tbuckley/cabot-search huggingface dataset:
Abstract 18582: Correlation Between Reductions in LDL-cholesterol, Apolipoprotein B, and Lipoprotein(a) with Mipomersen in FH and Other Hypercholesterolemic Patients at High Risk for Coronary Disease
Authors: Raul D Santos, Frederick J Raal
Journal: Circulation (2012)

Introduction: Familial hypercholesterolemia (FH) is characterized by markedly elevated LDL-cholesterol (LDL-c) and, if untreated, premature atherosclerosis. Current treatment modalities are directed toward lowering LDL-c, although other atherogenic lipoproteins such as lipoprotein(a) [Lp(a)] are also considered independent causal risk factors for CHD. Lp(a) levels are about 2-fold higher in FH patients. However the LDL receptor is probably not the major route of Lp(a) clearance as statin therapy does not lower Lp(a). As Apo B is an integral component of Lp(a), inhibiting Apo B would be expected to reduce Lp(a) levels. Methods : We evaluated the relationship between the reduction in LDL-c, Apo B, and Lp(a) levels in patients with FH or hypercholesterolemia at high risk for CHD (N=256)and already receiving maximum tolerated lipid-lowering therapy, following treatment with mipomersen, an antisense Apo B synthesis inhibitor. Results: Table shows the absolute and percent changes in lipoprotein parameters pre/post mipomersen 200mg SC weekly for 26 weeks.Percent reductions in LDL-c and Apo B pre/post treatment were tightly correlated (r =0.95, p&lt;0.0001). There was also a positive, but moderate, linear correlation between the percent reductions in Apo B and Lp(a) pre/post treatment (r =0.43, p&lt;0.0001 ). Conclusion: Inhibiting Apo B synthesis with mipomersen reduced not only LDL-c and Apo B, but also Lp(a), and therefore represents a novel potential approach to reducing all three of these atherogenic lipid fractions. *LDL-c and Apo B results are in mean (SD) and Lp(a) in median (CI)
Risk of acute renal failure among breast cancer patients and chemotherapy treatment of breast cancer patients with a history of renal insufficiency in a commercially-insured population in the United States
Authors: W. J. Langeberg, C. D. O'Malley, C. W. Critchlow, J. P. Fryzek
Journal: Journal of Clinical Oncology (2009)

e22104 Background: Risk of acute renal failure (ARF) among breast cancer (BC) patients may increase with nephrotoxic chemotherapy and other exposures, but this risk is not well characterized. Furthermore, among patients who present with renal insufficiencies (RI) at cancer diagnosis, subsequent treatment patterns are not well described. Methods: We performed a retrospective cohort study using a large national commercial claims database. The cohort included all women diagnosed with BC from 2000 to 2007 who were 18–64 years at diagnosis with no history of cancer (n=13,296). We defined a diagnosis of BC as at least one inpatient or two outpatient claims more than 30 days apart with an ICD-9 code of 174. Among patients with no history of RI (n=13,150), we calculated the cumulative incidence (CI) of ARF_the proportion with at least one inpatient or two outpatient claims with an ICD-9 code of 584 or 586 in the first year following cancer diagnosis. Treatment for BC patients with a history of RI (n=146) was also assessed. Results: Among BC patients with no history of RI, 0.3% were diagnosed with ARF within a year after cancer diagnosis. The CI of ARF was higher in patients with metastases: 0.7% for any metastasis, 2.3% for bone metastasis, and 0.1% for no metastasis. The CI of ARF among patients undergoing radiation or mastectomy was similar to the overall rate (0.3%) but was higher in patients receiving nephrotoxic chemotherapy (1.0%) or intravenous bisphosphonates (IV BPs) (2.1%). The CI of ARF was higher in patients with congestive heart failure (1.4%), diabetes (0.9%), and/or hypertension (0.8%) at cancer diagnosis compared to patients without these comorbidities (0.2%). Among BC patients with a history of RI, 7.5% were administered nephrotoxic chemotherapy, 30.1% received potentially nephrotoxic chemotherapy, and 1.4% were given IV BPs. Conclusions: Breast cancer patients who present with comorbidities, develop metastases, or are given nephrotoxic chemotherapy or IV bisphosphonates are at higher risk of acute renal failure in the first year after breast cancer diagnosis. More research is warranted on the treatment of breast cancer patients with a history of renal insufficiency. [Table: see text]
Effect of treatment with sunitinib malate, a multitargeted tyrosine kinase inhibitor, on circulating plasma levels of VEGF, soluble VEGF receptors 2 and 3, and soluble KIT in patients with metastatic breast cancer
Authors: S. E. Deprimo, C. Friece, X. Huang, J. Smeraglia, L. Sherman, M. Collier, C. Baum, A. D. Elias, H. J. Burstein, K. D. Miller
Journal: Journal of Clinical Oncology (2006)

