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Effects of Goshajinkigan (TJ-107) for oxaliplatin-induced peripheral neurotoxicity using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire in a Phase II, multicenter, randomized, double-blind, placebo-controlled trial.
Aoyama, T, Morita, S, Kono, T, Hata, T, Mishima, H, Sakamoto, J
Journal of cancer research and therapeutics. 2021;(6):1473-1478
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BACKGROUND The aim of the present study was to evaluate the efficacy of TJ-107 for oxaliplatin-induced peripheral neurotoxicity in prospective, multi-institutional, randomized, double-blind, placebo-controlled Phase II trials using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire (FACT-GOG-NTX-12). PATIENTS AND METHODS The patients who were registered to the Goshajinkigan oxaliplatin neurotoxicity evaluation study (UMIN000002211) were analyzed. A NTX-12 from the validated FACT/GOG-NTX-12 was assessed before treatment and at the end of every 2 cycles. RESULTS The comparisons of the median scores for TJ-107 and the placebo at 8 and 26 weeks were as follows: numbness or tingling in the hands (P = 0.5820), numbness or tingling in the feet (P = 0.3236), feeling of discomfort in the hands (P = 0.8219), feeling of discomfort in the feet (P = 0.5361), joint pain or muscle cramps (P = 0.1974), feeling weak all over (P = 0.2771), trouble hearing (P = 0.2832), ringing or buzzing in ears (P = 0.1031), trouble buttoning buttons (P = 0.1653), trouble feeling the shape of small objects when held in hand (P = 0.2919), trouble walking (P = 0.5406), and pain in the hands or feet when exposed to cold temperatures (P = 0.1872). CONCLUSION There might be no clinically significant difference between the use of TJ-107 and the severity and quality of life for patients treated with oxaliplatin.
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A placebo-controlled, double-blind, randomized study of recombinant thrombomodulin (ART-123) to prevent oxaliplatin-induced peripheral neuropathy.
Kotaka, M, Saito, Y, Kato, T, Satake, H, Makiyama, A, Tsuji, Y, Shinozaki, K, Fujiwara, T, Mizushima, T, Harihara, Y, et al
Cancer chemotherapy and pharmacology. 2020;(5):607-618
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PURPOSE The purpose of this clinical study was to be the first to explore whether ART-123, a recombinant human soluble thrombomodulin, prevents oxaliplatin-induced peripheral neuropathy (OIPN). METHODS This randomized, phase IIa trial enrolled stage II/III colon cancer patients who received adjuvant mFOLFOX6 chemotherapy. Participants were randomly allocated to 3 arms in a double-blind manner: placebo (placebo: days 1-3); 1-day ART (ART-123: day 1, placebo: days 2-3); and 3-day ART (ART-123: days 1-3). ART-123 (380 U/kg/day) or placebo was infused intravenously before each 2-week cycle of mFOLFOX6. OIPN was assessed with the Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity-12 (FACT/GOG-Ntx-12) score by participants and the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) by investigators. RESULTS Seventy-nine participants (placebo n = 28, 1-day ART n = 27, 3-day ART n = 24) received study drugs. The least-squares mean FACT/GOG-Ntx-12 scores at cycle 12 from the mixed effect model for repeated measures were 28.9 with placebo, 36.3 with 1-day ART (vs. placebo: 7.3 [95% CI 1.9 to12.8, p = 0.009]), and 32.3 with 3-day ART (vs. placebo: 3.4 [95% CI -.1 to 9.0, p = 0.222]). The cumulative incidence of NCI-CTCAE grade ≥ 2 sensory neuropathy at cycle 12 was 64.3% with placebo, 40.7% with 1-day ART (vs. placebo: -23.5 [95% CI -48.4 to 4.0], p = 0.108), and 45.8% with 3-day ART (vs. placebo: -18.5 [95% CI -44.2 to 9.4], p = 0.264). Common adverse events were consistent with those reported with mFOLFOX6; no severe bleeding adverse events occurred. CONCLUSION ART-123 showed a potential preventive effect against OIPN with good tolerability. A larger study with 1-day ART is warranted. NCT02792842, registration date: June 8, 2016.
