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A Phase Ib Study of Durvalumab (MEDI4736) in Combination with Carbon-Ion Radiotherapy and Weekly Cisplatin for Patients with Locally Advanced Cervical Cancer (DECISION Study): The Early Safety and Efficacy Results.
Okonogi, N, Murata, K, Yamada, S, Habu, Y, Hori, M, Kurokawa, T, Inaba, Y, Fujiwara, T, Fujii, Y, Hanawa, M, et al
International journal of molecular sciences. 2023;(13)
Abstract
We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m2. Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study.
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Phase I/II study of adding intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis.
Yamada, S, Fujii, T, Yamamoto, T, Takami, H, Yoshioka, I, Yamaki, S, Sonohara, F, Shibuya, K, Motoi, F, Hirano, S, et al
The British journal of surgery. 2020;(13):1811-1817
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Abstract
BACKGROUND Intraperitoneal chemotherapy using paclitaxel is considered an experimental approach for treating peritoneal carcinomatosis. This study aimed to determine the recommended dose, and to evaluate the clinical efficacy and safety, of the combination of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis. METHODS The frequencies of dose-limiting toxicities were evaluated, and the recommended dose was determined in phase I. The primary endpoint of the phase II analysis was overall survival rate at 1 year. Secondary endpoints were antitumour effects, symptom-relieving effects, safety and overall survival. RESULTS The recommended doses of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel were 800, 75 and 20 mg/m2 respectively. Among 46 patients enrolled in phase II, the median time to treatment failure was 6·0 (range 0-22·6) months. The response and disease control rates were 21 of 43 and 41 of 43 respectively. Ascites disappeared in 12 of 30 patients, and cytology became negative in 18 of 46. The median survival time was 14·5 months, and the 1-year overall survival rate was 61 per cent. Conversion surgery was performed in eight of 46 patients, and those who underwent resection survived significantly longer than those who were not treated surgically (median survival not reached versus 12·4 months). Grade 3-4 haematological toxicities developed in 35 of 46 patients, whereas non-haematological adverse events occurred in seven patients. CONCLUSION Adding intraperitoneal paclitaxel had clinical efficacy with acceptable tolerability.
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JOIN trial: treatment outcome and recovery status of peripheral sensory neuropathy during a 3-year follow-up in patients receiving modified FOLFOX6 as adjuvant treatment for stage II/III colon cancer.
Yoshino, T, Kotaka, M, Shinozaki, K, Touyama, T, Manaka, D, Matsui, T, Ishigure, K, Hasegawa, J, Inoue, K, Munemoto, Y, et al
Cancer chemotherapy and pharmacology. 2019;(6):1269-1277
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Abstract
PURPOSE Adjuvant FOLFOX therapy is an established standard-of-care for resected colon cancer. Peripheral sensory neuropathy (PSN) is regarded as the major toxicity issue related to FOLFOX therapy. There have been a few reports on the recovery status from PSN thereafter. JOIN trial investigated the tolerability and efficacy of adjuvant modified FOLFOX6 (mFOLFOX6) in Japanese patients with stage II/III colon cancer. METHODS Twelve cycles of mFOLFOX6 were given to patients with stage II/III curatively resected colon cancer. Treatment outcomes, including disease-free survival (DFS), relapse-free survival (RFS), overall survival (OS), and recovery status of PSN during 3-year follow-up, were investigated. RESULTS Of the 882 patients enrolled from 2010 to 2012, 864 were eligible for the efficacy analyses. Three-year DFS, RFS, and OS were favorable in 92.1, 92.8, and 97.4% of stage II patients; 76.4, 77.9, and 93.8% of stage IIIA/B; and 61.6, 62.7, and 85.9% of stage IIIC, respectively. The cumulative incidence of PSN during treatment was 47.8% in grade 1 (G1), 30.3% in G2, and 5.8% in G3. For those with G3 PSN during treatment, there was gradual recovery in 1.1% of patients at 12 months after enrollment, 0.5% at 24 months, and 0.2% at 36 months. However, G1 or G2 residual PSN after 3 years was observed in 21.0% (18.7%, G1; 2.3%, G2). CONCLUSIONS Adjuvant mFOLFOX6 therapy was effective and well tolerated in patients with stage II/III colon cancer. Most patients recovered from G3 PSN related to oxaliplatin, but approximately 20% of patients had G1 or G2 PSN at 3-year follow-up.