578 Background: Sunitinib malate (SU11248) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity that specifically inhibits VEGFR, PDGFR, KIT, RET and FLT3. In a phase II trial of 64 patients with refractory, metastatic breast cancer, sunitinib treatment resulted in an ∼11% objective response rate (Miller et al, ASCO 2005). To characterize potential biomarkers of biological response to sunitinib, we analyzed plasma levels of a panel of soluble proteins from patients in this trial. Methods: Patients received sunitinib in 6-week cycles comprised of 50 mg/day for 4 weeks followed by 2 weeks off treatment. Pre-dose plasma samples from 62 patients were obtained on days 1, 14, and 28 of the first cycle and days 1 and 28 of subsequent cycles. Plasma levels of VEGF, soluble VEGF receptor 2 (sVEGFR-2), soluble KIT (sKIT), and a novel biomarker, sVEGFR-3, were measured via ELISA analysis. Results: Plasma levels of each protein were modulated in most patients during the course of treatment. At the end of the first cycle, VEGF levels were increased more than 3-fold relative to baseline in 73% of cases, while sVEGFR-2 levels decreased by at least 30% in 88% of cases, and by &gt;20% in all but 4 cases. In addition, levels of sVEGFR-3 were decreased by &gt;30% in 82% of cases during the first cycle. For each of these markers, levels tended to return to near-baseline after 2 weeks off treatment. Longitudinal decreases in sKIT were also observed; decreases &gt;50% by the end of cycle 2 were correlated with treatment outcomes for time-to-progression (P &lt; 0.001) and survival (P = 0.03). Further analysis of correlations with pharmacokinetic and clinical parameters is ongoing. Conclusions: Sunitinib therapy is associated with increases in plasma VEGF and decreases in soluble VEGFRs and KIT. This panel of circulating proteins may have utility as pharmacodynamic biomarkers of sunitinib activity in patients with metastatic breast cancer. sVEGFR-3 may be a novel biomarker of the biological activity of sunitinib, while sKIT may be correlated with clinical response. Analysis of these and other biomarkers in larger studies of sunitinib in breast cancer may be warranted. [Table: see text]
Sequential axitinib (AG-013736) therapy of patients (pts) with metastatic clear cell renal cell cancer (RCC) refractory to sunitinib and sorafenib, cytokines and sorafenib, or sorafenib alone
Authors: J. P. Dutcher, G. Wilding, G. R. Hudes, W. M. Stadler, S. Kim, J. C. Tarazi, B. Rosbrook, B. I. Rini
Journal: Journal of Clinical Oncology (2008)

5127 Background: Axitinib is an oral, potent, and selective inhibitor of VEGFR 1, 2, 3. Efficacy and safety of axitinib in pts with metastatic RCC refractory to prior multiple sequential therapies is of clinical interest. Methods: Pts with sorafenib-refractory (progression or unacceptable toxicity) metastatic RCC and measurable disease, regardless of additional prior therapies, were enrolled in this multicenter, open-label, phase II study. Eligibility criteria included ECOG performance status 0–1, controlled CNS metastases (if present) and adequate organ function. All pts received a starting dose of axitinib 5 mg orally BID, which was titrated to 7 mg BID and then to 10 mg BID according to tolerance. Dose reduction was performed for drug-related adverse events. A one-arm, single-stage design was used to estimate the primary endpoint of objective response rate (ORR), as defined by RECIST, for patients refractory to sorafenib. Post-hoc analysis was performed on 3 subgroups based on prior therapy. Results: 14 pts were refractory to sunitinib and sorafenib (Group 1), 29 patients were refractory to cytokines and sorafenib (Group 2) and 15 patients were refractory to sorafenib alone (Group 3). For Groups 1, 2, and 3, the ORR was 7%, 28% and 27% and the median progression-free survival was 7.1 months, 9 months and 7.7 months, respectively, with a median follow-up of 10.3 months. 12 pts (21%) and 21 pts (34%) were dose titrated to 9–10 mg BID (mean duration: 8 cycles) and to 6–8 mg BID (mean duration: 2 cycles) respectively. 9 pts were dose reduced to 2–4 mg BID (mean duration: 4 cycles). Overall, Grade 3/4 treatment-related adverse events included fatigue (13%), hypertension (11%), hand foot syndrome (11%), diarrhea (5%) and dyspnea (5%). Conclusions: Axitinib appears to have antitumor activity in pts with metastatic RCC refractory to sunitinib and sorafenib, cytokines and sorafenib or sorafenib alone, suggesting an absence of total cross-resistance between axitinib and the other agents. A randomized phase 3 trial is being planned in patients with metastatic RCC refractory to a prior treatment. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Inc. Bayer-Onyx, Genentech, Pfizer Inc. Pfizer Inc. Bayer-Onyx, Novartis, Pfizer Inc., Wyeth Bayer-Onyx, Genentech, Novartis, Pfizer Inc., Wyeth Novartis
Chinas eugenics law on maternal and infant health care [letter]
Authors: Reichman Jm, Brezis M, Steinberg A
Journal: Annals of Internal Medicine (1996)

