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Sample records for short-time oxaliplatin capecitabine

  1. A randomized study comparing short-time infusion of oxaliplatin in combination with capecitabine XELOX(30) and chronomodulated XELOX(30) as first-line therapy in patients with advanced colorectal cancer.

    PubMed

    Qvortrup, C; Jensen, B V; Fokstuen, T; Nielsen, S E; Keldsen, N; Glimelius, B; Bjerregaard, B; Mejer, J; Larsen, F O; Pfeiffer, P

    2010-01-01

    Chronotherapy is one of the several approaches to increase efficacy and reduce toxicity of chemotherapy. In a phase II study in the second-line in patients with metastatic colorectal cancer (mCRC), we found that chronomodulated XELOX (XELOX(30Chron)) was a well-tolerated regimen with potentially reduced toxicity. One hundred and forty-one patients with unresectable mCRC were enrolled in a randomized study comparing standard XELOX (XELOX(30)), arm A, and XELOX(30Chron), arm B-both with short-time infusion of oxaliplatin-with the primary aim of reducing overall toxicity. Overall toxicity grade 2-4 was 90% versus 85%, P = 0.47 and grade 3-4 was 31% versus 37%, P = 0.6 in arm A and B, respectively. We found no significant differences in median overall survival (17.6 versus 15.5 months; P = 0.068) and median progression-free survival (8.9 versus 8.8 months; P = 0.7). The incidence of grade 3 neuropathy was 16% in arm A and 19% in arm B (P = 0.7) after a cumulative dose of oxaliplatin of 1000 mg/m(2). XELOX(30Chron) does not reduce toxicity or improve efficacy. A 30-min infusion of oxaliplatin is safe and does not increase the severity of chronic neuropathy.

  2. Phase I study of sunitinib plus capecitabine/cisplatin or capecitabine/oxaliplatin in advanced gastric cancer.

    PubMed

    Lee, K-W; Park, S R; Oh, D-Y; Park, Y-I; Khosravan, R; Lin, X; Lee, S-Y; Roh, E-J; Valota, O; Lechuga, M J; Bang, Y-J

    2013-12-01

    We evaluated the maximum tolerated dose (MTD) and safety of sunitinib plus capecitabine/cisplatin (XP) or capecitabine/oxaliplatin (XELOX) in Korean patients with advanced gastric cancer (GC). Sunitinib (37.5 or 25 mg/day) was administered on a 2-week-on/1-week-off schedule with chemotherapy. Assessments included dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity. Twenty-eight patients received sunitinib/XP; 48 received sunitinib/XELOX. The MTDs were: sunitinib 25 mg/day, cisplatin 80 mg/m(2), and capecitabine 1,000 mg/m(2); sunitinib 37.5 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 800 mg/m(2); and sunitinib 25 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 1,000 mg/m(2). DLTs at the MTDs comprised grade (G) 4 febrile neutropenia plus G3 diarrhea (n = 1; sunitinib/XP), dose delays due to hematologic toxicity (n = 2; both sunitinib/XP), G3 bleeding (menorrhagia; n = 1; sunitinib/XELOX), and G3 increased alanine aminotransferase levels (n = 1; sunitinib/XELOX). There was a high frequency of G3/4 hematologic adverse events observed with both treatment regimens, particularly with sunitinib/XP. Frequent non-hematologic, G3/4 adverse events were nausea, stomatitis, and hypophosphatemia with sunitinib/XP and hypophosphatemia and pulmonary embolism with sunitinib/XELOX. No drug-drug interactions were apparent. At the MTDs, median progression-free survival was 6.4 months and 5.5-8.0 months for sunitinib/XP and sunitinib/XELOX, respectively; and the objective response rate was 46.7% and 43.5-45.5% for sunitinib/XP and sunitinib/XELOX, respectively. At the MTD, sunitinib/XELOX had an acceptable safety profile in patients with advanced GC.

  3. Phase I Study of Capecitabine, Oxaliplatin, Bevacizumab, and Everolimus in Advanced Solid Tumors

    PubMed Central

    Rangwala, F.; Bendell, J.; Kozloff, M.; Arrowood, C.; Dellinger, A.; Meadows, J.; Tourt-Uhlig, S.; Murphy, J.; Meadows, K.L.; Starr, A.; Broderick, S.; Brady, J.C.; Cushman, S. M.; Morse, M.; Uronis, H.; Hsu, S.D.; Zafar, S.Y.; Wallace, J.; Starodub, A.; Strickler, J.; Pang, H.; Nixon, A.B.; Hurwitz, H.

    2014-01-01

    Purpose To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients. Design This was a standard “3+3” dose-escalation trial. All subjects received bevacizumab 7.5mg/kg on day one of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms. Results Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; eight of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival. Conclusions Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5mg daily; capecitabine 680mg/m2 BID days 1-14; oxaliplatin 100mg/m2 and bevacizumab 7.5mg/kg, day one. Activity was noted in mCRC. PMID:24711126

  4. 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

  5. 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.

  6. 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.

  7. [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.

  8. Colon carcinoma treated with oxaliplatin and capecitabine in a 12-year-old child.

    PubMed

    Hu, Dong-Lai; Guo, Xiao-Dong; Sun, Zhi-Nan; Zhao, Yan-Min

    2014-02-01

    XELOX (oxaliplatin 130 mg/m(2) iv, capecitabine 1000 mg/m(2) bid oral d1-14, q3w) chemotherapy has never been used in children. In this report, we present a case of a 12-year-old girl with colon adenocarcinoma, treated with surgery and XELOX chemotherapy. On admission, the girl complained of abdominal pain and intestinal obstruction. Physical examination revealed a distended abdomen with tenderness on the left upper quadrant. Barium enema revealed a stenotic lesion at the distal end of the transverse colon, and abdominal computed tomography showed acute obstruction and a colonic mass. Laparotomy was performed after the failure of conservative treatment. The mass was originated from the transverse colon. Frozen sections of the specimens revealed an adenocarcinoma. Transverse colectomy was performed and regional lymph nodes were removed. Pathological examination confirmed that the mass was a poorly differentiated adenocarcinoma, and XELOX chemotherapy was used. No evidence of recurrent or metastatic tumor was found after 18 months. Although complete resection is the most effective treatment, XELOX chemotherapy is beneficial to the improvement of clinical outcome of patients with colon adenocarcinoma.

  9. 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.

  10. Capecitabine

    MedlinePlus

    ... alone to treat breast cancer that has not improved after treatment with other medications. Capecitabine is also ... breakfast and dinner) and with a glass of water. Your doctor will decide how many times you ...

  11. Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer

    PubMed Central

    Koeberle, D; Burkhard, R; von Moos, R; Winterhalder, R; Hess, V; Heitzmann, F; Ruhstaller, T; Terraciano, L; Neuweiler, J; Bieri, G; Rust, C; Toepfer, M

    2008-01-01

    This multicentre phase II study evaluated the efficacy and safety of preoperative capecitabine plus oxaliplatin and radiotherapy (RT) in patients with locally advanced rectal cancer (T3/T4 rectal adenocarcinoma with or without nodal involvement). Treatment consisted of one cycle of XELOX (capecitabine 1000 mg m−2 bid on days 1–14 and oxaliplatin 130 mg m−2 on day 1), followed by RT (1.8 Gy fractions 5 days per week for 5 weeks) plus CAPOX (capecitabine 825 mg m−2 bid on days 22–35 and 43–56, and oxaliplatin 50 mg m−2 on days 22, 29, 43 and 50). Surgery was recommended 5 weeks after completion of chemoradiotherapy. The primary end point was pathological complete tumour response (pCR). Sixty patients were enrolled. In the intent-to-treat population, the pCR rate was 23% (95% CI: 13–36%). 58 patients underwent surgery; R0 resection was achieved in 57 (98%) patients, including all 5 patients with T4 tumours. Sphincter preservation was achieved in 49 (84%) patients. Tumour and/or nodal downstaging was observed in 39 (65%) patients. The most common grade 3/4 adverse events were diarrhoea (20%) and lymphocytopaenia (43%). Preoperative capecitabine, oxaliplatin and RT achieved encouraging rates of pCR, R0 resection, sphincter preservation and tumour downstaging in patients with locally advanced rectal cancer. PMID:18349837

  12. Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer.

    PubMed

    Koeberle, D; Burkhard, R; von Moos, R; Winterhalder, R; Hess, V; Heitzmann, F; Ruhstaller, T; Terraciano, L; Neuweiler, J; Bieri, G; Rust, C; Toepfer, M

    2008-04-08

    This multicentre phase II study evaluated the efficacy and safety of preoperative capecitabine plus oxaliplatin and radiotherapy (RT) in patients with locally advanced rectal cancer (T3/T4 rectal adenocarcinoma with or without nodal involvement). Treatment consisted of one cycle of XELOX (capecitabine 1000 mg m(-2) bid on days 1-14 and oxaliplatin 130 mg m(-2) on day 1), followed by RT (1.8 Gy fractions 5 days per week for 5 weeks) plus CAPOX (capecitabine 825 mg m(-2) bid on days 22-35 and 43-56, and oxaliplatin 50 mg m(-2) on days 22, 29, 43 and 50). Surgery was recommended 5 weeks after completion of chemoradiotherapy. The primary end point was pathological complete tumour response (pCR). Sixty patients were enrolled. In the intent-to-treat population, the pCR rate was 23% (95% CI: 13-36%). 58 patients underwent surgery; R0 resection was achieved in 57 (98%) patients, including all 5 patients with T4 tumours. Sphincter preservation was achieved in 49 (84%) patients. Tumour and/or nodal downstaging was observed in 39 (65%) patients. The most common grade 3/4 adverse events were diarrhoea (20%) and lymphocytopaenia (43%). Preoperative capecitabine, oxaliplatin and RT achieved encouraging rates of pCR, R0 resection, sphincter preservation and tumour downstaging in patients with locally advanced rectal cancer.

  13. Evaluation of Outcome and Tolerability of Combination Chemotherapy with Capecitabine and Oxaliplatin as First Line Therapy in Advanced Gastric Cancer

    PubMed Central

    Mashhadi, Mohammad Ali; Sepehri, Zahra; Bakhshipour, Ali Reza; Zivari, Ali; Danesh, Hossein Ali; Metanat, Hasan Ali; Karimkoshteh, Azra; Hashemi, Seyed Mehdi; Rahimi, Hossein; Kiani, Zohre

    2016-01-01

    Background: Combination chemotherapy is accepted as a high efficacy treatment for gastric cancer, whereas choice of standard treatment is unclear. Multiple chemotherapeutic regimens have been used to achieve higher efficacy and lower toxicity. This study was designed to evaluate the treatment results of advanced gastric cancer with Capecitabine and Oxaliplatin regimen. Subjects and Methods : All cases with documented gastric adenocarcinoma and advanced disease were candidates for receiving Xelox regimen (Capecitabine – 750 mg/m2/twice daily/ 1-14 days and Oxaliplatin 125 mg/m2 in 1st day). Results: Twenty five cases with advanced gastric cancer entered in study while 24 cases continued treatment protocol and were evaluated. Mean age was 59.5 ± 12.1 years (range: 20-75), male and female cases were 66.7% and 33.3%, respectively. All cases received at least four cycles of Xelox regimen. Overall response rate was 74.99% with 29.16% complete response. Overall survival rate was 13 ± 0.53 months and DFS (disease-free survival) was 6 ± 1.09 months. Extremities neuropathy (62.5%), headache (45.8%) and muscle cramps (29.2%) were the most common complains. Haematological changes were rare and 16.7% of cases had mild cytopenia. Treatment related death was not observed. Conclusion: Xelox regimen is a safe and highly effective first line treatment for gastric cancer; however, considering it as first line therapy needs larger studies. PMID:27928475

  14. Evaluation of Outcome and Tolerability of Combination Chemotherapy with Capecitabine and Oxaliplatin as First Line Therapy in Advanced Gastric Cancer.

    PubMed

    Mashhadi, Mohammad Ali; Sepehri, Zahra; Bakhshipour, Ali Reza; Zivari, Ali; Danesh, Hossein Ali; Metanat, Hasan Ali; Karimkoshteh, Azra; Hashemi, Seyed Mehdi; Rahimi, Hossein; Kiani, Zohre

    2016-10-01

    Background: Combination chemotherapy is accepted as a high efficacy treatment for gastric cancer, whereas choice of standard treatment is unclear. Multiple chemotherapeutic regimens have been used to achieve higher efficacy and lower toxicity. This study was designed to evaluate the treatment results of advanced gastric cancer with Capecitabine and Oxaliplatin regimen. Subjects and Methods: All cases with documented gastric adenocarcinoma and advanced disease were candidates for receiving Xelox regimen (Capecitabine - 750 mg/m(2)/twice daily/ 1-14 days and Oxaliplatin 125 mg/m(2) in 1st day). Results: Twenty five cases with advanced gastric cancer entered in study while 24 cases continued treatment protocol and were evaluated. Mean age was 59.5 ± 12.1 years (range: 20-75), male and female cases were 66.7% and 33.3%, respectively. All cases received at least four cycles of Xelox regimen. Overall response rate was 74.99% with 29.16% complete response. Overall survival rate was 13 ± 0.53 months and DFS (disease-free survival) was 6 ± 1.09 months. Extremities neuropathy (62.5%), headache (45.8%) and muscle cramps (29.2%) were the most common complains. Haematological changes were rare and 16.7% of cases had mild cytopenia. Treatment related death was not observed. Conclusion: Xelox regimen is a safe and highly effective first line treatment for gastric cancer; however, considering it as first line therapy needs larger studies.

  15. First-line bevacizumab and capecitabine-oxaliplatin in elderly patients with mCRC: GEMCAD phase II BECOX study.

    PubMed

    Feliu, J; Salud, A; Safont, M J; García-Girón, C; Aparicio, J; Vera, R; Serra, O; Casado, E; Jorge, M; Escudero, P; Bosch, C; Bohn, U; Pérez-Carrión, R; Carmona, A; Martínez-Marín, V; Maurel, J

    2014-07-15

    Subgroup analyses of clinical studies suggest that bevacizumab plus XELOX is effective and tolerable in elderly patients with metastatic colorectal cancer (mCRC). The prospective BECOX study examined the efficacy and safety of bevacizumab plus XELOX, followed by bevacizumab plus capecitabine in elderly patients with mCRC. Patients aged ⩾70 years with Eastern Cooperative Oncology Group performance status 0 out of 1 and confirmed mCRC were included. Patients received bevacizumab 7.5 mg kg(-1) and oxaliplatin 130 mg m(-2) on day 1, plus capecitabine 1000 mg m(-2) bid orally on days 1-14 every 21 days; oxaliplatin was discontinued after 6 cycles. The primary end point was time to progression (TTP). The intent-to-treat population comprised 68 patients (65% male, median age 76 years). Median TTP was 11.1 months; median overall survival was 20.4 months; overall response rate was 46%. Grade 3 or 4 adverse events included diarrhoea (18%) and asthenia (16%). Grade 3 or 4 adverse events of special interest for bevacizumab included deep-vein thrombosis (6%) and pulmonary embolism (4%). Bevacizumab plus XELOX was effective and well tolerated in elderly patients in the BECOX study. The adverse-event profile was similar to previous reports; no new safety concerns were identified. Fit elderly patients with mCRC should be considered for treatment with bevacizumab plus XELOX.

  16. Phase I trial of GTI-2040, oxaliplatin, and capecitabine in the treatment of advanced metastatic solid tumors: a California Cancer Consortium Study

    PubMed Central

    Doroshow, James H.; Frankel, Paul; Synold, Timothy W.; Yen, Yun; Gandara, David R.; Lenz, Heinz-Josef; Chow, Warren A.; Leong, Lucille A.; Lim, Dean; Margolin, Kim A.; Morgan, Robert J.; Somlo, George; Newman, Edward M.

    2011-01-01

    Background GTI-2040 is a 20-mer antisense oligonucleotide targeting the mRNA of ribonucleotide reductase M2. It was combined with oxaliplatin and capecitabine in a phase I trial in patients with advance solid tumors based on previous studies demonstrating potentiation of chemotherapy with ribonucleotide reductase inhibitors. Methods Patients at least 18 years of age with advanced incurable solid tumors and normal organ function as well as a Karnofsky performance status of ≥60% were eligible. One prior chemotherapy regimen for advanced disease or relapse within 12 months of adjuvant chemotherapy was required. Patients could have received prior fluoropyrimidines, including capecitabine, but not oxaliplatin. Treatment cycles were 21 days. In each cycle, GTI-2040 was given as a continuous intravenous infusion over 14 days, oxaliplatin as a 2-h intravenous infusion on day 1, and capecitabine orally twice a day for 14 days. In cycle 1 only, oxaliplatin and capecitabine were started on day 2 to allow ribonucleotide reductase mRNA levels to be measured with and without oxaliplatin and capecitabine. Doses were escalated in cohorts of three patients using a standard 3 + 3 design until the maximum tolerated dose was established, defned as no more than one first-cycle dose-limiting toxicity among six patients treated at a given dose level. Results The maximum tolerated dose was estimated to be the combination of GTI-2040 3 mg/kg per day for 14 days, capecitabine 600 mg/m2 twice daily for 14 days, and oxaliplatin 100 mg/m2 every 21 days. Dose-limiting toxicities were hematologic. GTI-2040 pharmacokinetics, obtained at steady-state on days 7 and 14, showed the high inter-patient variability previously reported. Two of six patients had stable disease at the maximum tolerated dose and one patient, with heavily pre-treated non-small cell lung cancer, had a partial response at a higher dose level. In samples from a limited number of patients, there was no clear decrease in

  17. 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

  18. Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial

    PubMed Central

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

    2015-01-01

    Background: National Surgical Adjuvant Breast and Bowel Project R-04 was designed to determine whether the oral fluoropyrimidine capecitabine could be substituted for continuous infusion 5-FU in the curative setting of stage II/III rectal cancer during neoadjuvant radiation therapy and whether the addition of oxaliplatin could further enhance the activity of fluoropyrimidine-sensitized radiation. Methods: Patients with clinical stage II or III rectal cancer undergoing preoperative radiation were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU or oral capecitabine with or without oxaliplatin. The primary endpoint was local-regional tumor control. Time-to-event endpoint distributions were estimated using the Kaplan-Meier method. Hazard ratios were estimated from Cox proportional hazard models. All statistical tests were two-sided. Results: Among 1608 randomized patients there were no statistically significant differences between regimens using 5-FU vs capecitabine in three-year local-regional tumor event rates (11.2% vs 11.8%), 5-year DFS (66.4% vs 67.7%), or 5-year OS (79.9% vs 80.8%); or for oxaliplatin vs no oxaliplatin for the three endpoints of local-regional events, DFS, and OS (11.2% vs 12.1%, 69.2% vs 64.2%, and 81.3% vs 79.0%). The addition of oxaliplatin was associated with statistically significantly more overall and grade 3–4 diarrhea (P < .0001). Three-year rates of local-regional recurrence among patients who underwent R0 resection ranged from 3.1 to 5.1% depending on the study arm. Conclusions: Continuous infusion 5-FU produced outcomes for local-regional control, DFS, and OS similar to those obtained with oral capecitabine combined with radiation. This study establishes capecitabine as a standard of care in the pre-operative rectal setting. Oxaliplatin did not improve the local-regional failure rate, DFS, or OS for any patient risk group but did add considerable toxicity. PMID:26374429

  19. Phase 1a/1b and pharmacogenetic study of docetaxel, oxaliplatin and capecitabine in patients with advanced cancer of the stomach or the gastroesophageal junction.

    PubMed

    Deenen, Maarten J; Meulendijks, Didier; Boot, Henk; Legdeur, Marie-Cecile J C; Beijnen, Jos H; Schellens, Jan H M; Cats, Annemieke

    2015-12-01

    The prognosis of gastroesophageal cancer is poor, and current regimens are associated with limited efficacy. The purpose of this study was to explore the safety and preliminary efficacy of docetaxel, oxaliplatin plus capecitabine for advanced cancer of the stomach or the gastroesophageal junction (GEJ). Secondary objectives included pharmacokinetic and pharmacogenetic analyses. Patients were treated in escalating dose levels with docetaxel and oxaliplatin (both on day 1), plus capecitabine b.i.d. on days 1-14 every 3 weeks, to determine the dose-limiting toxicity and maximum tolerated dose (MTD). An expansion cohort was treated at the MTD. A total of ten polymorphisms in pharmacokinetic and pharmacodynamic candidate genes were analyzed and tested for association with treatment outcome. A total of 34 evaluable patients were enrolled. The MTD was docetaxel 50 mg/m(2), oxaliplatin 100 mg/m(2) plus capecitabine 850 mg/m(2) b.i.d. The median number of treatment cycles was 6 (range 2-8). Grade ≥ 3 toxicities included neutropenia (24 %), leukocytopenia (15 %), febrile neutropenia (12 %), fatigue (9 %) and diarrhea (6 %). The overall response rate was 45 %; two patients achieved a complete response. Median progression-free survival and overall survival were 6.5 months (95 % CI 5.4-7.6) and 11.0 months (95 % CI 7.9-14.1), respectively. The polymorphisms ERCC1 354C>T, TYMS 1053C>T and rs2612091 in ENOSF1 were associated with severe toxicity; ERCC1 354C>T and ERCC2 2251A>C were associated with poor progression-free survival. Docetaxel, oxaliplatin plus capecitabine are a well-tolerable, safe and effective treatment regimen for patients with advanced cancer of the stomach or GEJ. Pharmacogenetic markers in pharmacokinetic and pharmacodynamic candidate genes may be predictive for treatment outcome.

  20. 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

  1. Neoadjuvant Chemotherapy with Capecitabine, Oxaliplatin and Bevacizumab Followed by Concomitant Chemoradiation and Surgical Resection in Locally Advanced Rectal Cancer with High Risk of Recurrence - A Phase II Study.

    PubMed

    Eisterer, Wolfgang; Piringer, Gudrun; DE Vries, Alexander; Öfner, Dietmar; Greil, Richard; Tschmelitsch, Jörg; Samonigg, Hellmut; Sölkner, Lidija; Gnant, Michael; Thaler, Josef

    2017-05-01

    To evaluate feasibility and safety of neoadjuvant chemotherapy with capecitabine, oxaliplatin and bevacizumab followed by concomitant standard chemoradiation and surgical resection in patients with high-risk locally advanced rectal cancer. Magnetic resonance imaging (MRI)-defined high-risk cT3/4 rectal cancer patients were treated with 3 cycles of neoadjuvant chemotherapy with capecitabine (1,000 mg/m(2) twice daily days 1-14, 22-35, 43-56), oxaliplatin (130 mg/sqm on days 1, 22, 43) and bevacizumab (7.5 mg/kg on days 1, 22, 43) followed by capecitabine (825 mg/m(2) twice daily on radiotherapy days week 1-4) concomitantly with radiotherapy (1.8 Gy daily up to 45 Gy in 5 weeks) and surgical resection by total mesorectal excision. Feasibility, safety, response rate and postoperative morbidity were evaluated. Twenty-five patients were recruited. Median age was 62 years (range=24-78 years) and all patients had Eastern Cooperation Oncology Group (ECOG) performance status 0. From all patients, 79.2% finished neoadjuvant chemotherapy. Twenty patients underwent surgery. Pathologic complete remission rate, R0 resection and T-downstaging were achieved in 25%, 95% and 54.2% of the "intention to treat" (ITT) patients. The most common grade 3 adverse events (AEs) during neoadjuvant chemotherapy were diarrhea (16.6%) and mucositis (12.5%). In one patient, a grade 4 acute renal failure occurred (4.2%). During chemoradiation, skin reactions (5.3%) were the most common grade 3 AEs. Two major perioperative complications required re-intervention. Neoadjuvant chemotherapy with bevacizumab, capecitabine and oxaliplatin followed by concomitant standard chemoradiation is feasible in patients with high-risk locally advanced rectal cancer (LARC) and resulted in complete pathologic remission (pCR) rate of 25% and neoadjuvant chemotherapy completion rate of 80%. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  2. Preoperative Chemoradiotherapy with Capecitabine and Oxaliplatin in Locally Advanced Rectal Cancer. A Phase I–II Multicenter Study of the Dutch Colorectal Cancer Group

    PubMed Central

    Punt, Cornelis J. A.; Tesselaar, Margot E.; Cats, Annemieke; Havenga, Klaas; Leer, Jan W. H.; Marijnen, Corrie A.; Jansen, Edwin P.; Van Krieken, Han H. J. M.; Wiggers, Theo; Van de Velde, Cornelis J. H.; Mulder, Nanno H.

    2007-01-01

    Background We studied the maximum tolerated dose (MTD) and efficacy of oxaliplatin added to capecitabine and radiotherapy (Capox-RT) as neoadjuvant therapy for rectal cancer. Methods T3-4 rectal cancer patients received escalating doses of oxaliplatin (day 1 and 29) with a fixed dose of capecitabine of 1000 mg/m2 twice daily (days 1–14, 25–38) added to RT with 50.4 Gy and surgery after 6–8 weeks. The MTD, determined during phase I, was used in the subsequent phase II, in which R0 resection rate (a negative circumferential resection margin) was the primary end point. Results Twenty-one patients were evaluable. In the phase I part, oxaliplatin at 85 mg/m2 was established as MTD. In phase II, the main toxicity was grade III diarrhea (18%). All patients underwent surgery, and 20 patients had a resectable tumor. An R0 was achieved in 17/21 patients, downstaging to T0-2 in 7/21 and a pCR in 2/21. Conclusion Combination of Capox-RT has an acceptable acute toxicity profile and a high R0 resection rate of 81% in locally advanced rectal cancer. However the pCR rate was low. PMID:17653805

  3. 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.

  4. A phase II study of capecitabine and oxaliplatin combination chemotherapy in patients with inoperable adenocarcinoma of the gall bladder or biliary tract.

    PubMed

    Graham, J S; Boyd, K; Coxon, F Y; Wall, L R; Eatock, M M; Maughan, T S; Highley, M; Soulis, E; Harden, S; Bützberger-Zimmerli, P; Evans, T R J

    2016-03-12

    Advanced biliary tract carcinomas are associated with a poor prognosis, and palliative chemotherapy has only modest benefit. This multi-centre phase II study was conducted to determine the efficacy of capecitabine in combination with oxaliplatin in patients with inoperable gall bladder or biliary tract cancer. This was a Phase II, non-randomised, two-stage Simon design, multi-centre study. Ethics approval was sought and obtained by the North West MREC, and then locally by the West Glasgow Hospitals Research Ethics Committee. Eligible patients with inoperable locally advanced or metastatic adenocarcinoma of the gall bladder or biliary tract and with adequate performance status, haematologic, renal, and hepatic function were treated with capecitabine (1000 mg/m(2) po, twice daily, days 1-14) and oxaliplatin (130 mg/m(2) i.v., day 1) every 3 weeks for up to six cycles. The primary objective of the study was to determine the objective tumour response rates (complete and partial). The secondary objectives included assessment of toxicity, progression-free survival, and overall survival. Forty-three patients were recruited between July 2003 and December 2005. The regimen was well tolerated with no grade 3/4 neutropenia or thrombocytopenia. Grade 3/4 sensory neuropathy was observed in six patients. Two-thirds of patients received their chemotherapy without any dose delays. Overall response rate was 23.8% (95% CI 12.05-39.5%). Stable disease was observed in a further 13 patients (31%) and progressive disease observed in 12 (28.6%) of patients. The median progression-free survival was 4.6 months (95% CI 2.8-6.4 months; Fig. 1) and the median overall survival 7.9 months (95% CI 5.3-10.4 months; Fig. 2). Fig. 1 Progression-free survival Fig. 2 Overall survival Capecitabine combined with oxaliplatin has a lower disease control and shorter overall survival than the combination of cisplatin with gemcitabine which has subsequently become the standard of care in this disease

  5. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial.

    PubMed

    Díaz-Rubio, Eduardo; Tabernero, Jose; Gómez-España, Auxiliadora; Massutí, Bartomeu; Sastre, Javier; Chaves, Manuel; Abad, Alberto; Carrato, Alfredo; Queralt, Bernardo; Reina, Juan José; Maurel, Joan; González-Flores, Encarnación; Aparicio, Jorge; Rivera, Fernando; Losa, Ferrán; Aranda, Enrique

    2007-09-20

    The aim of this phase III trial was to compare the efficacy and safety of capecitabine plus oxaliplatin (XELOX) versus Spanish-based continuous-infusion high-dose fluorouracil (FU) plus oxaliplatin (FUOX) regimens as first-line therapy for metastatic colorectal cancer (MCRC). A total of 348 patients were randomly assigned to receive XELOX (oral capecitabine 1,000 mg/m2 bid for 14 days plus oxaliplatin 130 mg/m2 on day 1 every 3 weeks) or FUOX (continuous-infusion FU 2,250 mg/m2 during 48 hours on days 1, 8, 15, 22, 29, and 36 plus oxaliplatin 85 mg/m2 on days 1, 15, and 29 every 6 weeks). There were no significant differences in efficacy between XELOX and FUOX arms, which showed, respectively, median time to tumor progression (TTP; 8.9 v 9.5 months; P = .153); median overall survival (18.1 v 20.8 months; P = .145); and confirmed response rate (RR; 37% v 46%; P = .539). The safety profile of the two regimens was similar, although there were lower rates of grade 3/4 diarrhea (14% v 24%) and grade 1/2 stomatitis (28% v 43%), and higher rates of grade 1/2 hyperbilirubinemia (37% v 21%) and grade 1/2 hand-foot syndrome (14% v 5%) with XELOX versus FUOX, respectively. This randomized study shows a similar TTP of XELOX compared with FUOX in the first-line treatment of MCRC, although there was a trend for slightly lower RR and survival. XELOX can be considered as an alternative to FUOX.

  6. Perioperative Epirubicin, Oxaliplatin, and Capecitabine Chemotherapy in Locally Advanced Gastric Cancer: Safety and Feasibility in an Interim Survival Analysis

    PubMed Central

    Sahu, Arvind; Ramaswamy, Anant; Sirohi, Bhawna; Bose, Subhadeep; Talreja, Vikas; Goel, Mahesh; Patkar, Shraddha; Desouza, Ashwin; Shrikhande, Shailesh V.

    2017-01-01

    Purpose Perioperative chemotherapy improves survival outcomes in locally advanced (LA) gastric cancer. Materials and Methods We retrospectively analyzed patients with LA gastric cancer who were offered perioperative chemotherapy consisting of epirubicin, oxaliplatin, and capecitabine (EOX) from May 2013 to December 2015 at Tata Memorial Hospital in Mumbai. Results Among the 268 consecutive patients in our study, 260 patients (97.0%) completed neoadjuvant chemotherapy, 200 patients (74.6%) underwent D2 lymphadenectomy, and 178 patients (66.4%) completed adjuvant chemotherapy. The median follow-up period was 17 months. For the entire cohort, the median overall survival (OS), 3-year OS rate, median progression-free survival (PFS), and 3-year PFS rate were 37 months, 64.4%, 31 months, and 40%, respectively. PFS and OS were significantly inferior in patients who presented with features of obstruction than in those who did not (P=0.0001). There was no difference in survival with respect to tumor histology (well to moderately differentiated vs. poorly differentiated, signet ring vs. non-signet ring histology) or location (proximal vs. distal). Survival was prolonged in patients with an early pathological T stage and a pathological node-negative status. In a multivariate analysis, postoperative pathological nodal status and gastric outlet obstruction on presentation significantly correlated with survival. Conclusions EOX chemotherapy with curative resection and D2 lymphadenectomy is a suggested alternative to the existing perioperative regimens. The acceptable postoperative complication rate and relatively high resection, chemotherapy completion, and survival rates obtained in this study require further evaluation and validation in a clinical trial. PMID:28337360

  7. Phase I/II trial of capecitabine and oxaliplatin in combination with bevacizumab and imatinib in patients with metastatic colorectal cancer: AIO KRK 0205

    PubMed Central

    Hoehler, T; von Wichert, G; Schimanski, C; Kanzler, S; Moehler, M H; Hinke, A; Seufferlein, T; Siebler, J; Hochhaus, A; Arnold, D; Hallek, M; Hofheinz, R; Hacker, U T

    2013-01-01

    Background: Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer. Methods: Two dose levels (I/II) were defined: capecitabine 850/1000 mg m−2 twice daily on days 1–14; oxaliplatin 100/130 mg m−2 on day 1; bevacizumab 7.5 mg kg−1 on day 1; imatinib 300 mg day−1 on days 1–21 every 21 days. The primary study endpoint was safety. The phase II secondary endpoint was 6-month progression-free survival (PFS). Results: Dose level I was chosen for phase II testing because, even though further dose escalation was permitted by the protocol, gastrointestinal toxicities were considered to be clinically significant. A total of 49 patients were evaluated. The 6-month PFS rate was 76%, median PFS was 10.6 months and median overall survival was 23.2 months. Haematological toxicities were generally mild. Sensory neuropathy and diarrhoea were the most common grade 3 toxicities. Conclusion: The combination of XELOX with bevacizumab and imatinib is tolerable and has promising efficacy. PMID:23963139

  8. Oxaliplatin, irinotecan and capecitabine as first-line therapy in metastatic colorectal cancer (mCRC): a dose-finding study and pharmacogenomic analysis

    PubMed Central

    Zarate, R; Rodríguez, J; Bandres, E; Patiño-Garcia, A; Ponz-Sarvise, M; Viudez, A; Ramirez, N; Bitarte, N; Chopitea, A; Gacía-Foncillas, J

    2010-01-01

    Background: A dose-finding study was performed to evaluate the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and the recommended dose (RD) of escalating the doses of capecitabine and fixed doses of irinotecan and oxaliplatin on a biweekly schedule for metastatic colorectal cancer patients (mCRC). A pharmacogenomic analysis was performed to investigate the association between SNPs and treatment outcome. Methods: Eighty-seven chemotherapy-naïve mCRC patients were recruited through a two-step study design; 27 were included in the dose-finding study and 60 in the pharmacogenomic analysis. Oxaliplatin (85 mg m-2) and CPT-11 (150 mg m-2), both on day 1, and capecitabine doses ranging from 850 to 1500 mg m-2 bid on days 1–7 were explored. Peripheral blood samples were used to genotype 13 SNPs in 10 genes related to drug metabolism or efficacy. Univariate and multivariate Cox analysis was performed to examine associations between SNPs, ORR and PFS. Results: The capecitabine RD was 1000 mg m−2 bid. Diarrhoea and neutropenia were the DLTs. After a median follow-up of 52.5 months, the median PFS and OS were 12 (95% CI; 10.6–13.4) and 27 months (95% CI; 17.2–36.8), respectively. The GSTP1-G genotype, the Köhne low-risk category and use of a consolidation approach strongly correlated with decreased risk of progression. Patients with all favourable variables showed a median PFS of 42 months vs 3.4 months in the group with all adverse factors. A superior clinical response was obtained in patients with one GSTP1-G allele as compared with GSTP1-AA carriers (P=0.004). Conclusion: First-line therapy with oxaliplatin, irinotecan and capecitabine is efficient and well-tolerated. The GSTP1 polymorphism A>G status was significantly associated with ORR and PFS in mCRC treated with this triplet therapy. PMID:20216541

  9. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial

    PubMed Central

    Waddell, Tom; Chau, Ian; Cunningham, David; Gonzalez, David; Okines, Alicia Frances Clare; Wotherspoon, Andrew; Saffery, Claire; Middleton, Gary; Wadsley, Jonathan; Ferry, David; Mansoor, Wasat; Crosby, Tom; Coxon, Fareeda; Smith, David; Waters, Justin; Iveson, Timothy; Falk, Stephen; Slater, Sarah; Peckitt, Clare; Barbachano, Yolanda

    2013-01-01

    Summary Background EGFR overexpression occurs in 27–55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. Methods In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 and capecitabine 1250 mg/m2 per day on days 1–21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m2 and oxaliplatin 100 mg/m2 on day 1, capecitabine 1000 mg/m2 per day on days 1–21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. Findings Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11·3 months (95% CI 9·6–13·0) compared with 8·8 months (7·7–9·8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1·37, 95% CI 1·07–1·76; p=0·013). mEOC+P was associated with increased incidence of grade 3–4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two

  10. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.

    PubMed

    Waddell, Tom; Chau, Ian; Cunningham, David; Gonzalez, David; Okines, Alicia Frances Clare; Frances, Alicia; Okines, Clare; Wotherspoon, Andrew; Saffery, Claire; Middleton, Gary; Wadsley, Jonathan; Ferry, David; Mansoor, Wasat; Crosby, Tom; Coxon, Fareeda; Smith, David; Waters, Justin; Iveson, Timothy; Falk, Stephen; Slater, Sarah; Peckitt, Clare; Barbachano, Yolanda

    2013-05-01

    EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11.3 months (95% CI 9.6-13.0) compared with 8.8 months (7.7-9.8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1.37, 95% CI 1.07-1.76; p=0.013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and

  11. 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.

  12. Efficacy of Capecitabine Plus Oxaliplatin Combination Chemotherapy for Advanced Pancreatic Cancer after Failure of First-Line Gemcitabine-Based Therapy

    PubMed Central

    Chung, Kwang Hyun; Ryu, Ji Kon; Son, Jun Hyuk; Lee, Jae Woo; Jang, Dong Kee; Lee, Sang Hyub; Kim, Yong-Tae

    2017-01-01

    Background/Aims Second-line chemotherapy in patients with advanced pancreatic ductal adenocarcinoma (PDAC) that progresses following gemcitabine-based treatment has not been established. This study aimed to investigate the efficacy and safety of second-line combination chemotherapy with capecitabine and oxaliplatin (XELOX) in these patients. Methods Between August 2011 and May 2014, all patients who received at least one cycle of XELOX (capecitabine, 1,000 mg/m2 twice daily for 14 days; oxaliplatin, 130 mg/m2 on day 1 of a 3-week cycle) combination chemotherapy for unresectable or recurrent PDAC were retrospectively recruited. The response was evaluated every 9 weeks, and the tumor response rate, progression-free survival and overall survival, and adverse events were assessed. Results Sixty-two patients were included; seven patients (11.3%) had a partial tumor response, and 20 patients (32.3%) had stable disease. The median progression-free and overall survival were 88 days (range, 35.1 to 140.9 days) and 158 days (range, 118.1 to 197.9 days), respectively. Patients who remained stable longer with frontline therapy (≥120 days) exhibited significantly longer progression-free and overall survival. The most common grade 3 to 4 adverse events in patients were vomiting (8.1%) and anorexia (6.5%). There was one treatment-related mortality caused by severe neutropenia and typhlitis. Conclusions Second-line XELOX combination chemotherapy demonstrated an acceptable response and survival rate in patients with advanced PDAC who had failed gemcitabine-based chemotherapy. PMID:27965478

  13. Efficacy of preoperative chemotherapy regimens in patients with initially unresectable locally advanced gastric adenocarcinoma: capecitabine and oxaliplatin (XELOX) or with epirubicin (EOX)

    PubMed Central

    Wang, Yan; Zhuang, Rong-yuan; Yu, Yi-yi; Yu, Shan; Hou, Jun; Ji, Yuan; Sun, Yi-hong; Shen, Kun-tang; Shen, Zhen-bin; Liu, Feng-lin; Zhao, Nai-qing; Liu, Tian-shu

    2016-01-01

    Purpose We assessed the effectiveness of EOX (capecitabine, oxaliplatin and epirubicin) compared with XELOX (capecitabine and oxaliplatin) as preoperative chemotherapy for initially unresectable locally advanced gastric cancer. Methods This is a prospective observational study. Patients with unresectable locally advanced gastric cancer were performed EOX regimen or XELOX regimen at the discretion of the investigators. They were assessed for response every 2 cycles by CT (computed tomography) scan. A multidisciplinary team reassessed resectability after 4 cycles. The primary endpoint was the response rate. Secondary end points included the R0 resection rate, survival and adverse events. Results From November 2008 to May 2015, 242 patients were enrolled; 112 of them were assigned to EOX regimen and 130 to XELOX regimen. The response rates were 33.0% and 33.8% respectively in EOX group and XELOX group (P = 0.997). After 4 cycles of chemotherapy, 63 patients (56.3%) in EOX group and 81 patients (62.3%) in XELOX group received radical operation (P = 0.408). There was no significant difference in progress-free survival (PFS, 12.0m vs. 15.4m, P = 0.925) and overall survival (OS, 25.7m vs. 29.0m, P = 0.783) in two groups. In addition, more adverse effects occurred in EOX group, such as more leucopenia (22.3% vs. 10.0%, P = 0.014), neutropenia (23.2% vs. 11.5%, P = 0.025), fatigue (11.6% vs. 3.8%, P = 0.041) and vomiting (10.7% vs. 2.3%, P = 0.015). Conclusions For unresectable locally advanced gastric cancer patients, XELOX regimen showed similar effects in response rate, radical resection rate and survival benefits, but with less toxicity effects. PMID:27602586

  14. Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer

    PubMed Central

    Strickler, John H.; McCall, Shannon; Nixon, Andrew B.; Brady, John C.; Pang, Herbert; Rushing, Christel; Cohn, Allen; Starodub, Alexander; Arrowood, Christy; Haley, Sherri; Meadows, Kellen L.; Morse, Michael A.; Uronis, Hope E.; Blobe, Gerard C.; Hsu, S. David; Zafar, S. Yousuf; Hurwitz, Herbert I.

    2014-01-01

    Purpose Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). Methods Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a “3+3” design, twelve patients with advanced solid tumors received dasatinib (50mg twice daily or 70mg daily), capecitabine (850mg/m2 twice daily, days 1-14), oxaliplatin (130mg/m2 on day 1) and bevacizumab (7.5mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (srcact) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). Results Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50mg bid dasatinib cohort, and one DLT was observed in the 70mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70mg daily. The most common treatment-related adverse events were fatigue (20; 91%) and diarrhea (18; 82%). Biomarker analysis of srcact expression demonstrated that the overall response rate (ORR) was 75% (6/8) for patients with high srcact expression (IHC≥ 2), compared to 0% (0/8) for patients with low srcact expression (IHC 0 or 1); (p =0.007). Conclusions The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib. PMID:24173967

  15. Phase II study of bevacizumab, capecitabine, and oxaliplatin followed by bevacizumab plus erlotinib as first-line therapy in metastatic colorectal cancer.

    PubMed

    Muñoz, Alberto; Pericay, Carles; García-Girón, Carlos; Alonso, Vicente; Dueñas, Rosario; Cirera, Luis; Rivera, Fernando; Falcó, Esther; Bustos, Iñaki Alvarez; Salud, Antonieta

    2013-01-01

    This phase II trial investigated the efficacy of an induction regimen of bevacizumab, capecitabine plus oxaliplatin (XELOX) followed by maintenance therapy with bevacizumab plus erlotinib as first-line therapy in patients with metastatic colorectal cancer. Patients with metastatic colorectal cancer received intravenous bevacizumab 7.5 mg/kg plus oxaliplatin 130 mg/m(2) on day 1 followed by oral capecitabine 1,000 mg/m(2) twice daily on days 1-14 every 3 weeks for six cycles. In the absence of disease progression, patients then received bevacizumab 7.5 mg/kg every 3 weeks plus oral erlotinib 150 mg once daily. The primary study endpoint was progression-free survival. In the intention-to-treat population (n = 90), the median progression-free survival was 9.2 [95% confidence interval (CI): 7.9-11.9] months, and the median overall survival was 25.8 (95% CI: 18.0-30.9) months. In the patient subpopulation who received both induction and maintenance therapy (n = 52), median progression-free survival was 11.1 (95% CI: 9.0-15.7) months, and the median overall survival was 29.5 (95% CI: 23.7-36.7) months. KRAS status did not predict efficacy. The most common grade 3/4 adverse events were diarrhea, asthenia, and neutropenia. XELOX-bevacizumab for 6 cycles followed by bevacizumab-erlotinib maintenance therapy has been shown to be a highly active and well-tolerated first-line regimen in patients with metastatic colorectal cancer.

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

    PubMed Central

    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

    2016-01-01

    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. Feasibility of sequential adjuvant chemotherapy with a 3-month oxaliplatin-based regimen followed by 3 months of capecitabine in patients with stage III and high-risk stage II colorectal cancer: JSWOG-C2 study

    PubMed Central

    Tsuruta, Atsushi; Yamashita, Kazuki; Tanioka, Hiroaki; Tsuji, Akihito; Inukai, Michio; Yamakawa, Toshiki; Yamatsuji, Tomoki; Yoshimitsu, Masanori; Toyota, Kazuhiro; Yamano, Taketoshi; Nagasaka, Takeshi; Okajima, Masazumi

    2016-01-01

    Background Six months of oxaliplatin-based chemotherapy is the standard adjuvant chemotherapy for completely resected stage III colorectal cancer (CRC). Also, patients with stage II CRC who are considered to be at high risk of disease recurrence often receive the same adjuvant chemotherapy treatment. We prospectively investigated the extent and degree of neuropathy suffered by stage III and high-risk stage II resectable CRC patients who underwent sequential approach involving 3 months of an oxaliplatin-based regimen followed by 3 months of capecitabine. Patients and methods Patients with completely resected stage III and high-risk stage II CRC aged ≥20 years were eligible. Patients were treated with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) for 3 months followed by capecitabine (2,500 mg/m2 on days 1–14 every 3 weeks) for 3 months. Primary end points were frequency and the grade of oxaliplatin-induced neurotoxicity as evaluated using the physician-based Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) grading and the patient-based scale, self-reported Patient Neurotoxicity Questionnaire. Results Ninety-one patients were enrolled and 86 patients assessed. Eighty-four percent of patients completed the planned oxaliplatin-based therapy for 3 months, and 63% of patients completed all treatments for the full 6 months. Overall incidences of grade 3 or 4 peripheral sensory or motor neuropathy according to the CTCAE were 3.5% and 1.2%, respectively. Regarding the peripheral sensory neuropathy, the proportion of Patient Neurotoxicity Questionnaire (grade C–E) and CTCAE (grade 2–4) at months 1.5/3/6 were 11.3/22.1/29.4% and 5.3/4.4/11.3%, respectively (Spearman correlation coefficient: 0.47). Conclusion A sequential approach to adjuvant chemotherapy with 3 months of an oxaliplatin-based regimen followed by 3 months of capecitabine was tolerated by patients and associated with a low incidence of

  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. Interim analysis of a phase II trial evaluating the safety and efficacy of capecitabine plus oxaliplatin (XELOX) as adjuvant therapy in Japanese patients with operated stage III colon cancer.

    PubMed

    Danno, Katsuki; Hata, Taishi; Tamai, Koki; Fujie, Yujiro; Ide, Yoshihito; Kim, Ho Min; Ohnishi, Tadashi; Morita, Shunji; Yoshioka, Shinichi; Kudo, Toshihiro; Nishimura, Junichi; Matsuda, Chu; Akamatsu, Hiroki; Mizushima, Tsunekazu; Nezu, Riichiro; Doki, Yuichiro; Mori, Masaki

    2017-08-19

    Adjuvant oxaliplatin plus oral capecitabine (XELOX) is recommended for patients with curatively resected colon cancer. However, its safety and tolerability in Asian patients is unclear; therefore, we evaluated the safety and efficacy of adjuvant XELOX in Japanese patients with curatively resected stage III colon cancer (MCSCO-1024) and present the interim safety data. This prospective, multi-center, open-label, single-arm phase II study recruited patients with curatively resected stage III colon cancer. The protocol was a 120-min intravenous infusion of oxaliplatin (130 mg/m(2)) on day 1 and oral capecitabine (2000 mg/m(2)/day) in two divided doses for 14 days of a 3-week cycle, for a total of eight cycles (24 weeks). The primary endpoint was the 3-year disease-free survival, and secondary endpoints were the treatment completion rate, safety profile (rate and severity of adverse events), and correlation of adverse events, such as peripheral sensory neuropathy (PSN), with the administration period of oxaliplatin, etc. From November 2011 to August 2014 (34 months), 196 patients were enrolled. Safety was analyzed in 190 patients. The median total doses of capecitabine and oxaliplatin were 215,586.9 and 777.2 mg/m(2), respectively, while the median relative dose intensities were 82.5 and 76.0%, respectively. The overall treatment completion rate was 73.7%. The most frequent treatment-related adverse event was PSN (88.4%), while the most frequent grade ≥3 treatment-related adverse events were neutropenia (12.6%), PSN (6.3%), diarrhea (4.2%), and thrombocytopenia (4.2%). There were no treatment-related deaths. Adjuvant XELOX is tolerable for Japanese patients with Stage III colon cancer.

  3. Diabetes and Body Mass Index Are Associated with Neuropathy and Prognosis in Colon Cancer Patients Treated with Capecitabine and Oxaliplatin Adjuvant Chemotherapy.

    PubMed

    Ottaiano, Alessandro; Nappi, Anna; Tafuto, Salvatore; Nasti, Guglielmo; De Divitiis, Chiara; Romano, Carmela; Cassata, Antonino; Casaretti, Rossana; Silvestro, Lucrezia; Avallone, Antonio; Capuozzo, Maurizio; Capozzi, Monica; Maiolino, Piera; Quagliariello, Vincenzo; Scala, Stefania; Iaffaioli, Vincenzo Rosario

    2016-01-01

    There are few background data on the impact of clinical factors on neurotoxicity and prognosis in patients treated with adjuvant capecitabine and oxaliplatin (CAPOX) chemotherapy. 102 stage II high-risk and stage III colorectal cancer patients were treated for 6 months with adjuvant CAPOX, then they were followed up. Associations between clinical variables, metabolic syndrome components, smoking and neurotoxicity were evaluated by the x03C7;2 test. The Kaplan-Meier product limit method was applied to graph disease-free survival (DFS). Univariate analysis was done with the log-rank test. Cox's proportional hazards regression was used to analyze the effect of several risk factors on DFS. Significant associations were found between diabetes (p < 0.001), BMI (p = 0.01) and the occurrence of chronic neurotoxicity. After a median follow-up of 46 months, 14 patients (13.7%) had suffered recurrence. An analysis of the prognostic factors for DFS showed that prognosis is unfavorable for patients with high lymph-nodal involvement (HR: 5.23, p = 0.0007), diabetes (HR: 4.86; p = 0.03) and a BMI ≥25 (HR: 3.69, p = 0.002). Common mediators in diabetes and obesity could be involved in peripheral neuropathy and in stimulating micro-metastases. Further studies are necessary to explain this interesting connection between diabetes, obesity and colon cancer. © 2016 S. Karger AG, Basel.

  4. 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

  5. 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

  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. 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.

  8. Tissue microRNAs as predictors of outcome in patients with metastatic colorectal cancer treated with first line Capecitabine and Oxaliplatin with or without Bevacizumab.

    PubMed

    Boisen, Mogens K; Dehlendorff, Christian; Linnemann, Dorte; Nielsen, Boye S; Larsen, Jim S; Osterlind, Kell; Nielsen, Svend E; Tarpgaard, Line S; Qvortrup, Camilla; Pfeiffer, Per; Holländer, Niels H; Keldsen, Nina; Hansen, Torben F; Jensen, Brita B; Høgdall, Estrid V S; Jensen, Benny V; Johansen, Julia S

    2014-01-01

    We tested the hypothesis that expression of microRNAs (miRNAs) in cancer tissue can predict effectiveness of bevacizumab added to capecitabine and oxaliplatin (CAPEOX) in patients with metastatic colorectal cancer (mCRC). Patients with mCRC treated with first line CAPEOX and bevacizumab (CAPEOXBEV): screening (n = 212) and validation (n = 121) cohorts, or CAPEOX alone: control cohort (n = 127), were identified retrospectively and archival primary tumor samples were collected. Expression of 754 miRNAs was analyzed in the screening cohort using polymerase chain reaction (PCR) arrays and expression levels were related to time to disease progression (TTP) and overall survival (OS). Significant miRNAs from the screening study were analyzed in all three cohorts using custom PCR arrays. In situ hybridization (ISH) was done for selected miRNAs. In the screening study, 26 miRNAs were significantly correlated with outcome in multivariate analyses. Twenty-two miRNAs were selected for further study. Higher miR-664-3p expression and lower miR-455-5p expression were predictive of improved outcome in the CAPEOXBEV cohorts and showed a significant interaction with bevacizumab effectiveness. The effects were strongest for OS. Both miRNAs showed high expression in stromal cells. Higher expression of miR-196b-5p and miR-592 predicted improved outcome regardless of bevacizumab treatment, with similar effect estimates in all three cohorts. We have identified potentially predictive miRNAs for bevacizumab effectiveness and additional miRNAs that could be related to chemotherapy effectiveness or prognosis in patients with mCRC. Our findings need further validation in large cohorts, preferably from completed randomized trials.

  9. Tissue MicroRNAs as Predictors of Outcome in Patients with Metastatic Colorectal Cancer Treated with First Line Capecitabine and Oxaliplatin with or without Bevacizumab

    PubMed Central

    Boisen, Mogens K.; Dehlendorff, Christian; Linnemann, Dorte; Nielsen, Boye S.; Larsen, Jim S.; Østerlind, Kell; Nielsen, Svend E.; Tarpgaard, Line S.; Qvortrup, Camilla; Pfeiffer, Per; Holländer, Niels H.; Keldsen, Nina; Hansen, Torben F.; Jensen, Brita B.; Høgdall, Estrid V. S.; Jensen, Benny V.; Johansen, Julia S.

    2014-01-01

    Purpose We tested the hypothesis that expression of microRNAs (miRNAs) in cancer tissue can predict effectiveness of bevacizumab added to capecitabine and oxaliplatin (CAPEOX) in patients with metastatic colorectal cancer (mCRC). Experimental Design Patients with mCRC treated with first line CAPEOX and bevacizumab (CAPEOXBEV): screening (n = 212) and validation (n = 121) cohorts, or CAPEOX alone: control cohort (n = 127), were identified retrospectively and archival primary tumor samples were collected. Expression of 754 miRNAs was analyzed in the screening cohort using polymerase chain reaction (PCR) arrays and expression levels were related to time to disease progression (TTP) and overall survival (OS). Significant miRNAs from the screening study were analyzed in all three cohorts using custom PCR arrays. In situ hybridization (ISH) was done for selected miRNAs. Results In the screening study, 26 miRNAs were significantly correlated with outcome in multivariate analyses. Twenty-two miRNAs were selected for further study. Higher miR-664-3p expression and lower miR-455-5p expression were predictive of improved outcome in the CAPEOXBEV cohorts and showed a significant interaction with bevacizumab effectiveness. The effects were strongest for OS. Both miRNAs showed high expression in stromal cells. Higher expression of miR-196b-5p and miR-592 predicted improved outcome regardless of bevacizumab treatment, with similar effect estimates in all three cohorts. Conclusions We have identified potentially predictive miRNAs for bevacizumab effectiveness and additional miRNAs that could be related to chemotherapy effectiveness or prognosis in patients with mCRC. Our findings need further validation in large cohorts, preferably from completed randomized trials. PMID:25329796

  10. 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

  11. Phase II Study of Preoperative Capecitabine and Oxaliplatin-based Intensified Chemoradiotherapy With or Without Induction Chemotherapy in Patients With Locally Advanced Rectal Cancer and Synchronous Liver-limited Resectable Metastases

    PubMed Central

    Cho, Hyungwoo; Kim, Jeong Eun; Kim, Kyu-pyo; Yu, Chang Sik; Kim, Jin Cheon; Kim, Jong Hoon; Lee, Myung Ah; Jang, Hong Seok; Oh, Seong Taek; Kim, Sun Young; Oh, Jae Hwan; Kim, Dae Yong; Hong, Yong Sang

    2016-01-01

    Objectives: Controversy surrounds the management of patients with locally advanced rectal cancer with synchronous resectable liver metastases (LMs). This study was designed to improve both systemic and local control in these patients. Methods: Patients with locally advanced rectal cancer (cT3-4N0 or cTanyN1-2) and synchronous resectable liver-limited metastases (cM1a) were randomly assigned to receive either preoperative treatments of induction CapeOx, followed by chemoradiotherapy with CapeOx (CapeOx-RT) (arm A) or CapeOx-RT alone (arm B). Induction CapeOx consisted of oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily on days 1 to 14, every 3 weeks for 2 cycles; CapeOx-RT consisted of radiotherapy with 45 Gy/25 daily fractions±5.4 Gy/3 fractions, oxaliplatin 50 mg/m2 weekly for 5 weeks, and capecitabine 825 mg/m2 twice daily on days 1 to 38. Total mesorectal excision and simultaneous liver metastasectomy were planned within 6 weeks after completion of preoperative treatments. The primary endpoint was R0 resection rate of both the primary tumor and LMs. Results: Thirty-eight patients were randomly assigned to the present study, 18 to arm A and 20 to arm B. The overall R0 resection rate for both the primary tumor and LMs was 77.8% in arm A and 70.0% in arm B (P=0.72). The median progression-free survival was 14.2 versus 15.1 months (P=0.422) and the 3-year overall survival rate was 75.0% versus 88.8% (P=0.29), respectively. Conclusions: Both treatment strategies showed considerable R0 resection rates; however, further study will be warranted to apply these intensified strategies in clinical practice. PMID:27322695

  12. 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.

  13. Phase II Trial of Preoperative Radiation With Concurrent Capecitabine, Oxaliplatin, and Bevacizumab Followed by Surgery and Postoperative 5-Fluorouracil, Leucovorin, Oxaliplatin (FOLFOX), and Bevacizumab in Patients With Locally Advanced Rectal Cancer: 5-Year Clinical Outcomes ECOG-ACRIN Cancer Research Group E3204.

    PubMed

    Landry, Jerome C; Feng, Yang; Prabhu, Roshan S; Cohen, Steven J; Staley, Charles A; Whittington, Richard; Sigurdson, Elin Ruth; Nimeiri, Halla; Verma, Udit; Benson, Al Bowen

    2015-06-01

    The 5-year oncologic outcomes from the trial regimen were excellent. However, the neoadjuvant and surgical toxicity of this regimen was significant and was the primary reason for the low compliance with adjuvant systemic therapy.Due to the lack of an improvement in the pathologic complete response rate, the substantial associated toxicity, and the negative phase III trials of adjuvant bevacizumab in colon cancer, this regimen will not be pursued for further study. The addition of bevacizumab to chemotherapy improves overall survival for metastatic colorectal cancer. We initiated a phase II trial to evaluate preoperative capecitabine, oxaliplatin, and bevacizumab with radiation therapy (RT) followed by surgery and postoperative 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX), and bevacizumab for locally advanced rectal cancer. The purpose of this report is to describe the 5-year oncologic outcomes of this regimen. In a phase II Simon two-stage design study, we evaluated preoperative treatment with capecitabine (825 mg/m(2) b.i.d. Monday-Friday), oxaliplatin (50 mg/m(2) weekly), bevacizumab (5 mg/kg on days 1, 15, and 29), and RT (50.4 Gy). Surgery was performed by 8 weeks after RT. Beginning 8-12 weeks after surgery, patients received FOLFOX plus bevacizumab (5 mg/kg) every 2 weeks for 12 cycles (oxaliplatin stopped after 9 cycles). The primary endpoint was a pathologic complete response (path-CR) rate of 30%. Fifty-seven patients with resectable T3/T4 rectal adenocarcinoma were enrolled between 2006 and 2010. Of 57 enrolled patients, 53 were eligible and included in the analysis. Forty-eight (91%) patients completed preoperative therapy, all of whom underwent curative surgical resection. Nine patients (17%) achieved path-CR. There were 29 worst grade 3 events, 8 worst grade 4 events, and 2 patient deaths, 1 of which was attributed to study therapy. Twenty-six patients (54%) began adjuvant chemotherapy. After a median follow-up period of 41 months, the 5-year

  14. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study.

    PubMed

    Fernández-Martos, Carlos; Pericay, Carles; Aparicio, Jorge; Salud, Antonieta; Safont, Mariajose; Massuti, Bertomeu; Vera, Ruth; Escudero, Pilar; Maurel, Joan; Marcuello, Eugenio; Mengual, Jose Luis; Saigi, Eugenio; Estevan, Rafael; Mira, Moises; Polo, Sonia; Hernandez, Ana; Gallen, Manuel; Arias, Fernando; Serra, Javier; Alonso, Vicente

    2010-02-10

    PURPOSE The optimal therapeutic sequence of the adjuvant chemotherapy component of preoperative chemoradiotherapy (CRT) for patients with locally advanced rectal cancer is controversial. Induction chemotherapy before preoperative CRT may be associated with better efficacy and compliance. PATIENTS AND METHODS A total of 108 patients with locally advanced rectal cancer were randomly assigned to arm A-preoperative CRT with capecitabine, oxaliplatin, and concurrent radiation followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)-or arm B-induction CAPOX followed by CRT and surgery. The primary end point was pathologic complete response rate (pCR). Results On an intention-to-treat basis, the pCR for arms A and B were 13.5% (95% CI, 5.6% to 25.8%) and 14.3% (95% CI, 6.4% to 26.2%), respectively. There were no statistically significant differences in other end points, including downstaging, tumor regression, and R0 resection. Overall, chemotherapy treatment exposure was higher in arm B than in arm A for both oxaliplatin (P < .0001) and capecitabine (P < .0001). During CRT, grades 3 to 4 adverse events were similar in both arms but were significantly higher in arm A during postoperative adjuvant CT than with induction CT in arm B. There were three deaths in each arm during the treatment period. CONCLUSION Compared with postoperative adjuvant CAPOX, induction CAPOX before CRT had similar pCR and complete resection rates. It did achieve more favorable compliance and toxicity profiles. On the basis of these findings, a phase III study to definitively test the induction strategy is warranted.

