tbuckley/cabot-search huggingface dataset:
Chronomodulated fluorouracil (F), leucovorin (L), oxaliplatin (O) with or without irinotecan (I) (chrono FLO or IFLO) in elderly patients (EP) with metastatic colorectal cancer (MCC): A single institution experience
Authors: D. Gholam, S. Giacchetti, D. Hauteville, M. Bouchahda, P. Chaibi, C. Jasmin, F. Lévi
Journal: Journal of Clinical Oncology (2005)

8218 Background: Nearly 2/3 of MCC patients (pts) are over 70 years (y) old (Yancik, Cancer, 2002). O, I, F, and L are the mainstay of MCC treatment (Grothey, JCO, 2004). Chronotherapy (CT) enhances tolerability and/or activity of these drugs (Lévi, Cancer 2003). Methods: This study assessed the relevance of a combined Comprehensive Geriatric Assessment (CGA, Balducci, Oncology, 2000) and drug dose adjustment, at baseline, for improving outcome of 35 MCC pts ≥ 70 y receiving high dose CT. Dose adjustments are based on CGA result as well as on tolerability of prior O, I, F-containing regimens, if it existed. Treatment consisted of either 4-day chrono FLO q 2 weeks (w) through a multichannel pump (Mélodie, Aguettant, F) (15 pts, starting doses: F, 2800, L, 1200, O, 80 mg/m2/c) or 5-day chrono IFLO through Mélodie q 3 w (20 pts, starting dose: I, 180; F, 2800; L, 1200; O, 80 mg/m2/c). A CGA was performed at baseline for 24 pts (69%). Results: Median age: 74 years (70–85); Female/Male: 15/20; number of organs involved: 1/2/3+: 13/14/8 pts; sites of metastases: Liver/Lung/Peritoneum: 30/18/7 pts. Prior chemotherapy lines: 0/1/2+: 10/5/20 pts. 51% pts had drug doses reduction at first course (c) by ≥15%. A total of 239 c were administered, with a median of 6 c (2–28). Main grade 3–4 CTC toxicities were fatigue (66% pts, 18% c), neutropenia (31% pts, 9% c), diarrhea (31% pts, 5% c), sensory neuropathy (57% pts). Major toxicities requiring hospitalization were observed in 31% pts (7% c). One pt died of grade 4 febrile neutropenia with septic shock. Stable disease and objective response were obtained in 19 and 9 pts, respectively (RR= 26%). Median time to progression is 4.6 months (m). At 1 year, overall survival rate is 38% [95% CI, 23 to 56]. The CT regimen did not influence survival. Pts who had both CGA and dose adjustment experienced fewer hospitalizations for toxicity (p < 0.0001), less fatigue (p = 0.02) and tended to survive longer (48 vs 13% at 1-year, p = 0.02). Conclusion: Elderly pts with MCC benefit from systemic chronotherapy. Efficacy and tolerability of administered drugs are improved by a combined geriatric and oncologic management. No significant financial relationships to disclose.
Preparation and physical properties of itraconazole-loaded nanoemulsions using pineapple starch as co-emulsifier
Authors: Su Su Latt, Kanit Boontara, Tanapourn Teeraprasatkul, Warisa Yangngam, Vipaluk Patomchaiviwat, Pornsak Sriamornsak, Suchada Piriyaprasarth
Journal: Asian Journal of Pharmaceutical Sciences (2015)
New rules on driver licensing for patients with obstructive sleep apnoea: EU Directive 2014/85/EU
Authors: Maria R. Bonsignore, Winfried Randerath, Renata Riha, Dan Smyth, Christina Gratziou, Marta Goncalves, Walter T. McNicholas
Journal: European Respiratory Journal (2015)

The widespread recognition that obstructive sleep apnoea (OSA) represents an important risk factor for motor vehicle accidents (MVA), which is reversed by successful therapy with continuous positive airway pressure (CPAP), has led to a revision of annex III of the European Union (EU) directive on driving licences that is subject to mandatory implementation by all member states from December 31, 2015 [1]. This directive was the result of recommendations from a working group established by the Transport and Mobility Directorate of the European Commission in 2012 [2]. The directive states [1] Joint ERS/ESRS working group on the EU directive on issuing driving licences in obstructive sleep apnoea patients <http://ow.ly/UNchD>
Impact of adjuvant chemotherapy with respect to level of hormone receptor expression in patients with hormone responsive breast cancer: Implications for endocrine resistance
Authors: Y. Eralp, B. Sakallioglu, S. Kucucuk, S. Tuzlali, P. Saip, A. Igci, M. Muslumanoglu, A. Aydiner, E. Topuz
Journal: Journal of Clinical Oncology (2008)

