tbuckley/cabot-search huggingface dataset:
Long-term treatment with intravenous bisphosphonates in metastatic breast cancer (MBC)
Authors: T. Onishi, V. Singh, M. Rosenzweig, S. Sereika, A. M. Brufsky
Journal: Journal of Clinical Oncology (2009)

1035 Background: Intravenous bisphosphonates (IV BPs) are safe and effective in reducing skeletal related events in MBC. The effects of IV BPs after 24 months of therapy are unknown. The incidence of osteonecrosis of the jaw (ONJ) and renal insufficiency (RI) among women with MBC receiving &gt;= 24 months of IV BPs is also poorly defined. We studied the long term effect of IV BPs in a cohort of women with MBC. Methods: We maintain an ongoing prospective database of &gt;600 women with MBC diagnosed and treated at our institution from January 1999. A long-term cohort (LTC) of 159 women with metastatic breast cancer to bone treated for &gt;= 24 months with pamidronate (n = 9), zoledronic acid (n = 110), or both (n = 40) was identified. A control cohort (CC) of 62 women with MBC to bone treated with IV BPs for 12–23 months was also identified. RI was defined as an increase in serum creatinine (scr) of &gt; 0.5 mg/dl or an absolute level of scr &gt;1.5mg/dl; ONJ was diagnosed by dental consultation. Results: Median follow-up of the LTC was 39 months (range 24–99) months. Median overall survival in this cohort was 43 months (range 24–114). The vast majority of women in the LTC (140/159, 88.1%) continued to receive IV BPs at standard dose every 3–4 weeks. The incidence of ONJ in the LTC was 6/159 (3.8%), after a mean 42.2 treatment cycles, with a median time to ONJ of 44 months. Three of six patients with ONJ (50%) underwent surgical resection, and 3/6 (50%) were managed conservatively, and 3/6 (50%) resumed IV BPs after a mean 12 month hold. The incidence of RI (all pts had baseline scr &lt; 1.4 mg/dl) in the LTC was 19/159 (11.9%), occurring after a mean 43.4 treatment cycles, with a median time to RI of 43 months. Eleven of 19 patients (57.9%) recovered to baseline scr and 7/19 (36.7%) patients showed partial recovery. Seventeen of 19 patients (89.4%) were able to resume therapy after temporary discontinuation, decreasing the dose, or increasing the interval of the IV BP. Incidence of ONJ in the CC was 1/62 (1.6%) and RI in the CC was 6/62 (9.7%). Conclusions: Long term (&gt;=24 month) IV BP use in MBC is well tolerated and safe, with relatively low incidence of ONJ and RI. Most patients were able to resume IV BP therapy after a therapy hold without further complication. No significant financial relationships to disclose.
Safety and Antiviral Activity of Tmc435350 in Treatment-name Genotype 1 Hcv-infected Patients
Authors: Michael P. Manns, Yves Horsmans, Hendrik W. Reesink, Christophe Moreno, Thomas Berg, Yves Benhamou, Geoffrey M. Dusheiko, Robert Flisiak, Paul Meyvisch, Oliver Lenz, Kenneth Simmen, Rene Verloes
Journal: Hepatology (2008)
Biodistribution of paclitaxel poliglumex (PPX) in lung: Analysis of gender-related alterations in a preclinical model
Authors: C. Allievi, I. Strepponi, U. Bastrup, L. Piazzoni, S. Tavazzi, R. Pisano, G. Pezzoni, M. Fornasier, A. Bernareggi, J. W. Singer
Journal: Journal of Clinical Oncology (2006)