  15. Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin

    PubMed Central

    Overman, Michael J.; Morris, Van; Moinova, Helen; Manyam, Ganiraju; Ensor, Joe; Lee, Michael S.; Eng, Cathy; Kee, Bryan; Fogelman, David; Shroff, Rachna T.; LaFramboise, Thomas; Mazard, Thibault; Feng, Tian; Hamilton, Stanley; Broom, Bradley; Lutterbaugh, James; Issa, Jean-Pierre; Markowitz, Sanford D.; Kopetz, Scott

    2016-01-01

    Purpose Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and is implicated in the pathogenesis of a subset of colorectal cancers (CRCs) termed CIMP-high. Experimental Design This phase I/II study in CRC (phase II portion restricted to CIMP-high CRC), treated fluoropyrimidine/oxaliplatin refractory patients with azacitidine (75 mg/m2/day subcutaneously D1-5) and CAPOX (capecitibine and oxaliplatin) every three weeks. Results Twenty-six patients (pts) were enrolled in this study: 15 pts (12 treated at MTD) in phase I and 11 pts in phase II. No dose limiting toxicities were observed. A total of 14 pts were CIMP-high. No responses were seen. CIMP-high status did not correlate with efficacy endpoints [stable disease (SD) or progression-free survival (PFS)] or baseline vimentin methylation level. Changes in vimentin methylation over time did not correlate with efficacy outcomes. Baseline methylated vimentin correlated with tumor volume (P<0.001) and higher levels of baseline methylation correlated with the obtainment of stable disease (P=0.04). Conclusions Azacitidine and CAPOX were well tolerated with high rates of stable disease in CIMP-high pts, but no objective responses. Serum methylated vimentin may be associated with benefit from a regimen including a hypomethylation agent, although this study is not able to separate a potential prognostic or predictive role for the biomarker. PMID:27542211

  16. Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin.

    PubMed

    Overman, Michael J; Morris, Van; Moinova, Helen; Manyam, Ganiraju; Ensor, Joe; Lee, Michael S; Eng, Cathy; Kee, Bryan; Fogelman, David; Shroff, Rachna T; LaFramboise, Thomas; Mazard, Thibault; Feng, Tian; Hamilton, Stanley; Broom, Bradley; Lutterbaugh, James; Issa, Jean-Pierre; Markowitz, Sanford D; Kopetz, Scott

    2016-10-11

    Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and is implicated in the pathogenesis of a subset of colorectal cancers (CRCs) termed CIMP-high. This phase I/II study in CRC (phase II portion restricted to CIMP-high CRC), treated fluoropyrimidine/oxaliplatin refractory patients with azacitidine (75 mg/m2/day subcutaneously D1-5) and CAPOX (capecitibine and oxaliplatin) every three weeks. Twenty-six patients (pts) were enrolled in this study: 15 pts (12 treated at MTD) in phase I and 11 pts in phase II. No dose limiting toxicities were observed. A total of 14 pts were CIMP-high. No responses were seen. CIMP-high status did not correlate with efficacy endpoints [stable disease (SD) or progression-free survival (PFS)] or baseline vimentin methylation level. Changes in vimentin methylation over time did not correlate with efficacy outcomes. Baseline methylated vimentin correlated with tumor volume (P<0.001) and higher levels of baseline methylation correlated with the obtainment of stable disease (P=0.04). Azacitidine and CAPOX were well tolerated with high rates of stable disease in CIMP-high pts, but no objective responses. Serum methylated vimentin may be associated with benefit from a regimen including a hypomethylation agent, although this study is not able to separate a potential prognostic or predictive role for the biomarker.

  17. Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC--A Randomized Phase III Trial.

    PubMed

    Hecht, J Randolph; Bang, Yung-Jue; Qin, Shukui K; Chung, Hyun C; Xu, Jianming M; Park, Joon O; Jeziorski, Krzysztof; Shparyk, Yaroslav; Hoff, Paulo M; Sobrero, Alberto; Salman, Pamela; Li, Jin; Protsenko, Svetlana A; Wainberg, Zev A; Buyse, Marc; Afenjar, Karen; Houé, Vincent; Garcia, Agathe; Kaneko, Tomomi; Huang, Yingjie; Khan-Wasti, Saba; Santillana, Sergio; Press, Michael F; Slamon, Dennis

    2016-02-10

    To evaluate the efficacy of adding lapatinib to capecitabine and oxaliplatin (CapeOx) in patients with previously untreated human epidermal growth factor receptor 2 (HER2) -amplified advanced gastroesophageal adenocarcinoma. Patients with HER2-positive advanced gastroesophageal adenocarcinoma were randomly assigned at a one-to-one ratio to CapeOx plus lapatinib 1,250 mg or placebo daily. Primary end point was overall survival (OS) in patients with centrally confirmed HER2 amplification in the primary efficacy population. A total of 545 patients were randomly assigned, and 487 patients comprised the primary efficacy population. Median OS in the lapatinib and placebo arms was 12.2 (95% CI, 10.6 to 14.2) and 10.5 months (95% CI, 9.0 to 11.3), respectively, which was not significantly different (hazard ratio, 0.91; 95% CI, 0.73 to 1.12). Median progression-free survival in the lapatinib and placebo arms was 6.0 (95% CI, 5.6 to 7.0) and 5.4 months (95% CI, 4.4 to 5.7), respectively (hazard ratio, 0.82; 95% CI, 0.68 to 1.00; P = .0381). Response rate was significantly higher in the lapatinib arm: 53% (95% CI, 46.4 to 58.8) compared with 39% (95% CI, 32.9 to 45.3) in the placebo arm (P = .0031). Preplanned exploratory subgroup analyses showed OS in the lapatinib arm was prolonged in Asian and younger patients. No correlation was observed between HER2 immunohistochemistry status and survival. There were increased toxicities in the lapatinib arm, particularly diarrhea. Addition of lapatinib to CapeOx did not increase OS in patients with HER2-amplified gastroesophageal adenocarcinoma. There were clear differences in the effect of lapatinib depending on region and age. Future studies could examine this correlation. © 2015 by American Society of Clinical Oncology.

  18. Capecitabine: a review.

    PubMed

    Walko, Christine M; Lindley, Celeste

    2005-01-01

    L/min. The drug is contraindicated if CrCl is < 30 mL/min. Capecitabine has shown varying degrees of efficacy with acceptable tolerability in numerous cancers including prostate, renal cell, ovarian, and pancreatic, with the largest amount of evidence in metastatic breast and colorectal cancer. Single-agent capecitabine was compared with IV FU/leucovorin (LV) using the bolus Mayo Clinic regimen in 2 Phase III trials as first-line treatment for patients with metastatic colorectal cancer. Overall response rate (RR) favored the capecitabine arm (26% vs 17%, P < 0.001); however, this did not translate into a difference in time to progression (TTP) (4.6 months vs 4.7 months) or overall survival (OS) (12.9 months vs 12.8 months). In Phase II noncomparative trials, combinations of capecitabine with oxaliplatin or irinotecan have produced results similar to regimens combining FU/LV with the same agents in patients with colorectal cancer. In metastatic breast cancer patients who had received prior treatment with an anthracycline-based regimen, a Phase III trial comparing the combination of capecitabine with docetaxel versus docetaxel alone demonstrated superior objective tumor RR (42% vs 30%, P = 0.006), median TTP (6.1 months vs 4.2 months, P < 0.001), and median OS (14.5 months vs 11.5 months, P = 0.013) with the combination treatment. Noncomparative Phase II studies have also supported efficacy in patients with metastatic breast cancer pretreated with both anthracyclines and taxanes, yielding an overall RR of 15% to 29% and median OS of 9.4 to 15.2 months. The most common dose-limiting adverse effects associated with capecitabine monotherapy are hyperbilirubinemia, diarrhea, and hand-foot syndrome. Myelosuppression, fatigue and weakness, abdominal pain, and nausea have also been reported. Compared with bolus FU/LV, capecitabine was associated with more hand-foot syndrome but less stomatitis, alopecia, neutropenia requiring medical management, diarrhea, and nausea. Capecitabine has

  19. Oxaliplatin-related neuropathy in Indian patients – no difference between generic and original molecules

    PubMed Central

    Sirohi, Bhawna; Ostwal, Vikas; Dawood, Shaheenah; Lopes, Gilberto; Talole, Sanjay; Nashikkar, Chaitali; Shrikhande, Shailesh

    2016-01-01

    Background: Oxaliplatin-induced neuropathy is a dose-limiting toxicity that significantly affects patients’ quality of life. The aim of this study was to compare its occurrence between a generic versus the original molecule in Indian patients. Materials and Methods: Between August 2012 and July 2013, 163 patients receiving oxaliplatin were prospectively enrolled. A data recording form was used in the clinic to record detailed information. Results: The median age of patients was 55 years (range, 19–79). Chemotherapy regimens used included: capecitabine, oxaliplatin (59), epirubicin, oxaliplatin, and capecitabine (20), docetaxel, oxaliplatin, and capecitabine (11), 5-FU, leucovorin, oxaliplatin (9), and gemcitabine-oxaliplatin (64). The median cumulative dose of oxaliplatin was 780 mg/m2. Eighty patients received the original version and 83 the generic one. Overall, 63 patients (38%) developed neuropathy. There was no significant difference in the incidence of neuropathy between the two forms of oxaliplatin used (P = 0.50). Forty-nine percent of female patients had neuropathy as compared to 30% of male patients (P = 0.014). Older patients had a trend toward a higher incidence of neuropathy: 44% of patients above age fifty developed neuropathy compared to 30% of patients younger than 50 (P = 0.06). Conclusion: This is the first study to specifically show that neuropathy rates do not vary with the use of generic versus original oxaliplatin. PMID:28144095

  20. Oxaliplatin-related neuropathy in Indian patients - no difference between generic and original molecules.

    PubMed

    Sirohi, Bhawna; Ostwal, Vikas; Dawood, Shaheenah; Lopes, Gilberto; Talole, Sanjay; Nashikkar, Chaitali; Shrikhande, Shailesh

    2016-01-01

    Oxaliplatin-induced neuropathy is a dose-limiting toxicity that significantly affects patients' quality of life. The aim of this study was to compare its occurrence between a generic versus the original molecule in Indian patients. Between August 2012 and July 2013, 163 patients receiving oxaliplatin were prospectively enrolled. A data recording form was used in the clinic to record detailed information. The median age of patients was 55 years (range, 19-79). Chemotherapy regimens used included: capecitabine, oxaliplatin (59), epirubicin, oxaliplatin, and capecitabine (20), docetaxel, oxaliplatin, and capecitabine (11), 5-FU, leucovorin, oxaliplatin (9), and gemcitabine-oxaliplatin (64). The median cumulative dose of oxaliplatin was 780 mg/m(2). Eighty patients received the original version and 83 the generic one. Overall, 63 patients (38%) developed neuropathy. There was no significant difference in the incidence of neuropathy between the two forms of oxaliplatin used (P = 0.50). Forty-nine percent of female patients had neuropathy as compared to 30% of male patients (P = 0.014). Older patients had a trend toward a higher incidence of neuropathy: 44% of patients above age fifty developed neuropathy compared to 30% of patients younger than 50 (P = 0.06). This is the first study to specifically show that neuropathy rates do not vary with the use of generic versus original oxaliplatin.

  1. Oxaliplatin Injection

    MedlinePlus

    ... other medications to treat advanced colon or rectal cancer (cancer that begins in the large intestine). Oxaliplatin is also used with other medications to prevent colon cancer from spreading in people who have had surgery ...

  2. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial.

    PubMed

    Al-Batran, Salah-Eddin; Hofheinz, Ralf D; Pauligk, Claudia; Kopp, Hans-Georg; Haag, Georg Martin; Luley, Kim Barbara; Meiler, Johannes; Homann, Nils; Lorenzen, Sylvie; Schmalenberg, Harald; Probst, Stephan; Koenigsmann, Michael; Egger, Matthias; Prasnikar, Nicole; Caca, Karel; Trojan, Jörg; Martens, Uwe M; Block, Andreas; Fischbach, Wolfgang; Mahlberg, Rolf; Clemens, Michael; Illerhaus, Gerald; Zirlik, Katja; Behringer, Dirk M; Schmiegel, Wolff; Pohl, Michael; Heike, Michael; Ronellenfitsch, Ulrich; Schuler, Martin; Bechstein, Wolf O; Königsrainer, Alfred; Gaiser, Timo; Schirmacher, Peter; Hozaeel, Wael; Reichart, Alexander; Goetze, Thorsten O; Sievert, Mark; Jäger, Elke; Mönig, Stefan; Tannapfel, Andrea

    2016-12-01

    Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma, but has not yet been evaluated in the context of resectable patients. Here we report findings from the phase 2 part of the phase 2/3 FLOT4 trial, which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based triplet chemotherapy before surgical resection. In this randomised, open-label, phase 2/3 study, eligible participants were recruited from 28 German oncology centres. Patients with resectable gastric or gastro-oesophageal junction cancer who had clinical stage cT2 or higher, nodal positive (cN+) disease, or both were randomly assigned (1:1) to either three preoperative and three postoperative 3-week cycles of intravenous epirubicin 50 mg/m(2) on day 1, intravenous cisplatin 60 mg/m(2) on day 1, and either fluorouracil 200 mg/m(2) as continuous intravenous infusion or capecitabine 1250 mg/m(2) orally (two doses of 625 mg/m(2) per day) on days 1 to 21 (ECF/ECX group) or four preoperative and four postoperative 2-week cycles of docetaxel 50 mg/m(2), intravenous oxaliplatin 85 mg/m(2), intravenous leucovorin 200 mg/m(2), and fluorouracil 2600 mg/m(2) as a 24 h infusion, all on day 1 (FLOT group). Randomisation was done centrally with an interactive web-response system based on a sequence generated with blocks (block size 2) stratified by Eastern Cooperative Oncology Group performance status, location of primary tumour, age, and nodal status. No masking was done. Central assessment of pathological regression was done according to the Becker criteria. The primary endpoint was pathological complete regression (tumour regression grade TRG1a) and was analysed in the modified intention-to-treat population, defined as all patients who were randomly assigned to treatment excluding patients who had surgery but did not provide resection specimens for central evaluation. The study (including

  3. Patients’ self-reported adherence to capecitabine on XELOX treatment in metastatic colorectal cancer: findings from a retrospective cohort analysis

    PubMed Central

    Kawakami, Kazuyoshi; Nakamoto, Eri; Yokokawa, Takashi; Sugita, Kazuo; Mae, Yutarou; Hagino, Akane; Suenaga, Mitsukuni; Mizunuma, Nobuyuki; Oniyama, Sayaka; Machida, Yoshiaki; Yamaguchi, Toshiharu; Hama, Toshihiro

    2015-01-01

    Background Capecitabine plus oxaliplatin (XELOX) has been established as a first-line treatment for metastatic colorectal cancer. Adherence is particularly important with capecitabine to maintain appropriate curative effect. In this study, we monitored the adherence to capecitabine on XELOX treatment and investigated which factors might decrease compliance. Methods The study included 242 consecutive patients who received XELOX treatment for metastatic colorectal cancer between October 2009 and March 2012. Adherence to capecitabine was checked by pharmacists with a patient-reported treatment diary at a pharmaceutical outpatient clinic. Adherence rate was defined as the number of times that a patient took capecitabine in a 14-day cycle/28 prescribed doses. We retrospectively surveyed median relative dose intensities of capecitabine and the factors deteriorating adherence across eight cycles from electronic patient records and examined differences in compliance rates according to age. Results The study included 144 male and 98 female patients. The overadherence rate was 1.5% (n=23). The median adherence rate was 93.5% (n=242) in the first cycle of XELOX treatment, which gradually rose to 96.1% (n=148) in the eighth cycle. The median relative dose intensity of capecitabine was 79.2%. The main factors contributing to decreased adherence to capecitabine were diarrhea (22.5%, 352 instances) and nausea/vomiting (13.8%, 215 instances). The rate of missed dose was 12.1%. Analysis of adherence issues in relation to patient age showed a trend toward worse adherence to capecitabine therapy in the group of patients aged ≥80 years (hazard ratio =3.83; 95% confidence interval 2.48–5.91, P<0.001 versus 70–80 years group and versus <70 years group, chi-square test). Conclusion Patient-reported adherence to capecitabine on XELOX treatment in clinical practice is high but adversely affected by side effects. Patients aged 80 years or more exhibit a significant decrease in

  4. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial.

    PubMed

    Cunningham, David; Lang, Istvan; Marcuello, Eugenio; Lorusso, Vito; Ocvirk, Janja; Shin, Dong Bok; Jonker, Derek; Osborne, Stuart; Andre, Niko; Waterkamp, Daniel; Saunders, Mark P

    2013-10-01

    Elderly patients are often under-represented in clinical trials of metastatic colorectal cancer. We aimed to assess the efficacy and safety of bevacizumab plus capecitabine compared with capecitabine alone in elderly patients with metastatic colorectal cancer. For this open-label, randomised phase 3 trial, patients aged 70 years and older with previously untreated, unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were randomly assigned in a 1:1 ratio via an interactive voice-response system, stratified by performance status and geographical region. Treatment consisted of capecitabine (1000 mg/m(2) orally twice a day on days 1-14) alone or with bevacizumab (7·5 mg/kg intravenously on day 1), given every 3 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Efficacy analyses were based on the intention-to-treat population. The primary endpoint was progression-free survival. The trial is registered with ClinicalTrials.gov, number NCT00484939. From July 9, 2007, to Dec 14, 2010, 280 patients with a median age of 76 years (range 70-87) were recruited from 40 sites across ten countries. Patients were randomly assigned to receive either bevacizumab plus capecitabine (n=140) or capecitabine only (n=140). Progression-free survival was significantly longer with bevacizumab and capecitabine than with capecitabine alone (median 9·1 months [95% CI 7·3-11·4] vs 5·1 months [4·2-6·3]; hazard ratio 0·53 [0·41-0·69]; p<0·0001). Treatment-related adverse events of grade 3 or worse occurred in 53 (40%) patients in the combination group and 30 (22%) in the capecitabine group, and treatment-related serious adverse events in 19 (14%) and 11 (8%) patients. The most common grade 3 or worse adverse events of special interest for bevacizumab or chemotherapy were hand-foot syndrome (21 [16%] vs nine [7%]), diarrhoea (nine [7%] vs nine [7%]), and venous

  5. 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

  6. Capecitabine-Induced Coronary Vasospasm

    PubMed Central

    Henry, Danish; Rudzik, Francine; Butts, Allison; Mathew, Aju

    2016-01-01

    Capecitabine, an oral prodrug of 5-fluorouracil (5-FU), is approved for early-stage and advanced colorectal cancer and metastatic breast cancer. Cardiotoxicity of 5-FU is well described in the literature. However, cardiac adverse effects of capecitabine are poorly described. We report a case of coronary vasospasm induced by capecitabine. A 41-year-old female with metastatic breast cancer presented with chest pain 3 days after starting capecitabine. The chest pain was relieved by rest and exacerbated by exertion. Her physical examination was unremarkable except for a rapid heart rate of 100 bpm. Electrocardiogram test showed no acute ischemic changes. Troponin tests were negative. CT angiography of the chest was negative for acute pulmonary embolism. An echocardiogram showed a left ventricular ejection fraction of 60% without any wall motion abnormalities. The chest pain resolved with aspirin and analgesic use. She was discharged following an inconclusive cardiac workup. Further use of capecitabine was discontinued. PMID:27920693

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

    PubMed

    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

    2006-04-24

    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 pound3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings pound1318), 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.

  8. Longitudinal melanonychia induced by capecitabine.

    PubMed

    Paravar, Taraneh; Hymes, Sharon R

    2009-10-15

    Capecitabine is an oral prodrug of 5-fluorouracil (5-FU), used in the treatment of metastatic colon and breast cancers; it is also under investigation for use in gastric cancers. Multiple cutaneous adverse effects have been reported with the use of capecitabine including acral erythema, pyogenic granulomas, inflammation of actinic keratoses, cutaneous and mucosal hyperpigmentation, leopardlike vitiligo, radiation recall, onycholysis, onychomadesis, and subacute cutaneous lupus. To our knowledge, no cases of capecitabine-induced linear melanonychia have been reported to date in the literature.

  9. The effect of COX-2 inhibitor on capecitabine-induced hand-foot syndrome in patients with stage II/III colorectal cancer: a phase II randomized prospective study.

    PubMed

    Zhang, Rong-Xin; Wu, Xiao-Jun; Lu, Shi-Xun; Pan, Zhi-Zhong; Wan, De-Sen; Chen, Gong

    2011-06-01

    Hand-foot syndrome (HFS) is a common adverse event that can be induced by capecitabine. It is hypothesized that capecitabine (Hoffmann-La Roche Inc.) based chemotherapy can cause overexpression of COX-2 in tumor and healthy tissue, which finally induced HFS in hands and feet. Based on this, we believed that a selected COX-2 inhibitor (celecoxib, Pfizer Pharmaceuticals LLC) could ease HFS. We designed a prospective clinical study to test the hypothesis. From August 2008 to January 2010, 110 patients with stage II/III colorectal cancer who were eligible for adjuvant chemotherapy were enrolled in the study and divided into 4 groups by random, but 9 patients did not finish at least 4 cycles of chemotherapy. There were sixteen patients in capecitabine group, and fifteen patients in capecitabine and celecoxib group. Thirty-four patients were in XELOX (capecitabine plus oxaliplatine) group, and thirty-six patients in XELOX+ celecoxib group. All 101 patients finished chemotherapy and follow-up interviews. The group that had received capecitabine and celecoxib had a significantly reduced frequency of  >grade 1 hand-foot syndrome (29 vs. 72% P < 0.001), and >grade 2 (11.76% vs. 30% P = 0.024). Five patients experienced grade 3 HFS in capecitabine group and only 1 patient had grade 3 HFS in capecitabine and celecoxib group. There were 5 patients in capecitabine group who refused to go on chemotherapy because of HFS, but there was none in capecitabine and celecoxib group. From the result of this study, we could learn that celecoxib could reduce HFS that was induced by capecitabine. So we recommend that celecoxib can be used in capecitabine-based chemotherapy.

  10. Toxicity and efficacy of 5-fluorouracil and capecitabine in a patient with TYMS gene polymorphism: A challenge or a dilemma?

    PubMed

    Shahrokni, Armin; Rajebi, Mohammad Reza; Saif, Muhammad Wasif

    2009-10-01

    5-Fluorouracil (5-FU) is an antimetabolite that acts during the S phase of the cell cycle. The active metabolite, 5-fluorodeoxyuridine monophosphate inhibits thymidylate synthase (TS), thus preventing DNA synthesis, which leads to imbalanced cell growth and ultimately cell death. 5-FU and its oral prodrug capecitabine are used in the treatment of a number of solid tumors, including colorectal, breast, gastric, pancreatic, prostate, and bladder cancers. Common side effects include leukopenia, diarrhea, stomatitis, nausea, vomiting, and alopecia. Hand-foot syndrome (HFS) is a relatively common side effect of cytotoxic chemotherapy. It is more frequently associated with 5-FU, capecitabine, and cytarabine. This article reports on the case of a 55-year-old black man with metastatic colorectal carcinoma that was refractory to recommended treatment measures who developed grade 3 HFS after treatment with modified FOLFOX6 (leucovorin [LV]/5-FU/oxaliplatin) and bFOL (bolus 5-FU/LV/oxaliplatin) regimens. Treatment was discontinued despite excellent response to chemotherapy. The patient had progression of disease on IROX (irinotecan/oxaliplatin) and irinotecan/cetuximab regimens. He was started on gemcitabine/capecitabine and developed HFS again, which was controlled with aggressive skin care and vitamin B6 treatment. Full sequencing of the dihydropyrimidine dehydrogenase (DPYD) gene and analysis of the human TS gene (TYMS) promoter region was performed. Pharmacogenetic testing revealed 2R/2R genotype of TYMS gene, which is associated with up to a 2.5-fold risk of toxicity to 5-FU therapy. Hand-foot syndrome has proven to be a dose-limiting toxicity of 5-FU, especially of capecitabine, leading to significant morbidity. Hand-foot syndrome seems to be dose dependent, and both peak drug concentration and total cumulative dose determine its occurrence. Genetic variations such as polymorphic abnormality of TYMS are potential causative factors for a significant portion of serious

  11. Incidence of hand-foot syndrome with capecitabine in combination with chemotherapy as first-line treatment in patients with advanced and/or metastatic gastric cancer suitable for treatment with a fluoropyrimidine-based regimen.

    PubMed

    Gómez-Martin, Carlos; Sánchez, Antonio; Irigoyen, Antonio; Llorente, Beatriz; Pérez, Begoña; Serrano, Raquel; Safont, M José; Falcó, Esther; Lacasta, Adelaida; Reboredo, Margarita; Aparicio, Jorge; Dueñas, Rosario; Muñoz, Marta Llanos; Regueiro, Pilar; Sanchez-Viñes, Elena; López, Rafael López

    2012-09-01

    Hand-foot syndrome (HFS) is a limiting toxicity of capecitabine, which is not life-threatening but could compromise capecitabine efficacy. This phase II, multicenter, non-controlled study assessed the safety, particularly grade three HFS incidence, and efficacy of four capecitabine-based chemotherapy regimens [cisplatin/capecitabine (CX), epirubicin/cisplatin/capecitabine (ECX), epirubicin/oxaliplatin/capecitabine (EOX) and docetaxel/cisplatin/capecitabine (DCX)] as first-line treatment for advanced and/or metastatic gastric cancer. One hundred and eight patients were assigned to one of the four treatment groups, according to investigator's criteria, and grouped together for both safety and efficacy primary analyses. HFS was reported in 31 patients (19.6%) and its first presentation occurred at a median of 72 days (range 19-209 days). Grade 3 HFS developed in 6.3, 5.2, 3.7 and 2.4%, of patients receiving ECX, DCX, EOX or CX chemotherapy regimen, respectively. Capecitabine dose reduction/discontinuation due to HFS was required in 5.7% of patients (9/158). The most common (> 10%) grade 3-4 treatment-related AEs were neutropenia (15.2%), asthenia (12.0%) and diarrhoea (11.4%). A moderate incidence of HFS was reported in patients treated with capecitabine, which generally presented late and required dose reduction in < 1/3 of patients. The results suggest that capecitabine may be useful in combination with standard fluorouracil-based regimens in patients with advanced and/or metastatic gastric cancer with favourable safety profile.

  12. Oxaliplatin-induced lung fibrosis

    PubMed Central

    Shah, Arpan; Udwadia, Zarir F.; Almel, Sachin

    2009-01-01

    Oxaliplatin has been approved for use as an adjuvant treatment in stage III colorectal carcinoma by the US-FDA. The majority of toxicity caused by this drug is manageable. However, rare, isolated cases of pulmonary fibrosis induced by this drug have been reported in literature. We report one such case of rapidly evolving pulmonary fibrosis following treatment with oxaliplatin. PMID:20838550

  13. 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.

  14. Faster FOLFOX: Oxaliplatin Can Be Safely Infused at a Rate of 1 mg/m2/min.

    PubMed

    Cercek, Andrea; Park, Vivian; Yaeger, Rona; Reidy-Lagunes, Diane; Kemeny, Nancy E; Stadler, Zsofia K; Segal, Neil H; Varghese, Anna; Saltz, Leonard B

    2016-05-01

    Oxaliplatin at a dose of 85 mg/m(2) traditionally has been administered over 120 min in the standard FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) regimen. CapeOx (capecitabine plus oxaliplatin), in which the dose of oxaliplatin is 130 mg/m(2), has also been infused over 120 min. Maintenance of a prolonged infusion time has been largely based on the concern for a potential hypersensitivity reaction (HSR) if administered too quickly. We first performed a retrospective review of our institutional experience to assess whether HSR rates were similar in FOLFOX and CapeOx by using computerized pharmacy records between January 1, 2011, and December 31, 2013. We then instituted a new policy to infuse all nonresearch doses of oxaliplatin at a set rate of 1 mg/m(2)/min (85 mg/m(2) given over 85 min; 68 mg/m(2) over 68 min, etc). The incidence of HSRs with the new infusion rate was actively monitored. Of 2,097 patients who previously received oxaliplatin over 120 min, 1,936 received a dose of 85 mg/m(2) (± 10%), and 161 received a dose of 130 mg/m(2). The incidence of HSRs in the 85 mg/m(2) group was 11% versus 7% in the 130 mg/m(2) group (P = .13). Then between December 1, 2014, and June 4, 2015, 667 patients received oxaliplatin at a rate of 1 mg/m(2)/min for all doses. The incidence of HSRs in patients treated at this fixed infusion rate was 8%. Infusing oxaliplatin at a rate of 1 mg/m(2)/min does not increase the rate of HSRs and does not compromise patient safety. This infusion rate is safe for use in routine practice. Copyright © 2016 by American Society of Clinical Oncology.

  15. Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer.

    PubMed

    Feliu, J; Safont, M J; Salud, A; Losa, F; García-Girón, C; Bosch, C; Escudero, P; López, R; Madroñal, C; Bolaños, M; Gil, M; Llombart, A; Castro-Carpeño, J; González-Barón, M

    2010-05-11

    The efficacy and safety of capecitabine and bevacizumab in elderly patients with metastatic colorectal cancer (mCRC) considered unsuitable for receiving first-line chemotherapy with an irinotecan or oxaliplatin-based combination were assessed in a phase II, open, multicentre, uncontrolled study. Treatment consisted of capecitabine 1250 mg m(-2) (or 950 mg m(-2) for patients with a creatinine clearance of 30-50 ml min(-1)) twice daily on days 1-14 and bevacizumab (7.5 mg kg(-1)) on day 1 every 3 weeks. A total of 59 patients aged >or=70 years with mCRC were enrolled. In an intention-to-treat analysis, the overall response rate was 34%, with 71% of patients achieving disease control. Median progression-free survival and overall survival were 10.8 months and 18 months, respectively. In all, 32 patients (54%) had grade 3/4 adverse events (AEs), the most common being hand-foot syndrome (19%), diarrhoea (9%) and deep venous thrombosis (7%). Four patients died because of treatment-related AEs. A relationship was detected between creatinine clearance capecitabine represents a valid therapeutic alternative in elderly patients considered to be unsuitable for receiving polychemotherapy.

  16. Comparison between three oxaliplatin-based regimens with bevacizumab in patients with metastatic colorectal cancer

    PubMed Central

    Ohhara, Yoshihito; Suenaga, Mitsukuni; Matsusaka, Satoshi; Shinozaki, Eiji; Mizunuma, Nobuyuki; Yamaguchi, Toshiharu

    2015-01-01

    Background A previous pivotal Phase III study (NO16966) demonstrated the benefit of the addition of bevacizumab (BV) to oxaliplatin-based regimens in metastatic colorectal cancer (MCRC). Our study evaluated the safety and efficacy of three oxaliplatin-based chemotherapy regimens (FOLFOX4 [intravenous twice-bolus and twice-infusional 5-fluorouracil/folinic acid plus oxaliplatin], mFOLFOX6 [intravenous once-bolus and once-infusional 5-fluorouracil/folinic acid plus oxaliplatin], and XELOX [capecitabine plus oxaliplatin]) plus BV in the first-line treatment of MCRC patients. Methods Patients with MCRC who started treatment between June 2007 and September 2010 were evaluated in this retrospective cohort study. We also evaluated early objective tumor response (EOTR) within 12 weeks, which was defined as a relative change of ≥30% in the sum of the longest diameters of target lesions when compared with baseline. The primary study endpoints were progression-free survival (PFS) and response rate. Results A total of 185 patients received the following chemotherapy: FOLFOX4 + BV (FF4 arm, n=85), mFOLFOX6 + BV (FF6 arm, n=40), and XELOX + BV (XELOX arm, n=60). The overall response rates were 61.2%, 72.5%, and 75.0% (95% confidence interval: 50.6%–71.8%, 58.0%–87.0%, and 63.7%–86.3%). Median PFS was 18.0, 15.5, and 13.7 months, respectively (log-rank: P=0.254; data cut-off: May 2013). Patients with EOTR (n=117) had significantly better PFS than those without-EOTR (n=68) (17.5 versus 12.7 months, P=0.004). Conclusion This study suggests that these three BV plus oxaliplatin-based treatments might have comparable benefit in terms of tumor response and PFS. Moreover, EOTR may be a predictive factor for PFS in patients with MCRC. PMID:25767397

  17. Oxaliplatin-Based Chemotherapy in Advanced Neuroendocrine Tumors: Clinical Outcomes and Preliminary Correlation with Biological Factors.

    PubMed

    Spada, Francesca; Antonuzzo, Lorenzo; Marconcini, Riccardo; Radice, Davide; Antonuzzo, Andrea; Ricci, Sergio; Di Costanzo, Francesco; Fontana, Annalisa; Gelsomino, Fabio; Luppi, Gabriele; Nobili, Elisabetta; Galdy, Salvatore; Cella, Chiara Alessandra; Sonzogni, Angelica; Pisa, Eleonora; Barberis, Massimo; Fazio, Nicola

    2016-01-01

    The role of chemotherapy in low-/intermediate-grade neuroendocrine tumors (NETs) is still debated. We present the results of an Italian multicenter retrospective study evaluating activity and toxicity of oxaliplatin-based chemotherapy in patients with advanced NETs. Clinical records from 5 referral centers were reviewed. Disease control rate (DCR) corresponding to PR + SD (partial response + stable disease) at 6 months, progression-free survival (PFS), overall survival (OS) and toxicity were calculated. Ki67 labeling index, grade of differentiation and excision- repair-cross-complementing group 1 (ERCC-1) were analyzed in tissue tumor samples. Seventy-eight patients entered the study. Primary sites were: pancreas in 46, gastrointestinal in 24, lung in 19 and unknown in 10% of patients. The vast majority were G2 (2010 WHO classification). Eighty-six percent of the patients were metastatic, and 87% were pretreated and progressive to previous therapies. Sixty-five percent of the patients received capecitabine/oxaliplatin (CAPOX), 6% gemcitabine/oxaliplatin (GEMOX), and 29% leucovorin/fluorouracil/oxaliplatin (FOLFOX-6). PR occurred in 26% of the patients, half of them with pancreatic NETs, and SD in 54%. With a median follow-up of 21 months, the median PFS and OS were 8 and 32 months with 70 and 45 events, respectively. The most frequent G3 toxicities were neurological and gastrointestinal. ERCC-1 immunohistochemical overexpression was positive in 4/28 evaluated samples, with no significant correlation with clinical outcome. This analysis suggests that oxaliplatin-based chemotherapy can be active with a manageable safety profile in advanced NETs irrespective of the primary sites and tumor grade. The 80% DCR and 8-month PFS could justify a prospective study in NETs with intermediate biological characteristics, especially with pancreatic primary tumors. © 2016 S. Karger AG, Basel.

  18. Ganglioside-monosialic acid (GM1) prevents oxaliplatin-induced peripheral neurotoxicity in patients with gastrointestinal tumors.

    PubMed

    Zhu, Yanyun; Yang, Junlan; Jiao, Shunchang; Ji, Tiefeng

    2013-01-25

    Oxaliplatin, an effective antineoplastic agent againstgastrointestinal tumors, can cause severe peripheral neurotoxicity, which seriously limits its clinical application. To date, there are no effective treatments for this complication. Ganglioside-monosialic acid (GM1) has been shown to protect neurons against injuries and degeneration. The aim of this study was to evaluate the effects of GM1 on preventing oxaliplatin-induced neurotoxicity in patients with gastrointestinal tumors. In this study, 120 patients with gastrointestinal tumors were enrolled, andthey received the treatment of XELOX (oxaliplatin and capecitabine) and FOLFOX4 (oxaliplatin, leukovolin and 5-fluorouracil). The patients were randomly divided into two groups, the experimental group and control group, with60 patients ineach. On the day chemotherapy was initiated, the experimental group received GM1 intravenously (100 mg once daily) for 3 days, while no neuroprotective agents were applied in the control group. The incidence rates and classification of neurotoxicity in the two groups were evaluated and the differences between the two groups were examined. Furthermore, whether GM1 affected the therapeutic effects of chemotherapy was also examined. The grade of neurotoxicity in the experimental group was significantly lower than in the control group (P<0.05, Mann-Whitney U test). The probability of occurrence of low-grade neurotoxicity (grade 0 and 1) in the experimental group was higher than that in the control group (logistic ordinal regression); whereas the probability of occurrence of high-grade neurotoxicity (grade 2 and 3) in the experimental group was lower than in the control group (logistic ordinal regression). The data suggested that GM1 could reduce the grade of oxaliplatin-induced neurotoxicity and was an effective neuroprotective agent against oxaliplatin-induced high-grade neurotoxicity in patients with gastrointestinal tumors.

  19. Ganglioside-monosialic acid (GM1) prevents oxaliplatin-induced peripheral neurotoxicity in patients with gastrointestinal tumors

    PubMed Central

    2013-01-01

    Background Oxaliplatin, an effective antineoplastic agent againstgastrointestinal tumors, can cause severe peripheral neurotoxicity, which seriously limits its clinical application. To date, there are no effective treatments for this complication. Ganglioside-monosialic acid (GM1) has been shown to protect neurons against injuries and degeneration. The aim of this study was to evaluate the effects of GM1 on preventing oxaliplatin-induced neurotoxicity in patients with gastrointestinal tumors. Methods In this study, 120 patients with gastrointestinal tumors were enrolled, andthey received the treatment of XELOX (oxaliplatin and capecitabine) and FOLFOX4 (oxaliplatin, leukovolin and 5-fluorouracil). The patients were randomly divided into two groups, the experimental group and control group, with60 patients ineach. On the day chemotherapy was initiated, the experimental group received GM1 intravenously (100 mg once daily) for 3 days, while no neuroprotective agents were applied in the control group. The incidence rates and classification of neurotoxicity in the two groups were evaluated and the differences between the two groups were examined. Furthermore, whether GM1 affected the therapeutic effects of chemotherapy was also examined. Results The grade of neurotoxicity in the experimental group was significantly lower than in the control group (P<0.05, Mann–Whitney U test). The probability of occurrence of low-grade neurotoxicity (grade 0 and 1) in the experimental group was higher than that in the control group (logistic ordinal regression); whereas the probability of occurrence of high-grade neurotoxicity (grade 2 and 3) in the experimental group was lower than in the control group (logistic ordinal regression). Conclusion The data suggested that GM1 could reduce the grade of oxaliplatin-induced neurotoxicity and was an effective neuroprotective agent against oxaliplatin-induced high-grade neurotoxicity in patients with gastrointestinal tumors. PMID:23351188

  20. Cost-effectiveness of capecitabine and bevacizumab maintenance treatment after first-line induction treatment in metastatic colorectal cancer.

    PubMed

    Franken, M D; van Rooijen, E M; May, A M; Koffijberg, H; van Tinteren, H; Mol, L; Ten Tije, A J; Creemers, G J; van der Velden, A M T; Tanis, B C; Uyl-de Groot, C A; Punt, C J A; Koopman, M; van Oijen, M G H

    2017-04-01

    Capecitabine and bevacizumab (CAP-B) maintenance therapy has shown to be more effective compared with observation in metastatic colorectal cancer patients achieving stable disease or better after six cycles of first-line capecitabine, oxaliplatin, bevacizumab treatment in terms of progression-free survival. We evaluated the cost-effectiveness of CAP-B maintenance treatment. Decision analysis with Markov modelling to evaluate the cost-effectiveness of CAP-B maintenance compared with observation was performed based on CAIRO3 study results (n = 558). An additional analysis was performed in patients with complete or partial response. The primary outcomes were the incremental cost-effectiveness ratio (ICER) defined as the additional cost per life year (LY) and quality-adjusted life years (QALY) gained, calculated from EQ-5D questionnaires and literature and LYs gained. Univariable sensitivity analysis was performed to assess the influence of input parameters on the ICER, and a probabilistic sensitivity analysis represents uncertainty in model parameters. CAP-B maintenance compared with observation resulted in 0.21 QALYs (0.18LYs) gained at a mean cost increase of €36,845, yielding an ICER of €175,452 per QALY (€204,694 per LY). Varying the difference in health-related quality of life between CAP-B maintenance and observation influenced the ICER most. For patients achieving complete or partial response on capecitabine, oxaliplatin, bevacizumab induction treatment, an ICER of €149,300 per QALY was calculated. CAP-B maintenance results in improved health outcomes measured in QALYs and LYs compared with observation, but also in a relevant increase in costs. Despite the fact that there is no consensus on cost-effectiveness thresholds in cancer treatment, CAP-B maintenance may not be considered cost-effective. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Capecitabine-induced lichenoid drug eruption: a case report.

    PubMed

    Gehlhausen, Jeff R; Strausburg, Matthew B; Aouthmany, Mouhammad; Katona, Terrence M; Turner, Matthew J

    2017-02-15

    Capecitabine is a 5-fluorouracil basedchemotherapeutic drug widely used in the treatmentof solid tumors, especially colorectal and breast. Someof the most common side effects of capecitabine arecutaneous in nature, including hand-foot syndrome(palmar-plantar erythrodysesthesia). Several reports inthe literature link capecitabine use with photosensitivelichenoid eruptions. Herein, we present a case ofcapecitabine-induced lichenoid eruption in an elderlyfemale with metastatic breast cancer and discuss ourfindings in relationship to previously reported cases ofthis and other capecitabine-induced skin pathologies.

  2. 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.

  3. Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer

    PubMed Central

    Feliu, J; Safont, M J; Salud, A; Losa, F; García-Girón, C; Bosch, C; Escudero, P; López, R; Madroñal, C; Bolaños, M; Gil, M; Llombart, A; Castro-Carpeño, J; González-Barón, M

    2010-01-01

    Background: The efficacy and safety of capecitabine and bevacizumab in elderly patients with metastatic colorectal cancer (mCRC) considered unsuitable for receiving first-line chemotherapy with an irinotecan or oxaliplatin-based combination were assessed in a phase II, open, multicentre, uncontrolled study. Methods: Treatment consisted of capecitabine 1250 mg m−2 (or 950 mg m−2 for patients with a creatinine clearance of 30–50 ml min−1) twice daily on days 1–14 and bevacizumab (7.5 mg kg−1) on day 1 every 3 weeks. Results: A total of 59 patients aged ⩾70 years with mCRC were enrolled. In an intention-to-treat analysis, the overall response rate was 34%, with 71% of patients achieving disease control. Median progression-free survival and overall survival were 10.8 months and 18 months, respectively. In all, 32 patients (54%) had grade 3/4 adverse events (AEs), the most common being hand–foot syndrome (19%), diarrhoea (9%) and deep venous thrombosis (7%). Four patients died because of treatment-related AEs. A relationship was detected between creatinine clearance ⩽50 ml min−1 and the development of non-bevacizumab-related grade 3/4 AEs. The incidence of bevacizumab-associated AEs (hypertension, thromboembolic events and proteinuria) was consistent with that of previous reports in elderly patients. Conclusion: Bevacizumab combined with capecitabine represents a valid therapeutic alternative in elderly patients considered to be unsuitable for receiving polychemotherapy. PMID:20424611

  4. First-line bevacizumab and capecitabine–oxaliplatin in elderly patients with mCRC: GEMCAD phase II BECOX study

    PubMed Central

    Feliu, J; Salud, A; Safont, M J; García-Girón, C; Aparicio, J; Vera, R; Serra, O; Casado, E; Jorge, M; Escudero, P; Bosch, C; Bohn, U; Pérez-Carrión, R; Carmona, A; Martínez-Marín, V; Maurel, J

    2014-01-01

    Background: Subgroup analyses of clinical studies suggest that bevacizumab plus XELOX is effective and tolerable in elderly patients with metastatic colorectal cancer (mCRC). The prospective BECOX study examined the efficacy and safety of bevacizumab plus XELOX, followed by bevacizumab plus capecitabine in elderly patients with mCRC. Methods: Patients aged ⩾70 years with Eastern Cooperative Oncology Group performance status 0 out of 1 and confirmed mCRC were included. Patients received bevacizumab 7.5 mg kg−1 and oxaliplatin 130 mg m−2 on day 1, plus capecitabine 1000 mg m−2 bid orally on days 1–14 every 21 days; oxaliplatin was discontinued after 6 cycles. The primary end point was time to progression (TTP). Results: The intent-to-treat population comprised 68 patients (65% male, median age 76 years). Median TTP was 11.1 months; median overall survival was 20.4 months; overall response rate was 46%. Grade 3 or 4 adverse events included diarrhoea (18%) and asthenia (16%). Grade 3 or 4 adverse events of special interest for bevacizumab included deep-vein thrombosis (6%) and pulmonary embolism (4%). Conclusions: Bevacizumab plus XELOX was effective and well tolerated in elderly patients in the BECOX study. The adverse-event profile was similar to previous reports; no new safety concerns were identified. Fit elderly patients with mCRC should be considered for treatment with bevacizumab plus XELOX. PMID:24946000

  5. Short-time diffusivity of dicolloids

    NASA Astrophysics Data System (ADS)

    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), 10.1098/rspa.2007.1872].

  6. Transient nanobubbles in short-time electrolysis.

    PubMed

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

    2013-05-08

    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.

  7. Short-time Lyapunov exponent analysis

    NASA Technical Reports Server (NTRS)

    Vastano, J. A.

    1990-01-01

    A new technique for analyzing complicated fluid flows in numerical simulations has been successfully tested. The analysis uses short time Lyapunov exponent contributions and the associated Lyapunov perturbation fields. A direct simulation of the Taylor-Couette flow just past the onset of chaos demonstrated that this new technique marks important times during the system evolution and identifies the important flow features at those times. This new technique will now be applied to a 'minimal' turbulent channel.

  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. Effectiveness of oxaliplatin desensitization protocols.

    PubMed

    Cortijo-Cascajares, Susana; Nacle-López, Inmaculada; García-Escobar, Ignacio; Aguilella-Vizcaíno, María José; Herreros-de-Tejada, Alberto; Cortés-Funes Castro, Hernán; Calleja-Hernández, Miguel-Ángel

    2013-03-01

    Hypersensitivity reaction (HSR) to antineoplastic drugs can force doctors to stop treatment and seek other alternatives. These alternatives may be less effective, not as well tolerated and/or more expensive. Another option is to use desensitization protocols that induce a temporary state of tolerance by gradually administering small quantities of the antineoplastic drug until the therapeutic dosage is reached. The aim of this study is to assess the effectiveness of oxaliplatin desensitization protocols. A retrospective observational study was carried out between January 2006 and May 2011. The inclusion criteria were patients undergoing chemotherapy treatment with oxaliplatin who had developed an HSR to the drug and who were candidates for continuing the treatment using a desensitization protocol. The patients' clinical records were reviewed and variables were gathered relating to the patient, the treatment, the HSR, and the desensitization protocol administered. The data were analysed using version 18.0 of the statistics program SPSS. A total of 53 desensitization protocols were administered to 21 patients. In 89 % of these cases, no new reactions occurred while the drug was being administered. New reactions of mild severity only occurred in 11 % of cases, and none of these reactions were severe enough for treatment to be stopped. All patients were able to complete the desensitization protocol. This study confirms that oxaliplatin desensitization protocols are safe and effective and allow patients to continue with the treatment that initially caused an HSR.

  10. Capecitabine maintenance therapy following docetaxel/capecitabine combination treatment in patients with metastatic breast cancer.

    PubMed

    Surmeli, Zeki Gokhan; Varol, Umut; Cakar, Burcu; Degirmenci, Mustafa; Arslan, Cagatay; Piskin, Gonul Demir; Zengel, Baha; Karaca, Burcak; Sanli, Ulus Ali; Uslu, Ruchan

    2015-10-01

    The present study aimed to analyze the efficacy of maintenance therapy with single agent capecitabine for human epidermal growth factor receptor (HER2) negative metastatic breast cancer (MBC) patients following disease control with 6 cycles of docetaxel plus capecitabine chemotherapy as the first-line treatment. As an initial treatment, 6 cycles of docetaxel plus capecitabine followed by maintenance therapy with capecitabine were administered. A total of 55 patients received combination therapy and 48 patients proceeded to maintenance therapy: Of these, 32 patients (66.7%) were postmenopausal and 37 (77.1%) had estrogen and progesterone receptor positive disease. The median progression-free survival rate with maintenance therapy was 5.5 months (95% CI, 0-11.4 months) and the median overall survival (OS) was 26.6 months (95% CI, 21.8-30.1 months). The use of maintenance therapy improved previous responses in 4 patients (8.3%; 2 partial and 2 complete responses) and 32 patients (66.7%) had stable disease. The median number of maintenance therapy cycles applied was 6.5 (range 1-28, total 441). The observation of side effects, including grade 3/4 neutropenia, febrile neutropenia and fatigue was more common during combination therapy. The results of the present study indicate that maintenance with single agent capecitabine therapy is an effective and tolerable treatment option for HER2 negative MBC patients in which disease control with 6 cycles of docetaxel plus capecitabine chemotherapy is achieved in the first-line setting.

  11. 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.

  12. Carbocisteine reduces the cytotoxicity of oxaliplatin.

    PubMed

    Zhai, Qing; Bian, Xiao-Lan; Lu, Sheng-Rong; Zhu, Bin; Yu, Bo

    2012-01-01

    Hepatic injury induced by oxaliplatin has been reported. Even though agents are available that reduce oxaliplatin-induced hepatocyte toxicity, their mode of action has remained obscure. In the present study, hepatic L02 cells were incubated with different combinations of oxaliplatin and carbocisteine. Significantly increased levels of reactive oxygen species (ROS) were found in L02 cells treated with oxaliplatin. Using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) as an indicator of cell viability and flow cytometry, we found that carbocisteine could reverse oxaliplatin-induced apoptosis of L02 cells. Western blot analysis demonstrated that oxaliplatin could induce apoptosis of L02 cells by reducing the Bcl-2/Bim ratio, stimulating the cytochrome c release, and activating caspase-3. All of these effects could be suppressed by carbocisteine. We further found that carbocisteine did not affect the anticancer effect of oxaliplatin against HT-29 cells. This is the first report opening prospects for the clinical use of carbocisteine in the pretreatment against liver injury accompanying the chemotherapy regimen with oxaliplatin.

  13. Hurst exponents for short time series

    NASA Astrophysics Data System (ADS)

    Qi, Jingchao; Yang, Huijie

    2011-12-01

    A concept called balanced estimator of diffusion entropy is proposed to detect quantitatively scalings in short time series. The effectiveness is verified by detecting successfully scaling properties for a large number of artificial fractional Brownian motions. Calculations show that this method can give reliable scalings for short time series with length ˜102. It is also used to detect scalings in the Shanghai Stock Index, five stock catalogs, and a total of 134 stocks collected from the Shanghai Stock Exchange Market. The scaling exponent for each catalog is significantly larger compared with that for the stocks included in the catalog. Selecting a window with size 650, the evolution of scaling for the Shanghai Stock Index is obtained by the window's sliding along the series. Global patterns in the evolutionary process are captured from the smoothed evolutionary curve. By comparing the patterns with the important event list in the history of the considered stock market, the evolution of scaling is matched with the stock index series. We can find that the important events fit very well with global transitions of the scaling behaviors.

  14. Hurst exponents for short time series.

    PubMed

    Qi, Jingchao; Yang, Huijie

    2011-12-01

    A concept called balanced estimator of diffusion entropy is proposed to detect quantitatively scalings in short time series. The effectiveness is verified by detecting successfully scaling properties for a large number of artificial fractional Brownian motions. Calculations show that this method can give reliable scalings for short time series with length ~10(2). It is also used to detect scalings in the Shanghai Stock Index, five stock catalogs, and a total of 134 stocks collected from the Shanghai Stock Exchange Market. The scaling exponent for each catalog is significantly larger compared with that for the stocks included in the catalog. Selecting a window with size 650, the evolution of scaling for the Shanghai Stock Index is obtained by the window's sliding along the series. Global patterns in the evolutionary process are captured from the smoothed evolutionary curve. By comparing the patterns with the important event list in the history of the considered stock market, the evolution of scaling is matched with the stock index series. We can find that the important events fit very well with global transitions of the scaling behaviors.

  15. 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

  16. 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

  17. Combined-modality therapy of rectal cancer with oxaliplatin-based regimens.

    PubMed

    Minsky, Bruce D

    2004-06-01

    There are 2 conventional treatments for clinically resectable rectal cancer. First is surgery and, if the tumor is stage T3 and/or N1/2, this is followed by postoperative combined modality therapy. The second is preoperative combined modality therapy followed by surgery and postoperative combined modality therapy if the tumor is stage uT3/4 and/or node-positive. There are a number of new chemotherapeutic agents that have been developed for the treatment of patients with colorectal cancer. Phase I/II trials examining the use of these new chemotherapeutic agents in combination with pelvic radiation therapy, most commonly in the preoperative setting are in progress and suggest higher complete response rates. There is considerable interest in integrating oxaliplatin into preoperative combined modality therapy regimens for rectal cancer. Based on results from phase I/II trials, the recommended regimen for patients who receive oxaliplatin-based combined modality therapy is continuous infusion 5-fluorouracil or capecitabine with pelvic radiation.

  18. 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.

  19. [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.

  20. Cerebrospinal Fluid Oxaliplatin Contributes to the Acute Pain Induced by Systemic Administration of Oxaliplatin.

    PubMed

    Huang, Zhen-Zhen; Li, Dai; Ou-Yang, Han-Dong; Liu, Cui-Cui; Liu, Xian-Guo; Ma, Chao; Wei, Jia-You; Liu, Yong; Xin, Wen-Jun

    2016-05-01

    Systemic administration of oxaliplatin has no effect on the tumors in the central nervous system (CNS) due to the limited concentration of oxaliplatin in the cerebrospinal fluid (CSF), while it was clinically reported that oxaliplatin can induce acute encephalopathy. Currently, the impairment of neuronal functions in the CNS after systemic administration of oxaliplatin remains uninvestigated. The von Frey test and the plantar test were performed to evaluate neuropathic pain behavior after a single intraperitoneal administration of oxaliplatin (4 mg/kg) in rats. Inductively coupled plasma-mass spectrometry, electrophysiologic recording, real-time quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, Western blot, immunohistochemistry, and small interfering RNA were applied to understand the mechanisms. Concentration of oxaliplatin in CSF showed a time-dependent increase after a single administration of oxaliplatin. Spinal application of oxaliplatin at the detected concentration (6.6 nM) significantly increased the field potentials in the dorsal horn, induced acute mechanical allodynia (n = 12 each) and thermal hyperalgesia (n = 12 each), and enhanced the evoked excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in the projection neurokinin 1 receptor-expressing lamina I to II neurons. The authors further found that oxaliplatin significantly increased the nuclear factor-κB p65 binding and histone H4 acetylation in cx3cl1 promoter region. Thus, the upregulated spinal CX3CL1 markedly mediated the induction of central sensitization and acute pain behavior after oxaliplatin administration. The findings of this study suggested that oxaliplatin in CSF may directly impair the normal function of central neurons and contribute to the rapid development of CNS-related side effects during chemotherapy. This provides novel targets to prevent oxaliplatin-induced acute painful neuropathy and encephalopathy.

  1. Capecitabine maintenance therapy following docetaxel/capecitabine combination treatment in patients with metastatic breast cancer

    PubMed Central

    SURMELI, ZEKI GOKHAN; VAROL, UMUT; CAKAR, BURCU; DEGIRMENCI, MUSTAFA; ARSLAN, CAGATAY; PISKIN, GONUL DEMIR; ZENGEL, BAHA; KARACA, BURCAK; SANLI, ULUS ALI; USLU, RUCHAN

    2015-01-01

    The present study aimed to analyze the efficacy of maintenance therapy with single agent capecitabine for human epidermal growth factor receptor (HER2) negative metastatic breast cancer (MBC) patients following disease control with 6 cycles of docetaxel plus capecitabine chemotherapy as the first-line treatment. As an initial treatment, 6 cycles of docetaxel plus capecitabine followed by maintenance therapy with capecitabine were administered. A total of 55 patients received combination therapy and 48 patients proceeded to maintenance therapy: Of these, 32 patients (66.7%) were postmenopausal and 37 (77.1%) had estrogen and progesterone receptor positive disease. The median progression-free survival rate with maintenance therapy was 5.5 months (95% CI, 0–11.4 months) and the median overall survival (OS) was 26.6 months (95% CI, 21.8–30.1 months). The use of maintenance therapy improved previous responses in 4 patients (8.3%; 2 partial and 2 complete responses) and 32 patients (66.7%) had stable disease. The median number of maintenance therapy cycles applied was 6.5 (range 1–28, total 441). The observation of side effects, including grade 3/4 neutropenia, febrile neutropenia and fatigue was more common during combination therapy. The results of the present study indicate that maintenance with single agent capecitabine therapy is an effective and tolerable treatment option for HER2 negative MBC patients in which disease control with 6 cycles of docetaxel plus capecitabine chemotherapy is achieved in the first-line setting. PMID:26622896

  2. Predicting effects on oxaliplatin clearance: in vitro, kinetic and clinical studies of calcium- and magnesium-mediated oxaliplatin degradation.

    PubMed

    Han, Catherine H; Khwaounjoo, Prashannata; Hill, Andrew G; Miskelly, Gordon M; McKeage, Mark J

    2017-06-22

    This study evaluated the impact of calcium and magnesium on the in vitro degradation and in vivo clearance of oxaliplatin. Intact oxaliplatin and Pt(DACH)Cl2 were measured in incubation solutions by HPLC-UV. A clinical study determined changes in plasma concentrations of calcium and magnesium in cancer patients and their impact on oxaliplatin clearance. Kinetic analyses modelled oxaliplatin degradation reactions in vitro and contributions to oxaliplatin clearance in vivo. Calcium and magnesium accelerated oxaliplatin degradation to Pt(DACH)Cl2 in chloride-containing solutions in vitro. Kinetic models based on calcium and magnesium binding to a monochloro-monooxalato ring-opened anionic oxaliplatin intermediate fitted the in vitro degradation time-course data. In cancer patients, calcium and magnesium plasma concentrations varied and were increased by giving calcium gluconate and magnesium sulfate infusions, but did not alter or correlate with oxaliplatin clearance. The intrinsic in vitro clearance of oxaliplatin attributed to chloride-, calcium- and magnesium-mediated degradation predicted contributions of <2.5% to the total in vivo clearance of oxaliplatin. In conclusion, calcium and magnesium accelerate the in vitro degradation of oxaliplatin by binding to a monochloro-monooxalato ring-opened anionic intermediate. Kinetic analysis of in vitro oxaliplatin stability data can be used for in vitro prediction of potential effects on oxaliplatin clearance in vivo.

  3. T3+ and T4 rectal cancer patients seem to benefit from the addition of oxaliplatin to the neoadjuvant chemoradiation regimen.

    PubMed

    Martijnse, Ingrid S; Dudink, Ralph L; Kusters, Miranda; Vermeer, Thomas A; West, Nicholas P; Nieuwenhuijzen, Grard A; van Lijnschoten, Ineke; Martijn, Hendrik; Creemers, Geert-Jan; Lemmens, Valery E; van de Velde, Cornelis J; Sebag-Montefiore, David; Glynne-Jones, Robert; Quirke, Phil; Rutten, Harm J

    2012-02-01

    To achieve T-downstaging and better resectability in locally advanced rectal cancer, neoadjuvant radiochemotherapy (RCT) has become the current standard of treatment. A variety of schemes have been used. This study investigates which scheme had the best effect on these parameters. Our institution is a referral center for locally advanced rectal cancer. Different neoadjuvant radiochemotherapy regimens were administered: long course radiotherapy (RTH), 5-FU and leucovorin (5FUBolus), a combination of capecitabine and oxaliplatin (CORE), and capecitabine only (CAP). Selection of patients for 1 of the regimens was based on hospital policy rather than patient or tumor characteristics. The data of 504 consecutive patients (n = 181 T3+, n = 323 T4) without metastatic disease (cM0) who underwent surgery for advanced rectal carcinoma between 1994 and 2010 were reviewed. The RTH, 5FUBolus, CORE, and CAP scheme were administered to 106, 137, 155, and 106 patients, respectively. Odds ratios for downstaging were less effective for RTH, 5FUBolus, and CAP (0.31, 0.44, and 0.31; P < .0001) when compared with the CORE scheme. Odds ratios for a R1 resection (3.74, 1.94, 1.14; P = .003) or CRM+ resection (3.78, 2.73, 1.34; P = .001) were also in favor of the CORE. Hazard ratios for CSS were significantly better for the CORE scheme. Downstaging with neoadjuvant treatment results in an increased number of radical resections. In our study, the combination of capecitabine and oxaliplatin appears to be the most effective regimen for locally advanced rectal cancer tumors. However, longer follow-up will be necessary to confirm this conclusion.

