tbuckley/cabot-search huggingface dataset:
Safety and pharmacokinetics (PK) of motesanib diphosphate in combination with gemcitabine (G) and erlotinib (E) for the treatment of patients (pts) with solid tumors
Authors: D. Kotasek, N. C. Tebbutt, S. Welch, V. Wagner, S. McCoy, Y. Sun, T. J. Price
Journal: Journal of Clinical Oncology (2008)

3560 Background: Motesanib diphosphate is an oral investigational, highly selective inhibitor of VEGF, PDGF and Kit receptors. In advanced cancer, inhibition of EGFR and VEGFR, with or without chemotherapy, has shown promising activity. Methods: Ongoing, open-label, dose-finding, phase 1b study of motesanib diphosphate plus G and E in pts with solid tumors. Objectives are to establish the motesanib diphosphate maximum-tolerated dose (MTD), safety, PK and tumor response (Q12W). Pts had documented solid tumors, ECOG 0–2 and no prior G, E or anti-VEGF therapy. Control (ctrl) received G (1,000 mg/m2 IV QW for 7/8 wks, cycle 1; then 3/4 wks, cycle 2+) and E (100mg QD) from day 1; cohorts (C) 1–4 received G and E plus escalating doses of motesanib diphosphate (see table) continuously from day 9, cycle 1; C5 and C6 received E plus motesanib diphosphate only (see table). Dose-limiting toxicities (DLTs) were any treatment-related hematologic or nonhematologic gr 3 or 4 toxicities (except alopecia) through wk 5. Results: 48 pts (63% female, 90% disease stage IV) are enrolled (C1/2/3/4/5/ctrl, N=7/8/9/10/6/8), receiving ≥1 dose of motesanib diphosphate. Dose escalation and DLTs are shown below. The MTD in C1–4 was 100mg QD. Most pts (78%) experienced motesanib diphosphate-related adverse events (gr 3/4, N=11/4 in C1–4; N=0/0 in C5), including gr 3 deep vein thrombosis (N=2, C3), congestive cardiac failure (N=1, C2) and cholecystitis (N=1, C3); and gr 4 febrile neutropenia (N=1, C1), neutropenia (N=1, C4) and pulmonary embolism (N=2, C3). G/E coadministration did not markedly change median motesanib PK parameter values at 50–125mg QD; E exposures were 10%-40% (Cmax) and 40%-60% (AUC) lower with motesanib. There was 1 confirmed partial response in C4 (non-small cell lung cancer). Conclusions: Combining motesanib diphosphate with G and E was tolerable, with little effect on its PK, while exposure for E appeared to be lower. Updated data including cohort 6 will be presented. Summary of Dose Cohorts and Dose-limiting Toxicities (DLTs) Motesanib Diphosphate Dose Cohort DLTs Cohort 1 G/E + 50mg QD, N=7 N=1 grade 4 febrile neutropenia Cohort 2 G/E + 100mg QD, N=8 N=0 Cohort 3 G/E + 125mg QD, N=9 N=3 grade 3 cholecystitis, vomiting/nausea, and nausea/jaundice/subdural hematoma/cognitive disorder Cohort 4 G/E + 75mg BID, N=10 N=3 grade 3 neutropenia, nausea, and tumor necrosis Cohort 5 E (100mg QD) + 100mg QD *, N=6 N=0 Cohort 6 E (150mg QD) + 125mg QD Now enrolling * Motesanib diphosphate dose selected on the basis of the MTD established for cohorts 1–4 (100mg QD) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Inc. Amgen Inc. Amgen Inc. Amgen Inc.
Likelihood of subsequent chemotherapy after acute rehabilitation in patients with advanced cancer.
Authors: Isaac Martin Bromberg, Louise Knight, Sydney Morss Dy
Journal: Journal of Clinical Oncology (2014)

32 Background: Patients with advanced cancer suffer acute declines in their functional status for a variety of reasons, including progression of disease, adverse effects of medical or surgical treatment, and exacerbation of a chronic non-cancer condition. The use of rehabilitation services to improve functional status for patients with advanced cancer has been increasing, but the likelihood that a patient will achieve the goals of continued cancer treatment or extended survival has not yet been demonstrated. Times of transition in a patient’s course of illness present opportunities for discussion of goals of care. Methods: The objective of this study was to determine how often patients who were referred to acute rehabilitation (AR) returned to the cancer center for further chemotherapy. A secondary end-point was length of survival after referral. Records of patients admitted to the medical oncology service of an academic cancer center who were referred to AR between January 1, and December 31, 2012, were retrospectively reviewed for the following information: age, gender, race, primary malignancy type, subsequent chemotherapy, and date of death. Results: A total of 43 individual patients were referred for AR. Of these, 22 (51.2%) were 65 years of age or older, 30 (69.8%) were male, 32 (74.4%) were of white race. Primary hematologic malignancies accounted for 26 (60.5%) of the patients, 12 (27.9%) had non-brain solid primary tumors, and 5 (11.6%) had a primary brain tumor. For the 43 patients who qualified for AR, 33 (76.7%) were transferred to an AR facility, 9 (20.9%) were discharged to home, and 1 (2.3%) died in the hospital prior to discharge. Of those 33 patients who went to AR, 17 (51.5%) received further chemotherapy. Of note, 18 (54.5%) of the patients referred to AR died within 6 months (range 17-158 days), and 22 (66.6%) died within one year. Conclusions: Furthercancer treatment after an acute rehabilitation admission is a reasonable goal for patients with advanced cancer; however, these patients frequently have a limited life expectancy and should be considered for palliative care consultation prior to discharge to ensure a discussion about goals of care, in light of their overall prognosis.
The conventional NSAID sulindac sulfide arrests ovarian cancer cell growth through NSAID-activated gene (NAG-1)
Authors: Jong-Sik Kim, Seung Joon Baek, Tina Sali, Thomas E. Eling
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

