tbuckley/cabot-search huggingface dataset:
Pharmacokinetics of paclitaxel and carboplatin after orthotopic liver transplantation
Authors: A. Gurpide, A. Aldaz, J. L. Perez-Gracia, J. M. Lopez-Picazo, L. Zufia, F. Pardo, J. Espinos, L. Arbea, A. Viudez, S. Martin-Algarra
Journal: Journal of Clinical Oncology (2004)

2095 Background: Paclitaxel is one of the most widely used chemotherapy agents and its metabolism and excretion takes place mainly through hepatic extraction and billiary secretion. Liver transplantation has become a frequent therapy for some hepatic diseases, and some patients become long term survivors after transplant. Those patients require immunosupresive therapy, and are at increased risk to develop tumors. Despite these facts, nothing is known about metabolism and pharmacokinetics of Paclitaxel in recipients of transplanted livers, since no studies have ever been reported. Methods: A 65 year old, male patient that received a transplanted liver in 1995 for ethylic cirrhosis developed metastatic non-small cell lung cancer in 2003. Chemotherapy with Paclitaxel 175 mg/ m2 and Carboplatin AUC =6 was offered, but due to lack of knowledge of Paclitaxel metabolism by transplanted livers, pharmacokinetic studies were done in order to make appropriate dose modifications if required. Blood levels of Paclitaxel and Carboplatin were assessed at different time intervals following drug infusion. Drug concentrations were determined by a validated reverse-phase HPLC method with ultraviolet detection. Pharmacokinetic parameters were estimated by noncompartimental analysis with WinNonlin v.1.5. Results: During the first cycle, pharmacokinetic parameters of Paclitaxel were: AUC 8,63 μ mol x h/ L; Cmax = 2,46 μ mol/ L; CL = 37,1 L/ h.. Similar results were obtained in subsequent cycles. These values are within the expected range in non-transplanted patients with normal liver function (Huizing MT, et al. J Clin Oncol 1993) and therefore can be considered normal. Carboplatin AUC during the first cycle was 7,67mg h/L, reflecting the well-known margin of error for AUC calculated by clinical equations. Conclusions: Recipients of normally functioning transplanted livers can adequately metabolize Paclitaxel and achieve normal plasmatic levels of the drug. Pharmacokinetic monitoring allows treatment with full dose Paclitaxel and Carboplatin to liver transplanted patients if they develop tumors in which these drugs are active. No significant financial relationships to disclose.
Randomized phase III trial of conventional paclitaxel and carboplatin (c-TC) versus dose dense weekly paclitaxel and carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Japanese Gynecologic Oncology
Authors: S. Isonishi, M. Yasuda, F. Takahashi, N. Katsumata, E. Kimura, D. Aoki, T. Jobo, F. Terauchi, H. Tsuda, T. Sugiyama
Journal: Journal of Clinical Oncology (2008)

5506 Background: Tri-weekly administration with paclitaxel and carboplatin (c-TC) is considered the standard of care for treatment of ovarian carcinoma. We compared the c-TC with dose dense weekly administration with TC (dd-TC) as first-line chemotherapy for stage II-IV epithelial ovarian, fallopian tube or primary peritoneal cancer. Methods: We randomly assigned patients to receive carboplatin to an area under the plasma concentration-time curve of 6 with either paclitaxel at 180 mg/m2 on day 1 or paclitaxel at 80 mg/m2 on days 1, 8, and 15. The treatments were repeated every 3 weeks for six cycles; in responding patients, additional three cycles were administered. Primary endpoint was progression-free survival (PFS) to be compared by log-rank test. Assuming 300 eligible patients in each arm, the study had 0.8 power to detect 5 months increase in median PFS at 0.05 two-sided alpha. Results: Of 637 patients who underwent randomization, 631 were eligible. After median follow-up of 29 months, median duration of PFS in the c-TC group and dd-TC group was 17.1 and 27.9 months, respectively (P=0.0014 by the log-rank test), and overall survival at 2 years was 77.7% and 83.6%, respectively (P=0.05). Among 282 patients with measurable disease, objective response rates were 53.3% and 55.8% in the c-TC and dd-TC groups respectively (P=0.91). Grade 3 and 4 anemia was reported more frequently in the dd-TC group, and other toxicities were similar in both groups. Conclusions: The dd-TC improves PFS as compared with c-TC in patients with advanced epithelial ovarian cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Aska, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Kyowa Hakko Kogyo, Mochida, Nippon Kayaku, Pfizer Oncology, sanofi-aventis, Yakult Bristol-Myers Squibb, Yakult
Ki-67/MIB-1 as prognostic factor for locoregional recurrence after adjuvant radiation therapy in early breast cancer: A population-based study
Authors: C. Mucciarini, F. Giovanardi, F. Masoni, C. Cirilli, F. Artioli, K. Cagossi, S. Sarti, R. Hakim, A. Iop, M. Federico
Journal: Journal of Clinical Oncology (2006)