  4. [Formation of oxalate in oxaliplatin injection diluted with infusion solutions].

    PubMed

    Eto, Seiji; Yamamoto, Kie; Shimazu, Kounosuke; Sugiura, Toshimune; Baba, Kaori; Sato, Ayaka; Goromaru, Takeshi; Hagiwara, Yoshiaki; Hara, Keiko; Shinohara, Yoshitake; Takahashi, Kojiro

    2014-01-01

    Oxaliplatin use can cause acute peripheral neuropathy characterized by sensory paresthesias, which are markedly exacerbated by exposure to cold temperatures, and is a dose-limiting factor in the treatment of colorectal cancer.Oxalate is eliminated in a series of nonenzymatic conversions of oxaliplatin in infusion solutions or biological fluids.Elimination of oxalate from oxaliplatin has been suggested as one of the reasons for the development of acute neuropathy.In this study, we developed a high-performance liquid chromatography(HPLC)-based method to detect oxalate formation, and investigated the time dependent formation of oxalate in oxaliplatin diluted with infusion solutions.The results obtained showed that the amount of oxalate in the solution corresponded to 1.6% of oxaliplatin 8 h after oxaliplatin dilution with a 5% glucose solution. On the other hand, oxalate formation from oxaliplatin diluted with a saline solution was ten-fold higher than that from oxaliplatin diluted with the 5% glucose solution.Most patients who were intravenously injected with oxaliplatin experienced venous pain.As a preventive measure against venous pain, dexamethasone was added to the oxaliplatin injection.We measured the amount of oxalate formed in the dexamethasone-containing oxaliplatin injection diluted with a 5% glucose solution.The amount of oxalate formed when dexamethasone was added did not differ significantly from that formed when dexamethasone was not added.Thus, there are no clinical problems associated with the stability of oxaliplatin solutions.

  5. Fixed Drug Eruption Late in the Course of Capecitabine Therapy.

    PubMed

    Del Rosario, Michael; Tsai, Henry; Dasanu, Constantin A

    2016-04-01

    A fixed drug eruption (FDE) is a toxic skin effect thought to be caused by delayed cell-mediated hypersensitivity to a pharmaceutical agent. We report herein the first known patient with capecitabine-induced FDE that appeared relatively late in the course of adjuvant therapy for rectal cancer. The temporal association with capecitabine use and prompt disappearance after capecitabine discontinuation make this relationship probable. Knowledge about this dermatologic skin effect seen with oral fluoropyrimidines should avoid unnecessary diagnostic workup and provide the necessary patient reassurance.

  6. [A case of palmoplantar dysesthesia syndrome caused by capecitabine].

    PubMed

    Elmas, Ömer Faruk; Metin, Mahmut Sami; Kızılyel, Okan; Aktaş, Akın; Birdal, Canan

    2016-01-01

    Palmoplantar dysesthesia is a dermatologic toxic reaction caused by chemotherapeutics. Also known as hand-foot syndrome, it is not life-threatening, but does decrease quality of life. Dysesthesia, erythema, edema, and desquamation on palmoplantar region are observed clinically. Palmoplantar dysesthesia syndrome may be caused by chemotherapeutics including cytarabine, doxorubicin, capecitabine, epirubicin, docetaxel, vinorelbine, and 5-fluorouracil. The case of a 62-year-old woman who presented with diffuse erythema on palmoplantar area after use of capecitabine for metastatic breast carcinoma is described in the present report. Palmoplantar dysesthesia syndrome caused by capecitabine may affect patient compliance.

  7. Orofacial neuropathic pain induced by oxaliplatin

    PubMed Central

    Ling, Jennifer; Erol, Ferhat; Viatchenko-Karpinski, Viacheslav; Kanda, Hirosato

    2017-01-01

    Neuropathic pain induced by chemotherapy drugs such as oxaliplatin is a dose-limiting side effect in cancer treatment. The mechanisms underlying chemotherapy-induced neuropathic pain are not fully understood. KCNQ2 channels are low-threshold voltage-gated K+ channels that play a role in controlling neuronal excitability. Downregulation of KCNQ2 channels has been proposed to be an underlying mechanism of sensory hypersensitivity that leads to neuropathic pain. However, it is currently unknown whether KCNQ channels may be downregulated by chemotherapy drugs in trigeminal ganglion neurons to contribute to the pathogenesis of chemotherapy-induced orofacial neuropathic pain. In the present study, mechanical sensitivity in orofacial regions is measured using the operant behavioral test in rats treated with oxaliplatin. Operant behaviors in these animals show the gradual development of orofacial neuropathic pain that manifests with orofacial mechanical allodynia. Immunostaining shows strong KCNQ2 immunoreactivity in small-sized V2 trigeminal ganglion neurons in controls, and the numbers of KCNQ2 immunoreactivity positive V2 trigeminal ganglion neurons are significantly reduced in oxaliplatin-treated animals. Immunostaining is also performed in brainstem and shows strong KCNQ2 immunoreactivity at the trigeminal afferent central terminals innervating the caudal spinal trigeminal nucleus (Vc) in controls, but the KCNQ2 immunoreactivity intensity is significantly reduced in oxaliplatin-treated animals. We further show with the operant behavioral test that oxaliplatin-induced orofacial mechanical allodynia can be alleviated by the KCNQ2 potentiator retigabine. Taken together, these findings suggest that KCNQ2 downregulation may be a cause of oxaliplatin-induced orofacial neuropathic pain and KCNQ2 potentiators may be useful for alleviating the neuropathic pain. PMID:28741430

  8. Addition of erlotinib to fluoropyrimidine-oxaliplatin-based chemotherapy with or without bevacizumab: Two sequential phase I trials.

    PubMed

    Carlomagno, Chiara; Daniele, Gennaro; Bianco, Roberto; Marciano, Roberta; Damiano, Vincenzo; Matano, Elide; Nappi, Lucia; Pepe, Stefano; DE Placido, Sabino; Tortora, Giampaolo

    2011-05-01

    The combination of EGFR inhibitors and anti-angiogenic drugs has a strong pre-clinical rationale, yet its use has produced controversial clinical results. We conducted two sequential phase I trials to evaluate the feasibility and the recommended dose of erlotinib when combined with fluoropyrimidine-oxaliplatin-based chemotherapy with or without bevacizumab. A total of 21 metastatic colorectal cancer (mCRC) patients were treated in two sequential phase I trials. In the first trial, 12 patients were treated with escalating doses of erlotinib plus FOLFOX. In the second, 9 patients were treated with escalating doses of erlotinib combined with oxaliplatin, capecitabine and bevacizumab. No MTD was reached in either of the trials. The only dose-limiting toxicities observed were neutropenia and diarrhea. No unexpected toxicities were noted. Hematological toxicity was the most frequently noted adverse event with infusional 5FU therapy, while gastrointestinal toxicity was the most common adverse event. In the second trial most patients withdrew from treatment due to toxicity, and less than half completed the therapeutic program as per protocol, mostly due to toxicity. In conclusion, the present study confirms the disappointing results of the double combination of EGFR inhibitors and anti-angiogenic drugs in mCRC patients.

  9. Addition of erlotinib to fluoropyrimidine-oxaliplatin-based chemotherapy with or without bevacizumab: Two sequential phase I trials

    PubMed Central

    CARLOMAGNO, CHIARA; DANIELE, GENNARO; BIANCO, ROBERTO; MARCIANO, ROBERTA; DAMIANO, VINCENZO; MATANO, ELIDE; NAPPI, LUCIA; PEPE, STEFANO; DE PLACIDO, SABINO; TORTORA, GIAMPAOLO

    2011-01-01

    The combination of EGFR inhibitors and anti-angiogenic drugs has a strong pre-clinical rationale, yet its use has produced controversial clinical results. We conducted two sequential phase I trials to evaluate the feasibility and the recommended dose of erlotinib when combined with fluoropyrimidine-oxaliplatin-based chemotherapy with or without bevacizumab. A total of 21 metastatic colorectal cancer (mCRC) patients were treated in two sequential phase I trials. In the first trial, 12 patients were treated with escalating doses of erlotinib plus FOLFOX. In the second, 9 patients were treated with escalating doses of erlotinib combined with oxaliplatin, capecitabine and bevacizumab. No MTD was reached in either of the trials. The only dose-limiting toxicities observed were neutropenia and diarrhea. No unexpected toxicities were noted. Hematological toxicity was the most frequently noted adverse event with infusional 5FU therapy, while gastrointestinal toxicity was the most common adverse event. In the second trial most patients withdrew from treatment due to toxicity, and less than half completed the therapeutic program as per protocol, mostly due to toxicity. In conclusion, the present study confirms the disappointing results of the double combination of EGFR inhibitors and anti-angiogenic drugs in mCRC patients. PMID:22977524

  10. Signal Estimation from Short-Time Spectral Magnitude.

    DTIC Science & Technology

    1982-05-01

    Procesing ............................................. 8 1.3 Previous Investigations...disadvantage in several applications, par- ticularly those involving speech and images . For example, a speech waveform consists of voiced and unvoiced sections...respect to the origin. Consequently, the short-time spectrum is generally a complex function. In many short-time spectral procesing applications both the

  11. Durable response of breast cancer leptomeningeal metastasis to capecitabine monotherapy

    PubMed Central

    Rogers, Lisa R.; Remer, Sandra E.; Tejwani, Sheela

    2004-01-01

    We report a durable (12-month) response to capecitabine monotherapy, shown clinically, by MRI, and by cerebrospinal fluid analysis, in a patient with leptomeningeal metastasis from breast cancer. PMID:14769142

  12. Isolated hypomagnesemia in a patient treated with capecitabine.

    PubMed

    Rajapakse, Senaka; Rodrigo, Chaturaka; Rajapakse, Anoja C

    2013-09-01

    Hypomagnesemia is known to occur for a variety of renal, gastrointestinal and other causes, and is often associated with other electrolyte and metabolic disturbances. We present a case of isolated hypomagnesemia in a patient who had been treated with the chemotherapy agent capecitabine. The approach to diagnosis and treatment is discussed. We postulate that capecitabine may cause isolated hypomagnesemia, possibly due to renal magnesium loss.

  13. 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.

  14. Short time-series microarray analysis: Methods and challenges

    PubMed Central

    Wang, Xuewei; Wu, Ming; Li, Zheng; Chan, Christina

    2008-01-01

    The detection and analysis of steady-state gene expression has become routine. Time-series microarrays are of growing interest to systems biologists for deciphering the dynamic nature and complex regulation of biosystems. Most temporal microarray data only contain a limited number of time points, giving rise to short-time-series data, which imposes challenges for traditional methods of extracting meaningful information. To obtain useful information from the wealth of short-time series data requires addressing the problems that arise due to limited sampling. Current efforts have shown promise in improving the analysis of short time-series microarray data, although challenges remain. This commentary addresses recent advances in methods for short-time series analysis including simplification-based approaches and the integration of multi-source information. Nevertheless, further studies and development of computational methods are needed to provide practical solutions to fully exploit the potential of this data. PMID:18605994

  15. Topical henna for capecitabine induced hand-foot syndrome.

    PubMed

    Yucel, Idris; Guzin, Gonullu

    2008-04-01

    Capecitabine is a chemotherapeutic drug for use in cancers. Hand-foot syndrome (HFS) is side effect of capecitabine which can lead the cessation of the therapy or dose reduction. Henna (Lawsonia inermis) is a traditionally used plant of Middle-East that is applied on hands and feet. Some of cancer patients in capecitabine treatment who developed HFS, we recommended to apply henna. In these patients, six patients were grade 3 HFS and four were grade 2 HFS. Complete response (CR) were seen in four of grade 3 HFS and all of grade 2; two grade 3 HFS improved to grade 1. So far, in the chemotherapy, there was no need of dose reduction and also no side effect of henna seen. Clinical improvement in these patients may relate to anti-inflammatory, antipyretic and analgesic effects of henna. Prospective studies are needed to show this therapeutic effect of henna.

  16. 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

  17. Short-Time Behavior and Criticality of Driven Lattice Gases

    NASA Astrophysics Data System (ADS)

    Basu, Urna; Volpati, Valerio; Caracciolo, Sergio; Gambassi, Andrea

    2017-02-01

    The nonequilibrium short-time critical behaviors of driven and undriven lattice gases are investigated via Monte Carlo simulations in two spatial dimensions starting from a fully disordered initial configuration. In particular, we study the time evolution of suitably defined order parameters, which account for the strong anisotropy introduced by the homogeneous drive. We demonstrate that, at short times, the dynamics of all these models is unexpectedly described by an effective continuum theory in which transverse fluctuations, i.e., fluctuations averaged along the drive, are Gaussian, irrespective of this being actually the case in the stationary state. Strong numerical evidence is provided, in remarkable agreement with that theory, both for the driven and undriven lattice gases, which therefore turn out to display the same short-time dynamics.

  18. Short-time quantum propagator and Bohmian trajectories☆

    PubMed Central

    de Gosson, Maurice; Hiley, Basil

    2013-01-01

    We begin by giving correct expressions for the short-time action following the work Makri–Miller. We use these estimates to derive an accurate expression modulo Δt2 for the quantum propagator and we show that the quantum potential is negligible modulo Δt2 for a point source, thus justifying an unfortunately largely ignored observation of Holland made twenty years ago. We finally prove that this implies that the quantum motion is classical for very short times. PMID:24319313

  19. Capecitabine and docetaxel combination for the treatment of breast cancer.

    PubMed

    Morishita, Mariko; Leonard, Robert C

    2008-01-01

    The management of breast cancer depends on the tumor and patient's characteristics. Anthracycline-based regimens have been proven to decrease the risk of relapse and prolong survival time in breast cancer. Taxanes have been incorporated not only into metastatic breast cancer but also into adjuvant regimens. Capecitabine, an oral fluoropyrimidine carbamate, has good single-agent activity and, together with docetaxel, demonstrated preclinical synergy and a survival benefit in metastatic breast cancer. Recent analyses show that capecitabine/docetaxel dosing flexibility for managing side effects does not compromise efficacy, and define this combination regimen as an important treatment option for its efficacy, tolerability and cost-effectiveness.

  20. Short-time dynamics of molecular junctions after projective measurement

    NASA Astrophysics Data System (ADS)

    Tang, Gaomin; Xing, Yanxia; Wang, Jian

    2017-08-01

    In this work, we study the short-time dynamics of a molecular junction described by Anderson-Holstein model using full-counting statistics after projective measurement. The coupling between the central quantum dot (QD) and two leads was turned on at remote past and the system is evolved to steady state at time t =0 , when we perform the projective measurement in one of the lead. Generating function for the charge transfer is expressed as a Fredholm determinant in terms of Keldysh nonequilibrium Green's function in the time domain. It is found that the current is not constant at short times indicating that the measurement does perturb the system. We numerically compare the current behaviors after the projective measurement with those in the transient regime where the subsystems are connected at t =0 . The universal scaling for high-order cumulants is observed for the case with zero QD occupation due to the unidirectional transport at short times. The influences of electron-phonon interaction on short-time dynamics of electric current, shot noise, and differential conductance are analyzed.

  1. Preparation and evaluations in vitro of oxaliplatin polylactic acid nanoparticles.

    PubMed

    Cui, Zhaoyuan; Sun, Yong; Liu, Xiaohong; Ju, Fang; Chen, Qian; Gao, Wen; Wei, Haitian

    2013-08-01

    The oxaliplatin nanoparticles were prepared with polylactic acid matrix, orthogonal test was applied to optimize the prescriptions, and the qualities of oxaliplatin nanoparticles were characterized by the shape, particle size, encapsulation efficiency (EE), and drug loading (DL). Oxaliplatin nanoparticle was prepared by solution replacement method. The formation of 0.25% Tween80, DMF-water 1:8 (v/v), oxaliplatin-polylactic acid 1:5 (w/w), and 20 mg/ml polylactic acid showed the suitable EE (17.4 ± 0.47%), DL (3.52 ± 0.07%). We observed the shape of oxaliplatin nanoparticles through SEM. The average size of the particles was 120.5 ± 8.7 nm, which was detected by N5 submicron particle size analyzer.

  2. Desensitization with oxaliplatin in patients intolerant of carboplatin desensitization.

    PubMed

    Rose, Peter G; Metz, Carol; Link, Nicolas

    2014-11-01

    The tolerance and efficacy of oxaliplatin desensitization in patients who were intolerant of carboplatin desensitization were determined. We retrospectively reviewed the Gynecologic Oncology patients who received carboplatin or oxaliplatin from December 2007 until August 2014. The number of treatments and number of patients of carboplatin standard infusions, carboplatin desensitizations, and oxaliplatin desensitizations were determined. Carboplatin infusions (2294) were administered to 281 patients. Twenty-eight (10%) of these patients developed carboplatin hypersensitivity and were treated with 205 carboplatin desensitizations. Nine (29%) patients were subsequently treated with 61 oxaliplatin desensitizations due to intolerance of carboplatin desensitization. Nine of the 10 patients tolerated this infusion well. Four of 9 evaluable patients had an objective response, 2 complete and 2 partial. Oxaliplatin desensitization seems well tolerated and effective in most patients who are intolerant of carboplatin desensitization.

  3. 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

  4. Capecitabine treatment patterns in patients with gastroesophageal cancer in the United States

    PubMed Central

    Saif, Muhammad Wasif; Shi, Nianwen; Zelt, Susan

    2009-01-01

    AIM: To assess the use of capecitabine-based therapy and associated complication rates in patients with gastroesophageal cancer (GEC) in a real-world treatment setting. METHODS: Patients with claims between 2004 and 2005 were identified from the Thomson Reuters MarketScan® databases. Capecitabine regimens were compared with 5-fluorouracil (5-FU) and other chemotherapy regimens, and were stratified by treatment setting. RESULTS: We identified 1013 patients with GEC: approximately half had treatment initiated with a 5-FU regimen, whereas 11% had therapy initiated with a capecitabine regimen. The mean capecitabine dose overall was 2382 ± 1118 mg/d, and capecitabine was used as monotherapy more often than in combination. Overall, 5-FU regimens were the most common treatment option in neoadjuvant and adjuvant settings, while other non-capecitabine regimens were used more widely in first- and second-line settings. The overall unadjusted complication rate for capecitabine regimens was about half of that seen with 5-FU regimens. In multivariate analyses, capecitabine recipients had a 51% (95% CI: 26%-81%) lower risk of developing any complication than 5-FU recipients did. The risk of developing bone marrow, constitutional, gastrointestinal tract, infectious, or skin complications was lower with capecitabine therapy than with 5-FU. CONCLUSION: Capecitabine appeared to have a favorable side effect profile compared with 5-FU, which indicates that it may be a treatment option for GEC. PMID:19764093

  5. Minimal model for short-time diffusion in periodic potentials.

    PubMed

    Emary, Clive; Gernert, Robert; Klapp, Sabine H L

    2012-12-01

    We investigate the dynamics of a single, overdamped colloidal particle, which is driven by a constant force through a one-dimensional periodic potential. We focus on systems with large barrier heights where the lowest-order cumulants of the density field, that is, average position and the mean-squared displacement, show nontrivial (nondiffusive) short-time behavior characterized by the appearance of plateaus. We demonstrate that this "cage-like" dynamics can be well described by a discretized master equation model involving two states (related to two positions) within each potential valley. Nontrivial predictions of our approach include analytic expressions for the plateau heights and an estimate of the "de-caging time" obtained from the study of deviations from Gaussian behavior. The simplicity of our approach means that it offers a minimal model to describe the short-time behavior of systems with hindered dynamics.

  6. Universal short-time quantum critical dynamics in imaginary time

    NASA Astrophysics Data System (ADS)

    Yin, Shuai; Mai, Peizhi; Zhong, Fan

    2014-04-01

    We propose a scaling theory for the universal imaginary-time quantum critical dynamics for both short and long times. We discover that there exists a universal critical initial slip related to a small initial order parameter M0. In this stage, the order parameter M increases with the imaginary time τ as M ∝M0τθ with a universal initial-slip exponent θ. For the one-dimensional transverse-field Ising model, we estimate θ to be 0.373, which is markedly distinct from its classical counterpart. Apart from the local order parameter, we also show that the entanglement entropy exhibits universal behavior in the short-time region. As the critical exponents in the early stage and in equilibrium are identical, we apply the short-time dynamics method to determine quantum critical properties. The method is generally applicable in both the Landau-Ginzburg-Wilson paradigm and topological phase transitions.

  7. Identification of new SNPs associated with severe toxicity to capecitabine.

    PubMed

    Pellicer, Marta; García-González, Xandra; García, María I; Robles, Luis; Grávalos, Cristina; García-Alfonso, Pilar; Pachón, Vanessa; Longo, Federico; Martínez, Virginia; Blanco, Carolina; Iglesias, Irene; Sanjurjo, María; López-Fernández, Luis A

    2017-06-01

    Predicting individual risk of chemotherapy-induced severe adverse reaction is a critical issue when selecting the best treatment for cancer patients. SNPs have been identified in genes involved in the pharmacodynamics of fluoropyrimidines, and guidelines even recommend genotyping some DPYD variants in order to estimate the risk of toxicity. However, the predictive value of this approach remains insufficient, thus limiting its clinical implementation. The aim of the present study was to identify new genetic variants by selecting a group of tag SNPs in genes associated with the pharmacodynamics of fluoropyrimidines (CDA, DPYD, ENOSF1, CES1, TYMS, SLC22A7, TYMP, and UMPS). For this purpose, 23 selected SNPs were genotyped on an OpenArray™ platform in a cohort of 301 colorectal cancer patients receiving capecitabine-based chemotherapy. Univariate and multivariate statistical analysis by logistic regression revealed 10 SNPs associated with severe adverse reactions to capecitabine (P<0.05): rs1048977, rs12726436, and rs2072671 in CDA; rs12119882 in DPYD; rs2853741 in TYMS; rs699517 in TYMS/ENOSF1; rs2270860 and rs4149178 in SLC22A7; and rs2279199 and rs4678145 in UMPS. Except for rs2072671, no association had previously been reported between these SNPs and the risk of capecitabine-induced toxicity. The use of tag SNPs to find new polymorphisms related to adverse reactions to capecitabine was successful. These new variants could increase the predictive power of currently available tests and thus prevent severe adverse reactions to capecitabine. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. 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.

  9. Bernstein polynomials for evolutionary algebraic prediction of short time series

    NASA Astrophysics Data System (ADS)

    Lukoseviciute, Kristina; Howard, Daniel; Ragulskis, Minvydas

    2017-07-01

    Short time series prediction technique based on Bernstein polynomials is presented in this paper. Firstly, the straightforward Bernstein polynomial extrapolation scheme is improved by extending the interval of approximation. Secondly, the forecasting scheme is designed in the evolutionary computational setup which is based on the conciliation between the coarseness of the algebraic prediction and the smoothness of the time average prediction. Computational experiments with the test time series suggest that this time series prediction technique could be applicable for various forecasting applications.

  10. Distinguishing quasiperiodic dynamics from chaos in short-time series.

    PubMed

    Zou, Y; Pazó, D; Romano, M C; Thiel, M; Kurths, J

    2007-07-01

    We propose a procedure to distinguish quasiperiodic from chaotic orbits in short-time series, which is based on the recurrence properties in phase space. The histogram of the return times in a recurrence plot is introduced to disclose the recurrence property consisting of only three peaks imposed by Slater's theorem. Noise effects on the statistics are studied. Our approach is demonstrated to be efficient in recognizing regular and chaotic trajectories of a Hamiltonian system with mixed phase space.

  11. 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.

  12. 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

    2016-06-30

    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.

  13. 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. PMID:27493845

  14. Protection against oxaliplatin acute neurosensory toxicity by venlafaxine.

    PubMed

    Durand, Jean-Philippe; Brezault, Catherine; Goldwasser, François

    2003-07-01

    Venlafaxine (Effexor; Wyeth Lederlé) has previously shown therapeutic effects for the management of chronic and neuropathic pains. We report here the efficacy of venlafaxine upon acute neurosensory symptoms secondary to oxaliplatin toxicity. A dose of 50 mg of venlafaxine was given orally at the beginning of the oxaliplatin infusion. Patients did not experience any or very low paresthesias, even in the cold. As the results were very dramatic and reproducible, we propose that venlafaxine may be of use in the daily management of oxaliplatin-related neurosensory toxicity.

  15. Safety and pharmacokinetics of sorafenib combined with capecitabine in patients with advanced solid tumors: results of a phase 1 trial.

    PubMed

    Awada, Ahmad; Gil, Thierry; Whenham, Nicolas; Van Hamme, Julie; Besse-Hammer, Tatiana; Brendel, Erich; Delesen, Heinz; Joosten, Miranda C; Lathia, Chetan D; Loembé, Bienvenu A; Piccart-Ghebart, Martine; Hendlisz, Alain

    2011-12-01

    Sorafenib (twice daily [bid]) plus capecitabine (2 weeks on schedule/1 week off schedule) safety and pharmacokinetics were investigated in patients with advanced solid tumors (N = 35). Cohort 1 (n = 13) included sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid; cohort 2 (n = 4), sorafenib 400 mg bid and capecitabine 1050 mg/m(2) bid; cohort 3 (n = 6), sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid (cycles 1 and 2), then 400 mg bid and capecitabine 1050 mg/m(2) bid (cycle 3 onwards); and cohort 4 (n = 12), sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid. The combination of sorafenib and capecitabine was generally well tolerated. Most frequent drug-related adverse events were hand-foot skin reaction (HFSR, 89%), diarrhea (71%), and fatigue (69%). The HFSR was dose-limiting toxicities in 6 patients. Sorafenib exposure (C(max) and AUC(0-12)) was unaffected by concomitant capecitabine. Concomitant sorafenib moderately increased capecitabine and 5-fluorouracil (metabolite) exposure when the capecitabine dose was 1050 mg/m(2) bid. Simultaneous administration of 400 mg bid sorafenib and 850 mg/m(2) bid capecitabine, however, had only minor effects on the exposure to capecitabine and 5-fluorouracil. Based on the overall toxicity profile and pharmacokinetic parameters, the recommended phase 2 doses were therefore sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid, as scheduled above.

  16. Liposomal pegylated doxorubicin and oxaliplatin as salvage chemotherapy in patients with metastatic gastric cancer treated earlier.

    PubMed

    Recchia, Francesco; Candeloro, Giampiero; Guerriero, Gabriele; Piazze, Juan; Desideri, Giovambattista; Necozione, Stefano; Rea, Silvio

    2010-06-01

    The aim of this study was to evaluate the activity and safety of pegylated liposomal doxorubicin (PLD) and oxaliplatin (LOHP) as salvage chemotherapy in patients with metastatic gastric cancer (MGC) who had earlier been treated with docetaxel, capecitabine, 5-fluorouracil, and leucovorin. Treatment consisted of PLD (40 mg/m(2)) and LOHP (120 mg/m(2)) administered over 2 days, every 3 weeks. Response to therapy was assessed using the Response Evaluation Criteria In Solid Tumors; toxicity was evaluated by the National Cancer Institute common toxicity criteria (version 2.0). Thirty-six patients with pretreated MGC and a mean age of 66 years were recruited for the study. After a median follow-up of 11 months and 202 courses of chemotherapy administered (median, five courses per patient), the overall response rate in the 36 evaluable patients was estimated to be 28%. Grades 3 and 4 hematological toxicities were neutropenia in 44% of patients, grade 2-3 diarrhea in 14% of patients, and grade 2 neuropathy in 12 patients. Median progression-free survival and overall survival were 5.8 and 9.2 months, respectively, with 1-year survival rate of 36%, [95% confidence interval (CI): 21-54%]. Median survival time from the diagnosis of metastatic disease was 31.5 months. Seventy-two percent of patients (n=26) (95% CI: 58-88%) obtained a clinical benefit from this chemotherapy regimen. PLD and LOHP is an active regimen, able to give palliation in a substantial percentage of MCG patients who have been pretreated with taxanes.

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. Evaluation of scaling invariance embedded in short time series.

    PubMed

    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 ~10(2). Calculations with specified Hurst exponent values of 0.2,0.3,...,0.9 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 (≤0.03) and sharp confidential interval (standard deviation ≤0.05). 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.

  2. 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.).

  3. Acute chest pain in a patient treated with capecitabine

    PubMed Central

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

    2009-01-01

    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®) 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;17:288-91.19789697) PMID:19789697

  4. Molecular Mechanisms of Taste Disorder in Oxaliplatin-administered Rats.

    PubMed

    Nishida, Kentaro

    2016-01-01

    Taste disorder is one of the adverse effects of cancer chemotherapy resulting in a loss of appetite, leading to malnutrition and a decrease in the quality of life of the patient. Oxaliplatin, a platinum anticancer drug, has a critical role in colon cancer chemotherapy and is known to induce taste disorder. Here, we evaluated the taste functions in oxaliplatin-administered rats. Among the taste receptors, expression levels of T1R2, one of the sweet receptor subunits, increased in the circumvallate papillae of the oxaliplatin-administered rats. In a brief-access test, i.e., behavioral analysis of the taste response, oxaliplatin-administered rats showed a decreased response to sweet taste. However, we did not detect any differences in the plasma levels of zinc, number of taste cells, or morphology of taste buds between control and oxaliplatin-administered rats. In conclusion, the decreased response to sweet taste by oxaliplatin administration may be due to the upregulation of T1R2 expression.

  5. Network insights on oxaliplatin anti-cancer mechanisms.

    PubMed

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

    2012-10-29

    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.

  6. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes.

    PubMed

    Hortobagyi, Gabriel N; Gomez, Henry L; Li, Rubi K; Chung, Hyun-Cheol; Fein, Luis E; Chan, Valorie F; Jassem, Jacek; Lerzo, Guillermo L; Pivot, Xavier B; Hurtado de Mendoza, Fernando; Xu, Binghe; Vahdat, Linda T; Peck, Ronald A; Mukhopadhyay, Pralay; Roché, Henri H

    2010-07-01

    Limited proven treatment options exist for patients with metastatic breast cancer (MBC) resistant to anthracycline and taxane treatment. Ixabepilone, a novel semisynthetic analog of epothilone B, has demonstrated single-agent activity in MBC resistant to anthracyclines and taxanes. In combination with capecitabine in a phase III trial (CA163-046) in this setting, ixabepilone prolonged progression-free survival and increased objective response rate relative to capecitabine (Thomas et al. J Clin Oncol 25:5210-5217, 2007). Here, we report the results of overall survival (OS), a secondary efficacy endpoint from the CA163-046 trial. Seven hundred fifty-two patients with MBC resistant to anthracyclines and taxanes were randomized to ixabepilone (40 mg/m(2) intravenously on day 1 of a 21-day cycle) plus capecitabine (2,000 mg/m(2) orally on days 1 through 14 of a 21-day cycle) or capecitabine alone (2,500 mg/m(2) on the same schedule). Patients receiving ixabepilone plus capecitabine treatment had a median survival of 12.9 months compared to 11.1 months for patients receiving capecitabine alone (HR = 0.9; 95%CI: 077-1.05; P = 0.19). This observed increase in median OS favored the combination; however, the difference was not statistically significant. Predefined subset analyses showed a clinically meaningful increase in OS in KPS 70-80 patients receiving ixabepilone plus capecitabine (HR = 0.75; 95% CI: 0.58-0.98). Ixabepilone plus capecitabine did not show a significant improvement in survival compared to capecitabine alone in patients with MBC resistant to anthracyclines and taxanes. The observed differences in survival favored the combination arm. A clinical benefit was also seen in patients in the KPS 70-80 subgroup.

  7. Capecitabine for skin cancer prevention in solid organ transplant recipients.

    PubMed

    Jirakulaporn, Tanawat; Endrizzi, Bart; Lindgren, Bruce; Mathew, Josy; Lee, Peter K; Dudek, Arkadiusz Z

    2011-01-01

    Skin cancers are the most common malignancies in solid organ transplant recipients (SOTR). A case-observational, retrospective study was performed to determine the efficacy of low-dose capecitabine in the secondary prevention of skin cancers in SOTRs treated at a single institution. SOTRs with recurrent squamous cell carcinoma (SCC) and/or basal cell carcinoma (BCC) were given low-dose capecitabine 1 g/m(2) daily, days 1-14 of a 21-d treatment cycle. Skin surveillance was performed by dermatologists every 1-3 months. Cumulative incidence rates of SCC, BCC, and actinic keratosis (AK) before and after treatment were scored and statistically compared for each patient using a non-parametric Wilcoxon signed rank test. Fifteen patients (13 men and two women) with a median age of 57 yr (range 40-73) were treated. Incidence rates as measured by mean number of events per month declined by 0.33 for SCC, 0.04 for BCC, and 2.45 for AK (p < 0.05). The most common grade 3 and 4 toxicities included fatigue (40.0%), hand-foot syndrome (20.0%), and diarrhea (20.0%). The discontinuation rate at one yr was approximately 33.3%. We conclude that oral capecitabine significantly decreases the incidence rates of recurrent SCC, BCC, and AK in SOTRs and is associated with manageable toxicity. © 2010 John Wiley & Sons A/S.

  8. EphA2 affects the sensitivity of oxaliplatin by inducing EMT in oxaliplatin-resistant gastric cancer cells.

    PubMed

    Wen, Qiaocheng; Chen, Zihua; Chen, Zhikang; Chen, Jinxiang; Wang, Ran; Huang, Changhao; Yuan, Weijie

    2017-07-18

    Erythropoietin-producing hepatocellular receptor A2 (EphA2) is upregulated in gastric cancer tissues and cells, which is accompanied by epithelial-mesenchymal transition (EMT). The current study was designed to establish the oxaliplatin-resistant human gastric cancer cell line SGC-7901/L-OHP, to determine if EMT in these cells could be reversed, and to determine if the susceptibility of these cells to oxaliplatin was affected by silencing EphA2 expression. We found that EphA2 expression levels were upregulated in gastric cancer and associated with chemotherapy sensitivity. EphA2 and the EMT molecular markers N-cadherin and Snail were upregulated in SGC-7901/L-OHP cells, while silencing of EphA2 using small interfering RNA had the opposite effect. Moreover, silencing of EphA2 inhibited cell migration and invasion, and significantly enhanced the sensitivity of oxaliplatin-resistant gastric cancer cells to oxaliplatin. These observations demonstrate that EphA2 affects the sensitivity to oxaliplatin by inducing EMT in oxaliplatin-resistant gastric cancer cells.

  9. 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.

  10. Ischemic subglottic damage following a short-time intubation.

    PubMed

    Silva, Marta João; Aparício, José; Mota, Teresa; Spratley, Jorge; Ribeiro, Augusto

    2008-12-01

    The objective of this study is to report a case of ischemic subglottic damage after a short-time intubation with a large, overinflated endotracheal tube cuff in a child. The study uses individual case report. A 6-year-old boy was admitted to the pediatric intensive care unit after a head trauma intubated with a 5.5-mm inner diameter cuffed endotracheal tube overinflated with 16 ml of air that produced a pressure of more than 120 cm H2O. The endotracheal tube cuff pressure produced by inflation was reduced after 4 h. The child presented postextubation stridor with subglottic edema. Inappropriate handling of tracheal intubation without accurate measurement of endotracheal tube size and intracuff pressures of endotracheal tubes, can cause airway trauma and place patients at risk.

  11. Permutation test for periodicity in short time series data

    PubMed Central

    Ptitsyn, Andrey A; Zvonic, Sanjin; Gimble, Jeffrey M

    2006-01-01

    Background Periodic processes, such as the circadian rhythm, are important factors modulating and coordinating transcription of genes governing key metabolic pathways. Theoretically, even small fluctuations in the orchestration of circadian gene expression patterns among different tissues may result in functional asynchrony at the organism level and may contribute to a wide range of pathologic disorders. Identification of circadian expression pattern in time series data is important, but equally challenging. Microarray technology allows estimation of relative expression of thousands of genes at each time point. However, this estimation often lacks precision and microarray experiments are prohibitively expensive, limiting the number of data points in a time series expression profile. The data produced in these experiments carries a high degree of stochastic variation, obscuring the periodic pattern and a limited number of replicates, typically covering not more than two complete periods of oscillation. Results To address this issue, we have developed a simple, but effective, computational technique for the identification of a periodic pattern in relatively short time series, typical for microarray studies of circadian expression. This test is based on a random permutation of time points in order to estimate non-randomness of a periodogram. The Permutated time, or Pt-test, is able to detect oscillations within a given period in expression profiles dominated by a high degree of stochastic fluctuations or oscillations of different irrelevant frequencies. We have conducted a comprehensive study of circadian expression on a large data set produced at PBRC, representing three different peripheral murine tissues. We have also re-analyzed a number of similar time series data sets produced and published independently by other research groups over the past few years. Conclusion The Permutated time test (Pt-test) is demonstrated to be effective for detection of periodicity in

  12. Preoperative Modified FOLFIRINOX Treatment Followed by Capecitabine-Based Chemoradiation for Borderline Resectable Pancreatic Cancer

    PubMed Central

    Katz, Matthew H. G.; Shi, Qian; Ahmad, Syed A.; Herman, Joseph M.; Marsh, Robert de W.; Collisson, Eric; Schwartz, Lawrence; Frankel, Wendy; Martin, Robert; Conway, William; Truty, Mark; Kindler, Hedy; Lowy, Andrew M.; Bekaii-Saab, Tanios; Philip, Philip; Talamonti, Mark; Cardin, Dana; LoConte, Noelle; Shen, Perry; Hoffman, John P.; Venook, Alan P.

    2016-01-01

    IMPORTANCE Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported. OBJECTIVE To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting. DESIGN, SETTING, AND PARTICIPANTS A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50–76 years]; 55% female). Patients registered between May 29, 2013, and February 7,2014. INTERVENTIONS Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan hydrochloride, 400 mg/m2 of leucovorin calcium, and then 2400 mg/m2 of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2 orally twice daily) prior to pancreatectomy. MAIN OUTCOMES AND MEASURES Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate. RESULTS The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%–83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%–88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins

  13. Pharmacokinetics and exposure-effect relationships of capecitabine in elderly patients with breast or colorectal cancer

    PubMed Central

    Daher-Abdi, Zeinab; Lavau-Denes, Sandrine; Prémaud, Aurélie; Urien, Saik; Sauvage, François-Ludovic; MARTIN, Jean; Leobon, Sophie; Marquet, Pierre; Tubiana-Mathieu, Nicole; Rousseau, Annick

    2014-01-01

    Purpose The aims of the present study were (i) to investigate the impact of great age on pharmacokinetics of capecitabine and its metabolites and (ii) to evaluate the exposure/effect relationship of capecitabine in elderly patients. Methods Data collected from 20 elderly patients (75–92 years old) with breast or colorectal cancer, who received oral capecitabine were analyzed. In order to study the old age effect on pharmacokinetics, data collected from two phase I studies involving 40 younger adults (<75 years old) with metastatic cancer who received oral capecitabine, were added in the database. The population pharmacokinetic analysis was based on a four compartment model describing the sequence of capecitabine and three of its metabolites. Results The absorption rate constant was found lower in the oldest patient group (≥75 y) compared to the youngest group, and the constant rate elimination of the 5-fluorouracil metabolite was found decreased over time (i.e. after 2 consecutive weeks of capecitabine administration). This time effect was not found different between the two age groups. In elderly patients, the exposure-safety analysis showed, from the second cycle of chemotherapy, significantly higher median exposures of capecitabine and its metabolites (5′-deoxy-5-fluorocytidine,5′-deoxy-5-fluorouridine and 5-fluorouracil) in patients who experienced hand-foot syndrome compared to patients who did not. Conclusion This study puts forward new arguments for the treatment of elderly cancer patients who could benefit from capecitabine chemotherapy with acceptable toxicity. PMID:24801171

  14. Dramatic regression of multiple brain metastases from breast cancer with Capecitabine: another arrow at the bow?

    PubMed

    Fabi, A; Vidiri, A; Ferretti, G; Felici, A; Papaldo, P; Carlini, P; Mirri, A; Nuzzo, C; Cognetti, F

    2006-01-01

    Several chemotherapic agents, which are active against breast cancer, penetrate poorly into the central nervous system. Despite its limited brain penetration, 5-fluorouracil has been a component of effective regimens for brain metastases. Capecitabine is a recently developed oral prodrug that is converted into 5-fluorouracil by sequential enzymatic steps. Thymidine phosphorylase (TP) is the final enzyme responsible for Capecitabine activation. Studies have demonstrated that high intratumoral levels of TP and low levels of its catabolite dihydropyrimidine-dehydrogenase are correlated with the capecitabine response. The penetration of Capecitabine across the brain-blood barrier remains unknown; we report the case of and discuss a breast cancer patient who had an interesting response of brain metastases with Capecitabine in monochemotherapy before brain irradiation.

  15. Role of capecitabine in treating metastatic colorectal cancer in Chinese patients

    PubMed Central

    Wang, Feng; Wang, Feng-Hua; Bai, Long; Xu, Rui-Hua

    2014-01-01

    The China Food and Drug Administration approved the use of capecitabine in patients with metastatic colorectal cancer (mCRC) in 2004. This paper reviews the available information of capecitabine in Chinese patients with mCRC, focusing on its effectiveness and safety against mCRC. Identification of all eligible studies was made by searching the PubMed and Wanfang database from 2000 to 2013. Published data examining various aspects of clinical response and tolerability with capecitabine alone or in combination with other chemotherapeutic or biological agents for first- and second-line mCRC were examined. Capecitabine and its combination displayed high efficacy in Chinese patients with mCRC. Toxicities are generally manageable, and elderly patients can tolerate capecitabine well. PMID:24729715

  16. Self-identification and management of hand-foot syndrome (HFS): effect of a structured teaching program on patients receiving capecitabine-based chemotherapy for colon cancer.

    PubMed

    Murugan, Kalaivani; Ostwal, Vikas; Carvalho, Maria Deo; D'souza, Anita; Achrekar, Meera S; Govindarajan, Shrinivasan; Gupta, Sudeep

    2016-06-01

    Capecitabine is an oral prodrug of 5-fluorouracil and is commonly used oral chemotherapeutic drugs for advanced gastric and colorectal cancer. However, hand-foot syndrome (HFS) has high incidence, and once developed, the symptoms significantly impair quality of life (QOL), leading to a reduction in the dosage or discontinuation of the treatment. Effective health education should be offered to patients to promote self-identification and management on how to recognize HFS and use self-management techniques at the very beginning of chemotherapy. The present study intended to evaluate the effectiveness of structured teaching program on knowledge related to self-identification and management of HFS among patients receiving chemotherapy for colon cancer at tertiary cancer care center. Participants who fulfilled the criteria were selected using non-probability purposive sampling. The sample selected were 40 participants (20 participants in experimental group and 20 participants in control group). Among the group of 40 patients, 17 (85 %) participants in the experimental group and 17 (85 %) participants in the control group were receiving capecitabine and oxaliplatin (CAPOX) chemotherapy treatment protocol. Five (25 %) participants in the experimental group and ten (50 %) participants in the control group were receiving drug capecitabine at a dose of 2500 mg. The mean knowledge (knowledge related to self-identification and management of HFS) pretest score was 6.75 and mean knowledge posttest score was 10.25 in the experimental group which was statistically significant (p = 0.000) (p < 0.05). The mean knowledge pretest score of participants was 6.45 and mean knowledge posttest score of participants was 6.75 in the control group which was not statistically significant (p = 0.67) (p > 0.05). The study showed a statistically significant improvement in knowledge scores of participants that occurred due to intervention of structured teaching program. This

  17. Measurement of hyperpolarized gas diffusion at very short time scales

    PubMed Central

    Carl, Michael; Wilson Miller, G.; Mugler, John P.; Rohrbaugh, Scott; Tobias, William A.; Cates, Gordon D.

    2007-01-01

    We present a new pulse sequence for measuring very-short-time-scale restricted diffusion of hyperpolarized noble gases. The pulse sequence is based on concatenating a large number of bipolar diffusion-sensitizing gradients to increase the diffusion attenuation of the MR signal while maintaining a fundamentally short diffusion time. However, it differs in several respects from existing methods that use oscillating diffusion gradients for this purpose. First, a wait time is inserted between neighboring pairs of gradient pulses; second, consecutive pulse pairs may be applied along orthogonal axes; and finally, the diffusion-attenuated signal is not simply read out at the end of the gradient train but is periodically sampled during the wait times between neighboring pulse pairs. The first two features minimize systematic differences between the measured (apparent) diffusion coefficient and the actual time-dependent diffusivity, while the third feature optimizes the use of the available MR signal to improve the precision of the diffusivity measurement in the face of noise. The benefits of this technique are demonstrated using theoretical calculations, Monte-Carlo simulations of gas diffusion in simple geometries, and experimental phantom measurements in a glass sphere containing hyperpolarized 3He gas. The advantages over the conventional single-bipolar approach were found to increase with decreasing diffusion time, and thus represent a significant step toward making accurate surface-to-volume measurements in the lung airspaces. PMID:17936048

  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. 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

  20. Capecitabine-Associated Loss of Fingerprints: Report of Capecitabine-Induced Adermatoglyphia in Two Women with Breast Cancer and Review of Acquired Dermatoglyphic Absence in Oncology Patients Treated with Capecitabine

    PubMed Central

    2017-01-01

    Capecitabine, an oral 5-fluorouracil prodrug, is currently used in the treatment of metastatic colorectal carcinoma and breast cancer. Fingerprints, also referred to as dermatoglyphics and characterized by the pattern of ridges and furrows on the fingertips, are used for identification by government agencies and personal electronic devices. Two women with breast cancer who were treated with capecitabine and developed drug-associated loss of their fingerprints are described. PubMed was used to search the following terms separately and in combination: absence, adermatoglyphia, breast, cancer, capecitabine, carcinoma, colon, colorectal, dermatoglyphics, fingerprint, fluorouracil, foot, hand, loss, malignancy, nasopharyngeal, oncology, reaction, rectal, skin, syndrome, tumor, and xeloda. The papers identified were reviewed and appropriate references were evaluated. The characteristics of capecitabine-induced adermatoglyphia in 20 oncology patients are reviewed. Most of the patients received either 2000 mg/m2 or 3500 mg, in divided doses, each day. Hand-foot syndrome, varying in severity from grade 1 to grade 4, always preceded the onset of fingerprint loss. The discovery of adermatoglyphia occurred as early as two weeks to as late as 3½ years after starting capecitabine. Patients were often unaware of their fingerprint loss until they experienced delays attempting to enter the United States, were unable to process government documents or obtain a driver’s license, or could not obtain access to their telephone, computer or gym which required fingerprint identification scanning. The loss of fingerprints was reversible for some of the individuals; however, several of the patients did not recover their dermatoglyphics, the functional quality of their fingerprints, or both after discontinuing the drug. The significance of capecitabine-induced adermatoglyphia will continue to increase as fingerprint identification continues to advance not only in scanning technology

  1. Capecitabine-Associated Loss of Fingerprints: Report of Capecitabine-Induced Adermatoglyphia in Two Women with Breast Cancer and Review of Acquired Dermatoglyphic Absence in Oncology Patients Treated with Capecitabine.

    PubMed

    Cohen, Philip R

    2017-01-09

    Capecitabine, an oral 5-fluorouracil prodrug, is currently used in the treatment of metastatic colorectal carcinoma and breast cancer. Fingerprints, also referred to as dermatoglyphics and characterized by the pattern of ridges and furrows on the fingertips, are used for identification by government agencies and personal electronic devices. Two women with breast cancer who were treated with capecitabine and developed drug-associated loss of their fingerprints are described. PubMed was used to search the following terms separately and in combination: absence, adermatoglyphia, breast, cancer, capecitabine, carcinoma, colon, colorectal, dermatoglyphics, fingerprint, fluorouracil, foot, hand, loss, malignancy, nasopharyngeal, oncology, reaction, rectal, skin, syndrome, tumor, and xeloda. The papers identified were reviewed and appropriate references were evaluated. The characteristics of capecitabine-induced adermatoglyphia in 20 oncology patients are reviewed. Most of the patients received either 2000 mg/m(2) or 3500 mg, in divided doses, each day. Hand-foot syndrome, varying in severity from grade 1 to grade 4, always preceded the onset of fingerprint loss. The discovery of adermatoglyphia occurred as early as two weeks to as late as 3½ years after starting capecitabine. Patients were often unaware of their fingerprint loss until they experienced delays attempting to enter the United States, were unable to process government documents or obtain a driver's license, or could not obtain access to their telephone, computer or gym which required fingerprint identification scanning. The loss of fingerprints was reversible for some of the individuals; however, several of the patients did not recover their dermatoglyphics, the functional quality of their fingerprints, or both after discontinuing the drug. The significance of capecitabine-induced adermatoglyphia will continue to increase as fingerprint identification continues to advance not only in scanning technology

  2. [Expression of allergic reactions to oxaliplatin].

    PubMed

    Arii, Daisuke; Ikeno, Yohei; Murooka, Kunihiko; Nojima, Michio; Kidokoro, Akio

    2012-04-01

    Oxaliplatin (L-OHP), a platinum-containing antineoplastic agent, is a key drug for the treatment of colorectal cancer. However, it is often difficult to continue with its treatment because of the expression of allergic reactions. This study was an investigation of the expression of allergic reactions resulting from administration of L-OHP. A retrospective analysis was performed on patients undergoing therapeutic regimens including L-OHP, from April 2009 to November 2010 in Juntendo University Urayasu Hospital. The results showed that allergic reactions were expressed in 15 out of 81 patients (18. 5%). A high correlation was found between the time from administration until expression of the allergic reaction, and the number of treatment courses (r=-0. 521, p=0. 047). When patient characteristics were compared between the allergic reaction group and the no-reaction group, it was suggested that differences due to the regimen or the presence or absence of liver metastasis, which is considered to be related to drug metabolism, had no effect. Items showing significant differences were sexual difference(p=0. 022)and the effect of changes depending on the dose form of L-OHP(p=0. 003). It was possible to continue treatment with L-OHP in six patients even after expression of allergic reactions. Anti-allergy measures such as additional administration of steroids or antihistamines were suggested to be useful for continuing treatment.

  3. CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer.

    PubMed

    Pivot, Xavier; Manikhas, Alexey; Żurawski, Bogdan; Chmielowska, Ewa; Karaszewska, Boguslawa; Allerton, Rozenn; Chan, Stephen; Fabi, Alessandra; Bidoli, Paolo; Gori, Stefania; Ciruelos, Eva; Dank, Magdolna; Hornyak, Lajos; Margolin, Sara; Nusch, Arnd; Parikh, Roma; Nagi, Fareha; DeSilvio, Michelle; Santillana, Sergio; Swaby, Ramona F; Semiglazov, Vladimir

    2015-05-10

    CEREBEL compared the incidence of CNS metastases as first site of relapse in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer receiving lapatinib-capecitabine or trastuzumab-capecitabine. Patients without baseline CNS metastases were randomly assigned (1:1) to receive lapatinib-capecitabine (lapatinib 1,250 mg per day; capecitabine 2,000 mg/m(2) per day on days 1 to 14 every 21 days) or trastuzumab-capecitabine (trastuzumab loading dose of 8 mg/kg followed by an infusion of 6 mg/kg every 3 weeks; capecitabine 2,500 mg/m(2) per day on days 1 to 14 every 21 days). The primary end point was incidence of CNS metastases as first site of relapse. Secondary end points included progression-free survival (PFS) and overall survival (OS). The study was terminated early with 540 enrolled patients (271 received lapatinib-capecitabine, and 269 received trastuzumab-capecitabine). Incidence of CNS metastases as first site of relapse was 3% (eight of 251 patients) for lapatinib-capecitabine and 5% (12 of 250 patients) for trastuzumab-capecitabine (treatment differences, -1.6%; 95% CI, -2% to 5%; P = .360). PFS and OS were longer with trastuzumab-capecitabine versus lapatinib-capecitabine (hazard ratio [HR] for PFS, 1.30; 95% CI, 1.04 to 1.64; HR for OS, 1.34; 95% CI, 0.95 to 1.64). Serious adverse events were reported in 13% (34 of 269 patients) and 17% (45 of 267 patients) of patients in the lapatinib-capecitabine and trastuzumab-capecitabine arms, respectively. CEREBEL is inconclusive for the primary end point, and no difference was detected between lapatinb-capecitabine and trastuzumab-capecitabine for the incidence of CNS metastases. A better outcome was observed with trastuzumab-capecitabine in the overall population. However, lapatinib-capecitabine efficacy may have been affected by previous exposure to a trastuzumab regimen and/or when treatment was given as first- or second-line therapy in the metastatic setting. © 2015 by American

  4. 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.

  5. The frequency and severity of capecitabine-induced hypertriglyceridaemia in routine clinical practice: a prospective study.

    PubMed

    Michie, C O; Sakala, M; Rivans, I; Strachan, M W J; Clive, S

    2010-08-24

    Capecitabine is known to rarely cause raised serum triglycerides (TG). In our centre, several patients receiving capecitabine developed raised TG levels corresponding to the 'very high risk' category for potentially serious acute pancreatitis. A fasting blood lipid screening protocol was introduced into clinical practice for patients receiving capecitabine. Patients with TGs >5 mmol l(-1) were treated and followed up. An 18-month prospective audit was performed to establish the incidence and severity of capecitabine-induced hypertriglyceridaemia (CIHT). A total of 304 patients received capecitabine for colorectal cancer between January 2008 and June 2009. Of these, 212 patients (70%) were screened and 8 (3.7%) developed clinically significant hypertriglyceridaemia requiring lipid-lowering therapy. Two of the eight patients had diabetes and one had pre-existing dyslipidaemia. One suffered cerebral infarction during chemotherapy. There were no cases of acute pancreatitis. Follow-up showed that serum TGs safely and rapidly returned to normal with appropriate treatment without discontinuation of capecitabine. This is the first prospective study evaluating CIHT. These results suggest that it should be classed as a 'common' undesired effect of capecitabine. Despite this, the incidence does not justify routine screening in all patients. Targeted screening in those with diabetes or pre-existing hyperlipidaemia is recommended, together with adoption of a clear management policy.

  6. The frequency and severity of capecitabine-induced hypertriglyceridaemia in routine clinical practice: a prospective study

    PubMed Central

    Michie, C O; Sakala, M; Rivans, I; Strachan, M W J; Clive, S

    2010-01-01

    Background: Capecitabine is known to rarely cause raised serum triglycerides (TG). In our centre, several patients receiving capecitabine developed raised TG levels corresponding to the ‘very high risk' category for potentially serious acute pancreatitis. Methods: A fasting blood lipid screening protocol was introduced into clinical practice for patients receiving capecitabine. Patients with TGs >5 mmol l−1 were treated and followed up. An 18-month prospective audit was performed to establish the incidence and severity of capecitabine-induced hypertriglyceridaemia (CIHT). Results: A total of 304 patients received capecitabine for colorectal cancer between January 2008 and June 2009. Of these, 212 patients (70%) were screened and 8 (3.7%) developed clinically significant hypertriglyceridaemia requiring lipid-lowering therapy. Two of the eight patients had diabetes and one had pre-existing dyslipidaemia. One suffered cerebral infarction during chemotherapy. There were no cases of acute pancreatitis. Follow-up showed that serum TGs safely and rapidly returned to normal with appropriate treatment without discontinuation of capecitabine. Conclusions: This is the first prospective study evaluating CIHT. These results suggest that it should be classed as a ‘common' undesired effect of capecitabine. Despite this, the incidence does not justify routine screening in all patients. Targeted screening in those with diabetes or pre-existing hyperlipidaemia is recommended, together with adoption of a clear management policy. PMID:20664584

  7. 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.

  8. 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

  9. Capecitabine-induced radiation recall phenomenon: a case report

    PubMed Central

    Aguilar, José

    2013-01-01

    Radiation recall dermatitis is defined as an inflammatory reaction of the skin at the site of previous irradiation. Different drugs have been associated with triggering this phenomenon, and it can also affect other areas and organs where previous radiotherapy has been administered. The time gap between the inflammatory reaction and previous radiation can range from days to several years. We report a case of capecitabine-induced Radiation Therapy Oncology Group (RTOG) grade 4 (ulcerating dermatitis) recall skin toxicity of skin irradiated 3 years previously. To our knowledge, this is the first reported case of capecitabine-induced RTOG grade 4 (ulcerating dermatitis) recall skin toxicity of previously irradiated skin. Clinicians should be aware of this phenomenon, even when considering patients for whom it has been a long time since previous radiation therapy. This unusual and late drug side effect should be borne in mind in the differential diagnosis and management of advanced-disease patients as it may be confused with local relapse or infectious complication of previously operated areas. PMID:24555020

  10. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial.

    PubMed

    Kerr, Rachel S; Love, Sharon; Segelov, Eva; Johnstone, Elaine; Falcon, Beverly; Hewett, Peter; Weaver, Andrew; Church, David; Scudder, Claire; Pearson, Sarah; Julier, Patrick; Pezzella, Francesco; Tomlinson, Ian; Domingo, Enric; Kerr, David J

    2016-11-01

    Antiangiogenic agents have established efficacy in the treatment of metastatic colorectal cancer. We investigated whether bevacizumab could improve disease-free survival in the adjuvant setting after resection of the primary tumour. For the open-label, randomised, controlled QUASAR 2 trial, which was done at 170 hospitals in seven countries, we recruited patients aged 18 years or older with WHO performance status scores of 0 or 1 who had undergone potentially curative surgery for histologically proven stage III or high-risk stage II colorectal cancer. Patients were randomly assigned (1:1) to receive eight 3-week cycles of oral capecitabine alone (1250 mg/m(2) twice daily for 14 days followed by a break for 7 days) or the same regimen of oral capecitabine plus 16 cycles of 7·5 mg/kg bevacizumab by intravenous infusion over 90 min on day 1 of each cycle. Randomisation was done by a computer-generated schedule with use of minimisation with a random element stratified by age, disease stage, tumour site, and country. The study was open label and no-one was masked to treatment assignment. The primary endpoint was 3-year disease-free survival, assessed in the intention-to-treat population. Toxic effects were assessed in patients who received at least one dose of randomised treatment. This trial is registered with the ISRCTN registry, number ISRCTN45133151. Between April 25, 2005, and Oct 12, 2010, 1952 eligible patients were enrolled, of whom 1941 had assessable data (968 in the capecitabine alone group and 973 in the capecitabine and bevacizumab group). Median follow-up was 4·92 years (IQR 4·00-5·16). Disease-free survival at 3 years did not differ between the groups (75·4%, 95% CI 72·5-78·0 in the capecitabine and bevacizumab group vs 78·4%, 75·7-80·9 in the capecitabine alone group; hazard ratio 1·06, 95% CI 0·89-1·25, p=0·54). The most common grade 3-4 adverse events were hand-foot syndrome (201 [21%] of 963 in the capecitabine alone group vs 257 [27

  11. The use of capecitabine in the combined-modality therapy for rectal cancer.

    PubMed

    Liauw, Stanley L; Minsky, Bruce D

    2008-03-01

    Locally advanced rectal adenocarcinoma is treated by combined-modality therapy, which consists of surgery, chemotherapy, and radiation therapy. A series of randomized trials established a preferred treatment sequence of preoperative radiation therapy and 5-fluorouracil(5-FU)-based chemotherapy, total mesorectal excision, and adjuvant 5-FU-based chemotherapy for patients with stage II/III disease. Capecitabine is an oral prodrug of 5-FU that has potential advantages compared with intravenous 5-FU, including ease of administration and potentially increased therapeutic effect. Capecitabine is converted by a 3-step enzymatic process; the last step involves the enzyme thymidine phosphorylase, which is overexpressed in tumor tissues and is stimulated by concurrent radiation therapy. Over the past 5 years, several phase I/II trials of capecitabine-based therapy were reported. This review discusses the evolution of combined-modality therapy for rectal cancer with specific attention given to the use of capecitabine in conjunction with radiation therapy.

  12. First Case of Foot Drop Associated with Capecitabine in a Patient with Thymidylate Synthase Polymorphism

    PubMed Central

    Wilks, Andrew B

    2017-01-01

    Capecitabine, an oral prodrug of 5-FU, has been approved by the FDA for use in patients with breast and colon cancers. In addition, capecitabine is commonly used in patients with other malignancies such as pancreatic, gastroesophageal, and hepatobiliary tract cancers. Though cerebellar toxicity is a rare but well-known side effect of intravenous 5-FU therapy, peripheral neuropathy with capecitabine has only been described in rare cases. In this case report, we describe a 79-year-old patient with locally advanced adenocarcinoma of the pancreas undergoing chemoradiation therapy with capecitabine who developed peripheral sensorimotor neuropathy. To the best of our knowledge, this is the first patient in the literature who was found to have two mutations (2R) of a 28 base-pair tandem repeat in the 5’ promoter enhancer region (5’-TSER) on both alleles (2R/2R) of thymidylate synthetase (TYMS) gene, possibly responsible for the neurotoxicity. PMID:28280649

  13. Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy.