17003 Background: PPX is a macromolecular drug conjugate that links paclitaxel with poly-L-glutamic acid; the release of paclitaxel is dependent on metabolism by lysosomal proteases, particularly cathepsin B. Cathepsin B is upregulated by estrogen in both reproductive and somatic tissues that express estrogen beta receptors, including normal lung epithelial cells. Cathepsin B mRNA is also increased by estrogen and decreased by anti-estrogens in the 201T NSCLC cell line (P. Hershberger, personal comm.). Clinical data from Phase III studies in NSCLC showed improved survival in women receiving PPX compared to women in the control-arm, particularly those that were pre-menopausal or with pretreatment estradiol levels &gt;30 pg/ml. In contrast, men had similar survival regardless of treatment. Methods: To examine the effect of estrogen on PPX biodistribution and metabolism, male, sham-operated female, and oopherectemized (OPX) female adolescent rats were treated with [ 14 C]PPX (25 mg paclitaxel eq/kg). Radioactivity, as well as total and unconjugated paclitaxel, were measured in plasma, liver, and lung weekly for 4 wks. Results: Plasma t half values for radioactivity were appr. 3- and 1.5-fold higher in OPX females and intact females, respectively, compared to males; plasma AUCs were increased 1.8- and 1.5-fold, respectively. The lung AUC for radioactive PPX was similar for male and OPX females (11.8 and 15.1 hr*mg eq /g, respectively) but significantly higher for intact females (39.3 hr*mg eq /g). Total paclitaxel concentrations in the lung were 2-fold higher for females compared with either male or OPX rats (p &lt; 0.05 at 1 wk, and p &lt; 0.01 at 4 wks post dosing). No significant differences were observed in liver. Conclusions: OPX is associated with prolonged PPX plasma clearance compared to controls, and intact ovarian function is associated with enhanced distribution of PPX to lung tissue. These data provide the first evidence that ovarian function affects PPX pharmacokinetics and biodistribution; continued preclinical investigations will further characterize the mechanism for its apparent enhanced clinical efficacy in chemotherapy-naïve women with advanced NSCLC and intact ovarian function. [Table: see text]
Outcome of trimodality-eligible esophagogastric cancer (EC) patients who declined surgery after preoperative chemoradiation.
Authors: Takashi Taketa, Arlene M Correa, Akihiro Suzuki, Mariela Anabel Blum, Jeffrey Edwin Lee, James Welsh, Steven H. Lin, Dipen Maru, Jeremy J. Erasmus, Manoop S. Bhutani, Brian Weston, David C. Rice, Stephen Swisher, Wayne Lewis Hofstetter, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2012)

6 Background: Patients with localized EC eligible for resection at presentation should receive trimodality therapy (chemoradiation and surgery). However, surgical resection is not always performed in these patients because of poor performance status or reluctance in eligible patients to proceed with surgical resection after preoperative chemoradiation. Reports on the outcome of such patients are rare. Methods: Between 2002 and 2010, we identified 599 trimodality-eligible EC patients in our prospective database. All patients had extensive baseline staging, preoperative chemoradiation, and preoperative staging that included endoscopic biopsy and PET-CT. Of 599 patients, 32 patients declined surgery. Results: The median age was 70 years (range, 55-81), 29 patients (90.6%) were men and 30 (93.8%) were Caucasian. Majority had baseline stage II (44%) or III (38%) cancer. All 32 patients had an adenocarcinoma (moderate: 53.1%, poorly: 46.9%) and reached a clinical complete response (negative biopsy and PET in the physiologic range) post-chemoradiation. Four patients had salvage surgery and 3 are alive. Overall, 22 patients remain alive at a median follow up of 33.1 months (95% CI, 28.1-38.1). 3-year overall survival (OS) and relapse-free survival (RFS) were 65.1±10.4% and 37.5±10.3%. Median OS and RFS were 54.2 months (95% CI, 25.7-82.7), 30.4 months (95% CI, 16.3-44.5). Conclusions: Although the outcome of patients with EC who decline surgical resection after chemoradiation is reasonable, the lack of a validated approach to esophageal preservation dictates that trimodality therapy remains the standard of care in patients with potentially resectable EC.
Abstract 12264: Coronary Artery Calcium Stratifies Risk Across Varying Levels of Dyslipidemia: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Seth S Martin, Michael J Blaha, Ron Blankstein, Donald Lloyd-Jones, Arthur Agatston, Juan J Rivera, Salim Virani, Pamela Ouyang, Steven R Jones, Roger S Blumenthal, Matthew J Budoff, Khurram Nasir
Journal: Circulation (2012)

