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Sample records for short-time oxaliplatin capecitabine

  1. Bevacizumab, Oxaliplatin, and Capecitabine With Radiation Therapy in Rectal Cancer: Phase I Trial Results

    SciTech Connect

    Czito, Brian G. . E-mail: czito001@mc.duke.edu; Bendell, Johanna C.; Willett, Christopher G.; Morse, Michael A.; Blobe, Gerard C.; Tyler, Douglas S.; Thomas, John; Ludwig, Kirk A.; Mantyh, Christopher R.; Ashton, Jill; Yu Daohai; Hurwitz, Herbert I.

    2007-06-01

    Purpose: The overexpression of vascular endothelial growth factor (VEGF) is associated with poor outcomes in colorectal cancer patients. Bevacizumab, a VEGF inhibitor, enhances the effects of chemotherapy and radiation therapy on tumor cytotoxicity in preclinical models, including colorectal cancer. A Phase I trial was undertaken to evaluate the combination of bevacizumab, capecitabine, oxaliplatin, and radiation therapy in patients with rectal cancer. Methods and Materials: Patients with pathologically confirmed adenocarcinoma of the rectum were eligible. Pretreatment staging included computerized tomography, endoscopic ultrasound, and surgical evaluation. Patients received 50.4 Gy of external beam radiation therapy (EBRT) to the tumor in 28 fractions. Capecitabine, oxaliplatin, and bevacizumab were administered concurrently with radiation therapy. After EBRT completion, patients were restaged and evaluated for surgery. Primary endpoints included the determination of dose-limiting toxicity and a recommended Phase II dose, non dose-limiting toxicity, and preliminary radiographic and pathologic response rates. Results: Eleven patients were enrolled. All were evaluable for toxicity and efficacy. Dose level 2 was associated with unacceptable toxicity (primarily diarrhea). Dose level 1 had an acceptable toxicity profile. The recommended Phase II dose in our study was bevacizumab 15 mg/kg Day 1 + 10 mg/kg Days 8 and 22, oxaliplatin 50 mg/m{sup 2} weekly, and capecitabine 625 mg/m{sup 2} bid during radiation days. Six patients had clinical responses. Two patients had a pathologic complete response, and 3 had microscopic disease only. One patient experienced a postoperative abscess, one a syncopal episode during adjuvant chemotherapy, and one a subclinical myocardial infarction during adjuvant chemotherapy. Conclusions: The combination of bevacizumab, capecitabine, oxaliplatin, and radiation therapy in rectal cancer was tolerable, with encouraging response rates. Further

  2. Phase I-II Trial of Cetuximab, Capecitabine, Oxaliplatin, and Radiotherapy as Preoperative Treatment in Rectal Cancer

    SciTech Connect

    Roedel, Claus Arnold, Dirk; Hipp, Matthias; Liersch, Torsten; Dellas, Kathrin; Iesalnieks, Igors; Hermann, Robert Michael; Lordick, Florian; Hohenberger, Werner; Sauer, Rolf

    2008-03-15

    Purpose: To evaluate the safety and activity of preoperative radiotherapy (RT) with concurrent cetuximab, capecitabine, and oxaliplatin in rectal cancer patients. Patients and Methods: A total of 60 patients with rectal cancer (T3-T4 or N+, M1 allowed) entered the trial at five investigator sites; the data from 58 patients were assessable. Cetuximab was given as an initial dose of 400 mg/m{sup 2} 7 days before the start of RT, and then at 250 mg/m{sup 2} once weekly during RT (50.4 Gy in 28 fractions). Capecitabine and oxaliplatin were administered according to an established schedule of oxaliplatin (50 mg/m{sup 2} on Days 1, 8, 22, and 29) and capecitabine (Days 1-14 and 22-35) at three dose levels: 1,000, 1,300, and 1,650 mg/m{sup 2}/d during the Phase I part of the study. The main endpoint of the Phase II was the pathologic complete response rate. Results: Thirteen patients were included in the Phase I part of the study, and the maximal tolerated dose was not reached. Overall, 48 patients were treated at the recommended dose of capecitabine (1,650 mg/m{sup 2}) and 45 patients (94%) underwent surgery. A pathologic complete response was observed in 4 patients (9%), and moderate (n = 12), minimal (n = 10), and no tumor regression (n = 2) was noted in 24 (53%) of 45 patients. The mean radiation dose intensity, cetuximab, capecitabine, oxaliplatin was 98%, 95%, 94%, and 94%, respectively. The incidence of Grade 3-4 diarrhea was restricted to 19%. Postoperative complications of any grade occurred in 33% of patients. Conclusions: The results of our study have shown that cetuximab can be combined safely with capecitabine and oxaliplatin plus RT. The low pathologic complete response rate achieved should stimulate additional preclinical investigations to establish the best sequence of triple combinations.

  3. A Phase II Study of Sequential Capecitabine Plus Oxaliplatin Followed by Docetaxel Plus Capecitabine in Patients With Unresectable Gastric Adenocarcinoma: The TCOG 3211 Clinical Trial.

    PubMed

    Chen, Ming-Huang; Lin, Johnson; Hsiao, Chin-Fu; Shan, Yan-Shen; Chen, Yeu-Chin; Chen, Li-Tzong; Liu, Tsang-Wu; Li, Chung-Pin; Chao, Yee

    2016-01-01

    Fluorouracil and platinum are considered the standard treatment options for advanced gastric cancer. Docetaxel is also an effective agent and it shows no cross-resistance with fluorouracil and platinum. The combination treatment of docetaxel with fluorouracil and platinum has been explored, but it demonstrated intolerable toxicities. An alternative approach in the first-line treatment of gastric adenocarcinoma may be to use these agents sequentially. We aimed to evaluate the activity and safety profile of sequential chemotherapy with capecitabine plus oxaliplatin, followed by docetaxel plus capecitabine in the first-line treatment of unresectable gastric cancer.We conducted a phase II study of sequential first-line chemotherapy in advanced gastric cancer. Treatment consisted of 6 cycles of capecitabine plus oxaliplatin (capecitabine 1000 mg/m bid on days 1-10 and oxaliplatin 85 mg/m on day 1, every 2 weeks), followed by 4 cycles of docetaxel plus capecitabine (docetaxel 30 mg/m on days 1 and 8, capecitabine 825 mg/m bid on days 1-14, every 3 weeks). The primary end-point was the objective response rate.Fifty-one patients were enrolled: median age, 63 years; male/female: 37/14. The main grade 3 to 4 toxicities were a decreased absolute neutrophil count (25.4%), diarrhea (9.8%), and hand-foot syndrome (15.7%). The objective response rate was 61.7%. The median progression-free survival and overall survival were 8.6 and 11.0 months, respectively. Six patients (11.8%) received surgery after chemotherapy and 5 are still disease-free.This sequential treatment demonstrated feasibility with a favorable safety profile and produced encouraging results in terms of activity and efficacy. PMID:26817912

  4. Oxaliplatin and Capecitabine-Based Chemoradiotherapy for Gastric Cancer-An Extended Phase I MARGIT and AIO Trial

    SciTech Connect

    Hofheinz, Ralf-Dieter Wenz, Frederik; Lukan, Nadine; Mai, Sabine; Kripp, Melanie; Staiger, Wilko; Schwarzbach, Matthias; Willeke, Frank; Moehler, Markus; Post, Stefan; Hochhaus, Andreas

    2009-01-01

    Purpose: Adjuvant 5-fluorouracil-based chemoradiotherapy has been shown to improve the prognosis of gastric cancer. To optimize these results, in the present study oxaliplatin and capecitabine were used instead of 5-fluorouracil. We sought to determine the maximum tolerated dose and the dose-limiting toxicities (DLT) of these drugs in combination with intensity-modulated radiotherapy. Methods and Materials: Patients with resected adenocarcinoma of the stomach or the gastroesophageal junction were included. They received two cycles of induction chemotherapy (oxaliplatin and capecitabine [XelOx] regimen). Using standard Phase I methodology, patients received 45 Gy in 1.8-Gy fractions either in combination with capecitabine 825 mg m{sup -1} twice a day (Dose Level [DL] I) or capecitabine in combination with weekly oxaliplatin 40 or 50 mg m{sup -1} (DL II and III). After the completion of chemoradiation, two additional cycles of XelOx were scheduled. Results: A total of 32 patients were recruited. Only 1 of 6 patients evaluable on DL I had DLT. Of the first 6 patients on DL II, 1 patient experienced DLT, and 3 of the remaining patients had Grade 3 toxicity. Therefore, DL II was defined as the maximum tolerated dose and a total of 20 patients were treated at this DL. The most frequently observed toxicities (Common Toxicity Criteria Grades 1, 2 and 3) were, respectively, leukocytopenia in 5, 5, and 4 patients; nausea in 3, 7, and 3; and diarrhea in 4, 0, and 1. Conclusions: In summary, capecitabine 825 mg m{sup -1} twice a day (Days 1-33) and weekly oxaliplatin 40 mg m{sup -1} was safe and tolerable in combination with intensity-modulated radiotherapy. Furthermore, four cycles of XelOx could be applied before and after chemoradiotherapy in two thirds of the patients.

  5. Economic comparison of capecitabine + oxaliplatin and 5-fluorouracil + oxaliplatin in the adjuvant treatment of colon cancer

    PubMed Central

    Aitini, Enrico; Rossi, Anna; Morselli, Patrizia; Vivorio, Beatrice; Bruschi, Alessandra; Bottura, Chiara; Colombo, Giorgio L

    2012-01-01

    Background Colorectal cancer is one of the most frequent and lethal cancers. The aim of this study was to analyze the costs relating to treatment of colorectal cancer between Xelox and Folfox-4 at a regional level according to the clinical experience at an Italian hospital in Lombardy. Methods A cost analysis was carried out regarding resource consumption by patients suffering from colorectal cancer based on data collected over a 12-month period between 2010 and 2011. The analysis involved 40 patients who attended the Department of Medical Oncology and Hematology at Carlo Poma Hospital to undergo adjuvant therapy for colorectal cancer. A chart was created for each patient containing their medical history, their pharmacological therapy indicating the number and duration of chemotherapy cycles, dose in mg administered for each cycle, number of day hospital visits for each cycle, number of days spent in hospital to position the central vein catheter, type of infusion pump used, any subsequent supportive therapy, and any side effects and outpatient visits connected with side effects. Results The cost analysis shows the savings involved in using Xelox for a single cycle of treatment, ie, approximately €1414.00 per patient (53% compared with Folfox-4). For each single cycle of treatment, the savings generated by using capecitabine compared with 5-FU can be attributed mostly to the fact that oral administration of chemotherapy requires fewer resources and does not require use of a central vein catheter (approximately 70% of overall cost) which amply compensates for the higher cost of capecitabine compared with 5-FU-LV. Sensibility analysis confirms the results of the base-case scenario. Conclusion The results of our study indicate that infusion via a central vein catheter represents a significant cost, and that substitution with an oral therapy, even when associated with drugs administered intravenously, represents a consistent saving of hospital resources. PMID

  6. [A Case of Colon Cancer with Multiple Liver Metastases Successfully Treated with Capecitabine/Oxaliplatin plus Bevacizumab].

    PubMed

    Suematsu, Yuki; Ishibashi, Yuji; Hiratsuka, Miyuki; Suda, Hiroshi; Takahashi, Miyuki; Saito, Hiroyuki; Omori, Keita; Morita, Akihiko; Wakabayashi, Kazuhiko; Ito, Yutaka

    2015-11-01

    A 69-year-old woman was diagnosed with descending colon cancer with multiple liver metastases, and a left hemicolectomy was performed. The patient was treated with capecitabine/oxaliplatin (CapeOX) plus bevacizumab (Bmab). After 5 courses of chemotherapy, the number and size of liver metastases remarkably reduced, and after the 12th course, because of peripheral neuropathy, a "stop-and-go"fashion of administering oxaliplatin (L-OHP) was initiated. After 14 courses, the liver metastases had disappeared. After the 33rd course of L-OHP treatment, the patient started receiving capecitabine therapy. The patient is recurrence-free 3 years after surgery, 14 months after achieving a complete response (CR). We report a case of long-term CR after surgery for descending colon cancer with multiple liver metastases, followed by a "stop-and-go" method of administering L-OHP or CapeOX plus Bmab therapy. PMID:26805277

  7. Multicentre phase II trial of capecitabine plus oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma: FFCD 03-03 trial

    PubMed Central

    Boige, V; Raoul, J-L; Pignon, J-P; Bouché, O; Blanc, J-F; Dahan, L; Jouve, J-L; Dupouy, N; Ducreux, M

    2007-01-01

    Evaluation of new drug combinations is needed to improve patients' prognosis in advanced hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the safety and efficacy of the capecitabine–oxaliplatine combination (XELOX) in HCC patients. First-line chemotherapy with XELOX regimen consisting of a 3-week cycle of intravenous oxaliplatin (130 mg m−2) on Day 1, and oral capecitabine twice daily from Days 1–14 (1000 mg m−2) was administered in patients with measurable, unresectable HCC. Fifty patients (male, 88%; median age, 68 years) received a total of 295 cycles (median, 6) of treatment. Disease control (three partial responses, 29 stable diseases) rate was 72% (95% CI 57–83%). Median overall and median progression-free (PFS) survival was 9.3 months and 4.1 months, respectively. Progression-free survival rates at 6 and 12 months were 38% (95% CI 26–52%) and 14% (95% CI 7–26%), respectively. Main grade 3–4 drug-related toxicities included diarrhoea (16%), elevation of aminotransferases and/or bilirubin (16%), thrombocytopenia (12%), and neurotoxicity (6%). Capecitabine plus oxaliplatin regimen showed modest anti-tumour activity with tolerable toxicities in patients with advanced HCC. However, the manageable toxicity profile and the encouraging disease control rate deserve further attention for this convenient, outpatient-based chemotherapy regimen. PMID:17876335

  8. A Phase I study of weekly intravenous oxaliplatin in combination with oral daily capecitabine and radiation therapy in the neoadjuvant treatment of rectal adenocarcinoma

    SciTech Connect

    Fakih, Marwan G. . E-mail: marwan.fakih@roswellpark.org; Rajput, Ashwani; Yang, Gary Y.; Pendyala, Lakshmi; Toth, Karoly; Smith, Judy L.; Lawrence, David D.; Rustum, Youcef M.

    2006-08-01

    Purpose: We conducted a Phase I study to determine the maximum tolerated dose (MTD) of neoadjuvant capecitabine, oxaliplatin, and radiation therapy (RT) in Stage II to III rectal adenocarcinoma. Methods and Materials: Capecitabine was given orally twice daily Monday through Friday concurrently with RT. Oxaliplatin was given i.v. once weekly x 5 (for 5 weeks) starting the first day of RT. RT was given daily except on weekends and holidays at 1.8 Gy per fraction x 28. Escalation for capecitabine or oxaliplatin was to occur in cohorts of three patients until the maximum tolerated dose (MTD) was defined. Endorectal tumor biopsy samples were obtained before and on Day 3 of treatment to explore the effects of treatment on thymidine phosphorylase, thymidylate synthase, dihydropyrimidine dehydrogenase, DNA repair, and apoptosis. Results: Twelve patients were enrolled on this study. Two of 6 patients at dose level (DL) 1 (capecitabine 825 mg/m{sup 2} orally (p.o.) given twice daily (b.i.d.); oxaliplatin 50 mg/m{sup 2}/week) had a dose-limiting diarrhea. One of 6 patients at DL (-)1 (capecitabine 725 mg/m{sup 2} p.o., b.i.d.; oxaliplatin 50 mg/m{sup 2}/week) experienced-dose-limiting diarrhea. Three of 11 patients who underwent resection had a complete pathologic response. No remarkable variations in rectal tumor biologic endpoints were noted on Day 3 of treatment in comparison to baseline. However, a higher apotosis index was observed at baseline and on Day 3 in complete pathologic responders (no statistical analysis performed). Conclusions: Capecitabine 725 mg/m{sup 2} p.o., twice daily in combination with oxaliplatin 50 mg/m{sup 2}/week and RT 50.4 Gy in 28 fractions is the recommended dose for future studies.

  9. Efficacy Endpoints of RTOG 0247: A Randomized Phase II Study of Neoadjuvant Radiation Therapy Plus Concurrent Capecitabine and Irinotecan or Capecitabine and Oxaliplatin for Patients with Locally Advanced Rectal Cancer

    PubMed Central

    Wong, Stuart J.; Moughan, J.; Meropol, Neal J.; Anne, Pramila Rani; Kachnic, Lisa A.; Rashid, Asif; Watson, James C.; Mitchell, Edith P.; Pollock, Jondavid; Lee, R. Jeffrey; Haddock, Michael; Erickson, Beth A.; Willett, Christopher G.

    2015-01-01

    Purpose/Objectives Primary endpoint analysis of RTOG 0247 demonstrated preoperative RT with capecitabine plus oxaliplatin achieved a pCR pre-specified threshold (21%) to merit further study, whereas the RT with capecitabine plus irinotecan arm did not (10%). Secondary efficacy endpoints are reported here. Methods and Materials A randomized phase II trial evaluated preoperative RT (50.4 Gy in 1.8 Gy fractions) with two concurrent chemotherapy regimens: 1—capecitabine (1200 mg/m2/d M-F) plus irinotecan (50 mg/m2 /week × 4); and 2—capecitabine (1650 mg/m2/d M-F) plus oxaliplatin (50 mg/m2 /week × 5) for clinical T3 or T4 rectal cancer. Surgery was performed 4-8 weeks following chemoradiation, then 4-6 weeks later, adjuvant chemotherapy (oxaliplatin 85 mg/m2; leucovorin 400 mg/m2; 5FU 400 mg/m2; 5FU 2400 mg/m2) every 2 weeks × 9. Disease-free survival (DFS) and overall survival (OS) were estimated univariately by the Kaplan-Meier method. Local-regional failure (LRF), distant failure (DF), and second primary failure (SP) were estimated by the cumulative incidence method. No statistical comparisons were made between arms as each was evaluated individually. Results 104 patients (median age 57) were treated; characteristics were similar for both arms. Median follow-up for RT with capecitabine/irinotecan arm was 3.77 years and for RT with capecitabine/oxaliplatin arm was 3.97 years. Four-year DFS, OS, LRF, DF, and SP estimates for capecitabine/irinotecan arm are 68%, 85%, 16%, 24%, and 2%, respectively. The 4-year DFS, OS, LRF, DF, and SP failure estimates for capecitabine/oxaliplatin arm are 62%, 75%, 18%, 30%, and 6%, respectively. Conclusions Efficacy results for both arms are similar to other reported studies but suggest that pCR is an unsuitable surrogate for traditional survival metrics of clinical outcome. While it remains uncertain if the addition of a second cytotoxic agent enhances the effectiveness of fluorouracil plus RT, these results suggest further

  10. Efficacy Endpoints of Radiation Therapy Group Protocol 0247: A Randomized, Phase 2 Study of Neoadjuvant Radiation Therapy Plus Concurrent Capecitabine and Irinotecan or Capecitabine and Oxaliplatin for Patients With Locally Advanced Rectal Cancer

    SciTech Connect

    Wong, Stuart J.; Moughan, Jennifer; Meropol, Neal J.; Anne, Pramila Rani; Kachnic, Lisa A.; Rashid, Asif; Watson, James C.; Mitchell, Edith P.; Pollock, Jondavid; Lee, R. Jeffrey; Haddock, Michael; Erickson, Beth A.; Willett, Christopher G.

    2015-01-01

    Purpose: To report secondary efficacy endpoints of Radiation Therapy Oncology Group protocol 0247, primary endpoint analysis of which demonstrated that preoperative radiation therapy (RT) with capecitabine plus oxaliplatin achieved a pathologic complete remission prespecified threshold (21%) to merit further study, whereas RT with capecitabine plus irinotecan did not (10%). Methods and Materials: A randomized, phase 2 trial evaluated preoperative RT (50.4 Gy in 1.8-Gy fractions) with 2 concurrent chemotherapy regimens: (1) capecitabine (1200 mg/m{sup 2}/d Monday-Friday) plus irinotecan (50 mg/m{sup 2}/wk × 4); and (2) capecitabine (1650 mg/m{sup 2}/d Monday-Friday) plus oxaliplatin (50 mg/m{sup 2}/wk × 5) for clinical T3 or T4 rectal cancer. Surgery was performed 4 to 8 weeks after chemoradiation, then 4 to 6 weeks later, adjuvant chemotherapy (oxaliplatin 85 mg/m{sup 2}; leucovorin 400 mg/m{sup 2}; 5-fluorouracil 400 mg/m{sup 2}; 5-fluorouracil 2400 mg/m{sup 2}) every 2 weeks × 9. Disease-free survival (DFS) and overall survival (OS) were estimated univariately by the Kaplan-Meier method. Local–regional failure (LRF), distant failure (DF), and second primary failure (SP) were estimated by the cumulative incidence method. No statistical comparisons were made between arms because each was evaluated individually. Results: A total of 104 patients (median age, 57 years) were treated; characteristics were similar for both arms. Median follow-up for RT with capecitabine/irinotecan arm was 3.77 years and for RT with capecitabine/oxaliplatin arm was 3.97 years. Four-year DFS, OS, LRF, DF, and SP estimates for capecitabine/irinotecan arm were 68%, 85%, 16%, 24%, and 2%, respectively. The 4-year DFS, OS, LRF, DF, and SP failure estimates for capecitabine/oxaliplatin arm were 62%, 75%, 18%, 30%, and 6%, respectively. Conclusions: Efficacy results for both arms are similar to other reported studies but suggest that pathologic complete remission is an

  11. Capecitabine and Oxaliplatin in the Preoperative Multimodality Treatment of Rectal Cancer: Surgical End Points From National Surgical Adjuvant Breast and Bowel Project Trial R-04

    PubMed Central

    O'Connell, Michael J.; Colangelo, Linda H.; Beart, Robert W.; Petrelli, Nicholas J.; Allegra, Carmen J.; Sharif, Saima; Pitot, Henry C.; Shields, Anthony F.; Landry, Jerome C.; Ryan, David P.; Parda, David S.; Mohiuddin, Mohammed; Arora, Amit; Evans, Lisa S.; Bahary, Nathan; Soori, Gamini S.; Eakle, Janice; Robertson, John M.; Moore, Dennis F.; Mullane, Michael R.; Marchello, Benjamin T.; Ward, Patrick J.; Wozniak, Timothy F.; Roh, Mark S.; Yothers, Greg; Wolmark, Norman

    2014-01-01

    Purpose The optimal chemotherapy regimen administered concurrently with preoperative radiation therapy (RT) for patients with rectal cancer is unknown. National Surgical Adjuvant Breast and Bowel Project trial R-04 compared four chemotherapy regimens administered concomitantly with RT. Patients and Methods Patients with clinical stage II or III rectal cancer who were undergoing preoperative RT (45 Gy in 25 fractions over 5 weeks plus a boost of 5.4 Gy to 10.8 Gy in three to six daily fractions) were randomly assigned to one of the following chemotherapy regimens: continuous intravenous infusional fluorouracil (CVI FU; 225 mg/m2, 5 days per week), with or without intravenous oxaliplatin (50 mg/m2 once per week for 5 weeks) or oral capecitabine (825 mg/m2 twice per day, 5 days per week), with or without oxaliplatin (50 mg/m2 once per week for 5 weeks). Before random assignment, the surgeon indicated whether the patient was eligible for sphincter-sparing surgery based on clinical staging. The surgical end points were complete pathologic response (pCR), sphincter-sparing surgery, and surgical downstaging (conversion to sphincter-sparing surgery). Results From September 2004 to August 2010, 1,608 patients were randomly assigned. No significant differences in the rates of pCR, sphincter-sparing surgery, or surgical downstaging were identified between the CVI FU and capecitabine regimens or between the two regimens with or without oxaliplatin. Patients treated with oxaliplatin experienced significantly more grade 3 or 4 diarrhea (P < .001). Conclusion Administering capecitabine with preoperative RT achieved similar rates of pCR, sphincter-sparing surgery, and surgical downstaging compared with CVI FU. Adding oxaliplatin did not improve surgical outcomes but added significant toxicity. The definitive analysis of local tumor control, disease-free survival, and overall survival will be performed when the protocol-specified number of events has occurred. PMID:24799484

  12. Phase II Study of Weekly Intravenous Oxaliplatin Combined With Oral Daily Capecitabine and Radiotherapy With Biologic Correlates in Neoadjuvant Treatment of Rectal Adenocarcinoma

    SciTech Connect

    Fakih, Marwan G. BullardDunn, Kelli; Yang, Gary Y.; Pendyala, Lakshmi; Toth, Karoly; Andrews, Chris; Rustum, Youcef M.; Ross, Mary Ellen; LeVea, Charles; Puthillath, Ajithkumar; Park, Young-Mee; Rajput, Ashwani

    2008-11-01

    Purpose: To evaluate the efficacy of a combination of capecitabine, oxaliplatin, and radiotherapy (RT) in the neoadjuvant treatment of Stage II and III rectal cancers. Methods: Capecitabine was given at 725 mg/m{sup 2} orally twice daily Monday through Friday concurrently with RT. Oxaliplatin was given intravenously at 50 mg/m{sup 2} once weekly five times starting the first day of RT. The radiation dose was 50.4 Gy in 28 fractions (1.8 Gy/fraction), five fractions weekly. Endorectal tumor biopsies were obtained before treatment and on the third day of treatment to explore the effects of treatment on thymidine phosphorylase, thymidylate synthase, excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1), and apoptosis. Results: A total of 25 patients were enrolled in this study; 6 patients (24%) had a complete pathologic response. T-downstaging occurred in 52% of patients, and N-downstaging occurred in 53%. Grade 3 diarrhea was the most common Grade 3-4 toxicity, occurring in 20% of patients. Only 2 patients experienced disease recurrence, with a median of 20 months of follow-up. Thymidylate synthase, thymidine phosphorylase, ERCC1, and apoptosis did not vary significantly between the pretreatment and Day 3 tumor biopsies, nor did they predict for T-downstaging or a complete pathologic response. Conclusion: Capecitabine at 725 mg/m{sup 2} orally twice daily, oxaliplatin 50 mg/m{sup 2}/wk, and RT at 50.4 Gy is an effective neoadjuvant combination for Stage II and III rectal cancer and results in a greater rate of complete pathologic responses than historically shown in fluoropyrimidine plus RT controls.

  13. Superior antitumor activity of trastuzumab combined with capecitabine plus oxaliplatin in a human epidermal growth factor receptor 2-positive human gastric cancer xenograft model

    PubMed Central

    HARADA, SUGURU; YANAGISAWA, MIEKO; KANEKO, SAORI; YOROZU, KEIGO; YAMAMOTO, KANAME; MORIYA, YOICHIRO; HARADA, NAOKI

    2015-01-01

    In the treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction cancer, it has been reported that the combination of trastuzumab with capecitabine plus cisplatin, or with 5-fluorouracil (5-FU) plus cisplatin, significantly increased overall survival compared with chemotherapy alone (ToGA trial). In addition, adjuvant therapy with capecitabine plus oxaliplatin (XELOX) improved the survival of patients who received curative D2 gastrectomy (CLASSIC trial). However, the efficacy of the combination of trastuzumab with XELOX for patients with HER2-positive gastric cancer remains unknown. The aim of this study, was to investigate the efficacy of the combination of trastuzumab with XELOX in a HER2-positive human gastric cancer xenograft model. Combination treatment with these three agents (trastuzumab 20 mg/kg, capecitabine 359 mg/kg and oxaliplatin 10 mg/kg), was found to exhibit a significantly stronger antitumor activity in NCI-N87 xenografts compared with either trastuzumab or XELOX alone. In this model, treatment with trastuzumab alone or trastuzumab plus oxaliplatin enhanced the expression of thymidine phosphorylase (TP), a key enzyme in the generation of 5-FU from capecitabine in tumor tissues. In in vitro experiments, trastuzumab induced TP mRNA expression in NCI-N87 cells. In addition, NCI-N87 cells co-cultured with the natural killer (NK) cell line CD16(158V)/NK-92 exhibited increased expression of TP mRNA. When NCI-N87 cells were cultured with CD16(158V)/NK-92 cells in the presence of trastuzumab, the mRNA expression of cytokines reported to have the ability to induce TP was upregulated in tumor cells. Furthermore, a medium conditioned by CD16(158V)/NK-92 cells also upregulated the expression of TP mRNA in NCI-N87 cells. These results suggest that trastuzumab promotes TP expression, either by acting directly on NCI-N87 cells, or indirectly via a mechanism that includes trastuzumab-mediated interactions

  14. Phase I/II trial of capecitabine, oxaliplatin, and irinotecan in combination with bevacizumab in first line treatment of metastatic colorectal cancer

    PubMed Central

    Bazarbashi, Shouki; Aljubran, Ali; Alzahrani, Ahmad; Mohieldin, Ahmed; Soudy, Hussein; Shoukri, Mohammed

    2015-01-01

    Phase III studies have demonstrated the efficacy of FOLFOXIRI regimens (5-fluorouracil/leucovorin, oxaliplatin, irinotecan) with/without bevacizumab in metastatic colorectal cancer (mCRC). Capecitabine is an orally administered fluoropyrimidine that may be used instead of 5-fluorouracil/leucovorin. We evaluated a triple-chemotherapy regimen of capecitabine, oxaliplatin, and irinotecan, plus bevacizumab in 53 patients with mCRC. A Phase I study identified the maximum tolerated dose of irinotecan as 150 mg/m2. Median follow-up in a subsequent Phase II study using this dose was 28 months (74% progressed). For all patients, a complete response was achieved in 4% and a partial response in 60%; median progression-free survival (PFS) was 16 months and median overall survival (OS) was 28 months. Median PFS was longer for patients with an early treatment response (28 vs. 9 months for others; P = 0.024), or early tumor shrinkage (25 vs. 9 months for others; P = 0.006), or for patients suitable for surgical removal of metastases with curative intent (median not reached vs. 9 months for others; P = 0.001). Median OS was longer for patients with early tumor shrinkage (median not reached vs. 22 months for others; P = 0.006) or surgery (median not reached vs. 22 months for others, P = 0.002). K-ras mutations status did not influence PFS (P = 0.88) or OS (P = 0.82). Considerable Grade 3/4 toxicity was encountered (36% for diarrhea, 21% for vomiting and 17% for fatigue). In conclusion, the 3-weekly triple-chemotherapy regimen of capecitabine, oxaliplatin, and irinotecan, plus bevacizumab, was active in the first-line treatment of mCRC, although at the expense of a high level of toxicity. PMID:26207614

  15. Phase 2 Trial of Induction Gemcitabine, Oxaliplatin, and Cetuximab Followed by Selective Capecitabine-Based Chemoradiation in Patients With Borderline Resectable or Unresectable Locally Advanced Pancreatic Cancer

    SciTech Connect

    Esnaola, Nestor F.; Chaudhary, Uzair B.; O'Brien, Paul; Garrett-Mayer, Elizabeth; Camp, E. Ramsay; Thomas, Melanie B.; Cole, David J.; Montero, Alberto J.; Hoffman, Brenda J.; Romagnuolo, Joseph; Orwat, Kelly P.; Marshall, David T.

    2014-03-15

    Purpose: To evaluate, in a phase 2 study, the safety and efficacy of induction gemcitabine, oxaliplatin, and cetuximab followed by selective capecitabine-based chemoradiation in patients with borderline resectable or unresectable locally advanced pancreatic cancer (BRPC or LAPC, respectively). Methods and Materials: Patients received gemcitabine and oxaliplatin chemotherapy repeated every 14 days for 6 cycles, combined with weekly cetuximab. Patients were then restaged; “downstaged” patients with resectable disease underwent attempted resection. Remaining patients were treated with chemoradiation consisting of intensity modulated radiation therapy (54 Gy) and concurrent capecitabine; patients with borderline resectable disease or better at restaging underwent attempted resection. Results: A total of 39 patients were enrolled, of whom 37 were evaluable. Protocol treatment was generally well tolerated. Median follow-up for all patients was 11.9 months. Overall, 29.7% of patients underwent R0 surgical resection (69.2% of patients with BRPC; 8.3% of patients with LAPC). Overall 6-month progression-free survival (PFS) was 62%, and median PFS was 10.4 months. Median overall survival (OS) was 11.8 months. In patients with LAPC, median OS was 9.3 months; in patients with BRPC, median OS was 24.1 months. In the group of patients who underwent R0 resection (all of which were R0 resections), median survival had not yet been reached at the time of analysis. Conclusions: This regimen was well tolerated in patients with BRPC or LAPC, and almost one-third of patients underwent R0 resection. Although OS for the entire cohort was comparable to that in historical controls, PFS and OS in patients with BRPC and/or who underwent R0 resection was markedly improved.

  16. Prospective phase II trial of pazopanib plus CapeOX (capecitabine and oxaliplatin) in previously untreated patients with advanced gastric cancer.

    PubMed

    Kim, Seung Tae; Lee, Jeeyun; Lee, Su Jin; Park, Se Hoon; Jung, Sin-Ho; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki; Park, Joon Oh

    2016-04-26

    We designed a single-arm, open label phase II study to determine the efficacy and toxicity of the combination of pazopanib with CapeOx (capecitabine and oxaliplatin) in metastatic /recurrent advanced gastric cancer (AGC) patients. Previously untreated AGC patients received capecitabine (850 mg/m2 bid, day 1-14) plus oxaliplatin (130 mg/m2, day 1) in combination with pazopanib (800 mg, day 1-21) every three weeks. Treatment was continued until progression of the disease or intolerable toxicity was observed. In all, 66 patients were treated with pazopanib plus CapeOx. The median age of the patients was 51.5 years (range, 23.0-77), and the median ECOG performance status was 1 (0-1). Among all 66 patients, one complete response and 37 partial responses were observed (overall response rate, 62.4%; 95% confidence interval (CI), 45.7-73.5% accounting for the 2-stage design of this trial). Stable disease was observed in 23 patients (34.8%), revealing a 92.4% disease control rate. The median progression free survival and overall survival were 6.5 months (95% CI, 5.6-7.4) and 10.5 months (95% CI, 8.1-12.9), respectively. Thirty-four patients (51.5%) experienced a treatment-related toxicity of grade 3 or more. The most common toxicities of grade 3 or more were neutropenia (15.1%), anemia (10.6%), thrombocytopenia (10.6%), anorexia (7.6%), nausea (3.0%), and vomiting (3.0%). There were no treatment-related deaths. The combination of pazopanib and CapeOx showed moderate activity and an acceptable toxicity profile as a first-line treatment in metastatic / recurrent AGC patients (ClinicalTrials.gov NCT01130805). PMID:27003363

  17. Four-Week Neoadjuvant Intensity-Modulated Radiation Therapy With Concurrent Capecitabine and Oxaliplatin in Locally Advanced Rectal Cancer Patients: A Validation Phase II Trial

    SciTech Connect

    Arbea, Leire; Martinez-Monge, Rafael; Diaz-Gonzalez, Juan A.; Moreno, Marta; Rodriguez, Javier; Hernandez, Jose Luis; Sola, Jesus Javier; Ramos, Luis Isaac; Subtil, Jose Carlos; Nunez, Jorge; Chopitea, Ana; Cambeiro, Mauricio; Gaztanaga, Miren; Garcia-Foncillas, Jesus; Aristu, Javier

    2012-06-01

    Purpose: To validate tolerance and pathological complete response rate (pCR) of a 4-week preoperative course of intensity-modulated radiation therapy (IMRT) with concurrent capecitabine and oxaliplatin (CAPOX) in patients with locally advanced rectal cancer. Methods and Materials: Patients with T3 to T4 and/or N+ rectal cancer received preoperative IMRT (47.5 Gy in 19 fractions) with concurrent capecitabine (825 mg/m{sup 2} b.i.d., Monday to Friday) and oxaliplatin (60 mg/m{sup 2} on Days 1, 8, and 15). Surgery was scheduled 4 to 6 weeks after the completion of chemoradiation. Primary end points were toxicity and pathological response rate. Local control (LC), disease-free survival (DFS), and overall survival (OS) were also analyzed. Results: A total of 100 patients were evaluated. Grade 1 to 2 proctitis was observed in 73 patients (73%). Grade 3 diarrhea occurred in 9% of the patients. Grade 3 proctitis in 18% of the first 50 patients led to reduction of the dose per fraction to 47.5 Gy in 20 treatments. The rate of Grade 3 proctitis decreased to 4% thereafter (odds ratio, 0.27). A total of 99 patients underwent surgery. A pCR was observed in 13% of the patients, major response (96-100% of histological response) in 48%, and pN downstaging in 78%. An R0 resection was performed in 97% of the patients. After a median follow-up of 55 months, the LC, DFS, and OS rates were 100%, 84%, and 87%, respectively. Conclusions: Preoperative CAPOX-IMRT therapy (47.5 Gy in 20 fractions) is feasible and safe, and produces major pathological responses in approximately 50% of patients.

  18. Phase I-II Trial of Concurrent Capecitabine and Oxaliplatin With Preoperative Intensity-Modulated Radiotherapy in Patients With Locally Advanced Rectal Cancer

    SciTech Connect

    Aristu, Jose Javier Arbea, Leire; Rodriguez, Javier; Hernandez-Lizoain, Jose Luis; Sola, Jesus Javier; Moreno, Marta M.D.; Azcona, Juan Diego; Diaz-Gonzalez, Juan Antonio; Garcia-Foncillas, Jesus Miguel; Martinez-Monge, Rafael

    2008-07-01

    Purpose: To identify the maximal tolerated dose level of preoperative intensity-modulated radiotherapy combined with capecitabine and oxaliplatin and to evaluate the efficacy. Patients and Methods: Patients with rectal T3-T4 and/or N0-N+ rectal cancer received capecitabine 825 mg/m{sup 2} twice daily Monday through Friday and oxaliplatin 60 mg/m{sup 2} intravenously on Days 1, 8, and 15, concurrently with intensity-modulated radiotherapy. The radiation dose was increased in 5.0-Gy steps in cohorts of 3 patients starting from 37.5 Gy in 15 fractions (dose level [DL] 1). DL2 and DL3 were designed to reach 42.5 Gy in 17 fractions and 47.5 Gy in 19 fractions, respectively. Results: No dose-limiting toxicity was observed at DL1 or DL2. Of the 3 patients treated at DL3, 1 presented with Grade 3 diarrhea, which was considered a dose-limiting toxicity, and 3 additional patients were added. Of the 6 patients treated at DL3, no new dose-limiting toxicities were observed, and DL3 was identified as the recommended dose in this study. Eight additional patients were treated at 47.5 Gy. Grade 2 proctitis was the most frequent adverse event (40%); Grade 3 diarrhea occurred in 2 patients (10%). All patients underwent surgery, and 17 patients (85%) underwent R0 resection. Four patients (20%) presented with a histologic response of Grade 4, 11 (55%) with Grade 3+, 2 (15%) with Grade 3, and 2 patients (10%) with Grade 2. Conclusion: The maximal tolerated dose in this study was 47.5 Gy. The high rates of pathologic response of Grade 3+ and 4 must be confirmed through the accrual of new patients in the Phase II study.

  19. Radiation Therapy Oncology Group 0247: A Randomized Phase II Study of Neoadjuvant Capecitabine and Irinotecan or Capecitabine and Oxaliplatin With Concurrent Radiotherapy for Patients With Locally Advanced Rectal Cancer

    SciTech Connect

    Wong, Stuart J.; Winter, Kathryn; Meropol, Neal J.; Anne, Pramila Rani; Kachnic, Lisa; Rashid, Asif; Watson, James C.; Mitchell, Edith; Pollock, Jondavid; Lee, Robert Jeffrey; Haddock, Michael; Erickson, Beth A.; Willett, Christopher G.

    2012-03-15

    Purpose: To evaluate the rate of pathologic complete response (pCR) and the toxicity of two neoadjuvant chemoradiotherapy (chemoRT) regimens for Stage T3-T4 rectal cancer in a randomized Phase II study. Methods and Materials: Patients with Stage T3 or T4 rectal cancer of <12 cm from the anal verge were randomized to preoperative RT (50.4 Gy in 1.8-Gy fractions) with concurrent capecitabine (1,200 mg/m{sup 2}/d Mondays through Friday) and irinotecan (50 mg/m{sup 2} weekly in four doses) (Arm 1) or concurrent capecitabine (1,650 mg/m{sup 2}/d Monday through Friday) and oxaliplatin (50 mg/m{sup 2} weekly in five doses) (Arm 2). Surgery was performed 4-8 weeks after chemoRT, and adjuvant chemotherapy 4-6 weeks after surgery. The primary endpoint was the pCR rate, requiring 48 evaluable patients per arm. Results: A total of 146 patients were enrolled. The protocol chemotherapy was modified because of excessive gastrointestinal toxicity after treatment of 35 patients; 96 were assessed for the primary endpoint-the final regimen described above. The patient characteristics were similar for both arms. After chemoRT, the rate of tumor downstaging was 52% and 60% and the rate of nodal downstaging (excluding N0 patients) was 46% and 40%, for Arms 1 and 2, respectively. The pCR rate for Arm 1 was 10% and for Arm 2 was 21%. For Arm 1 and 2, the preoperative chemoRT rate of Grade 3-4 hematologic toxicity was 9% and 4% and the rate of Grade 3-4 nonhematologic toxicity was 26% and 27%, respectively. Conclusions: Preoperative chemoRT with capecitabine plus oxaliplatin for distal rectal cancer has significant clinical activity (10 of 48 pCRs) and acceptable toxicity. This regimen is currently being evaluated in a Phase III randomized trial (National Surgical Adjuvant Breast and Bowel Project R04).

  20. Phase I Study of Oxaliplatin in Combination With Capecitabine and Radiotherapy as Postoperative Treatment for Stage II and III Rectal Cancer

    SciTech Connect

    Jin Jing

    2008-11-01

    Purpose: A Phase I study was conducted to determine the maximal tolerated dose and the dose-limiting toxicity (DLT) of oxaliplatin (OXA) combined with capecitabine and radiotherapy as adjuvant treatment in patients with operable rectal cancer. Patients and Methods: A total of 21 patients with Stage II or III rectal adenocarcinoma after curative surgery were treated with radiotherapy to a total dose of 50 Gy in 5 weeks. OXA was administered at a dosage of 40 (n = 6), 50 (n = 3),60 (n = 3), 70 (n = 3), or 80 mg/m{sup 2} (n = 6) once a week for 2 weeks (first cycle) followed by a second cycle after a 7-day break. Capecitabine at a fixed dose of 1,300 mg/m{sup 2}/d was administered orally at the same schedule as for OXA. DLT was defined as Grade 3 or 4 hematologic and nonhematologic toxicity. Results: Grade 1-3 leukopenia, diarrhea, and nausea/vomiting were the most common toxic side effects, and most were Grade 1-2. A DLT was first observed in 1 of 3 patients at 40 mg/m{sup 2} (Grade 3 diarrhea) but was not observed in the next 3 patients at the same level or in patients who received a dose level of 50-70 mg/m{sup 2}. At 80 mg/m{sup 2}, DLT occurred in 3 of 6 patients (1 Grade 4 leukopenia and 2 Grade 3 diarrhea). Conclusions: OXA combined with a fixed dose of capecitabine at 625 mg/m{sup 2} twice daily by mouth plus radiotherapy in the adjuvant setting was tolerable and clinically feasible. The maximal tolerated dose of OXA in this setting was 80 mg/m{sup 2}, comparable to the maximal tolerated dose of OXA in the neoadjuvant setting.