    PubMed

    Areti, Aparna; Komirishetty, Prashanth; Akuthota, Manasaveena; Malik, Rayaz A; Kumar, Ashutosh

    2017-04-01

    Oxaliplatin, an organoplatinum compound, is used in the treatment of colorectal cancer, but its clinical use can be limited due to the development of peripheral neuropathy. Whilst mitochondrial dysfunction has been implicated as a major pathomechanism for oxaliplatin-induced neurotoxicity, the prevention of autophagy may also aggravate neuronal cell death. Melatonin, a well-known mitoprotectant and autophagy inducer, was used to examine its neuroprotective role in oxaliplatin-induced peripheral neuropathy (OIPN). Melatonin prevented the loss of mitochondrial membrane potential (Ψm) and promoted neuritogenesis in oxaliplatin-challenged neuro-2a cells. It did not interfere with the cytotoxic activity of oxaliplatin in human colon cancer cell line, HT-29. Melatonin treatment significantly alleviated oxaliplatin-induced pain behavior and neuropathic deficits in rats. It also ameliorated nitro-oxidative stress mediated by oxaliplatin, thus prevented nitrosylation of proteins and loss of antioxidant enzymes, and therefore, it improved mitochondrial electron transport chain function and maintained cellular bioenergetics by improving the ATP levels. The protective effects of melatonin were attributed to preventing oxaliplatin-induced neuronal apoptosis by increasing the autophagy pathway (via LC3A/3B) in peripheral nerves and dorsal root ganglion (DRG). Hence, it preserved the epidermal nerve fiber density in oxaliplatin-induced neuropathic rats. Taken together, we provide detailed molecular mechanisms for the neuroprotective effect of melatonin and suggest it has translational potential for oxaliplatin-induced neuropathy. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. 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.

  15. 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.

  16. The Role of Capecitabine/Temozolomide in Metastatic Neuroendocrine Tumors

    PubMed Central

    Beyer, David T.; Chauhan, Aman; Boudreaux, J. Philip; Wang, Yi-Zarn; Woltering, Eugene A.

    2016-01-01

    Background. Neuroendocrine tumors (NETs) are commonly treated with multimodality therapy. The combination of capecitabine and temozolomide (CAPTEM) has been suggested as a treatment option for patients with metastatic NETs. We present our experience with CAPTEM. Methods. Data on NET patients who were placed on CAPTEM and received at least one cycle were obtained from a Velos eResearch database. Response rate was calculated by RECIST 1.1. Overall survival and progression-free survival (PFS) were calculated by the Kaplan-Meier survival method. Results. A total of 29 patients (17 male and 12 female) were included. Median age at CAPTEM initiation was 58 years (range: 26–77). Primary tumors included 9 small bowel (31%), 15 pancreas (52%), 3 lung (10%), and 2 rectum (7%). Median number of CAPTEM cycles was 8 (range: 1–55). Partial response occurred in 5 patients (5 of 29, 17%); 14 patients (14 of 29, 48%) had stable disease, and 10 patients (10 of 29, 34%) had progressive disease. A total of 3 (20%) and 5 (33%) pancreatic NETs experienced partial response and stable disease, respectively. A total of 2 (14%) and 9 (64%) nonpancreatic NETs experienced partial response and stable disease, respectively. Partial response was noted in 1 patient (13%) and stable disease in 5 patients (63%) with Ki-67 values of less than 2%. In patients with Ki-67 values of 2%–20%, partial response was noted in 3 (19%) and stable disease in 8 (50%). Partial response and stable disease were noted in 1 patient each (20%) with Ki-67 values greater than 20%. Median PFS was 12 months. Adverse reactions caused dose reductions in 24% of patients. Conclusion. Although adverse reactions were experienced, most patients tolerated this regimen. CAPTEM should be considered as a reasonable treatment option for metastatic NET patients. Implications for Practice: The role of chemotherapy in neuroendocrine tumors has evolved in recent years. The results of this study suggest that the combination of

  17. A curious case of oxaliplatin-induced neurotoxicity: recurrent, self-limiting dysarthria.

    PubMed

    Joseph, Ranjit; Dasanu, Constantin A

    2014-10-01

    This report presents a unique case of oxaliplatin-induced neurotoxicity featuring acute, recurrent, self-limiting dysarthria following multiple subsequent infusions of oxaliplatin. A 65-year-old man started chemotherapy for metastatic pancreatic adenocarcinoma with oxaliplatin-irinotecan-leucovorin-5-fluorouracil (FOLFIRINOX). During the first and subsequent infusions of oxaliplatin, the patient developed episodes of dysarthria that lasted between 2 and 4 h after oxaliplatin infusions, followed by their complete and uneventful resolution. A thorough neurological examination showed no new neurologic deficits except for very fine tongue fasciculations. Recognizing this self-limiting toxic effect of oxaliplatin is important in order to avoid dose reductions that may affect clinical outcomes.

  18. Skin test protocol for the prevention of hypersensitivity reactions to oxaliplatin.

    PubMed

    Pagani, Mauro; Bonadonna, Patrizia

    2014-01-01

    Several hypersensitivity reactions (HSRs) to oxaliplatin have been reported. Presently, there is no reliable way to predict the development of this adverse reaction. The aim of the present study was to evaluate the reliability of skin tests in the detection of patients at risk of developing HSRs to oxaliplatin. Patients under treatment with oxaliplatin underwent the prick test at a concentration of 1 mg/ml and, if negative, intradermal injection at a concentration of 0.1 mg/ml, one hour before each course of oxaliplatin, starting from the second administration. A group of 101 patients were submitted to skin tests: two were positive, whereas five developed HSR despite negative tests (false-negative rate: 5.05%). These patients underwent desensitization, which permitted to conclude the planned schedule in five cases. A negative skin test to oxaliplatin has a good reliability in predicting HSRs. We suggest performing tests only in patients that have received at least five courses of oxaliplatin.

  19. 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.

  20. Salmon calcitonin reduces oxaliplatin-induced cold and mechanical allodynia in rats.

    PubMed

    Aoki, Manahito; Mori, Asami; Nakahara, Tsutomu; Sakamoto, Kenji; Ishii, Kunio

    2013-01-01

    Oxaliplatin is commonly used anti-cancer drugs, but it frequently causes peripheral neuropathic pain. Recently, we reported that elcatonin, a synthetic analog of eel calcitonin, attenuated the oxaliplatin- and paclitaxel-induced cold and mechanical allodynia in rats. In the present study, we determined whether salmon calcitonin also had anti-allodynic effects on oxaliplatin-induced neuropathy in rats. The rats were treated with a single dose of oxaliplatin (6 mg/kg, intraperitoneally (i.p.)). Oxaliplatin resulted in cold and mechanical allodynia. We assessed the anti-allodynic effects of subcutaneously administered salmon calcitonin (20 U/kg/d) by cold stimulation (8°C) directly to the hind paw of the rats and by using the von Frey test. Salmon calcitonin almost completely reversed the effects of both cold and mechanical allodynia. These results suggest that salmon calcitonin is also useful for treatment of oxaliplatin-induced neuropathy clinically.

  1. Acute immune-mediated thrombocytopenia due to oxaliplatin administration: a case report.

    PubMed

    Pietrantonio, Filippo; Di Bartolomeo, Maria; Buzzoni, Roberto; Bajetta, Emilio

    2010-01-01

    Drug-induced acute thrombocytopenia is an extremely rare side effect that may occur immediately after oxaliplatin infusion. This potentially fatal reaction is immune mediated and can be anticipated by mild hemorrhagic signs during previous administrations. This is the first report of acute thrombocytopenia occurring during adjuvant treatment of colorectal cancer with oxaliplatin. Clinicians should be aware of this adverse event in order to prevent possible serious consequences and stop further oxaliplatin administration.

  2. PKC/MEK inhibitors suppress oxaliplatin-induced neuropathy and potentiate the antitumor effects.

    PubMed

    Tsubaki, Masanobu; Takeda, Tomoya; Tani, Tadahumi; Shimaoka, Hirotaka; Suzuyama, Naohiro; Sakamoto, Kotaro; Fujita, Arisa; Ogawa, Naoki; Itoh, Tatsuki; Imano, Motohiro; Funakami, Yoshinori; Ichida, Seiji; Satou, Takao; Nishida, Shozo

    2015-07-01

    Oxaliplatin is a key drug commonly used in colorectal cancer treatment. Despite high clinical efficacy, its therapeutic application is limited by common, dose-limiting occurrence of neuropathy. As usual symptomatic neuropathy treatments fail to improve the patients' condition, there is an urgent need to advance our understanding of the pathogenesis of neuropathy to propose effective therapy and ensure adequate pain management. Oxaliplatin-induced neuropathy was recently reported to be associated with protein kinase C (PKC) activation. It is unclear, however, whether PKC inhibition can prevent neuropathy. In our current studies, we found that a PKC inhibitor, tamoxifen, inhibited oxaliplatin-induced neuropathy via the PKC/extracellular signal-regulated kinase (ERK)/c-Fos pathway in lumbar spinal cords (lumbar segments 4-6). Additionally, tamoxifen was shown to act in synergy with oxaliplatin to inhibit growth in tumor cells-implanted mice. Moreover, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, PD0325901, suppressed oxaliplatin-induced neuropathy and enhanced oxaliplatin efficacy. Our results indicate that oxaliplatin-induced neuropathy is associated with PKC/ERK/c-Fos pathway in lumbar spinal cord. Additionally, we demonstrate that disruption of this pathway by PKC and MEK inhibitors suppresses oxaliplatin-induced neuropathy, thereby suggesting that PKC and MEK inhibitors may be therapeutically useful in preventing oxaliplatin-induced neuropathy and could aid in combination antitumor pharmacotherapy. © 2014 UICC.

  3. Randomised phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group.

    PubMed

    Kwakman, J J M; Simkens, L H J; van Rooijen, J M; van de Wouw, A J; Ten Tije, A J; Creemers, G J M; Hendriks, M P; Los, M; van Alphen, R J; Polée, M B; Muller, E W; van der Velden, A M T; van Voorthuizen, T; Koopman, M; Mol, L; van Werkhoven, E; Punt, C J A

    2017-04-05

    Hand-foot syndrome (HFS) is a common side effect of capecitabine. S-1 is an oral fluoropyrimidine with comparable efficacy to capecitabine in gastrointestinal cancers but associated with a lower incidence of HFS in Asian patients. This study compares the incidence of HFS between S-1 and capecitabine as first-line treatment in Western metastatic colorectal cancer (mCRC) patients.

  4. Addition of Bevacizumab to XELOX Induction Therapy Plus Concomitant Capecitabine-Based Chemoradiotherapy in Magnetic Resonance Imaging–Defined Poor-Prognosis Locally Advanced Rectal Cancer: The AVACROSS Study

    PubMed Central

    Salud, Antonieta; Vicente, Pilar; Arriví, Antonio; Roca, José María; Losa, Ferran; Ponce, José; Safont, María José; Guasch, Inmaculada; Moreno, Isabel; Ruiz, Ana; Pericay, Carles

    2011-01-01

    Background. Concomitant chemoradiotherapy followed by total mesorectal excision is standard treatment for locally advanced rectal cancer. This approach, however, focuses on local disease control and delays systemic treatment. Induction chemotherapy has the advantage of earlier administration of systemic therapy and may improve distant control. The objective of the current study was to assess the efficacy and toxicity of adding bevacizumab to induction chemotherapy followed by preoperative bevacizumab-based chemoradiotherapy in patients with locally advanced rectal cancer. Patients and Methods. Eligible patients had high-risk rectal adenocarcinoma defined by magnetic resonance imaging criteria. Treatment consisted of four 21-day cycles of bevacizumab (7.5 mg/kg) and XELOX (capecitabine plus oxaliplatin), followed by concomitant radiotherapy (50.4 Gy) plus bevacizumab (5 mg/kg every 2 weeks) and capecitabine (825 mg/m2 twice daily on days 1–15). Surgery was scheduled for 6–8 weeks after chemoradiotherapy. The primary endpoint was pathologic complete response (pCR). Results. Between July 2007 and July 2008, 47 patients were recruited. Among 45 patients who underwent surgery, pCR was achieved in 16 patients (36%; 95% confidence interval: 22.29%–51.27%), and an additional 17 patients (38%) had Dworak tumor regression grade 3. R0 resection was performed in 44 patients (98%). Most grade 3/4 adverse events occurred during the induction phase and included diarrhea (11%), asthenia (4%), neutropenia (6%), and thrombocytopenia (4%). Eleven patients (24%) required surgical reintervention. Conclusions. Addition of bevacizumab to induction chemotherapy and chemoradiotherapy is feasible, with impressive activity and manageable toxicity. However, caution is recommended regarding surgical complications. PMID:21467148

  5. Addition of bevacizumab to XELOX induction therapy plus concomitant capecitabine-based chemoradiotherapy in magnetic resonance imaging-defined poor-prognosis locally advanced rectal cancer: the AVACROSS study.

    PubMed

    Nogué, Miguel; Salud, Antonieta; Vicente, Pilar; Arriví, Antonio; Roca, José María; Losa, Ferran; Ponce, José; Safont, María José; Guasch, Inmaculada; Moreno, Isabel; Ruiz, Ana; Pericay, Carles

    2011-01-01

    Concomitant chemoradiotherapy followed by total mesorectal excision is standard treatment for locally advanced rectal cancer. This approach, however, focuses on local disease control and delays systemic treatment. Induction chemotherapy has the advantage of earlier administration of systemic therapy and may improve distant control. The objective of the current study was to assess the efficacy and toxicity of adding bevacizumab to induction chemotherapy followed by preoperative bevacizumab-based chemoradiotherapy in patients with locally advanced rectal cancer. Eligible patients had high-risk rectal adenocarcinoma defined by magnetic resonance imaging criteria. Treatment consisted of four 21-day cycles of bevacizumab (7.5 mg/kg) and XELOX (capecitabine plus oxaliplatin), followed by concomitant radiotherapy (50.4 Gy) plus bevacizumab (5 mg/kg every 2 weeks) and capecitabine (825 mg/m2 twice daily on days 1-15). Surgery was scheduled for 6-8 weeks after chemoradiotherapy. The primary endpoint was pathologic complete response (pCR). Between July 2007 and July 2008, 47 patients were recruited. Among 45 patients who underwent surgery, pCR was achieved in 16 patients (36%; 95% confidence interval: 22.29%-51.27%), and an additional 17 patients (38%) had Dworak tumor regression grade 3. R0 resection was performed in 44 patients (98%). Most grade 3/4 adverse events occurred during the induction phase and included diarrhea (11%), asthenia (4%), neutropenia (6%), and thrombocytopenia (4%). Eleven patients (24%) required surgical reintervention. Addition of bevacizumab to induction chemotherapy and chemoradiotherapy is feasible, with impressive activity and manageable toxicity. However, caution is recommended regarding surgical complications.

  6. 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

  7. Dragon (RGMb) induces oxaliplatin resistance in colon cancer cells.

    PubMed

    Shi, Ying; Huang, Xiao-Xiao; Chen, Guo-Bin; Wang, Ying; Zhi, Qiang; Liu, Yuan-Sheng; Wu, Xiao-Ling; Wang, Li-Fen; Yang, Bing; Xiao, Chuan-Xing; Xing, Hui-Qin; Ren, Jian-Lin; Xia, Yin; Guleng, Bayasi

    2016-07-26

    Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality. Chemotherapy resistance remains a major challenge for treating advanced CRC. Therefore, the identification of targets that induce drug resistance is a priority for the development of novel agents to overcome resistance. Dragon (also known as RGMb) is a member of the repulsive guidance molecule (RGM) family. We previously showed that Dragon expression increases with CRC progression in human patients. In the present study, we found that Dragon inhibited apoptosis and increased viability of CMT93 and HCT116 cells in the presence of oxaliplatin. Dragon induced resistance of xenograft tumor to oxaliplatinin treatment in mice. Mechanistically, Dragon inhibited oxaliplatin-induced JNK and p38 MAPK activation, and caspase-3 and PARP cleavages. Our results indicate that Dragon may be a novel target that induces drug resistance in CRC.

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

    PubMed

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

    2014-06-05

    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. 2014 BMJ Publishing Group Ltd.

  9. Immune-mediated thrombocytopenia resulting from sensitivity to oxaliplatin.

    PubMed

    Curtis, Brian R; Kaliszewski, James; Marques, Marisa B; Saif, M Wasif; Nabelle, Lisle; Blank, Jules; McFarland, Janice G; Aster, Richard H

    2006-03-01

    Thrombocytopenia developing in the course of chemotherapy for malignant disease is usually attributed to drug-induced marrow suppression and/or marrow replacement by tumor. We describe two patients who developed severe thrombocytopenia and hemorrhagic symptoms while being treated with oxaliplatin, 5-fluorouracil, and leukovorin for metastatic colon cancer in whom platelet destruction appears to have been caused by oxaliplatin-dependent antibodies specific for the platelet glycoprotein IIb/IIIa complex (alpha(IIb)/beta(3) integrin). Drug-induced immune thrombocytopenia (DITP) should be considered in patients who experience a sudden, isolated drop in platelet levels while being treated with chemotherapeutic agents, especially when adequate numbers of megakaryocytes are present in the bone marrow.

  10. 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

    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

    2011-06-18

    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. 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. 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) with chemotherapy alone to 64% (n=232) with

  11. 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

  12. Predicting Acute and Persistent Neuropathy Associated with Oxaliplatin

    PubMed Central

    Alejandro, Linh; Behrendt, Carolyn E.; Chen, Kim; Openshaw, Harry; Shibata, Stephen

    2014-01-01

    Objectives We sought to predict oxaliplatin-associated peripheral neuropathy during modified FOLFOX6 (mFOLFOX6) therapy. Methods In a 50% female sample, patients with previously untreated, primary or recurrent colorectal cancer were followed through a first course of mFOLFOX6 with oxaliplatin 85 mg/m2 every 2 weeks. Accounting for correlation among a subject's cycles, logistic regression estimated per-cycle risk of acute (under 14 days) and persistent (14 days or more) neuropathy. Proportional hazards regression predicted time to persistent neuropathy. Results Among mFOLFOX6 recipients (n=50, age 58.9 +10.1 years), 36% received concomitant bevacizumab. Of total cycles, 94.2% (422/448) were evaluable. Most (84%) subjects reported neuropathy at least once: 74% reported acute and 48% reported persistent symptoms. On multivariate analysis, risk factors shared by acute and persistent neuropathy were body-surface area >2.0, acute neuropathy in a past cycle, and lower body weight. In addition, risk of acute neuropathy decreased with age (adjusted for renal function and winter season), while risk of persistent neuropathy increased with cumulative dose of oxaliplatin and persistent neuropathy in a past cycle. Concomitant bevacizumab was not a risk factor when administered in Stage IV disease but was associated with persistent neuropathy when administered experimentally in Stage III. Females had no increased risk of either form of neuropathy. After 3 cycles, weight, body-surface area, and prior acute neuropathy predicted time to persistent neuropathy. Conclusions Routinely available clinical factors predict acute and persistent neuropathy associated with oxaliplatin. When validated, the proposed prognostic score for persistent neuropathy can help clinicians counsel patients about chemotherapy. PMID:22547012

  13. The effect of diabetes on oxaliplatin-induced peripheral neuropathy.

    PubMed

    Uwah, Augusta N; Ackler, Joan; Leighton, John C; Pomerantz, Sherry; Tester, William

    2012-12-01

    Chemotherapy-induced neurotoxicity is a significant source of morbidity for cancer patients. This study aimed to assess the relationship between preexisting diabetes and clinically significant (National Cancer Institute Common Toxicity Criteria grades 2 and 3) OXIPN; between diabetes, and the cumulative dose at onset of OXIPN; and between other preexisting medical conditions and the development of OXIPN. We reviewed medical records of all patients with stage II-IV colon cancer treated in the Albert Einstein Cancer Center, Philadelphia, with oxaliplatin from 2005 to 2009. Exclusion criteria included preexisting neuropathy, previous neurotoxic chemotherapy exposure, and incomplete medical records. The NCI Common Toxicity Criteria was used to grade sensory neuropathy. Univariate analysis was used to estimate odds ratios and confidence limits for prevalence of OXIPN in patients with and without diabetes. The mean level and cumulative doses were compared using the t test. Sixty-two patients met the study criteria; 23 oxaliplatin-treated patients were excluded. The crude incidence of any OXIPN was 65%. There was no relationship found between development of OXIPN and the presence of diabetes, smoking, hypertension, or statin use. However, the mean cumulative dose of oxaliplatin was significantly lower for patients with diabetes who developed neuropathy, compared with those without diabetes (388 vs. 610 mg/m(2); P = .021). Although the presence of diabetes did not appear to affect the severity of OXIPN, patients with diabetes developed OXIPN at a lower cumulative dose of oxaliplatin (P < .05). The results may have implications for treatment of patients with diabetes and colon cancer. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. [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.

  15. Self-reported compliance with capecitabine: findings from a prospective cohort analysis.

    PubMed

    Winterhalder, Ralph; Hoesli, Pierre; Delmore, Geoffrey; Pederiva, Stefanie; Bressoud, Albéric; Hermann, Frank; von Moos, Roger

    2011-01-01

    While oral anticancer treatment has increased the convenience for patients with no risk of venous access complications compared to intravenous drug administration, a high level of compliance cannot always be assumed. The aim of the present report was to evaluate real-life drug adherence in a prospective cohort analysis of patients with gastrointestinal or breast cancer treated with capecitabine-based chemotherapy. Twenty-nine Swiss oncologists recruited patients receiving capecitabine, either as monotherapy or in combination with other chemotherapeutic agents, in a prospective fashion. Patients recorded both their capecitabine intake and any adverse effects each day in patient diaries. A total of 177 patients were included, 143 (81%) with gastrointestinal tumours and 34 (19%) with breast cancer. Overall, 161 patients (91%) were considered as fully compliant, while 16 patients (9%) reported some kind of compliance error. Reasons for non-compliance included forgetting to take treatment (n = 9), side effects (n = 4) and misunderstanding instructions (n = 3). Self-reported compliance was not influenced by age or Eastern Cooperative Oncology Group performance status, but there was a trend towards better compliance with capecitabine therapy if fewer adverse effects occurred (p = 0.07, simple logistic regression). Self-reported compliance with capecitabine-based therapy in clinical practice is high and seems to be adversely affected by side effects. Copyright © 2011 S. Karger AG, Basel.

  16. RESILIENCE: Phase III Randomized, Double-Blind Trial Comparing Sorafenib With Capecitabine Versus Placebo With Capecitabine in Locally Advanced or Metastatic HER2-Negative Breast Cancer.

    PubMed

    Baselga, José; Zamagni, Claudio; Gómez, Patricia; Bermejo, Begoña; Nagai, Shigenori E; Melichar, Bohuslav; Chan, Arlene; Mángel, Lászlo; Bergh, Jonas; Costa, Frederico; Gómez, Henry L; Gradishar, William J; Hudis, Clifford A; Rapoport, Bernardo L; Roché, Henri; Maeda, Patricia; Huang, Liping; Meinhardt, Gerold; Zhang, Joshua; Schwartzberg, Lee S

    2017-05-22

    Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. In this randomized, double-blind, placebo-controlled phase III trial, we assessed first- or second-line capecitabine with sorafenib or placebo in patients with locally advanced/metastatic HER2-negative breast cancer resistant to a taxane and anthracycline and with known estrogen/progesterone receptor status. A total of 537 patients were randomized to capecitabine 1000 mg/m(2) orally twice per day for days 1 to 14 every 21 days with oral sorafenib 600 mg/d or placebo. The primary end point was progression-free survival (PFS). Patients were stratified according to hormone receptor status, previous chemotherapies for metastatic breast cancer, and geographic region. Treatment with sorafenib with capecitabine, compared with capecitabine with placebo, did not prolong median PFS (5.5 vs. 5.4 months; hazard ratio [HR], 0.973; 95% confidence interval [CI], 0.779-1.217; P = .811) or overall survival (OS; 18.9 vs. 20.3 months; HR, 1.195; 95% CI, 0.943-1.513; P = .140); or enhance overall response rate (ORR; 13.5% vs. 15.5%; P = .515). Any grade toxicities (sorafenib vs. placebo) included palmar-plantar erythrodysesthesia syndrome (PPES; 79.2% vs. 59.6%), diarrhea (47.3% vs. 37.8%), mucosal inflammation (15.4% vs. 6.7%), and hypertension (26.2% vs. 5.6%). Grade 3/4 toxicities included PPES (15.4% vs. 7.1%), diarrhea (4.2% vs. 6.4%), and vomiting (3.5% vs. 0.7%). The combination of sorafenib with capecitabine did not improve PFS, OS, or ORR in patients with HER2-negative advanced breast cancer. Rates of Grade 3 toxicities were higher in the sorafenib arm. Copyright © 2017. Published by Elsevier Inc.

  17. Effects of analgecine on oxaliplatin-induced neurotoxicity in patients with gastrointestinal cancer.

    PubMed

    Liu, Meng-Yan; Huang, Xin-En

    2015-01-01

    As the third generation of platinum-based antineoplastic agent aginst gastrointestinal cancer, oxaliplatin is considered to be associated with severe sensory neurotoxicity. Acorrding to previous studies, vitaminE, intravenous Ca/Mg and glutamine may partly reduce the incidence and severity of oxaliplatin-induced neurotoxicity. The aim of this study was to investigate the safety and efficacy of analgecine for preventing oxaliplatin-induced neurotoxicity in the patients with gastrointestinal tumors. In this study, patients undergoing oxaliplatin-based chemotherapy were assigned to analgecine (experimental) group or control group. Analgecine 6ml was administered once a day for seven days from the day of oxaliplatin treatment. The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) was used to evaluate oxaliplatin-induced neurotoxicity. The incidence rates and grade of neurotoxicity of patients were assessed before and during (after four and eight cycles) treatment. Totally, 82 patients were enrolled in this study, 42 in experimental group and 40 in control group. The occurrence of each grade neurotoxicity in the experimental group was significantly lower than that in control group. The overall occurrence rate was 31% vs 55% (P=0.043) after 4 cycles and 52% vs 75% (P=0.050) after 8 cycles. Analgecine appears could be effective in reducing oxaliplatin-induced neurotoxicity and be applicated for patients with gastrointestinal tumors who would be treated with oxaliplatin-based chemotherapy.

  18. 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.

  19. Oxaliplatin-induced severe anaphylactic reactions in metastatic colorectal cancer: case series analysis.

    PubMed

    Wang, Jui-Ho; King, Tai-Ming; Chang, Min-Chi; Hsu, Chao-Wen

    2012-10-14

    To investigate oxaliplatin-induced severe anaphylactic reactions (SAR) in metastatic colorectal cancer in a retrospective case series analysis and to conduct a systemic literature review. During a 6-year period from 2006 to 2011 at Kaohsiung Veterans General Hospital, a total of 412 patients exposed to oxaliplatin-related chemotherapy were retrospectively reviewed. Relevant English-language studies regarding life-threatening SAR following oxaliplatin were also reviewed in MEDLINE® and PubMed® search. Eight patients (1.9%, 8 of 412 cases) were identified. Seven patients were successful resuscitated without any sequelae and one patient expired. We changed the chemotherapy regimen in five patients and rechallenged oxaliplatin use in patient 3. Twenty-three relevant English-language studies with 66 patients were reported. Patients received a median of 10 cycles of oxaliplatin (range, 2 to 29). Most common symptoms were respiratory distress (60%), fever (55%), and hypotension (54%). Three fatal events were reported (4.5%). Eleven patients (16%) of the 66 cases were rechallenged by oxaliplatin. SAR must be considered in patients receiving oxaliplatin-related chemotherapy, especially in heavily pretreated patients. Further studies on the mechanism, predictors, preventive methods and management of oxaliplatin-related SAR are recommended.

  20. Oxaliplatin-induced severe anaphylactic reactions in metastatic colorectal cancer: Case series analysis

    PubMed Central

    Wang, Jui-Ho; King, Tai-Ming; Chang, Min-Chi; Hsu, Chao-Wen

    2012-01-01

    AIM: To investigate oxaliplatin-induced severe anaphylactic reactions (SAR) in metastatic colorectal cancer in a retrospective case series analysis and to conduct a systemic literature review. METHODS: During a 6-year period from 2006 to 2011 at Kaohsiung Veterans General Hospital, a total of 412 patients exposed to oxaliplatin-related chemotherapy were retrospectively reviewed. Relevant English-language studies regarding life-threatening SAR following oxaliplatin were also reviewed in MEDLINE® and PubMed® search. RESULTS: Eight patients (1.9%, 8 of 412 cases) were identified. Seven patients were successful resuscitated without any sequelae and one patient expired. We changed the chemotherapy regimen in five patients and rechallenged oxaliplatin use in patient 3. Twenty-three relevant English-language studies with 66 patients were reported. Patients received a median of 10 cycles of oxaliplatin (range, 2 to 29). Most common symptoms were respiratory distress (60%), fever (55%), and hypotension (54%). Three fatal events were reported (4.5%). Eleven patients (16%) of the 66 cases were rechallenged by oxaliplatin. CONCLUSION: SAR must be considered in patients receiving oxaliplatin-related chemotherapy, especially in heavily pretreated patients. Further studies on the mechanism, predictors, preventive methods and management of oxaliplatin-related SAR are recommended. PMID:23082060

  1. 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.

  2. Hypersensitivity Reactions to Oxaliplatin: Identifying the Risk Factors and Judging the Efficacy of a Desensitization Protocol.

    PubMed

    Okayama, Tetsuya; Ishikawa, Takeshi; Sugatani, Kazuko; Yoshida, Naohisa; Kokura, Satoshi; Matsuda, Kiyomi; Tsukamoto, Shigeru; Ihara, Norihiko; Kuriu, Yoshiaki; Nakanishi, Masayoshi; Nakamura, Terukazu; Kamada, Kazuhiro; Katada, Kazuhiro; Uchiyama, Kazuhiko; Takagi, Tomohisa; Handa, Osamu; Konishi, Hideyuki; Yagi, Nobuaki; Naito, Yuji; Otsuji, Eigo; Hosoi, Hajime; Miki, Tsuneharu; Itoh, Yoshito

    2015-06-01

    We examined the clinical data of patients treated with oxaliplatin to determine the risk factors of oxaliplatin-related hypersensitivity reaction (HSR). In addition, we evaluated the efficacy of rechallenging patients with HSRs with oxaliplatin using prophylactic agents or desensitization procedures. This study consisted of 162 patients with colorectal cancer (88 men and 74 women) who were treated consecutively at the outpatient chemotherapy department at University Hospital, Kyoto Prefectural University of Medicine. Patients underwent chemotherapy, including oxaliplatin, between March 2006 and June 2012. We analyzed the patients' clinical backgrounds (eg, age, sex, performance status, disease stage, and allergic history) to uncover any connections to the development of HSR to oxaliplatin. In addition, we rechallenged 10 patients who had oxaliplatin-related HSR using prophylactic agents or desensitization procedures. Of 162 patients, 28 (17.2%) developed oxaliplatin-related HSRs (16, 2, 9 and 1 patient had grade 1, 2, 3, and 4 HSRs, respectively). The total cumulative dose of oxaliplatin at the onset of the HSR was 301 to 1126 mg/m(2) (median, 582 mg/m(2)), and the first reactions developed in these patients after 5 to 17 infusions of oxaliplatin (median, 8 infusions). Logistic regression analysis indicated that sex (male: odds ratio = 3.624; 95% CI, 1.181-11.122; P = 0.024) and eosinophil count in peripheral blood (odds ratio = 35.118; 95% CI, 1.058-1166.007; P = 0.046) were independent variables for oxaliplatin-related HSRs. Rechallenging patients with prophylactic agents was successful in 2 (28.6%) of 7 patients who successfully completed their treatment. On the other hand, all 3 patients rechallenged with oxaliplatin using a desensitization protocol successfully completed their treatment without new HSRs. In this retrospective study, we observed that being male and having higher counts of peripheral eosinophil could be predictors for HSR to oxaliplatin. In

  3. 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.

  4. 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

  5. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial.

    PubMed

    Lee, Jeeyun; Lim, Do Hoon; Kim, Sung; Park, Se Hoon; Park, Joon Oh; Park, Young Suk; Lim, Ho Yeong; Choi, Min Gew; Sohn, Tae Sung; Noh, Jae Hyung; Bae, Jae Moon; Ahn, Yong Chan; Sohn, Insuk; Jung, Sin Ho; Park, Cheol Keun; Kim, Kyoung-Mee; Kang, Won Ki

    2012-01-20

    The ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer) trial was the first study to our knowledge to investigate the role of postoperative chemoradiotherapy therapy in patients with curatively resected gastric cancer with D2 lymph node dissection. This trial was designed to compare postoperative treatment with capecitabine plus cisplatin (XP) versus XP plus radiotherapy with capecitabine (XP/XRT/XP). The XP arm received six cycles of XP (capecitabine 2,000 mg/m2 per day on days 1 to 14 and cisplatin 60 mg/m2 on day 1, repeated every 3 weeks) chemotherapy. The XP/XRT/XP arm received two cycles of XP followed by 45-Gy XRT (capecitabine 1,650 mg/m2 per day for 5 weeks) and two cycles of XP. Of 458 patients, 228 were randomly assigned to the XP arm and 230 to the XP/XRT/XP arm. Treatment was completed as planned by 75.4% of patients (172 of 228) in the XP arm and 81.7% (188 of 230) in the XP/XRT/XP arm. Overall, the addition of XRT to XP chemotherapy did not significantly prolong disease-free survival (DFS; P = .0862). However, in the subgroup of patients with pathologic lymph node metastasis at the time of surgery (n = 396), patients randomly assigned to the XP/XRT/XP arm experienced superior DFS when compared with those who received XP alone (P = .0365), and the statistical significance was retained at multivariate analysis (estimated hazard ratio, 0.6865; 95% CI, 0.4735 to 0.9952; P = .0471). CONCLUSION The addition of XRT to XP chemotherapy did not significantly reduce recurrence after curative resection and D2 lymph node dissection in gastric cancer. A subsequent trial (ARTIST-II) in patients with lymph node-positive gastric cancer is planned.

  6. 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

  7. Hyperacute peripheral neuropathy is a predictor of oxaliplatin-induced persistent peripheral neuropathy.

    PubMed

    Tanishima, Hiroyuki; Tominaga, Toshiji; Kimura, Masamichi; Maeda, Tsunehiro; Shirai, Yasutsugu; Horiuchi, Tetsuya

    2017-05-01

    Chronic peripheral neuropathy is a major adverse response to oxaliplatin-containing chemotherapy regimens, but there are no established risk factors pertaining to it. We investigated the efficacy of hyperacute peripheral neuropathy (HAPN) as a predictor of oxaliplatin-induced persistent peripheral neuropathy (PPN). Forty-seven cases of stage III colorectal cancer who received adjuvant chemotherapy with oxaliplatin after curative surgery between January 2010 and August 2014 were retrospectively reviewed. HAPN was defined as acute peripheral neuropathy (APN) occurring on day 1 (≤24 h after oxaliplatin infusion) of the first cycle. PPN was defined as neuropathy lasting >1 year after oxaliplatin discontinuation. The average total dose of oxaliplatin was 625.8 mg/m(2), and the average relative dose intensity was 66.7%. Twenty-two of the 47 patients (46.8%) had PPN and 13 (27.7%) had HAPN. Male sex, treatment for neuropathy, HAPN, and APN were significantly more frequent in patients with PPN (p = 0.013, 0.02, <0.001, and 0.023, respectively). There was no significant difference in the total oxaliplatin dose between patients with and without PPN (p = 0.061). Multivariate analyses revealed total dose of oxaliplatin and HAPN as independent predictors of PPN [p = 0.015; odds ratio (OR) = 1.005, 95% confidence interval (CI), 1.001-1.009 and p = 0.001; OR = 75.307, 5.3-1070.123, respectively]. The total dose of oxaliplatin was relatively lower in patients with HAPN than that in those without HAPN in the PPN-positive group (not significant, p = 0.068). HAPN was found to be a predictor of oxaliplatin-induced PPN.

  8. Oxaliplatin neurotoxicity involves peroxisome alterations. PPARγ agonism as preventive pharmacological approach.

    PubMed

    Zanardelli, Matteo; Micheli, Laura; Cinci, Lorenzo; Failli, Paola; Ghelardini, Carla; Di Cesare Mannelli, Lorenzo

    2014-01-01

    The development of neuropathic syndromes is an important, dose limiting side effect of anticancer agents like platinum derivates, taxanes and vinca alkaloids. The causes of neurotoxicity are still unclear but the impairment of the oxidative equilibrium is strictly related to pain. Two intracellular organelles, mitochondria and peroxisomes cooperate to the maintaining of the redox cellular state. Whereas a relationship between chemotherapy-dependent mitochondrial alteration and neuropathy has been established, the role of peroxisome is poor explored. In order to study the mechanisms of oxaliplatin-induced neurotoxicity, peroxisomal involvement was evaluated in vitro and in vivo. In primary rat astrocyte cell culture, oxaliplatin (10 µM for 48 h or 1 µM for 5 days) increased the number of peroxisomes, nevertheless expression and functionality of catalase, the most important antioxidant defense enzyme in mammalian peroxisomes, were significantly reduced. Five day incubation with the selective Peroxisome Proliferator Activated Receptor-γ (PPAR-γ) antagonist G3335 (30 µM) induced a similar peroxisomal impairment suggesting a relationship between PPARγ signaling and oxaliplatin neurotoxicity. The PPARγ agonist rosiglitazone (10 µM) reduced the harmful effects induced both by G3335 and oxaliplatin. In vivo, in a rat model of oxaliplatin induced neuropathy, a repeated treatment with rosiglitazone (3 and 10 mg kg(-1) per os) significantly reduced neuropathic pain evoked by noxious (Paw pressure test) and non-noxious (Cold plate test) stimuli. The behavioral effect paralleled with the prevention of catalase impairment induced by oxaliplatin in dorsal root ganglia. In the spinal cord, catalase protection was showed by the lower rosiglitazone dosage without effect on the astrocyte density increase induced by oxaliplatin. Rosiglitazone did not alter the oxaliplatin-induced mortality of the human colon cancer cell line HT-29. These results highlight the role of

  9. Pharmacokinetic and pharmacodynamic analysis of hyperthermic intraperitoneal oxaliplatin-induced neutropenia in subjects with peritoneal carcinomatosis.

    PubMed

    Valenzuela, Belén; Nalda-Molina, Ricardo; Bretcha-Boix, Pere; Escudero-Ortíz, Vanesa; Duart, Maria José; Carbonell, Vicente; Sureda, Manuel; Rebollo, José Pascual; Farré, Josep; Brugarolas, Antonio; Pérez-Ruixo, Juan José

    2011-03-01

    The objective of this study was to characterize the pharmacokinetics and the time course of the neutropenia-induced by hyperthermic intraperitoneal oxaliplatin (HIO) after cytoreductive surgery in cancer patients with peritoneal carcinomatosis. Data from 30 patients who received 360 mg/m(2) of HIO following cytoreductive surgery were used for pharmacokinetic-pharmacodynamic (PK/PD) analysis. The oxaliplatin plasma concentrations were characterized by an open two-compartment pharmacokinetic model after first-order absorption from peritoneum to plasma. An oxaliplatin-sensitive progenitor cell compartment was used to describe the absolute neutrophil counts in blood. The reduction of the proliferation rate of the progenitor cells was modeled by a linear function of the oxaliplatin plasma concentrations. The typical values of oxaliplatin absorption and terminal half-lives were estimated to be 2.2 and 40 h, with moderate interindividual variability. Oxaliplatin reduced the proliferation rate of the progenitor cells by 18.2% per mg/L. No patient's covariates were related to oxaliplatin PK/PD parameters. Bootstrap and visual predictive check evidenced the model was deemed appropriate to describe oxaliplatin pharmacokinetics and the incidence and severity of neutropenia. A peritoneum oxaliplatin exposure of 65 and 120 mg·L/h was associated with a 20% and 33% incidence of neutropenia grade 4. The time course of neutropenia following HIO administration was well described by the semiphysiological PK/PD model. The maximum tolerated peritoneum oxaliplatin exposure is 120 mg L/h and higher exposures should be avoided in future studies. We suggest the prophylactic use of granulocyte colony stimulating factor for patients treated with HIO exposure higher than 65 mg L/h.

  10. Honokiol augments the anti-cancer effects of oxaliplatin in colon cancer cells.

    PubMed

    Hua, Hanju; Chen, Wenbin; Shen, Ling; Sheng, Qinsong; Teng, Lisong

    2013-09-01

    Oxaliplatin is an important drug in the chemotherapy of colorectal carcinoma, but its toxicity, especially dose-related neurosensory toxicity, is not well tolerated. In this study, we investigated whether honokiol could augment the anti-tumor effect of oxaliplatin in colon cancer HT-29 cells in vitro and whether honokiol could be used with oxaliplatin to decrease oxaliplatin dose. We used the normal colon cells, human colonic epithelial cells (HCoEpiCs) as control cells. Cell proliferation, apoptosis, prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) levels were also investigated. Expression levels of cyclo-oxygenase 2 (COX-2), VEGF, AKT/p-AKT, extracellular signal-related kinase (ERK)1/2/p-ERK1/2, nuclear factor kappa B (NF-κB) P65/p-P65, and caspase-3 were measured. Honokiol or oxaliplatin suppressed the proliferation of HT-29 cells in a concentration-dependent manner, but only high concentrations of honokiol would suppress the proliferation of HCoEpiCs. HT-29 cells were more sensitive to oxaliplatin treatment in the presence of honokiol. Oxaliplatin combined with honokiol improved the apoptosis rate of HT-29 cell and reduced PGE2 and VEGF secretion levels. Expression levels of COX-2 and VEGF protein and phosphorylation of AKT, ERK1/2, and NF-κB P65 were also inhibited. Caspase-3 levels were upregulated after honokiol treatment. Therefore, honokiol can be used in combination with oxaliplatin in the chemotherapy of colon cancer. This combination allows a reduction in oxaliplatin dose, and thereby reduces its adverse effects. It may also enhance the chemotherapeutic effect of oxaliplatin for this disease.

  11. Multimodal assessment of painful peripheral neuropathy induced by chronic oxaliplatin-based chemotherapy in mice

    PubMed Central

    2011-01-01

    Background A major clinical issue affecting 10-40% of cancer patients treated with oxaliplatin is severe peripheral neuropathy with symptoms including cold sensitivity and neuropathic pain. Rat models have been used to describe the pathological features of oxaliplatin-induced peripheral neuropathy; however, they are inadequate for parallel studies of oxaliplatin's antineoplastic activity and neurotoxicity because most cancer models are developed in mice. Thus, we characterized the effects of chronic, bi-weekly administration of oxaliplatin in BALB/c mice. We first studied oxaliplatin's effects on the peripheral nervous system by measuring caudal and digital nerve conduction velocities (NCV) followed by ultrastructural and morphometric analyses of dorsal root ganglia (DRG) and sciatic nerves. To further characterize the model, we examined nocifensive behavior and central nervous system excitability by in vivo electrophysiological recording of spinal dorsal horn (SDH) wide dynamic range neurons in oxaliplatin-treated mice Results We found significantly decreased NCV and action potential amplitude after oxaliplatin treatment along with neuronal atrophy and multinucleolated DRG neurons that have eccentric nucleoli. Oxaliplatin also induced significant mechanical allodynia and cold hyperalgesia, starting from the first week of treatment, and a significant increase in the activity of wide dynamic range neurons in the SDH. Conclusions Our findings demonstrate that chronic treatment with oxaliplatin produces neurotoxic changes in BALB/c mice, confirming that this model is a suitable tool to conduct further mechanistic studies of oxaliplatin-related antineoplastic activity, peripheral neurotoxicity and pain. Further, this model can be used for the preclinical discovery of new neuroprotective and analgesic compounds. PMID:21521528

  12. Research about vibration characteristics of timing chain system based on short-time Fourier transform

    NASA Astrophysics Data System (ADS)

    Xi, Jiaxin; Liu, Ning

    2017-09-01

    Vibration characteristic of timing chain system is very important for an engine. In this study, we used a bush roller chain drive system as an example to explain how to use mulitybody dynamic techniques and short-time Fourier transform to investigate vibration characteristics of timing chain system. Multibody dynamic simulation data as chain tension force and external excitation sources curves were provided for short-time Fourier transform study. The study results of short-time Fourier transform illustrate that there are two main vibration frequency domain of timing chain system, one is the low frequency vibration caused by crankshaft sprocket velocity and camshaft sprocket torque. Another is vibration around 1000Hz lead by hydraulic tensioner. Hence, short-time Fourier transform method is useful for basic research of vibration characteristics for timing chain system.

  13. 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.

  14. 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.

  15. 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.

  16. Phase II Trial of Cetuximab, Gemcitabine, and Oxaliplatin Followed by Chemoradiation With Cetuximab for Locally Advanced (T4) Pancreatic Adenocarcinoma: Correlation of Smad4(Dpc4) Immunostaining With Pattern of Disease Progression

    PubMed Central

    Crane, Christopher H.; Varadhachary, Gauri R.; Yordy, John S.; Staerkel, Gregg A.; Javle, Milind M.; Safran, Howard; Haque, Waqar; Hobbs, Bridgett D.; Krishnan, Sunil; Fleming, Jason B.; Das, Prajnan; Lee, Jeffrey E.; Abbruzzese, James L.; Wolff, Robert A.

    2011-01-01

    Purpose This phase II trial was designed to assess the efficacy and safety of cetuximab, gemcitabine, and oxaliplatin followed by cetuximab, capecitabine, and radiation therapy in locally advanced pancreatic cancer (LAPC). Patients and Methods Treatment-naive eligible patients (n = 69) received intravenous gemcitabine (1,000 mg/m2) and oxaliplatin (100 mg/m2) every 2 weeks for four doses, followed by radiation (50.4 Gy to the gross tumor only) with concurrent capecitabine (825 mg/m2 twice daily on radiation treatment days). Cetuximab (500 mg/m2) was started on day 1 of chemotherapy and was continued every 2 weeks during chemotherapy and chemoradiotherapy. Diagnostic cytology specimens were immunostained for Smad4(Dpc4) expression. Results Median overall survival time was 19.2 months (95% CI, 14.2 to 24.2 months), and 1-year, 2-year, and 4-year actuarial overall survival rates were 66.0%, 25.02%, and 11.3%, respectively. Acneiform rash correlated with improved survival (P = .001), but initial CA19-9, borderline resectable initial stage, and surgical resection (n = 7) did not. The 1-year and 2-year radiographic local progression rates were 22.8% and 61.0%, respectively. The worst acute toxic effects were GI toxicity (32% and 10% for grades 2 and 3, respectively); fatigue (26% and 6% for grades 2 and 3, respectively); sensory neuropathy (9% and 1% for grades 2 and 3, respectively); and acneiform rash (54% and 3% for grades 2 and 3, respectively). Smad4(Dpc4) expression correlated with a local rather than a distant dominant pattern of disease progression (P = .016). Conclusion This regimen appears effective and has acceptable toxicity. The primary end point (1-year overall survival rate > 45%) was met, with encouraging survival duration. Smad4(Dpc4) immunostaining correlated with the pattern of disease progression. Prospective validation of Smad4(Dpc4) expression in cytology specimens as a predictive biomarker is warranted and may lead to personalized treatment

  17. Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression.

    PubMed

    Crane, Christopher H; Varadhachary, Gauri R; Yordy, John S; Staerkel, Gregg A; Javle, Milind M; Safran, Howard; Haque, Waqar; Hobbs, Bridgett D; Krishnan, Sunil; Fleming, Jason B; Das, Prajnan; Lee, Jeffrey E; Abbruzzese, James L; Wolff, Robert A

    2011-08-01

    This phase II trial was designed to assess the efficacy and safety of cetuximab, gemcitabine, and oxaliplatin followed by cetuximab, capecitabine, and radiation therapy in locally advanced pancreatic cancer (LAPC). Treatment-naive eligible patients (n = 69) received intravenous gemcitabine (1,000 mg/m(2)) and oxaliplatin (100 mg/m(2)) every 2 weeks for four doses, followed by radiation (50.4 Gy to the gross tumor only) with concurrent capecitabine (825 mg/m(2) twice daily on radiation treatment days). Cetuximab (500 mg/m(2)) was started on day 1 of chemotherapy and was continued every 2 weeks during chemotherapy and chemoradiotherapy. Diagnostic cytology specimens were immunostained for Smad4(Dpc4) expression. Median overall survival time was 19.2 months (95% CI, 14.2 to 24.2 months), and 1-year, 2-year, and 4-year actuarial overall survival rates were 66.0%, 25.02%, and 11.3%, respectively. Acneiform rash correlated with improved survival (P = .001), but initial CA19-9, borderline resectable initial stage, and surgical resection (n = 7) did not. The 1-year and 2-year radiographic local progression rates were 22.8% and 61.0%, respectively. The worst acute toxic effects were GI toxicity (32% and 10% for grades 2 and 3, respectively); fatigue (26% and 6% for grades 2 and 3, respectively); sensory neuropathy (9% and 1% for grades 2 and 3, respectively); and acneiform rash (54% and 3% for grades 2 and 3, respectively). Smad4(Dpc4) expression correlated with a local rather than a distant dominant pattern of disease progression (P = .016). This regimen appears effective and has acceptable toxicity. The primary end point (1-year overall survival rate > 45%) was met, with encouraging survival duration. Smad4(Dpc4) immunostaining correlated with the pattern of disease progression. Prospective validation of Smad4(Dpc4) expression in cytology specimens as a predictive biomarker is warranted and may lead to personalized treatment strategies for patients with localized

  18. Oxaliplatin hypersensitivity: evaluation, implications of skin testing, and desensitization.

    PubMed

    Wong, Johnson T; Ling, Morris; Patil, Sarita; Banerji, Aleena; Long, Aidan

    2014-01-01

    Oxaliplatin hypersensitivity (OXS) presents a challenge in the treatment of oxaliplatin-sensitive malignancies. To analyze patient characteristics of patients with OXS, skin test results, and desensitization outcomes to optimize management. Over 5 years, 48 patients with OXS were referred to the allergy/immunology unit at Massachusetts General Hospital. Their clinical reaction patterns were analyzed. Immediate hypersensitivity skin testing was used for risk stratification, and drug desensitizations were performed by using 3 related continuous intravenous protocols that were chosen based on clinical history, skin test reactivity, and the patients' previous desensitization outcomes. OXS occurred in both sexes, with mostly gastrointestinal-related tumors. Hypersensitivity reaction (HSR) onset had occurred during any course of therapy (course nos. 1-28), with a median onset at course no. 8. HSR to oxaliplatin was similar to those observed with cisplatin and carboplatin, including cutaneous, cardiovascular, pulmonary, and gastrointestinal symptoms. However, neurologic symptoms, including tingling, and systemic symptoms, including fever and chills, occurred more often in patients with OXS. Unique to OXS, 2 patients developed drug-induced thrombocytopenia; 1 patients also developed drug-induced hemolytic anemia. Skin testing was positive for the majority of patients with OXS (27/46 [59%]) and correlated with a greater likelihood of developing an HSR during subsequent desensitizations. We safely performed 200 desensitizations in 48 patients with OXS. OXS is common with much similarity to other platin agents but also have distinct differences in the onset of hypersensitivity, sex, tumor type, drug-induced hemolytic anemia, and drug-induced thrombocytopenia. Skin testing was helpful for risk stratification. All of the desensitizations were completed successfully. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights

  19. Variants in CDA and ABCB1 are predictors of capecitabine-related adverse reactions in colorectal cancer

    PubMed Central

    García, María I.; García-Alfonso, Pilar; Robles, Luis; Grávalos, Cristina; González-Haba, Eva; Marta, Pellicer; Sanjurjo, María; López-Fernández, Luis A.

    2015-01-01

    Adverse reactions to capecitabine-based chemotherapy limit full administration of cytotoxic agents. Likewise, genetic variations associated with capecitabine-related adverse reactions are associated with controversial results and a low predictive value. Thus, more evidence on the role of these variations is needed. We evaluated the association between nine polymorphisms in MTHFR, CDA, TYMS, ABCB1, and ENOSF1 and adverse reactions, dose reductions, treatment delays, and overall toxicity in 239 colorectal cancer patients treated with capecitabine-based regimens. The ABCB1*1 haplotype was associated with a high risk of delay in administration or reduction in the dose of capecitabine, diarrhea, and overall toxicity. CDA rs2072671 A was associated with a high risk of overall toxicity. TYMS rs45445694 was associated with a high risk of delay in administration or reduction in the dose of capecitabine, HFS >1 and HFS >2. Finally, ENOSF1 rs2612091 was associated with HFS >1, but was a poorer predictor than TYMS rs45445694. A score based on ABCB1-CDA polymorphisms efficiently predicts patients at high risk of severe overall toxicity (PPV, 54%; sensitivity, 43%) in colorectal cancer patients treated with regimens containing capecitabine. Polymorphisms in ABCB1, CDA, ENOSF1,and TYMS could help to predict specific and overall severe adverse reactions to capecitabine. PMID:25691056

  20. Variants in CDA and ABCB1 are predictors of capecitabine-related adverse reactions in colorectal cancer.

    PubMed

    García-González, Xandra; Cortejoso, Lucía; García, María I; García-Alfonso, Pilar; Robles, Luis; Grávalos, Cristina; González-Haba, Eva; Marta, Pellicer; Sanjurjo, María; López-Fernández, Luis A

    2015-03-20

    Adverse reactions to capecitabine-based chemotherapy limit full administration of cytotoxic agents. Likewise, genetic variations associated with capecitabine-related adverse reactions are associated with controversial results and a low predictive value. Thus, more evidence on the role of these variations is needed. We evaluated the association between nine polymorphisms in MTHFR, CDA, TYMS, ABCB1, and ENOSF1 and adverse reactions, dose reductions, treatment delays, and overall toxicity in 239 colorectal cancer patients treated with capecitabine-based regimens. The ABCB1*1 haplotype was associated with a high risk of delay in administration or reduction in the dose of capecitabine, diarrhea, and overall toxicity. CDA rs2072671 A was associated with a high risk of overall toxicity. TYMS rs45445694 was associated with a high risk of delay in administration or reduction in the dose of capecitabine, HFS >1 and HFS >2. Finally, ENOSF1 rs2612091 was associated with HFS >1, but was a poorer predictor than TYMS rs45445694. A score based on ABCB1-CDA polymorphisms efficiently predicts patients at high risk of severe overall toxicity (PPV, 54%; sensitivity, 43%) in colorectal cancer patients treated with regimens containing capecitabine. Polymorphisms in ABCB1, CDA, ENOSF1,and TYMS could help to predict specific and overall severe adverse reactions to capecitabine.

  1. Development of an extended-release formulation of capecitabine making use of in vitro-in vivo correlation modelling.

    PubMed

    Meulenaar, Jelte; Keizer, Ron J; Beijnen, Jos H; Schellens, Jan H M; Huitema, Alwin D R; Nuijen, Bastiaan

    2014-02-01

    An oral extended-release (ER) formulation of capecitabine was developed for twice daily dosing, theoretically providing a continuous exposure to capecitabine, thus avoiding the undesirable in-between dosing gap inherent to the dosing schedule of the marketed capecitabine immediate-release formulation (Xeloda(®)). The target 12-hour in vivo release profile was correlated to an in vitro dissolution profile using an in vitro-in vivo correlation model based on the pharmacokinetic (PK) and dissolution characteristics of Xeloda(®). Making use of the slow dissolution characteristics of amorphous capecitabine as reported previously and screening of a panel of ER excipients, an ER formulation was designed. Kollidon(®) SR induced the most prominent ER. Moreover, it was shown that tablets prepared from CoSD capecitabine and Kollidon(®) SR have an additional threefold delay in dissolution compared with tablets prepared from the same but only physically mixed components. Therefore, a prototype tablet formulation composed of co-spray-dried capecitabine and Kollidon(®) SR (98/2%, w/w) mixed with colloidal silicon dioxide (0.5%, w/w) and magnesium stearate (2.5%, w/w) was defined. This prototype shows similar dissolution characteristics as the modelled dissolution profile. Currently, the in vivo PK of our designed ER capecitabine formulations is investigated in a clinical study. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

  2. Metronomic capecitabine versus best supportive care as second-line treatment in hepatocellular carcinoma: a retrospective study

    PubMed Central

    Casadei Gardini, Andrea; Foca, Flavia; Scartozzi, Mario; Silvestris, Nicola; Tamburini, Emiliano; Faloppi, Luca; Brunetti, Oronzo; Rudnas, Britt; Pisconti, Salvatore; Valgiusti, Martina; Marisi, Giorgia; Foschi, Francesco Giuseppe; Ercolani, Giorgio; Tassinari, Davide; Cascinu, Stefano; Frassineti, Giovanni Luca

    2017-01-01

    Preliminary studies suggest that capecitabine may be safe and effective in HCC patients. The aim of this study was to retrospectively evaluate the safety and efficacy of metronomic capecitabine as second-line treatment. This multicentric study retrospectively analyzed data of HCC patients unresponsive or intolerant to sorafenib treatment with metronomic capecitabine or best supportive care (BSC).Median progression free survival was 3.1 months in patients treated with capecitabine (95%CI: 2.7–3.5). Median overall survival was 12.0 months (95% CI: 10.7–15.8) in patients receiving capecitabine, while 9.0 months (95% CI: 6.5–13.9) in patients receiving BSC. The result of univariate unweighted Cox regression model shows a 46% reduction in death risk for patients on capecitabine (95%CI: 0.357–0.829; p  =0.005) compared to patients receiving BSC alone. After weighting for potential confounders, death risk remained essentially unaltered (45%; 95%CI: 0.354–0.883; p = 0.013). Metronomic capecitabine seems a safe second-line treatment for HCC patients in terms of management of adverse events, showing a potential anti-tumour activity which needs further evaluation in phase III studies. PMID:28211921

  3. Oxaliplatin-based combined-modality therapy for rectal cancer.

    PubMed

    Minsky, Bruce D

    2003-08-01

    There are two conventional treatments for clinically resectable rectal cancer. The first is surgery, and, if the tumor is T3 and/or N1-2, this is followed by postoperative combined-modality therapy. The second, for patients with ultrasound T3 or clinical T4 disease, is preoperative combined-modality therapy followed by surgery and postoperative chemotherapy. In this review, the results of these approaches as well as novel combined-modality approaches using oxaliplatin-based regimens will be presented.

  4. 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.

  5. 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

  6. Mice with cisplatin and oxaliplatin-induced painful neuropathy develop distinct early responses to thermal stimuli

    PubMed Central

    Ta, Lauren E; Low, Philip A; Windebank, Anthony J

    2009-01-01

    Background Cisplatin has been in use for 40 years for treatment of germ line and other forms of cancer. Oxaliplatin is approved for treatment of metastatic colorectal cancer. Thirty to forty percent of cancer patients receiving these agents develop pain and sensory loss. Oxaliplatin induces distinctive cold-associated dysesthesias in up to 80% of patients. Results We have established mouse models of cisplatin and oxaliplatin-induced neuropathy using doses similar to those used in patients. Adult male C57BL6J mice were treated with daily intraperitoneal injection for 5 days, followed by 5 days of rest, for two cycles. Total cumulative doses of 23 mg/kg cisplatin and 30 mg/kg oxaliplatin were used. Behavioral evaluations included cold plate, von Frey, radiant heat, tail immersion, grip strength and exploratory behavior at baseline and at weekly intervals for 8 weeks. Following two treatment cycles, mice in the cisplatin and oxaliplatin treatment groups demonstrated significant mechanical allodynia compared to control mice. In addition, the cisplatin group exhibited significant thermal hyperalgesia in hind paws and tail, and the oxaliplatin group developed significant cold hyperalgesia in hind paws. Conclusion We have therefore established a model of platinum drug-induced painful peripheral neuropathy that reflects the differences in early thermal pain responses that are observed in patients treated with either cisplatin or oxaliplatin. This model should be useful in studying the molecular basis for these different pain responses and in designing protective therapeutic strategies. PMID:19245717

  7. 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

  8. A pilot phase II study of capecitabine in advanced or recurrent breast cancer.

    PubMed

    Saeki, Toshiaki; Kimura, Tsunehito; Toi, Masakazu; Taguchi, Tetsuo

    2006-01-01

    A pilot phase II study was conducted to evaluate the efficacy and safety of the Japanese intermittent regimen of capecitabine (Xeloda) in patients with advanced or recurrent breast cancer. A total of 23 patients who had received no more than one prior chemotherapy regimen received oral 828 mg/m2 capecitabine twice daily for 3 weeks followed by a 1-week rest period. The response to capecitabine was evaluated in 22 patients (one patient ineligible). The overall response rate was 45.5% (95% CI, 24.4-67.8%), including 1 complete response (4.5%) and 9 patients with partial response (40.9%). A further 7 patients (31.8%) had stable disease. The median duration of response was 7.2 months (range, 3.0-15.8 months) and the median time to progression was 6.4 months (95% CI, 4.1-15.1 months). Treatment-related adverse events >or= grade 3 were observed in 7 patients (30.1%). Intermittent capecitabine therapy (828 mg/m(2) twice daily for 3 weeks followed by a 1-week rest period) was shown to be effective and well tolerated as second-line treatment for advanced or recurrent breast cancer. The Japanese regimen is worthy of further study in larger numbers of patients in phase II / III clinical trials.