Background: The performance of the coronary artery calcium (CAC) score in risk assessment across the wide spectrum of dyslipidemia is uncertain, but relevant to the Adult Treatment Panel goal to ma...
Survival efficacy of adjuvant cytosine-analog CS-682 in a fluorescent orthotopic model of human pancreatic cancer
Authors: M. Katz, M. Bouvet, S. Takimoto, D. Spivack, A. Moossa, R. M. Hoffman
Journal: Journal of Clinical Oncology (2004)

2077 Background: We have previously shown that the cytosine analog CS-682 is active in orthotopic metastatic nude mouse models of human pancreatic cancer. The current study evaluates CS-682 in a novel adjuvant-treatment orthotopic nude mouse model of human pancreatic cancer with efficacy visualized in real-time with fluorescence imaging. Methods: Seven days after implantation, mice were randomized into eight groups, depending on whether they were to be treated by tumor resection, five weeks of CS-682 chemotherapy at 40–60 mg/kg qd or both. Throughout the course of treatment, non-invasive optical whole-body imaging based on brilliant red fluorescent protein (RFP) expression of the tumor permitted visualization and quantification of primary, metastatic, and recurrent disease. Results: Total tumor burden negatively correlated with survival. Untreated mice died of disseminated disease with a median survival of 26 days. Surgical resection alone conferred a small but significant survival advantage (median survival 28 days, p = 0.03). Primary CS-682 treatment at all doses also significantly prolonged survival compared to untreated animals (p < 0.05), and was more effective than surgery alone at doses of 50 mg/kg and 60 mg/kg (median survival 34 days, p = 0.045 and 38.5 days p = 0.03, respectively). Maximal survival (median 48 days, with 30% of animals surviving longer than 60 days) was achieved by adjuvant CS-682, 50 mg/kg, given after surgical resection of the primary pancreatic tumor (p = 0.004 compared to surgery alone). Conclusions: The results demonstrate that adjuvant oral administration of CS-682 for pancreatic cancer is highly effective with acceptable toxicity suggesting its potential for cure of this disease in appropriate combinations. No significant financial relationships to disclose.
Bevacizumab (Bev) plus chemotherapy for advanced gastroesophageal adenocarcinoma (GC): Combined U.S. experience.
Authors: E. C. Smyth, P. C. Enzinger, J. Li, M. Vincitore, J. Lacy, B. F. El-Rayes, P. L. Kunz, J. M. Ford, E. Robinson, D. P. Kelsen, M. A. Shah
Journal: Journal of Clinical Oncology (2011)