Last year China adopted a new law on maternal and infant health care.  The law mandates that all persons have a premarital medical examination to detect serious genetic diseases some infectious diseases and relevant mental disorders.  If a detected disorder is deemed serious the couple is not permitted to marry without committing to contraception or tubal ligation.  Prenatal testing is enforced and pregnancy is terminated if the fetus has a serious genetic or somatic abnormality.  A law  prevention of progeny with hereditary  is not a Chinese invention.  It was proclaimed in Germany in 1933 and enforced the sterilization of persons with congenital mental defects schizophrenia manic-depressive psychosis hereditary epilepsy ... and severe alcoholism.  This law endorsed by physicians was a harbinger of one of the darkest episodes of modern history--the Holocaust.  In China the ratio between male and female infants has increased to 1.1 because of prenatal sex selection (abortion of females) and (for lack of ultrasonography) the postnatal killing of females.  Only one child per family is permitted and male children are preferred for agricultural labor.  Chinas burgeoning population is unquestionably detrimental to its well-being and a legitimate goal is fewer but healthier babies.  Nonetheless the compulsory exclusion of some parents and fetuses is unethical.  No less disturbing is the impassive response by the world medical community.  Although some have expressed contempt for Chinas eugenics law others justify a nonpartisan stance claiming that it is perilous to impose western morality on China.  It is troubling that leading representatives of the medical community have not been at the forefront of protests against Chinas gross violation of medical ethics and human rights.  The danger lies not in the imposition of Western morality on China but in silence the equivalent of consent.  (full text)
A novel zinc-chelating small molecule exhibits cancer cell growth inhibition <i>in vitro</i> and <i>in vivo</i> by induction of tumor suppressors early growth response 1 (Egr-1) and Krüppel-Like Factor 4 (KLF4)
Authors: L. Lock, A. Khine, M. Huesca, V. Lawson, R. Peralta, E. Cammisa, M. Wang, H. Jin, Y. Lee, J. Wright, A. Young
Journal: Journal of Clinical Oncology (2007)

14084 Background: Lead compound LT-253 was selected from a group of 2-indolyl imidazol [4,5-d] phenanthroline derivatives with anticancer activity. It shows potent and selective anti-proliferative activity against several human cancer types in vitro, and in vivo in xenograft mouse models of human colon carcinoma (HT-29) and non-small cell lung carcinoma (H460). Methods: The mechanism of cell growth inhibition of LT-253 was investigated in HT-29 colon cancer cells using the XTT cell proliferation assay, flow cytometry and apoptosis assays. In vitro and in vivo zinc chelation was determined by competition assays using fluorescent and chromophoric chelators. Gene expression studies were performed by human genome microarray analysis and confirmed by quantitative real- time PCR. The transcription factor activity profile of LT-253-treated cells was determined by a multiplex transcription factor array and electrophoretic mobility shift assays. The functional role of specific genes was evaluated by siRNA gene knock-down. Results: LT-253 functions as chelator of zinc in vitro, and of intracellular labile zinc in HT-29 cells. Moreover, LT-253-mediated HT-29 cell growth inhibition was reversed by zinc supplementation. Gene expression profiling confirmed sustained changes in zinc-sensitive genes such as metallothionine and several zinc transporters, but not copper-sensitive or iron-sensitive genes. LT-253 induces cancer cell growth inhibition primarily through G1/S phase cell cycle arrest. Gene expression and transcription factor activities of both Egr-1 and KLF4 are induced within 4 hr post LT-253 treatment. Moreover, increased expression of both Egr-1 and KLF4 is observed in LT-253-sensitive cancer cell lines of various origins. Importantly, Egr-1 and KLF4 gene knock-down by siRNA reversed the LT-253-mediated cell growth inhibition of HT-29 cells. Conclusion: Selective chelation of intracellular labile zinc pool by LT-253 triggers immediate induction of stress-responsive tumor suppressor Egr-1 and sustained induction of zinc-responsive tumor suppressor KLF4, leading to G1/S phase cell cycle arrest and inhibition of tumor growth. No significant financial relationships to disclose.
Use of elevated bone turnover to predict bone metastasis
Authors: A. Lipton, J. W. Chapman, L. Demers, L. E. Shepherd, L. Han, C. F. Wilson, K. I. Pritchard, K. Leitzel, S. M. Ali, M. N. Pollak
Journal: Journal of Clinical Oncology (2008)