  9. Study on adherence to capecitabine among patients with colorectal cancer and metastatic breast cancer.

    PubMed

    Figueiredo Junior, Adiel Goes de; Forones, Nora Manoukian

    2014-01-01

    Capecitabine, an oral drug, is as effective as traditional chemotherapy drugs. To investigate the adhesion to treatment with oral capecitabine in breast and colorectal cancer, and to determine any correlation with changes in patient's quality of life. Patients with colorectal cancer or breast cancer using capecitabine were included. The patients were asked to bring any medication left at the time of scheduled visits. The QLQ-C30 questionnaire was applied at the first visit and 8-12 weeks after treatment. Thirty patients were evaluated. Adherence was 88.3% for metastatic colon cancer, 90.4% for non-metastatic colon cancer, 94.3% for rectal cancer and 96.2% for metastatic breast cancer. No strong correlation between adherence and European Organisation for Research and Treatment of Cancer QLQ-C30 functional or symptom scale rates had been found. There was no statistically significant correlation between compliance and the functional and symptom scales of the questionnaire before and after chemotherapy, with the exception of dyspnea. Although no absolute adherence to oral capecitabine treatment had been observed, the level of adherence was good. Health professionals therefore need a greater focus in the monitoring the involvement of patients with oral treatment regimens. Patients with lesser degrees of dyspnea had greater compliance.

  10. Treatment of capecitabine-induced hand-foot syndrome using a topical retinoid: A case report

    PubMed Central

    INOKUCHI, MASAFUMI; ISHIKAWA, SATOKO; FURUKAWA, HIROYUKI; TAKAMURA, HIROYUKI; NINOMIYA, ITASU; KITAGAWA, HIROHISA; FUSHIDA, SACHIO; FUJIMURA, TAKASHI; OHTA, TETSUO

    2014-01-01

    Capecitabine is a chemotherapeutic drug used in patients with breast, colon and gastric cancer. Hand-foot syndrome (HFS) is a type of dermatitis that frequently occurs as a reaction to capecitabine. To date, no effective strategies have been found to prevent or reverse HFS. Furthermore, chemotherapy induces an elevation in the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF), and this activation represents a critical mechanism for the induction of chemotherapeutic resistance. Adapalene is a third-generation synthetic retinoid. Topical retinoids are important therapeutic anti-aging agents for managing photodamaged skin, and are known to increase HB-EGF levels, which is important for skin wound healing. Accordingly, the current report focused on the topical retinoids that increase HB-EGF expression in the skin, and we hypothesized that these topical retinoids induce local chemotherapeutic resistance in the skin of patients receiving chemotherapy and consequently, decrease the cutaneous side-effects of chemotherapy. This report presents a case of the successful treatment of refractory HFS induced by capecitabine using the topical application of adapalene. Topical adapalene was applied for 3 months and significantly reduced inflammation and pain following chemotherapy. Topical retinoids may have the potential to effectively treat capecitabine-induced HFS by increasing HB-EGF expression and decreasing cutaneous side-effects. Further studies are required to establish the therapeutic efficacy of topical retinoids on HFS. PMID:24396465

  11. Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience.

    PubMed

    Blesch, Karen S; Gieschke, Ronald; Tsukamoto, Yuko; Reigner, Bruno G; Burger, Hans U; Steimer, Jean-Louis

    2003-05-01

    Preclinical studies, along with Phase I, II, and III clinical trials demonstrate the pharmacokinetics, pharmacodynamics, safety and efficacy of a new drug under well controlled circumstances in relatively homogeneous populations. However, these types of studies generally do not answer important questions about variability in specific factors that predict pharmacokinetic and pharmacodynamic (PKPD) activity, in turn affecting safety and efficacy. Semi-physiological and clinical PKPD modeling and simulation offer the possibility of utilizing data obtained in the laboratory and the clinic to make accurate characterizations and predictions of PKPD activity in the target population, based on variability in predictive factors. Capecitabine is an orally administered pro-drug of 5-fluorouracil (5-FU), designed to exploit tissue-specific differences in metabolic enzyme activities in order to enhance efficacy and safety. It undergoes extensive metabolism in multiple physiologic compartments, and presents particular challenges for predicting pharmacokinetic and pharmacodynamic activity in humans. Clinical and physiologically based pharmacokinetic (PBPK) and pharmacodynamic models were developed to characterize the activity of capecitabine and its metabolites, and the clinical consequences under varying physiological conditions such as creatinine clearance or activity of key metabolic enzymes. The results of the modeling investigations were consistent with capecitabine's rational design as a triple pro-drug of 5-FU. This paper reviews and discusses the PKPD and PBPK modeling approaches used in capecitabine development to provide a more thorough understanding of what the key predictors of its PBPK activity are, and how variability in these predictors may affect its PKPD, and ultimately, clinical outcomes.

  12. DETERMINANTS OF ADJUVANT OXALIPLATIN RECEIPT AMONG OLDER STAGE II AND III COLORECTAL CANCER PATIENTS

    PubMed Central

    Lund, Jennifer L; Stürmer, Til; Sanoff, Hanna K; Brookhart, Alan; Sandler, Robert S; Warren, Joan L

    2013-01-01

    Purpose Controversy exists regarding adjuvant oxaliplatin treatment among older stage II and III colorectal cancer (CRC) patients. We sought to identify patient/tumor, physician, hospital, and geographic factors associated with oxaliplatin use among older patients. Methods Individuals diagnosed at age>65 with stage II/III CRC from 2004–2007 undergoing surgical resection and receiving adjuvant chemotherapy were identified using the Surveillance, Epidemiology and End Results program (SEER)-Medicare, a database including patient/tumor and hospital characteristics. Physician information was obtained from the American Medical Association. We used Poisson regression to identify independent predictors of oxaliplatin receipt. The discriminatory ability of each category of characteristics to predict oxaliplatin receipt was assessed by comparing the area under the receiver operating curve (AUC) from logistic regression models. Results We identified 4,388 individuals who underwent surgical resection at 773 hospitals and received chemotherapy from 1,517 physicians. Adjuvant oxaliplatin use was higher among stage III (colon=56%, rectum=51%) compared to stage II patients (colon=37%, rectum=35%). Overall, patients who were older, diagnosed before 2006, separated, divorced or widowed, living in a higher poverty census tract or in the East or Midwest, or with higher levels of comorbidity were less likely to receive oxaliplatin. Patient factors and calendar year accounted for most of the variation in oxaliplatin receipt (AUC=75.8%). Conclusion Adjuvant oxaliplatin use increased rapidly from 2004–2007 despite uncertainties regarding its effectiveness in older patients. Physician and hospital characteristics had little influence on adjuvant oxaliplatin receipt among older patients. PMID:23512326

  13. The use of capecitabine in daily practice: a study on adherence and patients’ experiences

    PubMed Central

    Timmers, Lonneke; Swart, Eleonora L; Boons, Christel CLM; Mangnus, Dirk; van de Ven, Peter M; Peters, Godefridus J; Boven, Epie; Hugtenburg, Jacqueline G

    2012-01-01

    Background Adherence to pharmacological therapy is a complex and multifactorial issue that can substantially alter the outcome of treatment. Especially when using long-term medication, cancer patients have adherence rates similar to those of patients with other diseases. The consequences of poor adherence are poor health outcomes and increased health care costs. Only few studies have focused on the use of oral anticancer agents in daily practice. Information about the reasons for nonadherence is essential for the development of interventions that may improve adherence. This report presents the CAPER-capecitabine protocol, which is designed to study the adherence to capecitabine and the influence of patient attitudes towards medication and self-reported side effects. Furthermore, the relationships between patient characteristics, disease characteristics, side effects, quality of life, patient beliefs and attitudes towards disease and medication, dose adjustments, reasons for discontinuation, and plasma concentration of three of the main metabolites, including the active compound 5-fluorouracil, will be explored. Methods In this multicenter, prospective, observational cohort study, 90 patients aged 18 years or older starting treatment with capecitabine will be included and followed for a period up to five cycles. The main study parameters are adherence, patient attitudes towards medication, and the number and grade of patient-reported side effects. At baseline and during week 2 of cycles 1, 3 and 5, patients will be asked to donate blood and fill out a questionnaire. Blood samples will be analyzed for plasma concentration of the metabolites, 5′-deoxy-5-fluorouridine, 5-fluorouracil, and α-fluoro-β-alanine. The CAPER-capecitabine trial is closely related to the CAPER-erlotinib trial. Discussion The aim of the present study is to get more insight into patient experiences with the use of capecitabine in daily practice and the various aspects that govern adherence

  14. Adherence to capecitabine treatment and contributing factors among cancer patients in Malaysia.

    PubMed

    Zahrina, Abdul Kadir; Norsa'adah, Bachok; Hassan, Norul Badriah; Norazwany, Yaacob; Norhayati, Isa; Roslan, Mohd Haron; Wan Nazuha, Wan Rusik

    2014-01-01

    Ensuring adherence to chemotherapy is important to prevent disease progression, prolong survival and sustain good quality of life. Capecitabine is a complex chemotherapeutic agent with many side effects that might affect patient adherence to treatment. This cross sectional study aimed to determine adherence to capecitabine and its contributing factors among cancer outpatients in Malaysia. One hundred and thirteen patients on single regime capecitabine were recruited from Hospital Sultan Ismail and Hospital Kuala Lumpur from October 2013 to March 2014. Adherence was determined based on adherence score using validated Medication Compliance Questionnaire. Patient socio-demographics, disease, and treatment characteristics were obtained from medical records. Satisfaction score was measured using the validated Patient Satisfaction with Healthcare questionnaire. The mean adherence score was 96.1% (standard deviation: 3.29%). The significant contributing factors of adherence to capecitabine were Malay ethnicity [β=1.3; 95% confidence interval (CI): 0.21, 2.43; p value=0.020], being female [β=1.8; 95%CI: 0.61, 2.99; p value=0.003]), satisfaction score [β=0.08; 95%CI: 0.06, 1.46; p value=0.035], presence of nausea or vomiting [β=2.3; 95%CI: 1.12, 3.48; p value <0.001] and other side effects [β=1.45; 95%CI: 0.24, 2.65; p value=0.019]. Adherence to capecitabine was generally high in our local population. Attention should be given to non-Malay males and patients having nausea, vomiting or other side effects. Sufficient information, proactive assessment and appropriate management of side effects would improve patient satisfaction and thus create motivation to adhere to treatment plans.

  15. 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.

  16. Hypertriglyceridemia and hyperglycemia induced by capecitabine: a report of two cases and review of the literature.

    PubMed

    Han, Gao-Hua; Huang, Jun-Xing

    2015-10-01

    Capecitabine is a tumor-activated oral fluoropyrimidine used in breast and colorectal cancer. Hypertriglyceridemia associated with this drug has rarely been reported in the literature. Two patients with colorectal carcinoma who developed capecitabine-induced hypertriglyceridemia (including a patient who developed hyperglycemia concurrently) were described, treatment modalities were discussed, and the literatures were reviewed. The first patient, a 43-year-old man, developed hyperlipidemia and hyperglycemia after two cycles of XELOX regimen chemotherapy for colorectal cancer. His triglyceride was 2.47 mmol/L (normal range 0.34-1.7 mmol/L) and total cholesterol was 6.93 mmol/L (normal range 3.12-5.9 mmol/L), while blood glucose was abnormal (fasting blood glucose was 10.58-11.9 mmol/L and 2 h postprandial glucose was 14.5-17.2 mmol/L) and glucose was positive in the urine(3+). The second patient, a 47-year-old woman, developed abnormalities in the lipid profile after the sixth cycle of XELOX regimen chemotherapy for colorectal cancer. Her serum triglyceride was 2.41 mmol/L (normal range 0.34-1.7 mmol/L), while the cholesterol level was 7.73 mmol/L (normal range 3.12-5.9 mmol/L). The profile of lipid improved gradually with reduced doses of capecitabine and was well restored after chemotherapy without any lipid-lowering agents. The Naranjo score for capecitabine-induced hypertriglyceridemia was 9 (definite). An analysis of the underlying pathogenic mechanisms was provided. It is important of physicians and pharmacists to be aware of the possibility of dyslipidemia, particularly hypertriglyceridemia induced by capecitabine. © The Author(s) 2014.

  17. 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.

  18. Adherence with capecitabine: A population-based analysis based on prescription refill data.

    PubMed

    Kovacic, Laurel; de Haan, Neil; de Lemos, Mário L; Schaff, Kimberly; Walisser, Susan

    2017-06-01

    Background Patient adherence is important with the increasing use of oral anticancer drugs. Recent studies reported different capecitabine adherence rates based on self-reporting and microelectronic monitoring of the medication bottle. Patient's awareness of being monitored may confound these results. Prescription records provide a larger and more objective dataset for adherence investigation. We report the use of computer algorithm and manual review of prescription and medical documentation to determine the rate of capecitabine adherence. Methods Two years of capecitabine prescription records from five ambulatory cancer centres were reviewed. Prescription data were extracted using a custom Java-based software tool to compare the predicted vs. actual dispensing date. The difference between the dates was the primary adherence measure (altered treatment date incident) and estimated using a computer algorithm and by manual review of medical charts. Results Of 4412 refill prescriptions, 45.2% was associated with an altered treatment date incident based on the initial computer algorithm. This was reduced to 29.5% after adjusting for clinic scheduling processes and 10.2% after manual chart review to adjust for valid reasons for delay. The reasons for altered treatment date incident were not identified in 52.2% of prescriptions. Conclusions Adherence rate of capecitabine based on refill data seem to be high and consistent with other findings based on patient self-report. Population analysis of prescription data with custom computer algorithm may identify trends in capecitabine adherence with some efficiency. Manual review would likely be required to verify these results. The accuracy of using altered prescription refill dates as an adherence measure requires further studies.

  19. Improvement in the Mechanical Behavior of Mechanically Alloyed Aluminum Using Short-Time NH3 Flow

    NASA Astrophysics Data System (ADS)

    Caballero, E. S.; Cintas, J.; Cuevas, F. G.; Montes, J. M.; Herrera-García, M.

    2016-12-01

    In order to study the influence of a short-time ammonia gas flow during mechanical alloying (MA) of aluminum powders, samples were prepared using a simple press and sinter method. All milling experiments were performed at room temperature for a total of 10 hours. A short-time ammonia flow was incorporated into the milling process, allowing for the appearance of nitrogen-rich second phases, mainly oxycarbonitride and oxynitride aluminum (Al3CON and Al5O6N, respectively), during powder sintering. Testing of the sintering parts showed that the use of a short-time ammonia gas flow during vacuum milling substantially improved the mechanical properties at room and high temperatures.

  20. Short-time scale behavior modeling within long-time scale fuel cycle evaluations

    SciTech Connect

    Johnson, M.; Tsvetkov, P.; Lucas, S.

    2012-07-01

    Typically, short-time and long-time scales in nuclear energy system behavior are accounted for with entirely separate models. However, long-term changes in system characteristics do affect short-term transients through material variations. This paper presents an approach to consistently account for short-time scales within a nuclear system lifespan. The reported findings and developments are of significant importance for small modular reactors and other nuclear energy systems operating in autonomous modes. It is necessary to simulate the short time-scale kinetic behavior of the reactor as well as the long time-scale dynamics that occur with fuel burnup. The former is modeled using the point kinetics equations, while the latter is modeled by the Bateman equations. (authors)

  1. Integrating random matrix theory predictions with short-time dynamical effects in chaotic systems.

    PubMed

    Smith, A Matthew; Kaplan, Lev

    2010-07-01

    We discuss a modification to random matrix theory eigenstate statistics that systematically takes into account the nonuniversal short-time behavior of chaotic systems. The method avoids diagonalization of the Hamiltonian; instead it requires only knowledge of short-time dynamics for a chaotic system or ensemble of similar systems. Standard random matrix theory and semiclassical predictions are recovered in the limits of zero Ehrenfest time and infinite Heisenberg time, respectively. As examples, we discuss wave-function autocorrelations and cross correlations, and show that significant improvement in accuracy is obtained for simple chaotic systems where comparison can be made with brute-force diagonalization. The accuracy of the method persists even when the short-time dynamics of the system or ensemble is known only in a classical approximation. Further improvement in the rate of convergence is obtained when the method is combined with the correlation function bootstrapping approach introduced previously.

  2. NMR measurement and Brownian movement in the short-time limit

    NASA Astrophysics Data System (ADS)

    Stepišnik, Janez

    1994-05-01

    This study is carried out to find relations between the time-dependent molecular self-diffusion and the attenuation of NMR spin-echo. Two cases of diffusion are considered: the Brownian motion in Ornstein's short-time limit and the random walk with memory [13]. The friction and the correlation time describe the mechanism of entrapping interactions between molecules or their bonding to macromolecule chains. The obtained formula for the self-diffusion attenuation is valid at short times and it develops into the well-known Torrey's result in the long-time limit. It fits very efficiently into the NMR data from Refs. [19-20].

  3. Universal short-time dynamics: Boundary functional renormalization group for a temperature quench

    NASA Astrophysics Data System (ADS)

    Chiocchetta, Alessio; Gambassi, Andrea; Diehl, Sebastian; Marino, Jamir

    2016-11-01

    We present a method to calculate short-time nonequilibrium universal exponents within the functional-renormalization-group scheme. As an example, we consider the classical critical dynamics of the relaxational model A after a quench of the temperature of the system and calculate the initial-slip exponent which characterizes the nonequilibrium universal short-time behavior of both the order parameter and correlation functions. The value of this exponent is found to be consistent with the result of a perturbative dimensional expansion and of Monte Carlo simulations in three spatial dimensions.

  4. Method to modify random matrix theory using short-time behavior in chaotic systems.

    PubMed

    Smith, A Matthew; Kaplan, Lev

    2009-09-01

    We discuss a modification to random matrix theory (RMT) eigenstate statistics that systematically takes into account the nonuniversal short-time behavior of chaotic systems. The method avoids diagonalization of the Hamiltonian, instead requiring only knowledge of short-time dynamics for a chaotic system or ensemble of similar systems. Standard RMT and semiclassical predictions are recovered in the limits of zero Ehrenfest time and infinite Heisenberg time, respectively. As examples, we discuss wave-function autocorrelations and cross correlations and show how the approach leads to a significant improvement in the accuracy for simple chaotic systems where comparison can be made with brute-force diagonalization.

  5. Capecitabine pattern of usage, rate of febrile neutropaenia and treatment related death in asian cancer patients in clinical practice.

    PubMed

    Phua, Vincent Chee Ee; Wong, Wei Quan; Tan, Pei Lin; Bustam, Anita Zarina; Saad, Marniza; Alip, Adlinda; Wan Ishak, Wan Zamaniah

    2015-01-01

    Oral capecitabine is increasingly replacing intravenous 5-fluorouracil in many chemotherapy regimens. However, data on the risk of febrile neutropaenia (FN) and treatment related death (TRD) with the drug remain sparse outside of clinical trial settings despite its widespread usage. This study aimed to determine these rates in a large cohort of patients treated in the University of Malaya Medical Centre (UMMC). We reviewed the clinical notes of all patients prescribed with oral capecitabine chemotherapy for any tumour sites in University Malaya Medical Centre (UMMC) from 1st January 2009 till 31st June 2010. Information collected included patient demographics, histopathological features, treatment received including the different chemotherapy regimens and intent of treatment whether the chemotherapy was given for neoadjuvant, concurrent with radiation, adjuvant or palliative intent. The aim of this study is to establish the pattern of usage, FN and TRD rates with capecitabine in clinical practice outside of clinical trial setting. FN is defined as an oral temperature >38.5°or two consecutive readings of >38.0° for 2 hours and an absolute neutrophil count <0.5 x 109/L, or expected to fall below 0.5 x 109/L (de Naurois et al., 2010). Treatment related death was defined as death occurring during or within 30 days of last chemotherapy treatment. Between 1st January 2009 and 30th June 2010, 274 patients were treated with capecitabine chemotherapy in UMMC. The mean age was 58 years (range 22 to 82 years). Capecitabine was used in 14 different tumour sites with the colorectal site predominating with a total of 128 cases (46.7%), followed by breast cancer (35.8%). Capecitabine was most commonly used in the palliative setting accounting for 63.9% of the cases, followed by the adjuvant setting (19.7%). The most common regimen was single agent capecitabine with 129 cases (47.1%). The other common regimens were XELOX (21.5%) and ECX (10.2%). The main result of this study

  6. [A multicenter clinical study for the comparison of S-1 versus capecitabine in the treatment of advanced breast cancer].

    PubMed

    Li, Y; Jiang, D; Wu, Y Y; Li, L L; Cui, Y Z; Dong, Q

    2017-08-23

    Objective: To investigate the safety, efficacy and prognostic factors of S-1 versus capecitabine in patients with advanced breast cancer (ABC). Methods: From January 1, 2012 to December 31, 2014, 154 ABC patients with pathological diagnosis were separated into two groups: S-1 with or without the 3rd generation chemotherapy drug (group S-1) and capecitabine with or without the 3rd generation chemotherapy drug (Group capecitabine). The efficacy, side effects and prognostic factors were compared between the two groups. Results: There were 70 patients in group S-1 and 84 patients in group capecitabine. The objective response rates (ORR) were 31.4% (22/70) in group S-1 and 28.6% (24/84) in group capecitabine. The disease control rates (DCR) were 74.3% (52/70) and 83.3% (70/84), respectively. There were no significant differences in DCR and ORR between two groups (P>0.05). The DCR of patients treated with capecitabine monotherapy was significantly higher than that of S-1 monotherapy [94.4%(17/18) and 64.0%(16/25), P=0.028]. The median PFS was 7.5 and 8.9 months for the patients in the group S-1 and group capecitabine, with no statistically significant difference (P=0.423). The 1-year survival rates of group S-1 and group capecitabine were 81.4% and 66.7%, respectively, with no significant differences(P=0.020). Univariate analysis showed that ER and/or PR status (P=0.004), T stage (P=0.041), and molecular typing (P=0.046) were associated with PFS. Multivariate analysis showed ER and/or PR status (P=0.034) was an independent prognostic factor related with PFS. The incidence of hemoglobin reduction was 14.3% (10/70) and 36.9% (31/84) in the group S-1 and group capecitabine, and the differences were statistically significant (P=0.002). There was no significant difference in the incidence of leukopenia, neutropenia, thrombocytopenia and hand-foot syndrome between the two groups(P>0.05). Conclusions: S-1 and capecitabine are both effective for advanced breast cancer. Neither

  7. Fluorouracil-based neoadjuvant chemoradiotherapy with or without oxaliplatin for treatment of locally advanced rectal cancer: An updated systematic review and meta-analysis

    PubMed Central

    Li, Zhi-Wen; Zhao, Ling; Wu, Hong-Fen; Yue, Dan; Yang, Jin-Lei; Zhou, Zhi-Rui; Liu, Shi-Xin

    2016-01-01

    To measure the safety and efficacy of oxaliplatin (OX) application in neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC), EMBASE, PubMed, Cochrane Library, and Web of Science were used for a literature search. Cochrane's risk of bias tool of randomized controlled trials (RCTs) was used for quality evaluation. The statistical analyses were performed using RevMan 5.3. In addition, 95% confidence intervals (CIs) and pooled risk ratios (RRs) were calculated. Seven RCTs were included in our meta-analysis. After adding OX to fluoropyrimidine (FU), a marginal significant improvement in disease-free survival was noted compared with FU alone (RR = 0.89, 95% CI: 0.78–1.00; P = 0.05). Neoadjuvant CRT with OX significantly decreased the distant metastasis rate (RR = 0.79, 95% CI: 0.67–0.94, P = 0.007). However, no improvement in the local recurrence rate (RR = 0.86, 95% CI: 0.68–1.08; P = 0.19) was noted. In addition, neoadjuvant CRT with OX also significantly increased the pathologic complete response (RR = 1.24, 95% CI: 1.02–1.51; P = 0.03). Grade 3–4 acute toxicity and grade 3–4 diarrhea was considerably higher for OX/FU compared with FU alone. In conclusion, the use of OX on the basis of FU/capecitabine in preoperative CRT is feasible. LARC patients are likely to benefit from CRT regimens with OX. PMID:27322422

  8. 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

  9. 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.

  10. 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.

  11. A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours

    PubMed Central

    Pronk, L C; Vasey, P; Sparreboom, A; Reigner, B; Planting, A S Th; Gordon, R J; Osterwalder, B; Verweij, J; Twelves, C

    2000-01-01

    Capecitabine and docetaxel are both active against a variety of solid tumours, while their toxicity profiles only partly overlap. This phase I study was performed to determine the maximum tolerated dose (MTD) and side-effects of the combination, and to establish whether there is any pharmacokinetic interaction between the two compounds. Thirty-three patients were treated with capecitabine administered orally twice daily on days 1–14, and docetaxel given as a 1 h intravenous infusion on day 1. Treatment was repeated every 3 weeks. The dose of capecitabine ranged from 825 to 1250 mg m–2twice a day and of docetaxel from 75 to 100 mg m–2. The dose-limiting toxicity (DLT) was asthenia grade 2–3 at a dose of 1000 mg m–2bid of capecitabine combined with docetaxel 100 mg m–2. Neutropenia grade 3–4 was common (68% of courses), but complicated by fever in only 2.4% of courses. Other non-haematological toxicities were mild to moderate. There was no pharmacokinetic interaction between the two drugs. Tumour responses included two complete responses and three partial responses. Capecitabine 825 mg m–2twice a day plus docetaxel 100 mg m–2was tolerable, as was capecitabine 1250 mg m–2twice a day plus docetaxel 75 mg m–2. © 2000 Cancer Research Campaign PMID:10883663

  12. 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

  13. 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...

  14. 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...

  15. 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…

  16. 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.

  17. How Do Young Children's Spatio-Symbolic Skills Change over Short Time scales?

    ERIC Educational Resources Information Center

    Tsubota, Yoko; Chen, Zhe

    2012-01-01

    Three experiments were designed to examine how experience affects young children's spatio-symbolic skills over short time scales. Spatio-symbolic reasoning refers to the ability to interpret and use spatial relations, such as those encountered on a map, to solve symbolic tasks. We designed three tasks in which the featural and spatial…

  18. 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.

  19. 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.

  20. Oxaliplatin Alters Expression of T1R2 Receptor and Sensitivity to Sweet Taste in Rats.

    PubMed

    Ohishi, Akihiro; Nishida, Kentaro; Yamanaka, Yuri; Miyata, Ai; Ikukawa, Akiko; Yabu, Miharu; Miyamoto, Karin; Bansho, Saho; Nagasawa, Kazuki

    2016-01-01

    As one of the adverse effects of oxaliplatin, a key agent in colon cancer chemotherapy, a taste disorder is a severe issue in a clinical situation because it decreases the quality of life of patients. However, there is little information on the mechanism underlying the oxaliplatin-induced taste disorder. Here, we examined the molecular and behavioral characteristics of the oxaliplatin-induced taste disorder in rats. Oxaliplatin (4-16 mg/kg) was administered to Sprague-Dawley (SD) rats intraperitoneally for 2 d. Expression levels of mRNA and protein of taste receptors in circumvallate papillae (CP) were measured by real-time quantitative polymerase chain reaction (PCR) and immunohistochemistry, respectively. Taste sensitivity was assessed by their behavioral change using a brief-access test. Morphological change of the taste buds in CP was evaluated by hematoxyline-eosin (HE) staining, and the number of taste cells in taste buds was counted by immunohistochemical analysis. Among taste receptors, the expression levels of mRNA and protein of T1R2, a sweet taste receptor subunit, were increased transiently in CP of oxaliplatin-administered rats on day 7. In a brief-access test, the lick ratio was decreased in oxaliplatin-administered rats on day 7 and the alteration was recovered to the control level on day 14. There was no detectable alteration in the morphology of taste buds, number of taste cells or plasma zinc level in oxaliplatin-administered rats. These results suggest that decreased sensitivity to sweet taste in oxaliplatin-administered rats is due, at least in part, to increased expression of T1R2, while these alterations are reversible.

  1. Different Apoptotic Pathways Activated by Oxaliplatin in Primary Astrocytes vs. Colo-Rectal Cancer Cells

    PubMed Central

    Zanardelli, Matteo; Micheli, Laura; Nicolai, Raffaella; Failli, Paola; Ghelardini, Carla; Di Cesare Mannelli, Lorenzo

    2015-01-01

    Oxaliplatin-based chemotherapy improves the outcomes of metastatic colorectal cancer patients. Its most significant and dose-limiting side effect is the development of a neuropathic syndrome. The mechanism of the neurotoxicity is unclear. The limited knowledge about differences existing between neurotoxic and antitumor effects hinders the discovery of effective and safe adjuvant therapies. In vitro, we suggested cell-specific activation apoptotic pathways in normal nervous cells (astrocytes) vs. colon-cancer cells (HT-29). In the present research we compared the apoptotic signals evoked by oxaliplatin in astrocytes and HT-29 analyzing the intrinsic and extrinsic apoptotic pathways. In astrocytes, oxaliplatin induced a mitochondrial derangement measured as cytosolic release of cytochrome C, increase in superoxide anion levels and decreased expression of the antiapoptotic protein Bcl-2. Caspase-8, a main initiator of the extrinsic process remained unaltered. On the contrary, in HT-29 oxaliplatin increased caspase-8 activity and Bid expression, thus activating the extrinsic apoptosis, while the Bcl-2 increased expression blocked the mitochondrial damage. Data suggest the preferred activation of the intrinsic apoptosis as oxaliplatin damage signaling in normal nervous cells. The extrinsic pathway prevails in tumor cells indicating a possible strategy for planning new molecules to treat oxaliplatin-dependent neurotoxicity without negatively influence chemotherapy. PMID:25761243

  2. [Oxaliplatin neurotoxicity: a report of three cases with post-operative exacerbation].

    PubMed

    Cournede, Agnès; Ries, Pauline; Richard, Karine; Guillain, Alexandra; Dahan, Laëtitia; Grandval, Philippe; Pourroy, Bertrand; Moutardier, Vincent; Hardwigsen, Jean; Braguer, Diane; Seitz, Jean-François

    2005-04-01

    Liver metastases of colorectal cancer are rarely rapidly resectable. The efficacy of new chemotherapy regimen, in particular the combination of 5FU and oxaliplatin make further surgical resection possible in the case of an objective response in some patients. Three patients with metastatic colorectal cancer received oxaliplatin-based chemotherapy; only minimal and transient neurosensory toxicity occurred. After a partial response to treatment, surgical resection of metastases was performed. Patients reported major exacerbation of oxaliplatin-induced neurosensory toxicity following surgery (between day 7 and day 15). One patient experienced sensory loss of the extremities with functional impairment (grade 3 on Levi's scale). The symptoms persisted for 812 months after surgery in the three patients. Only seven similar cases have been reported. Toxicity could be associated with the concentration of oxaliplatin in the red blood cells: oxaliplatin binds irreversibly to erythrocytes. This exacerbation could be the consequence of peroperative hemolysis with a redistribution of the pool of intra-erythrocytic oxaliplatin biotransformation products into the plasma. We did not find any relationship with anesthesic or per-operative medications. Studies are necessary to define the precise mechanism and the frequency of this reaction.

  3. Characterization of and protection from neurotoxicity induced by oxaliplatin, bortezomib and epothilone-B.

    PubMed

    Ceresa, Cecilia; Avan, Abolfazl; Giovannetti, Elisa; Geldof, Albert A; Avan, Amir; Cavaletti, Guido; Peters, Godefridus J

    2014-01-01

    To characterize neurotoxicity induced by oxaliplatin, bortezomib, and epothilone-B as well as protection against their neurotoxicity using an in vitro model. Neurotoxicity was evaluated using the neurite outgrowth method in PC12 rat pheochromo-cytoma cells differentiated towards a mature neuronal phenotype, while neuroprotection was explored by simultaneous exposure to 0.5 mM amifostine. The potential markers of neuronal differentiation, cyclin-B2 (Ccnb2) and baculoviral inhibitor of apoptosis repeat-containing 5 (Birc5), were evaluated by quantitative reverse transcription polymerase chain reaction (RT-PCR). Bortezomib, epothilone-B, and oxaliplatin reduced neurite length to 68%, 78% and 66%, respectively (p<0.05). The percentage of neurite-forming-cells (discriminating neurotoxicity from general cytotoxicity) decreased from 70% (control) to 55% (bortezomib), 46% (epothilone-B), and 51% (oxaliplatin). Amifostine was neuroprotective against oxaliplatin-induced neurotoxicity, increasing both neurite length and neurite-forming-cells. Quantitative-RT-PCR showed a 2.7-fold decrease in Ccnb2 expression in differentiated PC12 vs. undifferentiated cells. Oxaliplatin, bortezomib, and epothilone-B are neurotoxic in the PC12 model. Amifostine has a neuroprotective effect only against oxaliplatin-induced neurotoxicity, suggesting that these compounds have different mechanisms of neurotoxicity.

  4. Glutathione alleviated peripheral neuropathy in oxaliplatin-treated mice by removing aluminum from dorsal root ganglia

    PubMed Central

    Lee, Minji; Cho, Sungrae; Roh, Kangsan; Chae, Jisook; Park, Jin-Hee; Park, Jaehyun; Lee, Myung-Ah; Kim, Jinheung; Auh, Chung-Kyoon; Yeom, Chang-Hwan; Lee, Sukchan

    2017-01-01

    Oxaliplatin, a platinum-based anti-cancer drug, induces peripheral neuropathy as a side effect and causes cold hyperalgesia in cancer patients receiving anti-cancer chemotherapy. In oxaliplatin-treated mice, aluminum was accumulated in the dorsal root ganglia (DRG), and accumulated aluminum in DRG or other organs aggravated oxaliplatin-induced neuropathic pain. To investigate whether aluminum oxalate, which is the compound of aluminum and oxaliplatin, might be the peripheral neuropathy inducer, the withdrawal responses of mice to coldness, the expression of transient receptor potential ankyrin 1 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays in DRG were analyzed in mice administered with aluminum oxalate. In addition, the concentrations of aluminum in aluminum oxalate-treated mice were significantly increased compared to those of mice treated with aluminum chloride. To alleviate neuropathic pain, glutathione (GSH), known as an antioxidant and a metal chelator, was injected into oxaliplatin-treated mice. The concentrations of aluminum in the DRG were decreased by the chelation action of GSH. Taken together, behavioral and molecular analyses also supported that aluminum accumulation on the DRG might be a factor for neuropathic pain. This result also suggested that the aluminum chelation by GSH can provide an alleviatory remedy of neuropathic pain for cancer patients with oxaliplatin-induced neuropathic pain. PMID:28386322

  5. Ibudilast reduces oxaliplatin-induced tactile allodynia and cognitive impairments in rats.

    PubMed

    Johnston, Ian N; Tan, Manuela; Cao, Jacob; Matsos, Antigone; Forrest, Daniel R L; Si, Emily; Fardell, Joanna E; Hutchinson, Mark R

    2017-09-15

    Chemotherapy can cause serious neurotoxic side effects, such as painful peripheral neuropathies and disabling cognitive impairments. Four experiments examined whether Ibudilast, a clinically approved neuroimmune therapy, would reduce tactile allodynia and memory impairments caused by oxaliplatin in laboratory rats. Rats received an intraperitoneal injection of oxaliplatin (6mg/kg i.p.) or vehicle and were assessed for tactile allodynia 3 or 5days after injection, memory impairments in the novel object and novel location recognition tests 10-12days after injection, and fear conditioning 14days after injection. Ibudilast (7.5mg/kg) or vehicle was administered prior to oxaliplatin (Experiments 1 and 3) or prior to behavioural testing (Experiments 2 and 4). Ibudilast treatment prior to oxaliplatin prevented the development of tactile allodynia and memory impairments. Ibudilast treatment prior to behavioural testing reduced oxaliplatin-induced tactile allodynia, memory impairments, and impaired renewal of fear conditioning. These results suggest that Ibudilast could be an effective treatment against oxaliplatin-induced neuropathies and cognitive impairments. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Glutathione alleviated peripheral neuropathy in oxaliplatin-treated mice by removing aluminum from dorsal root ganglia.

    PubMed

    Lee, Minji; Cho, Sungrae; Roh, Kangsan; Chae, Jisook; Park, Jin-Hee; Park, Jaehyun; Lee, Myung-Ah; Kim, Jinheung; Auh, Chung-Kyoon; Yeom, Chang-Hwan; Lee, Sukchan

    2017-01-01

    Oxaliplatin, a platinum-based anti-cancer drug, induces peripheral neuropathy as a side effect and causes cold hyperalgesia in cancer patients receiving anti-cancer chemotherapy. In oxaliplatin-treated mice, aluminum was accumulated in the dorsal root ganglia (DRG), and accumulated aluminum in DRG or other organs aggravated oxaliplatin-induced neuropathic pain. To investigate whether aluminum oxalate, which is the compound of aluminum and oxaliplatin, might be the peripheral neuropathy inducer, the withdrawal responses of mice to coldness, the expression of transient receptor potential ankyrin 1 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays in DRG were analyzed in mice administered with aluminum oxalate. In addition, the concentrations of aluminum in aluminum oxalate-treated mice were significantly increased compared to those of mice treated with aluminum chloride. To alleviate neuropathic pain, glutathione (GSH), known as an antioxidant and a metal chelator, was injected into oxaliplatin-treated mice. The concentrations of aluminum in the DRG were decreased by the chelation action of GSH. Taken together, behavioral and molecular analyses also supported that aluminum accumulation on the DRG might be a factor for neuropathic pain. This result also suggested that the aluminum chelation by GSH can provide an alleviatory remedy of neuropathic pain for cancer patients with oxaliplatin-induced neuropathic pain.

  7. In Vitro Circuit Stability of 5-Fluorouracil and Oxaliplatin in Support of Hyperthermic Isolated Hepatic Perfusion

    PubMed Central

    Colville, Heidi; Dzadony, Ryan; Kemp, Rebecca; Stewart, Stephen; Zeh, Herbert J.; Bartlett, David L.; Holleran, Julianne; Schombert, Kevin; Kosovec, Juliann E.; Egorin, Merrill J.; Beumer, Jan H.

    2010-01-01

    Abstract: Over the years, a large number of drugs have been used in isolated perfusion of extremities or organs. To interpret the pharmacokinetics of these drugs correctly, the contributions of tissue or organ clearance and chemical degradation, respectively, to overall drug elimination from the circuit need to be identified. In support of a phase I clinical trial of isolated hepatic perfusion (IHP), delivering 5-fluorouracil (5-FU) and oxaliplatin to patients with colorectal cancer hepatic metastases, we aimed to characterize the stability of 5-FU and oxaliplatin in the IHP circuit. Stability of 5-FU and oxaliplatin was assessed in human blood, lactated Ringer infusion (LRI), and in an in vitro IHP circuit consisting of both blood and LRI. Samples were analyzed with liquid chromatography tandem mass spectrometry (5-FU) and atomic absorption spectrophotometry (oxaliplatin). 5-FU was stable under all tested in vitro conditions, but ultrafilterable platinum concentrations decreased slowly with a half-life of 85 minutes in both IHP perfusate and whole blood. The stability of 5-FU in the media containing blood is likely attributable to saturation of dihydropyrimidine dehydrogenase. The decrease of ultrafilterable platinum in blood-containing media with an 85 minutes half-life is in agreement with previous reports on oxaliplatin biotransformation. Oxaliplatin and 5-FU are sufficiently stable in the circuit for the 1-hour perfusion in ongoing and planned clinical trials. PMID:20437796

  8. 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

  9. 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

  10. Benign dermoscopic parallel ridge pattern in plantar hyperpigmentation due to capecitabine

    PubMed Central

    Tognetti, Linda; Fimiani, Michele; Rubegni, Pietro

    2015-01-01

    We report the case of a 37-year-old woman (phototype II) who presented at our outpatient clinic with a two-month history of hyperpigmented plantar macules. Medical history revealed that the patient had taken capecitabine in the past three months as adjuvant chemotherapy for recurrent breast cancer. Dermoscopic examination of the plantar macules showed parallel ridge pattern with pigmentation in the furrows without obliteration of eccrine gland apertures. Besides in acral melanoma, parallel ridge pattern can also be observed in benign plantar lesions, such as congenital or acquired acral nevi, subcorneal hemorrhage, dye-related pigmentation and drug-induced hyperpigmentation, especially in patients with phototypes III–VI. The few reported cases of capecitabine-induced hyperpigmentation have been associated with hand and foot syndrome in patients with phototypes IV–V and palmar as well as plantar involvement. PMID:26114058

  11. [Hepatotoxicity of acetaminophen in a patient treated with capecitabine due to breast cancer].

    PubMed

    Karczmarek-Borowska, Bozenna; Drzymała, Małgorzata; Golon, Kamila

    2014-05-01

    Toxic liver injury is among the major side effects of paracetamol. It is a direct effect of the drug metabolite on the liver cells and is dependent on the dose. Unintentional overdose is often the result of several days of taking excessive doses of the drug for medical use. It is fostered by patients' self-treatment, the availability of non-prescription drugs and lack of awareness of the actual composition of the medication taken. The authors of this study reported a case of hepatotoxicity in a patient treated with capecitabine for breast cancer. Capecitabine therapy was completed several days before the use of paracetamol. The detailed interview with the patient revealed that the cause of hepatic dysfunction was the fact that she took paracetamol for 3 days in a daily dose of 5.5 grams (the permissible safe dose is 4 grams) due to the viral infection. After symptomatic treatment over several days improved took place.

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

    NASA Astrophysics Data System (ADS)

    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.

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

    SciTech Connect

    Castro, L.A. de Napolitano, R.D.J.

    2016-04-15

    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.

  14. Short-time Lyapunov exponent analysis and the transition to chaos in Taylor-Couette flow

    NASA Technical Reports Server (NTRS)

    Vastano, John A.; Moser, Robert D.

    1991-01-01

    The physical mechanism driving the weakly chaotic Taylor-Couette flow is investigated using the short-time Liapunov exponent analysis. In this procedure, the transition from quasi-periodicity to chaos is studied using direct numerical 3D simulations of axially periodic Taylor-Couette flow, and a partial Liapunov exponent spectrum for the flow is computed by simultaneously advancing the full solution and a set of perturbations. It is shown that the short-time Liapunov exponent analysis yields more information on the exponents and dimension than that obtained from the common Liapunov exponent calculations. Results show that the chaotic state studied here is caused by a Kelvin-Helmholtz-type instability of the outflow boundary jet of Taylor vortices.

  15. Short time properties, dynamic fragility and pressure effects in deeply supercooled polymer melts

    NASA Astrophysics Data System (ADS)

    Saltzman, Erica J.; Schweizer, Kenneth S.

    2007-05-01

    Our activated barrier hopping theory of segmental relaxation in deeply supercooled polymer melts is applied to compute short time properties including the glassy shear modulus, localization length and vibrational frequency. Numerical calculations for specific polymers suggest the theory simultaneously predicts a reasonable elastic modulus, localized state vibrational frequency, dynamic fragility and dynamic crossover and glass transition temperatures. The theory also provides explicit connections between short time-/length-scale properties and the slow alpha relaxation process. The extension of the theory to elevated pressures is initiated. Pressure is found to broaden the deeply supercooled regime and reduce the dynamic fragility. However, the predicted Rossler-Sokolov universal supra-Arrhenius law for the temperature dependence of the alpha relaxation time remains accurate at all pressures. A common theme is the essential role played by the ratio of the dynamic crossover temperature (ideal mode coupling critical temperature) and kinetic glass transition temperature even in the deeply supercooled regime where activated processes are dominant.

  16. Short-time Lyapunov exponent analysis and the transition to chaos in Taylor-Couette flow

    NASA Technical Reports Server (NTRS)

    Vastano, John A.; Moser, Robert D.

    1991-01-01

    The physical mechanism driving the weakly chaotic Taylor-Couette flow is investigated using the short-time Liapunov exponent analysis. In this procedure, the transition from quasi-periodicity to chaos is studied using direct numerical 3D simulations of axially periodic Taylor-Couette flow, and a partial Liapunov exponent spectrum for the flow is computed by simultaneously advancing the full solution and a set of perturbations. It is shown that the short-time Liapunov exponent analysis yields more information on the exponents and dimension than that obtained from the common Liapunov exponent calculations. Results show that the chaotic state studied here is caused by a Kelvin-Helmholtz-type instability of the outflow boundary jet of Taylor vortices.

  17. Semiclassical tunneling splittings from short time dynamics: Herman-Kluk-propagation and harmonic inversion.

    PubMed

    Giese, Kai; Kuhn, Oliver

    2004-03-01

    We investigate a recently proposed method [J. Chem. Phys. 108, 9206 (1998)] to obtain tunneling splittings from short time cross-correlation matrices that were propagated according to the semiclassical propagator of Herman and Kluk. The energy levels were extracted by harmonic inversion of the cross-correlation matrix using the filter diagonalization technique. The aim of this study is twofold: First, the short time behavior of the Herman-Kluk-propagator and the meaning of using cross-correlation matrices rather than autocorrelation functions is addressed. Numerical examples are given for one- and two-dimensional model potentials. Second, the performance of the method is investigated for a system with considerable anharmonicity and coupling. Here the proton transfer in 3,7-dichlorotropolone is considered using an ab initio reaction surface Hamiltonian approach. For this example also the extension to more dimensions is critically discussed.

  18. Combination capecitabine and bevacizumab in the treatment of metastatic hepatic epithelioid hemangioendothelioma

    PubMed Central

    Malangone, Steve; Green, Myke; Badari, Ambuga; Clarke, Kathryn; Elquza, Emad

    2015-01-01

    Hepatic epithelioid hemangioendothelioma (HEHE) is a rare, often misdiagnosed vascular neoplasm with clinical behaviors that range from indolent to highly aggressive. Even when the appropriate diagnosis is achieved, the best treatment for HEHE has not been defined or standardized, further complicating the care of these patients. We present a diagnostically challenging case of HEHE where we utilized capecitabine and bevacizumab as another novel treatment option. PMID:26136854

  19. 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.

  20. Contribution of capecitabine for therapy of patients with gastroesophageal cancer: an update of recent phase III results

    PubMed Central

    Cen, Putao; Tetzlaff, Eric D; Ajani, Jaffer A

    2008-01-01

    Background Capecitabine, an orally administered fluoropyrimidines, is widely used in the treatment of multiple malignancies. It has been extensively evaluated in patients with gastroesophageal carcinoma. Since recent reviews have discussed phase I/II trials (Cancer 107:221–231, 2006; Drugs 67:601–610, 2007), we focus on the impact of the results of the most current phase III trials using capectiabine in the treatment of advanced gastroesophageal cancers, primarily in the first-line setting. Methods To find published phase III trials, Medline was searched for English-language clinical trials published from 1996 through June 2007 along with relevant abstracts presented at the American Society of Clinical Oncology, and meetings of the European Cancer Conference and European Society of Medical Oncology. Only representative trials were chosen for this manuscript. Results The most frequently investigated combinations are capecitabine with taxanes, platinols, and camptothecins. Recent results of a large phase III trial (REAL-2) in untreated patients with gastroesophageal cancer suggest that capecitabine is a non-inferior substitute for intravenous 5-fluorouracil. These results of REAL-2 trial are substantiated by a smaller phase III trial. Previous analysis of multiple trials had suggested that capecitabine, when combined in doses lower than 1250 mg/m2 twice daily, consistently resulted in lower frequency of Grade 3 or 4 toxic effects. Conclusions Capecitabine provides much needed convenience to patients with gastroesophageal cancer. The recent data derived from two phase III trials confirm that capecitabine is a suitable substitute for intravenous 5-fluorouracil in patients whose swallowing is not greatly affected. Capecitabine remains a subject of further investigations in this group of patients with interest. PMID:18728703

  1. Phase I trial of cetuximab in combination with capecitabine, weekly irinotecan, and radiotherapy as neoadjuvant therapy for rectal cancer

    SciTech Connect

    Hofheinz, Ralf-Dieter . E-mail: ralf.hofheinz@med3.ma.uni-heidelberg.de; Horisberger, Karoline; Woernle, Christoph; Wenz, Frederik; Kraus-Tiefenbacher, Uta; Kaehler, Georg; Dinter, Dietmar; Grobholz, Rainer; Heeger, Steffen; Post, Stefan; Hochhaus, Andreas; Willeke, Frank

    2006-12-01

    Purpose: To establish the feasibility and efficacy of chemotherapy with capecitabine, weekly irinotecan, cetuximab, and pelvic radiotherapy for patients with locally advanced rectal cancer. Methods and materials: Twenty patients with rectal cancer (clinical Stage uT3-T4 or N+) received a standard dosing regimen of cetuximab (400 mg/m{sup 2} on Day 1 and 250 mg/m{sup 2} on Days 8, 15, 22, and 29) and escalating doses of irinotecan and capecitabine according to phase I methods: dose level I, irinotecan 40 mg/m{sup 2} on Days 1, 8, 15, 22, and 29 and capecitabine 800 mg/m{sup 2} on Days 1-38; dose level II, irinotecan 40 mg/m{sup 2} and capecitabine 1000 mg/m{sup 2}; and dose level III, irinotecan 50 mg/m{sup 2} and capecitabine 1000 mg/m{sup 2}. Radiotherapy was given to a dose of 50.4 Gy (45 Gy plus 5.4 Gy). Resection was scheduled 4-5 weeks after termination of chemoradiotherapy. Results: On dose level I, no dose-limiting toxicities occurred; however, Grade 3 diarrhea affected 1 of 6 patients on dose level II. Of 5 patients treated at dose level III, 2 exhibited dose-limiting toxicity (diarrhea in 2 and nausea/vomiting in 1). Therefore, dose level II was determined as the recommended dose for future studies. A total of 10 patients were treated on dose level II and received a mean relative dose intensity of 100% of cetuximab, 94% of irinotecan, and 95% of capecitabine. All patients underwent surgery. Five patients had a pathologically complete remission and six had microfoci of residual tumor only. Conclusion: Preoperative chemoradiotherapy with cetuximab, capecitabine, and weekly irinotecan is feasible and well tolerated. The preliminary efficacy is very promising. Larger phase II trials are ongoing.

  2. Rationally designed pharmacogenomic treatment using concurrent capecitabine and radiotherapy for glioblastoma; gene expression profiles associated with outcome

    PubMed Central

    Grunda, Jessica M.; Fiveash, John; Palmer, Cheryl A.; Cantor, Alan; Fathallah-Shaykh, Hassan M.; Nabors, L. Burt; Johnson, Martin R.

    2010-01-01

    Purpose Previous preclinical studies suggested that concurrent capecitabine and radiation could be an effective new treatment modality for glioblastoma (GBM). In the current study we investigate toxicity and response to this regimen and explore associations between gene expression and patient outcome. Experimental Design Eighteen newly diagnosed GBM patients received concurrent capecitabine at 625 mg/m2 BID (25% escalation) and irradiation (60 Gy total) for 6 weeks followed by 4 weeks of capecitabine only. Maintenance capecitabine was administered for 14 days every 3 weeks until progression or unacceptable toxicity. Expression analysis of 94 genes involved in capecitabine metabolism and radiation response was performed on tissues obtained prior to therapy. The relationship between gene expression with time-to-progression (TTP) and overall survival (OS) was investigated using univariate Cox proportional hazards regression, semi-supervised principle component analysis (SSPCA), and class prediction modeling. Results The maximum tolerated dose of capecitabine was 625 mg/m2 BID. Median patient TTP and OS were 247 and 367 days respectively. Cox regression identified 24 genes significantly (p<0.025) associated with patient outcome. SSPCA analysis identified two patient populations significantly different in both TTP (p=0.005) and OS (p=0.015). Class prediction modeling determined that 8 genes (RAD54B, MTOR, DCTD, APEX2, TK1, RRM2, SLC29A1, ERCC6) could collectively classify patients into outcome subgroups with 100% accuracy and precision. Conclusions Capecitabine and concurrent radiation for newly diagnosed GBM appears well tolerated and comparable to temozolomide and radiation. A gene expression profile predictive of patient outcome that may be useful in patient stratification for therapy was also elucidated. PMID:20460474

  3. Preoperative chemoradiotherapy with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer: A matched-pair analysis

    SciTech Connect

    Das, Prajnan . E-mail: PrajDas@mdanderson.org; Lin, Edward H.; Bhatia, Sumita; Skibber, John M.; Rodriguez-Bigas, Miguel A.; Feig, Barry W.; Chang, George J.; Hoff, Paulo M.; Eng, Cathy; Wolff, Robert A.; Delclos, Marc E.; Krishnan, Sunil; Janjan, Nora A.; Crane, Christopher H.

    2006-12-01

    Purpose: To retrospectively compare the acute toxicity, pathologic response, relapse rates, and survival in rectal cancer patients treated with preoperative radiotherapy (RT) and either concurrent capecitabine or concurrent protracted infusion 5-fluorouracil (5-FU). Methods: Between June 2001 and February 2004, 89 patients with nonmetastatic rectal adenocarcinoma were treated with preoperative RT and concurrent capecitabine, followed by mesorectal excision. These patients were individually matched by clinical T and N stage (as determined by endoscopic ultrasound and CT scans) with 89 control patients treated with preoperative RT and concurrent protracted infusion 5-FU between September 1997 and August 2002. Results: In each group, 5 patients (6%) had Grade 3-4 toxicity during chemoradiotherapy. The pathologic complete response rate was 21% with capecitabine and 12% with protracted infusion 5-FU (p = 0.19). Of the 89 patients in the capecitabine group and 89 in the 5-FU group, 46 (52%) and 55 (62%), respectively, had downstaging of the T stage after chemoradiotherapy (p = 0.20). The estimated 3-year local control (p = 0.15), distant control (p = 0.86), and overall survival (p = 0.12) rate was 94.4%, 86.3%, and 89.8% for patients treated with capecitabine and 98.6%, 86.6%, and 96.4% for patients treated with protracted infusion 5-FU, respectively. Conclusion: Preoperative concurrent capecitabine and concurrent protracted infusion 5-FU were both well tolerated, with similar, low rates of Grade 3-4 acute toxicity. No significant differences were seen in the pathologic response, local and distant recurrence, or overall survival among patients treated with preoperative RT and concurrent capecitabine compared with those treated with RT and concurrent protracted infusion 5-FU.

  4. Inner composition alignment for inferring directed networks from short time series.

    PubMed

    Hempel, S; Koseska, A; Kurths, J; Nikoloski, Z

    2011-07-29

    Identifying causal links (couplings) is a fundamental problem that facilitates the understanding of emerging structures in complex networks. We propose and analyze inner composition alignment-a novel, permutation-based asymmetric association measure to detect regulatory links from very short time series, currently applied to gene expression. The measure can be used to infer the direction of couplings, detect indirect (superfluous) links, and account for autoregulation. Applications to the gene regulatory network of E. coli are presented.

  5. Phase Retrieval From Multiple-Window Short-Time Fourier Measurements

    NASA Astrophysics Data System (ADS)

    Li, Lan; Cheng, Cheng; Han, Deguang; Sun, Qiyu; Shi, Guangming

    2017-04-01

    In this paper, we introduce two symmetric directed graphs depending on supports of signals and windows, and we show that the connectivity of those graphs provides either necessary and sufficient conditions to phase retrieval of a signal from magnitude measurements of its multiple-window short-time Fourier transform. Also we propose an algebraic reconstruction algorithm, and provide an error estimate to our algorithm when magnitude measurements are corrupted by deterministic/random noises.

  6. 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.

  7. Inner Composition Alignment for Inferring Directed Networks from Short Time Series

    NASA Astrophysics Data System (ADS)

    Hempel, S.; Koseska, A.; Kurths, J.; Nikoloski, Z.

    2011-07-01

    Identifying causal links (couplings) is a fundamental problem that facilitates the understanding of emerging structures in complex networks. We propose and analyze inner composition alignment—a novel, permutation-based asymmetric association measure to detect regulatory links from very short time series, currently applied to gene expression. The measure can be used to infer the direction of couplings, detect indirect (superfluous) links, and account for autoregulation. Applications to the gene regulatory network of E. coli are presented.

  8. Capecitabine and irinotecan with bevacizumab 2-weekly for metastatic colorectal cancer: the phase II AVAXIRI study.

    PubMed

    Garcia-Alfonso, Pilar; Chaves, Manuel; Muñoz, Andrés; Salud, Antonieta; García-Gonzalez, Maria; Grávalos, Cristina; Massuti, Bartomeu; González-Flores, Encarna; Queralt, Bernardo; López-Ladrón, Amelia; Losa, Ferran; Gómez, Maria Jose; Oltra, Amparo; Aranda, Enrique

    2015-04-29

    The optimal sequence of chemotherapeutic agents is not firmly established for the treatment of metastatic colorectal cancer (mCRC). This phase II multi-centre study investigated the efficacy and tolerability of a standard capecitabine plus irinotecan (XELIRI) regimen with bevacizumab in previously untreated patients with mCRC. Patients received intravenous irinotecan 175 mg/m(2) on day 1 and oral capecitabine 1000 mg/m(2) (800 mg/m(2) for patients >65 years of age) twice daily on days 2-8, followed by a 1-week rest, and bevacizumab 5 mg/kg as an intravenous infusion on day 1 every 2 weeks. Seventy-seven patients were included in the intention-to-treat and safety populations. Progression-free survival at 9 months was 61%. The overall response and disease control rates were 51% and 84%, respectively. Median progression-free and overall survival times were 11.9 and 24.8 months, respectively. 48 patients (62%) had at least one grade 3/4 adverse event, the most common being asthenia, diarrhoea and neutropenia. Quality of life varied little over the study period with mean visual analogue scale general health scores ranging from 71 to 76 over cycles 1-11. Our study found irinotecan and capecitabine administered fortnightly with bevacizumab in patients with mCRC to be an effective and tolerable regimen. clinicaltrials.gov identifier NCT00875771. Trial registration date: 04/02/2009.

  9. Adherence management for patients with cancer taking capecitabine: a prospective two-arm cohort study

    PubMed Central

    Krolop, Linda; Ko, Yon-Dschun; Schwindt, Peter Florian; Schumacher, Claudia; Fimmers, Rolf; Jaehde, Ulrich

    2013-01-01

    Objective To develop and evaluate a multiprofessional modular medication management to assure adherence to capecitabine. Methods The study was conducted as a prospective, multicentred observational cohort study. All participants received pharmaceutical care consisting of oral and written information. Daily adherence was defined as percentage of days with correctly administered capecitabine doses and assessed using medication event monitoring. According to their daily adherence during the first cycle, patients were identified as initially non-adherent (<90% adherence) or adherent (≥90% adherence). Initially non-adherent patients received additional adherence support. Results Seventy-three patients with various tumour entities were enrolled, 58 were initially adherent and 15 non-adherent. Median daily adherence of initially non-adherent patients increased from 85.7% to 97.6% during the observation period of six cycles. Throughout all cycles, median daily adherence of initially adherent patients was 100.0%. Daily adherence was not associated with sociodemographic and disease-related factors. No patient was non-persistent. Conclusions An early adherence screening effectively distinguishes between patients adhering and non-adhering to capecitabine. The provision of specific adherence support is associated with enhanced adherence of initially non-adherent patients, whereas initially adherent patients remain adherent for at least six cycles without specific support. Our needs-based approach helps to use available resources for adherence management efficiently. PMID:23872296

  10. Capecitabine and radiation therapy preceded and followed by combination chemotherapy in advanced pancreatic cancer

    SciTech Connect

    Schneider, Bryan J.; McGinn, Cornelius J.; Chang, Alfred E.; Colletti, Lisa M.; Normolle, Daniel P.; Hejna, Gwen F. P.A.; Zalupski, Mark M. . E-mail: Zalupski@umich.edu

    2005-12-01

    Purpose: The primary objective of this study was to evaluate the tolerance and toxicity of radiation therapy (RT) and capecitabine in patients with advanced, unresectable pancreatic carcinoma. To control micrometastatic disease, combination chemotherapy (gemcitabine and cisplatin) before and after combined modality therapy (CMT) was planned. Methods and Materials: Patients with unresectable or metastatic pancreatic cancer were eligible. Gemcitabine 1000 mg/m{sup 2} and cisplatin 35 mg/m{sup 2} were administered on Days 1 and 8 of a 21-day cycle for two cycles. RT was then given to a dose of 50.4 Gy in 1.8 Gy fractions. Patients were treated with capecitabine 1330 mg/m{sup 2} daily during RT. After CMT, two additional cycles of gemcitabine and cisplatin completed the treatment. Results: Twenty-three patients were treated. Eighteen patients completed CMT. One patient was removed from study during CMT for toxicity issues. Treatment delays and dose reductions were common during the final two cycles of gemcitabine and cisplatin as a result of myelosuppression. Median survival was 10.1 months (95% confidence interval [CI] = 7.6, 13.7) for all 23 patients and 12.8 months (95% CI = 8.2, 18.9) for 18 patients without metastasis. Conclusion: Combined modality therapy with RT and capecitabine was well tolerated. Chemotherapy after CMT was difficult to complete owing to cumulative myelosuppression. Survival, response, and toxicity were comparable to infusional 5-fluorouracil and RT.