20074 Background: Adjuvant radiotherapy (RT) has been shown to decrease the risk of locoregional recurrence (LRR) in women with infiltrating early breast cancer, with or without an associated systemic treatment. RT is more effective on high proliferating cells and we could evaluate the proliferative activity of any cancer through Ki-67/ MIB-1 antibodies. Adjuvant RT for breast cancer could show a greater efficacy to prevent LRR in the higher proliferating cancers. Methods: We conducted a retrospective analisys on all the 5004 cases of infiltrating early breast cancer diagnosed in the Province of Modena between 1989 and 2004 and registered in the Modena Cancer Registry. Beneath them we were able to find data about 1885 women who underwent adjuvant RT. We analyzed the data concerning this population on the basis of number of LRR and Ki-67 labeling index. Since the lack of a worldwide agreed Ki-67 cut off value representing an high proliferation rate of cell activity, we examinate our data in an univariate analisys establishing for the Ki-67 three different cut offs values ( 20%, 30% and 50%). Results: Between 1885 women who underwent RT, 91 ( 4.8%) had a LRR. Median follow-up was 6 years (range 1–15 years). Using a cut off for the Ki-67 of 20% to fix an high cell proliferation, 67 women had a Ki-67 &lt; 20% and 24 ≥ 20%. The p-value was 0.176. Increasing the cut off to the 30%, 75 women had a Ki-67 &lt; 30% and 16≥ 30%. The p-value was 0.048. Finally, considering the Ki-67 value to 50%, 87 women had a value &lt; 50% and 4 ≥ 50%, with a p-value of 0.992. In our analisys, it doesn’t seem that an increasing Ki-67 value would be correlated with a higher LRR. We are considering in a further analisys the weight of the different sistemic therapies on our results. Conclusions: The Ki-67 expression doesn’t seem to be considered a statistically significant prognostic factor for LRR in early breast cancer after adjuvant RT. No significant financial relationships to disclose.
Pemetrexed in combination with cisplatin in the treatment of chemonaive patients with malignant pleural mesothelioma (MPM): Outcomes on Expanded Access Program (EAP)
Authors: A. J. Wozniak, P. Janne, C. P. Belani, M. L. Keohan, H. Ross, J. Polikoff, D. Mintzer, C. Obasaju
Journal: Journal of Clinical Oncology (2004)

7192
Hematopoietic cell transplantation (HCT) after low-dose, total body irradiation-based regimen increased leukemia-free survival (LFS) in elderly patients with cytogenetic high-risk AML compared to chemotherapy (OSHO 97 study)
Authors: D. Niederwieser, C. Becker, R. Krahl, H. Al-Ali, T. Lange, A. Gerhardt, A. Schulze, D. Hähling, M. Schulze, M. Freund
Journal: Journal of Clinical Oncology (2007)

7003 Background: Even after reaching initial CR, most AML patients &gt; 60 years relapse within 2 years of diagnosis. Cytogenetic high risk AML (abn 3q26, abn 11q23, -5/5q-, -7/7q- and complex) has an even worse prognosis. Attempts to improve survival by intensifying consolidation chemotherapy have so far failed. We investigated the role of allogeneic HCT in comparison to chemotherapy among patients with high risk cytogenetics entered into the OSHO AML 97 protocol. Methods: Initial treatment consisted of a course of induction therapy (AraC 2 g/m 2 iv on day 1,3,5,7 + mitoxantrone 10 mg/m 2 iv day 1 –3, repeated once in case of PR) followed by one consolidation course (AraC 240 mg/m 2 iv day 1 –5 + mitoxantrone 10 mg/m 2 iv day 1 –2). Patients in CR1 after the consolidation I were either treated with an additional consolidation therapy or with an allogeneic HCT from related (n=2) or unrelated (n=10) donors. Transplant patients were conditioned with fludarabine and TBI 200 cGy and immunosuppressed with cyclosporine and mycofenolate mofetil. Results: A total of 347 patients are evaluable. Of 105 (33%) patients with high-risk cytogenetics, 53 (50%) went into remission after one or two cycles of induction chemotherapy. Of these 53 patients, 42 received consolidation I and 35 patients were available for either consolidation II (n=23) or HCT (n=12). Median age of the patients receiving chemotherapy was 64 (range 61–77) years and that of the transplant patients was 64 (range 61–68) years. LFS at 4 years was 42 ± 14% after HCT and 15 ± 8% after chemotherapy. Major differences in relapse incidences were seen between the two groups, with the lowest RI at 4 years after HCT (36 ± 15%) followed by chemotherapy (85±8%, p&lt;0.04). Treatment related mortality at 4 years was 35±17% and 0±0% for patients receiving HCT and chemotherapy, respectively (p&lt;0.05). Conclusions: From these results, we conclude that consolidation with allogeneic HCT after minimal conditioning is superior to chemotherapy even in older patients with high risk cytogenetics. While differences in TRM were seen between the treatment arms, a lower relapse incidence after related and unrelated HCT contributed to the improved LFS. No significant financial relationships to disclose.
A regional subgroup analysis of a multinational, double-blind, randomized, placebo-controlled, phase IIb study evaluating sorafenib (SOR) with paclitaxel (PAC) in patients (pts) with advanced breast cancer (BC).
Authors: T. P. Sahoo, V. G. Kaklamani, D. Lokanatha, V. Raina, S. Bondarde, M. Jain, L. S. Schwartzberg, W. J. Gradishar
Journal: Journal of Clinical Oncology (2010)