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Intravoxel Incoherent Motion of Colon Cancer Liver Metastases for the Assessment of Response to Antiangiogenic Treatment: Results from a Pilot Study.
Öz, A, Server, S, Koyuncu Sökmen, B, Namal, E, İnan, N, Balcı, NC
Medical principles and practice : international journal of the Kuwait University, Health Science Centre. 2020;(5):429-435
Abstract
OBJECTIVE This study was aimed at evaluating the intravoxel incoherent motion (IVIM) parameter alterations of liver metastases of colorectal carcinoma (CRC) during antiangiogenic bevacizumab combination therapy. METHODS Twenty-five patients with CRC liver metastases treated with bevacizumab in combination with FOLFOX-or-FOLFIRI protocols were enrolled in the study. MRI was performed using a 1.5-tesla scanner pre-treatment (PT) and at 3, 6, and 9 months of therapy. Routine abdominal MRI sequences and an IVIM-DWI (diffusion-weighted imaging) sequence were obtained. The IVIM-DWI sequence was executed with 16 b-values varying from 0 to 1,400 s/mm2. The mean values of apparent diffusion coefficient (ADC), true diffusion (D), pseudodiffusion (D*), and perfusion fraction (f) of each metastasis were obtained for all b-values, and the time-related changes were recorded to analyze the chronologic responses to antiangiogenic therapy. The RECIST 1.1 criteria were used for the evaluation of treatment response. RESULTS The diameters of the metastases diminished significantly at 9 months when compared with PT (p = 0.03). The D (p = 0.10) and ADC (p = 0.21) values of the metastases increased at 9 months of therapy. D* was the highest at 3 months (p =0.24); it decreased at 6 (p =0.97) and 9 months (p =0.87) of therapy. The f value had peaked at 3 months (p =0.51) and started to decrease thereafter. At 6 months, f decreased to the lowest values (p =0.12). CONCLUSION IVIM parameters, particularly the perfusion fraction, may quantitatively reflect the response to antiangiogenic treatment. The antiangiogenic response manifests after 3 months of therapy before the RECIST-related response.
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A Phase 2 Randomized Trial of DCL-101, a Novel Pill-Based Colonoscopy Prep, vs 4L Polyethylene Glycol-Electrolyte Solution.
Bachwich, DR, Lewis, JD, Kowal, VO, Jacobson, BC, Calderwood, AH, Kochman, ML
Clinical and translational gastroenterology. 2020;(12):e00264
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INTRODUCTION DCL-101, a novel Pill Prep, is compositionally identical to standard 4L polyethylene glycol-electrolyte solution (PEG-ELS) and delivers the salt encapsulated, with PEG 3350 coadministered as a taste-free oral solution. The aim of this study was to compare the safety, taste, and tolerability of DCL-101 with 4L PEG-ELS in outpatients preparing for colonoscopy, with a secondary objective to assess efficacy. METHODS This was a multicenter, randomized, investigator-blinded, phase 2 clinical trial of 45 adult patients undergoing outpatient colonoscopy. Patients were randomized 2:1 to either DCL-101 (3L in cohort 1; 4L in cohort 2) or 4L PEG-ELS, each administered with split dosing. Safety was assessed over 3 post-treatment clinic visits. Tolerability was measured using the Lawrance Bowel-Preparation Tolerability Questionnaire and the Mayo Clinic Bowel Prep Tolerability Questionnaire. Efficacy was determined by expert central readers, blinded to treatment, using the Ottawa Bowel Preparation Quality Scale, Boston Bowel Preparation Scale, and Aronchick scale. RESULTS Both DCL-101 doses had superior taste and tolerability relative to 4L PEG-ELS. All adverse events were grade 1 with no significant differences in adverse events among the 3 regimens. There were no significant differences in efficacy among the 3 treatments as defined by the centrally read Ottawa Bowel Preparation Quality Scale, Boston Bowel Preparation Scale, or Aronchick scores. There were no inadequate preps as judged by the site endoscopist. DISCUSSION DCL-101 Pill Prep is a novel strategy that vastly improves the taste and tolerability of PEG-ELS solutions with safety and efficacy comparable with split-dose 4L PEG-ELS solutions.
