFS) (hazard ratio = 0.49; P = 0.02) and overall survival (hazard ratio = 0.51; P = 0.03). In contrast, among patients without RAS mutations, there was no difference in RFS or overall survival between the adjuvant UFT group and surgery-alone group. We detected deficient DNA MMR in 23/304 (8%) patients. The MMR status was neither prognostic nor predictive for adjuvant chemotherapy. An interaction analysis showed that there was better RFS among patients treated with UFT with RAS mutations, but not for those without RAS mutations. Extended RAS (KRAS/NRAS) mutations are proposed as predictive indicators with respect to the efficacy of adjuvant UFT chemotherapy in patients with resected stage III colorectal cancer.
Bevacizumab in combination with irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) in patients with metastatic colorectal cancer who were previously treated with oxaliplatin-containing regimens: A multicenter observational cohort study (TCTG 2nd-BV study)
Moriwaki T.,University of Tsukuba |
Bando H.,National Cancer Center Hospital East |
Takashima A.,National Cancer Center Hospital |
Yamazaki K.,Shizuoka Cancer Center |
And 12 more authors.
Medical Oncology | Year: 2012
The efficacy of bevacizumab combined with infusional 5-fluorouracil/ leucovorin (5-FU/LV) plus irinotecan (FOLFIRI) as the second-line treatment for metastatic colorectal cancer (mCRC) has not been fully clarified, although bevacizumab combined with infusional 5-FU/LV plus oxaliplatin (FOLFOX) in the second-line setting has demonstrated a survival benefit. We investigated the efficacy of bevacizumab plus FOLFIRI in mCRC patients who failed oxaliplatin-containing regimens without bevacizumab. Patients who received bevacizumab plus FOLFIRI or bevacizumab plus FOLFOX as second-line chemotherapy between July 2007 and March 2008 were registered (trial registration: UMIN000001547). Patient background data and progression-free survival (PFS), overall survival (OS), response, and bevacizumab-related adverse events were prospectively collected every 6 months. A total of 195 patients were enrolled from 26 institutions. Among them, 115 patients received bevacizumab plus FOLFIRI after failure of oxaliplatin and fluoropyrimidine (FOLFIRI+BV after OX/FU group), and 45 patients received bevacizumab plus FOLFOX after failure of irinotecan and fluoropyrimidine (FOLFOX+BV after IRI/FU group). Median PFS was 8.3 months (95% confidence interval [CI], 6.7-9.9) for the FOLFIRI+BV after OX/FU group and 7.8 months (95% CI, 5.8-9.7) for the FOLFOX+BV after IRI/FU group. Median OS was 21.6 months (95% CI, 17.6-25.6) and 16.5 months (95% CI, 11.8-21.2), respectively. Overall response rates were 25 and 29%, respectively. The most common grade ≥3 bevacizumab-related adverse events were hypertension (5.0%) and bleeding (3.8%). FOLFIRI+BV after OX/FU showed comparable efficacy to FOLFOX+BV after IRI/FU. © 2011 Springer Science+Business Media, LLC.
PubMed | University of Tsukuba, National Hospital Organization and Ibaraki Prefectural Central Hospital and Cancer Center
Type: Clinical Trial, Phase I | Journal: Journal of hepato-biliary-pancreatic sciences | Year: 2015
To develop a triplet regimen containing gemcitabine, cisplatin, and S-1 (GPS), we assessed the recommended dose for patients with untreated advanced biliary tract cancer in this phase I study.Dose-limiting toxicities (DLTs) were evaluated for the following two dose levels: gemcitabine (1000mg/m(2) for level 1 and 1200mg/m(2) for level 2 on day 1), cisplatin (30mg/m(2) fixed dose on day 1), and S-1 (40-60mg/day fixed dose twice a day for 7days), every 2weeks until progression. DLTs for each level were evaluated in six or more patients during the first twocycles.A total of 18 patients were enrolled and 16 patients were evaluated. DLTs at level 1 were observed in two of 10 patients. At level 2, a DLT was observed in one of six patients. The main grade 3 or 4 treatment-related adverse events were neutropenia and leukopenia, and a few non-hematological toxicities were observed. Among 14 patients with measurable lesions, the best response rate was 50%.GPS with a relative dose intensity corresponding to 90% of the standard gemcitabine plus cisplatin regimen could be administered safely, and showed preliminary antitumor activity. Survival benefits will be studied subsequently.
Nakayama M.,Ibaraki Prefectural Central Hospital and Cancer Center |
Takahashi K.,Ibaraki Prefectural Central Hospital and Cancer Center |
Hori M.,Ibaraki Prefectural Central Hospital and Cancer Center |
Okumura T.,Ibaraki Prefectural Central Hospital and Cancer Center |
And 4 more authors.
Auris Nasus Larynx | Year: 2010
Langerhans cell sarcoma (LCS), a neoplastic proliferation of Langerhans cells with malignant cytologic features, is a very rare disease. We report the case of a 62-year-old male with LCS arising in a cervical lymph node. Histologic examination of a biopsy specimen of the lymph node demonstrated a proliferation of Langerhans cells with malignant cytologic features. Immunohistochemically, the tumor cells were positive for S-100 protein, CD1a, and Langerin (CD207). These histomorphological findings supported the diagnosis of LCS. The patient underwent radiotherapy. Neither local recurrence nor distant metastasis was observed at 45 months after radiotherapy. Characteristic immunohistochemical findings were helpful to identify LCS, and head and neck surgeons should be aware of this rare disease entity. © 2010 Elsevier Ireland Ltd.
Ashizawa K.,Ibaraki Prefectural Central Hospital and Cancer Center
Otolaryngology - Head and Neck Surgery (Tokyo) | Year: 2010
A 59-year-old man presenting with dysphagia showed trismus and stiffness of the cervical muscles after 6 days, and was then diagnosed as tetanus. Another 69-year-old man presented with trismus after a hand injury. A clinical diagnosis of tetanus was made. In both cases, respiratory care involving endotracheal intubation and anti-tetanus immunoglobulin injection and administration of penicillin G were performed, resulting in cure without any sequelae.
Tani K.,Ibaraki Prefectural Central Hospital and Cancer Center
Otolaryngology - Head and Neck Surgery (Tokyo) | Year: 2010
We reported two cases of a foreign body in the hypopharynx and esophagus, removed by an external neck incision. The first case was a 50-year-old female who complained of a sore throat after eating a fish. CT scan revealed a fish bone in her hypopharynx. The foreign body was removed by lateral neck incision. The second case was a 70-year-old male, who presented with anterior neck swelling after swallowing of a fish. CT scan revealed a fish bone in his esophagus, and an abscess formation was detected. The foreign body was removed following transcervical drainage of the abscess.