1114 Background: Previous studies indicate differences in BC pts from India versus the United States/European Union. We conducted a phase IIb trial in advanced BC pts enrolled in India (n=170), the United States (n=52), and Brazil (n=15). Use of SOR+PAC trended in favor of PL+PAC for the primary endpoint of progression-free survival (PFS): median, 6.9 vs. 5.6 mo (HR 0.79, 95% CI 0.56–1.11; 1-sided log rank p=0.09). Here we report baseline data by region with a planned subgroup analysis of PFS. Methods: Adultpts with HER2-negative, locally recurrent/metastatic BC were randomized to first-line PAC (90 mg/m2 weekly IV, 3 wk on/1 wk off) in combination with SOR (400 mg po, twice daily) or PL. Eligibility criteria allowed prior endocrine or radiation therapy and adjuvant use of taxanes and other chemotherapy. Pts with prior chemotherapy for advanced BC were not eligible. For this analysis, data were grouped by India versus non-India. Results: India pts were generally younger and presented with more aggressive disease than the non-India group, and prior use of taxanes and endocrine therapy was less frequent (Table). PFS results follow for SOR+PAC vs PL+PAC: India pts, 6.4 versus 5.6 mo (HR 0.80, 95% CI 0.53–1.19); non-India, 8.2 versus 6.3 mo (HR 0.79, 95% CI 0.40–1.56). Conclusions: In this study, pt differences for India versus non-India were consistent with the literature. Data are limited by selection criteria, noncentralized laboratory testing of BC markers, and pts with unknown ER/PR status. The potential impact of these differences on outcomes is unknown. Nonetheless, PFS data were consistent with primary results. India (N=170) Non-India (N=67) SOR+PAC, n (%) 88 (74) 31 (26) PL+PAC, n (%) 82 (69) 36 (31) Age, mean, y 48.6 60.1 Age ≥65 y, % 9 39 Premenopausal, % 32 18 ECOG status, % 0 44 48 1 55 59 AJCC stage, % III 48 31 IV 19 13 Hormone receptor status, % ER+ or PR+ 30 73 ER− and PR− 47 21 Unknown 22 6 Metastatic site, visceral, % 79 64 Time since initial diagnosis, mean, mo 24.8 71.2 Adjuvant tx to recurrent/metastatic diagnosis <24 mo, % 72 40 Time since metastatic diagnosis, mean, mo 4.2 11.4 Metastatic sites >3, % 17 9 Prior therapy, % Surgery 72 85 Radiation 36 49 Endocrine 18 51 Chemotherapy 52 72 Taxane 5 28 Anthracycline 38 57 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Onyx
Are there lower blood CO2-levels in asthmatic patients?
Authors: Sarah Ernst, Jörg D. Leuppi, Prashant N. Chhajed, David Miedinger
Journal: European Respiratory Journal (2011)