  1. Preoperative Chemoradiation Therapy With Capecitabine/Oxaliplatin and Cetuximab in Rectal Cancer: Long-Term Results of a Prospective Phase 1/2 Study

    SciTech Connect

    Fokas, Emmanouil; Conradi, Lena; Weiss, Christian; Sprenger, Thilo; Middel, Peter; Rau, Tillman; Dellas, Kathrin; Kitz, Julia; Rödel, Franz; Sauer, Rolf; Rüschoff, Josef; Beissbarth, Tim; Arnold, Dirk; Ghadimi, B. Michael; Rödel, Claus; Liersch, Torsten

    2013-12-01

    Purpose: We have previously shown that the addition of cetuximab to chemoradiation therapy failed to improve complete response rates (pCR) in rectal cancer. Here we report the long-term results of the cetuximab added to preoperative radiation therapy with capecitabine and oxaliplatin (CET-CAPOX-RT) phase 1/2 study that evaluated preoperative chemoradiation with cetuximab, capecitabine, and oxaliplatin in patients with rectal cancer. Methods and Materials: The median follow-up was 63 months (range, 5-73 months). Sixty patients were enrolled; 3 patients were excluded due to protocol violation, and 4 died before surgery. Total mesorectal excision was performed in 53 patients, in 85% (n=45) with curative intention (M0-status). Secondary end points including overall survival (OS) disease-free survival (DFS) and cancer-specific survival (CSS) were calculated. The prognostic value of KRAS mutation status was also assessed. Results: Histopathological examination confirmed ypUICC stages 0 (n=4; pCR), I (n=17), II (n=10), III (n=14), and IV (n=8). For patients who underwent surgery (n=53), OS at 1, 3, and 5 years was 88.7%, 83%, and 75.5%, respectively, whereas CSS rates were 94.1%, 88.1%, and 78.1%, respectively. In the 45 patients who were treated with curative intent (M0), the OS rates at 1, 3, and 5 years were 91.1%, 88.9%, and 86.7%, respectively; whereas CSS rates were 97.6%, 95.2%, and 90.3%, respectively; and DFS rates were 90.7%, 88.3%, and 88.3%, respectively. We did not find any locoregional failure in patients with M0-status (n=45). Chronic toxicity was rare. KRAS mutations, as detected in 33.3%, showed no correlation with the clinicopathological parameters nor significance for either OS (P=.112), CSS (P=.264), or DFS (P=.565). Conclusions: Taken together, chemoradiation therapy combined with cetuximab is safe, feasible, and offers excellent survival rates. KRAS mutation status was not a predictive factor. Importantly, lack of improvement in pCR rate did not

  2. Neoadjuvant Sandwich Treatment With Oxaliplatin and Capecitabine Administered Prior to, Concurrently With, and Following Radiation Therapy in Locally Advanced Rectal Cancer: A Prospective Phase 2 Trial

    SciTech Connect

    Gao, Yuan-Hong; Lin, Jun-Zhong; An, Xin; Luo, Jie-Lin; Cai, Mu-Yan; Cai, Pei-Qiang; Kong, Ling-Heng; Liu, Guo-Chen; Tang, Jing-Hua; Chen, Gong; Pan, Zhi-Zhong; Ding, Pei-Rong

    2014-12-01

    Purpose: Systemic failure remains the major challenge in management of locally advanced rectal cancer (LARC). To optimize the timing of neoadjuvant treatment and enhance systemic control, we initiated a phase 2 trial to evaluate a new strategy of neoadjuvant sandwich treatment, integrating induction chemotherapy, concurrent chemoradiation therapy, and consolidation chemotherapy. Here, we present preliminary results of this trial, reporting the tumor response, toxicities, and surgical complications. Methods and Materials: Fifty-one patients with LARC were enrolled, among which were two patients who were ineligible because of distant metastases before treatment. Patients were treated first with one cycle of induction chemotherapy consisting of oxaliplatin, 130 mg/m² on day 1, with capecitabine, 1000 mg/m² twice daily for 14 days every 3 weeks (the XELOX regimen), followed by chemoradiation therapy, 50 Gy over 5 weeks, with the modified XELOX regimen (oxaliplatin 100 mg/m²), and then with another cycle of consolidation chemotherapy with the XELOX regimen. Surgery was performed 6 to 8 weeks after completion of radiation therapy. Tumor responses, toxicities, and surgical complications were recorded. Results: All but one patent completed the planned schedule of neoadjuvant sandwich treatment. Neither life-threatening blood count decrease nor febrile neutropenia were observed. Forty-five patents underwent optimal surgery with total mesorectal excision (TME). Four patients refused surgery because of clinically complete response. There was no perioperative mortality in this cohort. Five patients (11.1%) developed postoperative complications. Among the 45 patients who underwent TME, pathologic complete response (pCR), pCR or major regression, and at least moderate regression were achieved in 19 (42.2%), 37 (82.2%), and 44 patients (97.8%), respectively. Conclusions: Preliminary results suggest that the strategy of neoadjuvant sandwich treatment using XELOX regimen

  3. The potential predictive role of nuclear NHERF1 expression in advanced gastric cancer patients treated with epirubicin/oxaliplatin/capecitabine first line chemotherapy.

    PubMed

    Mangia, Anita; Caldarola, Lucia; Dell'Endice, Stefania; Scarpi, Emanuela; Saragoni, Luca; Monti, Manlio; Santini, Daniele; Brunetti, Oronzo; Simone, Giovanni; Silvestris, Nicola

    2015-01-01

    Cellular resistance in advanced gastric cancer (GC) might be related to function of multidrug resistance (MDR) proteins. The adaptor protein NHERF1 (Na(+)/H(+) exchanger regulatory factor) is an important player in cancer progression for a number of solid malignancies, even if its role to develop drug resistance remains uncertain. Herein, we aimed to analyze the potential association between NHERF1 expression and P-gp, sorcin and HIF-1α MDR-related proteins in advanced GC patients treated with epirubicin/oxaliplatin/capecitabine (EOX) chemotherapy regimen, and its relation to response. Total number of 28 untreated patients were included into the study. Expression and subcellular localization of all proteins were assessed by immunohistochemistry on formalin-fixed paraffin embedded tumor samples. We did not found significant association between NHERF1 expression and the MDR-related proteins. A trend was observed between positive cytoplasmic NHERF1 (cNHERF1) expression and negative nuclear HIF-1α (nHIF-1α) expression (68.8% versus 31.3% respectively, P = 0.054). However, cytoplasmic P-gp (cP-gp) expression was positively correlated with both cHIF-1α and sorcin expression (P = 0.011; P = 0.002, respectively). Interestingly, nuclear NHERF1 (nNHERF1) staining was statistically associated with clinical response. In detail, 66.7% of patients with high nNHERF1 expression had a disease control rate, while 84.6% of subjects with negative nuclear expression of the protein showed progressive disease (P = 0.009). Multivariate analysis confirmed a significant correlation between nNHERF1 and clinical response (OR 0.06, P = 0.019). These results suggest that nuclear NHERF1 could be related to resistance to the EOX regimen in advanced GC patients, identifying this marker as a possible independent predictive factor. PMID:26126066

  4. The potential predictive role of nuclear NHERF1 expression in advanced gastric cancer patients treated with epirubicin/oxaliplatin/capecitabine first line chemotherapy

    PubMed Central

    Mangia, Anita; Caldarola, Lucia; Dell'Endice, Stefania; Scarpi, Emanuela; Saragoni, Luca; Monti, Manlio; Santini, Daniele; Brunetti, Oronzo; Simone, Giovanni; Silvestris, Nicola

    2015-01-01

    Cellular resistance in advanced gastric cancer (GC) might be related to function of multidrug resistance (MDR) proteins. The adaptor protein NHERF1 (Na+/H+ exchanger regulatory factor) is an important player in cancer progression for a number of solid malignancies, even if its role to develop drug resistance remains uncertain. Herein, we aimed to analyze the potential association between NHERF1 expression and P-gp, sorcin and HIF-1α MDR-related proteins in advanced GC patients treated with epirubicin/oxaliplatin/capecitabine (EOX) chemotherapy regimen, and its relation to response. Total number of 28 untreated patients were included into the study. Expression and subcellular localization of all proteins were assessed by immunohistochemistry on formalin-fixed paraffin embedded tumor samples. We did not found significant association between NHERF1 expression and the MDR-related proteins. A trend was observed between positive cytoplasmic NHERF1 (cNHERF1) expression and negative nuclear HIF-1α (nHIF-1α) expression (68.8% versus 31.3% respectively, P = 0.054). However, cytoplasmic P-gp (cP-gp) expression was positively correlated with both cHIF-1α and sorcin expression (P = 0.011; P = 0.002, respectively). Interestingly, nuclear NHERF1 (nNHERF1) staining was statistically associated with clinical response. In detail, 66.7% of patients with high nNHERF1 expression had a disease control rate, while 84.6% of subjects with negative nuclear expression of the protein showed progressive disease (P = 0.009). Multivariate analysis confirmed a significant correlation between nNHERF1 and clinical response (OR 0.06, P = 0.019). These results suggest that nuclear NHERF1 could be related to resistance to the EOX regimen in advanced GC patients, identifying this marker as a possible independent predictive factor. PMID:26126066

  5. Preoperative Radiotherapy of Advanced Rectal Cancer With Capecitabine and Oxaliplatin With or Without Cetuximab: A Pooled Analysis of Three Prospective Phase I-II Trials

    SciTech Connect

    Weiss, Christian; Arnold, Dirk; Dellas, Kathrin; Liersch, Torsten; Hipp, Matthias; Fietkau, Rainer; Sauer, Rolf; Hinke, Axel; Roedel, Claus

    2010-10-01

    Purpose: A pooled analysis of three prospective trials of preoperative radiochemotherapy (RCT) for rectal cancer by using oxaliplatin and capecitabine with or without cetuximab was performed to evaluate the impact of additional cetuximab on pathologic complete response (pCR) rates and tumor regression (TRG) grades. Methods and Materials: Of 202 patients, 172 patients met the inclusion criteria (primary tumor stage II/III, M0). All patients received concurrent RCT, and 46 patients received additional cetuximab therapy. A correlation of pretreatment clinicopathologic factors and cetuximab treatment with early pCR rates (TRG > 50%) was performed with univariate and multivariate analyses. Toxicity data were recorded for all patients. Results: Of 172 patients, 24 (14%) patients achieved a pCR, and 84 of 172 (71%) patients showed a TRG of >50% in the surgical specimen assessment after preoperative treatment. Age, gender, and T/N stages, as well as localization of the tumor, were not associated with pCR or good TRG. The pCR rate was 16% after preoperative RCT alone and 9% with concurrent cetuximab therapy (p = 0.32). A significantly reduced TRG of >50% was found after RCT with cetuximab compared to RCT alone (p = 0.0035). This was validated by a multivariate analysis with all available clinical factors (p = 0.0037). Acute toxicity and surgical complications were not increased with additional cetuximab. Conclusions: Triple therapy with RCT and cetuximab seems to be feasible, with no unexpected toxicity. Early response assessment (TRG), however, suggests subadditive interaction. A longer follow-up (and finally randomized trials) is needed to draw any firm conclusions with respect to local and distant failure rates.

  6. Patterns of Response After Preoperative Intensity-Modulated Radiation Therapy and Capecitabine/Oxaliplatin in Rectal Cancer: Is There Still a Place for Ecoendoscopic Ultrasound?

    SciTech Connect

    Arbea, Leire; Diaz-Gonzalez, Juan A.; Subtil, Jose Carlos; Sola, Josu; Hernandez-Lizoain, Jose Luis; Martinez-Monge, Rafael; Moreno, Marta; Aristu, Javier

    2011-10-01

    Purpose: The main goals of preoperative chemoradiotherapy (CHRT) in rectal cancer are to achieve pathological response and to ensure tumor control with functional surgery when possible. Assessment of the concordance between clinical and pathological responses is necessary to make decisions regarding alternative conservative procedures. The present study evaluates the patterns of response after a preoperative CHRT regimen, and the value of endoscopic ultrasound (EUS) in assessing response. Methods and Materials: A total of 51 EUS-staged T3 to T4 and/or N0 to N+ rectal cancer patients received preoperative CHRT (intensity-modulated radiation therapy and capecitabine/oxaliplatin (XELOX) followed by radical resection. Clinical response was assesed by EUS. Rates of pathological tumor regression grade (TRG) and lymph node (LN) involvement were determined in the surgical specimen. Clinical and pathological responses were compared, and the accuracy of EUS in assessing response was calculated. Results: Twenty-four patients (45%) achieved a major pathological response (complete or >95% pathological response (TRG 3+/4)). Sensitivity, specificity, negative predictive value, and positive predictive value of EUS in predicting pathological T response after preoperative CHRT were 77.8%, 37.5%, 60%, and 58%, respectively. The EUS sensitivity, specificity, negative predictive value, and positive predictive value for nodal staging were 44%, 88%, 88%, and 44%, respectively. Furthermore, EUS after CHRT accurately predicted the absence of LN involvement in 7 of 7 patients (100%) with major pathological response of the primary tumor. Conclusion: Preoperative IMRT with concomitant XELOX induces favorable rates of major pathological response. EUS has a limited ability to predict primary tumor response after preoperative CHRT, but it is useful for accurately determining LN status. EUS may have a potential value in identifying patients with a very low risk of LN involvement in association

  7. Protocol of a randomised phase III clinical trial of sequential capecitabine or 5-fluorouracil plus bevacizumab (Cape/5-FU-Bmab) to capecitabine or 5-fluorouracil plus oxaliplatin plus bevacizumab (CapeOX/mFOLFOX6-Bmab) versus combination CapeOX/mFOLFOX6-Bmab in advanced colorectal cancer: the C-cubed (C3) study

    PubMed Central

    Mishima, Hideyuki; Sawaki, Akira; Shimokawa, Mototsugu; Inukai, Michio; Shinozaki, Katsunori; Tanioka, Hiroaki; Nasu, Junichiro; Nishina, Tomohiro; Hazama, Shoichi; Okajima, Masazumi; Yamaguchi, Yoshiyuki

    2016-01-01

    Introduction Results from several randomised trials suggest that the sequential use of cytotoxic agents in patients with metastatic colorectal cancer (mCRC) has the potential to improve overall survival compared with combination chemotherapy. This study is designed to investigate whether sequential treatment with bevacizumab-based first-line treatment with oxaliplatin is superior to combination treatment of mCRC. Methods and analysis The C-cubed (C3) study is a two-arm, multicentre, open-label, randomised phase III trial in Japan comparing the efficacy and safety of sequential capecitabine or 5-fluorouracil plus bevacizumab (Cape/5-FU-Bmab) with escalation to capecitabine or 5-fluorouracil plus oxaliplatin plus bevacizumab (CapeOX/mFOLFOX6-Bmab) versus combination CapeOX/mFOLFOX6-Bmab as the first-line treatment of mCRC. In the sequential arm (Arm A: oxaliplatin ‘wait-and-go’), treatment escalation from Cape/5-FU-Bmab to CapeOX/mFOLFOX6-Bmab is recommended in the case of progressive disease. In the combination arm (Arm B: oxaliplatin ‘stop-and-go’), de-escalation from CapeOX/mFOLFOX6-Bmab to Cape/5-FU-Bmab is possible after 12 weeks of treatment. Re-escalation to CapeOX/mFOLFOX6-Bmab after progressive disease is considered only for patients who received de-escalation of oxaliplatin after 12 weeks of treatment not caused by oxaliplatin-associated toxicity. A target sample size of 304 evaluable patients is considered sufficient to validate an expected HR for time to failure of strategy of the sequential approach ‘wait-and-go’ compared to the combination approach ‘stop-and go’ with 80% power and 2-sided 5% α in case of a true HR<0.69. Ethics and dissemination This study is conducted according to the standards of Good Clinical Practice and in compliance with the Declaration of Helsinki 2013 and local regulations, and has been submitted and approved by the Ethical Committee of the Non-Profit Organization MINS Institutional Review Board. The protocol

  8. NRG Oncology Radiation Therapy Oncology Group 0822: A Phase 2 Study of Preoperative Chemoradiation Therapy Using Intensity Modulated Radiation Therapy in Combination With Capecitabine and Oxaliplatin for Patients With Locally Advanced Rectal Cancer

    SciTech Connect

    Hong, Theodore S.; Moughan, Jennifer; Garofalo, Michael C.; Bendell, Johanna; Berger, Adam C.; Oldenburg, Nicklas B.E.; Anne, Pramila Rani; Perera, Francisco; Jabbour, Salma K.; Nowlan, Adam; DeNittis, Albert; Crane, Christopher

    2015-09-01

    Purpose: To evaluate the rate of gastrointestinal (GI) toxicity of neoadjuvant chemoradiation with capecitabine, oxaliplatin, and intensity modulated radiation therapy (IMRT) in cT3-4 rectal cancer. Methods and Materials: Patients with localized, nonmetastatic T3 or T4 rectal cancer <12 cm from the anal verge were enrolled in a prospective, multi-institutional, single-arm study of preoperative chemoradiation. Patients received 45 Gy with IMRT in 25 fractions, followed by a 3-dimensional conformal boost of 5.4 Gy in 3 fractions with concurrent capecitabine/oxaliplatin (CAPOX). Surgery was performed 4 to 8 weeks after the completion of therapy. Patients were recommended to receive FOLFOX chemotherapy after surgery. The primary endpoint of the study was acute grade 2 to 5 GI toxicity. Seventy-one patients provided 80% probability to detect at least a 12% reduction in the specified GI toxicity with the treatment of CAPOX and IMRT, at a significance level of .10 (1-sided). Results: Seventy-nine patients were accrued, of whom 68 were evaluable. Sixty-one patients (89.7%) had cT3 disease, and 37 (54.4%) had cN (+) disease. Postoperative chemotherapy was given to 42 of 68 patients. Fifty-eight patients had target contours drawn per protocol, 5 patients with acceptable variation, and 5 patients with unacceptable variations. Thirty-five patients (51.5%) experienced grade ≥2 GI toxicity, 12 patients (17.6%) experienced grade 3 or 4 diarrhea, and pCR was achieved in 10 patients (14.7%). With a median follow-up time of 3.98 years, the 4-year rate of locoregional failure was 7.4% (95% confidence interval [CI]: 1.0%-13.7%). The 4-year rates of OS and DFS were 82.9% (95% CI: 70.1%-90.6%) and 60.6% (95% CI: 47.5%-71.4%), respectively. Conclusion: The use of IMRT in neoadjuvant chemoradiation for rectal cancer did not reduce the rate of GI toxicity.

  9. Combination therapies with oxaliplatin and oral capecitabine or intravenous 5-FU show similar toxicity profiles in gastrointestinal carcinoma patients if hand-food syndrome prophylaxis is performed continuously

    PubMed Central

    WEHLER, THOMAS C.; CAO, YANG; GALLE, PETER R.; THEOBALD, MATTHIAS; MOEHLER, MARKUS; SCHIMANSKI, CARL C.

    2012-01-01

    The use of anticancer drugs in palliative settings is often limited by their severe toxic effects. In gastrointestinal carcinomas the 5-fluorouracil-based palliative regimen FOLFOX-4 is often preferred to the equally effective, but more convenient oral capecitabine-based regimen XELOX. This preference is mainly based on the fact that the highly effective oral agent capecitabine induces hand-foot syndrome (HFS). In this study, we investigated whether the continuous administration of skin prophylaxis (10% urea, panthenol, bisabolol, vitamin A, C and E) is capable of protecting against capecitabine-induced HFS and allowing a more convenient oral therapeutic option. In this retrospective analysis, the toxicity profiles, according to NCI CTCAE 3.0 criteria, of 54 patients with gastrointestinal cancer who received either XELOX (34 patients) or FOLFOX-4 (20 patients) were compared using Fisher tests. The treatment protocols that were compared, herein, did not differ significantly in the majority of the analyzed items, with the exception of increased nausea (XELOX-70), fatigue (XELOX-130) and tumor pain (XELOX-70 and XELOX-130). No significant differences were observed among the various groups with regard to emesis, diarrhea, mucositis, exanthema, alopecia, loss of weight and the incidence of infections. In particular, no significant differences in toxicity levels occurred in terms of dose, and HFS was limited if skin prophylaxis was performed continuously. XELOX-based palliative regimens provide an equally effective and comparably toxic therapeutic alternative to FOLFOX-4 if HFS prophylaxis is performed continuously. Since the oral administration of capecitabine is a more convenient method of application, it provides patients with a quality of life-preserving therapeutic alternative. PMID:22783416

  10. Combination therapies with oxaliplatin and oral capecitabine or intravenous 5-FU show similar toxicity profiles in gastrointestinal carcinoma patients if hand-food syndrome prophylaxis is performed continuously.

    PubMed

    Wehler, Thomas C; Cao, Yang; Galle, Peter R; Theobald, Matthias; Moehler, Markus; Schimanski, Carl C

    2012-06-01

    The use of anticancer drugs in palliative settings is often limited by their severe toxic effects. In gastrointestinal carcinomas the 5-fluorouracil-based palliative regimen FOLFOX-4 is often preferred to the equally effective, but more convenient oral capecitabine-based regimen XELOX. This preference is mainly based on the fact that the highly effective oral agent capecitabine induces hand-foot syndrome (HFS). In this study, we investigated whether the continuous administration of skin prophylaxis (10% urea, panthenol, bisabolol, vitamin A, C and E) is capable of protecting against capecitabine-induced HFS and allowing a more convenient oral therapeutic option. In this retrospective analysis, the toxicity profiles, according to NCI CTCAE 3.0 criteria, of 54 patients with gastrointestinal cancer who received either XELOX (34 patients) or FOLFOX-4 (20 patients) were compared using Fisher tests. The treatment protocols that were compared, herein, did not differ significantly in the majority of the analyzed items, with the exception of increased nausea (XELOX-70), fatigue (XELOX-130) and tumor pain (XELOX-70 and XELOX-130). No significant differences were observed among the various groups with regard to emesis, diarrhea, mucositis, exanthema, alopecia, loss of weight and the incidence of infections. In particular, no significant differences in toxicity levels occurred in terms of dose, and HFS was limited if skin prophylaxis was performed continuously. XELOX-based palliative regimens provide an equally effective and comparably toxic therapeutic alternative to FOLFOX-4 if HFS prophylaxis is performed continuously. Since the oral administration of capecitabine is a more convenient method of application, it provides patients with a quality of life-preserving therapeutic alternative. PMID:22783416

  11. Future treatment options with capecitabine in solid tumours.

    PubMed

    Wilke, H

    2002-02-01

    The oral fluoropyrimidine, capecitabine is attracting great interest in the context of tumour-selective therapy and rationally designed combination regimens. Agents such as taxanes upregulate thymidine phosphorylase (TP), and there is therefore a clear rationale for their combination with capecitabine. Preclinical studies of capecitabine/taxane combination therapy demonstrated synergistic antitumour activity and phase I studies showed encouraging efficacy. Therefore, a randomised, phase III trial (docetaxel versus docetaxel/capecitabine) has been initiated in anthracycline-refractory metastatic breast cancer patients. Recruitment is complete. In colorectal cancer, capecitabine/oxaliplatin combination therapy is promising and a phase I, dose-finding trial has been conducted in patients with refractory metastatic solid tumours. A similar trial has evaluated capecitabine/irinotecan combination treatment. Capecitabine is also being investigated as adjuvant therapy for colorectal and breast cancers. The primary objective of the ongoing X-ACT trial in almost 2000 Dukes' C colon cancer patients is to demonstrate at least equivalent disease-free survival between capecitabine and the Mayo Clinic regimen. In addition, the CALGB is planning a randomised, phase III trial of capecitabine versus doxorubicin/cyclophosphamide or cyclophosphamide/methotrexate/5-fluorouracil (CMF) as adjuvant treatment in high-risk, node-negative breast cancer patients aged >65 years. PMID:11841932

  12. Correlation of bevacizumab-induced hypertension and outcome in the BOXER study, a phase II study of capecitabine, oxaliplatin (CAPOX) plus bevacizumab as peri-operative treatment in 45 patients with poor-risk colorectal liver-only metastases unsuitable for upfront resection

    PubMed Central

    Dewdney, A; Cunningham, D; Barbachano, Y; Chau, I

    2012-01-01

    Background: Bevacizumab is commonly used in combination with chemotherapy in the treatment of metastatic colorectal cancer, but to date, despite extensive research, no predictive or prognostic biomarkers for bevacizumab have been identified. The development of bevacizumab-induced arterial hypertension has recently been suggested as a potential predictive biomarker. Methods: Blood pressure was recorded during the BOXER study, a phase II study of capecitabine, oxaliplatin (CAPOX) plus bevacizumab as peri-operative treatment in 45 patients with poor-risk colorectal liver-only metastases unsuitable for upfront resection. In this analysis, the development of bevacizumab-induced hypertension was correlated with clinical outcomes. Results: Fifteen percent of patients developed ⩾grade 1 hypertension while receiving neoadjuvant chemotherapy, and 4% developed grade 3 hypertension. There was no correlation between the development of hypertension and radiological response rate (P=0.642), progression-free survival (P=0.644) or overall survival (P=0.480) in those who developed hypertension compared with those who did not. Conclusion: Bevacizumab-induced hypertension did not predict radiological response or survival in our study. The results highlight a number of important issues regarding the use of hypertension as a biomarker. PMID:22531628

  13. Capecitabine Induced Multifocal Leukoencephalopathy: Do We Have Always to Switch off the Chemotherapy?

    PubMed

    Bougea, Anastasia; Voskou, Panagiota; Kilidireas, Constantinos; Andreadou, Elisabeth

    2016-01-01

    Capecitabine is a well tolerated and safe 5-fluorouracil agent for adjuvant, neoadjuvant chemotherapy or metastatic cases. Neurological side effects require discontinuation of chemotherapy. We report this unique case of a 50-year-old female, who presented an isolated episode of dysarthria and ataxia under bevacizumab, capecitabine, and oxaliplatin treatment due to reversible multifocal leukoencephalopathy that did not recur after readministration of chemotherapy. PMID:26966603

  14. The integration of oral capecitabine into chemoradiation regimens for locally advanced rectal cancer: how successful have we been?

    PubMed

    Glynne-Jones, R; Dunst, J; Sebag-Montefiore, D

    2006-03-01

    The aim was to review available literature on capecitabine-based chemoradiation regimens for the preoperative treatment of patients with locally advanced rectal cancer (LARC) and determine efficacy and safety data for capecitabine in this setting. Medical literature databases (Pubmed, Medline) and abstracts/posters presented at recent scientific congresses (ASCO, ASTRO, ESTRO and ECCO) were screened and critically analysed to identify relevant data. A number of phase I/II studies have demonstrated that capecitabine is effective and well tolerated in combination with preoperative radiotherapy in patients with LARC. Phase III studies are ongoing. Continuous oral administration of capecitabine (825 mg/m(2) twice daily for 7 days/week) is an effective regimen and has similar tolerability to the less dose-intensive intermittent regimens of capecitabine given 5 days/week followed by 2 day's rest or 14 days followed by 7 day's rest as used in systemic chemotherapy for patients with colorectal or breast cancer. Capecitabine chemoradiation is associated with a relatively low rate of grade 3/4 adverse events. Capecitabine simplifies chemoradiation and provides a convenient treatment option for both patients and health care professionals. Combining capecitabine with cytotoxic agents such as oxaliplatin and irinotecan has the potential to further improve antitumour efficacy in patients receiving preoperative chemoradiation. Data from phase I/II single-agent and combination capecitabine chemoradiation studies provide a clear rationale for replacing infusional 5-FU with oral capecitabine as part of chemoradiation for patients with LARC. PMID:16500912

  15. Clinical Features of Oxaliplatin Induced Hypersensitivity Reactions and Therapeutic Approaches.

    PubMed

    Bano, Nusrat; Najam, Rahila; Qazi, Faaiza; Mateen, Ahmed

    2016-01-01

    Oxaliplatin, a third generation novel platinum compound is the most effective first line chemotherapeutic agent for colorectal cancer (CRC) in combination with 5FU and leucovorin. It is indicated for pancreatic, gastric and testicular cancers combined with bevacuzimab, capecitabine, irinotecan and other cytotoxic agents. However, moderate to severe hypersensitivity reactions (HSR) during or after oxaliplatin infusion usually require cessation of chemotherapy or substitution of the key therapeutic drug which largely interferes with improved patient prognosis. This mini- review showcases recent and accepted opinions/approaches in oxaliplatin induced HSR management. Physicians and oncologists have varying attitudes regarding the decision to rechallenge the patient after an HSR experience, efficacy of desensitization protocols, effectiveness and selection of drugs for premedication and possibilities of cross sensitivity to other platinum agents (e.g. carboplatin). A brief insight into underlying molecular mechanisms and clinical manifestations of oxaliplatin induced HSR is offered. We have also discussed the management of oxaliplatin induced HSR and risk stratification for a successful and complete chemotherapeutic plan. PMID:27221832

  16. A single-arm Phase II validation study of preventing oxaliplatin-induced hypersensitivity reactions by dexamethasone: the AVOID trial

    PubMed Central

    Yoshida, Yoichiro; Hirata, Keiji; Matsuoka, Hiroshi; Iwamoto, Shigeyoshi; Kotaka, Masahito; Fujita, Hideto; Aisu, Naoya; Hoshino, Seiichiro; Kosaka, Takeo; Maeda, Kotaro; Kiyomi, Fumiaki; Yamashita, Yuichi

    2015-01-01

    Background Patients with colorectal cancer treated with oxaliplatin are at risk of hypersensitivity reactions, with the incidence estimated to be 12%–20%. Coinfusion of dexamethasone and oxaliplatin could potentially reduce the incidence of these reactions, but oxaliplatin is reported to be incompatible with alkaline compounds in solution. However, in a previous retrospective study we found that the pH of a solution of dexamethasone and oxaliplatin was less than 7.4, and that hypersensitivity to oxaliplatin could have been prevented by coinfusion of dexamethasone. We aimed to evaluate the effectiveness of coinfusion of dexamethasone and oxaliplatin to prevent oxaliplatin-induced hypersensitivity reactions. Patients and methods The AVOID trial was a prospective, multicenter, open-label, single-arm Phase II trial conducted from January to September 2013. The study included 73 patients who received capecitabine plus oxaliplatin (XELOX) or XELOX plus bevacizumab therapy for colorectal cancer. In all patients, oxaliplatin was administered in combination with dexamethasone. The primary outcome measure was the presence of hypersensitivity reactions. Results Hypersensitivity reactions occurred in three patients (4.1%); all three experienced a cutaneous reaction (grade 1 erythema). None of the 73 patients developed respiratory symptoms, ocular symptoms, or anaphylaxis. Grade 3 or higher hemotoxicity occurred in 13.7% of the patients and grade 3 or higher nonhematological toxicity occurred in 13.7%. The response rate to treatment was 64.4%. Conclusion The coinfusion of dexamethasone and oxaliplatin effectively reduced oxaliplatin-induced hypersensitivity reactions in patients with colorectal cancer. This approach should be considered for all patients treated with oxaliplatin, allowing treatment to be completed as planned. PMID:26648694

  17. Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes' C colon cancer: the X-ACT trial

    PubMed Central

    Cassidy, J; Douillard, J-Y; Twelves, C; McKendrick, J J; Scheithauer, W; Bustová, I; Johnston, P G; Lesniewski-Kmak, K; Jelic, S; Fountzilas, G; Coxon, F; Díaz-Rubio, E; Maughan, T S; Malzyner, A; Bertetto, O; Beham, A; Figer, A; Dufour, P; Patel, K K; Cowell, W; Garrison, L P

    2006-01-01

    Oral capecitabine (Xeloda®) is an effective drug with favourable safety in adjuvant and metastatic colorectal cancer. Oxaliplatin-based therapy is becoming standard for Dukes' C colon cancer in patients suitable for combination therapy, but is not yet approved by the UK National Institute for Health and Clinical Excellence (NICE) in the adjuvant setting. Adjuvant capecitabine is at least as effective as 5-fluorouracil/leucovorin (5-FU/LV), with significant superiority in relapse-free survival and a trend towards improved disease-free and overall survival. We assessed the cost-effectiveness of adjuvant capecitabine from payer (UK National Health Service (NHS)) and societal perspectives. We used clinical trial data and published sources to estimate incremental direct and societal costs and gains in quality-adjusted life months (QALMs). Acquisition costs were higher for capecitabine than 5-FU/LV, but higher 5-FU/LV administration costs resulted in 57% lower chemotherapy costs for capecitabine. Capecitabine vs 5-FU/LV-associated adverse events required fewer medications and hospitalisations (cost savings £3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings £1318), with lifetime gain in QALMs of 9 months. Medical resource utilisation is significantly decreased with capecitabine vs 5-FU/LV, with cost savings to the NHS and society. Capecitabine is also projected to increase life expectancy vs 5-FU/LV. Cost savings and better outcomes make capecitabine a preferred adjuvant therapy for Dukes' C colon cancer. This pharmacoeconomic analysis strongly supports replacing 5-FU/LV with capecitabine in the adjuvant treatment of colon cancer in the UK. PMID:16622438

  18. Oxaliplatin-induced posterior reversible encephalopathy syndrome with isolated involvement of pons.

    PubMed

    Tang, Koay Hean

    2015-01-01

    Isolated pontine lesion can be caused by the posterior reversible encephalopathy syndrome (PRES). It does occur in the normotensive patient who is treated with oxaliplatin. We reported a case of 81-year-old Chinese man with metastatic colorectal carcinoma who was initially treated with capecitabine. No significant adverse effects were noted. However, the response to the treatment was poor. Subsequently, Xelox was given. He developed transient altered mental status. Oxaliplatin was thought to be the causative agent and was withheld. Magnetic resonance imaging brain revealed vasogenic edema in the pons that was reversible after 2 weeks, as well as complete resolution of clinical symptoms. Early identification of the reversible cause of isolated pontine lesion, such as chemo, triggered PRES is crucial to facilitate prompt treatment by removing the offending agent or reducing the dose. PMID:26881576

  19. Hypersensitivity reactions associated with oxaliplatin.

    PubMed

    Saif, M Wasif

    2006-09-01

    The reported incidence of hypersensitivity reactions (HSRs) associated with oxaliplatin in patients with colorectal cancer (CRC) is approximately 12%, with 1 - 2% of patients developing grade 3 or 4 in severity. However, the recent rising incidence of HSR to oxaliplatin observed is the result of increasing clinical use. HSR to oxaliplatin may manifest as facial flushing, rash/hives, tachycardia, dyspnoea, erythema, pruritus, fever, tongue swelling, headache, chills, weakness, vomiting, burning sensations, dizziness and oedema. Anaphylactic shock is rare but serious, and must be considered in the event of hypotension. No definitive approaches to prevent and treat HSR associated with oxaliplatin are available; however, few successful strategies have been reported. Such strategies include: slowing the infusion rate, use of steroids and antagonists of type 1 and 2 histamine receptors, and desensitisation. Successful implementation of oxaliplatin desensitisation protocols based on other platinum-containing compounds have been reported, which could enable a small number of patients who experience severe HSR to further receive an effective therapy for CRC. However, reintroductions have only been reported as single case studies or small cohorts. Large-scale validation on desensitisation strategies are still missing. Recently, subcutaneous adrenaline has also been utilised as an alternative approach to manage HSR to oxaliplatin. Knowledge of this rare but real toxicity of oxaliplatin is paramount because the use of this drug continues to increase not only for the treatment of patients with stage II-IV CRC, but also other solid malignancies. In this article, the author discusses the incidence, clinical presentation, pathogenesis, risk factors and current strategies of management of HSR associated with oxaliplatin. PMID:16907658

  20. Slow dissolution behaviour of amorphous capecitabine.

    PubMed

    Meulenaar, Jelte; Beijnen, Jos H; Schellens, Jan H M; Nuijen, Bastiaan

    2013-01-30

    In this article, we report the anomalous dissolution behaviour of amorphous capecitabine. In contrast to what is expected from thermodynamic theory, amorphous capecitabine dissolves significantly slower compared to its crystalline counterpart. Our experiments show that this is due to the "gelling" properties of amorphous capecitabine in an aqueous environment. The "gel", which is immediately formed upon contact with water, entraps the capecitabine and significantly slows down its dissolution. This "gelling" property is hypothesized to be related to the low glass transition temperature (Tg 19°C) of amorphous capecitabine, resulting in an instant collapse ("gelling") in an aqueous environment. From IR and DSC analysis it is shown that this collapsed capecitabine is remarkably stable and does not recrystallize upon an increased water content or temperature. This highly reproducible dissolution behaviour can be applied in the development of a sustained release dosage form as substantially less sustained release excipient is required in order to attain the desired release profile. As capecitabine is a high-dosed drug, this is highly favourable in view of the size and thus clinical feasibility of the final dosage form. Currently, we are developing and clinically testing a sustained release formulation making use of amorphous capecitabine and its remarkable dissolution behaviour. PMID:23219704

  1. Short-time diffusivity of dicolloids.

    PubMed

    Panczyk, Mark M; Wagner, Norman J; Furst, Eric M

    2014-06-01

    The short-time diffusivity of dicolloid particles as a function of particle volume fraction ϕ from 0.01 ≤ ϕ ≤ 0.6 is measured using diffusing wave spectroscopy. The diffusivities of symmetric and asymmetric dicolloids are compared with similarly sized spheres. The short-time diffusivity is independent of salt concentration and decreases with increasing volume fraction for both spheres and asymmetric dicolloids. Symmetric dicolloids have a higher diffusivity than spheres at similar volume fractions. This difference is accounted for by rescaling the dicolloid volume fraction based on the ratio of the random close-packing volume fractions of spheres and dicolloids. Finally, a useful method is provided for calculating the diffusivity of symmetric dicolloid particles of arbitrary aspect ratio based on the calculated hydrodynamic resistance of Zabarankin [Proc. R. Soc. A 463, 2329 (2007)]. PMID:25019780

  2. Transient nanobubbles in short-time electrolysis

    NASA Astrophysics Data System (ADS)

    Svetovoy, Vitaly B.; Sanders, Remco G. P.; Elwenspoek, Miko C.

    2013-05-01

    Water electrolysis in a microsystem is observed and analyzed on a short-time scale of ∼10 μs. The very unusual properties of the process are stressed. An extremely high current density is observed because the process is not limited by the diffusion of electroactive species. The high current is accompanied by a high relative supersaturation, S > 1000, that results in homogeneous nucleation of bubbles. On the short-time scale only nanobubbles can be formed. These nanobubbles densely cover the electrodes and aggregate at a later time to microbubbles. The effect is significantly intensified with a small increase of temperature. Application of alternating polarity voltage pulses produces bubbles containing a mixture of hydrogen and oxygen. Spontaneous reaction between gases is observed for stoichiometric bubbles with sizes smaller than ∼150 nm. Such bubbles disintegrate violently affecting the surfaces of the electrodes.

  3. Transient nanobubbles in short-time electrolysis.

    PubMed

    Svetovoy, Vitaly B; Sanders, Remco G P; Elwenspoek, Miko C

    2013-05-01

    Water electrolysis in a microsystem is observed and analyzed on a short-time scale of ∼10 μs. The very unusual properties of the process are stressed. An extremely high current density is observed because the process is not limited by the diffusion of electroactive species. The high current is accompanied by a high relative supersaturation, S > 1000, that results in homogeneous nucleation of bubbles. On the short-time scale only nanobubbles can be formed. These nanobubbles densely cover the electrodes and aggregate at a later time to microbubbles. The effect is significantly intensified with a small increase of temperature. Application of alternating polarity voltage pulses produces bubbles containing a mixture of hydrogen and oxygen. Spontaneous reaction between gases is observed for stoichiometric bubbles with sizes smaller than ∼150 nm. Such bubbles disintegrate violently affecting the surfaces of the electrodes. PMID:23598648

  4. Palliative oxaliplatin-based chemotherapy after exposure to oxaliplatin in the adjuvant setting for colon cancer

    PubMed Central

    Kumar, Aalok; Lim, Howard John

    2015-01-01

    Background Little is known regarding the efficacy of oxaliplatin-based chemotherapy for metastatic colon cancer patients who have already received adjuvant oxaliplatin-based chemotherapy. Methods We retrospectively reviewed 22 consecutive patients who developed recurrence after adjuvant oxaliplatin-based chemotherapy for stage III colon cancer and received another course of oxaliplatin-based chemotherapy for their metastatic disease. The main endpoint was progression-free survival (PFS). Results A total of 635 patients received oxaliplatin-based chemotherapy for stage III colon cancer at the British Columbia Cancer Agency from 2006 to 2011. A total of 176 patients recurred, 22 (12.5%) of whom were re-exposed to oxaliplatin in the metastatic scenario. Oxaliplatin in combination with fluoropyrimidine was given as first, second and third line in in 3 (13.6%), 14 (63.6%), and 5 (22.7%) patients respectively. Median time from the last cycle of adjuvant oxaliplatin-based chemotherapy to the first cycle of palliative oxaliplatin-based chemotherapy was 44.3 months. Median PFS and overall survival (OS) were 3.3 (95% CI, 1.4-5.1) and 10.0 months (95% CI, 5.3-14.6), respectively. There was no difference in PFS for patients re-exposed to oxaliplatin less than 36 months compared to longer (3.6 versus 3.1 months, P=0.793, HR =0.88). Conclusions In this population-based study, only a small proportion of pts who recurred after oxaliplatin-based adjuvant therapy received oxaliplatin in the metastatic setting. Re-exposure of oxaliplatin in combination with fluoropyrimidine is associated with only modest PFS benefit. Larger studies evaluating the role of oxaliplatin re-exposure are needed. PMID:26487941

  5. Clustering Short Time-Series Microarray

    NASA Astrophysics Data System (ADS)

    Ping, Loh Wei; Hasan, Yahya Abu

    2008-01-01

    Most microarray analyses are carried out on static gene expressions. However, the dynamical study of microarrays has lately gained more attention. Most researches on time-series microarray emphasize on the bioscience and medical aspects but few from the numerical aspect. This study attempts to analyze short time-series microarray mathematically using STEM clustering tool which formally preprocess data followed by clustering. We next introduce the Circular Mould Distance (CMD) algorithm with combinations of both preprocessing and clustering analysis. Both methods are subsequently compared in terms of efficiencies.

  6. Short-time dynamics of polypeptides.

    PubMed

    Arashiro, Everaldo; Drugowich de Felício, J R; Hansmann, Ulrich H E

    2007-01-28

    The authors study the short-time dynamics of helix-forming polypeptide chains using an all-atom representation of the molecules and an implicit solvation model to approximate the interaction with the surrounding solvent. The results confirm earlier observations that the helix-coil transition in proteins can be described by a set of critical exponents. The high statistics of the simulations allows the authors to determine the exponent values with increased precision and support universality of the helix-coil transition in homopolymers and (helical) proteins. PMID:17286517

  7. Failure Prevention by Short Time Corrosion Tests

    SciTech Connect

    MICKALONIS, JOHN

    2005-05-01

    Short time corrosion testing of perforated sheets and wire meshes fabricated from Type 304L stainless steel, Alloy 600 and C276 showed that 304L stainless steel perforated sheet should perform well as the material of construction for dissolver baskets. The baskets will be exposed to hot nitric acid solutions and are limited life components. The corrosion rates of the other alloys and of wire meshes were too high for useful extended service. Test results also indicated that corrosion of the dissolver should drop quickly during the dissolutions due to the inhibiting effects of the corrosion products produced by the dissolution processes.