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Effects of Simulated Human Gastrointestinal Digestion of Two Purple-Fleshed Potato Cultivars on Anthocyanin Composition and Cytotoxicity in Colonic Cancer and Non-Tumorigenic Cells.
Kubow, S, Iskandar, MM, Melgar-Bermudez, E, Sleno, L, Sabally, K, Azadi, B, How, E, Prakash, S, Burgos, G, Felde, TZ
Nutrients. 2017;(9)
Abstract
A dynamic human gastrointestinal (GI) model was used to digest cooked tubers from purple-fleshed Amachi and Leona potato cultivars to study anthocyanin biotransformation in the stomach, small intestine and colonic vessels. Colonic Caco-2 cancer cells and non-tumorigenic colonic CCD-112CoN cells were tested for cytotoxicity and cell viability after 24 h exposure to colonic fecal water (FW) digests (0%, 10%, 25%, 75% and 100% FW in culture media). After 24 h digestion, liquid chromatography-mass spectrometry identified 36 and 15 anthocyanin species throughout the GI vessels for Amachi and Leona, respectively. The total anthocyanin concentration was over thirty-fold higher in Amachi compared to Leona digests but seven-fold higher anthocyanin concentrations were noted for Leona versus Amachi in descending colon digests. Leona FW showed greater potency to induce cytotoxicity and decrease viability of Caco-2 cells than observed with FW from Amachi. Amachi FW at 100% caused cytotoxicity in non-tumorigenic cells while FW from Leona showed no effect. The present findings indicate major variations in the pattern of anthocyanin breakdown and release during digestion of purple-fleshed cultivars. The differing microbial anthocyanin metabolite profiles in colonic vessels between cultivars could play a significant role in the impact of FW toxicity on tumor and non-tumorigenic cells.
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Phase III randomized, placebo-controlled, double-blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB/Alliance).
Loprinzi, CL, Qin, R, Dakhil, SR, Fehrenbacher, L, Flynn, KA, Atherton, P, Seisler, D, Qamar, R, Lewis, GC, Grothey, A
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;(10):997-1005
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PURPOSE Cumulative neurotoxicity is a prominent toxicity of oxaliplatin-based therapy. Intravenous calcium and magnesium have been extensively used to reduce oxaliplatin-induced neurotoxicity. This trial was designed to definitively test whether calcium/magnesium decreases oxaliplatin-related neurotoxicity. PATIENTS AND METHODS In all, 353 patients with colon cancer undergoing adjuvant therapy with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) were randomly assigned to intravenous calcium/magnesium before and after oxaliplatin, a placebo before and after, or calcium/magnesium before and placebo after. The primary end point was cumulative neurotoxicity measured by the sensory scale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 tool. RESULTS There were no statistically significant neuropathy differences among the study arms as measured by the primary end point or additional measures of neuropathy, including clinician-determined measurement of the time to grade 2 neuropathy by using the National Cancer Institute Common Terminology Criteria for Adverse Events scale or an oxaliplatin-specific neuropathy scale. In addition, calcium/magnesium did not substantially decrease oxaliplatin-induced acute neuropathy. CONCLUSION This study does not support using calcium/magnesium to protect against oxaliplatin-induced neurotoxicity.
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A phase I trial of thermal sensitization using induced oxidative stress in the context of HIPEC.