11563 Background: The efficacy of hormone therapy (HT) is controversial in patients with a lower level of estrogen receptor (ER) expression or absence of progesterone receptor (PR). The aim of this study is to compare the efficacy of adjuvant HT and chemotherapy (CT) +HT in patients with different levels of ER and PR expression. Methods: 190 patients with nonmetastatic hormone responsive breast cancer and a median follow-up period of 49 months were included in this study. Fifty percent of patients were premenopausal and 63% were node positive. Both HR were evaluated by immunohistochemistry. ER expression score, as assessed by the ratio or percentage of cells stained positive, was evaluated in 4 groups: negative (8%), <1/3 (29%), ≥1/3–2/3 (18%), >2/3 (45%); whereas, patients were classified as positive or negative (19%) with respect to PR expression. The number of patients who received CT/HT and HT in the high ER score group and ER+/PR- groups were 63 (77%)/19 (23%) and 27 (82%)/6 (18%), as compared to low ER 44 (83%)/9 (17) and ER+/PR+ groups 121 (81%)/7 (21%), respectively. The prognostic impact of these factors on overall (OS) and disease-free survival (DFS) were analyzed by the Kaplan-Meier method. Results: The use of adjuvant CT was significantly higher in patients with node positive disease regardless of ER score or PR expression. OS and DFS were significantly lower in patients with a negative ER (p=0.02). There was no difference in either endpoint with respect to expression score. There was a trend for poorer DFS and OS (p=0.08) in PR negative patients. There was no additional efficacy of CT with respect to ER score or PR expression. Conclusions: In this data set adjuvant CT seems to offer no additional benefit in ER positive patients regardless of ER score of PR expression. Other factors should be evaluated to predict endocrine resistance in patients with hormone responsive disease. Mature data with longer follow-up is pending. No significant financial relationships to disclose.
Effect of mebendazole on melanoma xenograft growth through targeting of bcl-2
Authors: N. A. Doudican, R. Pennell, T. Tu, L. Liebes, A. Pavlick, R. Berman, R. Shapiro, J. D. Goldberg, I. Osman, S. Orlow
Journal: Journal of Clinical Oncology (2009)

9075 Background: Defects in apoptosis are thought to contribute to melanoma chemoresistance, making the anti-apoptotic protein Bcl-2 an attractive therapeutic target. We identified mebendazole (MBZ), a microtubule binding agent, as an inducer of melanoma cytotoxicity via a Bcl-2 dependent mechanism in vitro (Mol Cancer Res, Aug 2008). In the present study, we assessed the effect of MBZ on human melanoma tumor growth and progression in a mouse xenograft model and compared the ability of MBZ to inhibit growth of cultured melanoma cells to that of oblimersen (OBL), an antisense drug targeting Bcl-2. Methods: Growth of human M-14 melanoma xenografts in mice administered MBZ orally at doses from 0.1 to 2 mg were compared to tumor growth in mice receiving 100mg/kg intraperitoneal temozolomide (TMZ) or vehicle alone. Tumor diameter, volume, histopathology, and immunohistochemical staining of caspase 3 and Ki67 were assessed. Bcl-2 phosphorylation was determined by immunoblotting. MBZ and OBL-induced melanoma growth inhibition was analyzed by MTT assay. Results: Anti-melanoma effects of MBZ were dose- dependent up to 1 mg which displayed a 72% reduction in tumor volume compared to vehicle treated mice. This reduction in volume was accompanied by a 46% decrease in proliferating cells and an 81% increase in apoptotic cells. Moreover, 1 mg MBZ inhibited tumor growth as effectively as high dose TMZ, the current melanoma standard of care. Orally administered MBZ treatment resulted in Bcl-2 phosphorylation in vivo, further confirming its mechanism of action. MBZ inhibited growth of melanoma cells in culture more effectively than OBL with GI50 values of 0.32 uM and 7.45 uM, respectively. Conclusions: MBZ safely and effectively inhibits melanoma growth and progression in a xenograft model. A phase II clinical trial investigating MBZ's utility as adjuvant therapy in patients with stage IV, resected melanoma is planned. No significant financial relationships to disclose.
Phase I study using continuous intravenous (CI) KOS-862 (Epothilone D) in patients with solid tumors
Authors: K. D. Holen, S. Syed, A. L. Hannah, K. Binger, L. Wood, Y. Zhou, G. F. Cropp, R. G. Johnson, E. Rowinsky, G. Wilding
Journal: Journal of Clinical Oncology (2004)