  8. Effect of KRAS codon13 mutations in patients with advanced colorectal cancer (advanced CRC) under oxaliplatin containing chemotherapy. Results from a translational study of the AIO colorectal study group

    PubMed Central

    2012-01-01

    Background To evaluate the value of KRAS codon 13 mutations in patients with advanced colorectal cancer (advanced CRC) treated with oxaliplatin and fluoropyrimidines. Methods Tumor specimens from 201 patients with advanced CRC from a randomized, phase III trial comparing oxaliplatin/5-FU vs. oxaliplatin/capecitabine were retrospectively analyzed for KRAS mutations. Mutation data were correlated to response data (Overall response rate, ORR), progression-free survival (PFS) and overall survival (OS). Results 201 patients were analysed for KRAS mutation (61.2% males; mean age 64.2 ± 8.6 years). KRAS mutations were identified in 36.3% of tumors (28.8% in codon 12, 7.4% in codon 13). The ORR in codon 13 patients compared to codon 12 and wild type patients was significantly lower (p = 0.008). There was a tendency for a better overall survival in KRAS wild type patients compared to mutants (p = 0.085). PFS in all patients was not different in the three KRAS genetic groups (p = 0.72). However, we found a marked difference in PFS between patients with codon 12 and 13 mutant tumors treated with infusional 5-FU versus capecitabine based regimens. Conclusions Our data suggest that the type of KRAS mutation may be of clinical relevance under oxaliplatin combination chemotherapies without the addition of monoclonal antibodies in particular when overall response rates are important. Trial registration number 2002-04-017 PMID:22876876

  9. Capecitabine: fulfilling the promise of oral chemotherapy.

    PubMed

    Hwang, Jimmy J; Marshall, John L

    2002-06-01

    Capecitabine is a synthetic oral fluoropyrimidine carbamate that is sequentially activated in a three-step process, which results in the preferential production of 5-fluorouracil in tumours, rather than in the normal surrounding tissue. Capecitabine is proven to be as effective as the combination of 5-fluorouracil and leucovorin administered on the Mayo clinic schedule in patients with metastatic colorectal cancer. It has also been proven to be effective in patients with metastatic breast cancer that has progressed despite prior anthracyclines and taxoids. More recently, it has also been shown to increase survival in combination with docetaxel in patients with metastatic breast cancer in comparison to docetaxel alone. This article reviews the pharmacology and clinical activity of capecitabine, as well as combinations of capecitabine with other chemotherapeutic agents and future directions of investigation with this convenient and widely active antitumour therapy. PMID:12036413

  10. Short time cycles of purely quantum refrigerators.

    PubMed

    Feldmann, Tova; Kosloff, Ronnie

    2012-05-01

    Four stroke Otto refrigerator cycles with no classical analog are studied. Extremely short cycle times with respect to the internal timescale of the working medium characterize these refrigerators. Therefore, these cycles are termed sudden. The sudden cycles are characterized by the stable limit cycle, which is the invariant of the global cycle propagator. During their operation the states of the working medium possess significant coherence which is not erased in the equilibration segments due to the very short time allocated. This characteristic is reflected in a difference between the energy entropy and the Von Neumann entropy of the working medium. A classification scheme for sudden refrigerators is developed allowing simple approximations for the cooling power and coefficient of performance. PMID:23004710

  11. Management of oxaliplatin-induced peripheral neuropathy

    PubMed Central

    Saif, M Wasif; Reardon, John

    2005-01-01

    Neurotoxicity is the most frequent dose-limiting toxicity of oxaliplatin. Acute sensory neurotoxicity manifests as rapid onset of cold-induced distal dysesthesia and/or paresthesia, sometimes accompanied by cold-dependent muscular contractions of the extremities or the jaw. The symptoms, often occurring during or shortly after infusion, are usually transient and mild. A cumulative sensory peripheral neuropathy may also develop with prolonged treatment with oxaliplatin, eventually causing superficial and deep sensory loss, sensory ataxia, and functional impairment. Studies have shown patients with acute sensory symptoms to display little or no axonal degeneration. The similarity of acute symptoms induced by oxaliplatin to those caused by several drugs or toxins acting on neuronal or muscular ion channels suggests that these symptoms may result from a specific interaction of oxaliplatin with voltage-gated sodium (Na+) channels. The current recommendations for the management of the acute and cumulative neurotoxicity from oxaliplatin include education about exposure to cold, dose modification, “stop and go”, and use of neuromodulatory agents, in particular, intravenous calcium and magnesium infusion. Upon the approval of oxaliplatin-based regimens both for adjuvant and metastatic treatment of colon cancer, it is crucial to compile knowledge about the recognition and management of neurotoxicity from oxaliplatin. PMID:18360567

  12. Explorative study to identify novel candidate genes related to oxaliplatin efficacy and toxicity using a DNA repair array

    PubMed Central

    Kweekel, D M; Antonini, N F; Nortier, J W R; Punt, C J A; Gelderblom, H; Guchelaar, H-J

    2009-01-01

    Purpose: To identify new polymorphisms (single nucleotide polymorphisms, SNPs) in DNA repair pathways that are associated with efficacy and toxicity in patients receiving oxaliplatin and capecitabine for advanced colorectal cancer (ACC). Methods: We studied progression-free survival (PFS) in 91 ACC patients, of whom germ-line DNA was isolated and genotyped using an Asper Biotech array. Overall survival (OS) and toxicity were studied as secondary end points. A step-wise selection of SNPs was performed, involving univariate and multivariate log-rank tests and Cox regression analysis, with age and performance status as covariates. Results: A total of 81 SNPs in 46 genes on the array were selected for further analysis, based on genotyping success rates and minor allele frequencies. After step-wise selection, we found that homozygosity for the ataxia telangiectasia mutated gene (ATM) rs1801516 or excision repair cross-complementing gene (ERCC5) rs1047768 SNPs was associated with shorter PFS; however there were no significant associations (P>0.01) with OS or toxicity. Discussion: This is the first study describing the pathway gene approach for the selection of new candidate genes involved in oxaliplatin efficacy and toxicity. The results suggest that the ATM and ERCC5 genes may be associated with oxaliplatin efficacy in ACC. PMID:19536092

  13. Assessment of Injection Site Reactions for Peripheral Intravenous Oxaliplatin Infusion and Potential Remedies.

    PubMed

    Handa, Satoko; Kuroiwa, Ryohei; Miyano, Masahiro; Shimizu, Hisanori; Kamei, Daisuke; Takei, Hiromi; Sonou, Hiroko; Yamamoto, Hitomi; Murayama, JunIchiro; Sato, Atsushi; Kato, Yasuhisa

    2016-08-01

    We investigated the medical and nursing records of 19 patients with unresectable advanced recurrent colorectal cancers treated using oxaliplatin and capecitabine(CapeOX)with or without bevacizumab at the outpatient tumor center of Showa UniversityHospital between November 1, 2009 and November 30, 2011, to clarifydifferences in the incidence of injection site reactions according to the use or non-use of an intravenous infusion solution warming device. Vascular pain and other injection site reactions occurred in 13 patients(68.4%). Injection site reactions occurred in 33 of the total of 77 chemotherapytreatments (42.9%). No difference in incidence of injection site reactions was seen according to whether the intravenous infusion solution warmer was used. The most common time to onset of injection site reactions after commencing oxaliplatin administration was 60-90 min, and symptoms were seen to decrease when non-steroidal anti-inflammatorydrugs were coadministered. We intend to leverage these studyfindings to demonstrate the mechanism of onset for injection site reactions and to propose measures for handling adverse drug reactions. PMID:27539041

  14. Capecitabine cardiac toxicity presenting as effort angina: a case report.

    PubMed

    Lestuzzi, Chiara; Crivellari, Diana; Rigo, Fausto; Viel, Elda; Meneguzzo, Nereo

    2010-09-01

    We report a case of capecitabine-induced cardiotoxicity (effort angina) in a woman with metastatic breast carcinoma. Due to cancer progression, rechallenge of therapy with capecitabine was attempted, using several strategies in order to prevent cardiotoxicity. The most (even if not fully) effective strategy was reducing capecitabine dosage together with nitrates, calcium-channel blockers and trimetazidine therapy. PMID:20093950

  15. Capecitabine

    MedlinePlus

    ... 1 week break before repeating the next dosage cycle. It is usually taken after a meal (within 30 minutes of breakfast and dinner) and with a glass of water. Your doctor will decide how many times you ...

  16. Capecitabine

    MedlinePlus

    ... go away: stomach pain or upset stomach constipation loss of appetite change in ability to taste food increased thirst unusual tiredness or weakness dizziness headache hair loss skin rash back, join, or muscle pain red, ...

  17. Veliparib, Oxaliplatin, and Capecitabine in Treating Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2014-04-01

    Adenocarcinoma of the Pancreas; Adenocarcinoma of the Stomach; BRCA1 Mutation Carrier; BRCA2 Mutation Carrier; Ovarian Mucinous Cystadenocarcinoma; Recurrent Breast Cancer; Recurrent Colon Cancer; Recurrent Gastric Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Gastric Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Pancreatic Cancer; Stage IV Rectal Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  18. Phase II Study of Oxaliplatin, Irinotecan, and Capecitabine in Advanced Gastric/Gastroesophageal Junction Carcinoma

    ClinicalTrials.gov

    2015-04-15

    Adenocarcinoma of the Gastroesophageal Junction; Diffuse Adenocarcinoma of the Stomach; Intestinal Adenocarcinoma of the Stomach; Mixed Adenocarcinoma of the Stomach; Recurrent Gastric Cancer; Stage IIIA Gastric Cancer; Stage IIIB Gastric Cancer; Stage IIIC Gastric Cancer; Stage IV Gastric Cancer

  19. Optimal Sequence of Irinotecan and Oxaliplatin-Based Regimens in Metastatic Colorectal Cancer: A Population-Based Observational Study

    PubMed Central

    Lin, Ching-Heng; Hwang, Wen-Li

    2015-01-01

    The optimal sequence of irinotecan and oxaliplatin-based regimens for metastatic colorectal cancer remains unclear. We conducted a population-based observational study by retrospectively reviewing records from Taiwan’s National Health Insurance Research Database to explore this issue. Patients aged ≥20 years with metastatic colorectal cancer newly diagnosed between 2004 and 2008 (n = 9490) were enrolled in current study. Among these 9490 patients, 3895 patients (41.04%) did not receive any chemotherapy within the first three months after catastrophic illness registration. Patients who received best supportive care were older and had higher Charlson comorbidity indexes and incidences of comorbidities than those who received irinotecan-based regimens, oxaliplatin-based regimens, and 5-fluorouracil/capecitabine alone. Patients who received irinotecan followed by oxaliplatin-based regimens and those who received the reverse sequence were further stratified into arm A (n = 542) and arm B (n = 1156), respectively. The median first time to next treatment was not significantly different between arm A and arm B (210 days vs. 196 days; p = 0.17). However, the median second time to next treatment was longer in arm A than in arm B (155 days vs. 123 days; p = 0.006), which translated into a better overall survival (487 days vs. 454 days; p = 0.02). The crossover rate was higher in arm A than in arm B (47.84% vs. 41.61%; p<0.001). Multivariate Cox regression analyses showed that overall survival was comparable between the two chemotherapy sequences (p = 0.27). Our study suggested that irinotecan followed by oxaliplatin-based regimens might be a better chemotherapy treatment option for metastatic colorectal cancer than the reverse sequence given the higher crossover rate and potential overall survival benefit. PMID:26273837

  20. Oxaliplatin-Induced Tonic-Clonic Seizures

    PubMed Central

    Rahal, Ahmad K.; Truong, Phu V.; Kallail, K. James

    2015-01-01

    Oxaliplatin is a common chemotherapy drug used for colon and gastric cancers. Common side effects are peripheral neuropathy, hematological toxicity, and allergic reactions. A rare side effect is seizures which are usually associated with posterior reversible leukoencephalopathy syndrome (PRES). A 50-year-old male patient presented with severe abdominal pain. CT scan of the abdomen showed acute appendicitis. Appendectomy was done and pathology showed mixed adenoneuroendocrine carcinoma. Adjuvant chemotherapy was started with Folinic acid, Fluorouracil, and Oxaliplatin (FOLFOX). During the third cycle of FOLFOX, the patient developed tonic-clonic seizures. Laboratory workup was within normal limits. EEG and MRI of the brain showed no acute abnormality. The patient was rechallenged with FOLFOX but he had tonic-clonic seizures for the second time. His chemotherapy regimen was switched to Folinic acid, Fluorouracil, and Irinotecan (FOLFIRI). After 5 cycles of FOLFIRI, the patient did not develop any seizures, making Oxaliplatin the most likely culprit for his seizures. Oxaliplatin-induced seizures rarely occur in the absence of PRES. One case report has been described in the literature. We present a rare case of tonic-clonic seizures in a patient receiving Oxaliplatin in the absence of PRES. PMID:26491586

  1. A case of oxaliplatin-induced immune-mediated thrombocytopenia

    PubMed Central

    Suh, Seong Eun; Jang, Moon Ju; Chong, So Young; Aster, Richard H.; Curtis, Brian R.

    2014-01-01

    Oxaliplatin is a platinum compound used in patients with gastrointestinal malignancies. It is known to evoke a drug-induced immune-mediated thrombocytopenia, which has not been reported in Korea. We describe a 53-year-old man who developed oxaliplatin-induced immune-mediated thrombocytopenia during chemotherapy for colon cancer. Oxaliplatin-dependent IgG platelet antibodies were detected in his serum on flow cytometry. He was treated with immunoglobulin and corticosteroids without any complications. Physicians should consider oxaliplatin-induced immune-mediated thrombocytopenia, when a sudden, isolated thrombocytopenia develops during chemotherapy with oxaliplatin. PMID:24724069

  2. Prolonged Oxaliplatin Exposure Alters Intracellular Calcium Signaling: A New Mechanism To Explain Oxaliplatin-Associated Peripheral Neuropathy

    PubMed Central

    Schulze, Christin; McGowan, Margit; Jordt, Sven; Ehrlich, Barbara E

    2012-01-01

    Oxaliplatin is a platinum based cytotoxic agent commonly used to treat colorectal cancers. Despite its effectiveness, oxaliplatin administration is associated with the development of cold-induced peripheral neuropathy. This potentially permanent side effect is provoked by cold exposure and can range from mild and self limited to severe and debilitating. Even with tumor shrinkage, these painful side effects can force dose-reduction or discontinuation of treatment. Neither the mechanism of action of oxaliplatin nor that of cold-induced neuropathy is understood. Paclitaxel, an entirely different chemotherapeutic agent used to treat a variety of malignancies, also is associated with the development of peripheral neuropathy. Unlike oxaliplatin, neurotoxicity arising from paclitaxel treatment is better understood and was found to have profound effects on intracellular calcium signaling (1,2). In this study we examined the effects of oxaliplatin on calcium signaling pathways and found that acute exposure of either a neuroblastoma cell line or primary neurons with therapeutic concentrations of oxaliplatin had no effect on intracellular calcium signaling. We also found that cellular temperature sensors (TRP channels) were also not activated by oxaliplatin. Interestingly, prolonged exposure of oxaliplatin sensitized cells to subsequent stimuli and enhanced the magnitude of intracellular calcium responses. Taken together, our results suggest that acute oxaliplatin exposure will not induce abnormal calcium signaling but oxaliplatin-primed cells do exhibit enhanced sensitivity. These findings provide new insight to the mechanism behind oxaliplatin-induced neuropathy. PMID:21859566

  3. [A case of lacrimal duct obstruction caused by capecitabine].

    PubMed

    Noguchi, Yusuke; Mitani, Takuya; Kawara, Hiroko; Tokuyama, Yoko; Tamura, Yoshiko; Uchiyama, Kiyoshi; Shimizu, Yoshihiro

    2015-01-01

    In recent years, the incidence of adverse ocular reactions, including corneal problems and lacrimal duct obstruction, due to antineoplastic agents such as S-1 has increased. Very few reports of adverse ocular reactions caused by capecitabine, a fluorinated pyrimidine antineoplastic agent like S-1, exist, and consequently, the mechanism underlying these reactions is not well understood. This report describes our recent experience with a case of lacrimal duct obstruction caused by capecitabine. The patient was a 71-year-old woman who was being administered trastuzumab plus capecitabine combination chemotherapy for breast cancer-related bone metastasis. She complained of epiphora 7 days after capecitabine was initiated. Thereafter, her capecitabine dose was reduced owing to exacerbation of hand-foot syndrome, but the epiphora persisted. Capecitabine was discontinued 287 days after initiation owing to exacerbation of the hand-foot syndrome. However, because the epiphora persisted, the patient visited the ophthalmology department. The ophthalmologist diagnosed the patient with binocular nasolacrimal duct obstruction and cataract, and prescribed a 0.3% gatifloxacin ophthalmic solution and 0.1% fluorometholone ophthalmic suspension. Thereafter, the epiphora reduced. When the patient returned to the ophthalmology department, symptom improvement was confirmed. In this case, lacrimal duct obstruction likely developed due to capecitabine. The symptoms were reversible with discontinuation of capecitabine and ophthalmic treatment. We believe that reporting this case could be valuable in discussing capecitabine-induced lacrimal duct obstruction. PMID:25596694

  4. Potential barrier classification by short-time measurement

    SciTech Connect

    Granot, Er'el; Marchewka, Avi

    2006-03-15

    We investigate the short-time dynamics of a delta-function potential barrier on an initially confined wave packet. There are mainly two conclusions: (A) At short times the probability density of the first particles that passed through the barrier is unaffected by it. (B) When the barrier is absorptive (i.e., its potential is imaginary) it affects the transmitted wave function at shorter times than a real potential barrier. Therefore, it is possible to distinguish between an imaginary and a real potential barrier by measuring its effect at short times only on the transmitting wave function.

  5. Use of neostigmine in capecitabine-induced paralytic ileus.

    PubMed

    Mak, Gabriel; Ward, Robyn; Shehabi, Yahya; Venkateswaran, Ramya; Chin, Melvin

    2013-01-01

    Paralytic ileus is a recognised side effect of the oral agent capecitabine. We present this report on a patient with metastatic colorectal cancer who was treated with capecitabine and presented with persistent paralytic ileus which did not respond to standard conservative measures. Neostigmine was administered safely, resulting in resolution of the paralytic ileus. This approach merits further investigation. PMID:24362874

  6. Capecitabine-related liver lesions: sinusoidal dilatation mimicking liver metastasis.

    PubMed

    Groom, Katherine; Penna, Marta; Arul, Dhili; Steward, Michael; Leonard, Pauline; Wilson, Jonathan

    2016-06-01

    A 30-year-old lady treated with capecitabine for primary colon adenocarcinoma developed liver lesions suspicious for metastasis. Liver biopsies showed sinusoidal dilatation thought to be secondary to capecitabine. This case highlights the importance of differentiating between benign and malignant liver lesions during cancer surveillance preventing unnecessary liver resections for benign disease. PMID:27398193

  7. Antiplatelet antibodies in oxaliplatin-induced immune thrombocytopenia

    PubMed Central

    McNamara, Michael J; Curtis, Brian R; McCrae, Keith R

    2014-01-01

    Lesson Drug-induced immune thrombocytopenia may be potentially fatal; here we report the development of severe thrombocytopenia with strong oxaliplatin-dependent antiplatelet antibodies. PMID:25057402

  8. Fluorouracil-based preoperative chemoradiotherapy with or without oxaliplatin for stage II/III rectal cancer: a 3-year follow-up study

    PubMed Central

    Jiao, Dexin; Zhang, Rui; Gong, Zhiqiang; Liu, Fang; Chen, Yue; Yu, Qinrui; Sun, Liping; Duan, Hongyan; Zhu, Shendong; Liu, Fei; Wang, Jian

    2015-01-01

    Background Fluorouracil-based preoperative chemoradiotherapy has become the standard treatment for stage II/III rectal cancer. In order to improve the overall survival (OS) and disease-free survival (DFS), we added oxaliplatin to the standard treatment, and compared the effectiveness of these two treatment patterns. Methods A total of 206 patients enrolled in the prospective study had histologically confirmed rectal cancer of clinical stage II/III during July 2007 to July 2010. They were randomized into the experimental group received oxaliplatin and capecitabine in combination with radiotherapy, and the control group received capecitabine in combination with radiotherapy. All patients received surgery in 6−10 weeks after chemoradiotherapy and adjuvant chemotherapy with mFOLFOX6. The primary endpoints were DFS and OS, and the secondary endpoints included toxicity, compliance, and histopathological response. Results The 3-year OS in the experimental group and the control group was 90.29% vs. 86.41% (P>0.05), and the 3-year DFS was 80.58% vs. 69.90% (P>0.05). The pathological complete remission (pCR) rates were 23.30% and 19.42%, respectively (P=0.497). The 3-year local recurrence rates were 4.85% vs. 5.83% (P=0.694), and the 3-year distant metastasis rates were 16.50% and 28.16%, respectively (P=0.045). There were no significant differences in most grade 3−4 toxicities between two groups, however, grade 3−4 diarrhea occurred in 16.50% (17/103) of the experimental group, compared with 6.80% (7/103) of the control group (P=0.030). Also, the total grade 3−4 acute toxicity showed a significant difference (10.68% vs. 21.36%, P=0.037). Conclusions The experimental treatment did not lead significantly improved OS and DFS, and thus longer follow-up is warranted for our patient cohort. Adding oxaliplatin to capecitabine-based preoperative chemoradiotherapy can significantly reduce metastasis, but has only minimal impact on local recurrence. Although grade 3−4

  9. A case of delayed oxaliplatin-induced pseudo-obstruction: an atypical presentation of oxaliplatin neurotoxicity.

    PubMed

    Vandamme, M; Pauwels, W; Bleecker, J De

    2015-06-01

    Chemotherapy-induced neurotoxicity is a serious complication of cancer treatment. Oxaliplatin, a third-generation platinum drug, has become one of the first-line therapies used in the treatment of metastatic colorectal cancer. Peripheral neuropathy is a common complication of platinum-based chemotherapy. Most commonly a sensory neuropathy occurs with cold-triggered symptoms in the acute phase and numbness and painful paresthesias as a late presentation. Autonomic neurotoxicity and late presentation, months after cessation of the therapy, has rarely been described. We report a patient who clinically presented with a pseudo-obstruction months after treatment with oxaliplatin for metastatic colorectal cancer. Intestinal adhesions and relapsing malignancy were carefully excluded. By exclusion the pseudo-obstruction was attributed to a toxic oxaliplatin-induced autonomic neuropathy which slowly improved during months of follow-up. PMID:25523317

  10. β-elemene sensitizes hepatocellular carcinoma cells to oxaliplatin by preventing oxaliplatin-induced degradation of copper transporter 1.

    PubMed

    Li, Xiaoqiang; Lin, Zhenhai; Zhang, Bo; Guo, Lei; Liu, Shuang; Li, Hui; Zhang, Jubo; Ye, Qinghai

    2016-01-01

    β-elemene, a Curcuma wenyujin plant extract, has been used widely as a tumor adjuvant therapeutic agent. However, how to obtain optimum therapeutic effects by combining this compound with other agents remain unclear. In this study, we found that β-elemene, which alone had little effect on hepatocellular carcinoma (HCC) cell proliferation, exerted a synergistic anti-proliferative effect in HCC cells when dosed in combination with oxaliplatin, which increased the amounts of platinum accumulation and platinum-DNA adduct significantly and augmented the oxaliplatin-induced apoptosis. Western blot and laser scanning confocal microscopy studies indicated that β-elemene enhanced the sensitivity of HCC cells to oxaliplatin by upregulating copper transporter 1 (CTR1), a major controller of intracellular platinum accumulation. In an orthotopic transplantation HCC model in nude mice, HCC tumor growth was inhibited significantly by oxaliplatin combined with β-elemene, as compared with oxaliplatin alone. Notably, CTR1 protein expression in xenograft HCC was upregulated in mice who received β-elemene treatment. Taken together, our findings show that β-elemene can block the reduction of CTR1 resulting from oxaliplatin treatment, and therefore has a synergistic anti-HCC effect with oxaliplatin by enhancing cellular uptake of oxaliplatin. The synergistic effects of β-elemene and oxaliplatin deserve further evaluation in clinical settings. PMID:26867799

  11. β-elemene sensitizes hepatocellular carcinoma cells to oxaliplatin by preventing oxaliplatin-induced degradation of copper transporter 1

    PubMed Central

    Li, Xiaoqiang; Lin, Zhenhai; Zhang, Bo; Guo, Lei; Liu, Shuang; Li, Hui; Zhang, Jubo; Ye, Qinghai

    2016-01-01

    β-elemene, a Curcuma wenyujin plant extract, has been used widely as a tumor adjuvant therapeutic agent. However, how to obtain optimum therapeutic effects by combining this compound with other agents remain unclear. In this study, we found that β-elemene, which alone had little effect on hepatocellular carcinoma (HCC) cell proliferation, exerted a synergistic anti-proliferative effect in HCC cells when dosed in combination with oxaliplatin, which increased the amounts of platinum accumulation and platinum-DNA adduct significantly and augmented the oxaliplatin-induced apoptosis. Western blot and laser scanning confocal microscopy studies indicated that β-elemene enhanced the sensitivity of HCC cells to oxaliplatin by upregulating copper transporter 1 (CTR1), a major controller of intracellular platinum accumulation. In an orthotopic transplantation HCC model in nude mice, HCC tumor growth was inhibited significantly by oxaliplatin combined with β-elemene, as compared with oxaliplatin alone. Notably, CTR1 protein expression in xenograft HCC was upregulated in mice who received β-elemene treatment. Taken together, our findings show that β-elemene can block the reduction of CTR1 resulting from oxaliplatin treatment, and therefore has a synergistic anti-HCC effect with oxaliplatin by enhancing cellular uptake of oxaliplatin. The synergistic effects of β-elemene and oxaliplatin deserve further evaluation in clinical settings. PMID:26867799

  12. Ototoxic Model of Oxaliplatin and Protection from Nicotinamide Adenine Dinucleotide

    PubMed Central

    Dalian, Ding; Haiyan, Jiang; Yong, Fu; Yongqi, Li; Salvi, Richard

    2014-01-01

    Oxaliplatin, an anticancer drug commonly used to treat colorectal cancer and other tumors, has a number of serious side effects, most notably neuropathy and ototoxicity. To gain insights into its ototoxic profile, oxaliplatin was applied to rat cochlear organ cultures. Consistent with it neurotoxic propensity, oxaliplatin selectively damaged nerve fibers at a very low dose 1 μM. In contrast, the dose required to damage hair cells and spiral ganglion neurons was 50 fold higher (50 μM). Oxailiplatin-induced cochlear lesions initially increased with dose, but unexpectedly decreased at very high doses. This non-linear dose response could be related to depressed oxaliplatin uptake via active transport mechanisms. Previous studies have demonstrated that axonal degeneration involves biologically active processes which can be greatly attenuated by nicotinamide adenine dinucleotide (NAD+). To determine if NAD+ would protect spiral ganglion axons and the hair cells from oxaliplatin damage, cochlear cultures were treated with oxaliplatin alone at doses of 10 μM or 50 μM respectively as controls or combined with 20 mM NAD+. Treatment with 10 μM oxaliplatin for 48 hours resulted in minor damage to auditory nerve fibers, but spared cochlear hair cells. However, when cochlear cultures were treated with 10 μM oxaliplatin plus 20 mM NAD+, most auditory nerve fibers were intact. 50 μM oxaliplatin destroyed most of spiral ganglion neurons and cochlear hair cells with apoptotic characteristics of cell fragmentations. However, 50 μM oxaliplatin plus 20 mM NAD+ treatment greatly reduced neuronal degenerations and hair cell missing. The results suggested that NAD+ provides significant protection against oxaliplatin-induced neurotoxicity and ototoxicity, which may be due to its actions of antioxidant, antiapoptosis, and energy supply. PMID:25419212

  13. Vorinostat synergises with capecitabine through upregulation of thymidine phosphorylase

    PubMed Central

    Di Gennaro, E; Piro, G; Chianese, M I; Franco, R; Cintio, A Di; Moccia, T; Luciano, A; de Ruggiero, I; Bruzzese, F; Avallone, A; Arra, C; Budillon, A

    2010-01-01

    Background: Potentiation of anticancer activity of capecitabine is required to improve its therapeutic index. In colorectal cancer (CRC) cells, we evaluated whether the histone deacetylase-inhibitor vorinostat may induce synergistic antitumour effects in combination with capecitabine by modulating the expression of thymidine phosphorylase (TP), a key enzyme in the conversion of capecitabine to 5-florouracil (5-FU), and thymidylate synthase (TS), the target of 5-FU. Methods: Expression of TP and TS was measured by real-time PCR, western blotting and immunohistochemistry. Knockdown of TP was performed by specific small interfering RNA. Antitumour activity of vorinostat was assessed in vitro in combination with the capecitabine active metabolite deoxy-5-fluorouridine (5′-DFUR) according to the Chou and Talay method and by evaluating apoptosis as well as in xenografts-bearing nude mice in combination with capecitabine. Results: Vorinostat induced both in vitro and in vivo upregulation of TP as well as downregulation of TS in cancer cells, but not in ex vivo treated peripheral blood lymphocytes. Combined treatment with vorinostat and 5′-DFUR resulted in a synergistic antiproliferative effect and increased apoptotic cell death in vitro. This latter effect was impaired in cells where TP was knocked. In vivo, vorinostat plus capecitabine potently inhibited tumour growth, increased apoptosis and prolonged survival compared with control or single-agent treatments. Conclusions: Overall, this study suggests that the combination of vorinostat and capecitabine is an innovative antitumour strategy and warrants further clinical evaluation for the treatment of CRC. PMID:21045833

  14. Effects of oxaliplatin on mouse myenteric neurons and colonic motility

    PubMed Central

    Wafai, Linah; Taher, Mohammadali; Jovanovska, Valentina; Bornstein, Joel C.; Dass, Crispin R.; Nurgali, Kulmira

    2013-01-01

    Oxaliplatin, an anti-cancer chemotherapeutic agent used for the treatment of colorectal cancer, commonly causes gastrointestinal side-effects such as constipation, diarrhoea, nausea, and vomiting. Damage to enteric neurons may underlie some of these gastrointestinal side-effects, as the enteric nervous system (ENS) controls functions of the bowel. In this study, neuronal loss and changes to the structure and immunoreactivity of myenteric neuronal nitric oxide synthase (nNOS) neurons were examined in colonic segments from mice following exposure to oxaliplatin ex vivo and following repeated intraperitoneal injections of oxaliplatin over 3 weeks in vivo, using immunohistochemistry and confocal microscopy. Significant morphological alterations and increases in the proportion of NOS-immunoreactive (IR) neurons were associated with both short-term oxaliplatin exposure and long-term oxaliplatin administration, confirming that oxaliplatin causes changes to the myenteric neurons. Long-term oxaliplatin administration induced substantial neuronal loss that was correlated with a reduction in both the frequency and propagation speed of colonic migrating motor complexes (CMMCs) in vitro. Similar changes probably produce some symptoms experienced by patients undergoing oxaliplatin treatment. PMID:23486839

  15. Idiosyncratic Reaction with Cytokine Storm Associated with Oxaliplatin.

    PubMed

    Dembla, Vikas

    2016-01-01

    Oxaliplatin or irinotecan with 5-fluorouracil form the chemotherapy backbone of any systemic treatment of colorectal cancer. We successfully treated an idiosyncratic reaction to oxaliplatin consisting of severe chills, vomiting, diarrhea, and fever in a patient with metastatic colon cancer. PMID:27335720

  16. Idiosyncratic Reaction with Cytokine Storm Associated with Oxaliplatin

    PubMed Central

    2016-01-01

    Oxaliplatin or irinotecan with 5-fluorouracil form the chemotherapy backbone of any systemic treatment of colorectal cancer. We successfully treated an idiosyncratic reaction to oxaliplatin consisting of severe chills, vomiting, diarrhea, and fever in a patient with metastatic colon cancer.   PMID:27335720

  17. Fatal Pneumonitis Induced by Oxaliplatin: Description of Three Cases

    PubMed Central

    Pontes, L.B.; Armentano, D.P.D.; Soares, A.; Gansl, R.C.

    2012-01-01

    We describe 3 fatal cases of interstitial pneumonitis rapidly evolving to pulmonary fibrosis and death after the administration of oxaliplatin as part of the FOLFOX regimen. Due to the widespread use of oxaliplatin in oncology, clinicians should be aware of the risk and severity of oxalipatin-induced interstitial pneumonia. PMID:22539922

  18. Atypical presentation of fever as hypersensitivity reaction to oxaliplatin.

    PubMed

    Khurana, Arushi; Mitsis, Demytra; Kowlgi, Gurukripa N; Holle, Lisa M; Clement, Jessica M

    2016-04-01

    Oxaliplatin, a third-generation, platinum-based agent is widely used, most commonly in the FOLFOX (5-fluorouracil, leucovorin and oxaliplatin) regimen, which is the first-line therapy in metastatic colorectal adenocarcinoma and adjuvant chemotherapy in stage III colorectal cancer. Platinum-based products are well known for causing hypersensitivity reactions. Fever associated with oxaliplatin-hypersensitivity reactions typically follows a specific pattern. It usually starts during the oxaliplatin infusion or immediately after (within hours instead of days) and happens after several administrations (mean 2-25) with unpredictable clinical presentations. We report a case of oxaliplatin-induced hypersensitivity reaction manifesting as fever but with unusual presentation than the aforementioned features. PMID:25361599

  19. Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir

    PubMed Central

    Coriat, Romain; Alexandre, Jérôme; Nicco, Carole; Quinquis, Laurent; Benoit, Evelyne; Chéreau, Christiane; Lemaréchal, Hervé; Mir, Olivier; Borderie, Didier; Tréluyer, Jean-Marc; Weill, Bernard; Coste, Joel; Goldwasser, François; Batteux, Frédéric

    2013-01-01

    Background. The majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer. Methods. The effects of mangafodipir were examined in mice following treatment with oxaliplatin. Neurotoxicity, axon myelination, and advanced oxidized protein products (AOPPs) were monitored. In addition, we enrolled 23 cancer patients with grade ≥2 oxaliplatin-induced neuropathy in a phase II study, with 22 patients receiving i.v. mangafodipir following oxaliplatin. Neuropathic effects were monitored for up to 8 cycles of oxaliplatin and mangafodipir. Results. Mangafodipir prevented motor and sensory dysfunction and demyelinating lesion formation. In mice, serum AOPPs decreased after 4 weeks of mangafodipir treatment. In 77% of patients treated with oxaliplatin and mangafodipir, neuropathy improved or stabilized after 4 cycles. After 8 cycles, neurotoxicity was downgraded to grade ≥2 in 6 of 7 patients. Prior to enrollment, patients received an average of 880 ± 239 mg/m2 oxaliplatin. Patients treated with mangafodipir tolerated an additional dose of 458 ± 207 mg/m2 oxaliplatin despite preexisting neuropathy. Mangafodipir responders managed a cumulative dose of 1,426 ± 204 mg/m2 oxaliplatin. Serum AOPPs were lower in responders compared with those in nonresponders. Conclusion. Our study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients. Trial registration. Clinicaltrials.gov NCT00727922. Funding. Université Paris Descartes, Ministère de la Recherche et de l’Enseignement Supérieur, and Assistance Publique-Hôpitaux de Paris. PMID:24355920

  20. Performance of multifractal detrended fluctuation analysis on short time series

    NASA Astrophysics Data System (ADS)

    López, Juan Luis; Contreras, Jesús Guillermo

    2013-02-01

    The performance of the multifractal detrended analysis on short time series is evaluated for synthetic samples of several mono- and multifractal models. The reconstruction of the generalized Hurst exponents is used to determine the range of applicability of the method and the precision of its results as a function of the decreasing length of the series. As an application the series of the daily exchange rate between the U.S. dollar and the euro is studied.

  1. Short-time spectroscopic measurement of the temperature of solids

    NASA Astrophysics Data System (ADS)

    Mach, H.

    1984-02-01

    The short-time temperature rise dependent deformation caused by shocks on solids were measured with radiation pyrometric and spectroscopic methods. The methods can only be applied on solids emitting a measurable radiation and are based on spectral radiation and the temperature of the solid. The Planck-Kirchhoff radiation laws and the measuring method are presented. The measuring equipment consists of an image reproducing optical device and a photodetector with spectral or interference filters for wavelength selection.

  2. Capecitabine-induced ventricular fibrillation arrest: Possible Kounis syndrome.

    PubMed

    Kido, Kazuhiko; Adams, Val R; Morehead, Richard S; Flannery, Alexander H

    2016-04-01

    We report the case of capecitabine-induced ventricular fibrillation arrest, possibly secondary to type I Kounis syndrome. A 47-year-old man with a history of T3N1 moderately differentiated adenocarcinoma of the colon, status-post sigmoid resection, was started on adjuvant capecitabine approximately five months prior to presentation of cardiac arrest secondary to ventricular fibrillation. An electrocardiogram (EKG) revealed ST segment elevation on the lateral leads and the patient was taken emergently to the cardiac catheterization laboratory. The catheterization revealed no angiographically significant stenosis and coronary artery disease was ruled out. After ruling out other causes of cardiac arrest, the working diagnosis was capecitabine-induced ventricular fibrillation arrest. As such, an inflammatory work up was sent to evaluate for the possibility of a capecitabine hypersensitivity, or Kounis syndrome, and is the first documented report in the literature to do so when evaluating Kounis syndrome. Immunoglobulin E (IgE), tryptase, and C-reactive protein were normal but histamine, interleukin (IL)-6, and IL-10 were elevated. Histamine elevation supports the suspicion that our patient had type I Kounis syndrome. Naranjo adverse drug reaction probability scale indicates a probable adverse effect due to capecitabine with seven points. A case of capecitabine-induced ventricular fibrillation arrest is reported, with a potential for type 1 Kounis syndrome as an underlying pathology supported by immunologic work up. PMID:25870182

  3. Guadecitabine (SGI-110) priming sensitizes hepatocellular carcinoma cells to oxaliplatin.

    PubMed

    Kuang, Yuting; El-Khoueiry, Anthony; Taverna, Pietro; Ljungman, Mats; Neamati, Nouri

    2015-11-01

    Promoter DNA hypermethylation is an important biomarker of hepatocellular carcinoma (HCC), supporting the potential utility of demethylating agents in this disease. Guadecitabine (SGI-110) is a second-generation hypomethylating agent formulated as a dinucleotide of decitabine and deoxyguanosine that yields longer half-life and more extended decitabine exposure than decitabine IV infusion. Here we performed preclinical evaluation of SGI-110 in HCC models to guide the design of a phase I/II clinical trial. HCC cell lines and xenograft models were used to determine the antitumor activity of SGI-110 as a single agent and in combination with oxaliplatin. Pretreatment with low doses of SGI-110 significantly synergized with oxaliplatin yielding enhanced cytotoxicity. The combination of SGI-110 and oxaliplatin was well tolerated and significantly delayed tumor growth in mice compared to oxaliplatin alone. Bromouridine-labeled RNA sequencing (Bru-seq) was employed to elucidate the effects of SGI-110 and/or oxaliplatin on genome-wide transcription. SGI-110 and the combination treatment inhibited the expression of genes involved in WNT/EGF/IGF signaling. DNMT1 and survivin were identified as novel PD markers to monitor the efficacy of the combination treatment. In conclusion, SGI-110 priming sensitizes HCC cells to oxaliplatin by inhibiting distinct signaling pathways. We expect that this combination treatment will show low toxicity and high efficacy in patients. Our study supports the use of the combination of low doses of SGI-110 and oxaliplatin in HCC patients. PMID:26160429

  4. Short-time Chebyshev wave packet method for molecular photoionization

    NASA Astrophysics Data System (ADS)

    Sun, Zhaopeng; Zheng, Yujun

    2016-08-01

    In this letter we present the extended usage of short-time Chebyshev wave packet method in the laser induced molecular photoionization dynamics. In our extension, the polynomial expansion of the exponential in the time evolution operator, the Hamiltonian operator can act on the wave packet directly which neatly avoids the matrix diagonalization. This propagation scheme is of obvious advantages when the dynamical system has large Hamiltonian matrix. Computational simulations are performed for the calculation of photoelectronic distributions from intense short pulse ionization of K2 and NaI which represent the Born-Oppenheimer (BO) model and Non-BO one, respectively.

  5. Speech processing based on short-time Fourier analysis

    SciTech Connect

    Portnoff, M.R.

    1981-06-02

    Short-time Fourier analysis (STFA) is a mathematical technique that represents nonstationary signals, such as speech, music, and seismic signals in terms of time-varying spectra. This representation provides a formalism for such intuitive notions as time-varying frequency components and pitch contours. Consequently, STFA is useful for speech analysis and speech processing. This paper shows that STFA provides a convenient technique for estimating and modifying certain perceptual parameters of speech. As an example of an application of STFA of speech, the problem of time-compression or expansion of speech, while preserving pitch and time-varying frequency content is presented.

  6. Experimental Study of Short-Time Brownian Motion

    NASA Astrophysics Data System (ADS)

    Mo, Jianyong; Simha, Akarsh; Riegler, David; Raizen, Mark

    2015-03-01

    We report our progress on the study of short-time Brownian motion of optically-trapped microspheres. In earlier work, we observed the instantaneous velocity of microspheres in gas and in liquid, verifying a prediction by Albert Einstein from 1907. We now report a more accurate test of the energy equipartition theorem for a particle in liquid. We also observe boundary effects on Brownian motion in liquid by setting a wall near the trapped particle, which changes the dynamics of the motion. We find that the velocity autocorrelation of the particle decreases faster as the particle gets closer to the wall.

  7. Short time transient periodicities from Cyg X-1

    NASA Technical Reports Server (NTRS)

    Auriemma, G.; Cardini, D.; Costa, E.; Giovannelli, F.; Ranieri, M.

    1976-01-01

    The temporal behavior of three new events of modulated optical emission from Cyg X1, detected in July 1975, is presented. Short time periodicities in the optical band are investigated. Single photon pulses from the photomultiplier are recorded on magnetic tape together with a very accurate 1 kHz reference frequency. During playback of the tape, the reference signal gives a 1 ms timing to a scaler interfaced with a small processor and the number of photon per millisecond is recorded on a digital tape.

  8. Organic Cation Transporters Are Determinants of Oxaliplatin Cytotoxicity

    PubMed Central

    Zhang, Shuzhong; Lovejoy, Katherine S.; Shima, James E.; Lagpacan, Leah L.; Shu, Yan; Lapuk, Anna; Chen, Ying; Komori, Takafumi; Gray, Joe W.; Chen, Xin; Lippard, Stephen J.; Giacomini, Kathleen M.

    2009-01-01

    Although the platinum-based anticancer drugs cisplatin, carboplatin, and oxaliplatin have similar DNA-binding properties, only oxaliplatin is active against colorectal tumors. The mechanisms for this tumor specificity of platinum-based compounds are poorly understood but could be related to differences in uptake. This study shows that the human organic cation transporters (OCT) 1 and 2 (SLC22A1 and SLC22A2) markedly increase oxaliplatin, but not cisplatin or carboplatin, accumulation and cytotoxicity in transfected cells, indicating that oxaliplatin is an excellent substrate of these transporters. The cytotoxicity of oxaliplatin was greater than that of cisplatin in six colon cancer cell lines [mean ± SE of IC50 in the six cell lines, 3.9 ± 1.4 μmol/L (oxaliplatin) versus 11 ± 2.0 μmol/L (cisplatin)] but was reduced by an OCT inhibitor, cimetidine, to a level similar to, or even lower than that of, cisplatin (29 ± 11 μmol/L for oxaliplatin versus 19 ± 4.3 μmol/L for cisplatin). Structure-activity studies indicated that organic functionalities on nonleaving groups coordinated to platinum are critical for selective uptake by OCTs. These results indicate that OCT1 and OCT2 are major determinants of the anticancer activity of oxaliplatin and may contribute to its antitumor specificity. They also strongly suggest that expression of OCTs in tumors should be investigated as markers for selecting specific platinum-based therapies in individual patients. The development of new anticancer drugs, specifically targeted to OCTs, represents a novel strategy for targeted drug therapy. The results of the present structure-activity studies indicate specific tactics for realizing this goal. PMID:16951202

  9. Evaluation of Scaling Invariance Embedded in Short Time Series

    PubMed Central

    Pan, Xue; Hou, Lei; Stephen, Mutua; Yang, Huijie; Zhu, Chenping

    2014-01-01

    Scaling invariance of time series has been making great contributions in diverse research fields. But how to evaluate scaling exponent from a real-world series is still an open problem. Finite length of time series may induce unacceptable fluctuation and bias to statistical quantities and consequent invalidation of currently used standard methods. In this paper a new concept called correlation-dependent balanced estimation of diffusion entropy is developed to evaluate scale-invariance in very short time series with length . Calculations with specified Hurst exponent values of show that by using the standard central moving average de-trending procedure this method can evaluate the scaling exponents for short time series with ignorable bias () and sharp confidential interval (standard deviation ). Considering the stride series from ten volunteers along an approximate oval path of a specified length, we observe that though the averages and deviations of scaling exponents are close, their evolutionary behaviors display rich patterns. It has potential use in analyzing physiological signals, detecting early warning signals, and so on. As an emphasis, the our core contribution is that by means of the proposed method one can estimate precisely shannon entropy from limited records. PMID:25549356

  10. Network insights on oxaliplatin anti-cancer mechanisms.

    PubMed

    Alian, Osama M; Azmi, Asfar S; Mohammad, Ramzi M

    2012-01-01

    Oxaliplatin has been a crucial component of combination therapies since admission into the clinic causing modest gains in survival across multiple malignancies. However, oxaliplatin functions in a non-targeted manner, posing a difficulty in ascertaining precise efficacy mechanisms. While previously thought to only affect DNA repair mechanisms, Platinum-protein adducts (Pt-Protein) far outnumber Pt-DNA adducts leaving a big part of oxaliplatin function unknown. Through preliminary network modeling of high throughput data, this article critically reviews the efficacy of oxaliplatin as well as proposes a better model for enhanced efficacy based on a network approach. In our study, not only oxaliplatin's function in interrupting DNA-replication was confirmed, but also its role in initiating or intensifying tumorigenesis pathways was uncovered. From our data we present a novel picture of competing signaling networks that collectively provide a plausible explanation of chemotherapeutic resistance, cancer stem cell survival, as well as invasiveness and metastases. Here we highlight oxaliplatin signaling networks, their significance and the clinical implications of these interactions that verifies the importance of network modeling in rational drug design. PMID:23369220

  11. GTI-2040, Oxaliplatin, and Capecitabine in Treating Patients With Locally Advanced or Metastatic Colorectal Cancer or Other Solid Tumors

    ClinicalTrials.gov

    2013-03-26

    Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage IIIC Colon Cancer; Stage IIIC Rectal Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  12. Urban air pollution by odor sources: Short time prediction

    NASA Astrophysics Data System (ADS)

    Pettarin, Nicola; Campolo, Marina; Soldati, Alfredo

    2015-12-01

    A numerical approach is proposed to predict the short time dispersion of odors in the urban environment. The model is based on (i) a three dimensional computational domain describing the urban topography at fine spatial scale (1 m) and on (ii) highly time resolved (1 min frequency) meteorological data used as inflow conditions. The time dependent, three dimensional wind velocity field is reconstructed in the Eulerian framework using a fast response finite volume solver of Navier-Stokes equations. Odor dispersion is calculated using a Lagrangian approach. An application of the model to the historic city of Verona (Italy) is presented. Results confirm that this type of odor dispersion simulations can be used (i) to assess the impact of odor emissions in urban areas and (ii) to evaluate the potential mitigation produced by odor abatement systems.