Harrison, LE, Tiesi, G, Razavi, R, Wang, CC
Annals of surgical oncology. 2013;(6):1843-50
Abstract
BACKGROUND Inducing oxidative stress under hyperthermic conditions significantly decreases tumor cell growth in a murine model of human colon cancer carcinomatosis. This phase I study examines the safety and pharmacokinetics of induced oxidative stress by the addition of hydrogen peroxide (H2O2) to the perfusate in patients undergoing cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced abdominal-only malignancies. METHODS Patients with advanced colon or appendiceal malignancies underwent maximal cytoreduction followed by HIPEC with mitomycin C (MMC). In addition, H2O2 was added to the perfusate at three concentrations (n = 3/level, 0.05, 0.075, 0.1 %). A control group consisted of patients perfused with MMC alone (n = 3). Perfusate, serum MMC, and H2O2 levels were measured, as were tissue levels of MMC. RESULTS Twelve patients were enrolled onto this trial. The median (range) peritoneal carcinomatosis index was 13 (3-20) requiring a median operative time of 6.3 (4-8.5) h. The median postoperative length of stay was 9 (5-34) days, with six patients requiring readmission within 30 days. Similar complications were observed at all three H2O2 levels, as well as in the control group. One patient required reexploration for a colon perforation (control group), and three patients developed enterocutaneous fistulas (0.075 % H2O2, 0.1 % H2O2 and control group). There were no operative mortalities. CONCLUSIONS Hyperthermic intraperitoneal chemotherapy with induced oxidative stress after maximal cytoreduction is well tolerated. On the basis of the encouraging toxicity profile after cytoreduction and HIPEC with induced oxidative stress, a phase II trial to verify activity is indicated.
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Compression anastomoses in colon and rectal surgery with the NiTi ColonRing™.
Avgoustou, C, Penlidis, P, Tsakpini, A, Sioros, C, Giannousis, D
Techniques in coloproctology. 2012;(1):29-35
Abstract
BACKGROUND The aim of this prospective study was to evaluate safety and efficacy of the NiTi ColonRing™ for anastomoses on the colon or rectum. METHODS During the period September 2008-June 2011, anastomosis using the NiTi ColonRing™ was scheduled to be performed on 60 patients (36 females, 24 males/mean aged 67 years), 53 of whom underwent colectomy for cancer and 7 reconstruction after Hartmann's procedure. Application of the device failed in one case due to anatomical reasons. Colorectal resections performed were as follows: Right hemicolectomy (5 patients), left colectomy (2), sigmoidectomy (15) and low anterior resection (31). A follow-up clinic visit after 1 month was planned for all patients. Ten patients among the first 14 had rectosigmoidoscopy at 2-3 months. All cancer patients were scheduled for colonoscopy at 12 months. RESULTS No intraoperative or postoperative bleeding related to the anastomotic technique was recorded. Median hospital stay after surgery was 10.2 days (9-22 days). One patient died on day 13 due to myocardial infarction. Clinically apparent leak was detected in one patient who had undergone reconstruction after Hartmann; the only treatment required was total parenteral nutrition for 12 days. Anastomotic stenosis occurred in another one patient who had undergone reconstruction after Hartmann; it was easily resolved by balloon dilatation. Mild complications were encountered in 23 other patients (39%). Oral feeding started after day 4. Anastomotic rings were expelled naturally within 7-17 days (mean, 9.2 days). A satisfactory anastomosis was revealed in patients examined colonoscopically at 2-3 and 12 months. Mean follow-up was 15.2 months (2-33 months). CONCLUSIONS NiTi ColonRing™ is reliable, safe and efficacious for large bowel anastomoses.
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Usefulness of an intensive bowel cleansing strategy for repeat colonoscopy after preparation failure.