4056 Background: AVAGAST, a large international phase III study, failed to show improved overall survival (OS) with the addition of Bev to chemotherapy for patients (pts) with advanced GC (HR 0.87 95%CI 0.73-1.03) (Kang ASCO 2010). Significant heterogeneity in efficacy was seen by geographic region; Pan-American pts (15%; 29 U.S.) demonstrated significantly improved OS (HR 0.63), whilst Asian region pts (49%) did not derive benefit (HR 0.97). We hypothesize that this regional variation in efficacy may be explained by regional variation in GC subtype. We describe the US experience of Bev with chemotherapy in advanced GC and contrast U.S. GC subtype enrollment with AVAGAST. Methods: Pts with metastatic/unresectable GC treated on 5 investigator initiated U.S. phase II studies from MSKCC, Dana-Farber/MGH, Yale and Stanford of chemo + Bev were pooled. Data were collected on pt age, sex, ECOG PS, ethnicity, site of disease/metastases, Lauren’s subtype, chemo regimen and duration, gastrectomy status, Bev specific toxicity, and survival. Results: 156 pts were identified. Chemo regimens included cisplatin/CPT11 (n=47), mDCF (n=44), docetaxel/cis/CPT11 (n=34), FOLFOX (n=20), and carboplatin/FU (n=11). Median age 59 (range 25-83), M/F 116/40, White/Other 127/29, Gastric/GEJ 64/92, diffuse/intestinal/not reported 42/74/40, gastrectomy 31(20%), measurable disease 144 (92%), ECOG PS 0/1 65/91. Significant differences with AVAGAST are seen in tumor location, histology, and extent of disease (Table). Median duration of treatment 6m (range 0-37m). Total ≥ G3 Bev attributable toxicities were consistent with AVAGAST. Median pooled OS 14m (95% CI 12-16m); median OS diffuse/GEJ/gastric non-diffuse 12m/20m/15m (p=0.02 log-rank test). Conclusions: Advanced GC pts treated on U.S. phase II trials with Bev differ significantly from the AVAGAST cohort. Bev may be active in some GC subtypes. Additional evaluation of bev + chemo in distinct GC subtypes is warranted. Comparison of AVAGAST versus U.S. pt cohorts. AVAGAST (n=774) U.S. data (n=156) P value Site Gastric 86% 41% GEJ 14% 59% <0.001 Lauren's classification Diffuse 46% 27% Nondiffuse 40% 47% 0.018 Measurable Disease 80% 92% 0.005 Liver metastases 34% 52% 0.0001
A multicenter phase 2 consortium (P2C) study of the mTOR inhibitor CCI-779 in advanced soft tissue sarcomas (STS)
Authors: S. H. Okuno, M. R. Mahoney, H. H. Bailey, D. R. Adkins, W. J. Maples, D. Ettinger, T. R. Fitch, B. M. Bot, C. E. Erlichman
Journal: Journal of Clinical Oncology (2006)

9504 Background: CCI-779 inhibits the mammalian target of rapamycin (mTOR), a Ser/Thr kinase involved with the initiation of mRNA translation, showing growth inhibition in many tumor cell types. The primary goal was to evaluate the confirmed response rate (RR) of CCI-779 in advanced STS. Methods: Eligibility included pts ≥ 18 yrs, measurable advanced STS, PS 0–2, adequate laboratory function (including Chol ≤ 350 mg/dL and TG ≤ 400 mg/dL), no prior chemo for advanced disease (adjuvant chemo allowed), and no brain metastases. Following premedication with an antihistamine, CCI-779 was given intravenously at 25 mg over 30 minutes on days 1, 8, 15, and 22, repeated q 4 wks. A total 50 pts were to be enrolled, if there were 2 responses at the time of an interim analysis conducted on the initial 20 patients. Pre- and post-treatment blood was collected to evaluate p70S6 kinase, S6 phosphorylation, inhibition of mTOR, and sirolimus levels. Pre-treatment paraffin-embedded tumor tissue was used to evaluate immunohistochemistry markers (including, EFGR, c-Myc, Her2, 4EBP1). Results: 41 eligible pts (18 male, median age 62 yrs with range 28–79) were enrolled from 11/04 to 9/05. 71% presented with high grade tumors. Histologic subtypes include: malignant fibrous histiocytoma (MFH) (7), sarcoma NOS (9), fibrosarcoma NOS (3), liposarcoma NOS (5), leiomyosarcoma (8), endometrial stromal (1), synovial (1), hemangio/angiosarcoma (2), hemangiopericytoma NOS (1), and neurofibrosarcoma (1). 42% (16/38) evaluable pts had Gr 3+ events at least possibly related to CCI-779, 1 of which was Gr 4 hyperglycemia (see table). One pt having extremity fibrosarcoma, achieved a PR after 2 cycles lasting at least 36 weeks. Twenty-eight pts have progressed and 10 have died. Estimated median time to progression is 2 months (95% CI 1.8–3.5). Conclusions: Despite an acceptable toxicity profile, CCI-779 failed to demonstrate promising activity in pts with advanced STS. Results of the correlative studies are pending. Supported by N01 CM17104. [Table: see text] No significant financial relationships to disclose.
Website launched on patients' experiences of illness
Authors: Rhona MacDonald
Journal: BMJ (2001)

The founder of a UK medical bulletin and an Oxford GP who had cancer have launched a website offering personal and informative health data for people with serious illnesses.