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Utility of Mesalazine in Familial Adenomatous Polyposis: Clinical Report of Reduction of Polyp Size in Patients with Ulcerative Colitis, and Safety Examination in Familial Adenomatous Polyposis Patients.
Ishikawa, H, Mutoh, M, Abe, T, Nakajima, T, Takeuchi, Y, Ezoe, Y, Wakabayashi, K, Doyama, H, Sakai, T
Pharmacology. 2019;(1-2):51-56
Abstract
Mesalazine is the gold standard drug for treatment of ulcerative colitis (UC). Here, we describe 4 cases of familial adenomatous polyposis (FAP) patients with UC that showed reduction of intestinal polyp diameter by mesalazine treatment. Of note, the effects of mesalazine on the development of intestinal polyps in FAP patients have not been reported, and we further investigated whether the short-term use of high-dose mesalazine (4 g/day) has harmful effects on FAP patients or not. The authors found that the treatment showed slightly adverse events in FAP patients. However, mesalazine tended to reduce the number of colon polyps in male subjects with FAP. This report provides basic information for planning a double-blind, randomized, clinical trial that aims to show mesalazine's potential to suppress intestinal polyp development in FAP.
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Alcohol Consumption and Multiple Dysplastic Lesions Increase Risk of Squamous Cell Carcinoma in the Esophagus, Head, and Neck.
Katada, C, Yokoyama, T, Yano, T, Kaneko, K, Oda, I, Shimizu, Y, Doyama, H, Koike, T, Takizawa, K, Hirao, M, et al
Gastroenterology. 2016;(5):860-869.e7
Abstract
BACKGROUND & AIMS Some patients develop multiple squamous cell carcinomas (SCCs) in the upper aerodigestive tract, attributed to field cancerization; alcohol consumption has been associated with this process. We examined the association between multiple areas of dysplastic squamous epithelium with the development of SCC of the esophagus or head and neck cancer, as well as alcohol consumption and smoking. METHODS We examined 331 patients with early stage esophageal SCC using Lugol chromoendoscopy to evaluate the dysplastic squamous epithelium in the esophagus. Patients then were assigned to 3 groups, based on the number of Lugol-voiding lesions: A, no lesion; B, 1-9 lesions; or C, 10 or more lesions. Participants completed lifestyle surveys on their history of drinking, smoking, and diet. All participants were evaluated by laryngopharyngoscopy before registration; only those without head and neck cancer were included, except for patients with superficial SCC limited to the subepithelial layer. Lesions detected in the esophagus and head and neck by surveillance were considered to be metachronous. The study end point was the cumulative incidence of metachronous SCCs in the esophagus and head and neck after endoscopic resection of esophageal SCC, according to the grade of Lugol-voiding lesions. At study entry, all patients were instructed to abstain from alcohol and smoking. RESULTS Over the 2-year study period, metachronous SCCs of the esophagus were detected in 4% of patients in group A, in 9.4% of patients in group B, and in 24.7% of patients in group C (P < .0001 for patients in group A vs B or B vs C). Head and neck SCCs were detected in none of the patients in group A, in 1.7% of the patients in group B, and in 8.6% of the patients in group C (P = .016 for patients in group A vs C and P = .008 for patients in group B vs C). SCC of the esophagus or head and neck developed in 4.0% of patients in group A, in 10.0% of patients in group B, and in 31.4% of patients in group C (P < .0001 for group A vs B or A vs C). Alcohol abstinence decreased the risk of multiple SCCs of the esophagus (adjusted hazard ratio, 0.47, 95% confidence interval, 0.25-0.91; P = .025), whereas smoking abstinence did not. CONCLUSIONS Multiple dysplastic lesions in the esophagus increase the risk of multiple SCCs. Alcohol abstinence reduces the risk of metachronous SCCs. Clinical Trials registry: UMIN000001676 and UMIN000005466.
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Phase II trial of an alternating regimen consisting of first-line mFOLFOX6 plus bevacizumab and FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer: FIREFOX plus bevacizumab trial (KSCC0801).