Background:  Dysfunctional breathing was shown to be common in people with asthma and therefore breathing retraining might be an additional therapy beside asthma medication. However it is unclear if dysfunctional breathing is associated with lower blood carbon dioxide (CO2) levels in a stable condition.   Objectives:  To find out if there is any relevant difference in blood CO2-levels comparing subjects with and without asthma.   Methods:  138 currently employed municipal firefighters and policemen from Basel, Switzerland, underwent methacholine-bronchoprovocation testing (MCH) according to a standardized protocol. We assigned a diagnosis of asthma according to three widely used definitions: Having 1) a positive MCH test (MCH+), 2) physician diagnosed asthma and 3) wheezing in the last twelve months and a positive MCH test (Wheeze/MCH+). We compared transcutaneously measured blood CO2-levels (TcCO2-levels) of subjects with and without asthma at rest prior (PRE), one and five minutes after (1MIN, 5MIN) MCH challenge.   Results:  At rest and at 5MIN, no significant differences were measured between asthmatic and non-asthmatic individuals for all three definitions. At 1 MIN, asthmatics had higher TcCO2-levels than non-asthmatics only if using the MCH+ definition (35.8 vs 33.4 mmHg, p = 0.023; physician diagnosed asthma: 35.8 vs 33.6 mmHg, p = 0.072; Wheeze/MCH+: 36.3 vs 33.6 mmHg, p = 0.052).   Conclusions:  Resting TcCO2-levels were not different in our sample of individuals with or without asthma according to diverse disease definitions and thus do not support the presence of relevant dysfunctional breathing at rest. At one minute after provocation challenge, metacholine positive subjects had higher TcCO2-levels than the negative ones.
Differently regulated proteins in sera of breast cancer patients and healthy donors.
Authors: K. Keller, D. Boehm, A. Lebrecht, M. Schmidt, J. Pieter, H. Koelbl, F. Grus
Journal: Journal of Clinical Oncology (2010)

e21022 Background: Breast cancer is the most common cancer type in women worldwide. Its early detection is a crucial step for the successful treatment. Although many serum biomarkers were described for breast cancer, all of them still lack of clinical specificity and sensitivity for the early detection. Therefore, we developed and evaluated a proteomics-approach for detection of biomarkers in serum of breast cancer patients and tried to identify differently regulated proteins. Methods: Blood samples of 50 women with breast cancer (CA) and 50 age-matched healthy women (CTRL) were drawn prior to surgery and respective sera were obtained. We used surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF-MS) for protein profiling with three active surfaces of the protein chips with different binding properties. Data was analyzed by multivariate statistical techniques and artificial neural networks. Results: We obtained a protein profile with 15 differently regulated proteins. Ten of them were upregulated in sera of breast cancer patients. The diagnostic pattern could discriminate CA from CRTL with specificity of 77% and sensitivity of 85%, the area under curve (AUC) of 0.85 was achieved. Two of upregulated proteins in breast cancer sera are Inter-a (globulin) inhibitor H4 (ITIH4) and Apolipoprotein C-I (ApoC-1). Conclusions: SELDI-TOF-MS is a promising, non-invasive tool for detection of breast cancer biomarkers with low sample amounts and high sensitivity and specificity. The next step of this project is the identification of all obtained biomarkers from our protein profiles and a validation serum study in a larger study population. The knowledge of different regulated proteins can help to understand the development of cancer, possibly leading to its early detection. No significant financial relationships to disclose.
Clinical pharmacology of a novel diarylsulfonylurea anticancer agent.
Authors: C W Taylor, D S Alberts, M A Ketcham, W G Satterlee, M T Holdsworth, P M Plezia, Y M Peng, T M McCloskey, D J Roe, M Hamilton
Journal: Journal of Clinical Oncology (1989)

LY186641 (diarylsulfonylurea, [DSU]) is a novel anticancer agent because of its unique diarylsulfonylurea chemical structure, broad-spectrum antisolid-tumor activity in preclinical models, presumed novel mechanism of action and preclinical toxicities of methemoglobinemia (Met Hgb) and decreased red blood cell (RBC) survival. In this study, the in vitro drug sensitivity of human tumors as well as clinical pharmacology and toxicology of DSU in patients with cancer were examined. DSU was administered orally, daily for 7 days with a 3-week treatment cycle. Dose-limiting toxicities were Met Hgb and RBC hemolysis. The maximum-tolerated dose was found to be 1,200 mg/m2/d for 7 days. In pharmacokinetic studies, DSU was found to have a prolonged serum half-life (approximately 30 hours) and a large area under the plasma disappearance curve (8,883.3 micrograms.hr/mL at 1,200 mg/m2/d). A partial remission was observed in one patient with refractory ovarian cancer. In conclusion, DSU can be safely administered to cancer patients and does display antitumor activity. Potential means of obviating the toxicities of this compound are discussed.
Phase II trial of capecitabine and irinotecan in combination with concurrent radiotherapy for neoadjuvant treatment of locally advanced rectal cancer
Authors: F. Willeke, U. Tiefenbacher, A. Hochhaus, F. Wenz, B. von Gerstenbergk, U. Gnad-Vogt, K. Horisberger, S. Post, R. Hofheinz
Journal: Journal of Clinical Oncology (2005)