The database of patient experiences of illness (DIPEx) is the brainchild of Andrew Herxheimer, former editor of the Drug and Therapeutics Bulletin, and GP Ann McPherson, who was diagnosed with breast cancer five years ago.

The site will answer questions about what a diagnosis means and what the person should do about it, in addition to having video clips of people relating their experiences of illness and the impact it has had on their lives.

The first two topics covered are hypertension and prostate cancer. They draw on research into patients' experiences of their illness, which involved extensive qualitative interviews with patients around the United Kingdom. Further topics will be added through the year.

DIPEx is based in Oxford University's department of primary care. For further information go to www.dipex.org or email ku.ca.xo.cphpd@xepid
Normalization and Accelerated Stabilization of VEGF-Induced Angiogenesis by Co-Delivery of Engineered PDGF-BB and VEGF Proteins From Fibrin Matrices
Authors: Veronica Sacchi, Mikael M. Martino, Roberto Gianni-Barrera, Michael Heberer, Jeffrey A. Hubbell, Andrea Banfi
Journal: Molecular Therapy (2014)
Tolerability of fluoropyrimidines appears to differ by region
Authors: D. G. Haller, J. Cassidy, S. Clarke, D. Cunningham, E. Van Cutsem, P. Hoff, M. Rothenberg, L. Saltz, H. J. Schmoll, C. Twelves
Journal: Journal of Clinical Oncology (2006)

3514 Background: Limited information is available regarding regional differences in tolerability for fluoropyrimidines. This is an initial assessment of the Roche phase III databases on patients treated for metastatic colorectal cancer (MCRC) and adjuvant colon cancer. Methods: Retrospective multivariate analyses (logistic regression) were performed using pooled data from two identical studies (n=1189) in MCRC comparing capecitabine (X) monotherapy with i.v. 5-FU/LV (Mayo regimen) [Hoff et al. and Van Cutsem et al. JCO 2001], and from an adjuvant study (n=1861) comparing XELOX (X+oxaliplatin) with either the Mayo or Roswell Park 5-FU/LV regimens [Schmoll et al. ASCO 2005]. Treatment-related safety parameters evaluated were: all grade 3/4 AEs, grade 3/4 GI events (diarrhea, nausea, vomiting, stomatitis), and grade 3/4 neutropenia events (febrile neutropenia, neutropenia reported as AE or lab value). Dependent variables for 1 st -line MCRC data were: US vs. non-US; and for adjuvant colon cancer: US vs. non-US, US vs. Asia, and RoW (rest of the world) vs. Asia. Factors in the adjusted relative risk model were: age, gender, PS, BSA, BMI, baseline creatinine clearance and treatment (X vs. 5-FU/LV; XELOX vs. Mayo vs. RP). Results: Region was significantly associated with grade 3/4 AEs and grade 3/4 GI events in both settings ( table ). There were no relevant interactions between region and type of fluoropyrimidine treatment. Reporting of grade 3/4 neurosensory toxicity was similar in the US and outside US. Conclusions: Differences in the rates of grade 3/4 toxicity were significantly associated with the region of the world in which the patients were treated. Patients treated in the US experienced the highest rates of grade 3/4 toxicity (see table ). This difference was observed for both X and for 5-FU. The reasons for these differences remain to be elucidated. Acknowledgements: C. Allegra, J. Bertino, J-Y Douillard, B. Gustavsson, G. Milano, M. O’Connell, Y. Rustum, J. Tabernero, J. Fagerberg, F. Gilberg, and F. Sirzen. [Table: see text] [Table: see text]
Immune damage to the mesangium
Authors: G M Hänsch, G Schieren, C Wagner, M Schönermark
Journal: Journal of the American Society of Nephrology (1992)