  13. Capecitabine-induced leukocytoclastic vasculitis under neoadjuvant chemotherapy for locally advanced colorectal cancer

    PubMed Central

    Kee, Bryan K.; Tetzlaff, Michael T.; Wolff, Robert A.

    2015-01-01

    We describe a case of capecitabine-induced leukocytoclastic vasculitis in a patient with locally advanced rectal cancer under curative neoadjuvant concurrent chemoradiation using capecitabine. After 5 days of the initiation of capecitabine the patient developed a pruritic maculopapular rash in her extremities consistent with vasculitis which was confirmed on skin biopsy without any signs of systemic involvement. Capecitabine was held and the rash was treated with topical steroids with complete resolution of both rash and pruritus. Due to a lack of other alternative chemotherapeutic options and the cutaneous-only involvement of vasculitis, the capecitabine was re-introduced. Two days later, the patient developed an identical maculopapular rash with a similar distribution. Prednisone was initiated while the capecitabine was continued with complete resolution of the rash. The patient successfully completed her curative neoadjuvant chemoradiation therapy treatment without the need to permanently discontinue the capecitabine. PMID:26029464

  14. Successful capecitabine rechallenge following 5-fluorouracil-induced Takotsubo syndrome

    PubMed Central

    Abdelrahman, Mohamed; McCarthy, Michael T.; Yusof, Haliana; Osman, Nemer

    2016-01-01

    Cardiac toxicity is a widely reported complication of fluoropyrimidine chemotherapies (5-fluorouracil and capecitabine); however, Takotsubo syndrome (TS) is less widely reported. There is little data available describing the viability of fluoropyrimidine rechallenge after fluoropyrimidine-induced TS. We report the case of Ms X, a 41-year-old woman with metastatic oesophageal cancer, who developed acute onset left ventricular dysfunction, with a measured left ventricular ejection fraction of 15% on cycle 1 day 3 of FOLFOX chemotherapy, after disconnection of the fluorouracil infusion pump. Her symptoms resolved over 2 days, and an echocardiogram returned to normal within 2 weeks. 5-Fluorouracil was discontinued, and replaced with capecitabine, without recurrence of symptoms. The remainder of her treatment was uneventful. This is the second case to describe successful capecitabine retreatment following 5-fluorouracil-induced TS. PMID:26989494

  15. Which is false: oxaliplatin or fluoropyrimidine? An analysis of patients with KRAS wild-type metastatic colorectal cancer treated with first-line epidermal growth factor receptor monoclonal antibody.

    PubMed

    Wen, Feng; Tang, Ruilei; Sang, Yaxiong; Li, Meng; Hu, Qiancheng; Du, Zedong; Zhou, Yi; Zhang, Pengfei; He, Xiaofeng; Li, Qiu

    2013-10-01

    This meta-analysis was performed to determine whether the addition of monoclonal antibodies (mAbs) of epidermal growth factor receptor (EGFR) to oxaliplatin-based chemotherapy treatment improves efficacy in KRAS wild-type metastatic colorectal cancer (mCRC), and whether infusional 5-fluorouracil (5-FU) and oxaliplatin is a preferred combination for EGFR mAbs. Oxaliplatin (including treatment), EGFR mAbs, first-line treatment, KRAS wild-type, and mCRC were used as key words. The PRIME, OPUS, COIN, and NORDIC VII trials were identified by two independent authors. Time-to-event outcomes of overall survival (OS) and progression-free survival (PFS) were analyzed using HRs (hazard ratios) with fixed effect, and response rate (RR) using odd ratios (OR) with fixed effect. A total of 1767 patients who were KRAS wild-type were included in this meta-analysis, with 866 patients in the mAbs and chemotherapy combination group and 901 patients in the chemotherapy alone group. The addition of mAbs to oxaliplatin-based chemotherapy in patients with KRAS wild-type mCRC as first-line treatment resulted in significant improvements in PFS (HR = 0.88; 95% confidence interval (CI), 0.79-0.99; P = 0.03) and response rate (RR) (OR = 1.38; 95% CI, 1.14-1.66; P = 0.009) compared with chemotherapy alone, but the difference in OS was not significant (HR = 0.96; 95% CI, 0.85-1.08; P = 0.48). However, the differences in OS and PFS were not significant when mAbs were added to bolus 5-FU or capecitabine-based regimens compared with chemotherapy alone, whereas PFS improved with an infusional 5-FU and oxaliplatin combination (P = 0.06; PFS, HR = 0.76; 95% CI, 0.65-0.86; P = 0.0002), and even OS was marginally significant, which was consistent with the subgroup analysis of cetuximab and panitumumab. EGFR mAbs combined with oxaliplatin and an infusional 5-FU regimen was associated with significantly improved RR, PFS and OS as first-line treatment in KRAS wild-type mCRC. PMID:23822592

  16. Network insights on oxaliplatin anti-cancer mechanisms

    PubMed Central

    2012-01-01

    Oxaliplatin has been a crucial component of combination therapies since admission into the clinic causing modest gains in survival across multiple malignancies. However, oxaliplatin functions in a non-targeted manner, posing a difficulty in ascertaining precise efficacy mechanisms. While previously thought to only affect DNA repair mechanisms, Platinum-protein adducts (Pt-Protein) far outnumber Pt-DNA adducts leaving a big part of oxaliplatin function unknown. Through preliminary network modeling of high throughput data, this article critically reviews the efficacy of oxaliplatin as well as proposes a better model for enhanced efficacy based on a network approach. In our study, not only oxaliplatin’s function in interrupting DNA-replication was confirmed, but also its role in initiating or intensifying tumorigenesis pathways was uncovered. From our data we present a novel picture of competing signaling networks that collectively provide a plausible explanation of chemotherapeutic resistance, cancer stem cell survival, as well as invasiveness and metastases. Here we highlight oxaliplatin signaling networks, their significance and the clinical implications of these interactions that verifies the importance of network modeling in rational drug design. PMID:23369220

  17. Anticancer Activity of Methyl-Substituted Oxaliplatin Analogs†

    PubMed Central

    Jungwirth, Ute; Xanthos, Dimitris N.; Gojo, Johannes; Bytzek, Anna K.; Körner, Wilfried; Heffeter, Petra; Abramkin, Sergey A.; Jakupec, Michael A.; Hartinger, Christian G.; Windberger, Ursula; Galanski, Markus; Keppler, Bernhard K.; Berger, Walter

    2012-01-01

    Oxaliplatin is successfully used in systemic cancer therapy. However, resistance development and severe adverse effects are limiting factors for curative cancer treatment with oxaliplatin. The purpose of this study was to comparatively investigate in vitro and in vivo anticancer properties as well as the adverse effects of two methyl-substituted enantiomerically pure oxaliplatin analogs [[(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine] oxalatoplatinum(II) (KP1537), and [(1R,2R,4S)-4-methyl-1,2-cyclohexanediamine]oxalatoplatinum(II) (KP1691)] and to evaluate the impact of stereoisomerism. Although the novel oxaliplatin analogs demonstrated in multiple aspects activities comparable with those of the parental compound, several key differences were discovered. The analogs were characterized by reduced vulnerability to resistance mechanisms such as p53 mutations, reduced dependence on immunogenic cell death induction, and distinctly attenuated adverse effects including weight loss and cold hyperalgesia. Stereoisomerism of the substituted methyl group had a complex and in some aspects even contradictory impact on drug accumulation and anticancer activity both in vitro and in vivo. To summarize, methyl-substituted oxaliplatin analogs harbor improved therapeutic characteristics including significantly reduced adverse effects. Hence, they might be promising metal-based anticancer drug candidates for further (pre)clinical evaluation. PMID:22331606

  18. Variations in solar Lyman alpha irradiance on short time scales

    NASA Technical Reports Server (NTRS)

    Pap, J. M.

    1992-01-01

    Variations in solar UV irradiance at Lyman alpha are studied on short time scales (from days to months) after removing the long-term changes over the solar cycle. The SME/Lyman alpha irradiance is estimated from various solar indices using linear regression analysis. In order to study the nonlinear effects, Lyman alpha irradiance is modeled with a 5th-degree polynomial as well. It is shown that the full-disk equivalent width of the He line at 1083 nm, which is used as a proxy for the plages and active network, can best reproduce the changes observed in Lyman alpha. Approximately 72 percent of the solar-activity-related changes in Lyman alpha irradiance arise from plages and the network. The network contribution is estimated by the correlation analysis to be about 19 percent. It is shown that significant variability remains in Lyman alpha irradiance, with periods around 300, 27, and 13.5d, which is not explained by the solar activity indices. It is shown that the nonlinear effects cannot account for a significant part of the unexplained variation in Lyman alpha irradiance. Therefore, additional events (e.g., large-scale motions and/or a systematic difference in the area and intensity of the plages and network observed in the lines of Ca-K, He 1083, and Lyman alpha) may explain the discrepancies found between the observed and estimated irradiance values.

  19. A short- time beltrami kernel for smoothing images and manifolds.

    PubMed

    Spira, Alon; Kimmel, Ron; Sochen, Nir

    2007-06-01

    We introduce a short-time kernel for the Beltrami image enhancing flow. The flow is implemented by "convolving" the image with a space dependent kernel in a similar fashion to the solution of the heat equation by a convolution with a Gaussian kernel. The kernel is appropriate for smoothing regular (flat) 2-D images, for smoothing images painted on manifolds, and for simultaneously smoothing images and the manifolds they are painted on. The kernel combines the geometry of the image and that of the manifold into one metric tensor, thus enabling a natural unified approach for the manipulation of both. Additionally, the derivation of the kernel gives a better geometrical understanding of the Beltrami flow and shows that the bilateral filter is a Euclidean approximation of it. On a practical level, the use of the kernel allows arbitrarily large time steps as opposed to the existing explicit numerical schemes for the Beltrami flow. In addition, the kernel works with equal ease on regular 2-D images and on images painted on parametric or triangulated manifolds. We demonstrate the denoising properties of the kernel by applying it to various types of images and manifolds. PMID:17547140

  20. Goshajinkigan reduces oxaliplatin-induced peripheral neuropathy without affecting anti-tumour efficacy in rodents.

    PubMed

    Ushio, Soichiro; Egashira, Nobuaki; Sada, Hikaru; Kawashiri, Takehiro; Shirahama, Masafumi; Masuguchi, Ken; Oishi, Ryozo

    2012-06-01

    Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic neuropathies in patients. Goshajinkigan (GJG) is a Kampo medicine that is used for the treatments of several neurological symptoms including pain and numbness. More recently, GJG has been reported to prevent the oxaliplatin-induced peripheral neuropathy in clinical studies. No experimental study, however, has been conducted to date to determine the effect of GJG on pain behaviour in a rat model of oxaliplatin-induced neuropathy. Moreover, the impact on the anti-tumour effect of oxaliplatin remains unknown. In the present study, we examined the effects of GJG on the peripheral neuropathy and anti-tumour activity of oxaliplatin in rodents. Repeated administration of oxaliplatin caused cold hyperalgesia from days 3 to 37 and mechanical allodynia from days 21 to 28. Repeated administration of GJG prevented the oxaliplatin-induced cold hyperalgesia but not mechanical allodynia and axonal degeneration in rat sciatic nerve. Single administration of GJG reduced both cold hyperalgesia and mechanical allodynia after the development of neuropathy. In addition, GJG did not affect the anti-tumour effect of oxaliplatin in the tumour cells or tumour cells-implanted mice. These results suggest that GJG relieves the oxaliplatin-induced cold hyperalgesia and mechanical allodynia without affecting anti-tumour activity of oxaliplatin, and, therefore, may be useful for the oxaliplatin-induced neuropathy in clinical practice. PMID:21907570

  1. Scleroderma in a Patient on Capecitabine: Is this a Variant of Hand-Foot Syndrome?

    PubMed

    Saif, Muhammad W; Agarwal, Archana; Hellinger, James; Park, Dorothy J; Volkmann, Elizabeth

    2016-01-01

    Drug-induced scleroderma is a rare adverse effect of some chemotherapeutic drugs, such as taxanes and bleomycin. Capecitabine, an oral fluoropyrimidine approved for the treatment of metastatic breast and colon cancer, commonly causes cutaneous side effects including the hand-and-foot syndrome (HFS). Scleroderma-like skin changes associated with HFS associated with capecitabine is rare. However, diffuse scleroderma has never before been reported. We report a case of capecitabine-induced diffuse/systemic scleroderma in an 86-year-old female treated with capecitabine for metastatic colorectal cancer. She developed progressive skin and visceral sclerosis involving the lungs. We discuss the association between chemotherapy and scleroderma. We believe this is the first case of diffuse/systemic capecitabine-induced scleroderma without the presence of HFS. Early diagnosis is essential as fibrosis might be prevented in early stages. The capecitabine should be discontinued as early as possible. PMID:27493845

  2. Scleroderma in a Patient on Capecitabine: Is this a Variant of Hand-Foot Syndrome?

    PubMed Central

    Agarwal, Archana; Hellinger, James; Park, Dorothy J; Volkmann, Elizabeth

    2016-01-01

    Drug-induced scleroderma is a rare adverse effect of some chemotherapeutic drugs, such as taxanes and bleomycin. Capecitabine, an oral fluoropyrimidine approved for the treatment of metastatic breast and colon cancer, commonly causes cutaneous side effects including the hand-and-foot syndrome (HFS). Scleroderma-like skin changes associated with HFS associated with capecitabine is rare. However, diffuse scleroderma has never before been reported. We report a case of capecitabine-induced diffuse/systemic scleroderma in an 86-year-old female treated with capecitabine for metastatic colorectal cancer. She developed progressive skin and visceral sclerosis involving the lungs. We discuss the association between chemotherapy and scleroderma. We believe this is the first case of diffuse/systemic capecitabine-induced scleroderma without the presence of HFS. Early diagnosis is essential as fibrosis might be prevented in early stages. The capecitabine should be discontinued as early as possible.

  3. Drop tower Beijing and short-time microgravity experiments

    NASA Astrophysics Data System (ADS)

    Wan, S. H.; Yin, M. G.; Guan, X. D.; Lin, H.; Xie, J. C.; Hu, Wen-Rui

    Being an important, large ground-based experiment facility for microgravity science, the drop tower of National Microgravity Lab, CAS was founded in 2003 and, since then, has been un-dertaking the experiments to meet the requirements in microgravity research. The 116 meters high drop tower is located in Zhong Guan Cun district, the scientific town of Beijing. Main components of the facility consist of the drop capsule, release mechanism and deceleration and recovery devices, and were developed with particular technical characteristics. Inner space of the drop tower was not vacuumed during the experiment, and a dual capsule system was adopted. The dual capsule comprises an inner and an outer capsule, and there is a space between in the evacuated atmosphere of 30 Pa. During the free fall, the outer capsule falls in normal atmospheric condition, and the inner capsule falls in vacuum. In addition, a single capsule configuration is also available for experiments w of lower gravity level. The residual acceleration is 10-5go or 10-3g0 related to dual capsule or single capsule arrangement respec-tively. An electric magnetic release system was used to release the capsule from position of 83 meters in height. The designed structure of the release mechanism guaranteed the release disturbance to be small enough. An elastic controllable decelerated system, consisted of the reversible mechanic/electric energy transducer, steel cables and rings, string bag, elastic rub-ber stringassembly, energy dissipation resistance, controlling computer system, was used in the drop tower facility. This system is effective to reduce the impact acceleration to a level of 15g0. The experiment data can be recorded by an on-board data acquisition and control system, and transmitted wirelessly to the control room. Many experiments related to the fluid physics, combustion, material science and other field have been successfully conducted by using the short-time microgravity facility of drop tower in

  4. Combining capecitabine and bevacizumab in metastatic breast cancer: a comprehensive review.

    PubMed

    Miles, David; Zielinski, Christoph; Martin, Miguel; Vrdoljak, Eduard; Robert, Nicholas

    2012-03-01

    Both capecitabine and bevacizumab are established agents in the treatment of metastatic breast cancer, but until recently clinical data supporting their use in combination were limited. We review available data on the capecitabine-bevacizumab combination in breast cancer, particularly results from the RIBBON-1 trial in the first-line setting, and we discuss these findings in light of previous studies. We also examine ongoing trials investigating capecitabine-bevacizumab combination therapy. PMID:22257791

  5. Severe ileitis associated with capecitabine: Two case reports and review of the literature

    PubMed Central

    LEE, SHING FUNG; CHIANG, CHI LEUNG; LEE, ANN SHING; WONG, FRANK CHI SHING; TUNG, STEWART YUK

    2015-01-01

    Capecitabine is a commonly used anticancer drug, which has been associated with adverse events, including skin and gastrointestinal symptoms, such as vomiting and diarrhea. We herein present treated two rare cases of capecitabine-associated ileitis. In one of the patients, ileitis occurred during combination chemotherapy for metastatic colon cancer, despite previous good tolerance to this drug; the other patient developed ileitis following adjuvant single-agent treatment. The first case is unlike previously reported cases, in which patients had no past exposure to capecitabine. Ileitis may be severe but reversible with early diagnosis and proper supportive treatment, and patients may resume chemotherapy following capecitabine discontinuation. PMID:26807255

  6. Neoadjuvant Bevacizumab, Oxaliplatin, 5-Fluorouracil, and Radiation for Rectal Cancer

    SciTech Connect

    Dipetrillo, Tom; Pricolo, Victor; Lagares-Garcia, Jorge; Vrees, Matt; Klipfel, Adam; Cataldo, Tom; Sikov, William; McNulty, Brendan; Shipley, Joshua; Anderson, Elliot; Khurshid, Humera; Oconnor, Brigid; Oldenburg, Nicklas B.E.; Radie-Keane, Kathy; Husain, Syed; Safran, Howard

    2012-01-01

    Purpose: To evaluate the feasibility and pathologic complete response rate of induction bevacizumab + modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen followed by concurrent bevacizumab, oxaliplatin, continuous infusion 5-fluorouracil (5-FU), and radiation for patients with rectal cancer. Methods and Materials: Eligible patients received 1 month of induction bevacizumab and mFOLFOX6. Patients then received 50.4 Gy of radiation and concurrent bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/m{sup 2}/week for 6 weeks), and continuous infusion 5-FU (200 mg/m{sup 2}/day). Because of gastrointestinal toxicity, the oxaliplatin dose was reduced to 40 mg/m{sup 2}/week. Resection was performed 4-8 weeks after the completion of chemoradiation. Results: The trial was terminated early because of toxicity after 26 eligible patients were treated. Only 1 patient had significant toxicity (arrhythmia) during induction treatment and was removed from the study. During chemoradiation, Grade 3/4 toxicity was experienced by 19 of 25 patients (76%). The most common Grade 3/4 toxicities were diarrhea, neutropenia, and pain. Five of 25 patients (20%) had a complete pathologic response. Nine of 25 patients (36%) developed postoperative complications including infection (n = 4), delayed healing (n = 3), leak/abscess (n = 2), sterile fluid collection (n = 2), ischemic colonic reservoir (n = 1), and fistula (n = 1). Conclusions: Concurrent oxaliplatin, bevacizumab, continuous infusion 5-FU, and radiation causes significant gastrointestinal toxicity. The pathologic complete response rate of this regimen was similar to other fluorouracil chemoradiation regimens. The high incidence of postoperative wound complications is concerning and consistent with other reports utilizing bevacizumab with chemoradiation before major surgical resections.

  7. Rationally designed oxaliplatin-nanoparticle for enhanced antitumor efficacy

    NASA Astrophysics Data System (ADS)

    Paraskar, Abhimanyu; Soni, Shivani; Roy, Bhaskar; Papa, Anne-Laure; Sengupta, Shiladitya

    2012-02-01

    Nanoscale drug delivery vehicles have been extensively studied as carriers for cancer chemotherapeutics. However, the formulation of platinum chemotherapeutics in nanoparticles has been a challenge arising from their physicochemical properties. There are only a few reports describing oxaliplatin nanoparticles. In this study, we derivatized the monomeric units of a polyisobutylene maleic acid copolymer with glucosamine, which chelates trans-1,2-diaminocyclohexane (DACH) platinum (II) through a novel monocarboxylato and O → Pt coordination linkage. At a specific polymer to platinum ratio, the complex self-assembled into a nanoparticle, where the polymeric units act as the leaving group, releasing DACH-platinum in a sustained pH-dependent manner. Sizing was done using dynamic light scatter and electron microscopy. The nanoparticles were evaluated for efficacy in vitro and in vivo. Biodistribution was quantified using inductively coupled plasma atomic absorption spectroscopy (ICP-AAS). The PIMA-GA-DACH-platinum nanoparticle was found to be more active than free oxaliplatin in vitro. In vivo, the nanoparticles resulted in greater tumor inhibition than oxaliplatin (equivalent to 5 mg kg-1 platinum dose) with minimal nephrotoxicity or body weight loss. ICP-AAS revealed significant preferential tumor accumulation of platinum with reduced biodistribution to the kidney or liver following PIMA-GA-DACH-platinum nanoparticle administration as compared with free oxaliplatin. These results indicate that the rational engineering of a novel polymeric nanoparticle inspired by the bioactivation of oxaliplatin results in increased antitumor potency with reduced systemic toxicity compared with the parent cytotoxic. Rational design can emerge as an exciting strategy in the synthesis of nanomedicines for cancer chemotherapy.

  8. Capecitabine-induced leukoencephalopathy involving the bilateral corticospinal tracts

    PubMed Central

    Tan, Mark Bang-Wei; McAdory, Louis Elliott

    2016-01-01

    An 80 year old lady with a history of metastatic sigmoid carcinoma presented with expressive dysphasia and unsteady gait 4 days after commencement of adjuvant capecitabine chemotherapy. MRI demonstrated restricted diffusion and T2/FLAIR hyperintensity involving the course of the bilateral corticospinal tracts, the corpus callosum and the middle cerebellar peduncles. Discontinuation of chemotherapy lead to symptom resolution in 2 days; repeat MRI at 2 months demonstrated reversal of the diffusion changes and improvement of the previous T2W/FLAIR hyperintensity. This report describes the first case of capecitabine induced leukoencephalopathy causing restricted diffusion along the corticospinal tracts, which should be differentiated from other entities that involve the corticospinal tracts (i.e. amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), hypoglycemic coma, etc.) PMID:27200161

  9. Acute chest pain in a patient treated with capecitabine.

    PubMed

    Camaro, C; Danse, P W; Bosker, H A

    2009-08-01

    A 61-year-old male with a history of metastatic colorectal cancer was referred to our hospital for primary coronary intervention because of acute ST-elevation myocardial infarction. Coronary angiography, however, revealed no significant stenoses. When asked, the patient revealed that capecitabine (Xeloda(R)) was started by his oncologist one day before admission. It is known that this oral 5-FU analogue drug, used in metastatic colorectal cancer, can cause coronary artery spasms. The main treatment of capecitabine-induced vasospasm is discontinuation of the drug. Indeed, after cessation of the drug the patient remained free of symptoms and the ECG abnormalities normalised. (Neth Heart J 2009;17:288-91.). PMID:19789697

  10. DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan

    PubMed Central

    Falvella, Felicia Stefania; Cheli, Stefania; Martinetti, Antonia; Mazzali, Cristina; Iacovelli, Roberto; Maggi, Claudia; Gariboldi, Manuela; Pierotti, Marco Alessandro; Di Bartolomeo, Maria; Sottotetti, Elisa; Mennitto, Roberta; Bossi, Ilaria; de Braud, Filippo; Clementi, Emilio; Pietrantonio, Filippo

    2015-01-01

    Aims Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated but more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not. rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations. Methods Germline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G, c.1129-5923C > G, c.1896 T > C), hsa-mir-27a (rs895819) and UGT1A1 (*28) genes to assess their association with grade 3–4 AEs. Results None of the patients carried rare DPYD variants. We found DPYD c.496A > G, c.1129-5923C > G, c.1896 T > C in heterozygosity in 19%, 5% and 8%, respectively, homozygous rs895819 in hsa-mir-27a in 9% and homozygous UGT1A1*28 in 8%. Grade 3–4 AEs were observed in 36% patients and were associated with DPYD c.496A > G (odds ratio (OR) 4.93, 95% CI 1.29, 18.87; P = 0.021) and homozygous rs895819 in hsa-mir-27a (OR 11.11, 95% CI 1.21, 102.09; P = 0.020). Carriers of DPYD c.1896 T > C and homozygous UGT1A1*28 showed an OR of 8.42 (95% CI 0.88, 80.56; P = 0.052). Multivariate analysis confirmed an independent value for DPYD c.496A > G and c.1896 T > C. Conclusions Concomitant assessment of DPYD variants and the UGT1A1*28 allele is a promising strategy needing further validation for dose personalization. PMID:25782327

  11. Sudden hearing loss due to oxaliplatin use in a patient with colon cancer.

    PubMed

    Güvenç, M Güven; Dizdar, Denizhan; Dizdar, Senem Kurt; Okutur, Sadi Kerem; Demir, Gökhan

    2016-08-01

    Oxaliplatin is used to treat advanced colorectal cancer. Platinum-containing chemotherapeutic agents are known to be ototoxic. However, ototoxicity is rare with newer generation platinum-derived agents, such as oxaliplatin. This case report presents a rare case of sudden unilateral sensorineural hearing loss following intravenous (IV) infusion of oxaliplatin in a 64-year-old woman with advanced colon cancer. The hearing loss was severe and did not respond to treatment. To the best of our knowledge, this is the fifth reported case of oxaliplatin ototoxicity. Although oxaliplatin ototoxicity is rare, physicians must be aware of this important adverse effect, and an audiometric evaluation must be performed when necessary. Patients treated with oxaliplatin should be followed closely for early signs and symptoms of hearing loss, and if hearing loss is detected, treatment should be stopped immediately. PMID:25872564

  12. Hydrolysis of oxaliplatin-evaluation of the acid dissociation constant for the oxalato monodentate complex.

    PubMed

    Jerremalm, Elin; Eksborg, Staffan; Ehrsson, Hans

    2003-02-01

    Alkaline hydrolysis of the platinum anticancer drug oxaliplatin gives the oxalato monodentate complex and the dihydrated oxaliplatin complex in two consecutive steps. The acid dissociation constant for the oxalato monodentate intermediate was determined by a kinetic approach. The pK(a) value was estimated as 7.23. The monodentate intermediate is assumed to rapidly react with endogenous compounds, resulting in a continuous conversion of oxaliplatin via the monodentate form. PMID:12532393

  13. Pharmacological characterization of standard analgesics on oxaliplatin-induced acute cold hypersensitivity in mice.

    PubMed

    Zhao, Meng; Nakamura, Saki; Miyake, Takahito; So, Kanako; Shirakawa, Hisashi; Tokuyama, Shogo; Narita, Minoru; Nakagawa, Takayuki; Kaneko, Shuji

    2014-01-01

    Oxaliplatin, a platinum-based chemotherapeutic agent, causes an acute peripheral neuropathy triggered by cold in almost all patients during or within hours after its infusion. We recently reported that a single administration of oxaliplatin induced cold hypersensitivity 2 h after the administration in mice. In this study, we examined whether standard analgesics relieve the oxaliplatin-induced acute cold hypersensitivity. Gabapentin, tramadol, mexiletine, and calcium gluconate significantly inhibited and morphine and milnacipran decreased the acute cold hypersensitivity, while diclofenac and amitriptyline had no effects. These results suggest that gabapentin, tramadol, mexiletine, and calcium gluconate are effective against oxaliplatin-induced acute peripheral neuropathy. PMID:24671055

  14. A midline for oxaliplatin infusion: the myth of safety devices

    PubMed Central

    Masters, Ben; Hickish, Tamas; Uña Cidon, Esther

    2014-01-01

    Oxaliplatin is a platinum compound mainly used in the treatment of colorectal cancer. According to its manufacturer it is not considered vesicant agent though it has been shown to cause severe tissue damage if extravasation occurs in large doses. Several cases of extravasation have been reported; most of them from incorrectly placed peripheral cannula or incorrect use of central venous access devices. To reduce these risks, peripherally inserted central catheters and midline catheters have been increasingly used and are especially helpful if poor peripheral venous access. Midlines are mainly used for patients not receiving vesicant drugs, and are generally inserted without radiological guidance. They are believed to be safe, but we present the first ever-documented oxaliplatin extravasation injury from a midline catheter. PMID:24903726

  15. [A Case of Colorectal Cancer with Anaphylactic Shock to Oxaliplatin].

    PubMed

    Machida, Tomohiko; Tanaka, Jun-ichi; Terashima, Takeshi

    2015-11-01

    We present the case of a 61-year-old woman with cecum cancer, ileal and multiple hepatic metastases, and peritoneal dissemination. Surgery (right hemicolectomy) was performed on December 2013. After surgery, 7 courses of mFOLFOX6 plus bevacizumab were administered. In May 2014, 4 minutes after starting the 8th course of oxaliplatin, dyspnea, nausea, vomiting, and general malaise were observed. Oxaliplatin administration was immediately discontinued and an injection of an antiemetic drug was administered, but the patient's blood pressure dropped to 87/53 mmHg and the SpO2 decreased to 87% (room air). The patient showed facial pallor; oxygen administration was initiated. Although blood pressure recovered to 124/69 mmHg 3 minutes after oxygen administration, reddening of the palms, pruritus, and headache were observed. The dyspnea eased 8 minutes after oxygen administration, the SpO2 recovered 18 minutes after oxygen administration, and the headache ceased. The patient subsequently was admitted to the hospital for observation, but no significant change was observed, and she was discharged the following day. Anaphylaxis due to oxaliplatin occurring after the 6th course is commonly reported, and the symptoms in this case were comparable to those described in the literature. PMID:26805295

  16. SNPs in transporter and metabolizing genes as predictive markers for oxaliplatin treatment in colorectal cancer patients.

    PubMed

    Kap, Elisabeth J; Seibold, Petra; Scherer, Dominique; Habermann, Nina; Balavarca, Yesilda; Jansen, Lina; Zucknick, Manuela; Becker, Natalia; Hoffmeister, Michael; Ulrich, Alexis; Benner, Axel; Ulrich, Cornelia M; Burwinkel, Barbara; Brenner, Hermann; Chang-Claude, Jenny

    2016-06-15

    Oxaliplatin is frequently used as part of a chemotherapeutic regimen with 5-fluorouracil in the treatment of colorectal cancer (CRC). The cellular availability of oxaliplatin is dependent on metabolic and transporter enzymes. Variants in genes encoding these enzymes may cause variation in response to oxaliplatin and could be potential predictive markers. Therefore, we used a two-step procedure to comprehensively investigate 1,444 single nucleotide polymorphisms (SNPs) from these pathways for their potential as predictive markers for oxaliplatin treatment, using 623 stage II-IV CRC patients (of whom 201 patients received oxaliplatin) from a German prospective patient cohort treated with adjuvant or palliative chemotherapy. First, all genes were screened using the global test that evaluated SNP*oxaliplatin interaction terms per gene. Second, one model was created by backward elimination on all SNP*oxaliplatin interactions of the selected genes. The statistical procedure was evaluated using bootstrap analyses. Nine genes differentially associated with overall survival according to oxaliplatin treatment (unadjusted p values < 0.05) were selected. Model selection resulted in the inclusion of 14 SNPs from eight genes (six transporter genes, ABCA9, ABCB11, ABCC10, ATP1A1, ATP1B2, ATP8B3, and two metabolism genes GSTM5, GRHPR), which significantly improved model fit. Using bootstrap analysis we show an improvement of the prediction error of 3.7% in patients treated with oxaliplatin. Several variants in genes involved in metabolism and transport could thus be potential predictive markers for oxaliplatin treatment in CRC patients. If confirmed, inclusion of these variants in a predictive test could identify patients who are more likely to benefit from treatment with oxaliplatin. PMID:26835885

  17. Synergistic Activity of the Src Family Kinase Inhibitor Dasatinib and Oxaliplatin in Colon Carcinoma Cells is Mediated by Oxidative Stress

    PubMed Central

    Kopetz, Scott; Lesslie, Donald P.; Dallas, Nikolas A.; Park, Serk I.; Johnson, Marjorie; Parikh, Nila U.; Kim, Michael P.; Abbruzzese, James L.; Ellis, Lee M.; Chandra, Joya; Gallick, Gary E.

    2009-01-01

    Chemotherapeutic regimens for the treatment of colorectal cancer generally include oxaliplatin, although inherent and acquired resistance is common. One potential mediator of oxaliplatin sensitivity is the non-receptor protein tyrosine kinase, Src, the activity of which correlates with disease stage and patient survival. Therefore, we investigated the effects of Src inhibition using the tyrosine kinase inhibitor dasatinib on oxaliplatin sensitivity. We demonstrate that oxaliplatin acutely activates Src and that combination treatment with dasatinib is synergistic in a cell-line dependent manner, with the level of Src activation correlating with extent of synergy in a panel of six cell lines. Intracellular reactive oxygen species (ROS) are generated after oxaliplatin treatment, and ROS potently activates Src. Pretreatment with antioxidants inhibits oxaliplatin-induced Src activation. In oxaliplatin resistant cell lines, Src activity is constitutively increased. In a mouse model of colorectal liver metastases, treatment with oxaliplatin also results in chronic Src activation. The combination of dasatinib and oxaliplatin results in significantly smaller tumors compared to single agent treatment, corresponding with reduced proliferation and angiogenesis. Therefore, we conclude that oxaliplatin activates Src through a ROS-dependent mechanism. Src inhibition increases oxaliplatin activity both in vitro and in vivo. These results suggest that Src inhibitors combined with oxaliplatin may have efficacy in metastatic colon cancer, and may provide the first indication of a molecular phenotype that might be susceptible to such combinations. PMID:19383922

  18. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial

    PubMed Central

    Maughan, Timothy S; Adams, Richard A; Smith, Christopher G; Meade, Angela M; Seymour, Matthew T; Wilson, Richard H; Idziaszczyk, Shelley; Harris, Rebecca; Fisher, David; Kenny, Sarah L; Kay, Edward; Mitchell, Jenna K; Madi, Ayman; Jasani, Bharat; James, Michelle D; Bridgewater, John; Kennedy, M John; Claes, Bart; Lambrechts, Diether; Kaplan, Richard; Cheadle, Jeremy P

    2011-01-01

    Summary Background In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival. Methods In this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448. Findings 1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3–29·2] in the control group vs 17·0 months [9·4–30·1] in the cetuximab group; HR 1·04, 95% CI 0·87–1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0–12·5] in the control group vs 8·6 months [5·1–13·8] in the cetuximab group; HR 0·96, 0·82–1·12, p=0·60). Overall response rate increased from 57% (n=209

  19. Detection of capecitabine (Xeloda®) on the skin surface after oral administration

    NASA Astrophysics Data System (ADS)

    Huang, Mao-Dong; Fuss, Harald; Lademann, Jürgen; Florek, Stefan; Patzelt, Alexa; Meinke, Martina C.; Jung, Sora

    2016-04-01

    Palmoplantar erythrodysesthesia (PPE), or hand-foot syndrome, is a cutaneous toxicity under various chemotherapeutics contributing to the most frequent side effects in patients treated with capecitabine (Xeloda®). The pathomechanism of PPE has been unclear. Here, the topical detection of capecitabine in the skin after oral application was shown in 10 patients receiving 2500 mg/m2/day capecitabine. Sweat samples were taken prior to and one week after oral administration of capecitabine. Using high-resolution continuum source absorption spectrometry, the changes in concentrations of fluorine, which is an ingredient of capecitabine, were quantified and statistically analyzed. Here, we show an increase in fluorine concentrations from 40±10 ppb (2±0.5 pM) before capecitabine administration to 27.7±11.8 ppm (14.6±6.5 nM) after application, p<0.001. The results show the secretion of capecitabine on the skin surface after oral administration, indicating a local toxic effect as a possible pathomechanism of PPE.

  20. Concurrent capecitabine and whole-brain radiotherapy for treatment of brain metastases in breast cancer patients.

    PubMed

    Chargari, Cyrus; Kirova, Youlia M; Diéras, Véronique; Castro Pena, Pablo; Pena, Pablo Castro; Campana, Francois; Cottu, Paul H; Pierga, JeanYves; Fourquet, Alain

    2009-07-01

    Preclinical data have demonstrated that ionizing radiation acts synergistically with capecitabine. This report retrospectively assessed the use of capecitabine concurrently with whole-brain radiotherapy (WBRT) in patients with brain metastases from breast cancer. From January 2003 to March 2005, five breast cancer patients with brain metastases were referred for WBRT with concurrent capecitabine. Median age was 44 years (range: 38-53). The median dose of capecitabine was 1,000 mg/m(2) twice daily for 14 days (day1-14). Treatment cycles were repeated every 21 days, concurrently with WBRT (30 Gy, 3 Gy per fraction, 5 days per week). Median survival after starting WBRT plus capecitabine was 6.5 months (range 1-34 months). One patient achieved a complete response. Two patients achieved partial response, including one with local control lasting until most recent follow-up. One patient had stable disease. The remaining patient was not assessable for response because of early death. Most commonly reported adverse events were nausea (n = 2) and headache (n = 2), always grade 1. Other toxicities were grade 3 hand/foot syndrome (n = 1), moderate anemia requiring transfusion and dose reduction of capecitabine (n = 1), and grade 1 mucositis (n = 1). Although promising, these preliminary data warrant further assessment of capecitabine-based chemoradiation in brain metastases from breast cancer and need to be further validated in the setting of a clinical trial. PMID:19169856

  1. Oxaliplatin enhances gap junction-mediated coupling in cell cultures of mouse trigeminal ganglia.

    PubMed

    Poulsen, Jeppe Nørgaard; Warwick, Rebekah; Duroux, Meg; Hanani, Menachem; Gazerani, Parisa

    2015-08-01

    Communications between satellite glial cells and neighboring neurons within sensory ganglia may contribute to neuropathic and inflammatory pain. To elucidate the role of satellite glial cells in chemotherapy-induced pain, we examined the effects of oxaliplatin on the gap junction-mediated coupling between these cells. We also examined whether the gap junction blocker, carbenoxolone, can reverse the coupling. Primary cultures of mice trigeminal ganglia, 24-48h after cell isolation, were used. Satellite glial cells were injected with Lucifer yellow in the presence or absence of oxaliplatin (60 μM). In addition, the effect of carbenoxolone (100 μM) on coupling, and the expression of connexin 43 proteins were evaluated. Dye coupling between adjacent satellite glial cells was significantly increased (2.3-fold, P<0.05) following a 2h incubation with oxaliplatin. Adding carbenoxolone to the oxaliplatin-treated cultures reversed oxaliplatin-evoked coupling to baseline (P<0.05). Immunostaining showed no difference between expression of connexin 43 in control and oxaliplatin-treated cultures. Our findings indicated that oxaliplatin-increased gap junction-mediated coupling between satellite glial cells in primary cultures of mouse trigeminal ganglia, and carbenoxolone reversed this effect. Hence, it is proposed that increased gap junction-mediated coupling was seen between satellite glial cells in TG. This observation together with our previous data obtained from a behavioral study suggests that this phenomenon might contribute to chemotherapy-induced nociception following oxaliplatin treatment. PMID:25999145

  2. Randomized Phase III Trial of Ixabepilone Plus Capecitabine Versus Capecitabine in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane

    PubMed Central

    Sparano, Joseph A.; Vrdoljak, Eduard; Rixe, Oliver; Xu, Binghe; Manikhas, Alexey; Medina, Carlos; Ventilari Da Costa, Susanne Crocamo; Ro, Jungsil; Rubio, Gonzalo; Rondinon, Monica; Perez Manga, Gumersindo; Peck, Ronald; Poulart, Valerie; Conte, Pierfranco

    2010-01-01

    Purpose We sought to determine whether the combination of ixabepilone plus capecitabine improved overall survival (OS) compared with capecitabine alone in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. Patients and Methods A total of 1,221 patients with MBC previously treated with anthracycline and taxanes were randomly assigned to ixabepilone (40 mg/m2 intravenously on day 1) plus capecitabine (2,000 mg/m2 orally on days 1 through 14) or capecitabine alone (2,500 mg/m2 on the same schedule) given every 21 days. The trial was powered to detect a 20% reduction in the hazard ratio (HR) for death. Results There was no significant difference in OS between the combination and capecitabine monotherapy arm, the primary end point (median, 16.4 v 15.6 months; HR = 0.9; 95% CI, 078 to 1.03; P = .1162). The arms were well balanced with the exception of a higher prevalence of impaired performance status (Karnofsky performance status 70% to 80%) in the combination arm (32% v 25%). In a secondary Cox regression analysis adjusted for performance status and other prognostic factors, OS was improved for the combination (HR = 0.85; 95% CI, 0.75 to 0.98; P = .0231). In 79% of patients with measurable disease, the combination significantly improved progression-free survival (PFS; median, 6.2 v 4.2 months; HR = 0.79; P = .0005) and response rate (43% v 29%; P < .0001). Grade 3 to 4 neuropathy occurred in 24% treated with the combination, but was reversible. Conclusion This study confirmed a previous trial demonstrating improved PFS and response for the ixabepilone-capecitabine combination compared with capecitabine alone, although this did not result in improved survival. PMID:20530276

  3. Exenatide Facilitates Recovery from Oxaliplatin-Induced Peripheral Neuropathy in Rats

    PubMed Central

    Fujita, Shunsuke; Ushio, Soichiro; Ozawa, Nana; Masuguchi, Ken; Kawashiri, Takehiro; Oishi, Ryozo; Egashira, Nobuaki

    2015-01-01

    Background Oxaliplatin has widely been used as a key drug in the treatment of colorectal cancer; however, it causes peripheral neuropathy. Exenatide, a glucagon-like peptide-1 (GLP-1) agonist, is an incretin mimetic secreted from ileal L cells, which is clinically used to treat type 2 diabetes mellitus. GLP-1 receptor agonists have been reported to exhibit neuroprotective effects on the central and peripheral nervous systems. In this study, we investigated the effects of exenatide on oxaliplatin-induced neuropathy in rats and cultured cells. Methods Oxaliplatin (4 mg/kg) was administered intravenously twice per week for 4 weeks, and mechanical allodynia was evaluated using the von Frey test in rats. Axonal degeneration was assessed by toluidine blue staining of sciatic nerves. Results Repeated administration of oxaliplatin caused mechanical allodynia from day 14 to 49. Although the co-administration of extended-release exenatide (100 μg/kg) could not inhibit the incidence of oxaliplatin-induced mechanical allodynia, it facilitated recovery from the oxaliplatin-induced neuropathy with reparation of axonal degeneration. Inhibition of neurite outgrowth was evaluated in cultured pheochromocytoma 12 (PC12) cells. Exenatide inhibited oxaliplatin-induced neurite degeneration, but did not affect oxaliplatin-induced cell injury in cultured PC12 cells. Additionally, extended-release exenatide had no effect on the anti-tumor activity of oxaliplatin in cultured murine colon adenocarcinoma 26 (C-26) cells or C-26 cell-implanted mice. Conclusion These results suggest that exenatide may be useful for treating peripheral neuropathy induced by oxaliplatin in colorectal cancer patients with type 2 diabetes. PMID:26536615

  4. Oxaliplatin triggers necrosis as well as apoptosis in gastric cancer SGC-7901 cells

    SciTech Connect

    Wu, Ping; Zhu, Xueping; Jin, Wei; Hao, Shumei; Liu, Qi; Zhang, Linjie

    2015-05-01

    Intrinsic apoptotic pathway is considered to be responsible for cell death induced by platinum anticancer drugs. While in this study, we found that, necrosis is an indispensable pathway besides apoptosis in oxaliplatin-treated gastric cancer SGC-7901 cells. Upon exposure to oxaliplatin, both apoptotic and necrotic features were observed. The majority of dead cells were double positive for Annexin V and propidium iodide (PI). Moreover, mitochondrial membrane potential collapsed and caspase cascades were activated. However, ultrastructural changes under transmission electron microscope, coupled with the release of cellular contents, demonstrated the rupture of the plasma membrane. Oxaliplatin administration did not stimulate reactive oxygen species (ROS) production and autophagy, but elevated the protein level of Bmf. In addition, receptor interacting protein 1 (RIP1), but not receptor interacting protein 3 (RIP3) and its downstream components participated in this death process. Necrostatin-1 (Nec-1) blocked oxaliplatin-induced cell death nearly completely, whereas z-VAD-fmk could partially suppress cell death. Oxaliplatin treatment resulted in poly(ADP-ribose) polymerase-1 (PARP-1) overactivation, as indicated by the increase of poly(ADP-ribose) (PAR), which led to NAD{sup +} and ATP depletion. PARP-1 inhibitor, olaparib, could significantly block oxaliplatin-induced cell death, thus confirming that PARP-1 activation is mainly responsible for the cytotoxicity of oxaliplatin. Phosphorylation of H2AX at Ser139 and translocalization of apoptosis-inducing factor (AIF) are critical for this death process. Taken together, these results indicate that oxaliplatin can bypass canonical cell death pathways to kill gastric cancer cells, which may be of therapeutic advantage in the treatment of gastric cancer. - Highlights: • Oxaliplatin induces apoptotic and necrotic cell death. • Nec-1 can inhibit oxaliplatin-induced cell death nearly completely. • RIP3 and its

  5. Role of Reactive Oxygen Species in the Abrogation of Oxaliplatin Activity by Cetuximab in Colorectal Cancer

    PubMed Central

    Santoro, Valeria; Jia, Ruochen; Thompson, Hannah; Nijhuis, Anke; Jeffery, Rosemary; Kiakos, Konstantinos; Silver, Andrew R.; Hartley, John A.