2024 Background: Similar to taxanes, epothilones are a class of naturally occurring cytotoxic macrolides that stabilize microtubules and induce mitotic arrest, retaining potency in P-glycoprotein MDR cell lines. 6 schedules of KOS-862 were investigated in phase I trials. Methods: As the optimal schedule in the mouse xenograft model used prolonged exposure (6-hr IV infusion at 30 mg/kg) to reach plasma steady state Css=425 ng/mL, two CI schedules were attempted: a 24-hr CI (Schedule A) and up to 72-hr CI (Schedule B) q 2 weeks. Steady state is difficult to maintain for a drug with a rapid alpha distribution, hence a loading dose (75 mg/hr for 30 min) was incorporated, followed by maintenance dose. Results: 24 pts have been enrolled (median age 62 yrs, range 28–86 yrs; 7 F/17 M; median KPS 80; median prior regimens 3, range 0–10): 17 on Schedule A, 7 on Schedule B. Eighty total infusions have been administered. 4 dose levels have been tested on Schedule A (1, 2, 4 and 6 mg/hr rates); 2 dose levels on Schedule B (1 and 1.7 mg/hr). Drug-related toxicity includes mild-to-moderate fatigue, nausea/abdominal pain, dizziness, and neurosensory. One episode of grade 3 neurosensory occurred at 6 mg/hr x 24-hr CI; this dose group is being expanded. AUC=Css(SD) at this dose was 12300 ng/mL*h; constant dosing at 7 mg/h for 23.5 h would theoretically achieve a Css=423 ng/mL (Css=AUCSDτ n →τ n+1 /τ ). Pts dosed at 4 mg/h for 23.5h achieved Css=200 ng/mL. Comparison of PK between short infusion and CI showed similar results (mean±SD) CL=6.7±2.7 v 8.7±2.9 L/h/m2; half-life 10.3±2.9 v 10.8±2.3 hours; Vz 96±41 v136±59 L/m2; MRT 10.0±3.6 v 17.1±4.5 hours. As a marker of biologic activity, PBMCs were examined for microtubule bundle formation at the end of the CI. On Schedule A, 15 and 20% bundle formation at 4 and 6 mg/h was observed, respectively, indicating that there was significant polymerization over this period of time. Signs of antitumor activity included 1 pt with bladder ca (shrinkage of primarily nodal disease) and 1 pt with prostate ca (25% decline in PSA). Conclusions: Biologic activity at tolerable doses has been noted and accrual continues to define the recommended dose. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Kosan Biosciences, Inc. Kosan Biosciences, Inc. Kosan Biosciences, Inc. Kosan Biosciences, Inc. Kosan Biosciences, Inc.
Angiotensin receptor blockade improves myocardial beta-adrenergic receptor signaling in postinfarction left ventricular remodeling
Authors: Toshiyuki Takahashi, Toshihisa Anzai, Tsutomu Yoshikawa, Yuichiro Maekawa, Keitaro Mahara, Michikado Iwata, H.Kirk Hammond, Satoshi Ogawa
Journal: Journal of the American College of Cardiology (2004)
Astrocytoma in children: 14 years' experience at Stanford University Medical Center.
Authors: S Y Woo, S S Donaldson, R S Cox
Journal: Journal of Clinical Oncology (1988)

Between January 1, 1971 and December 31, 1984, 50 children (31 males, 19 females) ages 3 1/2 months to 18 years with primary CNS astrocytoma were seen in the Department of Therapeutic Radiology, Stanford University Medical Center. The actuarial survival and freedom from relapse (FFR) for the treated group is 46%, with a median follow-up of 7.2 years and a maximum follow-up of 14 years. The majority of relapses occurred within the first 2 years of diagnosis, and all relapses occurred at or adjacent to the initial site of tumor. Multivariate analysis revealed that factors correlated with poor survival are high histologic grade (including presence of necrosis) and primary tumor in the brain stem, while the only important prognostic factor associated with an adverse FFR is high histologic grade. Age, sex, degree of surgical resection, and total radiation dose to the tumor are not correlated with outcome. Patients with high-grade tumor were selected to receive whole brain irradiation and/or adjuvant chemotherapy; therefore, the findings of apparent poor prognosis associated with whole brain irradiation and adjuvant chemotherapy actually reflect patient selection. Current therapy is adequate for only half of children with astrocytoma. Thus, continued development of innovative therapies is indicated, particularly for those children with adverse prognostic factors.
Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma and vascular invasion or extrahepatic spread: A subanalysis from the SHARP trial
Authors: M. Sherman, V. Mazzaferro, D. Amadori, J. Seitz, M. Moscovici, M. Shan, A. Nadel, D. Voliotis, J. M. Llovet, J. Bruix
Journal: Journal of Clinical Oncology (2008)