The deposition of immune complexes in the tissue results in complement activation leading to the formation of the lytic C5b-9 complex. Tissue cells are relatively resistant to complement attack due to cellular mechanisms such as removing C5b-9 from the surface and the expression of membrane proteins, which regulate complement activation and attack on the cell surface. Hence, cell killing is not an important consequence of complement activation on nucleated cells. On the other hand, the sublethal C5b-9-membrane interaction leads to various cellular responses, among them the synthesis of eicosanoids, cytokines, matrix-degrading proteases, and extracellular matrix, resulting in the modification of cell proliferation, leukocyte function, matrix degradation, and the formation of scar tissue. Thus, the complement-dependent immune damage is caused by secondary mediators, either derived from leukocytes or mesangial cells, rather than by a direct C5b-9-mediated killing.
Discussion
Authors: Richard S. Vander Heide
 *, Keith A. Reimer
Journal: Cardiovascular Research (1997)

w x We recently reported in this journal 1 that intravenous administration of adenosine, given immediately prior to and continuing for 2.5 h into reperfusion, failed to limit infarct size in an open-chest canine model of regional myocardial infarction. Our study was designed to investigate the ability of adenosine, one putative inhibitor of lethal reperfusion injury, to limit myocardial necrosis following a regional ischemic insult. Both lethal and nonlethal reperfusion injury have been hypothesized to exist. There is strong evidence that myocardial stunning occurs, at least in part, through oxygen-derived free radicals generated upon the onset of arterial reperfusion and therefore stunning is generally accepted to be a form of non-lethal w x reperfusion injury 2 . However, the existence of lethal reperfusion injury is more controversial. The experimental protocol used in our study included therapy with adenosine, based on the dose, route, and timing of administration used in the study of Pitarys et al. w x Ž 3 . These investigators had reported a positive effect i.e., . limitation of infarct size of therapy in a closed-chest canine model. In addition, our experimental protocol was designed to reproduce the results previously reported by Homeister et al. who showed that adenosine plus bolus administration of lidocaine, but not adenosine alone, resulted in cardioprotection in a canine model of regional w x infarction 4 . We were unable to show any limitation of infarct size as a result of intravenous adenosine administration, with or without lidocaine, in our open-chest model. Our negative results were discordant with the reports of marked limitation of infarct size in studies by Forman and w x colleagues 3 . Both openand closed-chest models have been used successfully in many different experimental laboratories to w x study the pathophysiology of ischemia and reperfusion 5 .
Outcome of patients with nonmetastatic breast cancer receiving nitrogen-containing bisphosphonates: A comparative analysis from the Metropolitan Detroit Cancer Surveillance System (MDCSS).
Authors: Z. A. Nahleh, J. Abrams, A. Bhargava, K. Nirmal, J. J. Graff
Journal: Journal of Clinical Oncology (2010)

654 Background: Preclinical data suggest that bisphosphonates exhibit antitumor activity. However, clinical studies indicated conflicting results. In this study, we compared overall survival (OS) of postmenopausal patients with nonmetastatic invasive breast cancer who received any of the new generation nitrogen-containing bisphosphonates for osteopenia or osteoporosis, with the survival of those who did not. Methods: We conducted a retrospective study at the Wayne State University/Karmanos Cancer institute (KCI) in Detroit, Michigan and extracted data from the Metropolitan Detroit Cancer Surveillance System (MDCSS), a Surveillance, Epidemiology, and End Results (SEER) registry. Patients > 50 years with stage I, II, or III invasive breast cancer between the years 2000 and 2003 were included. Information regarding medications was extracted from the patients' medical records. Results: 696 women with stages I–III breast cancer were included. 97 women (14%) used nitrogen-containing bisphosphonates. The difference in OS between bisphosphonate users and non-users was not statistically significant (p = 0.32) at 3 years. After adjusting for differences between the groups in age, stage of disease, hormone receptor status, endocrine therapy, and vitamin D and calcium use, there was a marginally significant (p = 0.07) difference in survival; bisphosphonate users had poorer survival than non-users. Conclusions: Our results indicate that the use of the newer generation nitrogen-containing bisphosphonate is not associated with improved OS in patients with nonmetastatic breast cancer, even after adjusting for known prognostic factors, but with a marginally worse OS. Further research is awaited to clarify the role of bisphosphonates in the adjuvant setting. No significant financial relationships to disclose.