Miwa, K, Oki, E, Emi, Y, Saeki, H, Kusumoto, T, Akagi, Y, Ogata, Y, Samura, H, Tokunaga, S, Ishikawa, H, et al
International journal of clinical oncology. 2016;(1):110-7
Abstract
OBJECTIVES The purpose of this phase II study was to explore the efficacy and safety of an alternating regimen consisting of folinic acid, 5-fluorouracil (5-FU) and oxaliplatin (mFOLFOX6) plus bevacizumab, and folinic acid, 5-FU and irinotecan (FOLFIRI) plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer. METHODS Fifty-two patients with metastatic colorectal cancer received an alternating regimen consisting of four cycles of mFOLFOX6 plus bevacizumab followed by four cycles of FOLFIRI plus bevacizumab until disease progression. The primary endpoint was progression-free survival. RESULTS The median age was 60 years (range 37-75 years). Median progression-free survival was 14.2 months (95 % confidence interval [CI] 10.6-16.3) and median overall survival was 28.4 months (95 % CI 22.6-39.1). The overall response rate was 60.0 % (95 % CI 45.2-73.6). Regarding toxicity, the commonest grade 3-4 hematological adverse events were neutropenia (34.6 %) and leukopenia (7.7 %), and the commonest grade 3-4 non-hematological adverse events were anorexia (13.5 %), fatigue (9.6 %), nausea (9.6 %), and vomiting (9.6 %). Bevacizumab-related grade 3-4 adverse events included hypertension (1.9 %) and thrombosis (1.9 %). CONCLUSIONS An alternating regimen consisting of mFOLFOX6 plus bevacizumab and FOLFIRI plus bevacizumab is an effective and well-tolerated first-line chemotherapy combination for patients with metastatic colorectal cancer.
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Characterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct-acting antivirals daclatasvir and asunaprevir.
Karino, Y, Toyota, J, Ikeda, K, Suzuki, F, Chayama, K, Kawakami, Y, Ishikawa, H, Watanabe, H, Hernandez, D, Yu, F, et al
Journal of hepatology. 2013;(4):646-54
Abstract
BACKGROUND & AIMS Daclatasvir and asunaprevir are NS5A and NS3 protease-targeted antivirals currently under development for treatment of chronic hepatitis C virus infection. Clinical data on baseline and on-treatment correlates of drug resistance and response to these agents are currently limited. METHODS Hepatitis C virus genotype 1b Japanese patients (prior null responders to PegIFN-α/RBV [n=21] or PegIFN-α/RBV ineligible or intolerant [n=22]) were administered daclatasvir/asunaprevir for 24 weeks during a phase 2a open-label study. Genotypic and phenotypic analyses of NS3 and NS5A substitutions were performed at baseline, after virologic failure, and post-treatment through follow-up week 36. RESULTS There were three viral breakthroughs and four relapsers. Baseline NS3 polymorphisms (T54S, Q80L, V170M) at amino acid positions previously associated with low-level resistance (<9-fold) to select NS3 protease inhibitors were detected in four null responders and three ineligibles, but were not associated with virologic failure. Baseline NS5A polymorphisms (L28M, L31M, Y93H) associated with daclatasvir resistance (<25-fold) were detected in five null responders and six ineligibles. All three viral breakthroughs and 2/4 relapsers carried a baseline NS5A-Y93H polymorphism. NS3 and NS5A resistance-associated variants were detected together (NS3-D168A/V, NS5A-L31M/V-Y93H) after virologic failure. Generally, daclatasvir-resistant substitutions persisted through 48weeks post-treatment, whereas asunaprevir-resistant substitutions were no longer detectable. Overall, 5/10 patients with baseline NS5A-Y93H experienced virologic failure, while 5/10 achieved a sustained virologic response. CONCLUSIONS The potential association of a pre-existing NS5A-Y93H polymorphism with virologic failure on daclatasvir/asunaprevir combination treatment will be examined in larger studies. The persistence of treatment-emergent daclatasvir- and asunaprevir-resistant substitutions will require assessment in longer-term follow-up studies.
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Risk factors for rectal bleeding associated with I-125 brachytherapy for prostate cancer.