4584 Background: Liver cancer is the third leading cause of cancer death globally, with most deaths occurring within one year of diagnosis. The multi-kinase inhibitor sorafenib became the first treatment approved by the FDA and EMEA for the treatment of HCC based on data from the phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) trial, which demonstrated that sorafenib 400mg bid increased overall survival (OS) vs placebo in patients with advanced HCC. The influence of risk factors such as macroscopic vascular invasion (MVI) and/or extrahepatic spread (EHS), on the safety and efficacy of sorafenib has not previously been reported. Here we compare sorafenib versus placebo in patients with and without MVI and/or EHS. Methods: Patients with advanced, measurable HCC, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2 and Child-Pugh status A received either sorafenib (400mg bid) or placebo. Endpoints included OS, time to progression (TTP; based on independent tumor assessment), and safety. Presence of MVI was determined through radiological assessment. Results: In this analysis, 421 patients had MVI and/or EHS (sorafenib=209, placebo=212) and 181 (sorafenib=90, placebo=91) did not. For patients with MVI and/or EHS (sorafenib vs placebo), OS was 8.9 vs 6.7 months (HR: 0.77; 95% CI: 0.60, 0.99) and TTP was 4.1 vs 2.7 months (HR: 0.64; 95% CI: 0.48, 0.84). For patients without MVI and/or EHS, OS was 14.5 vs 10.2 months (HR: 0.52; 95% CI: 0.32, 0.85) and TTP was 9.6 vs 4.3 months (HR: 0.40; 95% CI: 0.23, 0.70). The most common grade 3–4 drug-related, treatment-emergent adverse events (AEs) in the sorafenib arm for patients with vs those without MVI and/or EHS were: diarrhea (5.3 vs 15.7%), hand-foot skin reaction (6.7 vs 10.1%) and fatigue (4.8 vs 1.1%). Conclusions: Sorafenib prolonged OS and TTP in patients with advanced HCC irrespective of presence or absence of MVI and/or EHS; furthermore, sorafenib was well tolerated and AEs were manageable. These data are consistent with those in the overall SHARP population and confirm that the survival benefit achieved with sorafenib extends to a wide range of patients with advanced HCC, including those with MVI and/or EHS. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer Bayer, Biocompatibles, Bristol-Myers Squibb, AstraZeneca, Eisai, MDS Nordion, sanofi-aventis Bayer, Biocompatibles, Bracco Bayer
Abstract 12235: Oxygenation Prevents Contrast-induced Nephropathy via Nitric Oxide Induction
Authors: Haruki Sekiguchi, Yoichi Ajiro, Yoshie Uchida, Issei Ishida, Hisao Otsuki, Hidetoshi Hattori, Hiroyuki Arashi, Yasunori Kobayashi, Kentaro Jujo, Jyunichi Yamaguchi, Fumiaki Mori, Masaaki, Michio Asahi, Kazunori Iwade, Naohide Tanaka, Ken Shimamoto, Yukio Tsurumi, Masatoshi Kawana, Nobuhisa Hagiwara
Journal: Circulation (2012)

Background: Direct toxicity of contrast media and subsequent renal ischemia are involved in the pathogenesis of contrast-induced nephropathy (CIN). Our hypothesis was that sufficient oxygenation be...
Design, synthesis and evaluation of novel Apogossypol derivatives targeting anti-apoptotic Bcl-2 family proteins
Authors: Jun Wei, Michele Rega, Shinichi kitada, Hongbin Yuan, John Reed, Maurizio Pellecchia
Journal: Cancer Research (2008)

2772  Apogossypol, a semi-synthetic compound derived from the natural product Gossypol, possess anti-cancer activity by targeting anti-apoptotic Bcl-2 family proteins such as Bcl-2 and Bcl-xL. Apogossypol retains most of cytotoxic activity against cancer cells but is much less toxic than Gossypol for normal cells because it lacks two reactive aldehyde functionalities. These observations make Apogossyol a better lead compound than Gossypol for further optimizations. In order to obtain compounds which have improved potency, stability and drug-like properties than Apogossypol, novel synthetic routes were designed to obtain novel derivatives. The resulting compounds are evaluated for their ability to bind in the BH3 binding groove of Bcl-xL, by using a combination of nuclear magnetic resonance (NMR) binding assays and in vitro displacement assays. Computer docking studies supported by the NMR data provide a detailed picture of the possible interaction mode of Apogossypol and its derivatives with Bcl-xL. Preliminary cell-based evaluations and in vivo studies with most promising compounds will be presented.
Study shows higher risk from hip fracture surgery than hip replacement even after adjustment for age
Authors: Jacqui Wise
Journal: BMJ (2015)