591 Background: A favorable "soil" has been suggested as an important factor for the growth of cancer cells. In this study, the ability of pretreatment serum beta C-terminal telopeptide (B-CTx) of type I collagen, a marker of bone resorption, to predict breast cancer relapse in bone was investigated in a randomized adjuvant breast cancer trial. Methods: Serum B-CTx concentration (Serum CrossLaps, Nordic Biosciences, Copenhagen, DN) was determined in pretreatment serum from 621 of 667 primary breast cancer patients enrolled in the NCIC CTG MA.14 phase III adjuvant clinical trial of tamoxifen (20 mg po daily, 323 pts.) ± octreotide (90 mg mo. for 2 years, 298 pts.) which has recently had its final analysis. Stratification was by administration of adjuvant chemotherapy, axillary lymph node status, and ER and/or PR status. Recurrence-free survival (RFS) was a secondary endpoint defined as the time from randomization to the time of recurrence of the primary disease alone; the focus here was bone-only recurrence. Continuous serum B-CTx was added to the factors indicated by the main trial event-free survival (EFS) analyses; as well, we performed step-wise forward multivariate Cox regression adjusted for the stratification factors using continuous serum B-CTx. Results: At this time, 123/621 patients have had a recurrence: 19/621 (3.1%) with bone-only recurrence; and 66/621 (10.6%) with bone plus other sites of recurrence. Higher serum B-CTx was associated with shorter bone- only RFS (p=0.02). In a step-wise Cox multivariate model, the factors associated with shorter bone-only RFS metastasis were pathologic T (tumor size) (p=0.0004) and higher serum B-CTx (p = 0.04). Serum B-CTx was not associated with any other type of recurrence (p>0.05). Conclusions: Higher pretreatment serum B-CTx is a significant predictor of shorter recurrence-free survival for bone-only metastasis. Increased bone resorption creates an environment that promotes the growth of breast cancer cells. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis
Phase II study of PRO95780 plus paclitaxel, carboplatin, and bevacizumab (PCB) in non-small cell lung cancer (NSCLC).
Authors: C. S. Karapetis, P. R. Clingan, N. B. Leighl, B. Durbin-Johnson, V. O'Neill, D. R. Spigel
Journal: Journal of Clinical Oncology (2010)

7535 Background: Treatment effect of PRO95780—a fully human affinity-matured IgG1 monoclonal antibody that induces DR5- mediated apoptosis in diverse cancer cell lines and xenograft models—was assessed in combination with PCB in previously untreated patients (pts) with advanced NSCLC. Methods: In this randomized, double-blind, placebo-controlled phase II trial, pts received PCB + PRO95780 (n=62) or PCB + placebo (n=62) for up to six 21-day cycles, then B + PRO95780/placebo for up to 28 more cycles. Adverse event (AE) and laboratory data were monitored. The primary efficacy measure was progression-free survival (PFS) as assessed by blinded, independent review. An exploratory objective was to evaluate prespecified biomarkers that might predict benefit from PRO95780. Results: Pts in the PRO95780 arm (median PRO95780 exposure = 6 cycles) had higher rates of grade 3-5 AEs (87%, vs. 68% for placebo), including higher rates of neutropenia, elevated ALT/AST, and supraventricular tachycardia. Efficacy data (with 95% confidence intervals) are shown below; none of the differences was statistically significant. Pts homozygous for a specific polymorphism of the Fcγ type IIa receptor that codes for a histidine residue at amino acid 131 showed a trend toward better PFS (HR=0.49; 95% CI=0.17-1.45) and objective response rate (odds ratio=2; 95% CI=0.38-10.58). Conclusions: Adding PRO95780 to PCB appeared to increase the rate of some AEs but did not appear to improve efficacy outcomes in unselected pts with advanced NSCLC. A possible trend for better outcomes among pts with H/H Fcγ receptor IIa genotype was seen. Placebo + PCB PRO95780 + PCB Median PFS, mo 7.0 (5.6-9.7) 7.9 (5.4-9.6) HR 1.06 (0.6-1.8) Median overall survival, mo 12.6 (9.8-16.8) 9.9 (8.3-15.8) HR 1.18 (0.71-1.98) Objective response rate*, % 42 (30-55) 40 (29-54) Abbreviation: HR, hazard ratio. * All partial responses. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Roche
Impact of age on the gynecologic adverse event (AE) profile of anastrozole (A) or tamoxifen (T) in the ATAC (‘Arimidex’, Tamoxifen, Alone or in Combination) trial
Authors: W. Distler
Journal: Journal of Clinical Oncology (2004)