  11. Phase II study of capecitabine and irinotecan combination chemotherapy in patients with advanced gastric cancer

    PubMed Central

    Baek, J H; Kim, J G; Jeon, S B; Chae, Y S; Kim, D H; Sohn, S K; Lee, K B; Choi, Y J; Shin, H J; Chung, J S; Cho, G J; Jung, H Y; Yu, W

    2006-01-01

    The present study was conducted to evaluate the efficacy and safety of a combination regimen of capecitabine plus irinotecan in patients with advanced gastric cancer. Patients with previously untreated metastatic or recurrent, measurable gastric cancer received oral capecitabine 1000 mg m−2 twice daily from day 1 to 14 and intravenous irinotecan 100 mg m−2 on days 1 and 8, based on a 3-week cycle. Forty-one patients were enrolled in the current study, among whom 38 were assessable for efficacy and 40 assessable for toxicity. Three complete responses and 16 partial responses were confirmed, giving an overall response rate of 46.3%. At a median follow-up of 269 days, the median time to progression and overall survival were 5.1 and 8.6 months, respectively. Grade 3/4 neutropenia occurred in four patients and grade 3 febrile neutropenia was observed in two patients. Grade 3 diarrhoea and grade 2 hand–foot syndrome occurred in six patients and eight patients, respectively. The combination of capecitabine and irinotecan was found to be well tolerated and effective in patients with advanced gastric cancer. Accordingly, this regimen can be regarded as one of first-line treatment options for advanced gastric cancer. PMID:16641916

  12. Complete response to capecitabine in a frail, elderly patient with metastatic colorectal cancer: A case report

    PubMed Central

    Fasano, Morena; Fabozzi, Alessio; Giordano, Guido; Venturini, Filippo; Aurilio, Gaetano; Cantile, Flavia; Fabozzi, Teresa; Ricci, Vincenzo; Santabarbara, Giuseppe; Morgillo, Floriana; Ciardiello, Fortunato; De Vita, Ferdinando

    2017-01-01

    The clinical management of frail, elderly patients affected by colorectal cancer (CRC) remains a subject of debate. The present study reports the case of an elderly man with metastatic CRC (mCRC) who was successfully treated with capecitabine. The patient survived for 29 months, thus highlighting its potential activity in terms of obtaining a complete response and high efficacy. A 77-year-old man presented with adenocarcinoma of the rectum with multiple and synchronous liver metastases, in addition to several comorbidities. The patient received single-agent capecitabine chemotherapy (825 mg/mq twice a day) on days 1–14 of a 21-day cycle. Following 12 cycles of well-tolerated therapy, a computed tomography scan revealed a complete response with no evidence of liver metastases. An overall survival of 29 months was documented, and the patient eventually succumbed to a diabetes-related complication. In compromised patients with mCRC, reduced-dose capecitabine is an excellent therapeutic option due to its positive safety profile, activity and efficacy. PMID:28356988

  13. Radiosensitization by the histone deacetylase inhibitor vorinostat under hypoxia and with capecitabine in experimental colorectal carcinoma

    PubMed Central

    2012-01-01

    Background The histone deacetylase inhibitor vorinostat is a candidate radiosensitizer in locally advanced rectal cancer (LARC). Radiosensitivity is critically influenced by hypoxia; hence, it is important to evaluate the efficacy of potential radiosensitizers under variable tissue oxygenation. Since fluoropyrimidine-based chemoradiotherapy (CRT) is the only clinically validated regimen in LARC, efficacy in combination with this established regimen should be assessed in preclinical models before a candidate drug enters clinical trials. Methods Radiosensitization by vorinostat under hypoxia was studied in four colorectal carcinoma cell lines and in one colorectal carcinoma xenograft model by analysis of clonogenic survival and tumor growth delay, respectively. Radiosensitizing effects of vorinostat in combination with capecitabine were assessed by evaluation of tumor growth delay in two colorectal carcinoma xenografts models. Results Under hypoxia, radiosensitization by vorinostat was demonstrated in vitro in terms of decreased clonogenicity and in vivo as inhibition of tumor growth. Adding vorinostat to capecitabine-based CRT increased radiosensitivity of xenografts in terms of inhibited tumor growth. Conclusions Vorinostat sensitized colorectal carcinoma cells to radiation under hypoxia in vitro and in vivo and improved therapeutic efficacy in combination with capecitabine-based CRT in vivo. The results encourage implementation of vorinostat into CRT in LARC trials. PMID:23017053

  14. 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™.

  15. 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.

  16. Dramatic influence of patchy attractions on short-time protein diffusion under crowded conditions

    PubMed Central

    Bucciarelli, Saskia; Myung, Jin Suk; Farago, Bela; Das, Shibananda; Vliegenthart, Gerard A.; Holderer, Olaf; Winkler, Roland G.; Schurtenberger, Peter; Gompper, Gerhard; Stradner, Anna

    2016-01-01

    In the dense and crowded environment of the cell cytoplasm, an individual protein feels the presence of and interacts with all surrounding proteins. While we expect this to strongly influence the short-time diffusion coefficient Ds of proteins on length scales comparable to the nearest-neighbor distance, this quantity is difficult to assess experimentally. We demonstrate that quantitative information about Ds can be obtained from quasi-elastic neutron scattering experiments using the neutron spin echo technique. We choose two well-characterized and highly stable eye lens proteins, bovine α-crystallin and γB-crystallin, and measure their diffusion at concentrations comparable to those present in the eye lens. While diffusion slows down with increasing concentration for both proteins, we find marked variations that are directly linked to subtle differences in their interaction potentials. A comparison with computer simulations shows that anisotropic and patchy interactions play an essential role in determining the local short-time dynamics. Hence, our study clearly demonstrates the enormous effect that weak attractions can have on the short-time diffusion of proteins at concentrations comparable to those in the cellular cytosol. PMID:27957539

  17. Short-time transport properties in dense suspensions: from neutral to charge-stabilized colloidal spheres.

    PubMed

    Banchio, Adolfo J; Nägele, Gerhard

    2008-03-14

    We present a detailed study of short-time dynamic properties in concentrated suspensions of charge-stabilized and of neutral colloidal spheres. The particles in many of these systems are subject to significant many-body hydrodynamic interactions. A recently developed accelerated Stokesian dynamics (ASD) simulation method is used to calculate hydrodynamic functions, wave-number-dependent collective diffusion coefficients, self-diffusion and sedimentation coefficients, and high-frequency limiting viscosities. The dynamic properties are discussed in dependence on the particle concentration and salt content. Our ASD simulation results are compared with existing theoretical predictions, notably those of the renormalized density fluctuation expansion method of Beenakker and Mazur [Physica A 126, 349 (1984)], and earlier simulation data on hard spheres. The range of applicability and the accuracy of various theoretical expressions for short-time properties are explored through comparison with the simulation data. We analyze, in particular, the validity of generalized Stokes-Einstein relations relating short-time diffusion properties to the high-frequency limiting viscosity, and we point to the distinctly different behavior of de-ionized charge-stabilized systems in comparison to hard spheres.

  18. Neural network incorporating meal information improves accuracy of short-time prediction of glucose concentration.

    PubMed

    Zecchin, Chiara; Facchinetti, Andrea; Sparacino, Giovanni; De Nicolao, Giuseppe; Cobelli, Claudio

    2012-06-01

    Diabetes mellitus is one of the most common chronic diseases, and a clinically important task in its management is the prevention of hypo/hyperglycemic events. This can be achieved by exploiting continuous glucose monitoring (CGM) devices and suitable short-term prediction algorithms able to infer future glycemia in real time. In the literature, several methods for short-time glucose prediction have been proposed, most of which do not exploit information on meals, and use past CGM readings only. In this paper, we propose an algorithm for short-time glucose prediction using past CGM sensor readings and information on carbohydrate intake. The predictor combines a neural network (NN) model and a first-order polynomial extrapolation algorithm, used in parallel to describe, respectively, the nonlinear and the linear components of glucose dynamics. Information on the glucose rate of appearance after a meal is described by a previously published physiological model. The method is assessed on 20 simulated datasets and on 9 real Abbott FreeStyle Navigator datasets, and its performance is successfully compared with that of a recently proposed NN glucose predictor. Results suggest that exploiting meal information improves the accuracy of short-time glucose prediction.

  19. Genetic polymorphisms of SCN9A are associated with oxaliplatin-induced neuropathy.

    PubMed

    Sereno, María; Gutiérrez-Gutiérrez, Gerardo; Rubio, Juan Moreno; Apellániz-Ruiz, María; Sánchez-Barroso, Lara; Casado, Enrique; Falagan, Sandra; López-Gómez, Miriam; Merino, María; Gómez-Raposo, César; Rodriguez-Salas, Nuria; Tébar, Francisco Zambrana; Rodríguez-Antona, Cristina

    2017-01-19

    Oxaliplatin is a chemotherapy agent active against digestive tumors. Peripheral neuropathy is one of the most important dose-limiting toxicity of this drug. It occurs in around 60-80% of the patients, and 15% of them develop severe neuropathy. The pathophysiology of oxaliplatin neurotoxicity remains unclear. SCN9A is a gene codifying for a subtype sodium channel (type IX, subunit α) and mutations in this gene are involved in neuropathic perception. In this study we investigated whether SCN9A genetic variants were associated with risk of neurotoxicity in patients diagnosed of cancer on treatment with oxaliplatin. Blood samples from 94 patients diagnosed of digestive cancer that had received oxaliplatin in adjuvant or metastatic setting were obtained from three hospitals in Madrid. These patients were classified into two groups: "cases" developed oxaliplatin-induced grade 3-4 neuropathy (n = 48), and "controls" (n = 46) had no neuropathy or grade 1. The neuropathy was evaluated by an expert neurologist and included a clinical examination and classification according to validated neurological scales: National Cancer Institute Common Toxicity Criteria (NCI-CTC), Oxaliplatin-Specific Neurotoxicity Scale (OSNS) and Total Neuropathy score (TNS). Genotyping was performed for 3 SCN9A missense polymorphisms: rs6746030 (R1150W), rs74401238 (R1110Q) and rs41268673 (P610T), and associations between genotypes and neuropathy were evaluated. We found that SCN9A rs6746030 was associated with protection for severe neuropathy (OR = 0.39, 95% CI = 0.16-0.96; p = 0.041). Multivariate analysis adjusting for diabetes provided similar results (p = 0.036). No significant differences in neuropathy risk were detected for rs74401238 and rs41268673. SCN9A rs6746030 was associated with protection for severe oxaliplatin-induced peripheral neuropathy. The validation of this exploratory study is ongoing in an independent series.

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

    PubMed

    Salehi, Zeinab; Roayaei, Mahnaz

    2015-01-01

    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. 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. 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). The results from this current trial demonstrate a lack of benefit for Vitamin E in preventing oxaliplatin-induced peripheral neuropathy.

  1. A Polyamine-Deficient Diet Prevents Oxaliplatin-Induced Acute Cold and Mechanical Hypersensitivity in Rats

    PubMed Central

    Ferrier, Jérémy; Bayet-Robert, Mathilde; Pereira, Bruno; Daulhac, Laurence; Eschalier, Alain; Pezet, Denis; Moulinoux, Jacques-Philippe; Balayssac, David

    2013-01-01

    Background Oxaliplatin is an anticancer drug used for the treatment of advanced colorectal cancer, but it can also cause painful peripheral neuropathies. The pathophysiology of these neuropathies has not been yet fully elucidated, but may involve spinal N-methyl-D-aspartate (NMDA) receptors, particularly the NR2B subunit. As polyamines are positive modulators of NMDA-NR2B receptors and mainly originate from dietary intake, the modulation of polyamines intake could represent an interesting way to prevent/modulate neuropathic pain symptoms by opposing glutamate neurotransmission. Methods The effect of a polyamine deficient diet was investigated in an animal model of oxaliplatin-induced acute pain hypersensitivity using behavioral tests (mechanical and cold hypersensitivity). The involvement of spinal glutamate neurotransmission was monitored by using a proton nuclear magnetic resonance spectroscopy based metabolomic approach and by assessing the expression and phosphorylation of the NR2B subunit of the NMDA receptor. Results A 7-day polyamine deficient diet totally prevented oxaliplatin-induced acute cold hypersensitivity and mechanical allodynia. Oxaliplatin-induced pain hypersensitivity was not associated with an increase in NR2B subunit expression or phosphorylation, but with an increase of glutamate level in the spinal dorsal horn which was completely prevented by a polyamine deficient diet. As a validation that the oxaliplatin-induced hypersensitivity could be due to an increased activity of the spinal glutamate system, an intrathecal administration of the specific NR2B antagonist, ifenprodil, totally reversed oxaliplatin-induced mechanical and cold hypersensitivity. Conclusion A polyamine deficient diet could represent a promising and valuable nutritional therapy to prevent oxaliplatin-induced acute pain hypersensitivity. PMID:24204988

  2. Comparison of oxaliplatin and paclitaxel-induced neuropathy (Alliance A151505).

    PubMed

    Pachman, Deirdre R; Qin, Rui; Seisler, Drew; Smith, Ellen M Lavoie; Kaggal, Suneetha; Novotny, Paul; Ruddy, Kathryn J; Lafky, Jacqueline M; Ta, Lauren E; Beutler, Andreas S; Wagner-Johnston, Nina D; Staff, Nathan P; Grothey, Axel; Dougherty, Patrick M; Cavaletti, Guido; Loprinzi, Charles L

    2016-12-01

    Oxaliplatin and paclitaxel are commonly used chemotherapies associated with acute and chronic neuropathies. There is a need to better understand the similarities and differences of these clinical syndromes. Neuropathy data were pooled from patients receiving adjuvant oxaliplatin and weekly paclitaxel or every 3 weeks of paclitaxel. Patients completed daily questionnaires after each chemotherapy dose and the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy before each chemotherapy cycle and for 12 months post-treatment. Acute neuropathy symptoms from both drugs peaked around day 3. Acute symptoms experienced in cycle 1 predicted occurrence in subsequent cycles. Paclitaxel-induced acute symptoms were similar in intensity in each cycle and largely resolved between cycles. Oxaliplatin-induced acute symptoms were about half as severe in the first cycle as in later cycles and did not resolve completely between cycles. Both drugs caused a predominantly sensory chronic neuropathy (with numbness and tingling being more common than pain). Oxaliplatin-induced neuropathy worsened after the completion of treatment and began to improve 3 months post-treatment. In contrast, paclitaxel-induced neuropathy began improving immediately after chemotherapy cessation. During treatment, the incidence of paclitaxel sensory symptoms was similar in the hands and feet; with oxaliplatin, the hands were affected more than the feet. Both paclitaxel- and oxaliplatin-induced acute neurotoxicity appeared to predict the severity of chronic neuropathy, more prominently with oxaliplatin. Knowledge of the similarities and differences between neuropathy syndromes may provide insight into their underlying pathophysiology and inform future research to identify preventative treatment approaches.

  3. Oxaliplatin-Induced Peripheral Neuropathy and Identification of Unique Severity Groups in Colorectal Cancer.

    PubMed

    Griffith, Kathleen A; Zhu, Shijun; Johantgen, Meg; Kessler, Michael D; Renn, Cynthia; Beutler, Andreas S; Kanwar, Rahul; Ambulos, Nicholas; Cavaletti, Guido; Bruna, Jordi; Briani, Chiara; Argyriou, Andreas A; Kalofonos, Haralabos P; Yerges-Armstrong, Laura M; Dorsey, Susan G

    2017-07-22

    Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose limiting toxicity of oxaliplatin and affects most colorectal cancer (CRC) patients. OIPN is commonly evaluated by patient symptom report, using scales to reflect impairment. They do not discriminate between unique grouping of symptoms and signs, which impedes prompt identification of OIPN. Our study objective was to identify clusters of symptoms and signs that differentiated underlying clinical severity and segregated patients within our population into OIPN subgroups. Chemotherapy naïve CRC patients (N=148) receiving oxaliplatin were administered the Total Neuropathy Score clinical (TNSc(©)), which includes symptom report (sensory, motor, autonomic) and sensory examination (pin sense, vibration, reflexes). The TNSc(©) was administered prior to chemotherapy initiation (T0), and following cumulative doses of oxaliplatin 510-520 mg/m(2) (T1) and 1020-1040 mg/ m(2) of oxaliplain (T2). Using mean T2 TNSc(©) scores, latent class analysis (LCA) grouped patients into OIPN severity cohorts. LCA categorized patients into 4 distinct OIPN groups: low symptoms and low signs (N=54); low symptoms and intermediate signs (n=44); low symptoms and high signs (n=21); and high symptoms and high signs (n=29). No differences were noted among OIPN groups on age, sex, chemotherapy regimen, or cumulative oxaliplatin dose. We identified OIPN patient groups with distinct symptoms/signs, demonstrating variability of OIPN presentation regardless of cumulative oxaliplatin dose. Over half of the sample had positive findings on OIPN examination despite little or no symptoms. Sensory examination of all patients receiving oxaliplatin is indicated for timely identification of OIPN, which will allow earlier symptom management. Copyright © 2017. Published by Elsevier Inc.

  4. Oxaliplatin retains HMGB1 intranuclearly and ameliorates collagen type II-induced arthritis

    PubMed Central

    Östberg, Therese; Wähämaa, Heidi; Palmblad, Karin; Ito, Norimasa; Stridh, Pernilla; Shoshan, Maria; Lotze, Michael T; Harris, Helena Erlandsson; Andersson, Ulf

    2008-01-01

    Introduction High mobility group box chromosomal protein 1 (HMGB1) is a nuclear protein that acts as a pro-inflammatory mediator following extracellular release. The protein is aberrantly expressed extracellularly in the settings of clinical and experimental synovitis. Therapy based on HMGB1 antagonists has shown encouraging results in experimental arthritis and warrants further scientific exploration using independent methods. In the present study we asked whether nuclear sequestration of HMGB1 preventing HMGB1 release would be beneficial for synovitis treatment. Methods Oxaliplatin-based therapy was evaluated in collagen type II-induced arthritis in DBA/1 mice by clinical scoring and immunostaining of articular tissue. Oxaliplatin is an antineoplastic platinum-based compound that generates DNA adducts which tightly bind HMGB1. Secretion and intracellular location of HMGB1 were assessed by a novel HMGB1-specific ELISPOT assay and immunofluorescent staining. Results Intraperitoneal injections of oxaliplatin in early collagen type II-induced arthritis trapped HMGB1 with a distinct biphasic response pattern. Oxaliplatin therapy showed beneficial results for approximately 1 week. Microscopic evaluation of synovitis during this period showed strong nuclear HMGB1 staining in the oxaliplatin treated animals with much lower quantities of extracellular HMGB1 when compared to control treated animals. Furthermore, cellular infiltration, as well as cartilage and bone damage, were all reduced in the oxaliplatin treated group. A dramatic and as yet unexplained clinical relapse occurred later in the oxaliplatin exposed animals, which coincided with a massive synovial tissue expression of extracellular HMGB1 in all treated animals. This rebound-like reaction was also accompanied by a significantly increased incidence of arthritis in the oxaliplatin treated group. These results indicate a distinct temporal and spatial relationship between the clinical course of disease and the

  5. Bosutinib plus capecitabine for selected advanced solid tumours: results of a phase 1 dose-escalation study.

    PubMed

    Isakoff, S J; Wang, D; Campone, M; Calles, A; Leip, E; Turnbull, K; Bardy-Bouxin, N; Duvillié, L; Calvo, E

    2014-11-25

    This phase 1 study evaluated the maximum tolerated dose (MTD), safety, and efficacy of bosutinib (competitive Src/Abl tyrosine kinase inhibitor) plus capecitabine. Patients with locally advanced/metastatic breast, pancreatic, or colorectal cancers; cholangiocarcinoma; or glioblastoma received bosutinib plus capecitabine at eight of nine possible dose combinations using an 'up-down' design to determine the toxicity contour of the combination. Among 32 enrolled patients, none of the 9 patients receiving MTD (bosutinib 300 mg once daily plus capecitabine 1000 mg m(-2) twice daily) experienced dose-limiting toxicities (DLTs). Overall, 2 out of 31 (6%) evaluable patients experienced DLTs (grade 3 neurologic pain (n=1); grade 3 pruritus/rash and increased alanine aminotransferase (n=1)). Most common treatment-related adverse events (AEs) were diarrhoea, nausea, vomiting, palmar-plantar erythrodysesthesia (PPE), fatigue; most frequent grade 3/4 AEs: PPE, fatigue, and increased alanine/aspartate aminotransferase. Although diarrhoea was common, 91% of affected patients experienced maximum grade 1/2 events that resolved. Best overall confirmed partial response or stable disease >24 weeks (all tumour types) was observed in 6 and 13% of patients. In this population of patients with advanced solid tumours, bosutinib plus capecitabine demonstrated a safety profile similar to that previously reported for bosutinib or capecitabine monotherapy; limited efficacy was observed.

  6. Bosutinib plus capecitabine for selected advanced solid tumours: results of a phase 1 dose-escalation study

    PubMed Central

    Isakoff, S J; Wang, D; Campone, M; Calles, A; Leip, E; Turnbull, K; Bardy-Bouxin, N; Duvillié, L; Calvo, E

    2014-01-01

    Background: This phase 1 study evaluated the maximum tolerated dose (MTD), safety, and efficacy of bosutinib (competitive Src/Abl tyrosine kinase inhibitor) plus capecitabine. Methods: Patients with locally advanced/metastatic breast, pancreatic, or colorectal cancers; cholangiocarcinoma; or glioblastoma received bosutinib plus capecitabine at eight of nine possible dose combinations using an ‘up-down' design to determine the toxicity contour of the combination. Results: Among 32 enrolled patients, none of the 9 patients receiving MTD (bosutinib 300 mg once daily plus capecitabine 1000 mg m−2 twice daily) experienced dose-limiting toxicities (DLTs). Overall, 2 out of 31 (6%) evaluable patients experienced DLTs (grade 3 neurologic pain (n=1); grade 3 pruritus/rash and increased alanine aminotransferase (n=1)). Most common treatment-related adverse events (AEs) were diarrhoea, nausea, vomiting, palmar-plantar erythrodysesthesia (PPE), fatigue; most frequent grade 3/4 AEs: PPE, fatigue, and increased alanine/aspartate aminotransferase. Although diarrhoea was common, 91% of affected patients experienced maximum grade 1/2 events that resolved. Best overall confirmed partial response or stable disease >24 weeks (all tumour types) was observed in 6 and 13% of patients. Conclusions: In this population of patients with advanced solid tumours, bosutinib plus capecitabine demonstrated a safety profile similar to that previously reported for bosutinib or capecitabine monotherapy; limited efficacy was observed. PMID:25290090

  7. Effects of Hypericum perforatum extract on oxaliplatin-induced neurotoxicity: in vitro evaluations.

    PubMed

    Cinci, Lorenzo; Di Cesare Mannelli, Lorenzo; Maidecchi, Anna; Mattoli, Luisa; Ghelardini, Carla

    2017-05-01

    Hypericum perforatum L. has been used for centuries as a natural remedy for the treatment of many disorders. Neuropathic pain is a common side effect of oxaliplatin-based chemotherapy and often the cause of therapy discontinuation. Thanks to its anti-inflammatory and analgesic effects, the use of H. perforatum may be a novel therapeutic strategy for neuropathy. The aim of this paper was to evaluate the effect of H. perforatum hydrophilic extract on an in vitro model of oxaliplatin-induced neurotoxicity. The antioxidant potential of extract was first evaluated in cell-free models by the thiobarbituric acid-reactive substances assay and nitro blue tetrazolium oxidation test; the ability of H. perforatum extract to reduce oxaliplatin-induced caspase-3 activity in rat astrocytes and its potential interference with the cytotoxic effects of oxaliplatin in a colorectal cancer in vitro model (HT-29 cells) were also evaluated. The extract showed a significant antioxidant effect and was able to reduce caspase-3 activity in rat astrocytes. Of note, the extract alone exerted a cytotoxic effect in HT-29 cells and did not reduce the cytotoxicity of oxaliplatin in HT-29 cells. These data suggest that H. perforatum could be used as a novel therapeutic strategy for counteracting chemotherapy-induced neuropathy.

  8. Astragali radix: could it be an adjuvant for oxaliplatin-induced neuropathy?

    PubMed

    Di Cesare Mannelli, Lorenzo; Pacini, Alessandra; Micheli, Laura; Femia, Angelo Pietro; Maresca, Mario; Zanardelli, Matteo; Vannacci, Alfredo; Gallo, Eugenia; Bilia, Anna Rita; Caderni, Giovanna; Firenzuoli, Fabio; Mugelli, Alessandro; Ghelardini, Carla

    2017-02-10

    Neurotoxicity is a major side effect of platinum derivatives both during and after treatment. In the absence of effective pharmacological compounds, the opportunity to identify safe adjuvant treatments among medicinal plants seems appropriate. Astragali radix is an adaptogenic herbal product recently analyzed in platinum-treated cancer patients. With the aim of evaluating the anti-neuropathic profile of Astragali radix, a previously characterized aqueous (Aqu) and two hydroalcoholic (20%HA and 50%HA) extracts were tested in a rat model of oxaliplatin-induced neuropathy. Repeated administrations significantly reduced oxaliplatin-dependent hypersensitivity with 50%HA, the most effective, fully preventing mechanical and thermal hypersensitivity. Ex vivo, 50%HA reduced morphometric and molecular alterations induced by oxaliplatin in peripheral nerve and dorsal-root-ganglia. In the spinal cord and in brain areas, 50%HA significantly decreased activation of microglia and astrocytes. Furthermore, 50%HA prevented the nephro- and hepato-toxicity induced by the anticancer drug. The protective effect of 50%HA did not alter oxaliplatin-induced apoptosis in colon tumors of Pirc rats, an Apc-driven model of colon carcinogenesis. The hydroalcoholic extract (50%HA) of Astragali radix relieves pain and promotes the rescue mechanisms that protect nervous tissue from the damages triggering chronic pain. A safe profile strongly suggests the usefulness of this natural product in oxaliplatin-induced neuropathy.

  9. The G2A receptor (GPR132) contributes to oxaliplatin-induced mechanical pain hypersensitivity.

    PubMed

    Hohmann, Stephan W; Angioni, Carlo; Tunaru, Sorin; Lee, Seungkyu; Woolf, Clifford J; Offermanns, Stefan; Geisslinger, Gerd; Scholich, Klaus; Sisignano, Marco

    2017-03-27

    Chemotherapy-induced peripheral neuropathic pain (CIPN) is a common and severe debilitating side effect of many widely used cytostatics. However, there is no approved pharmacological treatment for CIPN available. Among other substances, oxaliplatin causes CIPN in up to 80% of treated patients. Here, we report the involvement of the G-protein coupled receptor G2A (GPR132) in oxaliplatin-induced neuropathic pain in mice. We found that mice deficient in the G2A-receptor show decreased mechanical hypersensitivity after oxaliplatin treatment. Lipid ligands of G2A were found in increased concentrations in the sciatic nerve and dorsal root ganglia of oxaliplatin treated mice. Calcium imaging and patch-clamp experiments show that G2A activation sensitizes the ligand-gated ion channel TRPV1 in sensory neurons via activation of PKC. Based on these findings, we conclude that targeting G2A may be a promising approach to reduce oxaliplatin-induced TRPV1-sensitization and the hyperexcitability of sensory neurons and thereby to reduce pain in patients treated with this chemotherapeutic agent.

  10. Efficacy of Goshajinkigan for Oxaliplatin-Induced Peripheral Neuropathy in Colorectal Cancer Patients

    PubMed Central

    Hosokawa, Toyoshi; Ishikawa, Takeshi; Yagi, Nobuaki; Kokura, Satoshi; Naito, Yuji; Nakanishi, Masayoshi; Kokuba, Yukihito; Otsuji, Eigo; Kuroboshi, Haruo; Taniwaki, Masafumi; Taguchi, Tetsuya; Hosoi, Hajime; Nakamura, Terukazu; Miki, Tsuneharu

    2013-01-01

    Objective. To evaluate the efficacy of Goshajinkigan for oxaliplatin-induced peripheral neuropathy in colorectal cancer patients. Patients. Colorectal cancer patients (N = 29) who received ≥4 weeks of Goshajinkigan for oxaliplatin-induced peripheral neuropathy during chemotherapy at Kyoto Prefectural University of Medicine were (Goshajinkigan group) compared to 44 patients who had not received Goshajinkigan during the same period (non-Goshajinkigan group). Main Outcome Measures. The effect of Goshajinkigan was graded as curative, effective, stabilizing, or deleterious. The relationships between the grade of peripheral neuropathy and the dose of oxaliplatin in the Goshajinkigan and non-Goshajinkigan groups were evaluated. Results. The effect of Goshajinkigan on peripheral neuropathy in the Goshajinkigan group was curative, effective, stabilizing, and deleterious in 3.4, 20.7, 69.0, and 6.9% of patients, compared to the effect in the non-Goshajinkigan group (4.5, 15.9, 45.5, and 34.1%). The ratio of deleterious effects was significantly different between these two groups (P = 0.04). A Kaplan-Meier analysis in relation to the cumulative dose of oxaliplatin showed that the incidence of grade 3 peripheral neuropathy tended to be less in the Goshajinkigan group (P = 0.05). There were no significant differences in time to treatment failure and severe adverse events between these two groups. Conclusions. Goshajinkigan prevented exacerbation of oxaliplatin-induced peripheral neuropathy. This trial is registered with UMIN000009956 PMID:24307899

  11. Astragali radix: could it be an adjuvant for oxaliplatin-induced neuropathy?

    PubMed Central

    Di Cesare Mannelli, Lorenzo; Pacini, Alessandra; Micheli, Laura; Femia, Angelo Pietro; Maresca, Mario; Zanardelli, Matteo; Vannacci, Alfredo; Gallo, Eugenia; Bilia, Anna Rita; Caderni, Giovanna; Firenzuoli, Fabio; Mugelli, Alessandro; Ghelardini, Carla

    2017-01-01

    Neurotoxicity is a major side effect of platinum derivatives both during and after treatment. In the absence of effective pharmacological compounds, the opportunity to identify safe adjuvant treatments among medicinal plants seems appropriate. Astragali radix is an adaptogenic herbal product recently analyzed in platinum-treated cancer patients. With the aim of evaluating the anti-neuropathic profile of Astragali radix, a previously characterized aqueous (Aqu) and two hydroalcoholic (20%HA and 50%HA) extracts were tested in a rat model of oxaliplatin-induced neuropathy. Repeated administrations significantly reduced oxaliplatin-dependent hypersensitivity with 50%HA, the most effective, fully preventing mechanical and thermal hypersensitivity. Ex vivo, 50%HA reduced morphometric and molecular alterations induced by oxaliplatin in peripheral nerve and dorsal-root-ganglia. In the spinal cord and in brain areas, 50%HA significantly decreased activation of microglia and astrocytes. Furthermore, 50%HA prevented the nephro- and hepato-toxicity induced by the anticancer drug. The protective effect of 50%HA did not alter oxaliplatin-induced apoptosis in colon tumors of Pirc rats, an Apc-driven model of colon carcinogenesis. The hydroalcoholic extract (50%HA) of Astragali radix relieves pain and promotes the rescue mechanisms that protect nervous tissue from the damages triggering chronic pain. A safe profile strongly suggests the usefulness of this natural product in oxaliplatin-induced neuropathy. PMID:28186109

  12. Short time ion pulse extraction from the Dresden electron beam ion trapa)

    NASA Astrophysics Data System (ADS)

    Kentsch, U.; Zschornack, G.; Schwan, A.; Ullmann, F.

    2010-02-01

    We present measurements of the extraction of short time pulses of highly charged ions (4 keV, Ar16+) from the Dresden electron beam ion trap. Thereby the dependence of the extractable ionic charge on the extraction regime was investigated. The ion extraction time was varied between 20 ns and 1 μs. Furthermore the production of carbon ions and the influence of the extraction regime on the pulse widths was investigated to obtain information about the suitability of the Dresden EBIS-A in synchrotron based particle therapy facilities.

  13. Short time effect of Delta oscillation under microcurrent transcutaneous electrical nerve stimulation at ST36.

    PubMed

    Li, Shunan; Li, Donghui; Li, Huiyan; Wang, Jiang

    2014-01-01

    This paper was to study the short time effect of Delta brain oscillation under microcurrent transcutaneous electrical nerve stimulation (MTENS) at ST36 (Zusanli). The 64-channal electroencephalograph (EEG) signals from 12 healthy volunteers were recorded including baseline stage, during stimulation and after stimulation. Autoregressive (AR) Burg method was used to estimate the power spectrum. Then power variation rate (PVR) was calculated to quantify the effects compared with the baseline in Delta band. The results showed that MTENS at ST36 on right side led to increased Delta band power in left frontal.

  14. Short time dynamics of water coalescence on a flat water pool

    SciTech Connect

    Lim, Su Jin; Gim, Bopil; Fezzaa, Kamel; Weon, Byung Mook

    2016-12-01

    Coalescence is an important hydrodynamic event that frequently takes place in nature as well as in industry. Here we provide an experimental study on short time dynamics of water coalescence, particularly when a water droplet comes in contact with a flat water surface, by utilizing high-resolution high-penetration ultrafast X-ray microscopy. Our results demonstrate a possibility that an extreme curvature difference between a drop and a flat surface can significantly modify the hydrodynamics of water coalescence, which is unexpected in the existing theory. We suggest a plausible explanation for why coalescence can be modified by an extreme curvature difference.

  15. 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.

  16. Two dimensional entropy and short time Fourier Transform application on ground penetrating radar data analysis

    NASA Astrophysics Data System (ADS)

    Candra, Panglijen; Xia, Tian; Huston, Dryver; Wang, Guoan

    2013-04-01

    Accurate detection of rebar location using Ground Penetrating Radar (GPR) proves to be very useful in assessing roadway/bridge deck concrete structure. Due to large signal processing resource needed to locate and image rebar on a whole road structure, more efficient signal processing method is needed. This paper proposes to combine two-dimensional (2D) entropy algorithm to narrow down the scope of interested data from large radar data set and Short Time Fourier Transform (STFT) algorithm to perform further feature characterization. To validate the analysis, experiments with different rebar setups are conducted.

  17. A short time existence/uniqueness result for a nonlocal topology-preserving segmentation model

    NASA Astrophysics Data System (ADS)

    Forcadel, Nicolas; Le Guyader, Carole

    Motivated by a prior applied work of Vese and the second author dedicated to segmentation under topological constraints, we derive a slightly modified model phrased as a functional minimization problem, and propose to study it from a theoretical viewpoint. The mathematical model leads to a second order nonlinear PDE with a singularity at Du=0 and containing a nonlocal term. A suitable setting is thus the one of the viscosity solution theory and, in this framework, we establish a short time existence/uniqueness result as well as a Lipschitz regularity result for the solution.

  18. Efficacy of Bevacizumab-Capecitabine in Combination for the First-Line Treatment of Metastatic Breast Cancer

    PubMed Central

    Dyar, Stephen; Moreno-Aspitia, Alvaro

    2011-01-01

    There is an ongoing need for development of new chemotherapeutic regimens for metastatic breast cancer [mBC], especially when tumors lack therapeutic targets such as the estrogen or progesterone receptor [ER/PR], or the human epidermal growth factor receptor-2 [HER2]. Capecitabine is an orally bioavailable fluoropyrimidine approved for monotherapy in mBC, and bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor which has shown to be active in mBC and tolerable in combination with other chemotherapeutics. The combination of these two agents has been explored in multiple phase II and III clinical studies, with improvements in progression-free survival and overall response rates noted as compared to capecitabine monotherapy. However, the use of bevacizumab in combination with capecitabine and other chemotherapy agents for mBC remains beset with controversy due to safety concerns, cost issues, and pending regulatory decisions. PMID:22174585

  19. [Efficacy and side effects of combination therapy of oxaliplatin and S-1 for colorectal cancer].

    PubMed

    Zhu, Qing-chao; Jin, Zhi-ming

    2011-05-01

    To observe the efficacy and side effects of the combination therapy of oxaliplatin and S-1 in treating postoperative colorectal cancer patients. 54 postoperative colorectal cancer patients received the combination therapy of oxaliplatin and S-1 regimen, repeated every 3 weeks, and evaluate the efficacy after 3 cycles. All of the 54 patients but 2 (changed the chemotherapy regimen after the first cycle because of economic reason) finished 6 cycles of the chemotherapy treatment. There were 6 cases (11.5%) with complete response (CR), 28 cases (53.8%) with partial response (PR), and the overall response rate was 65.4%. Major adverse effects were hematological toxicities, gastrointestinal disturbance, neurosensory toxicity. There were no chemotherapy-related deaths. Oxaliplatin combined with S-1 is an effective and better tolerated chemotherapy treatment for postoperative colorectal cancer patients, with no serious side effects for liver and kidney. Therefore, it can be used as an alternative chemotherapy regimen for postoperative colorectal cancer patients.

  20. 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

  1. Serotonergic modulation in neuropathy induced by oxaliplatin: effect on the 5HT2C receptor.

    PubMed

    Baptista-de-Souza, Daniela; Di Cesare Mannelli, Lorenzo; Zanardelli, Matteo; Micheli, Laura; Nunes-de-Souza, Ricardo Luiz; Canto-de-Souza, Azair; Ghelardini, Carla

    2014-07-15

    Fluoxetine has been shown to be effective in clinical and experimental studies of neuropathic pain. Besides to increase serotonin levels in the synaptic cleft, fluoxetine is able to block the serotonergic 5-HT2C receptor subtype, which in turn has been involved in the modulation of neuropathic pain. This study investigated the effect of repeated treatments with fluoxetine on the neuropathic nociceptive response induced by oxaliplatin and the effects of both treatments on 5-HT2C receptor mRNA expression and protein levels in the rat spinal cord (SC), rostral ventral medulla (RVM), midbrain periaqueductal gray (PAG) and amygdala (Amy). Nociception was assessed by paw-pressure, cold plate and Von Frey tests. Fluoxetine prevented mechanical hypersensitivity and pain threshold alterations induced by oxaliplatin but did not prevent the impairment in weight gain induced by this anticancer drug. Ex vivo analysis revealed that oxaliplatin increased the 5-HT2C receptor mRNA expression and protein levels in the SC and PAG. Similar effects were observed in fluoxetine-treated animals but only within the PAG. While oxaliplatin decreased the 5-HT2C mRNA expression levels in the Amy, fluoxetine increased their protein levels in this area. Fluoxetine impaired the oxaliplatin effects on the 5-HT2C receptor mRNA expression in the SC and Amy and protein levels in the SC. All treatments increased of 5-HT2C receptor mRNA expression and protein levels in the PAG. These results suggest that the effects of fluoxetine on neuropathic pain induced by oxaliplatin are associated with quantitative changes in the 5-HT2C receptors located within important areas of the nociceptive system.

  2. Lhermitte sign and urinary retention: atypical presentation of oxaliplatin neurotoxicity in four patients.

    PubMed

    Taieb, Sarah; Trillet-Lenoir, Véronique; Rambaud, Loïc; Descos, Louis; Freyer, Gilles

    2002-05-01

    Regimens combining oxaliplatin with fluorouracil and folinic acid are standard therapeutic options for patients with metastatic colorectal carcinoma. Oxaliplatin has a good safety profile, although it is responsible for dose-limiting neurotoxicity typically consisting of two distinct clusters of symptoms. Cold-induced distal paresthesiae occur during or shortly after infusion in most patients and are usually transient and mild. A persistent sensory peripheral neuropathy may develop with prolonged treatment, eventually causing superficial and deep sensory loss, sensory ataxia and functional impairment. The authors report four cases of atypical neurotoxicity induced by oxaliplatin in patients treated for metastatic colorectal carcinoma. Two patients were male and two were female, with an age range of 52-59 years. Three patients experienced Lhermitte sign and two experienced urinary retention. In all cases, the cumulative dose of oxaliplatin was higher than 1000 mg (range, 1248-2040 mg). Brain and spinal magnetic resonance imaging was performed in two patients and was normal. Somatosensory evoked potentials were recorded in two patients and suggested cervical dorsal column dysfunction. Symptoms resolved a few weeks after discontinuation of oxaliplatin. Lhermitte sign may be induced via a neurotoxic effect on the ascending axons of these T-shaped neurons. An atonic bladder may be the result of damage to the sensory portion of the sacral reflex arc, either in the dorsal roots, as for example in diabetic neuropathy, or in the posterior columns, as in tabes dorsalis. Alternatively, it may result from a paralysis of the parasympathetic fibers that control the bladder musculature. It is unclear at present whether the micturition difficulties observed in patients in the current series are due to sensory neuropathy or to autonomic neuropathy, event if the former hypothesis seems more likely, as autonomic neuropathy has not been previously observed with oxaliplatin, and its

  3. Prospective phase II trial of nimotuzumab in combination with radiotherapy and concurrent capecitabine in locally advanced rectal cancer.

    PubMed

    Jin, Ting; Zhu, Yuan; Luo, Jia-Lin; Zhou, Ning; Li, De-Chuan; Ju, Hai-Xin; Fan, Yong-Tian; Liu, Yong; Zhu, Yu-Ping; Feng, Hai-Yang; Liu, Lu-Ying

    2015-03-01

    The aim of the study was to evaluate the safety and efficacy of adding concurrent nimotuzumab to preoperative radiotherapy with concurrent capecitabine in locally advanced rectal cancer. Patients with rectal cancer (clinical stage T3/4 or N+) were scheduled to receive weekly nimotuzumab (400 mg; days -6, 1, 8, 15, 22, and 29). Capecitabine (825 mg/m(2)) was delivered orally twice daily for the duration of radiotherapy. Radiotherapy was administered at 50.4 Gy (45 + 5.4 Gy). The main endpoint was the pathologic complete response (pCR) rate. Twenty-one patients with T3 or T4 disease were enrolled; 66.7 % were nodal-positive; the median distance from the anal verge was 5.5 cm. A pCR was achieved in four patients (19.0 %); 71.4 % patients obtained moderate or good tumor regression (Grade 2 and 3). Downstaging occurred in 15/21 (71.4 %) patients by T stage and 11/14 (78.6 %) by N stage. The actual dose intensities (median/mean, %) were nimotuzumab (100, 100) and capecitabine (100, 99.5). The most frequent Grade 1/2 toxicities were radiation dermatitis (57.1 %), nausea/vomiting (52.4 %), leukocytopenia (47.6 %), diarrhea (47.6 %), and proctitis (38.1 %). Grade 3 diarrhea was observed in 9.5 % of patients and Grade 3 leukocytopenia in 4.8 %. These preliminary results indicate that nimotuzumab can be safely combined with radiotherapy plus concurrent capecitabine. The efficacy of this regimen (pCR = 19.0 %) was significantly higher than that observed in previous phase II trials of preoperative radiotherapy with concurrent capecitabine and cetuximab in rectal cancer. Further investigation of concurrent nimotuzumab with radiotherapy plus capecitabine is warranted.

  4. Capecitabine: an evidence-based review of its effectiveness in the treatment of carcinoma of the pancreas

    PubMed Central

    Smith, David B.; Neoptolemos, John P.

    2007-01-01

    Introduction: More than 90% of patients with pancreatic cancer present either with incurable locally advanced or metastatic disease or relapse following surgery. For these patients systemic therapy offers the only prospect of salvage, but pancreatic cancer is one of the most chemoresistant of tumors; current chemotherapy can only delay progression in a limited proportion of patients and survival rates are poor. There is therefore a pressing need for more effective therapy. Capecitabine is a new oral prodrug of fluorouracil, which has shown activity in pancreatic cancer particularly when used in combination with gemcitabine. Aims: To review the emerging evidence for the clinical effectiveness of capecitabine in the management of carcinoma of the pancreas. Evidence review: There is evidence from phase II testing that capecitabine is active in pancreatic cancer. The Swiss Group for Clinical Cancer Research/Central European Cooperative Oncology Group (SAKK/CECOG) phase III trial found that the combination of gemcitabine and capecitabine did not improve overall median survival as compared with gemcitabine alone (8.4 vs 7.3 months, respectively; P=0.314) but subgroup analysis in patients with good performance score [Karnofsky Performance Scores (KPS) ≥90] revealed a significant survival improvement with the combination arm (10.1 months) compared with single-agent gemcitabine (7.5 months; P=0.033). Preliminary data from the GemCap phase III trial indicated significantly improved response rates and survival for the combination of gemcitabine with capecitabine (7.4 months) compared with gemcitabine alone (6 months; P=0.026) but analysis of the mature data with adequate follow-up awaits reporting. Clinical potential: The addition of capecitabine to gemcitabine may represent a small step forward in the management of advanced pancreatic cancer but further data are required in order to determine its full impact. PMID:21221179

  5. 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.

  6. 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.

  7. Ordering and short-time orientational diffusion in dipolar hard-spherical colloids.

    PubMed

    Alarcón-Waess, O; Diaz-Herrera, E

    2002-03-01

    Orientational hydrodynamic functions and short-time, self-orientational and collective orientational diffusion coefficients of dipolar hard-spherical colloids are performed on a homogeneous isotropic phase, as functions of the wave vector q, for various values of the volume fraction and the dipolar strength of the macroparticles. The calculation is based on the dynamic orientational structure factor, which is the time-dependent self-correlation of the orientation density. We assume that the time evolution of the orientation density is given by the Smoluchoswki's equation, taking into account the hydrodynamic interactions as well as the dipolar interaction. The former are considered assuming pairwise additivity. The importance of the dynamic orientational structure factor is that its initial slope can be measured in a depolarized light scattering experiment. The results predict a different behavior for dilute and for dense dipolar colloids. The ordering phenomena are studied via the ordering coefficients, which are the orientational hydrodynamic functions at q=0. The results show that as the dipolar colloid evolves to the instability line, the translational ordering velocity increases while the rotational one reduces. The short-time orientational diffusion coefficients at q=0 are also performed. They predict that near to the instability line, the dipolar colloid diffuses translationally more than rotationally. At very dilute concentration the dipolar colloid presents an unexpected dynamical behavior, which seems to indicate that the colloid could be evolving to a reentrant phase.

  8. 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.

  9. Research on resistance characteristics of YBCO tape under short-time DC large current impact

    NASA Astrophysics Data System (ADS)

    Zhang, Zhifeng; Yang, Jiabin; Qiu, Qingquan; Zhang, Guomin; Lin, Liangzhen

    2017-06-01

    Research of the resistance characteristics of YBCO tape under short-time DC large current impact is the foundation of the developing DC superconducting fault current limiter (SFCL) for voltage source converter-based high voltage direct current system (VSC-HVDC), which is one of the valid approaches to solve the problems of renewable energy integration. SFCL can limit DC short-circuit and enhance the interrupting capabilities of DC circuit breakers. In this paper, under short-time DC large current impacts, the resistance features of naked tape of YBCO tape are studied to find the resistance - temperature change rule and the maximum impact current. The influence of insulation for the resistance - temperature characteristics of YBCO tape is studied by comparison tests with naked tape and insulating tape in 77 K. The influence of operating temperature on the tape is also studied under subcooled liquid nitrogen condition. For the current impact security of YBCO tape, the critical current degradation and top temperature are analyzed and worked as judgment standards. The testing results is helpful for in developing SFCL in VSC-HVDC.

  10. 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.

  11. Acceleration of proliferative response of mouse fibroblasts by short-time pretreatment with polyphenols.

    PubMed

    Tsuruya, Makoto; Niwano, Yoshimi; Nakamura, Keisuke; Kanno, Taro; Nakashima, Takuji; Egusa, Hiroshi; Sasaki, Keiichi

    2014-11-01

    Under the hypothesis that photo-irradiated proanthocyanidin could accelerate wound healing through reactive oxygen species (ROS) formation, we examined the effect of proanthocyanidin on 3T3-L1 mouse fibroblasts with or without photo-irradiation. As a result, irrespective of presence or absence of photo-irradiation, only 1 min exposure of the cells to proanthocyanidin resulted in accelerated proliferation of the cells in a concentration-dependent manner. Similarly to proanthocyanidin, 1 min pretreatment with catechin, caffeic acid, and chlorogenic acid accelerated the proliferative response, but gallic acid, epicatechin gallate, epigallocatechin, and epigallocatechin gallate failed. If incorporated active ingredient such as proanthocyanidin for such a short time as 1 min accelerates the proliferation response, a bioassay was conducted by utilizing antioxidant potential of proanthocyanidin. That is, intracellular oxidation of 2',7'-dichlorodihydrofluorescin induced by H2O2 was significantly inhibited when the cells were pretreated with proanthocyanidin for 1 min, suggesting that incorporated proanthocyanidin into the cells exerted antioxidant effect. This was also supported by a liquid chromatography/mass spectrometry analysis in which incorporation of proanthocyanidin components such as catechin monomers and dimers into the cells within 1 min was confirmed. These results suggest that active polyphenolic compounds such as proanthocyanidin, catechin, caffeic acid, and chlorogenic acid incorporated into the cells in such a short time as 1 min could accelerate the proliferative response of the cells.

  12. 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.

  13. Separation of time variant vibration sources by short time coherent output power

    NASA Astrophysics Data System (ADS)

    Trethewey, Martin W.

    2011-02-01

    This effort describes the use of time variant coherence causality based analysis to separate the effects of nonstationary time variant vibration excitation sources. A time variant coherence function using the Short Time Fourier Transform (STFT) is first discussed. The concept of a time variant coherent output power for source separation of systems with time variant transfer functions is developed. A parametric study is performed to examine the coherent output power separation capabilities with respect to the data processing parameters. The study guided the selection of the time-frequency processing parameters judged to provide a suitable compromise between the time event localization and output amplitude source separation. The time variant coherent output power is then applied to separate the effects of the two possible excitation sources on the prototype vibration isolation floor. The application was a subscale prototype isolation floor for a proposed vibration sensitive equipment site adjacent to a busy freight rail line. The moving train created time variant transmission paths. As there was a direct line of sight between the prototype floor and the rail line there was an airborne acoustic excitation path in addition to a ground path. The short time coherent output power was applied to separate prototype isolation floor vibration into respective components related to the two candidate sources. The analysis and discussion of the results focuses upon the interpretation and issues in such a complicated realistic environment. Ultimately the application was successful providing an explanation as to why the observed vibration isolation was degraded at higher frequencies.

  14. Cross section calculations for electron scattering from platinum chemotherapeutic compounds. Electron scattering from carboplatin and oxaliplatin

    NASA Astrophysics Data System (ADS)

    Żywicka, B.; Możejko, P.

    2013-10-01

    Cross section for electron impact ionization of carboplatin, C6H12N2O4Pt, and oxaliplatin, C8H14N2O4Pt, have been calculated within binary-encounter-Bethe model for energies from the ionization threshold up to 5000 eV. Cross section for elastic electron scattering from carboplatin and oxaliplatin molecules have also been derived using independent atom method (IAM) and additivity rule for collision energies ranging from 50 eV to 3000 eV. Obtained cross sections have been compared with relevant cross sections for cisplatin molecules.

  15. Clinical Outcome From Oxaliplatin Treatment in Stage II/III Colon Cancer According to Intrinsic Subtypes

    PubMed Central

    Song, Nan; Pogue-Geile, Katherine L.; Gavin, Patrick G.; Yothers, Greg; Kim, S. Rim; Johnson, Nicole L.; Lipchik, Corey; Allegra, Carmen J.; Petrelli, Nicholas J.; O’Connell, Michael J.; Wolmark, Norman; Paik, Soonmyung

    2016-01-01

    IMPORTANCE Oxaliplatin added to fluorouracil plus leucovorin therapy for patients with colon cancer has been shown to provide significant but modest absolute benefit for disease-free survival. However, acute and chronic neurotoxic effects from this regimen underscore the need for markers that predict oxaliplatin benefit. OBJECTIVE To test our hypothesis that molecular subtypes of colon cancer would be associated with differential prognosis and benefit from oxaliplatin added to fluorouracil plus leucovorin therapy. DESIGN, SETTING, AND PARTICIPANTS Participants in the NSABP C-07 trial were divided into discovery (n = 848) and validation (n = 881) cohorts based on the order of tissue block submission. A reestimated centroid using 72 genes was used to determine Colorectal Cancer Assigner subtypes and their association with oxaliplatin benefit in the discovery cohort. The validation cohort was examined with a locked-down algorithm for subtype classification and statistical analysis plan. Post hoc analysis included examination of the entire cohort with Colorectal Cancer Assigner, Colorectal Cancer Subtype (CCS), and Consensus Molecular Subtype (CMS) methods. INTERVENTIONS Fluorouracil plus leucovorin with or without oxaliplatin. MAIN OUTCOMES AND MEASURES Percent recurrence-free survival. RESULTS Among 1729 patients, 744 (43%) were female and mean (SD) age was 58 (11) years. Although C-07 participants with stage III disease with an enterocyte subtype showed a statistically significant benefit from oxaliplatin in the discovery cohort (hazard ratio, 0.22 [95% CI, 0.09–0.56]; P = .001 [N = 65]), no statistically significant benefit was observed in the validation cohort (hazard ratio, 0.53 [95% CI, 0.22–1.24]; P = .14 [N = 70]). The stemlike subtype was associated with poor prognosis and lack of benefit from oxaliplatin treatment (HR, 0.99 [95% CI, 0.73–1.34]; P = .96 [N = 367]). Examination of the different subtyping methods shows that all 3 methods robustly

  16. Multidrug Resistance-Associated Protein 2 (MRP2) Mediated Transport of Oxaliplatin-Derived Platinum in Membrane Vesicles

    PubMed Central

    Myint, Khine; Li, Yan; Paxton, James; McKeage, Mark

    2015-01-01

    The platinum-based anticancer drug oxaliplatin is important clinically in cancer treatment. However, the role of multidrug resistance-associated protein 2 (MRP2) in controlling oxaliplatin membrane transport, in vivo handling, toxicity and therapeutic responses is unclear. In the current study, preparations of MRP2-expressing and control membrane vesicles, containing inside-out orientated vesicles, were used to directly characterise the membrane transport of oxaliplatin-derived platinum measured by inductively coupled plasma mass spectrometry. Oxaliplatin inhibited the ATP-dependent accumulation of the model MRP2 fluorescent probe, 5(6)-carboxy-2,'7'-dichlorofluorescein, in MRP2-expressing membrane vesicles. MRP2-expressing membrane vesicles accumulated up to 19-fold more platinum during their incubation with oxaliplatin and ATP as compared to control membrane vesicles and in the absence of ATP. The rate of ATP-dependent MRP2-mediated active transport of oxaliplatin-derived platinum increased non-linearly with increasing oxaliplatin exposure concentration, approaching a plateau value (Vmax) of 2680 pmol Pt/mg protein/10 minutes (95%CI, 2010 to 3360 pmol Pt/mg protein/10 minutes), with the half-maximal platinum accumulation rate (Km) at an oxaliplatin exposure concentration of 301 μM (95% CI, 163 to 438 μM), in accordance with Michaelis-Menten kinetics (r2 = 0.954). MRP2 inhibitors (myricetin and MK571) reduced the ATP-dependent accumulation of oxaliplatin-derived platinum in MRP2-expressing membrane vesicles in a concentration-dependent manner. To identify whether oxaliplatin, or perhaps a degradation product, was the likely substrate for this active transport, HPLC studies were undertaken showing that oxaliplatin degraded slowly in membrane vesicle incubation buffer containing chloride ions and glutathione, with approximately 95% remaining intact after a 10 minute incubation time and a degradation half-life of 2.24 hours (95%CI, 2.08 to 2.43 hours). In

  17. Multidrug Resistance-Associated Protein 2 (MRP2) Mediated Transport of Oxaliplatin-Derived Platinum in Membrane Vesicles.

    PubMed

    Myint, Khine; Li, Yan; Paxton, James; McKeage, Mark

    2015-01-01

    The platinum-based anticancer drug oxaliplatin is important clinically in cancer treatment. However, the role of multidrug resistance-associated protein 2 (MRP2) in controlling oxaliplatin membrane transport, in vivo handling, toxicity and therapeutic responses is unclear. In the current study, preparations of MRP2-expressing and control membrane vesicles, containing inside-out orientated vesicles, were used to directly characterise the membrane transport of oxaliplatin-derived platinum measured by inductively coupled plasma mass spectrometry. Oxaliplatin inhibited the ATP-dependent accumulation of the model MRP2 fluorescent probe, 5(6)-carboxy-2,'7'-dichlorofluorescein, in MRP2-expressing membrane vesicles. MRP2-expressing membrane vesicles accumulated up to 19-fold more platinum during their incubation with oxaliplatin and ATP as compared to control membrane vesicles and in the absence of ATP. The rate of ATP-dependent MRP2-mediated active transport of oxaliplatin-derived platinum increased non-linearly with increasing oxaliplatin exposure concentration, approaching a plateau value (Vmax) of 2680 pmol Pt/mg protein/10 minutes (95%CI, 2010 to 3360 pmol Pt/mg protein/10 minutes), with the half-maximal platinum accumulation rate (Km) at an oxaliplatin exposure concentration of 301 μM (95% CI, 163 to 438 μM), in accordance with Michaelis-Menten kinetics (r2 = 0.954). MRP2 inhibitors (myricetin and MK571) reduced the ATP-dependent accumulation of oxaliplatin-derived platinum in MRP2-expressing membrane vesicles in a concentration-dependent manner. To identify whether oxaliplatin, or perhaps a degradation product, was the likely substrate for this active transport, HPLC studies were undertaken showing that oxaliplatin degraded slowly in membrane vesicle incubation buffer containing chloride ions and glutathione, with approximately 95% remaining intact after a 10 minute incubation time and a degradation half-life of 2.24 hours (95%CI, 2.08 to 2.43 hours). In

  18. A phase II study of preoperative capecitabine in women with operable hormone receptor positive breast cancer

    PubMed Central

    Tolaney, Sara M; Jeong, Joon; Guo, Hao; Brock, Jane; Morganstern, Daniel; Come, Steven E; Golshan, Mehra; Bellon, Jennifer; Winer, Eric P; Krop, Ian E

    2014-01-01

    Conventional preoperative chemotherapy regimens have only limited efficacy in hormone receptor positive (HR+) breast cancer and new approaches are needed. We hypothesized that capecitabine, which is effective in metastatic breast cancer, may be an active preoperative treatment for HR+ breast cancer. Women with HR+, HER2-negative operable breast cancer received capecitabine, 2000 mg/m2 daily in divided doses for 14 days, followed by a 7-day rest period. Treatment was repeated every 21 days for a total of four cycles. The primary endpoint of the study was to determine the rate of pathological complete response (pCR). Because of slow accrual, the study was closed after 24 patients were enrolled. Three patients had a complete clinical response, and eight patients had a partial clinical response, for an overall clinical response rate of 45.8%. There were no cases of pCR. Of the 22 patients who had pathological response assessment by the Miller–Payne grading system, there were six grade 3 responses, and no grade 4 or 5 responses. Toxicity was manageable: the only grade 3 toxicities observed were one case each of diarrhea, palmar plantar erythrodysesthesia, hypokalemia, and mucositis. There was no association between baseline levels, or change in level from baseline to cycle 1, or from baseline to time of surgery, of thymidine phosphorylase (TYMP), thymidylate synthase (TYMS), dihydropyrimidine dehydrogenase (DPYD), or Ki67 and pathological, clinical, or radiographic response. Preoperative capecitabine is a well-tolerated regimen, but appears not lead to pCR when used as monotherapy in HR+ breast cancer. PMID:24464780

  19. Phase II study of preoperative bevacizumab, capecitabine and radiotherapy for resectable locally-advanced rectal cancer.