Patients who undergo surgery for a hip fracture have a higher risk of mortality and of developing major complications than do patients who undergo an elective total hip replacement, even after adjustment for the fact that hip fracture patients are usually older and have more comorbidities, a large cohort study has found.1

The research, published in JAMA , looked at 690 995 patients …
MicroRNA involvement in breast cancer multidrug resistance
Authors: Zhongxing Liang, Hui Wu, James Xia, Yuhua Li, Nick Wagar, Aizhi Zhu, Sijia Wang, Dean Blevins, Younghyoun Yoon, Santosh Reddy, Jeanine Southerland, Stefania Scala, Susan Bates, Hyunsuk Shim
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

2284 

Multidrug resistance (MDR) has been frequently associated with elevated expression of one or more ATP binding cassette (ABC) transporters such as three well-known drug efflux proteins: P-glycoprotein (MDR-1), multidrug resistance associated protein (MRP-1), and breast cancer resistance protein (BCRP). However, the regulation of these transporters remains controversial. A recently discovered class of small, functional, noncoding RNAs, named microRNAs (miRNAs), has been shown to function as regulatory molecules by inhibiting protein translation and to play an important role in development, differentiation, cell proliferation, and apoptosis. More recently, a few studies have suggested that miRNA deregulation may play a role in cancer progression, but very little is currently known about how changes in certain miRNA expression levels among drug resistant tumor cells affect breast cancer multidrug resistance. To determine whether expression of certain miRNAs is altered in various breast cancer MDR cell lines (adriamycin-resistant, taxol-resistant, and mitoxantrone-resistant MCF7 breast cancer cells), we performed analyses of miRNA expression in MDR cell lines (MCF7/Adr200, MCF7/TX200, MCF7/MX100) compared to their parent cell line (MCF7) using a microarray containing 463 human mature and precursor miRNA probes. Nine of the decreased expression and 24 of the increased expression of miRNAs were observed in MDR cells compared to their parent cells. The differentially expressed miRNAs detected in the microarray screen will be confirmed by Northern blot analysis. We will modulate the levels of these confirmed miRNAs in MCF7 cells to determine whether these altered expressions of miRNAs are involved in breast cancer MDR. Our findings will be beneficial for the prediction of multidrug resistance in patients as well as in the design of personalized therapy for breast cancer patients.
Outcome of patients with small-cell lung cancer: effect of changes in staging procedures and imaging technology on prognostic factors over 14 years.
Authors: M P Dearing, S M Steinberg, R Phelps, M J Anderson, J L Mulshine, D C Ihde, B E Johnson
Journal: Journal of Clinical Oncology (1990)

In a study of 411 patients with small-cell lung cancer (SCLC) entered on therapeutic clinical trials between 1973 and 1987, we analyzed whether changes in the prognostic importance of pretreatment factors had occurred during the 14-year time period. After adjusting for other prognostic factors, brain involvement was associated with shorter survival in patients treated before December 1979 (P = .024) but not in patients treated thereafter (P = .54). The patients diagnosed before 1979 had brain metastases documented by radionuclide scan while computed cranial tomography (CCT) was more commonly used after 1979. Patients who had brain metastases diagnosed by radionuclide scan lived a shorter period of time than patients who had the diagnosis made by the more sensitive CCT scan (P = .031). In contrast, Cox proportional hazards modeling showed that liver metastases in patients were associated with shorter survival in patients treated after 1979 (P = .0007) but not in patients treated before then (P = .30). A larger proportion of patients had a routine liver biopsy before 1979 than after 1979 when more patients had the liver staged with less sensitive imaging studies and biochemical parameters. Patients with SCLC whose cancer was confined to the thorax but had medical or anatomic contraindications to intensive chest radiotherapy had similar survival compared with patients with limited-stage SCLC who were treated with combination chemotherapy alone (P = .68). From these data we conclude: (1) the sensitivity of the staging procedures used can affect the impact on survival of cancer involvement of a given site; and (2) patients with cancer confined to their chest with medical or anatomic contraindications to chest radiotherapy do not have a shorter survival than patients with limited-stage disease treated with chemotherapy alone.