    2016-01-01

    Background: The antibody cetuximab, targeting epidermal growth factor receptor (EGFR), is used to treat metastatic colorectal cancer (mCRC). Clinical trials suggest reduced benefit from the combination of cetuximab with oxaliplatin. The aim of this study was to investigate potential negative interactions between cetuximab and oxaliplatin. Methods: Thiazolyl blue tetrazolium bromide (MTT) assay and Calcusyn software were used to characterize drug interactions. Reactive oxygen species (ROS) were measured by flow cytometry and real-time polymerase chain reaction oxidative stress arrays identified genes regulating ROS production. Chromatin immunoprecipitation (ChIP) measured signal transducer and activator of transcription 1 (STAT-1) binding to dual oxidase 2 (DUOX2) promoter. SW48, DLD-1 KRAS wild-type cell lines and DLD-1 xenograft models exposed to cetuximab, oxaliplatin, or oxaliplatin + cetuximab (control [saline]; n = 3 mice per treatment group) were used. Statistical tests were two-sided. Results: Cetuximab and oxaliplatin exhibited antagonistic effects on cellular proliferation and apoptosis (caspase 3/7 activity reduced by 1.4-fold, 95% confidence interval [CI] = 0.78 to 2.11, P = .003) as opposed to synergistic effects observed with the irinotecan metabolite 7-Ethyl-10-hydroxycamptothecin (SN-38). Although both oxaliplatin and SN-38 produced ROS, only oxaliplatin-mediated apoptosis was ROS dependent. Production of ROS by oxaliplatin was secondary to STAT1-mediated transcriptional upregulation of DUOX2 (3.1-fold, 95% CI = 1.75 to 2.41, P < .001). Inhibition of DUOX2 induction and p38 activation by cetuximab reduced oxaliplatin cytotoxicity. Conclusions: Inhibition of STAT1 and DUOX2-mediated ROS generation by cetuximab impairs p38-dependent apoptosis by oxaliplatin in preclinical models and may contribute to reduced efficacy in clinical settings. Understanding the rationale for unexpected trial results will inform improved rationales for combining EGFR

  6. Highly optimized fourth-order short-time approximation for pathintegrals

    SciTech Connect

    Predescu, Cristian

    2006-10-01

    We derive a fourth-order short-time approximation for use in imaginary-time path-integral simulations. The short-time approximation converges for all continuous and bounded from below potentials, attains quartic order of convergence for sufficiently smooth potentials, and utilizes statistically independent random variables for its construction. These properties recommend the approximation as a natural replacement of the trapezoidal Trotter-Suzuki approximation for physical systems with continuous distributions.

  7. Highly optimized fourth-order short-time approximation for path integrals.

    PubMed

    Predescu, Cristian

    2006-01-19

    We derive a fourth-order short-time approximation for use in imaginary-time path-integral simulations. The short-time approximation converges for all continuous and bounded-from-below potentials, attains quartic order of convergence for sufficiently smooth potentials, and utilizes statistically independent random variables for its construction. These properties recommend the approximation as a natural replacement of the trapezoidal Trotter-Suzuki approximation for physical systems with continuous distributions. PMID:16471584

  8. Involvement of mast cells and proteinase-activated receptor 2 in oxaliplatin-induced mechanical allodynia in mice.

    PubMed

    Sakamoto, Ayumi; Andoh, Tsugunobu; Kuraishi, Yasushi

    2016-03-01

    The chemotherapeutic agent oxaliplatin induces neuropathic pain, a dose-limiting side effect, but the underlying mechanisms are not fully understood. Here, we show the potential involvement of cutaneous mast cells in oxaliplatin-induced mechanical allodynia in mice. A single intraperitoneal injection of oxaliplatin induced mechanical allodynia, which peaked on day 10 after injection. Oxaliplatin-induced mechanical allodynia was almost completely prevented by congenital mast cell deficiency. The numbers of total and degranulated mast cells was significantly increased in the skin after oxaliplatin administration. Repetitive topical application of the mast cell stabilizer azelastine hydrochloride inhibited mechanical allodynia and the degranulation of mast cells without affecting the number of mast cells in oxaliplatin-treated mice. The serine protease inhibitor camostat mesilate and the proteinase-activated receptor 2 (PAR2) antagonist FSLLRY-NH2 significantly inhibited oxaliplatin-induced mechanical allodynia. However, it was not inhibited by the H1 histamine receptor antagonist terfenadine. Single oxaliplatin administration increased the activity of cutaneous serine proteases, which was attenuated by camostat and mast cell deficiency. Depletion of the capsaicin-sensitive primary afferents by neonatal capsaicin treatment almost completely prevented oxaliplatin-induced mechanical allodynia, the increase in the number of mast cells, and the activity of cutaneous serine proteases. These results suggest that serine protease(s) released from mast cells and PAR2 are involved in oxaliplatin-induced mechanical allodynia. Therefore, oxaliplatin may indirectly affect the functions of mast cells through its action on capsaicin-sensitive primary afferents. PMID:26804251

  9. Preparation, characterisation and antitumour activity of β-, γ- and HP-β-cyclodextrin inclusion complexes of oxaliplatin

    NASA Astrophysics Data System (ADS)

    Zhang, Da; Zhang, Jianqiang; Jiang, Kunming; Li, Ke; Cong, Yangwei; Pu, Shaoping; Jin, Yi; Lin, Jun

    2016-01-01

    Three water-soluble oxaliplatin complexes were prepared by inclusion complexation with β-cyclodextrin (β-CD), γ-CD and HP-β-CD. The structures of oxaliplatin/CDs were confirmed by NMR, FTIR, TGA, XRD as well as SEM analysis. The results show that the water solubility of oxaliplatin was increased in the complex with CDs in 1:1 stoichiometry inclusion modes, and the cyclohexane ring of oxaliplatin molecule was deeply inserted into the cavity of CDs. Moreover, the stoichiometry was established by a Job plot and the water stability constant (Kc) of oxaliplatin/CDs was calculated by phase solubility studies, all results show that the oxaliplatin/β-CD complex is more stable than free oxaliplatin, oxaliplatin/HP-β-CD and oxaliplatin/γ-CD. Meanwhile, the inclusion complexes displayed almost twice as high cytotoxicity compared to free oxaliplatin against HCT116 and MCF-7 cells. This satisfactory water solubility and higher cytotoxic activity of the oxaliplatin/CD complexes will potentially be useful for their application in anti-tumour therapy.

  10. Optimal time interval between capecitabine intake and radiotherapy in preoperative chemoradiation for locally advanced rectal cancer

    SciTech Connect

    Yu, Chang Sik; Kim, Tae Won; Kim, Jong Hoon . E-mail: jhkim2@amc.seoul.kr; Choi, Won Sik; Kim, Hee Cheol; Chang, Heung Moon; Ryu, Min Hee; Jang, Se Jin; Ahn, Seung Do; Lee, Sang-wook; Shin, Seong Soo; Choi, Eun Kyung; Kim, Jin Cheon

    2007-03-15

    Purpose: Capecitabine and its metabolites reach peak plasma concentrations 1 to 2 hours after a single oral administration, and concentrations rapidly decrease thereafter. We performed a retrospective analysis to find the optimal time interval between capecitabine administration and radiotherapy for rectal cancer. Methods and Materials: The time interval between capecitabine intake and radiotherapy was measured in patients who were treated with preoperative radiotherapy and concurrent capecitabine for rectal cancer. Patients were classified into the following groups. Group A1 included patients who took capecitabine 1 hour before radiotherapy, and Group B1 included all other patients. Group B1 was then subdivided into Group A2 (patients who took capecitabine 2 hours before radiotherapy) and Group B2. Group B2 was further divided into Group A3 and Group B3 with the same method. Total mesorectal excision was performed 6 weeks after completion of chemoradiation and the pathologic response was evaluated. Results: A total of 200 patients were enrolled in this study. Pathologic examination showed that Group A1 had higher rates of complete regression of primary tumors in the rectum (23.5% vs. 9.6%, p = 0.01), good response (44.7% vs. 25.2%, p = 0.006), and lower T stages (p = 0.021) compared with Group B1; however, Groups A2 and A3 did not show any improvement compared with Groups B2 and B3. Multivariate analysis showed that increases in primary tumors in the rectum and good response were only significant when capecitabine was administered 1 hour before radiotherapy. Conclusion: In preoperative chemoradiotherapy for rectal cancer, the pathologic response could be improved by administering capecitabine 1 hour before radiotherapy.

  11. [Search for Factors Related to Vascular Pain Expression upon Administration of Oxaliplatin into a Peripheral Vein].

    PubMed

    Takagi, Akiko; Yonemoto, Nao; Aoyama, Yuuya; Touma, Yuri; Kajiwara, Michiko; Watanabe, Kosuke; Miyazaki, Yoshiko; Koinuma, Masayoshi

    2015-07-01

    We investigated the relationship between vascular pain and various characteristics (age, sex, cancer stage, performance status [PS], height, weight, body mass index [BMI], body surface area, oxaliplatin dose, and presence and absence of the initial administration of dexamethasone) in colorectal cancer patients who were administered initial doses of oxaliplatin intravenously. The study population included 29 patients treated at Higashi Totsuka Memorial Hospital between June 2010 and April 2014. One-way analysis of variance showed that vascular pain was significantly associated with weight (p=0.015), body surface area (p=0.013), and oxaliplatin doses (p=0.0026), where the significance level was p=0.05. Logistic regression analysis and the likelihood ratio test demonstrated that the likelihood of vascular pain increased with the increase in the oxaliplatin dose. According to the cut-off value of vascular pain determined using the receiver operating characteristic (ROC) analysis, a single dose of oxaliplatin was determined to be 175 mg or more. According to the cut-off value established using the ROC analysis, a single dose of oxaliplatin at which vascular pain is expressed was determined to be 175 mg or more. At this dose, 13 patients complained of vascular pain and 8 did not. At doses less than 175 mg, none of the 8 patients complained of vascular pain. These results suggest that lowering the diluted concentration and reducing the infusion rate of intravenously administered oxaliplatin may reduce vascular pain. PMID:26197757

  12. Cetuximab-induced hypomagnesaemia aggravates peripheral sensory neurotoxicity caused by oxaliplatin.

    PubMed

    Kono, Toru; Satomi, Machiko; Asama, Toshiyuki; Ebisawa, Yoshiaki; Chisato, Naoyuki; Suno, Manabu; Karasaki, Hidenori; Furukawa, Hiroyuki; Matsubara, Kazuo

    2010-12-01

    Calcium and magnesium replacement is effective in reducing oxaliplatin-induced neurotoxicity. However, cetuximab treatment has been associated with severe hypomagnesaemia. Therefore, we retrospectively investigated whether cetuximab-induced hypomagnesaemia exacerbated oxaliplatin-induced neurotoxicity. Six patients with metastatic colorectal cancer who were previously treated with oxaliplatin-fluorouracil combination therapy were administered cetuximab in combination with irinotecan alone or irinotecan and fluorouracil as a second-line treatment. All patients had normal magnesium levels before receiving cetuximab. The Common Terminology Criteria for Adverse Events version 3.0 was used to evaluate the grade of neurotoxicity, hypomagnesaemia, hypocalcaemia, and hypokalemia every week. All six patients had grade 1 or higher hypomagnesaemia after starting cetuximab therapy. The serum calcium and potassium levels were within the normal range at the onset of hypomagnesaemia. Oxaliplatin-induced neurotoxicity occurred in all patients at the beginning of cetuximab therapy, with grade 1 neurotoxicity in five patients and grade 2 in one patient. After cetuximab administration, the neurotoxicity worsened in all six patients, and three progressed to grade 3. Among the three patients with grade 3 neurotoxicity, two required a dose reduction and one had to discontinue cetuximab therapy. A discontinuation or dose reduction in cetuximab therapy was associated with exacerbated oxaliplatin-induced neurotoxicity due to cetuximab-induced hypomagnesaemia in half of patients who had previously received oxaliplatin. Therefore, when administering cetuximab after oxaliplatin therapy, we suggest serially evaluating serum magnesium levels and neurotoxicity. PMID:22811813

  13. Cetuximab-induced hypomagnesaemia aggravates peripheral sensory neurotoxicity caused by oxaliplatin

    PubMed Central

    Satomi, Machiko; Asama, Toshiyuki; Ebisawa, Yoshiaki; Chisato, Naoyuki; Suno, Manabu; Karasaki, Hidenori; Furukawa, Hiroyuki; Matsubara, Kazuo

    2010-01-01

    Calcium and magnesium replacement is effective in reducing oxaliplatin-induced neurotoxicity. However, cetuximab treatment has been associated with severe hypomagnesaemia. Therefore, we retrospectively investigated whether cetuximab-induced hypomagnesaemia exacerbated oxaliplatin-induced neurotoxicity. Six patients with metastatic colorectal cancer who were previously treated with oxaliplatin-fluorouracil combination therapy were administered cetuximab in combination with irinotecan alone or irinotecan and fluorouracil as a second-line treatment. All patients had normal magnesium levels before receiving cetuximab. The Common Terminology Criteria for Adverse Events version 3.0 was used to evaluate the grade of neurotoxicity, hypomagnesaemia, hypocalcaemia, and hypokalemia every week. All six patients had grade 1 or higher hypomagnesaemia after starting cetuximab therapy. The serum calcium and potassium levels were within the normal range at the onset of hypomagnesaemia. Oxaliplatin-induced neurotoxicity occurred in all patients at the beginning of cetuximab therapy, with grade 1 neurotoxicity in five patients and grade 2 in one patient. After cetuximab administration, the neurotoxicity worsened in all six patients, and three progressed to grade 3. Among the three patients with grade 3 neurotoxicity, two required a dose reduction and one had to discontinue cetuximab therapy. A discontinuation or dose reduction in cetuximab therapy was associated with exacerbated oxaliplatin-induced neurotoxicity due to cetuximab-induced hypomagnesaemia in half of patients who had previously received oxaliplatin. Therefore, when administering cetuximab after oxaliplatin therapy, we suggest serially evaluating serum magnesium levels and neurotoxicity. PMID:22811813

  14. Preventive effect of oral goshajinkigan on chronic oxaliplatin-induced hypoesthesia in rats

    PubMed Central

    Kono, Toru; Suzuki, Yasuyuki; Mizuno, Keita; Miyagi, Chika; Omiya, Yuji; Sekine, Hitomi; Mizuhara, Yasuharu; Miyano, Kanako; Kase, Yoshio; Uezono, Yasuhito

    2015-01-01

    Oxaliplatin, a widely used chemotherapeutic agent, induces peripheral neuropathy that manifests itself as two distinct phases: acute cold hyperesthesia and chronic peripheral hypoesthesia/dysesthesia. The latter is a serious dose-limiting side effect that can often lead to withdrawal of treatment. We have developed a rat model expressing both phases and used the model to investigate the action of goshajinkigan (GJG), a traditional Japanese herbal medicine, which was reported to ameliorate oxaliplatin-induced neuropathy in a placebo-controlled double-blind randomized phase II study. In this study, neuropathy was induced by injection of oxaliplatin twice weekly for 8 wks. The maximum level of cold hyperesthesia was observed at 4 wks with heat hypoesthesia developing later. Microscopy studies revealed atrophy of axons of myelinated sciatic nerve fibers in oxaliplatin-treated rats at 8 wks. Co-administration of GJG ameliorated both abnormal sensations as well as histological damage to the sciatic nerve. A pharmacokinetic study revealed numerous neuroprotective components of GJG that are rapidly absorbed into the blood. GJG and some of its components attenuated the generation of oxaliplatin-induced reactive oxygen species, which is a possible mechanism of oxaliplatin-induced neurotoxicity. The present study provides a useful animal model for oxaliplatin-induced neurotoxicity as well as a promising prophylactic agent. PMID:26542342

  15. Capecitabine-phenytoin interaction is dose dependent with an unexpected time course.

    PubMed

    Privitera, Michael; de Los Ríos la Rosa, Felipe

    2011-11-01

    The main objective of this study was to further analyze the drug interaction between capecitabine and phenytoin with special emphasis on magnitude, timing, and the dose effect. A single patient had multiple phenytoin levels at various doses of capecitabine. Phenytoin levels were subjected to analysis of variance and the dose effect was approached using a multiple comparison test. All phenytoin levels meeting the criteria for steady state were subjected to box plot analysis. Analysis of 35 phenytoin levels over a 25-month period demonstrated a statistically significant interaction between the medications. The interaction onset was delayed by 4 weeks and persisted up to 9 weeks after capecitabine dose increases or decreases. The magnitude of interaction was directly proportional to the capecitabine dosage. We concluded that capecitabine caused a marked increase in phenytoin levels that was capecitine dose dependent, with a delayed time course not predicted by phenytoin kinetics, suggesting a novel interaction mechanism. The magnitude and complexity of this interaction suggest that alternate antiepileptic medications should be used in combination with capecitabine. PMID:21909021

  16. Delayed reversible posterior encephalopathy syndrome following chemotherapy with oxaliplatin.

    PubMed

    Sharief, Ubaidullah; Perry, David J

    2009-07-01

    Reversible posterior leukoencephalopathy (RPLS), also known as posterior reversible encephalopathy syndrome, is characterized by magnetic resonance imaging (MRI) findings of reversible vasogenic subcortical edema without infarction. The clinical presentation is usually nonspecific and typically involves global encephalopathy, seizures, headache, or visual symptoms. MRI of the brain is essential to the diagnosis of RPLS. Typical findings of RPLS include high-intensity signal on T2-weighted images predominantly in the posterior lobes of the brain that is caused by subcortical white matter vasogenic edema. Fluid-attenuated inversion recovery (FLAIR) sequences on MRI improve sensitivity and detect subtle peripheral lesions. This clinical radiographic syndrome has been described in a number of medical conditions, with hypertensive encephalopathy, eclampsia, and the use of immunosuppressant drugs (most notably calcineurin inhibitors) being the most common. It has occasionally been reported with cisplatin and rarely with carboplatin. Its occurrence with oxaliplatin is very unusual. An extensive literature search including PUBMED and direct contact with the drug manufacturer yielded only 2 known case reports. Herein, we describe a case that had classic clinical and radiologic features of RPLS. We also briefly describe 2 other patients who have been described to have RPLS with oxaliplatin in the literature. PMID:19632931

  17. (+)-Borneol attenuates oxaliplatin-induced neuropathic hyperalgesia in mice.

    PubMed

    Zhou, Hai-Hui; Zhang, Li; Zhou, Qi-Gang; Fang, Yun; Ge, Wei-Hong

    2016-02-10

    Common chemotherapeutic agents such as oxaliplatin often cause neuropathic pain during cancer treatment in patients. Such neuropathic pain is difficult to treat and responds poorly to common analgesics, which represents a clinical challenge. (+)-Borneol, a bicyclic monoterpene present in the essential oil of plants, is used for analgesia and anesthesia in traditional Chinese medicine. Although borneol has an antinociceptive effect on acute pain models, little is known about its effect on chemotherapy-induced neuropathic pain and its mechanism. We found that (+)-borneol exerted remarkable antihyperalgesic effects in a mouse model of oxaliplatin-induced neuropathic pain. In addition, (+)-borneol blocked the action of the transient receptor potential ankyrin 1 agonist in mechanical and cold stimulus tests. Repeated treatment with (+)-borneol did not lead to the development of antinociceptive tolerance and did not affect body weight and locomotor activity. (+)-Borneol showed robust analgesic efficacy in mice with neuropathic pain by blocking transient receptor potential ankyrin 1 in the spinal cord and may be a useful analgesic in the management of neuropathic pain. PMID:26730517

  18. A phase I/II study of biweekly capecitabine and irinotecan plus bevacizumab as second-line chemotherapy in patients with metastatic colorectal cancer

    PubMed Central

    Suenaga, Mitsukuni; Mizunuma, Nobuyuki; Matsusaka, Satoshi; Shinozaki, Eiji; Ozaka, Masato; Ogura, Mariko; Chin, Keisho; Yamaguchi, Toshiharu

    2015-01-01

    Background Triweekly capecitabine plus irinotecan (XELIRI) is not completely regarded as a valid substitute for fluorouracil, leucovorin, and irinotecan (FOLFIRI) in metastatic colorectal cancer (mCRC) because of the potential for greater toxicity. We conducted a phase I/II study to assess the efficacy and safety of biweekly XELIRI plus bevacizumab (BV) as second-line chemotherapy for mCRC. Methods Patients with mCRC who had received prior chemotherapy including oxaliplatin and BV and had a UGT1A1 genotype of wild-type or heterozygous for UGT1A1*6 or *28 were eligible for this study. Treatment comprised capecitabine 1,000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan on day 1, and BV 5 mg/kg on day 1 every 2 weeks. The phase I study consisted of two steps (irinotecan 150 and 180 mg/m2), and dose-limiting toxicity was assessed during the first treatment cycle. The primary endpoint of the phase II study was progression-free survival (PFS). Results The recommended dose of irinotecan was determined to be 180 mg/m2 in the phase I study. Between November 2010 and August 2013, 44 patients were enrolled in phase II. The patients’ characteristics were as follows (N=44): median age, 60 years (range 32–80); male/female, 21/23; and UGT1A1 wild-type/heterozygous, 29/15. The median PFS was 6.8 months (95% confidence interval, 5.3–8.2 months), and the primary endpoint was met. Median overall survival was 18.3 months. The response rate was 22.7%. There was no significant difference in PFS or overall survival according to UGT1A1 status. Grade 3 or higher adverse events were mainly neutropenia in six patients and diarrhea in five patients. There were no other severe adverse events or treatment-related deaths. Conclusion In mCRC patients with wild-type or heterozygous UGT1A1*6 or *28 genotype, biweekly XELIRI + BV is effective and feasible as second-line chemotherapy. Biweekly XELIRI + BV is considered a valid substitute for FOLFIRI

  19. A New Method to Evaluate the Short-Time Withstand Current for Air Circuit Breaker

    NASA Astrophysics Data System (ADS)

    Xiang, Honggang; Chen, Degui; Li, Xingwen; Tong, Weixiong

    Short-time withstand current is one of the crucial nominal parameters in air circuit breaker. A numerical method to evaluate the short-time withstand current is proposed. Cylindrical current carrying bridge is introduced to describe the contact spot between movable and fixed contacts. Taking into account the action of ferromagnetic splitter plates, the variation of the conductor properties with temperature and the variation of contact spot radius with the electro-dynamic repulsion force, a transient finite element calculation model is developed by coupling the electromagnetic field and thermal field. The loaded short circuit current is considered as the short-time withstand current once the highest temperature is near to the melting point of the contact material. It demonstrates that the method is useful to evaluate the performance of the air circuit breaker.

  20. Short-time evolution of Lagrangian velocity gradient correlations in isotropic turbulence

    NASA Astrophysics Data System (ADS)

    Fang, L.; Bos, W. J. T.; Jin, G. D.

    2015-12-01

    We show by direct numerical simulation (DNS) that the Lagrangian cross correlation of velocity gradients in homogeneous isotropic turbulence increases at short times, whereas its auto-correlation decreases. Kinematic considerations allow to show that two invariants of the turbulent velocity field determine the short-time velocity gradient correlations. In order to get a more intuitive understanding of the dynamics for longer times, heuristic models are proposed involving the combined action of local shear and rotation. These models quantitatively reproduce the effects and disentangle the different physical mechanisms leading to the observations in the DNS.

  1. Acute inflammatory demyelinating polyradiculoneuropathy in a patient receiving oxaliplatin-based chemotherapy.

    PubMed

    Yoon, Ju Young; Nam, Tai Seung; Kim, Myeong Kyu; Hwang, Jun Eul; Shim, Hyun-Jeong; Cho, Sang Hee; Chung, Ik Joo; Bae, Woo Kyun

    2012-06-01

    We report a case of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) that developed in a patient with cholangiocarcinoma after receiving oxaliplatin-based chemotherapy. A 62-year-old man had multiple hypodense lesions with delayed enhancement in the both lobes of the liver on abdominal computed tomography. He was treated with 5-fluorouracil, leucovorin and oxaliplatin (100 mg/m(2)). After eight cycles of treatment and a cumulative oxaliplatin dose of 780 mg/m(2), he developed an unsteady gait, dysphagia, weakness of both the upper and lower limbs and impairment of all sensory modalities. Nerve conduction studies confirmed the diagnosis of AIDP. Immunoglobulin G i.v. was administered for 5 days but the neurological deficits of both his upper and lower limbs did not improve. This case highlights unusual peripheral nervous system manifestations in a patient who received chemotherapy with oxaliplatin. PMID:22524580

  2. Milnacipran inhibits oxaliplatin-induced mechanical allodynia through spinal action in mice.

    PubMed

    Andoh, Tsugunobu; Kitamura, Ryo; Kuraishi, Yasushi

    2015-01-01

    We investigated whether milnacipran, a serotonin-noradrenaline reuptake inhibitor, would have therapeutic effect on oxaliplatin-induced mechanical allodynia in mice. A single intraperitoneal injection of oxaliplatin (3 mg/kg) induced mechanical allodynia, which peaked on day 10 after injection and almost completely subsided by day 20. Ten days post-oxaliplatin injection, the intraperitoneal administration of milnacipran (3-30 mg/kg) significantly and dose-dependently inhibited the established mechanical allodynia. Intrathecal injections of milnacipran (2.1-21 µg/site) also significantly and dose-dependently inhibited mechanical allodynia, but intracisternal and intracereboventricular injections at the same doses did not. The present results suggest that milnacipran is effective against oxaliplatin-induced mechanical allodynia and that the antiallodynic effect is mainly mediated by actions on the spinal cord. PMID:25744472

  3. Oxaliplatin-induced immune-mediated cytopenias: a case report and literature review.

    PubMed

    Forcello, Nicholas P; Khubchandani, Sapna; Patel, Shrina J; Brahaj, Driola

    2015-04-01

    Oxaliplatin is a third-generation platinum antineoplastic agent that commonly causes diarrhea, nausea, vomiting, myelosuppression, and peripheral neuropathy. Less common adverse effects that are increasingly being reported include acute immune-mediated thrombocytopenia, hemolytic anemia, and pancytopenia. Here, we report a patient case of suspected oxaliplatin-induced immune-mediated thrombocytopenia and a thorough literature evaluation of acute oxaliplatin-induced immune-mediated thrombocytopenia, hemolytic anemia, and pancytopenia that has yet to be reported until now. There have been 39 previously published reports of these cytopenic events with a median number of 16 treatment cycles prior to presentation. Patients experiencing unusual signs and symptoms such as chills, rigors, fever, back pain, abdominal pain, ecchymosis, hematemesis, hematuria, dark urine, hematochezia, petechiae, epistaxis, or mental status changes during or shortly after an oxaliplatin infusion should have complete blood counts ordered and evaluated promptly. PMID:24500808

  4. Cetuximab Plus Oxaliplatin May Not Be Effective Primary Treatment for Metastatic Colorectal Cancer

    Cancer.gov

    In a randomized phase III trial, the addition of the targeted therapy cetuximab to oxaliplatin and fluoropyrimidine chemotherapy did not prolong survival or time to disease progression of patients with advanced colorectal cancer.

  5. Sensitization of capsaicin and icilin responses in oxaliplatin treated adult rat DRG neurons

    PubMed Central

    2010-01-01

    Background Oxaliplatin chemotherapy induced neuropathy is a dose related cumulative toxicity that manifests as tingling, numbness, and chronic pain, compromising the quality of life and leading to discontinued chemotherapy. Patients report marked hypersensitivity to cold stimuli at early stages of treatment, when sensory testing reveals cold and heat hyperalgesia. This study examined the morphological and functional effects of oxaliplatin treatment in cultured adult rat DRG neurons. Results 48 hour exposure to oxaliplatin resulted in dose related reduction in neurite length, density, and number of neurons compared to vehicle treated controls, using Gap43 immunostaining. Neurons treated acutely with 20 μg/ml oxaliplatin showed significantly higher signal intensity for cyclic AMP immunofluorescence (160.5 ± 13 a.u., n = 3, P < 0.05), compared to controls (120.3 ± 4 a.u.). Calcium imaging showed significantly enhanced capsaicin (TRPV1 agonist), responses after acute 20 μg/ml oxaliplatin treatment where the second of paired capsaicin responses increased from 80.7 ± 0.6% without oxaliplatin, to 171.26 ± 29% with oxaliplatin, (n = 6 paired t test, P < 0.05); this was reduced to 81.42 ± 8.1% (P < 0.05), by pretretreatment with the cannabinoid CB2 receptor agonist GW 833972. Chronic oxaliplatin treatment also resulted in dose related increases in capsaicin responses. Similarly, second responses to icilin (TRPA1/TRPM8 agonist), were enhanced after acute (143.85 ± 7%, P = 0.004, unpaired t test, n = 3), and chronic (119.7 ± 11.8%, P < 0.05, n = 3) oxaliplatin treatment, compared to control (85.3 ± 1.7%). Responses to the selective TRPM8 agonist WS-12 were not affected. Conclusions Oxaliplatin treatment induces TRP sensitization mediated by increased intracellular cAMP, which may cause neuronal damage. These effects may be mitigated by co-treatment with adenylyl cyclase inhibitors, like CB2 agonists, to alleviate the neurotoxic effects of oxaliplatin. PMID:21106058

  6. Houttuynia cordata Thunb reverses oxaliplatin-induced neuropathic pain in rat by regulating Th17/Treg balance.

    PubMed

    Wan, Cheng-Fu; Zheng, Li-Li; Liu, Yan; Yu, Xue

    2016-01-01

    Oxaliplatin is a widely used anti-advanced colorectal cancer drug, while it could induce neuropathy. Houttuynia cordata Thunb (HCT) has a wide range of biological activities, such as anti-inflammation, anti-cancer, and immune regulation. In the present study, we investigated the effect of HCT on oxaliplatin-induced neuropathy in rat models. HCT (1000 mg/kg/day) significantly decreased the number of withdrawal responses and the withdrawal latency in oxaliplatin-treated rats. HCT could down-regulated the serum levels of Interleukin-6 (IL-6) and macrophage inflammatory protein1-α (MIP-1α) in oxaliplatin-treated rats. Th17/Treg balance was reversed by HCT in oxaliplatin-treated rats by regulating PI3K/Akt/mTOR signaling pathway. The present results suggest that HCT is useful as a therapeutic drug for oxaliplatin-induced neuropathic pain. PMID:27186286

  7. Houttuynia cordata Thunb reverses oxaliplatin-induced neuropathic pain in rat by regulating Th17/Treg balance

    PubMed Central

    Wan, Cheng-Fu; Zheng, Li-Li; Liu, Yan; Yu, Xue

    2016-01-01

    Oxaliplatin is a widely used anti-advanced colorectal cancer drug, while it could induce neuropathy. Houttuynia cordata Thunb (HCT) has a wide range of biological activities, such as anti-inflammation, anti-cancer, and immune regulation. In the present study, we investigated the effect of HCT on oxaliplatin-induced neuropathy in rat models. HCT (1000 mg/kg/day) significantly decreased the number of withdrawal responses and the withdrawal latency in oxaliplatin-treated rats. HCT could down-regulated the serum levels of Interleukin-6 (IL-6) and macrophage inflammatory protein1-α (MIP-1α) in oxaliplatin-treated rats. Th17/Treg balance was reversed by HCT in oxaliplatin-treated rats by regulating PI3K/Akt/mTOR signaling pathway. The present results suggest that HCT is useful as a therapeutic drug for oxaliplatin-induced neuropathic pain. PMID:27186286

  8. APPARATUS FOR SHORT TIME MEASUREMENTS IN A FIXED-BED, GAS/SOLID REACTOR

    EPA Science Inventory

    An apparatus for exposure of a solid to reactive process gas is described which makes possible short time (≥ 0.3 to 15 s) exposures in a fixed-bed reactor. Operating conditions for differential reaction with respect to the gas concentration and rapid quench for arresting hi...

  9. A search for short time scale TeV variability in Mkn501

    NASA Astrophysics Data System (ADS)

    Carson, Michael; McKernan, Barry; Yaqoob, Tahir; Fegan, David

    1999-06-01

    We analyse Whipple TeV gamma-ray data from active states of Mkn501 for short time scale variability using the new Excess Pair Fraction (EPF) method. No evidence is found for significant variability on time scales less than 10 minutes.

  10. Lay-Offs and Short-Time Working in Selected OECD Countries.

    ERIC Educational Resources Information Center

    Grais, Bernard; And Others

    This report, which includes the conclusions of the Organisation for Economic Cooperation and Development (OECD) Working Party on Employment and Unemployment Statistics, analyzes arrangements for compensating workers in the OECD countries who are temporarily laid-off or subject to short-time work. In introductory sections to part 1, the concepts of…

  11. Short time Fourier analysis of the electromyogram - Fast movements and constant contraction

    NASA Technical Reports Server (NTRS)

    Hannaford, Blake; Lehman, Steven

    1986-01-01

    Short-time Fourier analysis was applied to surface electromyograms (EMG) recorded during rapid movements, and during isometric contractions at constant forces. A portion of the data to be transformed by multiplying the signal by a Hamming window was selected, and then the discrete Fourier transform was computed. Shifting the window along the data record, a new spectrum was computed each 10 ms. The transformed data were displayed in spectograms or 'voiceprints'. This short-time technique made it possible to see time-dependencies in the EMG that are normally averaged in the Fourier analysis of these signals. Spectra of EMGs during isometric contractions at constant force vary in the short (10-20 ms) term. Short-time spectra from EMGs recorded during rapid movements were much less variable. The windowing technique picked out the typical 'three-burst pattern' in EMG's from both wrist and head movements. Spectra during the bursts were more consistent than those during isometric contractions. Furthermore, there was a consistent shift in spectral statistics in the course of the three bursts. Both the center frequency and the variance of the spectral energy distribution grew from the first burst to the second burst in the same muscle. The analogy between EMGs and speech signals is extended to argue for future applicability of short-time spectral analysis of EMG.

  12. Short-time dynamics of monomers and dimers in quasi-two-dimensional colloidal mixtures

    NASA Astrophysics Data System (ADS)

    Sarmiento-Gómez, Erick; Villanueva-Valencia, José Ramón; Herrera-Velarde, Salvador; Ruiz-Santoyo, José Arturo; Santana-Solano, Jesús; Arauz-Lara, José Luis; Castañeda-Priego, Ramón

    2016-07-01

    We report on the short-time dynamics in colloidal mixtures made up of monomers and dimers highly confined between two glass plates. At low concentrations, the experimental measurements of colloidal motion agree well with the solution of the Navier-Stokes equation at low Reynolds numbers; the latter takes into account the increase in the drag force on a colloidal particle due to wall-particle hydrodynamic forces. More importantly, we find that the ratio of the short-time diffusion coefficient of the monomer and that of the center of mass of the dimmer is almost independent of both the dimer molar fraction, xd, and the total packing fraction, ϕ , up to ϕ ≈0.5 . At higher concentrations, this ratio displays a small but systematic increase. A similar physical scenario is observed for the ratio between the parallel and the perpendicular components of the short-time diffusion coefficients of the dimer. This dynamical behavior is corroborated by means of molecular dynamics computer simulations that include explicitly the particle-particle hydrodynamic forces induced by the solvent. Our results suggest that the effects of colloid-colloid hydrodynamic interactions on the short-time diffusion coefficients are almost identical and factorable in both species.

  13. Short-time dynamics of monomers and dimers in quasi-two-dimensional colloidal mixtures.

    PubMed

    Sarmiento-Gómez, Erick; Villanueva-Valencia, José Ramón; Herrera-Velarde, Salvador; Ruiz-Santoyo, José Arturo; Santana-Solano, Jesús; Arauz-Lara, José Luis; Castañeda-Priego, Ramón

    2016-07-01

    We report on the short-time dynamics in colloidal mixtures made up of monomers and dimers highly confined between two glass plates. At low concentrations, the experimental measurements of colloidal motion agree well with the solution of the Navier-Stokes equation at low Reynolds numbers; the latter takes into account the increase in the drag force on a colloidal particle due to wall-particle hydrodynamic forces. More importantly, we find that the ratio of the short-time diffusion coefficient of the monomer and that of the center of mass of the dimmer is almost independent of both the dimer molar fraction, x_{d}, and the total packing fraction, ϕ, up to ϕ≈0.5. At higher concentrations, this ratio displays a small but systematic increase. A similar physical scenario is observed for the ratio between the parallel and the perpendicular components of the short-time diffusion coefficients of the dimer. This dynamical behavior is corroborated by means of molecular dynamics computer simulations that include explicitly the particle-particle hydrodynamic forces induced by the solvent. Our results suggest that the effects of colloid-colloid hydrodynamic interactions on the short-time diffusion coefficients are almost identical and factorable in both species. PMID:27575180

  14. Ursolic acid synergistically enhances the therapeutic effects of oxaliplatin in colorectal cancer.

    PubMed

    Shan, Jianzhen; Xuan, Yanyan; Zhang, Qi; Zhu, Chunpeng; Liu, Zhen; Zhang, Suzhan

    2016-08-01

    Oxaliplatin is a key drug in chemotherapy of colorectal cancer (CRC). However, its efficacy is unsatisfied due to drug resistance of cancer cells. In this study, we tested whether a natural agent, ursolic acid, was able to enhance the efficacy of oxaliplatin for CRC. Four CRC cell lines including SW480, SW620, LoVo, and RKO were used as in vitro models, and a SW620 xenograft mouse model was used in further in vivo study. We found that ursolic acid inhibited proliferation and induced apoptosis of all four cells and enhanced the cytotoxicity of oxaliplatin. This effect was associated with down-regulation of Bcl-xL, Bcl-2, survivin, activation of caspase-3, 8, 9, and inhibition of KRAS expression and BRAF, MEK1/2, ERK1/2, p-38, JNK, AKT, IKKα, IκBα, and p65 phosphorylation of the MAPK, PI3K/AKT, and NF-κB signaling pathways. The two agents also showed synergistic effects against tumor growth in vivo. In addition, ursolic acid restored liver function and body weight of the mice treated with oxaliplatin. Thus, we concluded that ursolic acid could enhance the therapeutic effects of oxaliplatin against CRC both in vitro and in vivo, which offers an effective strategy to minimize the burden of oxaliplatin-induced adverse events and provides the groundwork for a new clinical strategy to treat CRC. PMID:27472952

  15. Systemic capillary leak syndrome in a patient receiving adjuvant oxaliplatin for locally advanced colon cancer.

    PubMed

    Anderson, Brandon J; Peterson, Lindsay L

    2016-10-01

    Colorectal cancer is the third most common cancer diagnosed in the USA each year. Oxaliplatin, a platinum-based chemotherapy agent, is part of the standard adjuvant chemotherapy regimen FOLFOX (oxaliplatin with 5-fluorouracil [5-FU] and leucovorin [LV]) for the treatment of stage III and some high-risk stage II colorectal cancers. Although oxaliplatin is generally well tolerated, certain side effects such as nausea, vomiting, and peripheral neuropathy are common. We report a case of oxaliplatin-induced capillary-leak syndrome in a 63-year-old man undergoing his 12th and final cycle of FOLFOX for stage III colorectal cancer. To our knowledge, this is the first case of systemic capillary leak syndrome (SCLS) reported in association with oxaliplatin. Currently, there is no prevention for SCLS. Documenting future cases of SCLS attributed to oxaliplatin is vital, as SCLS is associated with significant morbidity and mortality and no standard treatments beyond supportive care measures exist. Early recognition and diagnosis are therefore essential to improving patient outcomes. PMID:26071595

  16. Preventive Effects of Bee Venom Derived Phospholipase A₂ on Oxaliplatin-Induced Neuropathic Pain in Mice.

    PubMed

    Li, Dongxing; Kim, Woojin; Shin, Dasom; Jung, Yongjae; Bae, Hyunsu; Kim, Sun Kwang

    2016-01-01

    Oxaliplatin, a chemotherapy drug used to treat colorectal cancer, induces specific sensory neurotoxicity signs that are aggravated by cold and mechanical stimuli. Here we examined the preventive effects of Bee Venom (BV) derived phospholipase A₂ (bvPLA₂) on oxaliplatin-induced neuropathic pain in mice and its immunological mechanism. The cold and mechanical allodynia signs were evaluated by acetone and von Frey hair test on the hind paw, respectively. The most significant allodynia signs were observed at three days after an injection of oxaliplatin (6 mg/kg, i.p.) and then decreased gradually to a normal level on days 7-9. The oxaliplatin injection also induced infiltration of macrophages and upregulated levels of the pro-inflammatory cytokine interleukin (IL)-1β in the lumbar dorsal root ganglia (DRG). Daily treatment with bvPLA₂ (0.2 mg/kg, i.p.) for five consecutive days prior to the oxaliplatin injection markedly inhibited the development of cold and mechanical allodynia, and suppressed infiltration of macrophages and the increase of IL-1β level in the DRG. Such preventive effects of bvPLA₂ were completely blocked by depleting regulatory T cells (Tregs) with CD25 antibody pre-treatments. These results suggest that bvPLA₂ may prevent oxaliplatin-induced neuropathic pain by suppressing immune responses in the DRG by Tregs. PMID:26797636

  17. Oxaliplatin activates the Keap1/Nrf2 antioxidant system conferring protection against the cytotoxicity of anticancer drugs.