770 Background: In ATAC 9366 postmenopausal women with early breast cancer were randomized to 5 years' adjuvant A (‘Arimidex’), T or A+T. At almost 4 years' median follow-up, disease-free survival was better for A than T (p=0.03). At a median duration of therapy of 36.9 months, the overall safety profile favored A. T has been associated with an increased risk of gynecologic AEs, and there was a significantly reduced incidence of the predefined AEs, endometrial cancer, vaginal bleeding and vaginal discharge in the A vs T group. Methods: Retrospective exploratory analysis of the impact of age on predefined gynecologic AEs in patients receiving A or T alone. A logistic regression model was fitted to test for treatment-age interaction. Results: Distribution of patients by age and the relative risk (RR) of predefined gynecologic AEs in each subgroup are shown. Conclusions: There was an overall significant advantage for A vs T in terms of the three endometrial side effects assessed. There was an even greater relative risk reduction in favor of A in women aged 60 years or older. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca
Randomized phase II trial of gemcitabine/cisplatin (GC) with or without cetuximab (CET) in patients (pts) with advanced urothelial carcinoma (UC).
Authors: Petros Grivas, Neeraj Agarwal, Arlene O. Siefker-Radtke, Stephanie Daignault, Igor Puzanov, Gary R. MacVicar, Ellis Glenn Levine, Sandy Srinivas, Przemyslaw Twardowski, Mario A. Eisenberger, David I. Quinn, Ulka N. Vaishampayan, Evan Y. Yu, Scott Dawsey, Kathleen C. Day, Mark L. Day, David C. Smith, Maha Hussain
Journal: Journal of Clinical Oncology (2012)

4506 Background: In UCpts EGFR over-expression correlates with high grade, stage, progression, short survival. Preclinical data show enhanced anti-tumor effect with CET + chemotherapy (CT). In several solid tumors CET added to CT improved survival. CET is hypothesized to improve UC response to CT. Methods: Pts with ECOG PS 0-2, adequate organ function, unresectable, locally recurrent or metastatic UC were stratified by disease state and randomized (1:2) to C 70mg/m 2 d1, G 1000mg/m 2 d1, d8, d15 (Arm A) or same CT + CET 500mg/m 2 d1, d15 (Arm B) q28 days. Due to high thromboembolic events rate in Arm B, G dose was reduced to 800 mg/m 2 . 6 GC cycles were planned. Arm A pts progressing after 2 GC cycles had CET added. Arm B pts were to continue on CET monotherapy after 4-6 CT cycles. Imaging was q8 weeks. Primary endpoint: RECIST response rate (RR); secondary: safety, PFS, survival. Since E-cadherin impacts UC response to CET in vitro, serum level (sE-cad) was assessed at baseline, after 2 cycles, end of CT and at progression. With 1-stage design, assuming RR 50% (Arm A) and at least 65% (Arm B), planned sample size was 27/54 pts. RR improvement of 5% has 81% probability if true difference is 15%. Results: 88 pts were eligible and randomized, Arm A/B: median age 66/61 years; bladder primary 71.4%/77.2%; metastatic disease 92.9%/89.5%, median CT cycles number 6/5. 28 Arm B pts continued CET (median 3 cycles, range 1-29); 1 Arm A pt had CET added. Most common G3/4 adverse events (AEs) (Arm A, B): neutropenia (34.5%, 33.9%), anemia (10.3%, 5.1%), thrombocytopenia (27.6%, 22%), thromboembolism (6.9%, 18.6%), hyponatremia (3.5%, 10.2%); Arm B only: rash 28.8%, fatigue 11.9%, hypomagnesemia 11.9% and 2 deaths. 84 pts were response evaluable (see table below). sE-cad did not correlate with outcome. sE-cad increased in Arm A, but decreased in Arm B over time. Conclusions: GC/CET was feasible with no outcome improvement but higher AEs. sE-cad did not correlate with outcome. Decreased sE-cad in Arm B suggests potential EGFR-mediated E-cad proteolysis. [Table: see text]