    PubMed

    García, Margarita; Martinez-Villacampa, Mercedes; Santos, Cristina; Navarro, Valentin; Teule, Alex; Losa, Ferran; Pisa, Aleydis; Cambray, Maria; Soler, Gemma; Lema, Laura; Kreisler, Esther; Figueras, Agnes; Juan, Xavier San; Viñals, Francesc; Biondo, Sebastiano; Salazar, Ramon

    2015-02-26

    To evaluate whether the addition of bevacizumab (BVZ) to capecitabine-based chemoradiotherapy in the preoperative treatment of locally advanced rectal cancer (LARC) improves efficacy measured by the pathological complete response (pCR) rate. A phase II two-step design was performed. Patients received four cycles of therapy consisting of: BVZ 10 mg/kg in first infusion on day 1 and 5 mg/kg on days 15, 29, 43, capecitabine 1800 mg/m(2)/day 5 days per week during radiotherapy, which consisted of external-beam irradiation (45 Gy in 1.8 Gy dose per session over 5 sessions/week for 5 weeks). Six to eight weeks after completion of all therapies surgery was undergone. To profile the biological behaviour during BVZ treatment we measured molecular biomarkers before treatment, during BVZ monotherapy, and during and after combination therapy. Microvessel density (MVD) was measured after surgery. Forty-three patients were assessed and 41 were included in the study. Three patients achieved a pathological complete response (3/40: 7.5%) and 27 (67.5%) had a pathological partial response, (overall pathological response rate of 75%). A further 8 patients (20%) had stable disease, giving a disease control rate of 95%. Downstaging occurred in 31 (31/40: 77.5%) of the patients evaluated. This treatment resulted in an actuarial 4-year disease-free and overall survival of 85.4 and 92.7% respectively. BVZ with chemoradiotherapy showed acceptable toxicity. No correlations were observed between biomarker results and efficacy variables. BVZ with capecitabine and radiotherapy seem safe and active and produce promising survival results in LARC. ClinicalTrials.gov Identifier NCT00847119 . Trial registration date: February 18, 2009.

  20. A randomised phase II study of combination chemotherapy with epirubicin, cisplatin and capecitabine (ECX) or cisplatin and capecitabine (CX) in advanced gastric cancer.

    PubMed

    Yun, Jina; Lee, Jeeyun; Park, Se Hoon; Park, Joon Oh; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki

    2010-03-01

    Both cisplatin/capecitabine (CX) and epirubicin plus CX (ECX) have clearly demonstrated efficacy against advanced gastric cancer (AGC). Chemotherapy-naïve patients with histologically confirmed, measurable AGC were randomised to receive CX (cisplatin 75mg/m(2) iv on day 1 and capecitabine 1000mg/m(2) bid po on days 1-14) or ECX (epirubicin 50mg/m(2) plus CX) every 3weeks. The primary endpoint was progression-free survival (PFS). Of the 91 registered patients, 45 patients were treated with CX and 44 with ECX. A total of 241 CX (median, 6; range, 1-12) and 201 ECX (median, 5; range, 1-11) cycles were delivered. Treatment duration was similar for both arms (4.4 for CX versus 4.2months for ECX). There was no relevant difference in the occurrence of overall grade 3 or 4 toxicities between the CX and ECX arms (80% versus 78%, respectively; P=0.516). However, none in the CX and 12% in the ECX arm discontinued treatment because of toxicity. There were no significant differences in therapeutic efficacy between CX and ECX with respect to the response rate (38% versus 37%, respectively) and PFS (6.4 versus 6.5months). Both CX and ECX appear to be active as first-line chemotherapy for AGC, and the safety profiles are acceptable. Given the comparable efficacy results, CX could be a reasonable standard chemotherapy for untreated AGC patients. Copyright 2009 Elsevier Ltd. All rights reserved.

  1. Neoadjuvant gemcitabine, docetaxel, and capecitabine followed by gemcitabine and capecitabine/radiation therapy and surgery in locally advanced, unresectable pancreatic adenocarcinoma.

    PubMed

    Sherman, William H; Chu, Kyung; Chabot, John; Allendorf, John; Schrope, Beth Ann; Hecht, Elizabeth; Jin, Brian; Leung, David; Remotti, Helen; Addeo, Gisella; Postolov, Inna; Tsai, Wei; Fine, Robert L

    2015-03-01

    This prospective study was undertaken to assess toxicity, resectability, and survival in pancreatic adenocarcinoma patients presenting with locally advanced, unresectable disease treated with neoadjuvant gemcitabine, docetaxel, and capecitabine (GTX) and gemcitabine and capecitabine (GX)/radiation therapy (RT). All patients presenting to the Pancreas Center were evaluated for eligibility. Forty-five patients (mean age, 64 years; range, 44-83 years)-34 patients deemed unresectable because of arterial involvement and 11 patients deemed unresectable because of extensive venous involvement-were treated with 6 cycles of GTX. Those with arterial involvement were treated with GX/RT after chemotherapy. The GTX and GX/RT treatments were tolerated with the expected drug-related toxicities. There were no bowel perforations, cases of pancreatitis, or delayed strictures. Among those with arterial involvement, 29 underwent subsequent resection, with 20 (69%) achieving R0 resections. All 11 patients with venous-only involvement underwent resection, with 8 achieving R0 resections and 3 achieving complete pathologic responses. For the arterial arm, the 1-year survival rate was 71% (24 of 34 patients), and the median survival was 29 months (95% confidence interval, 21-38 months). Thirteen patients (38%) have not relapsed (range, 5-49+ months). For the venous arm, the median survival has not been reached at more than 42 months. Six patients (55%) in the venous arm did not experience recurrence (range, 6.2-42+ months). GTX plus GX/RT is an effective neoadjuvant regimen that can be safely administered to patients up to at least the age of 83 years. It is associated with a high response rate, a high rate of R0 resections, and prolonged overall survival. © 2014 American Cancer Society.

  2. The comparison of maintenance treatment with capecitabine (CMT) and non-maintenance treatment with capecitabine (non-CMT) in patients with metastatic breast cancer.

    PubMed

    Dong, Guolei; Jia, Yan; Wang, Xiaorui; Li, Shufen; Wang, Chen; Shi, Yehui; Tong, Zhongsheng

    2015-01-01

    The study examined the response rate, response duration and toxicity of maintenance treatment (CMT) and non-maintenance treatment with capecitabine (non-CMT) in metastatic breast cancer (MBC). Between September 2009 and July 2013, a group of 82 patients with MBC, who had progressed after anthracycline/taxane chemotherapy, was treated with a capecitabine-based chemotherapy and divided into two groups. 54 patients received CMT 1.5 g twice a day from days 1 to 14, and 28 patients achieved non-CMT. Treatment was continued until disease progression or unacceptable toxicity. The median age of patients treated with CMT and non-CMT was 57 years (range 38-78) and 50 years (range 37-77). The evaluation of treatment effect was possible in all patients. The overall response rate (ORR) was 29.7% (16 cases), including 3 (5.6%) complete responses (CR) and 13 (24.1%) partial responses (PR). Stable disease (SD) was observed in 7.4% of patients receiving CMT (54 patients). In the group receiving non-CMT, ORR was 3.6% (1 case). The median PFS in CMT group was 36 weeks, while in non-CMT group was 24 weeks. The most common adverse event was hematologic toxicity (74.1%), with the incidence of grade 1-2/3-4 was 70.4% and 3.7%. Hand-foot syndrome was the most frequent non-hematologic form of toxicity, occurring in 70.4% of cases. There were no treatment-related deaths. CMT is an effective and safe treatment for pretreated metastatic breast cancer patients. And CMT appears to be a more efficacious treatment than non-CMT.

  3. Adherence and Patients' Experiences with the Use of Capecitabine in Daily Practice

    PubMed Central

    Timmers, Lonneke; Boons, Christel C. L. M.; Mangnus, Dirk; Van de Ven, Peter M.; Van den Berg, Pieter H.; Beeker, Aart; Swart, Eleonora L.; Honeywell, Richard J.; Peters, Godefridus J.; Boven, Epie; Hugtenburg, Jacqueline G.

    2016-01-01

    Introduction: Capecitabine is a widely prescribed oral anticancer agent. We studied medication adherence and explored its use in daily practice from a patients' perspective. Patients and Methods: Patients (n = 92) starting capecitabine were followed up to five 3-week cycles. Adherence was assessed using a pill count, pharmacy data and dosing information from the patients' medical file. Self-reported adherence was measured using the Medication Adherence Report Scale (MARS). At baseline and during week 2 of cycles 1, 3, and 5, patients filled out questionnaires about quality of life, symptoms, attitude toward medicines and disease and use in daily practice. Simultaneously, blood samples were taken to determine the area under the curve (AUC) of 5′-deoxy-5-fluorouridine (5′-DFUR), 5-fluorouracil (5-FU), and α-fluoro-β-alanine (FBAL) by a population pharmacokinetic model. Associations between AUCs and patient-reported symptoms were tested for cycles 3 and 5. Results: Most patients (84/92; 91%) had an adherence rate of ≥95 and ≤ 105%. The percentage of patients reporting any non-adherence behavior measured with MARS increased from 16% at cycle 1 to 29% at cycle 5. Symptoms were reported frequently and the dosing regimen was adjusted by the physician at least once in 62% of patients. In multivariate analysis the probability of an adjustment increased with the number of co-medication (OR 1.19, 95% CI: 1.03–1.39) and a stronger emotional response to the disease (OR 1.32, 95% CI: 1.10–1.59). The AUC of 5′-DFUR was associated with weight loss (OR 1.10, 95% CI: 1.01–1.19), AUC of FBAL with hand-foot syndrome (OR 0.90, 95% CI: 0.83–0.99), rhinorrhea (OR 1.21, 95% CI: 1.03–1.42 weight loss (OR 1.09, 95% CI: 1.00–1.20) and depression (OR 0.90, 95% CI: 0.82–0.99). Side effects were reported by one third of patients as the reason to discontinue treatment. Conclusion: Adherence to capecitabine was generally high. Nevertheless, adherence measured with MARS

  4. Phase I Trial of Consolidative Radiotherapy with Concurrent Bevacizumab, Erlotinib and Capecitabine for Unresectable Pancreatic Cancer

    PubMed Central

    Gunther, Jillian R.; Munsell, Mark F.; Das, Prajnan; Minsky, Bruce D.; Delclos, Marc E.; Chatterjee, Deyali; Wang, Huamin; Clemons, Marilyn; George, Geena; Singh, Pankaj K.; Katz, Matthew H.; Fleming, Jason B.; Javle, Milind M.; Wolff, Robert A.; Varadhachary, Gauri R.; Crane, Christopher H.; Krishnan, Sunil

    2016-01-01

    Purpose To determine the safety, tolerability and maximum tolerated dose (MTD) of addition of erlotinib to bevacizumab and capecitabine-based definitive chemoradiation (CRT) in unresectable pancreatic cancer. Methods Seventeen patients with CT-staged, biopsy-proven unresectable pancreatic cancer were enrolled between 3/2008 and 10/2010. Prior chemotherapy was permitted. Two patients each were enrolled at dose levels (DLs) 1–4 and 9 patients at DL 5. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose of each drug was escalated in 5 DLs using the continual reassessment method. Bevacizumab was escalated from 5mg/Kg q2weeks (DLs 1–4) to 10mg/Kg q2weeks (DL 5); daily erlotinib from 100mg/day (DLs 1–2) to 150 mg/Kg (DLs 3–5); and capecitabine from 400mg/m2 twice daily on days of radiation (DL 1) to 650mg/m2 (DLs 2–3) to 825 mg/m2 (DLs 4–5). Reassessment for potential resection was performed 6–8 weeks later. Results Sixteen patients received gemcitabine-based chemotherapy prior to CRT. With a median clinical follow-up of 10 months, no grade 3 toxicities were observed in DLs 1–4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrhea, 1 rash). No grade 4 or 5 toxicities were seen. DL 4 was selected as the MTD; therefore, the recommended doses in combination with radiation are: bevacizumab, 5mg/Kg q2weeks; erlotinib, 150 mg/Kg daily; and capecitabine, 825mg/m2 BID. Median survival was 17.4 months. Of the five patients who underwent resection, 4 were originally deemed locally advanced and 1 was borderline resectable. Three patients had excellent pathological response (2 complete response and 20% viable tumor) at surgery, and the 2 patients with complete response are still alive at 61 and 67 months of follow up with no local or distant failures. Conclusions This chemoradiation regimen at the recommended dose levels is safe and tolerable for patients with unresectable

  5. 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. Copyright © 2010 Elsevier Ltd. All rights reserved.

  6. Cardiotoxicity with 5-fluorouracil and capecitabine: more than just vasospastic angina.

    PubMed

    Stewart, T; Pavlakis, N; Ward, M

    2010-04-01

    In this case series we present a variety of different cardiac toxicities with 5-fluorouracil and its pro-drug capecitabine, including myocardial infarction, cardiomyopathy, sinoatrial and atrioventricular node dysfunction, takotsubo cardiomyopathy and QT prolongation with torsade-de pointes ventricular tachycardia. We stress the fact that while vasospasm is a well-recognized side-effect of this class of chemotherapeutic agent, broader cardiotoxicity is commonly seen and an increased awareness of the range of toxicity is necessary if repeat toxicity is to be avoided.

  7. Monte Carlo simulations of the short time dynamics of a first-order irreversible phase transition

    NASA Astrophysics Data System (ADS)

    Albano, Ezequiel V.

    2001-09-01

    The ZGB model (Ziff-Gulari-Barshad, Phys. Rev. Lett. 56 (1986) 2553) for the catalytic oxidation of carbon monoxide has a single parameter given by the normalized partial pressure of CO molecules ( PCO). For PCO⩾ PCOCoex≃0.52583 the surface of the catalyst becomes irreversibly covered by CO molecules and the system cannot escape from this state. However, for PCO slightly below PCOCoex the system reaches an active stationary state. So, just at PCOCoex a sharp first-order irreversible phase transition is observed. It is shown that a study of the short time dynamics of the ZGB model allows to obtain a fairly accurate evaluation of the upper spinodal point given by PCOUsp≃0.52675(5). This figure is in excellent agreement with extensive simulations performed using the constant coverage ensemble.

  8. Food Quality Improvement of Soy Milk Made from Short-Time Germinated Soybeans.

    PubMed

    Jiang, Susu; Cai, Weixi; Xu, Baojun

    2013-05-21

    The objectives of this study were to develop soy milk with improved food quality and to enhance the functional attributes by incorporating short-time germination into the processing. Changes in trypsin inhibitor activity (TIA), phytic acid content and total phenolic content (TPC) in soy milk produced from soybeans germinated within 72 h were investigated to determine the optimum germination condition. Results from the present research showed significant (p < 0.05) improvement of TPC in cooked germinated soybean milk, while both the TIA and phytic acid content were decreased significantly (p < 0.05). In the subsequent evaluation on the quality attributes under the optimum germination condition, soy milk made from 28 h-germinated soybeans presented enhanced nutritional value and comparable physicochemical properties to conventional soy milk. The current approach provides a feasible and convenient way for soy-based product innovation in both household and industrial settings.

  9. A combination of HARMONIE short time direct normal irradiance forecasts and machine learning: The #hashtdim procedure

    NASA Astrophysics Data System (ADS)

    Gastón, Martín; Fernández-Peruchena, Carlos; Körnich, Heiner; Landelius, Tomas

    2017-06-01

    The present work describes the first approach of a new procedure to forecast Direct Normal Irradiance (DNI): the #hashtdim that treats to combine ground information and Numerical Weather Predictions. The system is centered in generate predictions for the very short time. It combines the outputs from the Numerical Weather Prediction Model HARMONIE with an adaptive methodology based on Machine Learning. The DNI predictions are generated with 15-minute and hourly temporal resolutions and presents 3-hourly updates. Each update offers forecasts to the next 12 hours, the first nine hours are generated with 15-minute temporal resolution meanwhile the last three hours present hourly temporal resolution. The system is proved over a Spanish emplacement with BSRN operative station in south of Spain (PSA station). The #hashtdim has been implemented in the framework of the Direct Normal Irradiance Nowcasting methods for optimized operation of concentrating solar technologies (DNICast) project, under the European Union's Seventh Programme for research, technological development and demonstration framework.

  10. Instantaneous Heart Rate detection using short-time autocorrelation for wearable healthcare systems.

    PubMed

    Nakano, Masanao; Konishi, Toshihiro; Izumi, Shintaro; Kawaguchi, Hiroshi; Yoshimoto, Masahiko

    2012-01-01

    This report describes a robust method of Instantaneous Heart Rate (IHR) detection from noisy electrocardiogram (ECG) signals. Generally, the IHR is calculated from the interval of R-waves. Then, the R-waves are extracted from the ECG using a threshold. However, in wearable biosignal monitoring systems, various noises (e.g. muscle artifacts from myoelectric signals, electrode motion artifacts) increase incidences of misdetection and false detection because the power consumption and electrode distance of the wearable sensor are limited to reduce its size and weight. To prevent incorrect detection, we use a short-time autocorrelation technique. The proposed method uses similarity of the waveform of the QRS complex. Therefore, it has no threshold calculation Process and it is robust for noisy environment. Simulation results show that the proposed method improves the success rate of IHR detection by up to 37%.

  11. Intrinsic dynamics of heart regulatory systems on short time-scales: from experiment to modelling

    PubMed Central

    Khovanov, I. A.; Khovanova, N. A.; McClintock, P. V. E.; Stefanovska, A.

    2010-01-01

    We discuss open problems related to the stochastic modeling of cardiac function. The work is based on an experimental investigation of the dynamics of heart rate variability (HRV) in the absence of respiratory perturbations. We consider first the cardiac control system on short time scales via an analysis of HRV within the framework of a random walk approach. Our experiments show that HRV on timescales of less than a minute takes the form of free diffusion, close to Brownian motion, which can be described as a non-stationary process with stationary increments. Secondly, we consider the inverse problem of modeling the state of the control system so as to reproduce the experimentally observed HRV statistics of. We discuss some simple toy models and identify open problems for the modelling of heart dynamics. PMID:21151767

  12. 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.

  13. Short-time movement of E. coli chromosomal loci depends on coordinate and subcellular localization.

    PubMed

    Javer, Avelino; Long, Zhicheng; Nugent, Eileen; Grisi, Marco; Siriwatwetchakul, Kamin; Dorfman, Kevin D; Cicuta, Pietro; Cosentino Lagomarsino, Marco

    2013-01-01

    In bacteria, chromosomal architecture shows strong spatial and temporal organization, and regulates key cellular functions, such as transcription. Tracking the motion of chromosomal loci at short timescales provides information related to both the physical state of the nucleo-protein complex and its local environment, independent of large-scale motions related to genome segregation. Here we investigate the short-time (0.1-10 s) dynamics of fluorescently labelled chromosomal loci in Escherichia coli at different growth rates. At these timescales, we observe for the first time a dependence of the loci's apparent diffusion on both their subcellular localization and chromosomal coordinate, and we provide evidence that the properties of the chromosome are similar in the tested growth conditions. Our results indicate that either non-equilibrium fluctuations due to enzyme activity or the organization of the genome as a polymer-protein complex vary as a function of the distance from the origin of replication.

  14. Epileptic seizure classification of EEG time-series using rational discrete short-time fourier transform.

    PubMed

    Samiee, Kaveh; Kovács, Petér; Gabbouj, Moncef

    2015-02-01

    A system for epileptic seizure detection in electroencephalography (EEG) is described in this paper. One of the challenges is to distinguish rhythmic discharges from nonstationary patterns occurring during seizures. The proposed approach is based on an adaptive and localized time-frequency representation of EEG signals by means of rational functions. The corresponding rational discrete short-time Fourier transform (DSTFT) is a novel feature extraction technique for epileptic EEG data. A multilayer perceptron classifier is fed by the coefficients of the rational DSTFT in order to separate seizure epochs from seizure-free epochs. The effectiveness of the proposed method is compared with several state-of-art feature extraction algorithms used in offline epileptic seizure detection. The results of the comparative evaluations show that the proposed method outperforms competing techniques in terms of classification accuracy. In addition, it provides a compact representation of EEG time-series.

  15. Short Time Dynamics of Ionic Liquids in AIMD-Based Power Spectra.

    PubMed

    Wendler, Katharina; Brehm, Martin; Malberg, Friedrich; Kirchner, Barbara; Delle Site, Luigi

    2012-05-08

    Power spectra of several imidazolium-based ionic liquids, 1,3-dimethylimidazolium chloride, 1-ethyl-3-methylimidazolium thiocyanate, 1-ethyl-3-methylimidazolium dicyanamide 5, 1-butyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium thiocyanate, and 1-butyl-3-methylimidazolium dicyanamide, are presented based on ab initio molecular dynamics simulations. They provide an alternative tool of analysis of several electronic structure-based properties, in particular, those related to the strength of hydrogen bonding in liquids. Moreover, they can be employed to interpret experimental IR or Raman spectra, avoiding the additional calculations required for theoretical IR or Raman spectra. The obtained power spectra are shown to be in good agreement with experimental spectra, and electronic structure properties related to them are analyzed. Further, there are indications for a locality of the power spectra on a relatively short time scale of ≈10 ps or system size of about 8 ion pairs as already speculated in previous work.

  16. Spinodals and critical point using short-time dynamics for a simple model of liquid.

    PubMed

    Loscar, Ernesto S; Ferrara, C Gastón; Grigera, Tomás S

    2016-04-07

    We have applied the short-time dynamics method to the gas-liquid transition to detect the supercooled gas instability (gas spinodal) and the superheated liquid instability (liquid spinodal). Using Monte Carlo simulation, we have obtained the two spinodals for a wide range of pressure in sub-critical and critical conditions and estimated the critical temperature and pressure. Our method is faster than previous approaches and allows studying spinodals without needing equilibration of the system in the metastable region. It is thus free of the extrapolation problems present in other methods, and in principle could be applied to systems such as glass-forming liquids, where equilibration is very difficult even far from the spinodal. We have also done molecular dynamics simulations, where we find the method again able to detect the both spinodals. Our results are compared with different previous results in the literature and show a good agreement.

  17. 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.

  18. The contribution of Gi/o protein to opioid antinociception in an oxaliplatin-induced neuropathy rat model.

    PubMed

    Kanbara, Tomoe; Nakamura, Atsushi; Takasu, Keiko; Ogawa, Koichi; Shibasaki, Masahiro; Mori, Tomohisa; Suzuki, Tsutomu; Hasegawa, Minoru; Sakaguchi, Gaku; Kanemasa, Toshiyuki

    2014-01-01

    Oxaliplatin is a chemotherapeutic agent that induces chronic refractory neuropathy. To determine whether opioids effectively relieve this chronic neuropathy, we investigated the efficacies of morphine, oxycodone, and fentanyl, and the mechanisms underlying opioid antinociception, in oxaliplatin-induced neuropathy in rats. Rats exhibited significant mechanical allodynia following 2 weeks of chronic oxaliplatin administration. Within the range of doses that did not induce sedation and/or muscle rigidity, morphine (3 mg/kg, subcutaneously, s.c.) and oxycodone (0.3-0.56 mg/kg, s.c.) completely reversed oxaliplatin-induced mechanical allodynia, whereas fentanyl (0.017-0.03 mg/kg, s.c.) showed partial antinociception. The antinociception of the optimal doses of morphine and oxycodone were completely inhibited by pertussis toxin (PTX; 0.5 μg/rat, i.c.v.), a Gi/o protein inhibitor, while the partial effect of fentanyl was not affected in the oxaliplatin model. In the [(35)S]-GTPγS binding assay, activation of μ-opioid receptor by fentanyl, but not by morphine or oxycodone, in the mediodorsal thalamus was significantly reduced in oxaliplatin-treated rats. These results indicate that the lower antinociceptive potency of fentanyl in the oxaliplatin model might in part result from the loss of PTX-sensitive Gi/o protein activation, and the degree of Gi/o protein activation might be related to the potency of antinociception by opioids in this model.

  19. 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.

  20. Grape seed extracts modify the outcome of oxaliplatin in colon cancer cells by interfering with cellular mechanisms of drug cytotoxicity.

    PubMed

    Porcelli, Letizia; Iacobazzi, Rosa Maria; Quatrale, Anna Elisa; Bergamini, Carlo; Denora, Nunzio; Crupi, Pasquale; Antonacci, Donato; Mangia, Anita; Simone, Giovanni; Silvestris, Nicola; Azzariti, Amalia

    2017-08-01

    Grape seed extracts are commonly utilized as dietary supplements for their antioxidant properties, even from cancer patients. However, whether these natural extracts interfere with chemotherapeutics utilized in colon cancer treatment is still poorly investigated. The cytotoxicity of extracts from Italia and Palieri cultivars either alone or in combination with oxaliplatin was evaluated in colon cancer cells. Grape seed extracts displayed anti-proliferative activity depending on the concentration utilized through apoptosis induction. In combination, they affected the activation of Erk1/2 and counteracted the intrinsic and the extrinsic pathway of apoptosis, the DNA damage and the generation of ROS induced by oxaliplatin. Noteworthy grape seed extracts strongly enhanced the uptake of oxaliplatin into all cells, by affecting the cell transport system of platinum. The addition of these natural extracts to oxaliplatin strongly reduced the cellular response to oxaliplatin and allowed a huge accumulation of platinum into cells. Here, we shed light on the chemical biology underlying the combination of grape seed extracts and oxaliplatin, demonstrating that they might be detrimental to oxaliplatin effectiveness in colon cancer therapy.

  1. Carvedilol prevents functional deficits in peripheral nerve mitochondria of rats with oxaliplatin-evoked painful peripheral neuropathy.

    PubMed

    Areti, Aparna; Komirishetty, Prashanth; Kumar, Ashutosh

    2017-03-09

    Oxaliplatin use as chemotherapeutic agent is frequently limited by cumulative neurotoxicity which may compromise quality of life. Reports relate this neurotoxic effect to oxidative stress and mitochondrial dysfunction in peripheral nerves and dorsal root ganglion (DRG). Carvedilol is an antihypertensive drug, has also been appreciated for its antioxidant and mitoprotective properties. Carvedilol co-treatment did not reduce the anti-tumor effects of oxaliplatin in human colon cancer cells (HT-29), but exhibited free radical scavenging activity against oxaliplatin-induced oxidative stress in neuronal cells (Neuro-2a). Hence, the present study was designed to investigate the effect of carvedilol in the experimental model of oxaliplatin-induced peripheral neuropathy (OIPN) in Sprague-Dawley rats. Oxaliplatin reduced the sensory nerve conduction velocity and produced the thermal and mechanical nociception. Carvedilol significantly (P<0.001) attenuated these functional and sensorimotor deficits. It also counteracted oxidative/nitrosative stress by reducing the levels of nitrotyrosine and improving the mitochondrial superoxide dismutase expression in both sciatic nerve and DRG tissues. It improved the mitochondrial function and prevented the oxaliplatin-induced alteration in mitochondrial membrane potential in sciatic nerve thus prevented loss of intra epidermal nerve fiber density in the foot pads. Together the results prompt the use of carvedilol along with chemotherapy with oxaliplatin to prevent the peripheral neuropathy.

  2. Short time administration of antirheumatic drugs - Methotrexate as a strong inhibitor of osteoblast's proliferation in vitro

    PubMed Central

    2012-01-01

    Introduction Due to increasing use of disease modifying antirheumatic drugs (DMARDs) as first line therapy in rheumatic diseases, dental and maxillofacial practitioner should be aware of drug related adverse events. Especially effects on bone-metabolism and its cells are discussed controversially. Therefore we investigate the in vitro effect of short time administration of low dose methotrexate (MTX) on osteoblasts as essential part of bone remodelling cells. Methods Primary bovine osteoblasts (OBs) were incubated with various concentrations of MTX, related to tissue concentrations, over a period of fourteen days by using a previously established standard protocol. The effect on cell proliferation as well as mitochondrial activity was assessed by using 3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide (MTT) assay, imaging and counting of living cells. Additionally, immunostaining of extracellular matrix proteins was used to survey osteogenic differentiation. Results All methods indicate a strong inhibition of osteoblast`s proliferation by short time administration of low dose MTX within therapeutically relevant concentrations of 1 to 1000nM, without affecting cell differentiation of middle-stage differentiated OBs in general. More over a significant decrease of cell numbers and mitochondrial activity was found at these MTX concentrations. The most sensitive method seems to be the MTT-assay. MTX-concentration of 0,01nM and concentrations below had no inhibitory effects anymore. Conclusion Even low dose methotrexate acts as a potent inhibitor of osteoblast’s proliferation and mitochondrial metabolism in vitro, without affecting main differentiation of pre-differentiated osteoblasts. These results suggest possible negative effects of DMARDs concerning bone healing and for example osseointegration of dental implants. Especially the specifics of the jaw bone with its high vascularisation and physiological high tissue metabolism, suggests possible negative

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

    DOE PAGES

    Godfrin, P. Douglas; Hudson, Steven; Hong, Kunlun; ...

    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

  4. Universal short-time quantum critical dynamics of finite-size systems

    NASA Astrophysics Data System (ADS)

    Shu, Yu-Rong; Yin, Shuai; Yao, Dao-Xin

    2017-09-01

    We investigate the short-time quantum critical dynamics in the imaginary-time relaxation processes of finite-size systems. Universal scaling behaviors exist in the imaginary-time evolution. In particular, the system undergoes a critical initial slip stage characterized by an exponent θ , in which an initial power-law increase emerges in the imaginary-time correlation function when the initial state has a zero order parameter and a vanishing correlation length. Under different initial conditions, the quantum critical point and critical exponents can be determined from the universal scaling behaviors. We apply the method to the one- and two-dimensional transverse field Ising models using quantum Monte Carlo (QMC) simulations. In the one-dimensional case, we locate the quantum critical point at (h/J ) c=1.000 03 (8 ) in the thermodynamic limit, and we estimate the critical initial slip exponent θ =0.3734 (2 ) and the static exponent β /ν =0.1251 (2 ) by analyzing data on chains of length L =32 -256 and 48-256, respectively. For the two-dimensional square-lattice system, the critical coupling ratio is given by 3.044 51 (7 ) in the thermodynamic limit, while the critical exponents are θ =0.209 (4 ) and β /ν =0.518 (1 ) estimated by data on systems of size L =24 -64 and 32-64, respectively. Remarkably, the critical initial slip exponents obtained in both models are notably distinct from their classical counterparts due to the essential differences between classical and quantum dynamics. The short-time critical dynamics and the imaginary-time relaxation QMC approach can be readily adapted to various models.

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

    PubMed

    Tchagang, Alain B; Phan, Sieu; Famili, Fazel; Shearer, Heather; Fobert, Pierre; Huang, Yi; Zou, Jitao; Huang, Daiqing; Cutler, Adrian; Liu, Ziying; Pan, Youlian

    2012-04-04

    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. 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. 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.

  6. Short time administration of antirheumatic drugs - methotrexate as a strong inhibitor of osteoblast's proliferation in vitro.

    PubMed

    Annussek, Tobias; Kleinheinz, Johannes; Thomas, Szuwart; Joos, Ulrich; Wermker, Kai

    2012-09-29

    Due to increasing use of disease modifying antirheumatic drugs (DMARDs) as first line therapy in rheumatic diseases, dental and maxillofacial practitioner should be aware of drug related adverse events. Especially effects on bone-metabolism and its cells are discussed controversially. Therefore we investigate the in vitro effect of short time administration of low dose methotrexate (MTX) on osteoblasts as essential part of bone remodelling cells. Primary bovine osteoblasts (OBs) were incubated with various concentrations of MTX, related to tissue concentrations, over a period of fourteen days by using a previously established standard protocol. The effect on cell proliferation as well as mitochondrial activity was assessed by using 3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide (MTT) assay, imaging and counting of living cells. Additionally, immunostaining of extracellular matrix proteins was used to survey osteogenic differentiation. All methods indicate a strong inhibition of osteoblast`s proliferation by short time administration of low dose MTX within therapeutically relevant concentrations of 1 to 1000 nM, without affecting cell differentiation of middle-stage differentiated OBs in general. More over a significant decrease of cell numbers and mitochondrial activity was found at these MTX concentrations. The most sensitive method seems to be the MTT-assay. MTX-concentration of 0,01 nM and concentrations below had no inhibitory effects anymore. Even low dose methotrexate acts as a potent inhibitor of osteoblast's proliferation and mitochondrial metabolism in vitro, without affecting main differentiation of pre-differentiated osteoblasts. These results suggest possible negative effects of DMARDs concerning bone healing and for example osseointegration of dental implants. Especially the specifics of the jaw bone with its high vascularisation and physiological high tissue metabolism, suggests possible negative effects of DMARD therapy concerning

  7. Quantum Dynamics with Short-Time Trajectories and Minimal Adaptive Basis Sets.

    PubMed

    Saller, Maximilian A C; Habershon, Scott

    2017-07-11

    Methods for solving the time-dependent Schrödinger equation via basis set expansion of the wave function can generally be categorized as having either static (time-independent) or dynamic (time-dependent) basis functions. We have recently introduced an alternative simulation approach which represents a middle road between these two extremes, employing dynamic (classical-like) trajectories to create a static basis set of Gaussian wavepackets in regions of phase-space relevant to future propagation of the wave function [J. Chem. Theory Comput., 11, 8 (2015)]. Here, we propose and test a modification of our methodology which aims to reduce the size of basis sets generated in our original scheme. In particular, we employ short-time classical trajectories to continuously generate new basis functions for short-time quantum propagation of the wave function; to avoid the continued growth of the basis set describing the time-dependent wave function, we employ Matching Pursuit to periodically minimize the number of basis functions required to accurately describe the wave function. Overall, this approach generates a basis set which is adapted to evolution of the wave function while also being as small as possible. In applications to challenging benchmark problems, namely a 4-dimensional model of photoexcited pyrazine and three different double-well tunnelling problems, we find that our new scheme enables accurate wave function propagation with basis sets which are around an order-of-magnitude smaller than our original trajectory-guided basis set methodology, highlighting the benefits of adaptive strategies for wave function propagation.

  8. NONO and RALY proteins are required for YB-1 oxaliplatin induced resistance in colon adenocarcinoma cell lines

    PubMed Central

    2011-01-01

    Background YB-1 is a multifunctional protein that affects transcription, splicing, and translation. Overexpression of YB-1 in breast cancers causes cisplatin resistance. Recent data have shown that YB-1 is also overexpress in colorectal cancer. In this study, we tested the hypothesis that YB-1 also confers oxaliplatin resistance in colorectal adenocarcinomas. Results We show for the first time that transfection of YB-1 cDNA confers oxaliplatin resistance in two colorectal cancer cell lines (SW480 and HT29 cell lines). Furthermore, we identified by mass spectrometry analyses important YB-1 interactors required for such oxaliplatin resistance in these colorectal cancer cell lines. A tagged YB-1 construct was used to identify proteins interacting directly to YB-1 in such cells. We then focused on proteins that are potentially involved in colorectal cancer progression based on the Oncomine microarray database. Genes encoding for these YB-1 interactors were also examined in the public NCBI comparative genomic hybridization database to determine whether these genes are localized to regions of chromosomes rearranged in colorectal cancer tissues. From these analyses, we obtained a list of proteins interacting with YB-1 and potentially involved in oxaliplatin resistance. Oxaliplatin dose response curves of SW480 and HT29 colorectal cancer cell lines transfected with several siRNAs corresponding to each of these YB-1 interactors were obtained to identify proteins significantly affecting oxaliplatin sensitivity upon gene silencing. Only the depletion of either NONO or RALY sensitized both colorectal cancer cell lines to oxaliplatin. Furthermore, depletion of NONO or RALY sensitized otherwise oxaliplatin resistant overexpressing YB-1 SW480 or HT29 cells. Conclusion These results suggest knocking down NONO or RALY significant counteracts oxaliplatin resistance in colorectal cancers overexpressing the YB-1 protein. PMID:22118625

  9. 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

  10. 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.

  11. Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage-gated sodium channels.

    PubMed

    Webster, Richard G; Brain, Keith L; Wilson, Richard H; Grem, Jean L; Vincent, Angela

    2005-12-01

    Oxaliplatin, an effective cytotoxic treatment in combination with 5-fluorouracil for colorectal cancer, is associated with sensory, motor and autonomic neurotoxicity. Motor symptoms include hyperexcitability while autonomic effects include urinary retention, but the cause of these side-effects is unknown. We examined the effects on motor nerve function in the mouse hemidiaphragm and on the autonomic system in the vas deferens. In the mouse diaphragm, oxaliplatin (0.5 mM) induced multiple endplate potentials (EPPs) following a single stimulus, and was associated with an increase in spontaneous miniature EPP frequency. In the vas deferens, spontaneous excitatory junction potential frequency was increased after 30 min exposure to oxaliplatin; no changes in resting Ca(2+) concentration in nerve terminal varicosities were observed, and recovery after stimuli trains was unaffected. In both tissues, an oxaliplatin-induced increase in spontaneous activity was prevented by the voltage-gated Na(+) channel blocker tetrodotoxin (TTX). Carbamazepine (0.3 mM) also prevented multiple EPPs and the increase in spontaneous activity in both tissues. In diaphragm, beta-pompilidotoxin (100 microM), which slows Na(+) channel inactivation, induced multiple EPPs similar to oxaliplatin's effect. By contrast, blockers of K(+) channels (4-aminopyridine and apamin) did not replicate oxaliplatin-induced hyperexcitability in the diaphragm. The prevention of hyperexcitability by TTX blockade implies that oxaliplatin acts on nerve conduction rather than by effecting repolarisation. The similarity between beta-pompilidotoxin and oxaliplatin suggests that alteration of voltage-gated Na(+) channel kinetics is likely to underlie the acute neurotoxic actions of oxaliplatin.

  12. The X-ray structure of the complex formed in the reaction between oxaliplatin and lysozyme.

    PubMed

    Messori, Luigi; Marzo, Tiziano; Merlino, Antonello

    2014-08-07

    The X-ray structure of the adduct formed between oxaliplatin and the model protein hen egg white lysozyme is reported here. The structure is compared with those of cisplatin and carboplatin derivatives, previously solved. Relevant changes are highlighted among these crystal structures that are suggestive of significant differences in the reactivity of platinum drugs with this protein; possible biological implications are discussed.

  13. 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

  14. 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

  15. 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

  16. 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

    2016-01-22

    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.

  17. 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.

  18. [Role of Transient Receptor Potential Channels in Paclitaxel- and Oxaliplatin-induced Peripheral Neuropathy].

    PubMed

    Taguchi, Kyoji

    2016-01-01

    Peripheral neuropathy is a common adverse effect of paclitaxel and oxaliplatin treatment. The major dose-limiting side effect of these drugs is peripheral sensory neuropathy. The symptoms of paclitaxel-induced neuropathy are mostly sensory and peripheral in nature, consisting of mechanical allodynia/hyperalgesia, tingling, and numbness. Oxaliplatin-induced neurotoxicity manifests as rapid-onset neuropathic symptoms that are exacerbated by cold exposure and as chronic neuropathy that develops after several treatment cycles. Although many basic and clinical researchers have studied anticancer drug-induced peripheral neuropathy, the mechanism is not well understood. In this review, we focus on (1) analysis of transient receptor potential vanilloid 1 (TRPV1) channel expression in the rat dorsal root ganglion (DRG) after paclitaxel treatment and (2) analysis of transient receptor potential ankyrin 1 (TRPA1) channel in the DRG after oxaliplatin treatment. This review describes that (1) paclitaxel-induced neuropathic pain may be the result of up-regulation of TRPV1 in small- and medium-diameter DRG neurons. In addition, paclitaxel treatment increases the release of substance P, but not calcitonin gene-related peptide, in the superficial layers of the spinal dorsal horn. (2) TRPA1 expression via activation of p38 mitogen-activated protein kinase in small-diameter DRG neurons, at least in part, contributes to the development of oxaliplatin-induced acute cold hyperalgesia. We suggest that TRPV1 or TRPA1 antagonists may be potential therapeutic lead compounds for treating anticancer drug-induced peripheral neuropathy.

  19. A pilot study: dose adaptation of capecitabine using mobile phone toxicity monitoring - supporting patients in their homes.

    PubMed

    Weaver, Andrew; Love, Sharon B; Larsen, Mark; Shanyinde, Milensu; Waters, Rachel; Grainger, Lisa; Shearwood, Vanessa; Brooks, Claire; Gibson, Oliver; Young, Annie M; Tarassenko, Lionel

    2014-10-01

    Real-time symptom monitoring using a mobile phone is potentially advantageous for patients receiving oral chemotherapy. We therefore conducted a pilot study of patient dose adaptation using mobile phone monitoring of specific symptoms to investigate relative dose intensity of capecitabine, level of toxicity and perceived supportive care. Patients with breast or colorectal cancer receiving capecitabine completed a symptom, temperature and dose diary twice a day using a mobile phone application. This information was encrypted and automatically transmitted in real time to a secure server, with moderate levels of toxicity automatically prompting self-care symptom management messages on the screen of the patient's mobile phone or in severe cases, a call from a specialist nurse to advise on care according to an agreed protocol. Patients (n = 26) completed the mobile phone diary on 92.6 % of occasions. Twelve patients had a maximum toxicity grade of 3 (46.2 %). The average dose intensity for all patients as a percentage of standard dose was 90 %. In eight patients, the dose of capecitabine was reduced, and in eight patients, the dose of capecitabine was increased. Patients and healthcare professionals involved felt reassured by the novel monitoring system, in particular, during out of hours. It is possible to optimise the individual dose of oral chemotherapy safely including dose increase and to manage chemotherapy side effects effectively using real-time mobile phone monitoring of toxicity parameters entered by the patient.

  20. Q-TWiST analysis of lapatinib combined with capecitabine for the treatment of metastatic breast cancer.

    PubMed

    Sherrill, B; Amonkar, M M; Stein, S; Walker, M; Geyer, C; Cameron, D

    2008-09-02

    The addition of lapatinib (Tykerb/Tyverb) to capecitabine (Xeloda) delays disease progression more effectively than capecitabine monotherapy in women with previously treated HER2+ metastatic breast cancer (MBC). The quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWiST) method was used to compare treatments. The area under survival curves was partitioned into health states: toxicity (TOX), time without symptoms of disease progression or toxicity (TWiST), and relapse period until death or end of follow-up (REL). Average times spent in each state, weighted by utility, were derived and comparisons of Q-TWiST between groups performed with varying combinations of the utility weights. Utility weights of 0.5 for both TOX and REL, that is, counting 2 days of TOX or REL as 1 day of TWiST, resulted in a 7-week difference in quality-adjusted survival favouring combination therapy (P=0.0013). The Q-TWiST difference is clinically meaningful and was statistically significant across an entire matrix of possible utility weights. Results were robust in sensitivity analyses. An analysis with utilities based on EQ-5D scores was consistent with the above findings. Combination therapy of lapatinib with capecitabine resulted in greater quality-adjusted survival than capecitabine monotherapy in trastuzumab-refractory MBC patients.

  1. Temozolomide (Temodar®) and capecitabine (Xeloda®) treatment of an aggressive corticotroph pituitary tumor.

    PubMed

    Thearle, Marie S; Freda, Pamela U; Bruce, Jeffrey N; Isaacson, Steven R; Lee, Yoomi; Fine, Robert L

    2011-12-01

    Only rarely do corticotroph pituitary tumors become invasive leading to symptoms caused by compression of cranial nerves and other local structures. When aggressive pituitary neuroendocrine tumors do develop, conventional treatment options are of limited success. A 50-year-old man developed a giant invasive corticotroph pituitary tumor 2 years after initial presentation. His tumor and symptoms failed to respond to maximal surgical, radio-surgical, radiation and medical therapy and a bilateral adrenalectomy was done. He subsequently developed rapid growth of his tumor leading to multiple cranial nerve deficits. He was administered salvage chemotherapy with capecitabine and temozolomide (CAPTEM), a novel oral chemotherapy regimen developed at our institution for treatment of neuroendocrine tumors. After two cycles of CAPTEM, his tumor markedly decreased in size and ACTH levels fell by almost 90%. Despite further decreases in ACTH levels, his tumor recurred after 5 months with increased avidity on PET scan suggesting a transformation to a more aggressive phenotype. Temozolomide had been reported to be effective against other pituitary tumors and this case adds to this literature demonstrating its use along with capecitabine (CAPTEM) against a corticotroph tumor. Further evaluation of the CAPTEM regimen in patients with pituitary neuroendocrine tumors which fail to respond to classic treatments is warranted.

  2. Preparation and Characterization of a Gastric Floating Dosage Form of Capecitabine

    PubMed Central

    Taghizadeh Davoudi, Ehsan; Ibrahim Noordin, Mohamed; Kadivar, Ali; Kamalidehghan, Behnam; Farjam, Abdoreza Soleimani; Akbari Javar, Hamid

    2013-01-01

    Gastrointestinal disturbances, such as nausea and vomiting, are considered amongst the main adverse effects associated with oral anticancer drugs due to their fast release in the gastrointestinal tract (GIT). Sustained release formulations with proper release profiles can overcome some side effects of conventional formulations. The current study was designed to prepare sustained release tablets of Capecitabine, which is approved by the Food and Drug Administration (FDA) for the treatment of advanced breast cancer, using hydroxypropyl methylcellulose (HPMC), carbomer934P, sodium alginate, and sodium bicarbonate. Tablets were prepared using the wet granulation method and characterized such that floating lag time, total floating time, hardness, friability, drug content, weight uniformity, and in vitro drug release were investigated. The sustained release tablets showed good hardness and passed the friability test. The tablets' floating lag time was determined to be 30–200 seconds, and it floated more than 24 hours and released the drug for 24 hours. Then, the stability test was done and compared with the initial samples. In conclusion, by adjusting the right ratios of the excipients including release-retarding gel-forming polymers like HPMC K4M, Na alginate, carbomer934P, and sodium bicarbonate, sustained release Capecitabine floating tablet was formulated. PMID:24288681

  3. Modified docetaxel, cisplatin and capecitabine for stage IV gastric cancer in Japanese patients: A feasibility study

    PubMed Central

    Maeda, Osamu; Matsuoka, Ayumu; Miyahara, Ryoji; Funasaka, Kohei; Hirooka, Yoshiki; Fukaya, Masahide; Nagino, Masato; Kodera, Yasuhiro; Goto, Hidemi; Ando, Yuichi

    2017-01-01

    AIM To evaluate the feasibility of chemotherapy including fluoropyrimidine, platinum and taxane with modified dosages for unresectable gastric cancer in Japanese patients. METHODS We performed a feasibility study of a modified docetaxel, cisplatin and capecitabine (DCX) regimen for stage IV gastric cancer. In particular, 30 or 40 mg/m2 of docetaxel on day 1, 60 mg/m2 of cisplatin on day 1, and 2000 mg/m2 of capecitabine for 2 wk were administered every three weeks. RESULTS Three patients were treated with modified DCX (mDCX) with 30 mg/m2 docetaxel, and five patients were treated with this regimen with 40 mg/m2 docetaxel. Grade 3 or 4 neutropenia was observed in six of the eight patients; no patients exhibited febrile neutropenia. Partial response was achieved in four of the eight patients. Three patients underwent gastrectomy, which achieved R0 resection without residual tumors in dissected lymph nodes. In one of these three patients, resected specimens revealed pathological complete response in the primary lesion and in lymph nodes. CONCLUSION mDCX was well tolerated by Japanese patients with stage IV gastric cancer. This regimen might be useful for allowing gastric cancer patients with distant lymph node metastasis to undergo conversion surgery. PMID:28246483

  4. [Validation of a questionnaire assessing patients' adherence and skill level of management for oral capecitabine treatment].

    PubMed

    Baudot, Amandine; Oriol, Mathieu; Tinquaut, Fabien; Moine, Valentin; Moriceau, Guillaume; Muron, Thierry; Pacaut, Cécile; Collard, Olivier; Jacquin, Jean-Philippe; Saban-Roche, Léa; Bosacki, Claire; Regnier-Denois, Véronique; Chauvin, Franck; Bourmaud, Aurélie

    2016-03-01

    There is a plea for the development of tools allowing the screening of fragile patients under oral chemotherapy. Such tools would identify patients with difficulties for being adherent or for having low side effects management skills. The aim of this study is to validate psychometric characteristics of a questionnaire assessing patients' adherence and skill level of management for oral capecitabine treatment. Questionnaire's psychometric validation study. Prospective monocentric cohort. Cases-simulated questionnaire was constructed, according to recommendations, from the results of a socio-anthropological study. Validation phases included: a pre-testing and a field-testing including acceptability, scale reliability and internal consistency were conducted involving experts and patients sample. Pre-testing excluded 1 item. Acceptability phase included 15 patients, who did not change any of the questions. Reliability and internal consistency were tested with 67 patients. Cancer site did not statistically influence questionnaire answers. No correlation was identify with the analyse performed for the internal consistency testing. This questionnaire has shown to be a valid tool for the assessment of the adherence and side effect management skill for patients with capecitabine treatment. It can easily be uses as a screening tool for prescribers. It can also be used as an evaluation tool for a therapeutic education programme in this field. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  5. Goshajinkigan, a traditional Japanese medicine, prevents oxaliplatin-induced acute peripheral neuropathy by suppressing functional alteration of TRP channels in rat.

    PubMed

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

    2014-01-01

    The acute peripheral neuropathy induced by oxaliplatin treatment occurs very frequently and is aggravated by exposure to cold. Goshajinkigan (GJG), a traditional Japanese (kampo) medicine, was recently shown to be effective against oxaliplatin-induced acute neuropathy. However, because the effects of GJG and its mechanism in relation to those of its ingredients and its mechanism are not well understood, we examined the effects of GJG on acute neuropathy. Further, we investigated whether GJG affects the functions and gene expressions of transient receptor potential (TRP) channels using a rat model of oxaliplatin-induced neuropathy. Administration of oxaliplatin increased withdrawal responses from cold stimulation, and GJG or calcium gluconate/magnesium sulfate significantly inhibited the oxaliplatin-induced cold hypersensitivity. Application of menthol, a TRPA1/TRPM8 agonist, or allyl isothiocyanate (AITC), a selective TRPA1 agonist, to the hind paw of oxaliplatin-treated rats enhanced the nocifensive behaviors evoked by each agonist, whereas oxaliplatin had no significant effect on nocifensive behaviors evoked by capsaicin, a TRPV1 agonist. GJG treatment reduced menthol- or AITC-evoked withdrawal responses potentiated by oxaliplatin. Furthermore, GJG suppressed the increase of TRPA1 and TRPM8 mRNA expression induced by oxaliplatin in dorsal root ganglia. These findings suggest that GJG prevented oxaliplatin-induced acute peripheral neuropathy by suppressing functional alteration of TRP channels, especially TRPA1 and TRPM8.

  6. [Clinical and electrophysiological studies of oxaliplatin-induced peripheral neuropathy].

    PubMed

    Liu, L Z; Wu, J Y; Wu, Z Y; Chen, Z H; Ling, L; Sun, B; Li, Y F; Huang, X S

    2016-04-05

    To identify the sensitive scales and the early change of nerve conduction for chronic oxaliplatin-induced peripheral neuropathy (OXLIPN), and to investigate correlation between the symptoms of acute OXLIPN and chronic OXLIPN. Between December 2014 and August 2015, 16 colorectal cancer patients confirmed by pathology, from department of Oncology, Chinese PLA General Hospital, scheduled to receive XELOX, completed the acute neurotoxic symptoms questionnaire at the end of 1 cycles and the scales of TNSc and NCI-CTC at the baseline and the end of 4 cycles. Nerve conduction studies (bilateral peroneal nerves and sural nerves) were performed in 11 patients at the baseline and the end of 4 cycles. After chemotherapy, TNSc increased 1-9 points for all cases, while NCI-CTC increased 1 point for only 9 cases, the remaining 7 cases had the same NCI-CTC score before and after chemotherapy, where TNSc increased 1-6 points. Left sural nerve a-SNAP (amplitude of sensory nerve action potential) was (15.3±5.8)μV before chemotherapy and(12.3±5.0)μV after chemotherapy. Right sural nerve a-SNAP was (17.4±8.6)μV before chemotherapy and (13.3±6.7)μV after chemotherapy. After chemotherapy, these datum were significantly reduced for left peroneal nerve distal and proximal a-CMAP (amplitude of compound muscle action potential), bilateral sural nerve a-SNAP and left sural nerve SCV (sensory conduction velocity) (P<0.05). After chemotherapy, TNSc was correlated significantly with the acute neurotoxic symptoms questionnaire (Spearman r=0.698, P=0.003). TNSc is more sensitive to the severity and changes in chronic OXLIPN than NCI-CTC. Sural nerve a-SNAP has a higher sensitivity for the early changes of nerve conduction studies in chronic OXLIPN. Patients who have more symptoms of acute OXLIPN are those who eventually develop more severe chronic OXLIPN.

  7. Obtaining a male circumcision prevalence rate of 80% among adults in a short time

    PubMed Central

    Marshall, Esaie; Rain-Taljaard, Reathe; Tsepe, Motlalepule; Monkwe, Cornelius; Taljaard, Dirk; Hlatswayo, Florence; Xaba, Dumazile; Molomo, Tebogo; Lissouba, Pascale; Puren, Adrian; Auvert, Bertran

    2017-01-01

    Abstract World Health Organization recommends a target for the male circumcision prevalence rate of 80%. This rate will have a substantial impact on the human immunodeficiency virus-acquired immunodeficiency syndrome epidemic in Eastern and Southern Africa. The objective of the study was to assess whether an innovative intervention can lead to an increased voluntary male medical circumcision (VMMC) uptake among adults in a short time. This prospective observational study of a demand generation intervention was conducted in the township of Orange Farm (South Africa) in August to November 2015. In this community male circumcision prevalence rate among adults was stable between 2010 and 2015 at 55% and 57%, despite regular VMMC campaigns at community level and the presence of a VMMC clinic that offered free VMMC. The intervention took place in a random sample of 981 households where 522 men aged 18 to 49 years accepted to participate in the study. Among the 226 uncircumcised men, 212 accepted to be enrolled in the intervention study. A personal male circumcision adviser trained in interpersonal communication skills was assigned to each uncircumcised participant. The male circumcision advisers were trained to explain the risks and benefits of VMMC, and to discuss 24 possible reasons given by men for not being circumcised. Participants were then followed for 9 weeks. Each participant had a maximum of 3 motivational interviews at home. Participants who decided to be circumcised received financial compensation for their time equivalent to 2.5 days of work at the minimum South African salary rate. Among the 212 uncircumcised men enrolled in the intervention, 69.8% (148/212; 95% confidence interval [CI]; 63.4%–75.7%) agreed to be circumcised, which defines the uptake of the intervention. The male circumcision prevalence rate of the sample increased from 56.7% (296/522) to 81.4% (425/522; 77.9%–84.6%), P < 0.001, corresponding to a relative increase of 43.6% (95% CI

  8. The short-time intramolecular dynamics of solutes in liquids. II. Vibrational population relaxation

    NASA Astrophysics Data System (ADS)

    Goodyear, Grant; Stratt, Richard M.

    1997-08-01

    Events such as the vibrational relaxation of a solute are often well described by writing an effective equation of motion—a generalized Langevin equation—which expresses the surrounding medium's influence on the intramolecular dynamics in terms of a friction and a fluctuating force acting on the solute. These quantities, though, can be obtained from the instantaneous normal modes (INMs) of the system when the relaxation takes place in a fluid, suggesting that we should be able to analyze in some detail the solvent motions driving the relaxation, at least for short times. In this paper we show that this promise can indeed be realized for the specific case of a vibrating diatomic molecule dissolved in an atomic solvent. Despite the relatively long times typical of vibrational population relaxation, it turns out that understanding the behavior of the vibrational friction at the short times appropriate to INMs (a few hundred femtoseconds) often suffices to predict T1 times. We use this observation to probe the dependence of these relaxation rates on thermodynamic conditions and to look at the molecular mechanisms underlying the process. We find that raising the temperature at any given density or raising the density at any given temperature will invariably increase the rate of energy relaxation. However, since these two trends may be in conflict in a typical constant-pressure laboratory experiment, we also find that it is possible to make sense of the "anomalous" inverted temperature dependence recently seen experimentally. We find, as well, that the INM theory—which has no explicit collisions built into it—predicts exactly the same density dependence as the venerable independent-binary-collision (IBC) theory (an intriguing result in view of recent claims that experimental observations of this kind of dependence provide support for the IBC theory). The actual mechanisms behind vibrational population relaxation are revealed by looking in detail at the

  9. Gemcitabine-Based Combination Chemotherapy Followed by Radiation With Capecitabine as Adjuvant Therapy for Resected Pancreas Cancer

    SciTech Connect

    Desai, Sameer; Ben-Josef, Edgar; Griffith, Kent A.; Simeone, Diane; Greenson, Joel K.; Francis, Isaac R.; Hampton, Janet; Colletti, Lisa; Chang, Alfred E.; Lawrence, Theodore S.; Zalupski, Mark M.

    2009-12-01

    Purpose: To report outcomes for patients with resected pancreas cancer treated with an adjuvant regimen consisting of gemcitabine-based combination chemotherapy followed by capecitabine and radiation. Patients and Methods: We performed a retrospective review of a series of patients treated at a single institution with a common postoperative adjuvant program. Between January 2002 and August 2006, 43 resected pancreas cancer patients were offered treatment consisting of 4, 21-day cycles of gemcitabine 1 g/m{sup 2} intravenously over 30 min on Days 1 and 8, with either cisplatin 35 mg/m{sup 2} intravenously on Days 1 and 8 or capecitabine 1500 mg/m{sup 2} orally in divided doses on Days 1-14. After completion of combination chemotherapy, patients received a course of radiotherapy (54 Gy) with concurrent capecitabine (1330 mg/m{sup 2} orally in divided doses) day 1 to treatment completion. Results: Forty-one patients were treated. Median progression-free survival for the entire group was 21.7 months (95% confidence interval 13.9-34.5 months), and median overall survival was 45.9 months. In multivariate analysis a postoperative CA 19-9 level of >=180 U/mL predicted relapse and death. Toxicity was mild, with only two hospitalizations during adjuvant therapy. Conclusions: A postoperative adjuvant program using combination chemotherapy with gemcitabine and either cisplatin or capecitabine followed by radiotherapy with capecitabine is tolerable and efficacious and should be considered for Phase III testing in this group of patients.

  10. Replacing 5-fluorouracil by capecitabine in localised squamous cell carcinoma of the anal canal: systematic review and meta-analysis

    PubMed Central

    Souza, Karla T; Pereira, Allan AL; Araujo, Raphael L; Oliveira, Suilane Coelho Ribeiro; Hoff, Paulo M; Riechelmann, Rachel P

    2016-01-01

    Background The standard treatment for localised squamous cell carcinoma of the anal canal (SCCAC) is chemoradiotherapy (CRT) with infusional 5-fluorouracil (5-FU) and mitomycin. Because 5-FU and capecitabine have offered similar efficacy in many phase-III trials of solid tumours, studies have tested capecitabine in this setting of SCCAC. However, these studies are small and have reported variable results. Therefore, a systematic review and meta-analysis was performed. Methods Medline, Scopus and Embase were searched for studies that evaluated the efficacy outcomes of capecitabine used as a substitute of 5-FU in the CRT of localised SCCAC. The primary endpoint was complete response rate (CRR) at 6 months. Metaprop analysis of reported CRR-based on pooled estimates of proportions with corresponding 95% confidence intervals (95%CI) were calculated on the base of the Freeman-Tukey double arcsine transformation. Results We retrieved 300 studies, of which six met our eligibility criteria. The capecitabine dose ranged from 500 mg/m2 to 825 mg/m2 BID for 5 days per week during radiation. With a total of 218 patients, the median follow-up was 21.5 months (14–23). The pooled analysis of three trials (N = 132 patients) reported a CRR at 6 months of 88% (83%–94%), considering all clinical stages. The pooled analysis of overall CRR (N = 218 patients), evaluated at different intervals, showed an overall CRR of 91% (87%–95%). Rates of locoregional relapse varied from 3.2% to 21%. The majority of patients completed the planned radiotherapy dose (93.5%–100%) and any chemotherapy interruption was reported in up to 55.8% of patients. Conclusions Capecitabine is an acceptable and more convenient alternative to infusional 5-FU in the CRT for localised SCCAC, offering similar clinical CRR to those reported by phase-III trials. PMID:28105070

  11. A Phase I study of capecitabine, carboplatin, and paclitaxel with external beam radiation therapy for esophageal carcinoma

    SciTech Connect

    Czito, Brian G. . E-mail: czito@radonc.duke.edu; Kelsey, Chris R.; Hurwitz, Herbert I.; Willett, Chris G.; Morse, Michael A.; Blobe, Gerard C.; Fernando, Nishan H.; D'Amico, Thomas A.; Harpole, David H.; Honeycutt, Wanda R.N.; Yu Daohai; Bendell, Johanna C.