3589 Background: The safety of the combination of capecitabine, weekly irinotecan and concurrent radiotherapy (CapIri-RT) as neoadjuvant treatment in locally advanced rectal cancer has been established in a previous phase I trial. The present phase II study aimed at determing the efficacy and safety of CapIri-RT in a larger cohort of patients. Methods: Thirty-six patients with rectal cancer clinical stages T3/4 Nx or N+ were recruited to receive weekly neoadjuvant irinotecan 50mg/m2 (1 hour before radiation) and capecitabine (1000mg/m2; days 1–38) with a concurrent RT dose of 50.4 Gy (45+5.4 Gy). Surgery was scheduled 4–6 weeks after the completion of chemoradiation. Results: A total of 36 patients (median age 62; m/f: 27/9) were enclosed in the trial. The median distance of the tumor from the anal verge was 5 cm. Three patients suffered from a local recurrence. 30 patients have thus far completed chemoradiation. Main toxicity observed in these patients was (CTC grades 1/2/3/4 [n]): Anemia 22/8/-/- (median Hb decrease 2.1 g/dl; range 0–3.5); leukopenia 12/7/4/2 (grade 3/4 leucopenia lasting a median of 5 days; range 1–7), thrombocytopenia 1/-/-/-, diarrhea 13/11/4/-, nausea/vomiting 9/8/1/-, increased activity of transaminases 3/3/1/-. A 42-year old male patient had a reversible episode of ventricular fibrillation during chemoradiation, most probably caused by capecitabine. The relative dose intensity was (median/mean [%]): Irinotecan 100/90, capecitabine 100/90. In 13 patients dose reductions and/or postponement of chemotherapy was required. 28 patients underwent surgery thus far (deep-anterior resection n=22; exstirpation n=6). One patient died postoperative due to septic complications following a perirectal abscess. R0-resection was accomplished in all patients. Pathological complete remission was observed in five patients and a further nine patients showed microfoci of residual tumor only. Conclusions: Preoperative chemoradiation with CapIri-RT is feasible and more convenient than infusional 5-FU-based chemoradiation. The efficacy is promising with complete or nearly complete tumor remission in half of the patients. No significant financial relationships to disclose.
A phase IIa study of light-activated talaporfin sodium in patients with primary or recurrent glioblastoma multiforme
Authors: L. Keltner, J. C. Chen, S. Wang, M. L. Rakic
Journal: Journal of Clinical Oncology (2009)

e13026 Background: Preclinical studies have shown that talaporfin sodium (LS11) can concentrate in brain-tumor cells and be activated by red light (664nm wavelength) from light-emitting diodes (LEDs). Singlet oxygen is released that induces blood-vessel occlusion and apoptosis in target tumor cells, which results in direct tumor-cell death and a potential antitumor immunogenic effect on untreated tumors. Preferential talaporfin uptake in tumor and clearance from normal surrounding brain occur by 24 hours after injection. A single center, open label phase IIa study was conducted to establish safety and acute antitumor effect of light-activated drug therapy in glioblastoma patients. Methods: Nine patients (Karnofsky score &gt;90) with operable glioblastoma, four of which were recurrent in the right frontal or temporal lobe, were recruited at a neurosurgical center in Belgrade, Serbia. Tumor diameter ranged 4–9 cm. Treatment consisted of IV injection of 1mg/kg of LS11 with subsequent craniotomy after a 24-hour wait. A single LED device was inserted into the tumor center followed by different light doses, 250 joules in six patients and 500 joules in three patients. Treated tumors were then resected. Patients were assessed for 4 weeks with serial CT imaging, intracranial pressure monitoring, and clinical, neurologic, and lab examination. Results: No dose-limiting toxicity was noted at the higher light-dose level. Seven adverse events (2 neurologic) occurred in four patients, none treatment related. Apoptosis was evident by TUNEL stain, and vessel closure was seen histologically. No acute inflammatory changes or cerebral edema were noted; normal brain was unaffected. No adverse neurologic sequelae were ascribable to the therapy, and no post-operative ICP elevation was noted. At 4 weeks, all patients were alive; two patients progressed and died shortly thereafter. Conclusions: Treatment of glioblastoma with this light-activated drug therapy was safe and tolerable in this study. An antivascular effect and tumor-cell apoptosis were seen histologically and confined to tumor. [Table: see text]