    PubMed

    Wang, Xiu Jun; Li, Yinyan; Luo, Lin; Wang, Hongyan; Chi, Zhexu; Xin, Ai; Li, Xin; Wu, Jiaguo; Tang, Xiuwen

    2014-05-01

    Oxaliplatin is an important drug in the treatment of advanced metastatic colorectal cancer. NF-E2 p45-related factor 2 (Nrf2) is a key transcription factor that controls genes encoding cytoprotective and detoxifying enzymes through antioxidant-response elements (AREs) in their regulatory regions. Here, we report that oxaliplatin is an activator of the Nrf2 signaling pathway, with upregulation of ARE-driven genes and glutathione elevation. An injection of oxaliplatin into mice enhanced the expression of glutathione transferases and antioxidant enzymes in the small and large intestines of wild-type (WT) mice but not Nrf2(-/-) mice, indicating that oxaliplatin activates Nrf2 in vivo. Oxaliplatin failed to increase Nrf2 accumulation in non-small-cell lung cancer A549 cells, which harbor a dysfunctional somatic mutation of KEAP1. However, forced expression of WT mKeap1 restored the ability of oxaliplatin to activate the transcription factor. Cys(151) in Keap1 was required for the response stimulated by oxaliplatin. In addition, dichloro(1,2-diaminocyclohexane) platinum, a metabolite of oxaliplatin, was found to have the same effect in activating the ARE-gene battery as its parent drug, whereas another metabolite, oxalate, was ineffective. Moreover, two other platinum derivatives, cisplatin and carboplatin, had no effect on the Keap1/Nrf2 system. Furthermore, activation of Nrf2 by oxaliplatin reduced the sensitivity of colon cancer cells to therapeutic drugs. Conversely, knockdown of Nrf2 by Nrf2 siRNA reduced oxaliplatin-induced chemoresistance. Our study showed that oxaliplatin exerts protection against the cytotoxicity of anticancer drugs via Nrf2, indicating an important role of Nrf2 in oxaliplatin-based chemotherapy. PMID:24556415

  18. Hypersensitivity reactions to oxaliplatin and other antineoplastic agents.

    PubMed

    Syrigou, Ekaterini; Syrigos, Kostas; Saif, M Wasif

    2008-03-01

    Although the reported incidence of hypersensitivity reactions (HSR) to antineoplastic agents is considered to be uncommon, it is difficult to evaluate their exact prevalence, mainly because their definition is vast and pathogenic mechanisms are vague. HSR include facial flushing, erythema, pruritus, fever, tachycardia, dyspnea, tongue swelling, rash/hives, headache, chills, weakness, vomiting, burning sensations, dizziness, and edema. Treatment and prevention consists of slowing the infusion rate, steroids, and type 1 and 2 histamine receptor antagonists. Desensitization could allow the small number of patients who experience severe HSR to receive effective therapy for their cancer. Reintroductions have only been reported as single case studies or small cohorts. Large-scale validation on desensitization strategies is still missing. With regard to oxaliplatin, knowledge of its rare but eminent toxicity is paramount, because this drug is widely used in treating colorectal cancer, the second-highest cause of cancer mortality in the United States. PMID:18377776

  19. [Successful treatment of an elderly patient with pretreated recurrent breast cancer using low-dose capecitabine].

    PubMed

    Honma, Hideyuki

    2006-12-01

    The author reports the successful treatment of an 85-year-old recurrent breast cancer patient with low-dose capecitabine. Approximately 20 years ago, the patient received a left mastectomy and 2 years later was treated with unspecified chemotherapy for bone metastasis. In November 2001, metastatic tumors in thoracic vertebrae were removed by emergency laminectomy, followed by radiotherapy plus chemotherapy using mitoxantrone, cyclophosphamide and doxifluridine. In June 2005, abdominal computed tomography revealed a single metastatic tumor 20 mm in diameter in the liver. Treatment with paclitaxel at 70 mg/m(2)/day on days 1 and 14 resulted in no change in tumor size while serum levels of cancer antigen 15-3 increased from 22.1 to 98.1 U/ml. Subsequent daily treatment with capecitabine at 1,000 mg/m(2)/day for 21 days was associated with a 50% decrease in tumor size and a reduction in serum cancer antigen of 15-3 to 18.8 U/ml. Grade 2 hand-foot syndrome was noted,but no severe adverse effects were evident. Five months after the induction of capecitabine treatment, a partial response was obtained. These results suggest that low-dose capecitabine may be a safe and efficacious treatment for elderly patients with pretreated recurrent breast cancer. Clinical trials of low-dose capecitabine in such patients are therefore warranted. PMID:17197750

  20. Phase II study of reintroduction of oxaliplatin for advanced colorectal cancer in patients previously treated with oxaliplatin and irinotecan: RE-OPEN study

    PubMed Central

    Suenaga, Mitsukuni; Mizunuma, Nobuyuki; Matsusaka, Satoshi; Shinozaki, Eiji; Ozaka, Masato; Ogura, Mariko; Yamaguchi, Toshiharu

    2015-01-01

    Background The effectiveness of reintroducing oxaliplatin in patients with metastatic colorectal cancer refractory to standard chemotherapy has not been verified. We performed a single-arm, open-label, Phase II study to evaluate the safety and efficacy of reintroducing oxaliplatin. Methods Eligible patients had received prior chemotherapy including oxaliplatin and irinotecan that achieved a response or stable disease followed by confirmed disease progression ≥6 months previously during prior oxaliplatin-based therapy. The primary endpoint was the disease control rate (DCR) after 12 weeks of treatment starting. The DCR was defined as the sum of patients with complete response, partial response, and stable disease. Results Thirty-three patients were enrolled. The median age was 62 (range: 35–77) years and the male/female ratio was 19/14. Eastern Cooperative Oncology Group performance status was 0 in 84.8%. Fourteen primary tumors were in the colon and 19 were in the rectum. All patients received modified FOLFOX6 as the protocol treatment. After 12 weeks of treatment starting, the DCR was 39.4% (95% confidence interval 21.8–57.0) and the response rate (complete response and partial response) was 6.1%. The median number of chemotherapy cycles was five and the median total dose of oxaliplatin was 425 mg/m2. Median progression-free survival time was 98 days and median overall survival was 300 days. The incidence of grade ≥1 and grade ≥3 allergic reactions was 28.1% and 3.1%, respectively. The incidence of grade ≥1 and grade ≥3 peripheral sensory neuropathy was 53.1% and 0%, respectively. There were no other severe adverse events and no treatment-related deaths. Conclusion Reintroducing oxaliplatin can be both safe and effective. This may be a salvage option for patients with metastatic colorectal cancer who achieved a response or stable disease with prior oxaliplatin-based therapy followed by disease progression ≥6 months previously during prior

  1. A case of advanced intrahepatic cholangiocarcinoma accidentally, but successfully, treated with capecitabine plus oxaliplatin (CAPOX) therapy combined with bevacizumab: a case report.

    PubMed

    Uji, Masahito; Mizuno, Takashi; Ebata, Tomoki; Sugawara, Gen; Igami, Tsuyoshi; Uehara, Keisuke; Nagino, Masato

    2016-12-01

    Although surgical resection is the only way to cure biliary tract cancer (BTC), most BTCs are unresectable by the time they are diagnosed. Chemotherapy is usually used to treat unresectable BTC, but its impact on survival is small. Here, we report the case of a 70-year-old woman with a locally advanced intrahepatic cholangiocarcinoma that was initially diagnosed as an unresectable liver metastasis from colon cancer that had invaded all of the major hepatic veins. However, the tumor was noticeably reduced after treatment with CAPOX plus bevacizumab, which is an uncommon therapy for BTC. The tumor was finally resected by inferior right hepatic vein-preserving left hepatic trisectionectomy combined with a resection of the right hepatic vein after a right hepatic vein embolization. PMID:27342988

  2. Gc-protein-derived macrophage activating factor counteracts the neuronal damage induced by oxaliplatin.

    PubMed

    Morucci, Gabriele; Branca, Jacopo J V; Gulisano, Massimo; Ruggiero, Marco; Paternostro, Ferdinando; Pacini, Alessandra; Di Cesare Mannelli, Lorenzo; Pacini, Stefania

    2015-02-01

    Oxaliplatin-based regimens are effective in metastasized advanced cancers. However, a major limitation to their widespread use is represented by neurotoxicity that leads to peripheral neuropathy. In this study we evaluated the roles of a proven immunotherapeutic agent [Gc-protein-derived macrophage activating factor (GcMAF)] in preventing or decreasing oxaliplatin-induced neuronal damage and in modulating microglia activation following oxaliplatin-induced damage. The effects of oxaliplatin and of a commercially available formula of GcMAF [oleic acid-GcMAF (OA-GcMAF)] were studied in human neurons (SH-SY5Y cells) and in human microglial cells (C13NJ). Cell density, morphology and viability, as well as production of cAMP and expression of vascular endothelial growth factor (VEGF), markers of neuron regeneration [neuromodulin or growth associated protein-43 (Gap-43)] and markers of microglia activation [ionized calcium binding adaptor molecule 1 (Iba1) and B7-2], were determined. OA-GcMAF reverted the damage inflicted by oxaliplatin on human neurons and preserved their viability. The neuroprotective effect was accompanied by increased intracellular cAMP production, as well as by increased expression of VEGF and neuromodulin. OA-GcMAF did not revert the effects of oxaliplatin on microglial cell viability. However, it increased microglial activation following oxaliplatin-induced damage, resulting in an increased expression of the markers Iba1 and B7-2 without any concomitant increase in cell number. When neurons and microglial cells were co-cultured, the presence of OA-GcMAF significantly counteracted the toxic effects of oxaliplatin. Our results demonstrate that OA-GcMAF, already used in the immunotherapy of advanced cancers, may significantly contribute to neutralizing the neurotoxicity induced by oxaliplatin, at the same time possibly concurring to an integrated anticancer effect. The association between these two powerful anticancer molecules would probably produce

  3. Capecitabine-induced cardiotoxicity: more evidence or clinical approaches to protect the patients’ heart?

    PubMed Central

    Fontanella, Caterina; Aita, Marianna; Cinausero, Marika; Aprile, Giuseppe; Baldin, Maria Grazia; Dusi, Veronica; Lestuzzi, Chiara; Fasola, Gianpiero; Puglisi, Fabio

    2014-01-01

    Fluoropyrimidines, such as capecitabine and 5-fluorouracil, may cause cardiac toxicity. In recent years, the incidence of this side effect has increased and it is expected to further rise due to the population aging and the disproportionate incidence of breast and gastrointestinal cancers in older individuals. The spectrum of cardiac manifestations includes different signs and symptoms and the diagnosis may be difficult. Here, we report the case of a 43-year-old woman with advanced breast cancer who was rechallenged with a capecitabine-based regimen after experiencing a cardiac adverse event during the first fluoropyrimidine exposure. This real-practice case serves as a springboard for discussion about the current evidence on differential diagnosis of capecitabine-related cardiac toxicity, its risk factors, and the underpinning mechanisms of early onset. Moreover, we discussed whether a rechallenge with fluoropyrimidines could be safe in patients who had experienced a previous cardiac adverse event. PMID:25302025

  4. A case of capecitabine-induced coronary microspasm in a patient with rectal cancer

    PubMed Central

    Arbea, Leire; Coma-Canella, Isabel; Martinez-Monge, Rafael; García-Foncillas, Jesús

    2007-01-01

    5-Fluorouracil (5-FU) is the most frequently used chemotherapy agent concomitant with radiotherapy in the management of patients with rectal cancer. Capecitabine is an oral fluoropyrimidine that mimics the pharmaconkinetics of infusional 5-FU. This new drug is replacing 5-FU as a part of the combined-modality treatment of a number of gastrointestinal cancers. While cardiac events associated with the use of 5-FU are a well known side effect, capecitabine-induced cardiotoxicity has been only rarely reported. Here, we reviewed the case of a patient with rectal cancer who had a capecitabine-induced coronary vasospasm. The most prominent mutation of the dihydropyrimidine dehydrogenase gene was also analyzed. PMID:17465463

  5. Capecitabine: indications and future perspectives in the treatment of metastatic colorectal and breast cancer.

    PubMed

    Cassata, A; Procoplo, G; Alù, M; Ferrari, L; Ferrario, E; Beretta, E; Longarini, R; Busto, G; De Candis, D; Bajetta, E

    2001-01-01

    Fluoropyrimidines remain the most important drugs in the treatment of breast and colorectal carcinoma, but response rates and survival time have been disappointing. Optimal administration is by continuous intravenous infusion, which makes it cumbersome to use and compromises patient independence. Recently, a number of new agents, including fluorouracil prodrugs and selective dihydropyrimidine dehydrogenase inhibitors, have been studied, with promising results. Capecitabine is the first in a new class of fluoropyrimidines. It is an oral, tumor-activated anticancer drug whose activity mimics that of continuously infused 5-fluorouracil. Capecitabine circumvents dihydropyrimidine dehydrogenase catabolism and appears to be at least as active against metastatic colorectal and breast cancer as conventionally administered intravenous 5-fluorouracil, with significantly less toxicity, an improved quality of life, and lesser cost. Capecitabine may ultimately provide enhanced antitumor activity to fluorouracil-containing regimes for advanced colorectal and breast cancer. PMID:11989587

  6. Drug Induced Lupus Erythematosus Due to Capecitabine and Bevacizumab Treatment Presenting with Prolonged Thrombocytopenia.

    PubMed

    Ozaslan, Ersin; Eroglu, Eray; Gok, Kevser; Senel, Soner; Baldane, Suleyman; Akyol, Lutfi; Ozkan, Metin

    2015-01-01

    Drug induced lupus erythematosus (DLE) is a syndrome that is formed by lupus-like symptoms and laboratory characteristics. Capecitabine is an orally administered tumor-selective fluoropyrimidine that acts as a prodrug of 5-Fluorouracil and bevacizumab is an antivascular endothelial growth factor (anti-VEGF) antibody, both are used for the treatment of patients with colorectal cancer. Herein we report the first case of DILE in a 68-year-old woman who presented with arthralgia, myalgia and prolonged thrombocytopenia after receiving capecitabine and bevacizumab combination treatment as palliative treatment for metastatic colon cancer. Platelet-levels were increased and joint complaints disappeared in the first week of hydroxychloroquine and methylprednisolone treatment after chemotherapy had been discontinued. In conclusion, physicians should be alert to the possibility of DILE in patients presenting with thrombocytopenia under a capecitabine and bevacizumab chemotherapy regimen. PMID:26710505

  7. Error correction in short time steps during the application of quantum gates

    NASA Astrophysics Data System (ADS)

    de Castro, L. A.; Napolitano, R. d. J.

    2016-04-01

    We propose a modification of the standard quantum error-correction method to enable the correction of errors that occur due to the interaction with a noisy environment during quantum gates without modifying the codification used for memory qubits. Using a perturbation treatment of the noise that allows us to separate it from the ideal evolution of the quantum gate, we demonstrate that in certain cases it is necessary to divide the logical operation in short time steps intercalated by correction procedures. A prescription of how these gates can be constructed is provided, as well as a proof that, even for the cases when the division of the quantum gate in short time steps is not necessary, this method may be advantageous for reducing the total duration of the computation.

  8. Short-time dynamics of isotropic and anisotropic Bak-Sneppen model: extensive simulation results

    NASA Astrophysics Data System (ADS)

    Tirnakli, Ugur; Lyra, Marcelo L.

    2004-12-01

    In this work, the short-time dynamics of the isotropic and anisotropic versions of the Bak-Sneppen (BS) model has been investigated using the standard damage spreading technique. Since the system sizes attained in our simulations are larger than the ones employed in previous studies, our results for the dynamic scaling exponents are expected to be more accurate than the results of the existing literature. The obtained scaling exponents of both versions of the BS model are found to be greater than the ones given in previous works. These findings are in agreement with the recent claim of Cafiero et al. (Eur. Phys. J. B7 (1999) 505). Moreover, it is found that the short-time dynamics of the anisotropic model is only slightly affected by finite-size effects and the reported estimate of α≃0.53 can be considered as a good estimate of the true exponent in the thermodynamic limit.

  9. Critical short-time dynamics in a system with interacting static and diffusive populations.

    PubMed

    Argolo, C; Quintino, Yan; Gleria, Iram; Lyra, M L

    2012-01-01

    We study the critical short-time dynamical behavior of a one-dimensional model where diffusive individuals can infect a static population upon contact. The model presents an absorbing phase transition from an active to an inactive state. Previous calculations of the critical exponents based on quasistationary quantities have indicated an unusual crossover from the directed percolation to the diffusive contact process universality classes. Here we show that the critical exponents governing the slow short-time dynamic evolution of several relevant quantities, including the order parameter, its relative fluctuations, and correlation function, reinforce the lack of universality in this model. Accurate estimates show that the critical exponents are distinct in the regimes of low and high recovery rates. PMID:22400516

  10. Dispersion curves from short-time molecular dynamics simulation. 1. Diatomic chain results

    SciTech Connect

    Noid, D.W.; Broocks, B.T.; Gray, S.K.; Marple, S.L.

    1988-06-16

    The multiple signal classification method (MUSIC) for frequency estimation is used to compute the frequency dispersion curves of a diatomic chain from the time-dependent structure factor. In this paper, the authors demonstrate that MUSIC can accurately determine the frequencies from very short time trajectories. MUSIC is also used to show how the frequencies can vary in time, i.e., along a trajectory. The method is ideally suited for analyzing molecular dynamics simulations of large systems.

  11. Effect of Vitamin E on Oxaliplatin-induced Peripheral Neuropathy Prevention: A Randomized Controlled Trial

    PubMed Central

    Salehi, Zeinab; Roayaei, Mahnaz

    2015-01-01

    Background: Peripheral neuropathy is one of the most important limitations of oxaliplatin base regimen, which is the standard for the treatment of colorectal cancer. Evidence has shown that Vitamin E may be protective in chemotherapy-induced peripheral neuropathy. The aim of this study is to evaluate the effect of Vitamin E administration on prevention of oxaliplatin-induced peripheral neuropathy in patients with colorectal cancer. Methods: This was a prospective randomized, controlled clinical trial. Patients with colorectal cancer and scheduled to receive oxaliplatin-based regimens were enrolled in this study. Enrolled patients were randomized into two groups. The first group received Vitamin E at a dose of 400 mg daily and the second group observed, until after the sixth course of the oxaliplatin regimen. For oxaliplatin-induced peripheral neuropathy assessment, we used the symptom experience diary questionnaire that completed at baseline and after the sixth course of chemotherapy. Only patients with a score of zero at baseline were eligible for this study. Results: Thirty-two patients were randomized to the Vitamin E group and 33 to the control group. There was no difference in the mean peripheral neuropathy score changes (after − before) between two groups, after sixth course of the oxaliplatin base regimen (mean difference [after − before] of Vitamin E group = 6.37 ± 2.85, control group = 6.57 ± 2.94; P = 0.78). Peripheral neuropathy scores were significantly increased after intervention compared with a base line in each group (P < 0.001). Conclusions: The results from this current trial demonstrate a lack of benefit for Vitamin E in preventing oxaliplatin-induced peripheral neuropathy. PMID:26682028

  12. Short-Time Glassy-like Dynamics Observed in Viscous Protein Solutions with Competing Potential Features

    NASA Astrophysics Data System (ADS)

    Wagner, Norman; Godfrin, Doug; Liu, Yun

    Structures in concentrated protein solutions caused by the combination of short-range attraction (SA) and long-range repulsion (LR) have been extensively studied due to their importance in understanding therapeutic protein formulations and the phase behavior in general. Despite extensive studies of kinetically arrested states in colloidal systems with short-range attraction, less is understood for the effect of an additional longer-range repulsion on model colloidal systems with a SA interaction. Highly purified lysozyme is used a model experimental system due to its stable globular structure and SALR interactions at low ionic strength that can be quantitatively modeled. The fluid microstructure and protein short time self diffusion are measured across a broad range of conditions by small angle neutron scattering (SANS) and neutron spin echo (NSE), respectively. Newtonian liquid behavior is observed at all concentrations, even with an increase of zero shear viscosity by almost four orders of magnitude with increasing concentration. However, dynamic measurements demonstrate a sub-diffusive regime at relatively short time scales for concentrated samples at low temperature. The formation of a heterogeneous density distribution is shown to produce localized regions of high density that reduce protein motion, giving it a glassy-like behavior at the short time scale. This heterogeneity occurs at the length scale associated with the intermediate range order driven by the competing potential features, distinguishable from heterogeneous colloidal gels.

  13. A short-time fading study of Al2O3:C

    NASA Astrophysics Data System (ADS)

    Nascimento, L. F.; Vanhavere, F.; Silva, E. H.; Deene, Y. De

    2015-01-01

    This paper studies the short-time fading from Al2O3:C by measuring optically stimulated luminescence (OSL) signals (Total OSL: TOSL, and Peak OSL: POSL) from droplets and Luxel™ pellets. The influence of various bleaching regimes (blue, green and white) and light power is compared. The fading effect is the decay of the OSL signal in the dark at room temperature. Al2O3:C detectors were submitted to various bleaching regimes, irradiated with a reference dose and read out after different time spans. Investigations were carried out using 2 mm size droplet detectors, made of thin Al2O3:C powder mixed with a photocured polymer. Tests were compared to Luxel™-type detectors (Landauer Inc.). Short-time post-irradiation fading is present in OSL results (TOSL and POSL) droplets for time spans up to 200 s. The effect of short-time fading can be lowered/removed when treating the detectors with high-power and/or long time bleaching regimes; this result was observed in both TOSL and POSL from droplets and Luxel™.

  14. Metronomic capecitabine in gastroenteropancreatic neuroendrocrine tumors: a suitable regimen and review of the literature

    PubMed Central

    Bongiovanni, Alberto; Riva, Nada; Calpona, Sebastiano; Ricci, Marianna; Gunelli, Erica; Liverani, Chiara; La Manna, Federico; De Vita, Alessandro; Monti, Manuela; Severi, Stefano; Pieri, Federica; Amadori, Elena; Galassi, Riccardo; Cavaliere, Davide; Zaccaroni, Alberto; Tartaglia, Andreas; Lunedei, Veronica; Gardini, Andrea; Mercatali, Laura; Amadori, Dino; Ibrahim, Toni

    2014-01-01

    Background We present a retrospective analysis of metronomic capecitabine in metastatic gastroenteropancreatic neuroendrocrine tumors (GEP-NETs). A review of the literature is also presented. Methods From January 2007 to December 2013, ten patients with metastatic GEP-NETs (four pancreatic and six ileal) who progressed after treatment with somatostatin analogs and other cytotoxic agents received oral capecitabine 1,500 mg/day continuously. The median patient age was 68 (range 29–82) years. The median treatment duration was 8 months. Results Five (50%) patients achieved a partial radiographic response, four (40%) showed stable disease, and one (10%) progressed. Median overall survival was 56 months. Three of the four pancreatic patients achieved a partial radiographic response that lasted for a median of 15.5 months; overall survival and progression-free survival in this subgroup was 58 and 6 months, respectively. Conclusion Data in the literature show that capecitabine has only occasionally been used as a single agent, with increased toxicity. Only one study using single-agent capecitabine reported a progression-free survival of 9.9 months and overall survival of 36.5 months, without an objective response or major toxicity. In our experience, metronomic capecitabine was well tolerated, although minor side effects may have been underestimated due to the retrospective nature of our study. This regimen also seems to be feasible in elderly people. Although high response rates and prolonged response duration indicate the potential efficacy of this treatment, our results should be interpreted cautiously because of the small number of patients involved. Capecitabine was most effective in the pancreatic subgroup, which would seem to be more sensitive to chemotherapy. PMID:25364262

  15. Comparison of 5-fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer

    SciTech Connect

    Kim, Dae Yong; Jung, Kyung Hae . E-mail: khjung@ncc.re.kr; Kim, Tae Hyun; Kim, Duck-Woo; Chang, Hee Jin; Jeong, Jun Yong; Kim, Young Hoon; Son, Seok-Hyun; Yun, Tak; Hong, Chang Won; Sohn, Dae Kyung; Lim, Seok-Byung; Choi, Hyo Seong; Jeong, Seung-Yong; Park, Jae-Gahb

    2007-02-01

    Purpose: To describe our experience with a bolus injection of 5-fluorouracil and leucovorin (FL) vs. capecitabine in terms of radiologic and pathologic findings in preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. Methods: The study enrolled 278 patients scheduled for preoperative CRT using two protocols with different chemotherapeutic regimens. Pelvic radiotherapy (50.4 Gy) was delivered concurrently with FL (n = 145) or capecitabine (n = 133). Surgery was performed 6 weeks after CRT completion. Tumor responses to CRT were measured using both radiologic and pathologic examination. Magnetic resonance volumetry was performed at the initial workup and just before surgery after completion of preoperative CRT. Post-CRT pathology tests were used to determine tumor stage and regression. Results: Radiologic examination showed that tumor volume decreased by 68.2% {+-} 20.5% in the FL group and 68.3% {+-} 22.3% in the capecitabine group (p = 0.970). Postoperative pathologic T stage determination showed that downstaging occurred in 44.3% of FL and 49.9% of capecitabine patients (p = 0.571). The tumor regression grades after CRT were Grade 1 (minimal response) in 22.6% and 21.0%, Grade 2 (moderate response) in 53.2% and 50.0%, Grade 3 (near-complete response) in 12.9% and 12.9%, and Grade 4 (complete response) in 11.3% and 16.1% of the FL and capecitabine groups, respectively (p = 0.758). Conclusion: In the present study, the radiologic and pathologic findings did not reveal significant differences in short-term tumor responses between preoperative FL and capecitabine CRT for locally advanced rectal cancer. Long-term results and a prospective randomized trial are needed.

  16. Treatment with capecitabine + bevacizumab following induction treatment with FOLFIRI + bevacizumab in metastatic colorectal carcinoma

    PubMed Central

    Tatlı, Ali Murat; Coşkun, Hasan Şenol; Uysal, Mükremin; Arslan, Deniz; Sezgin Göksu, Sema; Güenay Gündüz, Şeyda; Çakal, Selda; Bozcuk, Hakan Şat; Savaş, Burhan

    2014-01-01

    Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor, and it has been found to increase both progression-free survival and overall survival when it is combined with chemotherapeutic agents in the first-line and subsequent treatment of metastatic colorectal carcinoma. The objective of this study was to show the efficacy of maintenance treatment with capecitabine plus bevacizumab in patients with metastatic colorectal cancer who responded to treatment with FOLFIRI plus bevacizumab. The study included patients with metastatic colorectal cancer who received FOLFIRI plus bevacizumab as a first-line treatment. Patients who had objective response with FOLFIRI plus bevacizumab treatment after an average period of 6 months received a maintenance treatment with capecitabine plus bevacizumab (capecitabine 2 x 1000 mg/m2, 1 - 14 days, every 21 days, bevacizumab 7.5 mg/m2, every 21 days) until disease progression or toxicity. The time to progression on bevacizumab treatment was evaluated. A total of 29 patients (15 male, 14 female) were included. The mean age was 62 years. The mean number of cycles for maintenance treatment with capecitabine plus bevacizumab was 12. The median PFS was 16 ± 3 months, and OS was 42 ± 11 months. PFS and OS were remarkably higher in patients with a complete or near complete response to induction treatment. Fourteen patients (48%) experienced hand-foot syndrome associated with capecitabine plus bevacizumab treatment, without any severe toxicity. Inselected patients with metastatic colorectal carcinoma who had a remarkable objective response to FOLFIRI plus bevacizumab treatment, a maintenance treatment with capecitabine plus bevacizumab following FOLFIRI plus bevacizumab until disease progression may be a suitable, effective and tolerable regimen, which requires further studies. PMID:25232406

  17. Oxaliplatin evokes P2X7-dependent glutamate release in the cerebral cortex: A pain mechanism mediated by Pannexin 1.

    PubMed

    Di Cesare Mannelli, Lorenzo; Marcoli, Manuela; Micheli, Laura; Zanardelli, Matteo; Maura, Guido; Ghelardini, Carla; Cervetto, Chiara

    2015-10-01

    Anticancer therapy based on the repeated administration of oxaliplatin is limited by the development of a neuropathic syndrome difficult to treat. Oxaliplatin neurotoxicity is based on complex nervous mechanisms, the comprehension of the role of single neurotransmitters and the knowledge of the signal flow among cells is matter of importance to improve therapeutic chances. In a rat model of oxaliplatin-induced neuropathy, we report increased P2X7-evoked glutamate release from cerebrocortical synaptosomes. The release was abolished by the P2X7 receptor (P2X7R) antagonists Brilliant-Blue-G (BBG) and A-438079, and significantly reduced by Carbenoxolone and the Pannexin 1 (Panx1) selective inhibitors Erioglaucine and (10)Panx suggesting the recruitment of Panx1. Aimed to evaluate the significance of P2X7R-Panx1 system activation in pain generated by oxaliplatin, pharmacological modulators were spinally infused by intrathecal catheter in oxaliplatin-treated animals. BBG, Erioglaucine and (10)Panx reverted oxaliplatin-dependent pain. Finally, the influence of the P2X7R-Panx1 system blockade on oxaliplatin anticancer activity was evaluated on the human colon cancer cell line HT-29. Prevention of HT-29 apoptosis and mortality was dependent by kind and concentration of P2X7R antagonists. On the contrary, the inhibition of Panx1 did not alter oxaliplatin lethality in tumor cells. It is concluded that glutamate release dependent on P2X7R is increased in cerebrocortical nerve terminals from oxaliplatin-treated rats; the increase is mediated by functional recruitment of Panx1; P2X7R antagonists and Panx1 inhibitors revert oxaliplatin-induced neuropathic pain; Panx1 inhibitors do not alter the oxaliplatin-induced mortality of cancer cells HT-29. The inhibition of Panx1 channel is suggested as a new and safe pharmacological target. PMID:26071109

  18. Maintenance therapy with capecitabine in patients with locally advanced unresectable pancreatic adenocarcinoma.

    PubMed

    Saif, Muhammad Wasif; Ledbetter, Leslie; Kaley, Kristin; Garcon, Marie Carmel; Rodriguez, Teresa; Syrigos, Kostas N

    2014-09-01

    Therapeutic options for locally advanced pancreatic cancer (LAPC) include concurrent chemoradiation, induction chemotherapy followed by chemoradiation or systemic therapy alone. The original Gastro-Intestinal Study Group and Eastern Cooperative Oncology Group studies defined fluorouracil (5-FU) with concurrent radiation therapy followed by maintenance 5-FU until progression, as the standard therapy for this subset of patients. Although this combined therapy has been demonstrated to increase local control and median survival from 8 to 12 months, almost all patients succumb to the disease secondary to either local or distant recurrence. Our earlier studies provided a strong rationale for the use of capecitabine in combination with concurrent radiation followed by maintenance capecitabine therapy. To report our clinical experience, we retrospectively evaluated our patients who were treated with maintenance capecitabine. We reviewed the medical records of patients with LAPC who received treatment with capecitabine and radiation, followed by a 4-week rest, then capecitabine alone 1,000 mg twice daily (ECOG performance status 2 or age >70 years) or 1,500 mg twice daily for 14 days every 3 weeks until progressive disease. We treated 43 patients between September 2004 and September 2012. The population consisted of 16 females and 25 males, with a median age of 64 years (range, 38-80 years). Patients received maintenance capecitabine for median duration of 9 months (range, 3-18 months). The median overall survival (OS) for these patients was 17 months, with two patients still living and receiving therapy. The 6-month survival rate was 91% (39/43), 1-year survival rate was 72% (31/43) and 2-year OS rate was 26% (11/43). Grade 3 or 4 toxicity was observed rarely: Hand-foot syndrome (HFS) in two patients, diarrhea in one patient and peripheral neuropathy in one patient, and there was no mortality directly related to treatment. Capecitabine maintenance therapy following

  19. Chemoradiation of Hepatic Malignancies: Prospective, Phase 1 Study of Full-Dose Capecitabine With Escalating Doses of Yttrium-90 Radioembolization

    SciTech Connect

    Hickey, Ryan; Mulcahy, Mary F.; Lewandowski, Robert J.; Gates, Vanessa L.; Vouche, Michael; Habib, Ali; Kircher, Sheetal; Newman, Steven; Nimeiri, Halla; Benson, Al B.; Salem, Riad

    2014-04-01

    Purpose: Radiosensitizing chemotherapy improves the outcomes in comparison with radiation alone for gastrointestinal cancers. The delivery of radiation therapy with yttrium90 ({sup 90}Y) radioembolization, in combination with the radiosensitizing chemotherapeutic agent capecitabine, provides the opportunity to enhance the effects of radiation on hepatic malignancies. This phase 1 study sought to determine the maximum tolerated dose (MTD) of {sup 90}Y plus capecitabine in patients with cholangiocarcinoma or liver metastases confined to the liver. Methods and Materials: Patients were given initial treatment at full-dose capecitabine during days 1 to 14 of a 21-day cycle. At days 1 to 7 of the second cycle, whole-liver {sup 90}Y was given at the test dose, after which time capecitabine was continued. Dose-limiting toxicity (DLT) was determined 6 weeks after {sup 90}Y infusion. If a DLT was not observed, the {sup 90}Y dose was escalated. The planned dose cohorts were 110, 130, 150, and 170 Gy. The primary endpoint was to determine the MTD of {sup 90}Y with full-dose capecitabine. Results: Sixteen patients were treated according to the study protocol. Two patients experienced DLTs. Nine patients required capecitabine dose reduction as a result of toxicities attributable to capecitabine alone. The criteria for establishing {sup 90}Y MTD were not met, indicating an MTD of >170 Gy. Conclusion: The MTD of {sup 90}Y delivered in conjunction with capecitabine in the setting of intrahepatic cholangiocarcinoma or metastatic disease confined to the liver exceeds 170 Gy. This is the highest {sup 90}Y dose reported to date and has important implications on combined therapy with the radiosensitizing oral chemotherapeutic capecitabine. Further studies are under way.

  20. A Phase I Study of EKB-569 in Combination with Capecitabine in Patients with Advanced Colorectal Cancer

    PubMed Central

    Laheru, Dan; Croghan, Gary; Bukowski, Ronald; Rudek, Michelle; Messersmith, Wells; Erlichman, Charles; Pelley, Robert; Jimeno, Antonio; Donehower, Ross; Boni, Joseph; Abbas, Richat; Martins, Patricia; Zacharchuk, Charles; Hidalgo, Manuel

    2011-01-01

    Purpose To determine the maximum tolerated dose (MTD), characterize the principal toxicities, and assess the pharmacokinetics of EKB-569, an oral selective irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with capecitabine in patients with advanced colorectal cancer. Experimental Design Patients were treated with EKB-569 daily for 21days and capecitabine twice daily for14 days of a 21-day cycle. The dose levels of EKB-569 (mg/day) and capecitabine (mg/m2 twice daily) assessed were 25/750, 50/750, 50/1,000 and 75/1,000. An expanded cohort was enrolled at the MTD to better study toxicity and efficacy. Samples of plasma were collected to characterize the pharmacokinetics of the agents. Treatment efficacy was assessed every other cycle. Results A total of 37 patients, the majority of whom had prior chemotherapy, received a total of 163 cycles of treatment. Twenty patients were treated at the MTD, 50 mg EKB-569, daily and 1,000 mg/m2 capecitabine twice daily. Dose-limiting toxicities were diarrhea and rash. No patients had complete or partial responses but 48% had stable disease. The conversion of capecitabine to 5-fluorouracil was higher for the combination of EKB-569 and capecitabine (321 ± 151 ng*h/mL) than for capecitabine alone (176 ± 62 ng*hours/mL; P = 0.0037). Conclusion In advanced colorectal cancer, 50 mg EKB-569 daily can be safely combined with 1,000 mg/m2 capecitabine twice a day. A statistically significant increase in plasma levels of 5-fluorouracil for the combination of EKB-569 and capecitabine may be due to the single-dose versus multiple-dose exposure difference, variability in exposure or a potential drug interaction. PMID:18765554

  1. A Statistical and Spectral Model for Representing Noisy Sounds with Short-Time Sinusoids

    NASA Astrophysics Data System (ADS)

    Hanna, Pierre; Desainte-Catherine, Myriam

    2005-12-01

    We propose an original model for noise analysis, transformation, and synthesis: the CNSS model. Noisy sounds are represented with short-time sinusoids whose frequencies and phases are random variables. This spectral and statistical model represents information about the spectral density of frequencies. This perceptually relevant property is modeled by three mathematical parameters that define the distribution of the frequencies. This model also represents the spectral envelope. The mathematical parameters are defined and the analysis algorithms to extract these parameters from sounds are introduced. Then algorithms for generating sounds from the parameters of the model are presented. Applications of this model include tools for composers, psychoacoustic experiments, and pedagogy.

  2. Detection systems for short-time stroboscopic neutron imaging and measurements on a rotating engine

    NASA Astrophysics Data System (ADS)

    Schillinger, B.; Abele, H.; Brunner, J.; Frei, G.; Gähler, R.; Gildemeister, A.; Hillenbach, A.; Lehmann, E.; Vontobel, P.

    2005-04-01

    Today's neutron sources do not deliver sufficient flux to examine singular short-time events in the millisecond range by neutron radiography. However, periodic processes can be examined if a triggered accumulating detector collects information of identical time-windows and positions over several cycles of the process. The same problem applies if the source signal itself carries information, like the energy-time dependence in the pulse of a spallation source. Several possible detection methods were considered; measurements were performed at the intense neutron beam H9 of ILL Grenoble, where an electrically driven BMW engine was examined at 1000 rpm with time resolution of 200 μs.

  3. Short-Time Glassy Dynamics in Viscous Protein Solutions with Competing Interactions

    NASA Astrophysics Data System (ADS)

    Godfrin, P. Douglas; Hudson, Steven D.; Hong, Kunlun; Porcar, Lionel; Falus, Peter; Wagner, Norman J.; Liu, Yun

    2015-11-01

    The glass transition of colloidal dispersions interacting with both a short-ranged attraction and long-ranged repulsion is studied using highly purified lysozyme solutions. Newtonian liquid behavior is observed at all conditions while measurements of the dynamics in the short-time limit show features typical of glassy colloidal systems at high protein concentrations. This interesting behavior is due to the competition of the attraction and repulsion that produces a heterogeneous microstructure only at intermediate range length scales. The results demonstrate that theories for the macroscopic properties of systems with competing interactions need to include intermediate range order.

  4. Extraction of self-diffusivity in systems with nondiffusive short-time behavior

    NASA Astrophysics Data System (ADS)

    Shanbhag, Sachin

    2013-10-01

    We consider a toy model that captures the short-time nondiffusive behavior seen in many physical systems, to study the extraction of self-diffusivity from particle trajectories. We propose and evaluate a simple method to automatically detect the transition to diffusive behavior. We simulate the toy model to generate data sets of varying quality and test different methods of extracting the self-diffusion coefficient and characterizing its uncertainty. We find that weighted least-squares with statistical bootstrap is the most accurate and efficient means for analyzing the trajectory data. The analysis suggests an iterative recipe for designing simulations to conform to a specified level of accuracy.

  5. 78 FR 48199 - Comment Request for Information Collection for Employers Survey of the Short-Time Compensation...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-07

    ... Short-Time Compensation Program (STC); New Collection AGENCY: Employment and Training Administration... data can be provided in the desired format, reporting burden (time and financial resources) is... Short-Time Compensation Program. OMB Number: 1205-0NEW. Affected Public: Private Sector,...

  6. Intravenous Calcium and Magnesium for Oxaliplatin-Induced Sensory Neurotoxicity in Adjuvant Colon Cancer: NCCTG N04C7

    PubMed Central

    Grothey, Axel; Nikcevich, Daniel A.; Sloan, Jeff A.; Kugler, John W.; Silberstein, Peter T.; Dentchev, Todor; Wender, Donald B.; Novotny, Paul J.; Chitaley, Umesh; Alberts, Steven R.; Loprinzi, Charles L.

    2011-01-01

    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. PMID:21189381

  7. Polysaccharide from Lentinus edodes combined with oxaliplatin possesses the synergy and attenuation effect in hepatocellular carcinoma.

    PubMed

    Zhang, Yu; Li, Qiang; Wang, Junfeng; Cheng, Fang; Huang, Xiao; Cheng, Yao; Wang, Kaiping

    2016-07-28

    Despite the great progress in the treatment of hepatocellular carcinoma, combination chemotherapy is still the main choice of treatment for patients with unresectable metastatic or recurrent hepatocellular cancer. Lentinan, which has been used as an immunomodulator in the treatment of cancer, possesses anti-tumor activities. However, the mechanisms by which Lentinan inhibits hepatocellular carcinoma remain unknown. Our study showed that Lentinan has a significantly synergistic anti-tumor effect with oxaliplatin against HepG2 cells in vitro and in H22 tumor-bearing mice through the mitochondria pathway and for the inhibition of NF-κB, Stat3 and survivin signaling. Moreover, Lentinan moderated side effects induced by oxaliplatin. These findings suggested that Lentinan may be an ideal agent for the combination therapy of oxaliplatin against hepatocellular carcinoma. PMID:27130669

  8. Non-covalent interactions involving halogenated derivatives of capecitabine and thymidylate synthase: a computational approach.

    PubMed

    Rahman, Adhip; Hoque, Mohammad Mazharol; Khan, Mohammad A K; Sarwar, Mohammed G; Halim, Mohammad A

    2016-01-01

    Capecitabine, a fluoropyrimidine prodrug, has been a frequently chosen ligand for the last one and half decades to inhibit thymidylate synthase (TYMS) for treatment of colorectal cancer. TYMS is a key enzyme for de novo synthesis of deoxythymidine monophosphate and subsequent synthesis of DNA. Recent years have also seen the trait of modifying ligands using halogens and trifluoromethyl (-CF3) group to ensure enhanced drug performance. In this study, in silico modification of capecitabine with Cl, Br, I atoms and -CF3 group has been performed. Density functional theory has been employed to optimize the drug molecules and elucidate their thermodynamic and electrical properties such as Gibbs free energy, enthalpy, electronic energy, dipole moment and frontier orbital features (HOMO-LUMO gap, hardness and softness). Flexible and rigid molecular docking have been implemented between drugs and the receptor TYMS. Both inter- and intra-molecular non-covalent interactions involving the amino acid residues of TYMS and the drug molecules are explored in details. The drugs were superimposed on the resolved crystal structure (at 1.9 Å) of ZD1694/dUMP/TYMS system to shed light on similarity of the binding of capecitabine, and its modifiers, to that of ZD1694. Together, these results may provide more insights prior to synthesizing halogen-directed derivatives of capecitabine for anticancer treatment. PMID:27026843

  9. [Assessment of hand-foot syndrome in cancer patients treated with capecitabine-containing chemotherapy].