    2007-03-15

    Purpose: Concurrent chemotherapy and radiation therapy (RT) are used to treat patients with esophageal cancer. The optimal combination of chemotherapeutic agents with RT is undefined. We evaluated a combination of capecitabine, carboplatin, and paclitaxel with RT in a phase I study. Methods and Materials: Patients with squamous cell carcinoma or adenocarcinoma of the esophagus initially received capecitabine, carboplatin, and paclitaxel with RT (1.8 Gy daily to 50.4 Gy). After completion, patients were restaged and evaluated for surgery. Primary endpoints included determination of dose-limiting toxicities (DLT) and a recommended phase II dose, non-DLT, and preliminary radiographic and pathologic response rates. Results: Thirteen patients were enrolled (10 men, 3 women). All were evaluable for toxicity and efficacy. Two of 3 patients at dose level 1 (capecitabine 825 mg/m{sup 2} twice daily on RT days, carboplatin area under the curve (AUC) 2 weekly, paclitaxel 60 mg/m{sup 2} weekly) had DLT (both Grade 4 esophagitis). Of these 3, 2 underwent esophagectomy and had pathologic complete response (pCR). Ten patients were then enrolled at dose level -1 (capecitabine 600 mg/m{sup 2} twice daily, carboplatin AUC 1.5, paclitaxel 45 mg/m{sup 2}). Overall, 3 of 10 patients at dose level -1 developed DLT (2 Grade 3 esophagitis, 1 Grade 3 hypotension). Esophagectomy was performed in 6 of 10 patients. All patients had pathologic downstaging and 2 of 6 had pCR. Conclusions: The maximally tolerated/recommended phase II doses were capecitabine 600 mg/m{sup 2} twice daily, carboplatin AUC 1.5 weekly, and paclitaxel 45 mg/m{sup 2} weekly with RT to 50.4 Gy. In our small study, this regimen appears active but is accompanied by significant toxicities, primarily esophagitis.

  12. Acquired resistance to oxaliplatin is not directly associated with increased resistance to DNA damage in SK-N-ASrOXALI4000, a newly established oxaliplatin-resistant sub-line of the neuroblastoma cell line SK-N-AS

    PubMed Central

    Saintas, Emily; Abrahams, Liam; Ahmad, Gulshan T.; Ajakaiye, Anu-Oluwa M.; AlHumaidi, Abdulaziz S. H. A. M.; Ashmore-Harris, Candice; Clark, Iain; Dura, Usha K.; Fixmer, Carine N.; Ike-Morris, Chinedu; Mato Prado, Mireia; Mccullough, Danielle; Mishra, Shishir; Schöler, Katia M. U.; Timur, Husne; Williamson, Maxwell D. C.; Alatsatianos, Markella; Bahsoun, Basma; Blackburn, Edith; Hogwood, Catherine E.; Lithgow, Pamela E.; Rowe, Michelle; Yiangou, Lyto; Rothweiler, Florian; Cinatl, Jindrich; Zehner, Richard; Baines, Anthony J.; Garrett, Michelle D.; Gourlay, Campbell W.; Griffin, Darren K.; Gullick, William J.; Hargreaves, Emma; Howard, Mark J.; Lloyd, Daniel R.; Rossman, Jeremy S.; Smales, C. Mark; Tsaousis, Anastasios D.; von der Haar, Tobias; Wass, Mark N.

    2017-01-01

    The formation of acquired drug resistance is a major reason for the failure of anti-cancer therapies after initial response. Here, we introduce a novel model of acquired oxaliplatin resistance, a sub-line of the non-MYCN-amplified neuroblastoma cell line SK-N-AS that was adapted to growth in the presence of 4000 ng/mL oxaliplatin (SK-N-ASrOXALI4000). SK-N-ASrOXALI4000 cells displayed enhanced chromosomal aberrations compared to SK-N-AS, as indicated by 24-chromosome fluorescence in situ hybridisation. Moreover, SK-N-ASrOXALI4000 cells were resistant not only to oxaliplatin but also to the two other commonly used anti-cancer platinum agents cisplatin and carboplatin. SK-N-ASrOXALI4000 cells exhibited a stable resistance phenotype that was not affected by culturing the cells for 10 weeks in the absence of oxaliplatin. Interestingly, SK-N-ASrOXALI4000 cells showed no cross resistance to gemcitabine and increased sensitivity to doxorubicin and UVC radiation, alternative treatments that like platinum drugs target DNA integrity. Notably, UVC-induced DNA damage is thought to be predominantly repaired by nucleotide excision repair and nucleotide excision repair has been described as the main oxaliplatin-induced DNA damage repair system. SK-N-ASrOXALI4000 cells were also more sensitive to lysis by influenza A virus, a candidate for oncolytic therapy, than SK-N-AS cells. In conclusion, we introduce a novel oxaliplatin resistance model. The oxaliplatin resistance mechanisms in SK-N-ASrOXALI4000 cells appear to be complex and not to directly depend on enhanced DNA repair capacity. Models of oxaliplatin resistance are of particular relevance since research on platinum drugs has so far predominantly focused on cisplatin and carboplatin. PMID:28192521

  13. Acquired resistance to oxaliplatin is not directly associated with increased resistance to DNA damage in SK-N-ASrOXALI4000, a newly established oxaliplatin-resistant sub-line of the neuroblastoma cell line SK-N-AS.

    PubMed

    Saintas, Emily; Abrahams, Liam; Ahmad, Gulshan T; Ajakaiye, Anu-Oluwa M; AlHumaidi, Abdulaziz S H A M; Ashmore-Harris, Candice; Clark, Iain; Dura, Usha K; Fixmer, Carine N; Ike-Morris, Chinedu; Mato Prado, Mireia; Mccullough, Danielle; Mishra, Shishir; Schöler, Katia M U; Timur, Husne; Williamson, Maxwell D C; Alatsatianos, Markella; Bahsoun, Basma; Blackburn, Edith; Hogwood, Catherine E; Lithgow, Pamela E; Rowe, Michelle; Yiangou, Lyto; Rothweiler, Florian; Cinatl, Jindrich; Zehner, Richard; Baines, Anthony J; Garrett, Michelle D; Gourlay, Campbell W; Griffin, Darren K; Gullick, William J; Hargreaves, Emma; Howard, Mark J; Lloyd, Daniel R; Rossman, Jeremy S; Smales, C Mark; Tsaousis, Anastasios D; von der Haar, Tobias; Wass, Mark N; Michaelis, Martin

    2017-01-01

    The formation of acquired drug resistance is a major reason for the failure of anti-cancer therapies after initial response. Here, we introduce a novel model of acquired oxaliplatin resistance, a sub-line of the non-MYCN-amplified neuroblastoma cell line SK-N-AS that was adapted to growth in the presence of 4000 ng/mL oxaliplatin (SK-N-ASrOXALI4000). SK-N-ASrOXALI4000 cells displayed enhanced chromosomal aberrations compared to SK-N-AS, as indicated by 24-chromosome fluorescence in situ hybridisation. Moreover, SK-N-ASrOXALI4000 cells were resistant not only to oxaliplatin but also to the two other commonly used anti-cancer platinum agents cisplatin and carboplatin. SK-N-ASrOXALI4000 cells exhibited a stable resistance phenotype that was not affected by culturing the cells for 10 weeks in the absence of oxaliplatin. Interestingly, SK-N-ASrOXALI4000 cells showed no cross resistance to gemcitabine and increased sensitivity to doxorubicin and UVC radiation, alternative treatments that like platinum drugs target DNA integrity. Notably, UVC-induced DNA damage is thought to be predominantly repaired by nucleotide excision repair and nucleotide excision repair has been described as the main oxaliplatin-induced DNA damage repair system. SK-N-ASrOXALI4000 cells were also more sensitive to lysis by influenza A virus, a candidate for oncolytic therapy, than SK-N-AS cells. In conclusion, we introduce a novel oxaliplatin resistance model. The oxaliplatin resistance mechanisms in SK-N-ASrOXALI4000 cells appear to be complex and not to directly depend on enhanced DNA repair capacity. Models of oxaliplatin resistance are of particular relevance since research on platinum drugs has so far predominantly focused on cisplatin and carboplatin.

  14. Predictive performance of the Short Time Exposure test for identifying eye irritation potential of chemical mixtures.

    PubMed

    Saito, Kazutoshi; Miyazawa, Masaaki; Nukada, Yuko; Ei, Kyo; Abo, Takayuki; Sakaguchi, Hitoshi

    2015-04-01

    The Short Time Exposure (STE) test is an in vitro eye irritation test based on the cytotoxicity in SIRC cells (rabbit corneal cell line) following a 5 min treatment of chemicals. This study evaluated the predictive performance of the STE test to identify the globally harmonized system (GHS) Not Classified category and other irritant categories (i.e., GHS Category 1 or 2) when used to test 40 chemical mixtures that included irritants. The STE test correctly identified 30 tested mixtures classified as GHS irritant categories and 5 out of 10 tested mixtures classified as GHS Not Classified. The sensitivity, specificity, positive predictivity, negative predictivity, and overall accuracy of the STE test were 100% (30/30), 50% (5/10), 86% (25/30), 100% (5/5), and 88% (35/40), respectively. These predictive performances were comparative to or greater than those in other in vitro eye irritation tests that have been accepted as test guideline by the Organisation for Economic Co-operation and Development. This suggests that the STE test has sufficient predictivity for identifying the eye irritation potential of chemical mixtures. Since no false negatives in this study were found, this indicates that the STE test is applicable as a part of the bottom-up approach. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. [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.

  16. Mechanical Properties, Short Time Creep, and Fatigue of an Austenitic Steel

    PubMed Central

    Brnic, Josip; Turkalj, Goran; Canadija, Marko; Lanc, Domagoj; Krscanski, Sanjin; Brcic, Marino; Li, Qiang; Niu, Jitai

    2016-01-01

    The correct choice of a material in the process of structural design is the most important task. This study deals with determining and analyzing the mechanical properties of the material, and the material resistance to short-time creep and fatigue. The material under consideration in this investigation is austenitic stainless steel X6CrNiTi18-10. The results presenting ultimate tensile strength and 0.2 offset yield strength at room and elevated temperatures are displayed in the form of engineering stress-strain diagrams. Besides, the creep behavior of the steel is presented in the form of creep curves. The material is consequently considered to be creep resistant at temperatures of 400 °C and 500 °C when subjected to a stress which is less than 0.9 of the yield strength at the mentioned temperatures. Even when the applied stress at a temperature of 600 °C is less than 0.5 of the yield strength, the steel may be considered as resistant to creep. Cyclic tensile fatigue tests were carried out at stress ratio R = 0.25 using a servo-pulser machine and the results were recorded. The analysis shows that the stress level of 434.33 MPa can be adopted as a fatigue limit. The impact energy was also determined and the fracture toughness assessed. PMID:28773424

  17. Mechanical Properties, Short Time Creep, and Fatigue of an Austenitic Steel.

    PubMed

    Brnic, Josip; Turkalj, Goran; Canadija, Marko; Lanc, Domagoj; Krscanski, Sanjin; Brcic, Marino; Li, Qiang; Niu, Jitai

    2016-04-20

    The correct choice of a material in the process of structural design is the most important task. This study deals with determining and analyzing the mechanical properties of the material, and the material resistance to short-time creep and fatigue. The material under consideration in this investigation is austenitic stainless steel X6CrNiTi18-10. The results presenting ultimate tensile strength and 0.2 offset yield strength at room and elevated temperatures are displayed in the form of engineering stress-strain diagrams. Besides, the creep behavior of the steel is presented in the form of creep curves. The material is consequently considered to be creep resistant at temperatures of 400 °C and 500 °C when subjected to a stress which is less than 0.9 of the yield strength at the mentioned temperatures. Even when the applied stress at a temperature of 600 °C is less than 0.5 of the yield strength, the steel may be considered as resistant to creep. Cyclic tensile fatigue tests were carried out at stress ratio R = 0.25 using a servo-pulser machine and the results were recorded. The analysis shows that the stress level of 434.33 MPa can be adopted as a fatigue limit. The impact energy was also determined and the fracture toughness assessed.

  18. Short-time diffusion in concentrated bidisperse hard-sphere suspensions.

    PubMed

    Wang, Mu; Heinen, Marco; Brady, John F

    2015-02-14

    Diffusion in bidisperse Brownian hard-sphere suspensions is studied by Stokesian Dynamics (SD) computer simulations and a semi-analytical theoretical scheme for colloidal short-time dynamics, based on Beenakker and Mazur's method [Physica A 120, 388-410 (1983); 126, 349-370 (1984)]. Two species of hard spheres are suspended in an overdamped viscous solvent that mediates the salient hydrodynamic interactions among all particles. In a comprehensive parameter scan that covers various packing fractions and suspension compositions, we employ numerically accurate SD simulations to compute the initial diffusive relaxation of density modulations at the Brownian time scale, quantified by the partial hydrodynamic functions. A revised version of Beenakker and Mazur's δγ-scheme for monodisperse suspensions is found to exhibit surprisingly good accuracy, when simple rescaling laws are invoked in its application to mixtures. The so-modified δγ scheme predicts hydrodynamic functions in very good agreement with our SD simulation results, for all densities from the very dilute limit up to packing fractions as high as 40%.

  19. 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.

  20. Zipf's law in short-time timbral codings of speech, music, and environmental sound signals.

    PubMed

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

    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.

  1. Estimation of ultrasound attenuation and dispersion using short time Fourier transform.

    PubMed

    Zhao, B; Basir, O A; Mittal, G S

    2005-03-01

    Determination of the acoustic attenuation and dispersion has important applications in ultrasound tissue characterization and non-destructive material testing. Current signal processing methods Fourier transform of ultrasound signals to get the spectra of amplitude and phase to estimate respectively the attenuation and dispersion of a given medium. These methods are frequency domain method and obsessed with ambiguity issue in the phase unwrapping calculation. Conventional ultrasound velocity measuring method detects the time of arrival of a pulse (or echo) signal, which is a time domain method to compute group velocity (not phase velocity). This paper presents a novel approach based on the short time Fourier transform (STFT)--a time-frequency analysis, to estimate the ultrasonic dispersion and attenuation. Only the amplitude information of the pulse-signal spectra is used. Based on the time-frequency presentation, the attenuation coefficient of the signal is obtained by computing the amplitude decay of pulse spectrum in time domain, while phase velocities are obtained based on the "time-of-flight" (TOF) of the mono frequency component of the pulse signals. As a result, we eliminate the ambiguity issue in phase angle calculation. Furthermore, the proposed method makes the phase velocity pedagogically intuitive for novice users. The paper presents experiments to evaluate demonstrate the performance of the proposed method.

  2. 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.

  3. Estimation of short-time cross-correlation between frequency bands of event related EEG.

    PubMed

    Zygierewicz, J; Mazurkiewicz, J; Durka, P J; Franaszczuk, P J; Crone, N E

    2006-10-30

    Simultaneous variations of the event-related power changes (ERD/ERS) are often observed in a number of frequency bands. ERD/ERS measures are usually based on the relative changes of power in a given single frequency band. Within such an approach one cannot answer questions concerning the mutual relations between the band-power variations observed in different frequency bands. This paper addresses the problem of estimating and assessing the significance of the average cross-correlation between ERD/ERS phenomena occurring in two frequency bands. The cross-correlation function in a natural way also provides estimation of the delay between ERD/ERS in those bands. The proposed method is based on estimating the short-time cross-correlation function between relative changes of power in two selected frequency bands. The cross-correlation function is estimated in each trial separately and then averaged across trials. The significance of those mean cross-correlation functions is evaluated by means of a nonparametric test. The basic properties of the method are presented on simulated signals, and an example application to real EEG and ECoG signals is given.

  4. On decoding the responses of a population of neurons from short time windows.

    PubMed

    Panzeri, S; Treves, A; Schultz, S; Rolls, E T

    1999-10-01

    The effectiveness of various stimulus identification (decoding) procedures for extracting the information carried by the responses of a population of neurons to a set of repeatedly presented stimuli is studied analytically, in the limit of short time windows. It is shown that in this limit, the entire information content of the responses can sometimes be decoded, and when this is not the case, the lost information is quantified. In particular, the mutual information extracted by taking into account only the most likely stimulus in each trial turns out to be, if not equal, much closer to the true value than that calculated from all the probabilities that each of the possible stimuli in the set was the actual one. The relation between the mutual information extracted by decoding and the percentage of correct stimulus decodings is also derived analytically in the same limit, showing that the metric content index can be estimated reliably from a few cells recorded from brief periods. Computer simulations as well as the activity of real neurons recorded in the primate hippocampus serve to confirm these results and illustrate the utility and limitations of the approach.

  5. Endocrine and cognitive effects of short-time soybean consumption in women.

    PubMed

    Celec, Peter; Ostatníková, Daniela; Cagánová, Marieta; Zuchová, Svetlana; Hodosy, Július; Putz, Zdenek; Bernadic, Marián; Kúdela, Matús

    2005-01-01

    Soy phytoestrogens are known to influence the hormonal status acting as partial estrogen agonists. Soy-derived food supplements are advised for hormone replacement therapy, prevention of atherosclerosis, age-related cognitive decline and even hormone-dependent cancer, although results from clinical studies are controversial. Whether increased soybean intake can affect the endocrine status and cognitive abilities is largely unknown. To observe the effects of 1 week of increased soybean intake on sex hormone levels and spatial cognitive abilities in women. 16 young healthy female volunteers were asked to eat 900 g of soybeans within 1 week. Salivary testosterone (T), free and total plasma T, salivary and plasma estradiol (E) were measured by radioimmunoassay before and after the study period. Mental rotation (MR) and spatial visualization (SV) psychological tests were done at the days of sampling. Soybean intake increased total plasma T levels (p < 0.02) while decreasing salivary T (p < 0.01) and not altering free plasma T levels. Salivary and plasma E levels were not changed. The results of MR and SV tests were improved after the study period. Short-time increased soybean intake alters the level of total plasma and salivary T and improves spatial cognition in women. Whether this effect is mediated by modulation of estrogen receptors, changes in sex hormone-binding globulin production or changes in activity of steroid-competent enzymes needs further study. Copyright 2005 S. Karger AG, Basel.

  6. Short-time hydrothermal synthesis and delamination of ion exchangeable Mg/Ga layered double hydroxides

    SciTech Connect

    Unal, Ugur

    2007-09-15

    The hydrothermal synthesis of magnesium-gallium layered double hydroxides (Mg/Ga LDHs) was studied under static and agitated conditions. Not only well-crystallized and large-sized Mg/Ga LDHs having hexagonal morphology were obtained but also the reaction time was comparatively decreased from 24 to 2 h by means of agitation during hydrothermal synthesis. In static conditions, mainly GaOOH and magnesite phases were formed. The elemental analysis results show that the final Mg/Ga ratio is significantly different from the initial ratio. The reason was attributed to the difference in the hydrolytic behavior of Mg{sup 2+} and Ga{sup 3+}. Furthermore, the anion exchange studies with glycine, dodecyl sulfate, ferrocyanide and ferricyanide were performed to investigate the intercalation behavior of the anions into Mg/Ga LDHs. In addition, delamination of Mg/Ga LDHs was performed in formamide for the glycine exchanged forms. Large size of nanosheets thus obtained can be utilized in the fabrication of functional thin films. - Graphical abstract: Hydrothermal synthesis under agitation resulted in highly crystalline Mg/Ga LDHs slabs in a short time. The LDHs slabs were delaminated into two-dimensional nanosize sheets.

  7. Effective description of the short-time dynamics in open quantum systems

    NASA Astrophysics Data System (ADS)

    Rossi, Matteo A. C.; Foti, Caterina; Cuccoli, Alessandro; Trapani, Jacopo; Verrucchi, Paola; Paris, Matteo G. A.

    2017-09-01

    We address the dynamics of a bosonic system coupled to either a bosonic or a magnetic environment and derive a set of sufficient conditions that allow one to describe the dynamics in terms of the effective interaction with a classical fluctuating field. We find that for short interaction times the dynamics of the open system is described by a Gaussian noise map for several different interaction models and independently on the temperature of the environment. In order to go beyond a qualitative understanding of the origin and physical meaning of the above short-time constraint, we take a general viewpoint and, based on an algebraic approach, suggest that any quantum environment can be described by classical fields whenever global symmetries lead to the definition of environmental operators that remain well defined when increasing the size, i.e., the number of dynamical variables, of the environment. In the case of the bosonic environment this statement is exactly demonstrated via a constructive procedure that explicitly shows why a large number of environmental dynamical variables and, necessarily, global symmetries, entail the set of conditions derived in the first part of the work.

  8. 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.

  9. Magnetic Reconnection Sites Observed by the Cluster Spacecraft: Measurement of Short time scale electron effects

    NASA Astrophysics Data System (ADS)

    Buckley, A. M.; Carozzi, T. C.; Gough, M. P.; Chambers, E. C.

    Several events have been observed by the Cluster spacecraft passing close to magnetic reconnection sites in the tail and magnetopause when the fleet configuration is at short spatial scale (spacecraft separation approximately 100 km). These events are studied in the context of corresponding short time scale electron behaviour which contribute to and result from the reconnection process. This is done primarily using Particle Correlator data from the DWP instruments on Cluster in conjunction with other data sets. The particle correlators use captured time series of electron particle counts accumulated in 12 microsecond time bins measured over the energy range of the PEACE HEEA sensor (40 eV to 26 KeV) and on which an auto-correlation is performed. The phenomena studied concerns beam properties, electron acceleration, interaction with waves and any indications of the electron diffusion processes that are occurring. These phenomena are quantified using measures of the strength of particle-particle interactions (general second order statistics on the electrons) and the Index of Dispersion (variance to mean ratio) indicating bunching or scattering processes.

  10. Multifractals embedded in short time series: An unbiased estimation of probability moment

    NASA Astrophysics Data System (ADS)

    Qiu, Lu; Yang, Tianguang; Yin, Yanhua; Gu, Changgui; Yang, Huijie

    2016-12-01

    An exact estimation of probability moments is the base for several essential concepts, such as the multifractals, the Tsallis entropy, and the transfer entropy. By means of approximation theory we propose a new method called factorial-moment-based estimation of probability moments. Theoretical prediction and computational results show that it can provide us an unbiased estimation of the probability moments of continuous order. Calculations on probability redistribution model verify that it can extract exactly multifractal behaviors from several hundred recordings. Its powerfulness in monitoring evolution of scaling behaviors is exemplified by two empirical cases, i.e., the gait time series for fast, normal, and slow trials of a healthy volunteer, and the closing price series for Shanghai stock market. By using short time series with several hundred lengths, a comparison with the well-established tools displays significant advantages of its performance over the other methods. The factorial-moment-based estimation can evaluate correctly the scaling behaviors in a scale range about three generations wider than the multifractal detrended fluctuation analysis and the basic estimation. The estimation of partition function given by the wavelet transform modulus maxima has unacceptable fluctuations. Besides the scaling invariance focused in the present paper, the proposed factorial moment of continuous order can find its various uses, such as finding nonextensive behaviors of a complex system and reconstructing the causality relationship network between elements of a complex system.

  11. 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.

  12. 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.

  13. 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

  14. The wide-angle equation and its solution through the short-time iterative Lanczos method.

    PubMed

    Campos-Martínez, José; Coalson, Rob D

    2003-03-20

    Properties of the wide-angle equation (WAEQ), a nonparaxial scalar wave equation used to propagate light through media characterized by inhomogeneous refractive-index profiles, are studied. In particular, it is shown that the WAEQ is not equivalent to the more complicated but more fundamental Helmholtz equation (HEQ) when the index of refraction profile depends on the position along the propagation axis. This includes all nonstraight waveguides. To study the quality of the WAEQ approximation, we present a novel method for computing solutions to the WAEQ. This method, based on a short-time iterative Lanczos (SIL) algorithm, can be applied directly to the full three-dimensional case, i.e., systems consisting of the propagation axis coordinate and two transverse coordinates. Furthermore, the SIL method avoids series-expansion procedures (e.g., Padé approximants) and thus convergence problems associated with such procedures. Detailed comparisons of solutions to the HEQ, WAEQ, and the paraxial equation (PEQ) are presented for two cases in which numerically exact solutions to the HEQ can be obtained by independent analysis, namely, (i) propagation in a uniform dielectric medium and (ii) propagation along a straight waveguide that has been tilted at an angle to the propagation axis. The quality of WAEQ and PEQ, compared with exact HEQ results, is investigated. Cases are found for which the WAEQ actually performs worse than the PEQ.

  15. Oxaliplatin scale and National Cancer Institute-Common Toxicity Criteria in the assessment of chemotherapy-induced peripheral neuropathy.

    PubMed

    Kautio, Anna-Liisa; Haanpää, Maija; Kautiainen, Hannu; Leminen, Arto; Kalso, Eija; Saarto, Tiina

    2011-10-01

    The aim of the study was to compare two different neurotoxicity scales in grading chemotherapy-induced neurotoxicity. The study sample consisted of 114 cancer patients who started chemotherapy with vinca alcaloids, platinum derivatives or taxanes. Neurotoxicity was evaluated with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) and oxaliplatin scales at baseline and after every third chemotherapy cycle thereafter. Neuropathy was detected in 60%, 55% and 75% at the second, third and fourth visits, respectively, with the NCI-CTC sensory scale and 59%, 55% and 80% with the oxalipalatin scale. Of the patients with grade 3-4 toxicity on the oxaliplatin scale, 23/53 had grade 1, 18/53 had grade 2 and 12/53 had grade 3 neurotoxicity on the NCI-CTC sensory scale. The oxaliplatin and NCI-CTC sensory scales were comparable in identifying chemotherapy-induced neuropathy, but the oxaliplatin scale more often detected the progression of the symptoms.

  16. The short-time spectrum analysis of real-time sampling speech with DSP TMS320VC5416 chip

    NASA Astrophysics Data System (ADS)

    Fan, Qinru; Ren, Wen-hua

    2013-07-01

    For automatic speech recognition (ASR), the research centers mainly on algorithm of improving robust, researchers put less emphasis on realization and application of better speech algorithm. Real-time proceeding of speech recognition directly influence on its application, so real-time proceeding of speech recognition is as important as study of algorithm. Speech transform domain method is a necessary technique of speech recognition, so real-time analysis of transform domain method is necessary. In transform domain methods, the short-time spectrum analysis is simple and easy to realize, especially the short-time FFT algorithm is applied to the short-time spectrum analysis. FFT algorithm reduces multiplications greatly. For the purpose, this paper presents short-time spectrum analysis of real-time sampling speech based on FFT algorithm. We use DSP TMS320VC5416 chip and speech codec ASIC TLV320AIC23 as hardware, the real-time speech signal is acquired by ASIC TLV320AIC23. When working frequency of TMS320VC5416 is set 160 MHz and sampling frequency is 44.1 kHz, the short-time FFT is radix-2 DIF-FFT algorithm and the length of short-time window is 128, the simulation waves and data show that the short-time FFT algorithm analysis based on TMS320VC5416 chip can meet real-time of system. For estimation of proceeding error, we make a calculation of radix- 2 DIT-IFFT. Comparing the result of DIT-IFFT and sampling speech data, error is less than 10-3.

  17. Systematic review and meta-analysis of preoperative chemoradiotherapy with or without oxaliplatin in locally advanced rectal cancer

    PubMed Central

    Zheng, Jiabin; Feng, Xingyu; Hu, Weixian; Wang, Junjiang; Li, Yong

    2017-01-01

    Abstract Background: Preoperative chemoradiotherapy has become the current standard regimen for locally advanced rectal cancer (LARC). However, the additional benefit of oxaliplatin to preoperative chemotherapy was still controversial. On one hand, oxaliplatin may improve the tumor response rate of even prolong the survival time. On the other hand, it can bring a series of adverse effects. Opinions vary from studies to studies. We aim to perform a meta-analysis to evaluate the efficacy, safety, and long-term survival of oxaliplatin in preoperative chemoradiotherapy for LARC. Method: To identify clinical trials fusing oxaliplatin in preoperative chemoradiotherapy for LARC published until December 2015, we searched PubMed, the Cochrane Library, and the Springer Link databases by combining various key words. We also search for relevant ASCO conferences. Data were extracted from every study to perform a meta-analysis using STATA 12.0 software. Result: Eleven articles or ASCO abstracts from 8 studies with a total of 5597 patients were included. Adding oxaliplatin to preoperative chemoradiotherapy can significantly improve the ypCR rate [risk ratio (RR) = 1.208, 95% confidence interval (95% CI): 1.070–1.364, P = 0.002, I2 = 14.5%], and decrease the preoperative metastasis (RR = 0.494, 95% CI: 0.256–0.954, P = 0.036, I2 = 53.9%) and local recurrence rate (RR = 0.761, 95% CI: 0.616–0.941, P = 0.012, I2 = 26.1%). What's more, oxaliplatin can prolong the disease-free survival (DFS) [hazard ratio (HR) = 0.867, 95% CI: 0.741–0.992, P = 0.000, I2 = 16.3%]. However, oxaliplatin can increase the chemoradiotherapy-related toxicities (RR = 1.858, 95% CI 1.427–2.419, P = 0.000, I2 = 84.7%). There was no significant difference between the groups with and without oxaliplatin in operation rate, R0 resection rate, sphincter preservation rate, permanent stoma rate, postoperative complication, mortality, and overall

  18. SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma

    PubMed Central

    Ben-Josef, Edgar; Guthrie, Katherine A.; El-Khoueiry, Anthony B.; Corless, Christopher L.; Zalupski, Mark M.; Lowy, Andrew M.; Thomas, Charles R.; Alberts, Steven R.; Dawson, Laura A.; Micetich, Kenneth C.; Thomas, Melanie B.; Siegel, Abby B.; Blanke, Charles D.

    2015-01-01

    Purpose The role of postoperative therapy in extrahepatic cholangiocarcinoma (EHCC) or gallbladder carcinoma (GBCA) is unknown. S0809 was designed to estimate 2-year survival (overall and after R0 or R1 resection), pattern of relapse, and toxicity in patients treated with this adjuvant regimen. Patients and Methods Eligibility criteria included diagnosis of EHCC or GBCA after radical resection, stage pT2-4 or N+ or positive resection margins, M0, and performance status 0 to 1. Patients received four cycles of gemcitabine (1,000 mg/m2 intravenously on days 1 and 8) and capecitabine (1,500 mg/m2 per day on days 1 to 14) every 21 days followed by concurrent capecitabine (1,330 mg/m2 per day) and radiotherapy (45 Gy to regional lymphatics; 54 to 59.4 Gy to tumor bed). With 80 evaluable patients, results would be promising if 2-year survival 95% CI were > 45% and R0 and R1 survival estimates were ≥ 65% and 45%, respectively. Results A total of 79 eligible patients (R0, n = 54; R1, n = 25; EHCC, 68%; GBCA, 32%) were treated (86% completed). For all patients, 2-year survival was 65% (95% CI, 53% to 74%); it was 67% and 60% in R0 and R1 patients, respectively. Median overall survival was 35 months (R0, 34 months; R1, 35 months). Local, distant, and combined relapse occurred in 14, 24, and nine patients. Grade 3 and 4 adverse effects were observed in 52% and 11% of patients, respectively. The most common grade 3 to 4 adverse effects were neutropenia (44%), hand-foot syndrome (11%), diarrhea (8%), lymphopenia (8%), and leukopenia (6%). There was one death resulting from GI hemorrhage. Conclusion This combination was well tolerated, has promising efficacy, and provides clinicians with a well-supported regimen. Our trial establishes the feasibility of conducting national adjuvant trials in EHCC and GBCA and provides baseline data for planning future phase III trials. PMID:25964250

  19. Oxaliplatin-induced neurotoxicity is mediated through gap junction channels and hemichannels and can be prevented by octanol.

    PubMed

    Kagiava, Alexia; Theophilidis, George; Sargiannidou, Irene; Kyriacou, Kyriacos; Kleopa, Kleopas A

    2015-10-01

    Oxaliplatin-induced neurotoxicity (OIN) is a common complication of chemotherapy without effective treatment. In order to clarify the mechanisms of both acute and chronic OIN, we used an ex-vivo mouse sciatic nerve model. Exposure to 25 μM oxaliplatin caused a marked prolongation in the duration of the nerve evoked compound action potential (CAP) by nearly 1200% within 300 min while amplitude remained constant for over 20 h. This oxaliplatin effect was almost completely reversed by the gap junction (GJ) inhibitor octanol in a concentration-dependent manner. Further GJ blockers showed similar effects although with a narrower therapeutic window. To clarify the target molecule we studied sciatic nerves from connexin32 (Cx32) and Cx29 knockout (KO) mice. The oxaliplatin effect and neuroprotection by octanol partially persisted in Cx29 better than in Cx32 KO nerves, suggesting that oxaliplatin affects both, but Cx32 GJ channels more than Cx29 hemichannels. Oxaliplatin also accelerated neurobiotin uptake in HeLa cells expressing the human ortholog of Cx29, Cx31.3, as well as dye transfer between cells expressing the human Cx32, and this effect was blocked by octanol. Oxaliplatin caused no morphological changes initially (up to 3 h of exposure), but prolonged nerve exposure caused juxtaparonodal axonal edema, which was prevented by octanol. Our study indicates that oxaliplatin causes forced opening of Cx32 channels and Cx29 hemichannels in peripheral myelinated fibers leading to disruption of axonal K(+) homeostasis. The GJ blocker octanol prevents OIN at very low concentrations and should be further studied as a neuroprotectant.

  20. Preoperative Capecitabine and Pelvic Radiation in Locally Advanced Rectal Cancer-Is it Equivalent to 5-FU Infusion Plus Leucovorin and Radiotherapy?

    SciTech Connect

    Chan, Alexander K.; Wong, Alfred O.; Jenken, Daryl A.

    2010-04-15

    Purpose: The aim of this retrospective case-matching study was to compare the treatment outcomes and acute toxicity of preoperative radiotherapy (RT) with capecitabine vs. preoperative RT with intermittent 5-fluorouracil (5-FU) infusion, leucovorin, and mitomycin C in rectal cancer. Methods and Materials: We matched 34 patients who were treated with preoperative concurrent capecitabine and 50 Gy of RT by their clinical T stage (T3 or T4) and the tumor location (<=7 cm or >7 cm from the anal verge) with another 68 patients who were treated with preoperative intermittent 5-FU infusion, leucovorin, mitomycin C, and 50 Gy of RT for a comparison of the pathologic tumor response, local control, distant failure, and survival rates. Results: The pathologic complete response rate was 21% with capecitabine and 18% with 5-FU and leucovorin (p = 0.72). The rate of T downstaging after chemoradiation was 59% for both groups. The rate of sphincter-sparing resection was 38% after capecitabine plus RT and 43% after 5-FU plus RT (p = 0.67). At 3 years, there was no significant difference in the local control rate (93% for capecitabine and 92% for 5-FU and leucovorin), relapse-free rate (74% for capecitabine and 73% for 5-FU and leucovorin), or disease-specific survival rate (86% for capecitabine and 77% for 5-FU and leucovorin). The acute toxicity profile was comparable, with little Grade 3 and 4 toxicity. Conclusions: When administered with concurrent preoperative RT, both capecitabine and intermittent 5-FU infusion with leucovorin modulation provided comparable pathologic tumor response, local control, relapse-free survival, and disease-specific survival rates in rectal cancer.

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

    PubMed Central

    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

  2. Antitumor effects of FP3 in combination with capecitabine on PDTT xenograft models of primary colon carcinoma and related lymphatic and hepatic metastases.

    PubMed

    Jin, Ketao; Lan, Huanrong; Xie, Bojian; He, Kuifeng; Xu, Zhenzhen; Li, Guangliang; Han, Na; Teng, Lisong; Cao, Feilin

    2012-07-01

    FP3 is an engineered protein which contains the extracellular domain 2 of VEGF receptor 1 (Flt-1) and extracellular domain 3 and 4 of VEGF receptor 2 (Flk-1, KDR) fused to the Fc portion of human immunoglobulin G 1. Previous studies demonstrated its antiangiogenic effects in vitro and in vivo, and its antitumor activity in vivo. In this study, patient-derived tumor tissue (PDTT) xenograft models of primary colon carcinoma and lymphatic and hepatic metastases were established for assessment of the antitumor activity of FP3 in combination with capecitabine. Xenografts were treated with FP3, capecitabine, alone or in combination. After tumor growth was confirmed, volume and microvessel density in tumors were evaluated. Levels of VEGF, and PCNA in the tumor were examined by immunohistonchamical staining, level of thymidine phosphorylase (TP) was examined by ELISA, and levels of related cell signaling pathways proteins expression were examined by western blotting. FP3 in combination with capecitabine showed significant antitumor activity in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis). The microvessel density in tumor tissues treated with FP3 in combination with capecitabine was lower than that of the control. Antitumor activity of FP3 in combination with capecitabine was significantly higher than that of each agent alone in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis). This study indicated that addition of FP3 to capecitabine significantly improved tumor growth inhibition in the PDTT xenograft models of primary colon carcinoma and lymphatic and hepatic metastases.

  3. Oxaliplatin induces different cellular and molecular chemoresistance patterns in colorectal cancer cell lines of identical origins

    PubMed Central

    2013-01-01

    Background Cancer cells frequently adopt cellular and molecular alterations and acquire resistance to cytostatic drugs. Chemotherapy with oxaliplatin is among the leading treatments for colorectal cancer with a response rate of 50%, inducing intrastrand cross-links on the DNA. Despite of this drug’s efficiency, resistance develops in nearly all metastatic patients. Chemoresistance being of crucial importance for the drug’s clinical efficiency this study aimed to contribute to the identification and description of some cellular and molecular alterations induced by prolonged oxaliplatin therapy. Resistance to oxaliplatin was induced in Colo320 (Colo320R) and HT-29 (HT-29R) colorectal adenocarcinoma cell lines by exposing the cells to increasing concentrations of the drug. Alterations in morphology, cytotoxicity, DNA cross-links formation and gene expression profiles were assessed in the parental and resistant variants with microscopy, MTT, alkaline comet and pangenomic microarray assays, respectively. Results Morphology analysis revealed epithelial-to-mesenchymal transition in the resistant vs parental cells suggesting alterations of the cells’ adhesion complexes, through which they acquire increased invasiveness and adherence. Cytotoxicity measurements demonstrated resistance to oxaliplatin in both cell lines; Colo320 being more sensitive than HT-29 to this drug (P < 0.001). The treatment with oxaliplatin caused major DNA cross-links in both parental cell lines; in Colo320R small amounts of DNA cross-links were still detectable, while in HT-29R not. We identified 441 differentially expressed genes in Colo320R and 613 in HT-29R as compared to their parental counterparts (at least 1.5 -fold up- or down- regulation, p < 0.05). More disrupted functions and pathways were detected in HT-29R cell line than in Colo320R, involving genes responsible for apoptosis inhibition, cellular proliferation and epithelial-to-mesenchymal transition. Several upstream

  4. Long and short time variations of the Na/K ratio in the exosphere of Mercury.

    NASA Astrophysics Data System (ADS)

    Mura, Alessandro; Lammer, Helmut; Wurz, Peter; Orsini, Stefano; Milillo, Anna; Mangano, Valeria; Lichtenegger, Herbert; Scherf, Manuel; Khodachenko, Maxim; Pfleger, Martin

    2014-05-01

    Here we present the results of our model for the short-time and yearly variations of the Sodium and Potassium exosphere of Mercury. Such surface-bounded exosphere is produced by release processes occurring at the planetary surface, such as ion sputtering, thermal- or photon-stimulated desorption. The amount of surface Sodium or Potassium that is available for release, however, is limited. Those release processes deplete the surface in Na and K, which is continuously refilled by diffusion from the interior of regolith grains or by chemical sputtering. Ejected particles may either escape the gravity field, assisted by the radiation pressure acceleration, or be photoionized, or fall back onto the surface. Falling particles will stick to the surface. A Montecarlo model, simulating all these processes, is used to obtain the exosphere densities and the Na/K ratio, taking into account the planet's orbit and rotation speed. The influence of variations of the solar wind precipitation (i.e., CMEs) is also included. We compare this model with either ground- and space-based observations of the exosphere and tail to evaluate the effectiveness of each source process. We find that including a source process which effectiveness is proportional to the precipitation of solar wind protons, is necessary to explain most of the available observations in both qualitative and quantitative way. We find that, to reproduce dawn-dusk asymmetries, we need to include the rotation of Mercury's surface in the model. After finding the correct model parameter by calibrating the model with observation, we simulate the short-term and yearly variations of Na/K.

  5. Short-time electrical effects during volcanic eruption: Experiments and field measurements

    NASA Astrophysics Data System (ADS)

    Büttner, Ralf; Zimanowski, Bernd; Röder, Helmut

    2000-02-01

    Laboratory experiments on the fragmentation and expansion of magmatic melt have been performed using remelted volcanic rock at magmatic temperatures as magma simulant. A specially designed dc amplifier in combination with high speed data recording was used to detect short-time electrostatic field effects related to the fragmentation and expansion history of the experimental system, as documented by simultaneous force and pressure recording, as well as by high-speed cinematography. It was found that (1) the voltage-time ratio of electrostatic field gradients (100 to 104 V/s) reflects different physical mechanisms of fragmentation and expansion and (2) the maximum voltage measured in 1 m distance (-0.1 to -180 V) can be correlated with the intensity of the respective processes. Based on these experimental results, a field method was developed and tested at Stromboli volcano in Italy. A 0.8 m rod antenna was used to detect the dc voltage against local ground (i.e., the electrostatic field gradient), at a distance of 60 to 260 m from the respective vent. Upwind position of the detection site was chosen to prevent interference caused by contact of charged ash particles with the antenna. A standard 8 Hz geophone was used to detect the accompanying seismicity. Three types of volcanic activity occurred during the surveillance operation; two of these could be clearly related to specific electrical and seismical signals. A typical delay time was found between the electrical and the seismical signal, corresponding to the seismic velocity within the crater deposits. Using a simple first-order electrostatic model, the field measurements were recalibrated to the laboratory scale. Comparison of field and laboratory data at first approximation revealed striking similarities, thus encouraging the further development of this technique for real-time surveillance operation at active volcanoes.

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

    NASA Astrophysics Data System (ADS)

    Stevens, Ben

    2016-11-01

    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. Although already considered by Coutand et al. [10] and Lindblad [17], we also make some brief comments on the case of a compressible liquid-vacuum interface, which is obtained from the vortex sheets problem by replacing one of the fluids by vacuum, where it is possible to obtain a structural stability result even without surface tension.

  7. Estimation of Missing Groundwater Levels Using Short-Time Fourier Transform

    NASA Astrophysics Data System (ADS)

    Hsu, C. H.; Ieok-Pan, L.; Chen, Y. W.; Chang, L. C.; Chiang, C. J.

    2016-12-01

    Groundwater plays an important role on regional water supply. To achieve the goal of sustainable management, the installation of observation wells is required. In Taiwan, an installation project of groundwater observation network has been processed since 1992 and a huge amount of groundwater levels has been obtained as the basis for sustainable management. However, because the pressure sensors might not be reliable enough, missing data might exist. To complete the records of groundwater levels, a fix-up method based on a Linear Regression (LR) and a Short-Time Fourier Transform (STFT) is proposed. The advantage of the proposed method is to estimate the missing data based on the features of frequency domain. The proposed method is composed by three steps. The first step is to estimate the trend of groundwater variation by using a LR model. In this step, the LR model is constructed to represent the relationship between signals from two observation wells. The trend of groundwater variation can approximately represent the variations with lower frequency such as 1 cycle/week to 1 cycle/year. The second step is to transform the time series with missing data into frequency domain via STFT. Because of the missing data, the amplitudes are approximately zero during the period of data missing. Because the estimation of LR model can represent the trend which also are the variation with lower frequencies, the spectrum of lower frequencies during the period of data missing can be completed by the spectrum of the trend of groundwater level. For higher frequencies, the amplitudes during the period of data missing is mirrored from the amplitudes without the absence of data. Finally, transform the spectrum to time domain with ISTFT. The result shows that the final data can fully keep features in time and frequency domains. It can also apply in analysis studies, such as data-mining of groundwater.

  8. Variational data assimilation for the optimized ozone initial state and the short-time forecasting

    NASA Astrophysics Data System (ADS)

    Park, Soon-Young; Kim, Dong-Hyeok; Lee, Soon-Hwan; Lee, Hwa Woon

    2016-03-01

    In this study, we apply the four-dimensional variational (4D-Var) data assimilation to optimize initial ozone state and to improve the predictability of air quality. The numerical modeling systems used for simulations of atmospheric condition and chemical formation are the Weather Research and Forecasting (WRF) model and the Community Multiscale Air Quality (CMAQ) model. The study area covers the capital region of South Korea, where the surface measurement sites are relatively evenly distributed. The 4D-Var code previously developed for the CMAQ model is modified to consider background error in matrix form, and various numerical tests are conducted. The results are evaluated with an idealized covariance function for the appropriateness of the modified codes. The background error is then constructed using the NMC method with long-term modeling results, and the characteristics of the spatial correlation scale related to local circulation are analyzed. The background error is applied in the 4D-Var research, and a surface observational assimilation is conducted to optimize the initial concentration of ozone. The statistical results for the 12 h assimilation periods and the 120 observatory sites show a 49.4 % decrease in the root mean squared error (RMSE), and a 59.9 % increase in the index of agreement (IOA). The temporal variation of spatial distribution of the analysis increments indicates that the optimized initial state of ozone concentration is transported to inland areas by the clockwise-rotating local circulation during the assimilation windows. To investigate the predictability of ozone concentration after the assimilation window, a short-time forecasting is carried out. The ratios of the RMSE (root mean squared error) with assimilation versus that without assimilation are 8 and 13 % for the +24 and +12 h, respectively. Such a significant improvement in the forecast accuracy is obtained solely by using the optimized initial state. The potential improvement in

  9. Variational data assimilation for the optimized ozone initial state and the short-time forecasting

    NASA Astrophysics Data System (ADS)

    Park, Soon-Young; Kim, Dong-Hyeok; Lee, Soon-Hwan; Lee, Hwa Woon

    2016-04-01

    In this study, we apply the four-dimensional variational (4D-Var) data assimilation to optimize initial ozone state and to improve the predictability of air quality. The numerical modeling systems used for simulations of atmospheric condition and chemical formation are the Weather Research and Forecasting (WRF) model and the Community Multiscale Air Quality (CMAQ) model . The study area covers the capital region of South Korea, where the surface measurement sites are relatively evenly distributed. The 4D-Var code previously developed for the CMAQ model is modified to consider background error in matrix form, and various numerical tests are conducted. The results are evaluated with an idealized covariance function for the appropriateness of the modified codes. The background error is then constructed using the NMC method with long-term modeling results, and the characteristics of the spatial correlation scale related to local circulation is analyzed. The background error is applied in the 4D-Var research, and a surface observational assimilation is conducted to optimize the initial concentration of ozone. The statistical results for the 12-hour assimilation periods and the 120 observatory sites show a 49.4% decrease in the root mean squred error (RMSE), and a 59.9% increase in the index of agreement (IOA). The temporal variation of spatial distribution of the analysis increments indicates that the optimized initial state of ozone concentration is transported to inland areas by the clockwise-rotating local circulation during the assimilation windows. To investigate the predictability of ozone concentration after the assimilation window, a short-time forecasting is carried out. The ratios of the RMSE with assimilation versus that without assimilation are 8% and 13% for the +24 and +12 hours, respectively. Such a significant improvement in the forecast accuracy is obtained solely by using the optimized initial state. The potential improvement in ozone prediction for

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

    PubMed

    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.

  11. A computer program to perform dynamic thermal analysis for bare overhead conductors during short-time overload conditions

    SciTech Connect

    Shrestha, P.; Pham, K.

    1995-12-31

    Under emergency conditions, a bare overhead conductor can carry an increased amount of current that is well in excess of its normal rating. When there is this increase in current flow on a bare overhead conductor, the temperature does not rise instantaneously. but increases along a curve determined by the current, the conductor properties and the ambient conditions. The conductor temperature at the end of a short-time overload period must be restricted to its maximum design value. This paper presents a simplified approach in analyzing the dynamic performance for bare overhead conductors during short-time overload condition. A computer program was developed to calculate the short-time ratings for bare overhead conductors. The following parameters: current induced heating. solar load, convective/conductive cooling, radiative cooling, altitude, wind velocity and ampacity of the bare conductor were considered. Several sample graphical output lots are included with the paper.

  12. Photoluminescence decay dynamics in γ-Ga2O3 nanocrystals: The role of exclusion distance at short time scales

    NASA Astrophysics Data System (ADS)

    Fernandes, Brian; Hegde, Manu; Stanish, Paul C.; Mišković, Zoran L.; Radovanovic, Pavle V.

    2017-09-01

    We developed a comprehensive theoretical model describing the photoluminescence decay dynamics at short and long time scales based on the donor-acceptor defect interactions in γ-Ga2O3 nanocrystals, and quantitatively determined the importance of exclusion distance and spatial distribution of defects. We allowed for donors and acceptors to be adjacent to each other or separated by different exclusion distances. The optimal exclusion distance was found to be comparable to the donor Bohr radius and have a strong effect on the photoluminescence decay curve at short times. The importance of the exclusion distance at short time scales was confirmed by Monte Carlo simulations.

  13. Hepatic colorectal cancer metastases showing a distinctive pattern of pathological response after metronomic capecitabine and bevacizumab.

    PubMed

    Pietrantonio, Filippo; Biondani, Pamela; Pellegrinelli, Alessandro; Marchianò, Alfonso; Dotti, Katia Fiorella; Buzzoni, Roberto; Di Bartolomeo, Maria

    2012-12-01

    A 48-year-old man was referred to our hospital with the diagnosis of colon cancer with multiple hepatic metastases. After right hemicolectomy, the rapid progression of liver disease was treated with metronomic capecitabine and bevacizumab according to a study protocol. A gradual regression of metastatic lesions was observed during a 9-month treatment period. After conversion of liver disease to resectability, the histological examination disclosed the complete necrosis of all lesions, with the exception of small neoplastic foci inside a single nodule. The comparison of this type of histological findings with the classic sclero-hyaline pathological response, as well as its importance as indicator of response to antiangiogenic treatment, is discussed.

  14. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial.

    PubMed

    Hegewisch-Becker, Susanna; Graeven, Ullrich; Lerchenmüller, Christian A; Killing, Birgitta; Depenbusch, Reinhard; Steffens, Claus-Christoph; Al-Batran, Salah-Eddin; Lange, Thoralf; Dietrich, Georg; Stoehlmacher, Jan; Tannapfel, Andrea; Reinacher-Schick, Anke; Quidde, Julia; Trarbach, Tanja; Hinke, Axel; Schmoll, Hans-Joachim; Arnold, Dirk

    2015-10-01

    The definition of a best maintenance strategy following combination chemotherapy plus bevacizumab in metastatic colorectal cancer is unclear. We investigated whether no continuation of therapy or bevacizumab alone are non-inferior to fluoropyrimidine plus bevacizumab, following induction treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab. In this open-label, non-inferiority, randomised phase 3 trial, we included patients aged 18 years or older with histologically confirmed, previously untreated metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate bone marrow, liver, and renal function, no pre-existing neuropathy greater than grade 1, and measurable disease, from 55 hospitals and 51 private practices in Germany. After 24 weeks of induction therapy with either fluorouracil plus leucovorin plus oxaliplatin or capecitabine plus oxaliplatin, both with bevacizumab, patients without disease progression were randomly assigned centrally by fax (1:1:1) to standard maintenance treatment with a fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. Both patients and investigators were aware of treatment assignment. Stratification criteria were response status, termination of oxaliplatin, previous adjuvant treatment with oxaliplatin, and ECOG performance status. At first progression, re-induction with all drugs of the induction treatment was a planned part of the protocol. Time to failure of strategy was the primary endpoint, defined as time from randomisation to second progression after maintenance (and if applicable re-induction), death, or initiation of further treatment including a new drug. Time to failure of strategy was equivalent to time to first progression for patients who did not receive re-induction (for any reason). The boundary for assessment of non-inferiority was upper limit of the one-sided 98·8% CI 1·43. Analyses were done by intention to treat. The study has completed

  15. Evaluation of oxaliplatin exposure of healthcare workers during heated intraperitoneal perioperative chemotherapy (HIPEC)

    PubMed Central

    VILLA, Antoine F.; EL BALKHI, Souleiman; ABOURA, Radia; SAGEOT, Herve; HASNI-PICHARD, Helene; POCARD, Marc; ELIAS, Dominique; JOLY, Nathalie; PAYEN, Didier; BLOT, François; POUPON, Joel; GARNIER, Robert

    2014-01-01

    The aim of this study was to evaluate air and surface contaminations, and internal contamination of healthcare workers during open-abdomen HIPEC using oxaliplatin. Platinum (Pt) was measured in urine of exposed workers and in multiple air and surface samples. Three successive HIPEC procedures were investigated in each of the two hospitals participating in the study. Analysis of air samples did not detect any oxaliplatin contamination. Heavy contamination of the operating table, the floor at the surgeon’s feet, and the surgeon’s overshoes were observed. Hand contamination was observed in surgeons using double gloves for intra-abdominal chemotherapy administration, but not in those using three sets of gloves. Pt was not detected in urine samples obtained after HIPEC (<5 ng/L). The main risk of HIPEC is related to direct or indirect skin exposure and can be prevented by correct use of adapted protective equipment. PMID:25327298

  16. Reversible bilateral blepharoptosis following oxaliplatin infusion: a case report and literature review.

    PubMed

    Fanetti, Giuseppe; Ferrari, Laura A M; Pietrantonio, Filippo; Buzzoni, Roberto

    2013-01-01

    Oxaliplatin, a platinum analogue employed in the treatment of colorectal cancer and various other neoplasms, is characterized by a broad range of adverse events. Peripheral neuropathy is probably the most peculiar and clinically relevant toxicity associated with its use and can be distinguished into two types: acute and chronic neurotoxicity.We report a case of acute reversible bilateral palpebral ptosis and dyspnea without bronchospasm or laryngospasm which occurred at the end of the third administration of adjuvant oxaliplatin by infusion for stage III colon cancer in a 54-year-old woman. Chlorphenamine and hydrocortisone were administered with fast resolution of dyspnea and slight improvement of ptosis. Complete resolution with no sequelae occurred in one hour. No further recurrence of blepharoptosis was described during the following days. The subsequent cycles were prescribed at reduced dosage without acute complications.

  17. Characterization of a liposome-based formulation of oxaliplatin using capillary electrophoresis: encapsulation and leakage.

    PubMed

    Franzen, Ulrik; Nguyen, Tam T T N; Vermehren, Charlotte; Gammelgaard, Bente; Ostergaard, Jesper

    2011-04-28

    A capillary electrophoresis-based method to characterize a PEGylated liposomal drug formulation of the anti-cancer agent oxaliplatin was developed. Pharmaceutical characterization in terms of determination of the free and total oxaliplatin concentrations in the liposomal formulation was successfully performed allowing calculation of the percentage of encapsulated drug and encapsulation efficiency. The trapping efficiency was likewise calculated. The capillary electrophoresis method allowed liposome characterization in the intended formulation media (sucrose solution with low electrolyte concentration), and the attained results were consistent with inductively coupled plasma mass spectrometry measurements. Accelerated drug leakage studies were initiated by the sonication of the PEGylated formulation, using an ultrasound probe, subsequently the drug leakage was determined by capillary electrophoresis. The results obtained with the PEGylated liposomes demonstrate that capillary electrophoresis may be a useful tool for the characterization of liposomal drug formulations. Copyright © 2011 Elsevier B.V. All rights reserved.

  18. Phase II Trial of Neoadjuvant Bevacizumab, Capecitabine, and Radiotherapy for Locally Advanced Rectal Cancer

    SciTech Connect

    Crane, Christopher H.; Eng, Cathy; Feig, Barry W.; Das, Prajnan; Skibber, John M.; Chang, George J.; Wolff, Robert A.; Krishnan, Sunil; Hamilton, Stanley; Janjan, Nora A.; Maru, Dipen M.; Ellis, Lee M.; Rodriguez-Bigas, Miguel A.

    2010-03-01

    Purpose: We designed this Phase II trial to assess the efficacy and safety of the addition of bevacizumab to concurrent neoadjuvant capecitabine-based chemoradiation in locally advanced rectal cancer. Methods: Between April 2004 and December 2007, 25 patients with clinically staged T3N1 (n = 20) or T3N0 (n = 5) rectal cancer received neoadjuvant therapy with radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks), bevacizumab every 2 weeks (3 doses of 5 mg/kg), and capecitabine (900 mg/m{sup 2} orally twice daily only on days of radiation), followed by surgical resection a median of 7.3 weeks later. Results: Procedures included abdominoperineal resection (APR; 6 patients), proctectomy with coloanal anastamosis (8 patients), low anterior resection (10 patients), and local excision (1 patient). Eight (32%) of 25 patients had a pathologic complete response, and 6 (24%) of 25 had <10% viable tumor cells in the specimen. No patient had Grade 3 hand-foot syndrome, gastrointestinal toxicity, or significant hematologic toxicity. Three wound complications required surgical intervention (one coloanal anastamostic dehiscence requiring completion APR and two perineal wound dehiscences after initial APR). Five minor complications occurred that resolved without operative intervention. With a median follow-up of 22.7 months (range, 4.5-32.4 months), all patients were alive; one patient has had a recurrence in the pelvis (2-year actuarial rate, 6.2%) and 3 had distant recurrences. Conclusions: The addition of bevacizumab to neoadjuvant chemoradiation resulted in encouraging pathologic complete response without an increase in acute toxicity. The impact of bevacizumab on perineal wound and anastamotic healing due to concurrent bevacizumab requires further study.

  19. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients

    PubMed Central

    Moehler, Markus; Sprinzl, Martin F; Abdelfattah, Murad; Schimanski, Carl C; Adami, Bernd; Godderz, Werner; Majer, Klaus; Flieger, Dimitri; Teufel, Andreas; Siebler, Juergen; Hoehler, Thomas; Galle, Peter R; Kanzler, Stephan

    2009-01-01

    AIM: To investigate the efficacy and safety of cape-citabine plus irinotecan ± bevacizumab in advanced or metastatic colorectal cancer patients. METHODS: Forty six patients with previously untreated, locally-advanced or metastatic colorectal cancer (mCRC) were recruited between 2001-2006 in a prospective open-label phase II trial, in German community-based outpatient clinics. Patients received a standard capecitabine plus irinotecan (CAPIRI) or CAPIRI plus bevacizumab (CAPIRI-BEV) regimen every 3 wk. Dose reductions were mandatory from the first cycle in cases of > grade 2 toxicity. The treatment choice of bevacizumab was at the discretion of the physician. The primary endpoints were response and toxicity and secondary endpoints included progression-free survival and overall survival. RESULTS: In the CAPIRI group vs the CAPRI-Bev group there were more female than male patients (47% vs 24%), and more patients had colon as the primary tumor site (58.8% vs 48.2%) with fewer patients having sigmoid colon as primary tumor site (5.9% vs 20.7%). Grade 3/4 toxicity was higher with CAPIRI than CAPIRI-Bev: 82% vs 58.6%. Partial response rates were 29.4% and 34.5%, and tumor control rates were 70.6% and 75.9%, respectively. No complete responses were observed. The median progression-free survival was 11.4 mo and 12.8 mo for CAPIRI and CAPIRI-Bev, respectively. The median overall survival for CAPIRI was 15 mo (458 d) and for CAPIRI-Bev 24 mo (733 d). These differences were not statistically different. In the CAPIRI-Bev, group, two patients underwent a full secondary tumor resection after treatment, whereas in the CAPIRI group no cases underwent this procedure. CONCLUSION: Both regimens were well tolerated and offered effective tumor growth control in this outpatient setting. Severe gastrointestinal toxicities and thromboembolic events were rare and if observed were never fatal. PMID:19152449

  20. Phase II study of docetaxel, cisplatin and capecitabine as preoperative chemotherapy in resectable gastric cancer.

    PubMed

    Dassen, Anneriet E; Bernards, Nienke; Lemmens, Valery E P P; van de Wouw, Yes A J; Bosscha, Koop; Creemers, Geert-Jan; Pruijt, Hans J F M

    2016-10-27

    To investigate the feasibility of preoperative docetaxel, cisplatin and capecitabine (DCC) in patients with resectable gastric cancer. Patients with resectable gastric cancer fulfilling the inclusion criteria, were treated with 4 cycles of docetaxel (60 mg/m(2)), cisplatin (60 mg/m(2)) and capecitabine (1.875 mg/m(2) orally on day 1-14, two daily doses) repeated every three weeks, followed by surgery. Primary end point was the feasibility and toxicity/safety profile of DCC, secondary endpoints were pathological complete resection rate and pathological complete response (pCR) rate. All of the patients (51) were assessable for the feasibility and safety of the regimen. The entire preoperative regimen was completed by 68.6% of the patients. Grade III/IV febrile neutropenia occurred in 10% of all courses. Three patients died due to treatment related toxicity (5.9%), one of them (also) because of refusing further treatment for toxicity. Of the 45 patients who were evaluable for secondary endpoints, four developed metastatic disease and 76.5% received a curative resection. In 3 patients a pCR was seen (5.9%), two patients underwent a R1 resection (3.9%). Four courses of DCC as a preoperative regimen for patients with primarily resectable gastric cancer is highly demanding. The high occurrence of febrile neutropenia is of concern. To decrease the occurrence of febrile neutropenia the prophylactic use of granulocyte colony-stimulating factor (G-CSF) should be explored. A curative resection rate of 76.5% is acceptable. The use of DCC without G-CSF support as preoperative regimen in resectable gastric cancer is debatable.