Harada, K, Ishikawa, H, Saito, Y, Nakamoto, S, Kawamura, H, Wakatsuki, M, Etsunaga, T, Takezawa, Y, Kobayashi, M, Nakano, T
Journal of radiation research. 2012;(6):923-9
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The purpose of this study was to determine the risk factors for rectal bleeding after prostate brachytherapy. Between April 2005 and September 2009, 89 patients with T1c-2cN0M0 prostate cancer were treated with permanent I-125 seed implantation alone. The prostate prescription dose was 145 Gy, and the grade of rectal bleeding was scored according to the Common Terminology Criteria for Adverse Events version 4.0. Post-treatment planning was performed with fusion images of computerized tomography and magnetic resonance imaging 4-5 weeks after brachytherapy. Patient characteristics and dosimetric parameters were evaluated to determine risk factors for bleeding. The calculated parameters included the rectal volume in cubic centimeters that received >50-200% of the prescribed dose (RV50-200) and the minimal doses received by 1-30% of the rectal volume (RD1-30). The median follow-up time was 42 months (ranging 18-73 months). Grade 1 rectal bleeding occurred in 24 (27.0%) patients, but no Grade 2 or severe bleeding was observed. Usage of anticoagulants had a significant correlation with the occurrence of bleeding (P = 0.007). The RV100-150 and RD1-10 were significantly higher in patients with rectal bleeding than in those without bleeding. The RV100 was identified as a possible threshold value; the 3-year rectal bleeding rate in patients with an RV100 > 1.0 cm(3) was 36%, whereas that with an RV100 ≤ 1.0 cm(3) was 14% (P < 0.05). Although no Grade 2 morbidity developed in this study, the RV100 should be kept below 1.0 cm(3), especially in additional dose-escalated brachytherapy.
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Myo-inositol treatment increases serum plasmalogens and decreases small dense LDL, particularly in hyperlipidemic subjects with metabolic syndrome.
Maeba, R, Hara, H, Ishikawa, H, Hayashi, S, Yoshimura, N, Kusano, J, Takeoka, Y, Yasuda, D, Okazaki, T, Kinoshita, M, et al
Journal of nutritional science and vitaminology. 2008;(3):196-202
Abstract
BACKGROUND AND AIM We have previously shown that serum plasmalogen levels positively correlate with HDL, and significantly decrease with aging, and may be related to LDL particle size. The objective of the present study was to investigate the effects of increased serum plasmalogens on lipidosis, particularly the appearance of atherogenic small dense LDL (sdLDL), of subjects with hyperlipidemia and metabolic syndrome (MetS). METHODS AND RESULTS The effects of increased serum plasmalogen levels, induced by 2 wk of myo-inositol treatment, on several clinical and biochemical parameters were examined in 17 hyperlipidemic subjects including some with MetS. After myo-inositol treatment, significant increases in plasmalogen-related parameters, particularly ChoPlas, and significant decreases in atherogenic cholesterols including sdLDL, were observed. Among the hyperlipidemic subjects treated with myo-inositol, compared to subjects without MetS, subjects with MetS had a significant increase in plasmalogens and a tendency towards reduced sdLDL, high sensitivity C-reactive protein (hsCRP), and blood glucose levels. Correlation analyses between the measured parameters showed that plasmalogens, as well as HDL, function as beneficial factors, and that sdLDL is a very important risk factor that shows positive correlations with many other risk factors. CONCLUSION These results suggest that increased plasmalogen biosynthesis and/or serum levels are especially effective in improving MetS among hyperlipidemic subjects with MetS.
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Randomized trial of dietary fiber and Lactobacillus casei administration for prevention of colorectal tumors.
Ishikawa, H, Akedo, I, Otani, T, Suzuki, T, Nakamura, T, Takeyama, I, Ishiguro, S, Miyaoka, E, Sobue, T, Kakizoe, T
International journal of cancer. 2005;(5):762-7
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The epidemiologic evidence that dietary fiber protects against colorectal cancer is equivocal. No large-scale clinical study of the administration of Lactobacillus casei has been reported. We examined whether dietary fiber and L. casei prevented the occurrence of colorectal tumors. Subjects were 398 men and women presently free from tumor who had had at least 2 colorectal tumors removed. Subjects were randomly assigned to 4 groups administered wheat bran, L. casei, both or neither. The primary end point was the presence or absence of new colorectal tumor(s) diagnosed by colonoscopy after 2 and 4 years. Among 380 subjects who completed the study, 95, 96, 96 and 93 were assigned to the wheat bran, L. casei, both and no treatment groups, respectively. Multivariate adjusted ORs for occurrence of tumors were 1.31 (95% CI 0.87-1.98) in the wheat bran group and 0.76 (0.50-1.15) in the L. casei group compared to the control group. There was a significantly higher number of large tumors after 4 years in the wheat bran group. The occurrence rate of tumors with a grade of moderate atypia or higher was significantly lower in the group administered L. casei. No significant difference in the development of new colorectal tumors was observed with administration of either wheat bran or L. casei. However, our results suggest that L. casei prevented atypia of colorectal tumors.