    PubMed

    Yamagiwa, Kouhei; Shigematsu, Tadashi; Takeda, Keiko; Shirai, Masahiro; Amemori, Keiko; Sunda, Kazumi; Koike, Chikayo; Yamada, Toshimi

    2013-12-01

    Capecitabine is one of the most effective oral chemotherapeutic drugs for advanced or recurrent colorectal cancer and gastric cancer. Capecitabine-containing chemotherapy is recommended as a first-line option for gastrointestinal tract cancer. The incidence of hand-foot syndrome (HFS), an adverse event of chemotherapy with capecitabine, is high. Moreover, once the symptoms of HFS are identified, they can significantly impair the quality of life (QOL) of patients. HFS should be managed by dose interruption and, if necessary, by dose reduction. Pharmacists and oncology nurses play an increasingly important role in the early identification and prevention of HFS through patient education and close clinical assessment. The aim of this study was to evaluate the efficacy of support tools for the early identification, prevention, and management of HFS and to assess the effectiveness of "patient self-check sheets". The patient was detected as having HFS of mild severity and had used a moisturizer at the time of initiation of therapy. Maintaining moisture retention is important in the management of HFS. The ambulatory team plays a key role by using self-check sheets to educate patients on how to recognize HFS, when to interrupt treatment, and how to adjust the dose so as to maintain effective therapy with capecitabine. For the continuation and completion of treatment and for maintaining an improved QOL in the home environment, supportive measures for adverse effects such as HFS and an ambulatory team are indispensable. PMID:24712132

  10. Capecitabine or infusional 5-fluorouracil for gastroesophageal cancer: a cost–consequence analysis

    PubMed Central

    Horgan, A.M.; Knox, J.J.; Liu, G.; Sahi, C.; Bradbury, P.A.; Leighl, N.B.

    2011-01-01

    Background In patients with advanced gastroesophageal cancer, the phase iii Randomized ECF for Advanced and Locally Advanced Esophagogastric Cancer 2 (real-2) trial demonstrated equivalent clinical efficacy when capecitabine (x) was substituted for 5-fluorouracil (5fu) in the epirubicin–cisplatin–5fu (ecf) regimen. The present analysis compares the direct medical costs associated with both regimens. Methods This cost–consequence analysis of direct medical costs took resource utilization data from the real-2 trial where available. Direct medical costs were derived from the perspective of the Canadian public health care system in 2008 Canadian dollars. Mean cost per patient on each treatment arm was calculated. Results Drug costs from start of treatment until first progression, including pre- and post-chemotherapy medications and administration costs, totalled $5,344 for ecx as compared with $3,187 for ecf. Costs for treatment of adverse events were estimated at $2,621 for ecx as compared with $3,397 for ecf. An additional cost of $873 was associated with insertion of an implanted venous access. Total incremental cost of ecx over ecf was $508. Conclusions In advanced gastroesophageal cancer, capecitabine is an attractive alternative to 5fu. Although the drug cost per se is greater, use of capecitabine is associated with decreased consumption of hospital resources. Not only does capecitabine fit with patient preference for oral therapy, it also avoids the inconvenience and complications of central venous access. PMID:21505591

  11. An adverse interaction between warfarin and capecitabine: a case report and review of the literature.

    PubMed

    Copur, M S; Ledakis, P; Bolton, M; Morse, A K; Werner, T; Norvell, M; Muhvic, J; Chu, E

    2001-11-01

    Warfarin is one of the most commonly used oral anticoagulants in the clinic. It is well established that a wide range of antineoplastic drugs interact with warfarin, resulting in altered coagulation parameters and/or bleeding sequelae. While altered coagulation parameters have been observed in patients taking the oral 5-fluorouracil prodrug, capecitabine, in combination with warfarin, no report to date has described clinically overt evidence of bleeding. Herein, we report 2 cancer patients who presented with bleeding episodes that most likely resulted from an adverse interaction between capecitabine and warfarin after 6 weeks of concomitant therapy. In each case, there was a marked elevation in both the prothrombin time and international normalized ratio (> 10), with subsequent gastrointestinal bleeding. The exact mechanism of this interaction is yet unknown, but it is possible that capecitabine might, in some manner, reduce the hepatic metabolism of warfarin. Close monitoring of coagulation parameters is recommended for all patients receiving concomitant warfarin and capecitabine, with appropriate adjustment of warfarin dosage. The nature and extent of this interaction requires further investigation. PMID:12450435

  12. Capecitabine Monotherapy: Review of Studies in First-Line HER-2-Negative Metastatic Breast Cancer

    PubMed Central

    Kaufmann, Manfred; Siedentopf, Friederike; Dalivoust, Philippe; Debled, Marc; Robert, Nicholas J.; Harbeck, Nadia

    2012-01-01

    The goals of treatment for metastatic breast cancer (MBC) are to prolong overall survival (OS) while maximizing quality of life, palliating symptoms, and delaying tumor progression. For many years, anthracyclines and taxanes have been the mainstay of treatment for MBC, but these agents are now commonly administered earlier in the course of the disease. A recent meta-analysis revealed adverse effects on OS and overall response rates in patients with MBC receiving first-line anthracycline-based chemotherapy following relapse on adjuvant chemotherapy. Noncrossresistant cytotoxic agents and combinations that combine high clinical activity and acceptable tolerability while being convenient for patients are therefore needed for the first-line treatment of MBC patients. Capecitabine has substantial antitumor activity in the first-line treatment of patients with MBC in prospective, randomized, phase II/III clinical trials as monotherapy and in combination with biologic and novel agents. First-line capecitabine monotherapy has a favorable safety profile, lacking myelosuppression and alopecia, and does not compromise the administration of further lines of chemotherapy. Capecitabine is suitable for long-term administration without the cumulative toxicity that can limit the prolonged use of other chemotherapy agents. Here, we review the available data on capecitabine as a single agent for first-line treatment of patients with human epidermal growth factor receptor 2–negative MBC. PMID:22418569

  13. Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option

    PubMed Central

    Meulendijks, D; Dewit, L; Tomasoa, N B; van Tinteren, H; Beijnen, J H; Schellens, J H M; Cats, A

    2014-01-01

    Background: Capecitabine is an established treatment alternative to intravenous 5-fluorouracil (5-FU) for patients with rectal cancer receiving chemoradiotherapy. Its place in the treatment of locally advanced anal carcinoma (AC), however, remains undetermined. We investigated whether capecitabine is as effective as 5-FU in the treatment of patients with locally advanced AC. Methods: One hundred and five patients with squamous cell AC stage T2-4 (T2>4 cm), N0-1, M0 or T1-4, N2-3, M0, were included in this retrospective study. Forty-seven patients were treated with continuous 5-FU (750 mg m−2) on days 1–5 and 29–33, mitomycin C (MMC, 10 mg m−2) on day 1, and radiotherapy; 58 patients were treated with capecitabine (825 mg m−2 b.i.d. on weekdays), MMC (10 mg m−2) on day 1, and radiotherapy. The primary end points of the study were: clinical complete response rate, locoregional control (LRC) and overall survival (OS). Secondary end points were: colostomy-free survival (CFS), toxicity and associations of genetic polymorphisms (GSTT1, GSTM1, GSTP1 and TYMS) with outcome and toxicity. Results: Clinical complete response was achieved in 41/46 patients (89.1%) with 5-FU and in 52/58 patients (89.7%) with capecitabine. Three-year LRC was 76% and 79% (P=0.690, log-rank test), 3-year OS was 78% and 86% (P=0.364, log-rank test) and CFS was 65% and 79% (P=0.115, log-rank test) for 5-FU and capecitabine, respectively. GSTT1 and TYMS genotypes were associated with severe (grade 3–4) toxicity. Conclusions: Capecitabine combined with MMC and radiotherapy was equally effective as 5-FU-based chemoradiotherapy. This study shows that capecitabine can be used as an acceptable alternative to 5-FU for the treatment of AC. PMID:25167226

  14. Antineuropathic Profile of N-Palmitoylethanolamine in a Rat Model of Oxaliplatin-Induced Neurotoxicity

    PubMed Central

    Di Cesare Mannelli, Lorenzo; Pacini, Alessandra; Corti, Francesca; Boccella, Serena; Luongo, Livio; Esposito, Emanuela; Cuzzocrea, Salvatore; Maione, Sabatino; Calignano, Antonio; Ghelardini, Carla

    2015-01-01

    Neurotoxicity is a main side effect of the anticancer drug oxaliplatin. The development of a neuropathic syndrome impairs quality of life and potentially results in chemotherapy dose reductions and/or early discontinuation. In the complex pattern of molecular and morphological alterations induced by oxaliplatin in the nervous system, an important activation of glia has been preclinically evidenced. N-Palmitoylethanolamine (PEA) modulates glial cells and exerts antinociceptive effects in several animal models. In order to improve the therapeutic chances for chemotherapy-dependent neuropathy management, the role of PEA was investigated in a rat model of oxaliplatin-induced neuropathy (2.4 mg kg-1 daily, intraperitoneally). On day 21, a single administration of PEA (30 mg kg-1 i.p.) was able to reduce oxaliplatin-dependent pain induced by mechanical and thermal stimuli. The repeated treatment with PEA (30 mg kg-1 daily i.p. for 21 days, from the first oxaliplatin injection) prevented lowering of pain threshold as well as increased pain on suprathreshold stimulation. Ex vivo histological and molecular analysis of dorsal root ganglia, peripheral nerves and spinal cord highlighted neuroprotective effects and glia-activation prevention induced by PEA repeated administration. The protective effect of PEA resulted in the normalization of the electrophysiological activity of the spinal nociceptive neurons. Finally, PEA did not alter the oxaliplatin-induced mortality of the human colon cancer cell line HT-29. The efficacy of PEA in neuropathic pain control and in preventing nervous tissue alteration candidates this endogenous compound as disease modifying agent. These characteristics, joined to the safety profile, suggest the usefulness of PEA in chemotherapy-induced neuropathy. PMID:26039098

  15. Oxaliplatin-induced hyperexcitation of rat sciatic nerve fibers: an intra-axonal study.

    PubMed

    Kagiava, Alexia; Kosmidis, Efstratios K; Theophilidis, George

    2013-02-01

    Oxaliplatin is an agent that is used extensively in gastrointestinal cancer chemotherapy. The agent's major dose-limiting toxicity is peripheral neuropathy that can manifest as a chronic or an acute syndrome. Oxaliplatin-induced acute neuropathy is purportedly caused by an alteration of the biophysical properties of voltage-gated sodium channels. However, sodium channel blockers have not been successful at preventing acute neuropathy in the clinical setting. We report intra-axonal recordings from the isolated rat sciatic nerve preparation under the effect of oxaliplatin. The depolarization phase of single action potentials remains intact with a duration of 0.52 ± 0.02 ms (n=68) before and 0.55 ± 0.01 ms (n=68) after 1-5 h of exposure to 150 μM oxaliplatin (unpaired t-test, P > 0.05) whereas there is a significant broadening of the repolarization phase (2.16 ± 0.10 ms, n=68, before and 5.90 ± 0.32 ms after, n=68, unpaired t-test, P < 0.05). Apart from changes in spike shape, oxaliplatin also had drastic concentration- and time-dependent effects on the firing responses of fibers to short stimuli. In the intra-axonal recordings, three groups of firing patterns were indentified. The first group shows bursting (internal frequency 90 - 130 Hz, n=88), the second shows a characteristic plateau (at -19.27�2.84 mV, n=31, with durations ranging from 45 - 140 ms depending on the exposure time), and the third combines a plateau and a bursting period. Our results implicate the voltage-gated potassium channels as additional oxaliplatin targets, opening up new perspectives for the pharmacological prevention of peripheral neuropathy. PMID:22721389

  16. Automated control and monitoring of thermal processing using high temperature, short time pasteurization.

    PubMed

    Schlesser, J E; Armstrong, D J; Cinar, A; Ramanauskas, P; Negiz, A

    1997-10-01

    High temperature, short time pasteurization was used to evaluate a computer-based system for controlling the pasteurization process, acquiring data, and monitoring records. Software was used for the control of hot water temperature, flow rate through the centrifugal timing pump, and diversion of under-processed product. Three types of control strategies were conducted: single loop, cascade, and multivariable. The single loop control strategy showed the most rapid responses to temperature changes, but the temperature response curve was slowest to return to its set point. The cascade control strategy showed slower recoveries to temperature changes, but the temperature response curve was smoother. The multivariable control strategy responded slightly faster than the cascade control strategy, and the temperature response curve was slightly smoother than the cascade control strategy. The multivariable control strategy was able to control the flow diversion valve by the use of a lethality controller. The data acquisition system, used to monitor the data obtained from the high temperature, short-time pasteurization system, was within +/- 0.1 degree C of the temperature recorded by the safety thermal limit recorder. Reliability was determined by examining the changes in the position of the flow diversion valve to identify process deviations and by comparing the changes to the event marker on circular charts. The data acquisition system was an effective alternative for monitoring the completeness of data. PMID:9361200

  17. Short-time transport properties of bidisperse suspensions and porous media: A Stokesian dynamics study

    NASA Astrophysics Data System (ADS)

    Wang, Mu; Brady, John F.

    2015-03-01

    We present a comprehensive computational study of the short-time transport properties of bidisperse hard-sphere colloidal suspensions and the corresponding porous media. Our study covers bidisperse particle size ratios up to 4 and total volume fractions up to and beyond the monodisperse hard-sphere close packing limit. The many-body hydrodynamic interactions are computed using conventional Stokesian Dynamics (SD) via a Monte-Carlo approach. We address suspension properties including the short-time translational and rotational self-diffusivities, the instantaneous sedimentation velocity, the wavenumber-dependent partial hydrodynamic functions, and the high-frequency shear and bulk viscosities and porous media properties including the permeability and the translational and rotational hindered diffusivities. We carefully compare the SD computations with existing theoretical and numerical results. For suspensions, we also explore the range of validity of various approximation schemes, notably the pairwise additive approximations with the Percus-Yevick structural input. We critically assess the strengths and weaknesses of the SD algorithm for various transport properties. For very dense systems, we discuss in detail the interplay between the hydrodynamic interactions and the structures due to the presence of a second species of a different size.

  18. Fractal analysis of the short time series in a visibility graph method

    NASA Astrophysics Data System (ADS)

    Li, Ruixue; Wang, Jiang; Yu, Haitao; Deng, Bin; Wei, Xile; Chen, Yingyuan

    2016-05-01

    The aim of this study is to evaluate the performance of the visibility graph (VG) method on short fractal time series. In this paper, the time series of Fractional Brownian motions (fBm), characterized by different Hurst exponent H, are simulated and then mapped into a scale-free visibility graph, of which the degree distributions show the power-law form. The maximum likelihood estimation (MLE) is applied to estimate power-law indexes of degree distribution, and in this progress, the Kolmogorov-Smirnov (KS) statistic is used to test the performance of estimation of power-law index, aiming to avoid the influence of droop head and heavy tail in degree distribution. As a result, we find that the MLE gives an optimal estimation of power-law index when KS statistic reaches its first local minimum. Based on the results from KS statistic, the relationship between the power-law index and the Hurst exponent is reexamined and then amended to meet short time series. Thus, a method combining VG, MLE and KS statistics is proposed to estimate Hurst exponents from short time series. Lastly, this paper also offers an exemplification to verify the effectiveness of the combined method. In addition, the corresponding results show that the VG can provide a reliable estimation of Hurst exponents.

  19. Short time spreading and wetting of offset printing liquids on model calcium carbonate coating structures.

    PubMed

    Koivula, Hanna; Toivakka, Martti; Gane, Patrick

    2012-03-01

    Spreading of oils and water on porous and pre-saturated model carbonate coating structures was studied with high speed video imaging. The short-time data were complemented with long time absorption and wicking experiments. The results indicate a strong dependence between surface structural features of the pigment tablets and water spreading at short times, both in non-saturated and water pre-saturated cases, while the oil spreading is mainly dependent on the liquid properties. Sodium polyacrylate dispersant on pigment surfaces is shown to contribute to water spreading and absorption. On pre-saturated structures the liquid-liquid interactions are dominant and the majority of results support spreading according to the molecular kinetic model. The evidence supports the hypothesis of S. Rousu, P. Gane, and D. Eklund, ["Influence of coating pigment chemistry and morphology on the chromatographic separation of offset ink constituents," in The Science of Papermaking Transactions of the 12th Fundamental Research Symposium, FRC The Pulp & Paper Fundamental Research Society, Oxford, UK, 2001, p. 1115] that at long times the oils absorb into the porous structure at a rate proportional to the ratio of viscosity and surface tension, provided there is no sorptive action with the binder. A combination of nanosized pores and large surface area is useful for providing sufficient absorption capability for carbonate based coatings. PMID:22196346

  20. EQUIVALENCE BETWEEN SHORT-TIME BIPHASIC AND INCOMPRESSIBLE ELASTIC MATERIAL RESPONSES

    PubMed Central

    Ateshian, Gerard A.; Ellis, Benjamin J.; Weiss, Jeffrey A.

    2009-01-01

    Porous-permeable tissues have often been modeled using porous media theories such as the biphasic theory. This study examines the equivalence of the short-time biphasic and incompressible elastic responses for arbitrary deformations and constitutive relations from first principles. This equivalence is illustrated in problems of unconfined compression of a disk, and of articular contact under finite deformation, using two different constitutive relations for the solid matrix of cartilage, one of which accounts for the large disparity observed between the tensile and compressive moduli in this tissue. Demonstrating this equivalence under general conditions provides a rationale for using available finite element codes for incompressible elastic materials as a practical substitute for biphasic analyses, so long as only the short-time biphasic response is sought. In practice, an incompressible elastic analysis is representative of a biphasic analysis over the short-term response δt≪Δ2/‖C4‖||K||, where Δ is a characteristic dimension, C4 is the elasticity tensor and K is the hydraulic permeability tensor of the solid matrix. Certain notes of caution are provided with regard to implementation issues, particularly when finite element formulations of incompressible elasticity employ an uncoupled strain energy function consisting of additive deviatoric and volumetric components. PMID:17536908

  1. Atmospheric Array Loss Statistics Derived from Short Time Scale Site Test Interferometer Phase Data

    NASA Astrophysics Data System (ADS)

    Morabito, David D.; D'Addario, Larry R.

    2014-08-01

    NASA is interested in using the technique of arraying smaller-diameter antennas to increase effective aperture to replace the aging 70-m-diameter antennas of the Deep Space Network (DSN). Downlink arraying using the 34-m-diameter and 70-m-diameter antennas is routinely performed. Future scenarios include extending the technique to uplink arraying where a downlink signal may not be available. Atmospheric turbulence causes decorrelation of the arrayed signal, and becomes more severe at higher frequencies such as at the uplink allocations near 34 GHz and 40 GHz. This article expands the study initiated in a previous article that focused on average array loss statistics extracted from Site Test Interferometer (STI) data. In that study, cumulative distributions of the annual and monthly expected phasing loss were derived from STI data collected at the Goldstone and Canberra DSN complexes. For a two-element array, the average array loss cannot exceed 3 dB. This article considers the instantaneous (short time scale) array loss that sometimes exceeds 3 dB for a two-element array. We also consider cases of three-element arrays, which behave somewhat differently. The short time scale statistics of array loss at 7.15 GHz and 34.5 GHz are compared against the average array loss statistics for the best-case and worst-case weather months for the Goldstone and Canberra DSN sites.

  2. Short-Time Glassy Dynamics in Viscous Protein Solutions with Competing Interactions

    SciTech Connect

    Godfrin, P. Douglas; Hudson, Steven; Hong, Kunlun; Porcar, Lionel; Falus, Peter; Wagner, Norman; Liu, Yun

    2015-11-24

    Although there have been numerous investigations of the glass transition for colloidal dispersions with only a short-ranged attraction, less is understood for systems interacting with a long-ranged repulsion in addition to this attraction, which is ubiquitous in aqueous protein solutions at low ionic strength. Highly puri ed concentrated lysozyme solutions are used as a model system and investigated over a large range of protein concentrations at very low ionic strength. Newtonian liquid behavior is observed at all concentrations, even up to 480 mg/mL, where the zero shear viscosity increases by more than three orders of magnitude with increasing concentration. Remarkably, despite this macroscopic liquid-like behavior, the measurements of the dynamics in the short-time limit shows features typical of glassy colloidal systems. Investigation of the inter-protein structure indicates that the reduced short-time mobility of the protein is caused by localized regions of high density within a heterogeneous density distribution. This structural heterogeneity occurs on intermediate range length scale, driven by the competing potential features, and is distinct from commonly studied colloidal gel systems in which a heterogeneous density distribution tends to extend to the whole system. The presence of long-ranged repulsion also allows for more mobility over large length and long time scales resulting in the macroscopic relaxation of the structure. The experimental results provide evidence for the need to explicitly include intermediate range order in theories for the macroscopic properties of protein solutions interacting via competing potential features.

  3. Decomposing a signal into short-time narrow-banded modes

    NASA Astrophysics Data System (ADS)

    McNeill, S. I.

    2016-07-01

    An algorithm for nonparametric decomposition of a signal into the sum of short-time narrow-banded modes (components) is introduced. Specifically, the signal data is augmented with its Hilbert transform to obtain the analytic signal. Then the set of constituent amplitude and frequency modulated (AM-FM) analytic sinusoids, each with slowly varying amplitude and frequency, is sought. The method for obtaining the short-time narrow-banded modes is derived by minimizing an objective function comprised of three criteria: smoothness of the instantaneous amplitude envelope, smoothness of the instantaneous frequency and complete reconstruction of the signal data. A minimum of the objective function is approached using a sequence of suboptimal updates of amplitude and phase. The updates are intuitive, efficient and simple to implement. For a given mode, the amplitude and phase are extracted from the band-pass filtered residual (signal after the other modes are removed), where the band-pass filter is applied about the previous modal instantaneous frequency estimate. The method is demonstrated by application to random output-only vibration data and order tracking data. It is demonstrated that vibration modal responses can be estimated from single channel data and order tracking can be performed without measured tachometer data.

  4. [The Molecular Aspect of the Antitumor Effect of Oxaliplatin in Combination with 5-FU].

    PubMed

    Kitao, Hiroyuki; Kiyonari, Shinichi; Iimori, Makoto; Niimi, Shinichiro; Kataoka, Yuki; Akiyama, Shingo; Edahiro, Keitaro; Nakanishi, Ryota; Tokunaga, Eriko; Saeki, Hiroshi; Oki, Eiji; Kanaji, Shingo; Kakeji, Yoshihiro; Maehara, Yoshihiko

    2016-06-01

    Platinum-based chemotherapeutic drugs as a component of combination chemotherapy are widely used in the treatment of cancer. In particular, oxaliplatin(L-OHP), one such platinum-based chemotherapeutic drug, has a synergistic effect in combination with 5-FU and Leucovorin for the treatment of advanced colorectal cancer. However, the underlying molecular mechanism of this synergistic effect has not been fully clarified yet. In this review, we summarize several updates about the in vitro action of oxaliplatin in human tumor cells and discuss the underlying mechanism of its synergistic effect with 5-FU. PMID:27306806

  5. A Phase I-II Study of Postoperative Capecitabine-Based Chemoradiotherapy in Gastric Cancer

    SciTech Connect

    Jansen, Edwin; Crosby, Tom D.L.; Dubbelman, Ria; Bartelink, Harry; Verheij, Marcel

    2007-12-01

    Background: The Intergroup 0116 randomized study showed that postoperative 5-fluorouracil-based chemoradiotherapy improved locoregional control and overall survival in patients with gastric cancer. We hypothesized that these results could be improved further by using a more effective, intensified, and convenient chemotherapy schedule. Therefore, this Phase I-II dose-escalation study was performed to determine the maximal tolerated dose and toxicity profile of postoperative radiotherapy combined with concurrent capecitabine. Patients and Methods: After recovery from surgery for adenocarcinoma of the gastroesophageal junction or stomach, all patients were treated with capecitabine monotherapy, 1,000 mg/m{sup 2} twice daily for 2 weeks. After a 1-week treatment-free interval, patients received capecitabine (650-1,000 mg/m{sup 2} orally twice daily 5 days/week) in a dose-escalation schedule combined with radiotherapy on weekdays for 5 weeks. Radiotherapy was delivered to a total dose of 45 Gy in 25 fractions to the gastric bed, anastomoses, and regional lymph nodes. Results: Sixty-six patients were treated accordingly. Two patients went off study before or shortly after the start of chemoradiotherapy because of progressive disease. Therefore, 64 patients completed treatment as planned. During the chemoradiotherapy phase, 4 patients developed four items of Grade III dose-limiting toxicity (3 patients in Dose Level II and 1 patient in Dose Level IV). The predefined highest dose of capecitabine, 1,000 mg/m{sup 2} twice daily orally, was tolerated well and, therefore, considered safe for further clinical evaluation. Conclusions: This Phase I-II study shows that intensified chemoradiotherapy with daily capecitabine is feasible in postoperative patients with gastroesophageal junction and gastric cancer.

  6. Capecitabine Initially Concomitant to Radiotherapy Then Perioperatively Administered in Locally Advanced Rectal Cancer

    SciTech Connect

    Zampino, Maria Giulia Magni, Elena; Leonardi, Maria Cristina; Petazzi, Elena; Santoro, Luigi; Luca, Fabrizio; Chiappa, Antonio; Petralia, Giuseppe; Trovato, Cristina; Fazio, Nicola; Orecchia, Roberto; Nole, Franco; Braud, Filippo de

    2009-10-01

    Purpose: To evaluate the impact of neoadjuvant capecitabine, concomitant to radiotherapy, followed by capecitabine monotherapy, in operable locally advanced rectal cancer (LARC) by measuring pathologic response and conservative surgery rate, toxicity profile, and disease-free survival (DFS). Methods and Materials: From October 2002 to July 2006, a total of 51 patients affected by LARC (T3-T4 or any node positive tumor), received capecitabine (825 mg/m{sup 2}, orally, twice daily continuously) concomitant to radiotherapy on the pelvis (50.4 Gy/ 28 fractions), followed by two cycles of capecitabine (1,250 mg/m{sup 2}, orally, twice daily, 14 days on 7 days off) up until 2 weeks before surgery. Tailored adjuvant systemic treatment was discussed according to pathologic stage. Results: Of 51 patients, (median age 61 years, range 38-82 years; 19 women and 32 men; ECOG performance status 0/1/2: 46/4/1), 50 were evaluable for response: 18% complete pathologic remission; 12% T-downstaging, and 30% N-downstaging. One patient died before surgery from mesenteric stroke. Grade 3 acute toxicities were 2% diarrhea, 8% dermatitis, 2% liver function test elevation, and 2% hand-foot syndrome. Sphincter preservation rates for tumors {<=}6 cm from the anal verge were 62% and 80% for the whole population. Median follow up was 43.0 months (range 0.8-68.6 months). Five-years DFS was 85.4% (95% CI = 75.3-95.4%). Conclusions: Based on our study results, we conclude that this regimen is well tolerated and active and compares favorably with existing capecitabine-based approaches.

  7. 5-FU-induced hyperammonemic encephalopathy in a case of metastatic rectal adenocarcinoid successfully rechallenged with the fluoropyrimidine analog, capecitabine.

    PubMed

    Advani, Pooja P; Fakih, Marwan G

    2011-01-01

    Neurological complications of both fluorouracil (5-FU) and its oral prodrug, capecitabine, have been described in the literature. This study reported the case of a 70-year-old female with metastatic adenocarcinoid of the rectum who developed hyperammonemic encephalopathy, following infusional 5-FU therapy, manifesting itself as intractable nausea, vomiting, confusion and disorientation. Interestingly, when the patient was rechallenged with the fluoropyrimidine analog, capecitabine, neither hyperammonemia nor symptom recurrence was observed. 5-FU is an integral component of effective anti-neoplastic treatment for metastatic colorectal cancer, but is often discontinued when neurotoxicity develops. This case highlighted the use of capecitabine as an alternative for patients who have demonstrated evidence of 5-FU-induced hyperammonemic encephalopathy. Re-challenging the patient with capecitabine, at a low daily dose intensity, accounted for the overall tolerability of the treatment, as demonstrated by normal ammonia levels and the lack of neurological symptoms. PMID:21273620

  8. Convection-enhancement delivery of liposomal formulation of oxaliplatin shows less toxicity than oxaliplatin yet maintains a similar median survival time in F98 glioma-bearing rat model.

    PubMed

    Shi, Minghan; Fortin, David; Paquette, Benoit; Sanche, Léon

    2016-06-01

    Results of clinical trials with oxaliplatin in treating glioblastoma are dismal. Previous works showed that intravenous (i.v.) delivery of oxaliplatin did not increase the survival of F98 glioma-bearing Fisher rats. Low accumulation of the drug in tumor cells is presumed to be responsible for the lack of antitumor effect. In the present study, convection-enhanced delivery (CED) was used to directly inject oxaliplatin in brain tumor implanted in rats. Since CED can led to severe toxicity, the liposomal formulation of oxaliplatin (Lipoxal™) was also assessed. The maximum tolerated dose (MTD) of oxaliplatin was 10 μg, while that of Lipoxal™ was increased by 3-times reaching 30 μg. Median survival time (MeST) of F98 glioma-bearing rats injected with 10 μg oxaliplatin by CED was 31 days, 7.5 days longer than untreated control (p = 0.0002); while CED of 30 μg Lipoxal™ reached the same result. Compared to previous study on i.v. delivery of these drugs, their injection by CED significantly increased their tumoral accumulations as well as MeSTs in the F98 glioma bearing rat model. The addition of radiotherapy (15 Gy) to CED of oxaliplatin or Lipoxal™ increased the MeST by 4.0 and 3.0 days, respectively. The timing of radiotherapy (4 h or 24 h after CED) produced similar results. However, the treatment was better tolerated when radiotherapy was performed 24 h after CED. In conclusion, a better tumoral accumulation was achieved when oxaliplatin and Lipoxal™ were injected by CED. The liposomal encapsulation of oxaliplatin reduced its toxic, while maintaining its antitumor potential. PMID:26961906

  9. Structure and short-time dynamics in concentrated suspensions of charged colloids

    NASA Astrophysics Data System (ADS)

    Westermeier, Fabian; Fischer, Birgit; Roseker, Wojciech; Grübel, Gerhard; Nägele, Gerhard; Heinen, Marco

    2012-09-01

    We report a comprehensive joint experimental-theoretical study of the equilibrium pair-structure and short-time diffusion in aqueous suspensions of highly charged poly-acrylate (PA) spheres in the colloidal fluid phase. Low-polydispersity PA sphere systems with two different hard-core radii, R0 = 542 and 1117 Å, are explored over a wide range of concentrations and salinities using static and dynamic light scattering (DLS), small angle x-ray scattering, and x-ray photon correlation spectroscopy (XPCS). The measured static and dynamic scattering functions are analyzed using state-of-the-art theoretical methods. For all samples, the measured static structure factor, S(Q), is in good agreement with results by an analytical integral equation method for particles interacting by a repulsive screened Coulomb plus hard-core pair potential. In our DLS and XPCS measurements, we have determined the short-time diffusion function D(Q) = D0 H(Q)/S(Q), comprising the free diffusion coefficient D0 and the hydrodynamic function H(Q). The latter is calculated analytically using a self-part corrected version of the δγ-scheme by Beenakker and Mazur which accounts approximately for many-body hydrodynamic interactions (HIs). Except for low-salinity systems at the highest investigated volume fraction ϕ ≈ 0.32, the theoretical predictions for H(Q) are in excellent agreement with the experimental data. In particular, the increase in the collective diffusion coefficient Dc = D(Q → 0), and the decrease of the self-diffusion coefficient, Ds = D(Q → ∞), with increasing ϕ is well described. In accord with the theoretical prediction, the peak value, H(Qm), of H(Q) relates to the nearest neighbor cage size ˜2π/Qm, for which concentration scaling relations are discussed. The peak values H(Qm) are globally bound from below by the corresponding neutral hard-spheres peak values, and from above by the limiting peak values for low-salinity charge-stabilized systems. HIs usually slow short-time

  10. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer

    PubMed Central

    Liu, Mei-Ching; Lee, Soo Chin; Vanlemmens, Laurence; Ferrero, Jean-Marc; Tabei, Toshio; Pivot, Xavier; Iwata, Hiroji; Aogi, Kenjiro; Lugo-Quintana, Roberto; Harbeck, Nadia; Brickman, Marla J.; Zhang, Ke; Kern, Kenneth A.; Martin, Miguel

    2010-01-01

    This multicenter, randomized, open-label phase III trial (planned enrollment: 700 patients) was conducted to test the hypothesis that single-agent sunitinib improves progression-free survival (PFS) compared with capecitabine as treatment for advanced breast cancer (ABC). Patients with HER2-negative ABC that recurred after anthracycline and taxane therapy were randomized (1:1) to sunitinib 37.5 mg/day or capecitabine 1,250 mg/m2 (1,000 mg/m2 in patients >65 years) BID on days 1–14 q3w. The independent data-monitoring committee (DMC) determined during the first interim analysis (238 patients randomized to sunitinib, 244 to capecitabine) that the trial be terminated due to futility in reaching the primary endpoint. No statistical evidence supported the hypothesis that sunitinib improved PFS compared with capecitabine (one-sided P = 0.999). The data indicated that PFS was shorter with sunitinib than capecitabine (median 2.8 vs. 4.2 months, respectively; HR, 1.47; 95% CI, 1.16–1.87; two-sided P = 0.002). Median overall survival (15.3 vs. 24.6 months; HR, 1.17; two-sided P = 0.350) and objective response rates (11 vs. 16%; odds ratio, 0.65; P = 0.109) were numerically inferior with sunitinib versus capecitabine. While no new or unexpected safety findings were reported, sunitinib treatment was associated with higher frequencies and greater severities of many common adverse events (AEs) compared with capecitabine, resulting in more temporary discontinuations due to AEs with sunitinib (66 vs. 51%). The relative dose intensity was lower with sunitinib than capecitabine (73 vs. 95%). Based on these efficacy and safety results, sunitinib should not be used as monotherapy for patients with ABC. PMID:20339913

  11. Upregulation of CYP2S1 by oxaliplatin is associated with p53 status in colorectal cancer cell lines.

    PubMed

    Yang, Chao; Zhou, Qian; Li, Minle; Tong, Xuemei; Sun, Jiayi; Qing, Yin; Sun, Liya; Yang, Xuhan; Hu, Xiaowen; Jiang, Jie; Yan, Xiaomei; He, Lin; Wan, Chunling

    2016-01-01

    Oxaliplatin displays a wide spectrum of antitumor activities and is widely used in the treatment of metastatic colorectal cancer (CRC). However, tumor responses to this agent are variable, and the underlying mechanisms are poorly understood. In the present study, oxaliplatin was found to strongly inhibit the growth of HCT116 cells harboring wild-type p53 but to only weakly inhibit SW480 cells, HT29 cells or p53-/- HCT116 cells, which all lack p53 expression. Administration of oxaliplatin significantly induced p53 accumulation and enhanced expression of CYP2S1 in HCT116 cells with wild-type p53. CYP2S1 knockdown conferred a cell survival advantage after oxaliplatin treatment to cells harboring wild-type p53 in vitro and in vivo. Interestingly, enzyme immunoassays, TOPFlash/FOPFlash reporter activity assays and western blotting analysis demonstrated oxaliplatin-mediated downregulation of PGE2 and Wnt/β-catenin signaling in a manner dependent on p53. Moreover, oxaliplatin treatment of mice with subcutaneous tumor xenografts drastically reduced the volume of wild-type p53 HCT116 tumors but had no effect on isogenic p53-/- HCT116 tumors. These results suggest that oxaliplatin exerts its inhibitory effects in human CRC cells via upregulation of CYP2S1 expression in a p53-dependent manner. PMID:27609465

  12. Upregulation of CYP2S1 by oxaliplatin is associated with p53 status in colorectal cancer cell lines

    PubMed Central

    Yang, Chao; Zhou, Qian; Li, Minle; Tong, Xuemei; Sun, Jiayi; Qing, Yin; Sun, Liya; Yang, Xuhan; Hu, Xiaowen; Jiang, Jie; Yan, Xiaomei; He, Lin; Wan, Chunling

    2016-01-01

    Oxaliplatin displays a wide spectrum of antitumor activities and is widely used in the treatment of metastatic colorectal cancer (CRC). However, tumor responses to this agent are variable, and the underlying mechanisms are poorly understood. In the present study, oxaliplatin was found to strongly inhibit the growth of HCT116 cells harboring wild-type p53 but to only weakly inhibit SW480 cells, HT29 cells or p53−/− HCT116 cells, which all lack p53 expression. Administration of oxaliplatin significantly induced p53 accumulation and enhanced expression of CYP2S1 in HCT116 cells with wild-type p53. CYP2S1 knockdown conferred a cell survival advantage after oxaliplatin treatment to cells harboring wild-type p53 in vitro and in vivo. Interestingly, enzyme immunoassays, TOPFlash/FOPFlash reporter activity assays and western blotting analysis demonstrated oxaliplatin-mediated downregulation of PGE2 and Wnt/β-catenin signaling in a manner dependent on p53. Moreover, oxaliplatin treatment of mice with subcutaneous tumor xenografts drastically reduced the volume of wild-type p53 HCT116 tumors but had no effect on isogenic p53−/− HCT116 tumors. These results suggest that oxaliplatin exerts its inhibitory effects in human CRC cells via upregulation of CYP2S1 expression in a p53-dependent manner. PMID:27609465

  13. Reactive oxygen species mediate oxaliplatin-induced epithelial-mesenchymal transition and invasive potential in colon cancer.

    PubMed

    Jiao, Lin; Li, Dan-Dan; Yang, Chen-Lu; Peng, Rui-Qing; Guo, Yi-Qun; Zhang, Xiao-Shi; Zhu, Xiao-Feng

    2016-06-01

    Therapeutic benefits offered by common chemotherapy drugs, such as oxaliplatin, are limited due to the development of resistance, which contributes to treatment failure and metastasis. The epithelial-mesenchymal transition (EMT) is a key event contributing to the development of resistance to chemotherapeutics. Although the relationship between oxaliplatin and chemotherapy resistance has been described for decades, the molecular mechanisms have remained elusive. The aim of the present study was to investigate the underlying mechanisms of oxaliplatin-mediated metastasis. Here, we identify reactive oxygen species (ROS) as mediators that promote the oxaliplatin-induced EMT. Following oxaliplatin treatment, the messenger RNA (mRNA) levels of most peroxiredoxin family genes, except for peroxiredoxin 1 (prdx1) gene, were constant or even decreased, resulting in ROS abundance. And the antioxidant guardian Nrf2 was unconspicuously raised both transcriptionally and translationally with oxaliplatin treatment as compared to those induced by topotecan treatment, which has been proved with no induced metastasis. In addition, the study evaluated high levels of ROS leading to EMT via activation of the known oncogenes Akt and Snail. Using the Akt inhibitor LY294002 or knocking down Snail expression via RNA interference (RNAi) reversed the effects of oxaliplatin on the EMT and metastasis. Our studies establish a role for the ROS-Akt-Snail axis as a mechanism by which chemotherapeutics induce EMT and cancer metastasis. PMID:26733168

  14. Oxaliplatin antagonizes HIV-1 latency by activating NF-κB without causing global T cell activation

    SciTech Connect

    Zhu, Xiaoli; Liu, Sijie; Wang, Pengfei; Qu, Xiying; Wang, Xiaohui; Zeng, Hanxian; Chen, Huabiao; Zhu, Huanzhang

    2014-07-18

    Highlights: • The chemotherapeutic drug oxaliplatin reactivates latent HIV-1 in this cell line model of HIV-1 latency. • Reactivation is synergized when oxaliplatin is used in combination with valproic acid. • Oxaliplatin reactivates latent HIV-1 through activation of NF-kB and does not induce T cell activation. - Abstract: Reactivation of latent HIV-1 is a promising strategy for the clearance of the viral reservoirs. Because of the limitations of current agents, identification of new latency activators is urgently required. Using an established model of HIV-1 latency, we examined the effect of Oxaliplatin on latent HIV-1 reactivation. We showed that Oxaliplatin, alone or in combination with valproic acid (VPA), was able to reactivate HIV-1 without inducing global T cell activation. We also provided evidence that Oxaliplatin reactivated HIV-1 expression by inducing nuclear factor kappa B (NF-κB) nuclear translocation. Our results indicated that Oxaliplatin could be a potential drug candidate for anti-latency therapies.

  15. Short time-scale variability of chromospheric Ca II in late-type stars

    NASA Technical Reports Server (NTRS)

    Baliunas, S. L.; Vaughan, A. H.; Hartmann, L.; Liller, W.; Dupree, A. K.

    1981-01-01

    The short time-scale variability of singly ionized calcium chromospheric emission has been investigated in a few late-type stars. Emission-line variations with time scales of a few minutes to hours are seen in Alpha Tau (K5 III), Lambda And (G8 III-IV), and Epsilon Eri (K2 V). The existence of substantial chromospheric flux changes (10 to the 30th to 10 to the 32nd ergs) over short periods of time suggests that the calcium emission arises from a few small, coherent regions. Frequencies present in the data are discussed in the context of acoustic wave predictions and estimated acoustic cutoff frequencies for giants and dwarfs.

  16. Short-Time Beta Relaxation in Glass-Forming Liquids Is Cooperative in Nature

    NASA Astrophysics Data System (ADS)

    Karmakar, Smarajit; Dasgupta, Chandan; Sastry, Srikanth

    2016-02-01

    Temporal relaxation of density fluctuations in supercooled liquids near the glass transition occurs in multiple steps. Using molecular dynamics simulations for three model glass-forming liquids, we show that the short-time β relaxation is cooperative in nature. Using finite-size scaling analysis, we extract a growing length scale associated with beta relaxation from the observed dependence of the beta relaxation time on the system size. We find, in qualitative agreement with the prediction of the inhomogeneous mode coupling theory, that the temperature dependence of this length scale is the same as that of the length scale that describes the spatial heterogeneity of local dynamics in the long-time α -relaxation regime.

  17. Ultra short-time dynamics of radiation damage in fcc metals

    SciTech Connect

    Hayoun, Marc; Coddens, Gerrit; Petite, Guillaume

    2009-11-01

    We have performed molecular-dynamics simulations of displacement cascades in copper in order to investigate the nonequilibrium ultra-short-time damage and to evaluate the possibility of observing it experimentally in situ (e.g., in a pump/probe laser experiment). The atomic trajectories have been analyzed by calculating their x-ray diffraction patterns as a function of time. The results show that an integrated x-ray intensity can indeed be used to evidence the irradiation effects. Even though the number of Frenkel defects is large, the main effect of the irradiation showing up in the x-ray intensities at ultrashort times is an important alteration of the lattice vibrations. On the basis of these results, a pump/probe setup is proposed.

  18. Super-resolution spectral estimation in short-time non-contact vital sign measurement

    NASA Astrophysics Data System (ADS)

    Sun, Li; Li, Yusheng; Hong, Hong; Xi, Feng; Cai, Weidong; Zhu, Xiaohua

    2015-04-01

    Non-contact techniques for measuring vital signs attract great interest due to the benefits shown in medical monitoring, military application, etc. However, the presence of respiration harmonics caused by nonlinear phase modulation will result in performance degradation. Suffering from smearing and leakage problems, conventional discrete Fourier transform (DFT) based methods cannot distinguish the heartbeat component from closely located respiration harmonics in frequency domain, especially in short-time processing. In this paper, the theory of sparse reconstruction is merged with an extended harmonic model of vital signals, aiming at achieving a super-resolution spectral estimation of vital signals by additionally exploiting the inherent sparse prior information. Both simulated and experimental results show that the proposed algorithm has superior performance to DFT-based methods and the recently applied multiple signal classification algorithm, and the required processing window length has been shortened to 5.12 s.

  19. Photoacoustic detection of blood in dental pulp by using short-time Fourier transform

    NASA Astrophysics Data System (ADS)

    Yamada, Azusa; Kakino, Satoko; Matsuura, Yuji

    2016-03-01

    A method based on photoacoustic analysis is proposed to diagnose dental pulp vitality. Photoacoustic analysis enables to get signal from deeper tissues than other optical analyses and therefore, signal detection from root canal of thick dental tissues such as molar teeth is expected. As a light source for excitation of photoacoustic waves, a microchip Q-switched YAG laser with a wavelength of 1064 nm was used and owing to large penetration depth of the near infrared laser, photoacoustic signals from dental root were successfully obtained. It was found that the photoacoustic signals from the teeth containing hemoglobin solution in the pulp cavity provide vibration in high frequency region. It was also shown that the intensities of the high frequency component have correlation with the hemoglobin concentration of solution. We applied short-time Fourier transform for evaluation of photoacoustic signals and this analysis clearly showed photoacoustic signals from dental root.