Ibáñez, M, Parra-Blanco, A, Zaballa, P, Jiménez, A, Fernández-Velázquez, R, Fernández-Sordo, JO, González-Bernardo, O, Rodrigo, L
Diseases of the colon and rectum. 2011;(12):1578-84
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BACKGROUND No consensus exists regarding the optimal bowel preparation regimen for patients with poor bowel cleansing at a previous colonoscopy. OBJECTIVE We investigated the usefulness of an intensive cleansing regimen for repeat colonoscopy after previous failure of bowel preparation. DESIGN AND SETTING A prospective observational study was performed in patients undergoing colonoscopy at a university-based, tertiary referral hospital. PATIENTS AND INTERVENTION Outpatients with inadequate preparation at an index colonoscopy were offered a repeat colonoscopy and instructed to follow an intensive preparation regimen consisting of a low-fiber diet for 72 hours, liquid diet for 24 hours, bisacodyl (10 mg) in the evening of the day before the colonoscopy, and a split dose of polyethylene glycol (1.5 L in the evening before and 1.5 L in the morning on the day of the colonoscopy). MAIN OUTCOME MEASURES The adequacy of bowel cleansing was assessed according to the Boston Bowel Preparation Scale (0 or 1 on any colon segment = inadequate bowel preparation). Procedural variables, detection rates for polyps and adenomas, compliance, and tolerability of the regimen were assessed. Satisfaction with the regimen was assessed with a 10-point visual analog scale. RESULTS Of 83 patients with inadequate bowel preparation at colonoscopy, 51 underwent a second colonoscopy and were analyzed; 46 patients (90.2%) had adequate bowel cleansing at the second colonoscopy, with a mean (SD) total Boston Bowel Preparation Scale score of 7.43 (1.5) and scores of 2.31 (0.6) for the right colon, 2.49 (0.6) for the transverse colon, and 2.63 (0.6) for the left colon. Polyps, flat lesions, or flat lesions proximal to the splenic flexure were found in significantly more patients at the second colonoscopy than at the index colonoscopy. The global satisfaction score was 6.6 (2.7). LIMITATIONS The study was limited because of its open observational design, possible patient learning effect for bowel preparation at the repeat colonoscopy, and the inclusion of only outpatients. CONCLUSIONS An intensive regimen consisting of a low-fiber diet, bisacodyl, and a split dose of polyethylene glycol can achieve good colon preparation with an improved detection rate for polyps and adenomas in most patients who have had poor bowel cleansing at a previous colonoscopy.
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Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7.
Grothey, A, Nikcevich, DA, Sloan, JA, Kugler, JW, Silberstein, PT, Dentchev, T, Wender, DB, Novotny, PJ, Chitaley, U, Alberts, SR, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;(4):421-7
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PURPOSE Cumulative sensory neurotoxicity (sNT) is the dose-limiting toxicity of oxaliplatin, which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant settings. In a nonrandomized, retrospective study, intravenous (IV) calcium/magnesium (Ca/Mg) was associated with reduced oxaliplatin-induced sNT. METHODS Patients with colon cancer undergoing adjuvant therapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) were randomly assigned to Ca/Mg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo, in a double-blinded manner. The primary end point was the percentage of patients with grade 2 or greater sNT at any time during or after oxaliplatin-based therapy by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) criteria. An oxaliplatin-specific sNT scale and patient questionnaires were also used to assess sNT. After 104 of 300 planned patients were enrolled, the study was closed. This was due to preliminary reports from another trial that suggested that Ca/Mg decreased treatment efficacy; these data were subsequently found to be incorrect. RESULTS Overall, 102 patients were available for analysis. Ca/Mg decreased the incidence of chronic, cumulative, grade 2 or greater sNT, as measured by NCI CTCAE (P = .038) and also by the oxaliplatin-specific sNT scale (P = .018). In addition, acute muscle spasms associated with oxaliplatin were significantly reduced (P = .01) No effect on acute, cold-induced sNT was found. No substantial differences in adverse effects were noted between Ca/Mg and placebo. CONCLUSION Despite early termination and decreased statistical power, this study supports IV Ca/Mg as an effective neuroprotectant against oxaliplatin-induced cumulative sNT in adjuvant colon cancer.