  20. Super-resolution spectral estimation in short-time non-contact vital sign measurement.

    PubMed

    Sun, Li; Li, Yusheng; Hong, Hong; Xi, Feng; Cai, Weidong; Zhu, Xiaohua

    2015-04-01

    Non-contact techniques for measuring vital signs attract great interest due to the benefits shown in medical monitoring, military application, etc. However, the presence of respiration harmonics caused by nonlinear phase modulation will result in performance degradation. Suffering from smearing and leakage problems, conventional discrete Fourier transform (DFT) based methods cannot distinguish the heartbeat component from closely located respiration harmonics in frequency domain, especially in short-time processing. In this paper, the theory of sparse reconstruction is merged with an extended harmonic model of vital signals, aiming at achieving a super-resolution spectral estimation of vital signals by additionally exploiting the inherent sparse prior information. Both simulated and experimental results show that the proposed algorithm has superior performance to DFT-based methods and the recently applied multiple signal classification algorithm, and the required processing window length has been shortened to 5.12 s. PMID:25933881

  1. Oxaliplatin-Induced Peripheral Neuropathy via TRPA1 Stimulation in Mice Dorsal Root Ganglion Is Correlated with Aluminum Accumulation.

    PubMed

    Park, Jin-Hee; Chae, Jisook; Roh, Kangsan; Kil, Eui-Joon; Lee, Minji; Auh, Chung-Kyun; Lee, Myung-Ah; Yeom, Chang-Hwan; Lee, Sukchan

    2015-01-01

    Oxaliplatin is a platinum-based anticancer drug used to treat metastatic colorectal, breast, and lung cancers. While oxaliplatin kills cancer cells effectively, it exhibits several side effects of varying severity. Neuropathic pain is commonly experienced during treatment with oxaliplatin. Patients describe symptoms of paresthesias or dysesthesias that are triggered by cold (acute neuropathy), or as abnormal sensory or motor function (chronic neuropathy). In particular, we found that aluminum levels were relatively high in some cancer patients suffering from neuropathic pain based on clinical observations. Based on these findings, we hypothesized that aluminum accumulation in the dorsal root ganglion (DRG) in the course of oxaliplatin treatment exacerbates neuropathic pain. In mice injected with oxaliplatin (three cycles of 3 mg/kg i.p. daily for 5 days, followed by 5 days of rest), we detected cold allodynia using the acetone test, but not heat hyperalgesia using a hot plate. However, co-treatment with aluminum chloride (AlCl3∙6H2O; 7 mg/kg i.p. for 14 days: equivalent 0.78 mg/kg of elemental Al) and oxaliplatin (1 cycle of 3 mg/kg i.p. daily for 5 days, followed by 5 days of rest) synergistically induced cold allodynia as well as increased TRPAl mRNA and protein expression. Inductively Coupled Plasma Mass Spectrometry (ICP-MS) analysis showed a significant increase in aluminum concentrations in the DRG of mice treated with aluminum chloride and oxaliplatin compared to aluminum chloride alone. Similarly, in a mouse induced-tumor model, aluminum concentrations were increased in DRG tissue and tumor cells after oxaliplatin treatment. Taken together, these findings suggest that aluminum accumulation in the DRG may exacerbate neuropathic pain in oxaliplatin-treated mice. PMID:25928068

  2. Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin-induced neuropathic cold hypersensitivity.

    PubMed

    Shidahara, Yuka; Ogawa, Shinya; Nakamura, Mari; Nemoto, Shingo; Awaga, Yuji; Takashima, Miyuki; Hama, Aldric; Matsuda, Akihisa; Takamatsu, Hiroyuki

    2016-02-01

    Oxaliplatin is a first-line treatment for colorectal cancer. However, shortly following treatment, cold-evoked hypersensitivity appears in the extremities and over time, the pain is such that oxaliplatin dosing may need to be markedly reduced or even terminated. There is currently a lack of efficacious treatments for oxaliplatin-induced peripheral neuropathy, which is due in part to the difficulty in translating findings obtained from preclinical rodent models of chemotherapy-induced peripheral neuropathy. Nonhuman primates (NHP) are phylogenetically closer to humans than rodents and may show drug responses that parallel those of humans. A significant decrease in tail withdrawal latency to 10°C water ("cold hypersensitivity") was observed beginning 3 days after intravenous infusion of oxaliplatin (5 mg/kg) in Macaca fascicularis. A single treatment of duloxetine (30 mg/kg, p.o.) ameliorated oxaliplatin-induced cold hypersensitivity, whereas pregabalin (30 mg/kg, p.o.) and tramadol (30 mg/kg, p.o.) did not. By contrast, in rats, no significant cold hypersensitivity, or increased responsiveness to acetone applied to the hind paws, was observed 3 days after the first injection of oxaliplatin (5 mg/kg, i.p., once per day, two injections). Therefore, rats were tested after six treatments of oxaliplatin, 17 days after the first treatment. All analgesics (30 mg/kg, p.o.) significantly ameliorated cold hypersensitivity in rats. The activity of analgesics in the oxaliplatin-treated macaques parallel clinical findings. The current results indicate that the NHP could serve as a bridge species to improve translatability of preclinical findings into clinically useful treatments for oxaliplatin-induced peripheral neuropathy. PMID:26977304

  3. Oxaliplatin-Induced Peripheral Neuropathy via TRPA1 Stimulation in Mice Dorsal Root Ganglion Is Correlated with Aluminum Accumulation

    PubMed Central

    Roh, Kangsan; Kil, Eui-Joon; Lee, Minji; Auh, Chung-Kyun; Lee, Myung-Ah; Yeom, Chang-Hwan; Lee, Sukchan

    2015-01-01

    Oxaliplatin is a platinum-based anticancer drug used to treat metastatic colorectal, breast, and lung cancers. While oxaliplatin kills cancer cells effectively, it exhibits several side effects of varying severity. Neuropathic pain is commonly experienced during treatment with oxaliplatin. Patients describe symptoms of paresthesias or dysesthesias that are triggered by cold (acute neuropathy), or as abnormal sensory or motor function (chronic neuropathy). In particular, we found that aluminum levels were relatively high in some cancer patients suffering from neuropathic pain based on clinical observations. Based on these findings, we hypothesized that aluminum accumulation in the dorsal root ganglion (DRG) in the course of oxaliplatin treatment exacerbates neuropathic pain. In mice injected with oxaliplatin (three cycles of 3 mg/kg i.p. daily for 5 days, followed by 5 days of rest), we detected cold allodynia using the acetone test, but not heat hyperalgesia using a hot plate. However, co-treatment with aluminum chloride (AlCl3∙6H2O; 7 mg/kg i.p. for 14 days: equivalent 0.78 mg/kg of elemental Al) and oxaliplatin (1 cycle of 3 mg/kg i.p. daily for 5 days, followed by 5 days of rest) synergistically induced cold allodynia as well as increased TRPAl mRNA and protein expression. Inductively Coupled Plasma Mass Spectrometry (ICP-MS) analysis showed a significant increase in aluminum concentrations in the DRG of mice treated with aluminum chloride and oxaliplatin compared to aluminum chloride alone. Similarly, in a mouse induced-tumor model, aluminum concentrations were increased in DRG tissue and tumor cells after oxaliplatin treatment. Taken together, these findings suggest that aluminum accumulation in the DRG may exacerbate neuropathic pain in oxaliplatin-treated mice. PMID:25928068

  4. Short-Time Glassy Dynamics in Viscous Protein Solutions with Competing Interactions

    DOE PAGESBeta

    Godfrin, P. Douglas; Hudson, Steven; Hong, Kunlun; Porcar, Lionel; Falus, Peter; Wagner, Norman; Liu, Yun

    2015-11-24

    Although there have been numerous investigations of the glass transition for colloidal dispersions with only a short-ranged attraction, less is understood for systems interacting with a long-ranged repulsion in addition to this attraction, which is ubiquitous in aqueous protein solutions at low ionic strength. Highly puri ed concentrated lysozyme solutions are used as a model system and investigated over a large range of protein concentrations at very low ionic strength. Newtonian liquid behavior is observed at all concentrations, even up to 480 mg/mL, where the zero shear viscosity increases by more than three orders of magnitude with increasing concentration. Remarkably,more » despite this macroscopic liquid-like behavior, the measurements of the dynamics in the short-time limit shows features typical of glassy colloidal systems. Investigation of the inter-protein structure indicates that the reduced short-time mobility of the protein is caused by localized regions of high density within a heterogeneous density distribution. This structural heterogeneity occurs on intermediate range length scale, driven by the competing potential features, and is distinct from commonly studied colloidal gel systems in which a heterogeneous density distribution tends to extend to the whole system. The presence of long-ranged repulsion also allows for more mobility over large length and long time scales resulting in the macroscopic relaxation of the structure. The experimental results provide evidence for the need to explicitly include intermediate range order in theories for the macroscopic properties of protein solutions interacting via competing potential features.« less

  5. Mining biological information from 3D short time-series gene expression data: the OPTricluster algorithm

    PubMed Central

    2012-01-01

    Background Nowadays, it is possible to collect expression levels of a set of genes from a set of biological samples during a series of time points. Such data have three dimensions: gene-sample-time (GST). Thus they are called 3D microarray gene expression data. To take advantage of the 3D data collected, and to fully understand the biological knowledge hidden in the GST data, novel subspace clustering algorithms have to be developed to effectively address the biological problem in the corresponding space. Results We developed a subspace clustering algorithm called Order Preserving Triclustering (OPTricluster), for 3D short time-series data mining. OPTricluster is able to identify 3D clusters with coherent evolution from a given 3D dataset using a combinatorial approach on the sample dimension, and the order preserving (OP) concept on the time dimension. The fusion of the two methodologies allows one to study similarities and differences between samples in terms of their temporal expression profile. OPTricluster has been successfully applied to four case studies: immune response in mice infected by malaria (Plasmodium chabaudi), systemic acquired resistance in Arabidopsis thaliana, similarities and differences between inner and outer cotyledon in Brassica napus during seed development, and to Brassica napus whole seed development. These studies showed that OPTricluster is robust to noise and is able to detect the similarities and differences between biological samples. Conclusions Our analysis showed that OPTricluster generally outperforms other well known clustering algorithms such as the TRICLUSTER, gTRICLUSTER and K-means; it is robust to noise and can effectively mine the biological knowledge hidden in the 3D short time-series gene expression data. PMID:22475802

  6. Efficacy and safety of capecitabine-based first-line chemotherapy in advanced or metastatic breast cancer: a meta-analysis of randomised controlled trials.

    PubMed

    Yin, Weijiao; Pei, Guangsheng; Liu, Gang; Huang, Li; Gao, Shegan; Feng, Xiaoshan

    2015-11-17

    We sought to evaluate the efficacy and safety of capecitabine-based therapy as first-line chemotherapy in advanced breast cancer. Randomised controlled trials of capecitabine monotherapy or combined treatment were included in the meta-analysis. PubMed, EMBASE, the Cochrane Library database and important meeting summaries were searched systematically. Outcomes were progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and grades 3-4 drug-related adverse events.Nine trials with 1798 patients were included. The results indicated a significant improvement with capecitabine-based chemotherapy compared with capecitabine-free chemotherapy in ORR (relative risk [RR] 1.14, 95% confidence interval [CI] 1.03 to 1.26, P = 0.013) and PFS (hazard ratio [HR] 0.77, 95% CI 0.69 to 0.87, P < 0.0001). Overall survival favoured capecitabine-based chemotherapy, but this was not significant. There were more incidences of neutropenia and neutropenic fever in the capecitabine-free chemotherapy group and more vomiting, diarrhoea and hand-foot syndrome in the capecitabine-based chemotherapy group. There were no significant differences in nausea, fatigue, cardiotoxicity or mucositis/stomatitis between the two treatment regimens.Capecitabine-based chemotherapy significantly improves ORR and PFS in patients with advanced breast cancer, but has no demonstrable impact on OS. Capecitabine-based regimens are suitable as first-line treatment for patients with advanced breast cancer. PMID:26420815

  7. Efficacy and safety of capecitabine-based first-line chemotherapy in advanced or metastatic breast cancer: a meta-analysis of randomised controlled trials

    PubMed Central

    Liu, Gang; Huang, Li; Gao, Shegan; Feng, Xiaoshan

    2015-01-01

    We sought to evaluate the efficacy and safety of capecitabine-based therapy as first-line chemotherapy in advanced breast cancer. Randomised controlled trials of capecitabine monotherapy or combined treatment were included in the meta-analysis. PubMed, EMBASE, the Cochrane Library database and important meeting summaries were searched systematically. Outcomes were progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and grades 3–4 drug-related adverse events. Nine trials with 1798 patients were included. The results indicated a significant improvement with capecitabine-based chemotherapy compared with capecitabine-free chemotherapy in ORR (relative risk [RR] 1.14, 95% confidence interval [CI] 1.03 to 1.26, P = 0.013) and PFS (hazard ratio [HR] 0.77, 95% CI 0.69 to 0.87, P < 0.0001). Overall survival favoured capecitabine-based chemotherapy, but this was not significant. There were more incidences of neutropenia and neutropenic fever in the capecitabine-free chemotherapy group and more vomiting, diarrhoea and hand–foot syndrome in the capecitabine-based chemotherapy group. There were no significant differences in nausea, fatigue, cardiotoxicity or mucositis/stomatitis between the two treatment regimens. Capecitabine-based chemotherapy significantly improves ORR and PFS in patients with advanced breast cancer, but has no demonstrable impact on OS. Capecitabine-based regimens are suitable as first-line treatment for patients with advanced breast cancer. PMID:26420815

  8. Oxaliplatin-induced sinusoidal obstruction syndrome mimicking metastatic colon cancer in the liver

    PubMed Central

    CHOI, JUNG-HYE; WON, YOUNG-WOONG; KIM, HYUN SUNG; OH, YOUNG-HA; LIM, SANGHYEOK; KIM, HAN-JOON

    2016-01-01

    Oxaliplatin is an effective chemotherapeutic agent for the treatment of colorectal cancer; however, it may cause liver injury, particularly sinusoidal obstruction syndrome (SOS). Although SOS does not usually present with focal lesions on radiological images, the present study describes the case of a 22-year-old woman with oxaliplatin-induced SOS mimicking metastatic colon cancer in the liver. An abdominal computed tomography revealed a novel 1 cm, low-density lesion in segment 1 of the liver following the administration of the fourth round of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer. Since the lesion was indistinguishable from metastasis, even with detailed imaging studies, including magnetic resonance imaging and positron emission tomography-computed tomography, an isolated caudate lobectomy was planned. The cut surface of the resected liver showed a localized reddish congested lesion measuring 1.4 cm in diameter. The adjacent hepatic parenchyma also demonstrated diffuse sinusoidal congestion with a nutmeg-like appearance. Histologically, the lesion exhibited severe sinusoidal congestion with peliosis hepatis-like features. The widened sinusoidal space was outlined by markedly attenuated hepatic cords and filled with erythrocytes. The final diagnosis was oxaliplatin-induced SOS. The patient recovered completely and was relapse-free at the time of writing. PMID:27073565

  9. Epididymitis following Cytoreductive Surgery with Intraperitoneal Oxaliplatin Chemotherapy: Two Case Reports

    PubMed Central

    Barbosa, Luiza Damian Ribeiro; Belotto, Marcos; Peixoto, Renata D'Alpino

    2016-01-01

    Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy has emerged as an aggressive treatment option with intent to either cure or extend disease-free survival of selected patients with peritoneal carcinomatosis. However, postoperative complications are common. We describe the cases of 2 men who underwent CRS with hyperthermic intraperitoneal oxaliplatin and developed scrotal pain, which was consistent with noninfectious epididymitis. PMID:27293401

  10. Oxaliplatin analogues with carboxy derivatives of boldine with enhanced antioxidant activity.

    PubMed

    Mellado, Marco; Jara, Carlos; Astudillo, David; Villena, Joan; Reveco, Patricio G; Thomet, Franz A

    2015-01-01

    A new oxaliplatin analog [Pt(dach)(L5)] (1) was synthesized and characterized as a continuation of a study of the previously reported [Pt(dach)(L6)] (2), where dach = (1R,2R)-diaminocyclohexane, L5 = 3-carboxyboldine, and L6 = 3-carboxypredicentrine. Compounds 1 and 2 exhibited a substantially enhanced antioxidant activity compared to oxaliplatin (130 and 30 times for 1 and 13 and 4 times for 2 using the DPPH and FRAP assays, resp.). In addition, 1 and 2 exhibited cytotoxic activity in the same range as oxaliplatin toward the two human tumor cell lines (MCF-7 and HT-29) studied and two to four times lower activity in the human colon nontumor cell line (CCD-841). Preadministration of L5 or L6 to the colon tumor (HT-29) and the colon nontumor (CCD-841) cell lines prior to oxaliplatin addition increased the viability of the nontumor cell line to a greater extent than that of the tumor cell line. PMID:25814916

  11. Oxaliplatin Analogues with Carboxy Derivatives of Boldine with Enhanced Antioxidant Activity

    PubMed Central

    Mellado, Marco; Jara, Carlos; Astudillo, David; Villena, Joan; Reveco, Patricio G.; Thomet, Franz A.

    2015-01-01

    A new oxaliplatin analog [Pt(dach)(L5)] (1) was synthesized and characterized as a continuation of a study of the previously reported [Pt(dach)(L6)] (2), where dach = (1R,2R)-diaminocyclohexane, L5 = 3-carboxyboldine, and L6 = 3-carboxypredicentrine. Compounds 1 and 2 exhibited a substantially enhanced antioxidant activity compared to oxaliplatin (130 and 30 times for 1 and 13 and 4 times for 2 using the DPPH and FRAP assays, resp.). In addition, 1 and 2 exhibited cytotoxic activity in the same range as oxaliplatin toward the two human tumor cell lines (MCF-7 and HT-29) studied and two to four times lower activity in the human colon nontumor cell line (CCD-841). Preadministration of L5 or L6 to the colon tumor (HT-29) and the colon nontumor (CCD-841) cell lines prior to oxaliplatin addition increased the viability of the nontumor cell line to a greater extent than that of the tumor cell line. PMID:25814916

  12. Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice

    PubMed Central

    Kim, Woojin; Kim, Min Joon; Go, Donghyun; Min, Byung-Il; Na, Heung Sik; Kim, Sun Kwang

    2016-01-01

    Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA) has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat different types of pain. Here, we investigated whether treatment with a combination of these two agents has an additive effect on oxaliplatin-induced neuropathic pain in mice. To assess cold and mechanical allodynia, acetone and von Frey filament tests were used, respectively. Significant allodynia signs were observed three days after an oxaliplatin injection (6 mg/kg, i.p.). BVA (0.25, 1, and 2.5 mg/kg, s.c., ST36) or morphine (0.5, 2, and 5 mg/kg, i.p.) alone showed dose-dependent anti-allodynic effects. The combination of BVA and morphine at intermediate doses showed a greater and longer effect than either BVA or morphine alone at the highest dose. Intrathecal pretreatment with the opioidergic (naloxone, 20 μg) or 5-HT3 (MDL-72222, 15 μg) receptor antagonist, but not with α2-adrenergic (idazoxan, 10 μg) receptor antagonist, blocked this additive effect. Therefore, we suggest that the combination effect of BVA and morphine is mediated by spinal opioidergic and 5-HT3 receptors and this combination has a robust and enduring analgesic action against oxaliplatin-induced neuropathic pain. PMID:26805884

  13. Clinical curative effect of oxaliplatin combined with flurouracil in the treatment of gastrointestinal tumor.

    PubMed

    Li, Baodong; Liu, Yonggang; Wang, Jinbang; Xu, Dongli; Feng, Weiyu; Zhuang, Jing

    2015-05-01

    Aiming at exploring clinical curative effect of oxaliplatin combined with flurouracil in the treatment of gastrointestinal tumor, this study divided 60 patients with gastrointestinal tumor into control and observation groups, each containing 30 patients. The observation group was treated with oxaliplatin combined with flurouracil, while the control was treated with FOLFOX4, i.e., intravenously dropping 85mg/m(2)Oxaliplatin (L-OHP), 200mg/m(2) calcium folinate (CF) and intravenously injecting 400mg/m(2) 5-fluorouracil (5-Fu), and 600mg/m(2) 5-Fu; then continuously performing intravenous drop infusion for 22h, every two weeks for a cycle. Hypodermic injection of granulocyte colony-stimulating factor (G-CSF) was conducted immediately when leukocytes occurred the III, IV degree of inhibition. The observation results of curative effect and negative reaction indicated higher effective rate with 83.33% in the observation and 50.00% in the control. Besides, in the observation, negative reactions possessed 10.00% that was much lower than 33.33% in the control. Thereby, the conclusion reached that the treatment of gastrointestinal tumor with oxaliplatin combined with flurouracil was worth promoting. PMID:26051738

  14. Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice.

    PubMed

    Kim, Woojin; Kim, Min Joon; Go, Donghyun; Min, Byung-Il; Na, Heung Sik; Kim, Sun Kwang

    2016-02-01

    Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA) has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat different types of pain. Here, we investigated whether treatment with a combination of these two agents has an additive effect on oxaliplatin-induced neuropathic pain in mice. To assess cold and mechanical allodynia, acetone and von Frey filament tests were used, respectively. Significant allodynia signs were observed three days after an oxaliplatin injection (6 mg/kg, i.p.). BVA (0.25, 1, and 2.5 mg/kg, s.c., ST36) or morphine (0.5, 2, and 5 mg/kg, i.p.) alone showed dose-dependent anti-allodynic effects. The combination of BVA and morphine at intermediate doses showed a greater and longer effect than either BVA or morphine alone at the highest dose. Intrathecal pretreatment with the opioidergic (naloxone, 20 μg) or 5-HT3 (MDL-72222, 15 μg) receptor antagonist, but not with α2 adrenergic (idazoxan, 10 μg) receptor antagonist, blocked this additive effect. Therefore, we suggest that the combination effect of BVA and morphine is mediated by spinal opioidergic and 5-HT3 receptors and this combination has a robust and enduring analgesic action against oxaliplatin-induced neuropathic pain. PMID:26805884

  15. Population pharmacokinetic analysis of oxaliplatin in adults and children identifies important covariates for dosing

    PubMed Central

    Nikanjam, Mina; Stewart, Clinton F.; Takimoto, Chris H.; Synold, Timothy W.; Beaty, Orren; Fouladi, Maryam; Capparelli, Edmund V.

    2015-01-01

    Purpose To characterize the determinants of variability for oxaliplatin pharmacokinetics including age, renal function, and hepatic function in children and adults. Methods Oxaliplatin pharmacokinetic data were combined from phase I and II clinical trials: 3 pediatric trials (Peds1–3) and 2 adult NCI organ dysfunction studies (Hepatic, Renal). A population pharmacokinetic model was developed utilizing platinum ultrafiltrate concentrations to characterize changes in oxaliplatin disposition with age and organ dysfunction along with other potential sources of oxaliplatin pharmacokinetic variability. Results A total of 1508 concentrations from 186 children and adults were used in the study. The data were well described by a three-compartment model. Serum creatinine was an independent predictor of clearance while age was an independent predictor of volume of distribution. While age was a significant covariate on clearance in the univariate analysis, age effects on clearance were entirely accounted for by serum creatinine. Gender, hepatic function, and race had no effect on clearance or volume of distribution. Median clearance values were 0.58 (Hepatic), 0.34 (Renal), 0.78 (Peds1), 0.74 (Peds2), and 0.81 (Peds3) (L/hr/kg0.75). Monte Carlo simulations of the final model with 130 mg/m2 yielded median AUC values of: 14.2 (2–6 yr), 16.8 (6–12 yr), 16.5 (12–18 yr), and 17.3 (>18 yr) (μg*hr/mL). Conclusions Renal function had the greatest effect on clearance with a small age effect seen on the distribution of oxaliplatin. Young pediatric patients had higher clearance values than adults as a result of better renal function. PMID:25557868

  16. [Case report of advanced breast cancer responding to capecitabine and trastuzumab combination therapy].

    PubMed

    Yoshidome, Katsuhide; Imabun, Shigeru; Nakahara, Masaaki; Hiraoka, Kazuya; Yamagami, Yuko; Tsujimoto, Masahiko; Nakao, Kazuyasu

    2006-10-01

    We conducted a concomitant administration of capecitabine (2,400 mg/day for 21 days followed by a 7-day interval) and trastuzumab (2 mg/kg weekly) to a 73-year-old female patient with impaired lower limb function diagnosed with bilateral breast cancer. The patient had a complete response (CR) to pulmonary metastases, and carcinoembryonic antigen (CEA) level had normalized from 46.4 ng/ml to 0.6 ng/ml. Left mastectomy was performed in order to control bleeding from tumors. No adverse events attributable to medication were observed. The concomitant administration of capecitabine and trastuzumab is a promising therapy with the potential to greatly improve patient quality of life (QOL). PMID:17033236

  17. Update on capecitabine alone and in combination regimens in colorectal cancer patients.

    PubMed

    Silvestris, N; Maiello, E; De Vita, F; Cinieri, S; Santini, D; Russo, A; Tommasi, S; Azzariti, A; Numico, G; Pisconti, S; Petriella, D; Lorusso, V; Millaku, A; Colucci, G

    2010-11-01

    Capecitabine is an orally administered fluoropyrimidine carbamate which has been developed as a prodrug of 5-FU with the goal to improve its tolerability and intratumoral drug concentration. The review aims to provide an evidence-based update of clinical trials investigating the clinical efficacy, adverse-event profile, dosage and administration of this drug, alone or in combination with conventional chemotherapeutics and/or new target-oriented drugs, in the management of colorectal cancer patients. PMID:21129610

  18. Preoperative Radiation Therapy With Concurrent Capecitabine, Bevacizumab, and Erlotinib for Rectal Cancer: A Phase 1 Trial

    SciTech Connect

    Das, Prajnan; Eng, Cathy; Rodriguez-Bigas, Miguel A.; Chang, George J.; Skibber, John M.; You, Y. Nancy; Maru, Dipen M.; Munsell, Mark F.; Clemons, Marilyn V.; Kopetz, Scott E.; Garrett, Christopher R.; Shureiqi, Imad; Delclos, Marc E.; Krishnan, Sunil; Crane, Christopher H.

    2014-02-01

    Purpose: The goal of this phase 1 trial was to determine the maximum tolerated dose (MTD) of concurrent capecitabine, bevacizumab, and erlotinib with preoperative radiation therapy for rectal cancer. Methods and Materials: Patients with clinical stage II to III rectal adenocarcinoma, within 12 cm from the anal verge, were treated in 4 escalating dose levels, using the continual reassessment method. Patients received preoperative radiation therapy with concurrent bevacizumab (5 mg/kg intravenously every 2 weeks), erlotinib, and capecitabine. Capecitabine dose was increased from 650 mg/m{sup 2} to 825 mg/m{sup 2} orally twice daily on the days of radiation therapy; erlotinib dose was increased from 50 mg orally daily in weeks 1 to 3, to 50 mg daily in weeks 1 to 6, to 100 mg daily in weeks 1 to 6. Patients underwent surgery at least 9 weeks after the last dose of bevacizumab. Results: A total of 19 patients were enrolled, and 18 patients were considered evaluable. No patient had grade 4 acute toxicity, and 1 patient had grade 3 acute toxicity (hypertension). The MTD was not reached. All 18 evaluable patients underwent surgery, with low anterior resection in 7 (39%), proctectomy with coloanal anastomosis in 4 patients (22%), posterior pelvic exenteration in 1 (6%), and abdominoperineal resection in 6 (33%). Of the 18 patients, 8 (44%) had pathologic complete response, and 1 had complete response of the primary tumor with positive nodes. Three patients (17%) had grade 3 postoperative complications (ileus, small bowel obstruction, and infection). With a median follow-up of 34 months, 1 patient developed distant metastasis, and no patient had local recurrence or died. The 3-year disease-free survival was 94%. Conclusions: The combination of preoperative radiation therapy with concurrent capecitabine, bevacizumab, and erlotinib was well tolerated. The pathologic complete response rate appears promising and may warrant further investigation.

  19. Predictive markers of capecitabine sensitivity identified from the expression profile of pyrimidine nucleoside-metabolizing enzymes.

    PubMed

    Yasuno, Hideyuki; Kurasawa, Mitsue; Yanagisawa, Mieko; Sato, Yasuko; Harada, Naoki; Mori, Kazushige

    2013-02-01

    Molecular markers predicting sensitivity to anticancer drugs are important and useful not only for selecting potential responders but also for developing new combinations. In the present study, we analyzed the difference in the sensitivity of xenograft models to capecitabine (Xeloda®), 5'-deoxy-5-fluorouridine (5'-DFUR, doxifluridine, Furtulon®) and 5-FU by comparing the mRNA levels of 12 pyrimidine nucleoside-metabolizing enzymes. Amounts of mRNA in the tumor tissues of 80 xenograft models were determined by real-time RT-PCR and mutual correlations were examined. A clustering analysis revealed that the 12 enzymes were divided into two groups; one group consisted of 8 enzymes, including orotate phosphoribosyl transferase (OPRT), TMP kinase (TMPK) and UMP kinase (UMPK), and was related to the de novo synthesis pathway for nucleotides, with mRNA expression levels showing significant mutual correlation. In the other group, 4 enzymes, including thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD), were involved in the salvage/degradation pathway of the nucleotides, and the mRNA levels of this group were dispersed more widely than that of the de novo group. Antitumor activity was assessed in 24 xenograft models for each drug. The antitumor activity of capecitabine and 5'-DFUR correlated significantly with the mRNA levels of TP and with the TP/DPD ratio, whereas the activity of 5-FU correlated significantly with OPRT, TMPK, UMPK and CD. In a stepwise regression analysis, TP and DPD were found to be independent predictive factors of sensitivity to capecitabine and 5'-DFUR, and UMPK was predictive of sensitivity to 5-FU. These results indicate that the predictive factors for sensitivity to capecitabine and 5'-DFUR in xenograft models may be different from those for 5-FU, suggesting that these drugs may have different responders in clinical usage. PMID:23229803

  20. Metronomic Capecitabine in Advanced Hepatocellular Carcinoma Patients: A Phase II Study

    PubMed Central

    de Rosa, Francesco; Agostini, Valentina; di Girolamo, Stefania; Andreone, Pietro; Bolondi, Luigi; Serra, Carla; Sama, Claudia; Golfieri, Rita; Gramenzi, Annagiulia; Cucchetti, Alessandro; Pinna, Antonio Daniele; Trevisani, Franco; Biasco, Guido

    2013-01-01

    Background. Anti-angiogenic treatment with targeted agents is effective in advanced hepatocellular carcinoma (HCC). This trial evaluated the safety and efficacy of metronomic capecitabine in patients with HCC. Methods. This single-institution phase II trial included 59 previously untreated patients with advanced HCC and 31 patients resistant to or intolerant of sorafenib. The treatment schedule was capecitabine 500 mg twice daily until progression of disease, unacceptable toxicity level, or withdrawal of informed consent. Progression-free survival (PFS) was chosen as the primary endpoint. Results. A total of 59 previously untreated and 31 previously treated patients with HCC were enrolled. The first cohort achieved a median PFS of 6.03 months and an overall survival (OS) of 14.47 months. Two patients achieved a complete response, 1 patient achieved partial response, and in 30 patients, stable disease was the best outcome. The second cohort achieved a median PFS of 3.27 months and a median OS of 9.77 months. No complete or partial responses were observed, but 10 patients had stable disease. An unscheduled comparison of the first cohort of patients with 3,027 untreated patients with HCC from the Italian Liver Cancer (ITA.LI.CA) database was performed. One-to-one matching according to demographic/etiologic/oncologic features was possible for 50 patients. The median OS for these 50 capecitabine-treated patients was 15.6 months, compared with a median OS of 8.0 months for the matched untreated patients (p = .043). Conclusion. Metronomic capecitabine is well tolerated by patients with advanced HCC and appears to have activity both in treatment-naive patients and in those previously treated with sorafenib. PMID:24232581

  1. Short-Time Structural Stability of Compressible Vortex Sheets with Surface Tension

    NASA Astrophysics Data System (ADS)

    Stevens, Ben

    2016-06-01

    Assume we start with an initial vortex-sheet configuration which consists of two inviscid fluids with density bounded below flowing smoothly past each other, where a strictly positive fixed coefficient of surface tension produces a surface tension force across the common interface, balanced by the pressure jump. We model the fluids by the compressible Euler equations in three space dimensions with a very general equation of state relating the pressure, entropy and density such that the sound speed is positive. We prove that, for a short time, there exists a unique solution of the equations with the same structure. The mathematical approach consists of introducing a carefully chosen artificial viscosity-type regularisation which allows one to linearise the system so as to obtain a collection of transport equations for the entropy, pressure and curl together with a parabolic-type equation for the velocity which becomes fairly standard after rotating the velocity according to the interface normal. We prove a high order energy estimate for the non-linear equations that is independent of the artificial viscosity parameter which allows us to send it to zero. This approach loosely follows that introduced by Shkoller et al. in the setting of a compressible liquid-vacuum interface.

  2. [Functional status of submariners after short-time submarine raid in the sea].

    PubMed

    Kalmanov, A S; Pisarev, A A; Khankevich, Yu R; Bloshchinskii, I A; Valskii, A V

    2015-10-01

    Short-time sea submarine raids (from a few days to a few weeks), performed during one working cycle, negatively influence on the functional state of the submariners organism. Upon returning to the point of basing the crew involved in the maintenance of the material and performs preparations for further access to the sea. Due to the high workload and lack of time personnel are not held in any correctional and rehabilitation activities, and therefore the time for the next release in the sea functional condition and functional reserves of the body does not have time to fully recover. The transfer of the submarine crew and referral to medical and psychological rehabilitation assumed only after the end of the operating cycle after the crew the task of further voyage. Based on the assessment of the functional systems of the submarine after a short voyage concluded on the need to develop a set of remedial measures for the recovery of submarine crews during inter-cruise period. PMID:26827506

  3. The influence of alcoholic intoxication on the short-time energy function of speech.

    PubMed

    Heinrich, Christian; Schiel, Florian

    2014-05-01

    This study investigates rhythmic features based on the short-time energy function of speech signals with the aim of finding robust, speaker-independent features that indicate speaker intoxication. Data from the German Alcohol Language Corpus, which comprises read, spontaneous, and command&control speech uttered by 162 speakers of both genders and various age groups when sober and intoxicated, were analyzed. Energy contours are compared directly (Root Mean Squared Error, statistical correlation, or the Euclidean distance in the spectral space of the contour) and by parameterization of the contour using the Discrete Cosine Transform (DCT) and the first and second moments of the lower DCT spectrum. Contours are also analyzed by Principal Components Analysis aiming at fundamental "eigen contour" changes that might encode intoxication. Energy contours differ significantly with intoxication in terms of distance measures, the second and fourth DCT coefficients, and the first and second moments of the lower DCT spectrum. Principal Components Analysis did not yield interpretable "eigen contours" that could be used in distinguishing intoxicated from sober contours. PMID:24815274

  4. Qualitative Features Extraction from Sensor Data using Short-time Fourier Transform

    NASA Technical Reports Server (NTRS)

    Amini, Abolfazl M.; Figueroa, Fernando

    2004-01-01

    The information gathered from sensors is used to determine the health of a sensor. Once a normal mode of operation is established any deviation from the normal behavior indicates a change. This change may be due to a malfunction of the sensor(s) or the system (or process). The step-up and step-down features, as well as sensor disturbances are assumed to be exponential. An RC network is used to model the main process, which is defined by a step-up (charging), drift, and step-down (discharging). The sensor disturbances and spike are added while the system is in drift. The system runs for a period of at least three time-constants of the main process every time a process feature occurs (e.g. step change). The Short-Time Fourier Transform of the Signal is taken using the Hamming window. Three window widths are used. The DC value is removed from the windowed data prior to taking the FFT. The resulting three dimensional spectral plots provide good time frequency resolution. The results indicate distinct shapes corresponding to each process.

  5. Zipf's Law in Short-Time Timbral Codings of Speech, Music, and Environmental Sound Signals

    PubMed Central

    Haro, Martín; Serrà, Joan; Herrera, Perfecto; Corral, Álvaro

    2012-01-01

    Timbre is a key perceptual feature that allows discrimination between different sounds. Timbral sensations are highly dependent on the temporal evolution of the power spectrum of an audio signal. In order to quantitatively characterize such sensations, the shape of the power spectrum has to be encoded in a way that preserves certain physical and perceptual properties. Therefore, it is common practice to encode short-time power spectra using psychoacoustical frequency scales. In this paper, we study and characterize the statistical properties of such encodings, here called timbral code-words. In particular, we report on rank-frequency distributions of timbral code-words extracted from 740 hours of audio coming from disparate sources such as speech, music, and environmental sounds. Analogously to text corpora, we find a heavy-tailed Zipfian distribution with exponent close to one. Importantly, this distribution is found independently of different encoding decisions and regardless of the audio source. Further analysis on the intrinsic characteristics of most and least frequent code-words reveals that the most frequent code-words tend to have a more homogeneous structure. We also find that speech and music databases have specific, distinctive code-words while, in the case of the environmental sounds, this database-specific code-words are not present. Finally, we find that a Yule-Simon process with memory provides a reasonable quantitative approximation for our data, suggesting the existence of a common simple generative mechanism for all considered sound sources. PMID:22479497

  6. Spatial convergent cross mapping to detect causal relationships from short time series.

    PubMed

    Clark, Thomas; Ye, Hao; Isbell, Forest; Deyle, Ethan R; Cowles, Jane; Tilman, G David; Sugihara, George

    2015-05-01

    Recent developments in complex systems analysis have led to new techniques for detecting causal relationships using relatively short time series, on the order of 30 sequential observations. Although many ecological observation series are even shorter, perhaps fewer than ten sequential observations, these shorter time series are often highly replicated in space (i.e., plot replication). Here, we combine the existing techniques of convergent cross mapping (CCM) and dewdrop regression to build a novel test of causal relations that leverages spatial replication, which we call multispatial CCM. Using examples from simulated and real-world ecological data, we test the ability of multispatial CCM to detect causal relationships between processes. We find that multispatial CCM successfully detects causal relationships with as few as five sequential observations, even in the presence of process noise and observation error. Our results suggest that this technique may constitute a useful test for causality in systems where experiments are difficult to perform and long time series are not available. This new technique is available in the multispatialCCM package for the R programming language. PMID:26236832

  7. Applying Short-Time Fourier Transform on Groundwater Fluctuation for the Estimation of Regional Groundwater Pumping

    NASA Astrophysics Data System (ADS)

    Chen, Y. W.; Yu, C. H.; Wang, Y.; Chang, L. C.; Chen, Y. C.

    2015-12-01

    For sustainable management of groundwater resource, precise records of regional groundwater pumping is crucial. However, the fact that number of private pumping wells is too huge makes obtaining precise pumping records of each wells become difficult. Because the most significant response of pumping is drawdown and the influence radius of pumping might over several hundred meters, a network of observation wells can be used to sense the regional pumping. Groundwater fluctuations are the synthetic effect of different physical mechanisms include pumping, recharge, tidal effect and others and an analysis of short-time Fourier transform is applied to identified the temporal effects of each mechanisms. Because pumping is a kind of human activity and the most significant frequency of human activity is daily, the temporal amplitude with daily frequency (TADF) is the response of regional pumping in the neighborhood of the observation well and TADF can be a linear indicator of regional groundwater pumping. The proposed method was applied in the Pingtung Plain and the horizontal of analysis period is from 2008 to 2011. The TADF of each observation well can reflect the temporal variation of regional groundwater pumping around the observation well. For the well in coast area, the shape of TADF looks like a sinusoid line with a half year cycle and the peaks of large pumping respectively are during January and July. The peaks of large pumping are mainly caused by fish farms.

  8. Evaluation of high-temperature and short-time sterilization of injection ampules by microwave heating.

    PubMed

    Sasaki, K; Honda, W; Miyake, Y

    1998-01-01

    The high-temperature and short-time sterilization by microwave heating with a continuous microwave sterilizer (MWS) was evaluated. The evaluation were performed with respect to: [1] lethal effect against microorganisms corresponding to F-value, and [2] reliability of MWS sterilization process. Bacillus stearothermophilus ATCC 7953 spores were used as the biological indicator and the heat-resistance of spores was evaluated with conventional heating method (121-129 degrees C). In MWS sterilization (125-135 degrees C), the actual lethal effect against B. stearothermophilus spores was almost in agreement with the F-value and the survival curve against the F-value was quite consistent with that for the autoclave. These results suggest that the actual lethal effect could be estimated by the F-value with heat-resistance parameters of spores from lower than actual temperatures and that there was no nonthermal effect of the microwave on B. stearothermophilus spores. The reliability of sterilization with the MWS was confirmed using more than 25,000 test ampules containing biological indicators. All biological indicators were killed, thus the present study shows that the MWS was completely reliable for all ampules. PMID:9542408

  9. Generalization of Clausius-Mossotti approximation in application to short-time transport properties of suspensions

    NASA Astrophysics Data System (ADS)

    Makuch, Karol

    2015-10-01

    In 1983, Felderhof, Ford, and Cohen gave microscopic explanation of the famous Clausius-Mossotti formula for the dielectric constant of nonpolar dielectric. They based their considerations on the cluster expansion of the dielectric constant, which relates this macroscopic property with the microscopic characteristics of the system. In this article, we analyze the cluster expansion of Felderhof, Ford, and Cohen by performing its resummation (renormalization). Our analysis leads to the ring expansion for the macroscopic characteristic of the system, which is an expression alternative to the cluster expansion. Using similarity of structures of the cluster expansion and the ring expansion, we generalize (renormalize) the Clausius-Mossotti approximation. We apply our renormalized Clausius-Mossotti approximation to the case of the short-time transport properties of suspensions, calculating the effective viscosity and the hydrodynamic function with the translational self-diffusion and the collective diffusion coefficient. We perform calculations for monodisperse hard-sphere suspensions in equilibrium with volume fraction up to 45 % . To assess the renormalized Clausius-Mossotti approximation, it is compared with numerical simulations and the Beenakker-Mazur method. The results of our renormalized Clausius-Mossotti approximation lead to comparable or much less error (with respect to the numerical simulations) than the Beenakker-Mazur method for the volume fractions below ϕ ≈30 % (apart from a small range of wave vectors in hydrodynamic function). For volume fractions above ϕ ≈30 % , the Beenakker-Mazur method gives in most cases lower error than the renormalized Clausius-Mossotti approximation.

  10. Laser-induced short time scale thermal chemistry of perfluoropolyether lubricant films

    SciTech Connect

    Heller, J.; Mate, C.J.; Poon, C.C.; Tam, A.C.

    1999-11-09

    The authors investigate the effect of heating a perfluoropolyether lubricant film in a localized area for relatively short time periods using laser irradiation versus conventional oven heating. These experiments help provide understanding on how flash temperatures generated at frictional contacts affect the thermal chemistry of lubricant films. In these experiments, a CO{sub 2} laser heats a 50 {micro}m wide area of a silicon wafer for time periods ranging from 0.1 to 60 s. The surface temperature within the heated area (up to 280 C in these experiments) is monitored with a second laser by measuring the change in reflectivity near the center of the heated area. A major difference observed for laser heating compared to oven heating is that the effective evaporation rate is orders of magnitude higher for laser heating. If the lubricant film is heated for sufficiently long enough time at high temperatures, the authors are able to observe thermal bonding of the lubricant via its alcohol end groups to the silicon oxide surface, followed by thermal decomposition of the lubricant molecules. After laser heating, the authors are able to observe the diffusion of lubricant back into the localized heated area using a combination of optical microscopy and imaging ellipsometry.