4281 

While the chemopreventive and anti-tumorigenic activities of NSAIDs against colorectal cancer are well established, the molecular mechanisms responsible for these properties in ovarian cancer have not been elucidated. Therefore, there is an urgent need to develop mechanism-based approaches for the management of ovarian cancer. To this end, the effect of several NSAIDs on ovarian cancer cells was investigated as assessed by the induction of NAG-1, a pro-apoptotic gene belonging to the TGF-β superfamily. Sulindac sulfide was the most significant NAG-1 inducer and its expression was inversely associated with cell viability as determined by cell viability assay. This growth suppression by sulindac sulfide was recovered by transfection of NAG-1 siRNA. These results indicate that NAG-1 is one of the genes responsible for growth suppression by sulindac sulfide. Furthermore, we observed down-regulation of p21WAF1/CIP1 by introduction of NAG-1 siRNA into sulindac sulfide treated cells. In addition, to elucidate other potential molecular mechanisms involved in sulindac sulfide treatment of ovarian cancer cells, we performed a membrane-based microarray experiment. We found that CCND1 (cylin D1), MMP-1, PIK3R1, and PLAU were down-regulated by sulindac sulfide. In conclusion, a novel molecular mechanism is proposed to explain the experimental results and provide a rationale for the chemopreventive activity of NSAIDs in ovarian cancer.
Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): Results of S9346 (INT-0162), an international phase III trial.
Authors: Maha Hussain, Catherine M. Tangen, Celestia S. Higano, E. David Crawford, Glenn Liu, George Wilding, Stephen Prescott, Atif Akdas, Eric Jay Small, Nancy Ann Dawson, Bryan J Donnelly, Peter Venner, Ulka N. Vaishampayan, Paul F. Schellhammer, David I. Quinn, Derek Raghavan, Nicholas J. Vogelzang, Ian Murchie Thompson
Journal: Journal of Clinical Oncology (2012)

4 The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Sunday, June 3, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Effects of steroidal and nonsteroidal aromatase inhibitors (AIs) on markers of bone turnover and lipid metabolism in healthy volunteers
Authors: M. Subar, P. E. Goss, T. Thomsen, J. Banke-Bochita
Journal: Journal of Clinical Oncology (2004)

8038 Background: Estrogen deprivation secondary to AI therapy raises concern about toxicities such as accelerated bone loss and consequent fracture risk in an elderly population, and alteration in lipid metabolism resulting in cardiovascular events. The steroidal AI exemestane (E) completely protects against ovariectomy (OVX)-induced bone loss in a menopausal rat model, while letrozole (L) does not. This may be related to weak androgenic activity of the principal metabolite of E, 17-hydroexemestane. Methods: Healthy postmenopausal volunteers were treated for 6 months with placebo (P), E, L or anastrozole (A). Assays at baseline and on wks 2, 4, 8, 12, 16, 20, 24, and 36 included: estradiol, estrone, estrone sulfate, serum (S) and urine (U) C-terminal telopeptide of type I collagen (S-CTx and U-CTx), S bone specific alkaline phosphatase (BAP), S procollagen type I aminoterminal propeptide (PINP), U N-terminal telopeptide of type I collagen (U-NTx) and lipids (total cholesterol, HDL, LDL, triglycerides [TG]). Primary bone endpoint was % change from baseline in biomarkers at 24 wks. Percent change in lipid profiles and estrogen concentrations were summarized by assessment time and treatment arm. Results: Data are available on 77 of 84 volunteers. Mean age: 58.2 yrs; mean BMI: 25 kg/m2. Avg time since menopause was 12.5 yrs; 100% Caucasian. Estrogens were suppressed below the level of detection by A, L, and E. Median % change of the bone resorption marker S-CTx at 12 wks was 12.82 (A), 22.05 (E), 17.17 (L), and 9.61(P). Median % change in the bone formation marker, P1NP from baseline at 12 wks was 2.43 (A), 16.89 (E), 0.38 (L), and 3.81 (P). The most striking finding in lipid assays was change in TGs: At 12 weeks, median TGs, as a % of baseline for each group were 78.7 (E), 107.4 (L), 98.3 (A), 101.8 (P). Conclusions: Bone resorption increased from all 3 AIs but E caused a presumptive androgenic increase in bone formation markers. TG levels were reduced by E in comparison to A and L. If this profile is confirmed, E could be the AI of choice in otherwise healthy postmenopausal women Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer, Inc. Pfizer, Inc. Pfizer, Inc.
The efficacy of I-131 metaiodobenzylguanidine (MIBG) treatment in previously heavily treated stage IV neuroblastoma patients (age more than 1 year): Preliminary experiences
Authors: C. Chotipanich, K. Cheuamsamakkee, W. Changmuang, P. Chouplywech, S. Wittayachokkitikhum, S. Musikarat, C. Sritara, C. Utamakul, S. Pakakasama, S. Hongeng
Journal: Journal of Clinical Oncology (2007)

20025 Background: The outcome of advanced stage neuroblastoma patients with multiple relapsed or refractory diseases is very dismal. We therefore would like to study the efficacy and the safety of I-131 MIBG treatment in this group of patients. Method: A retrospective study of six stage IV neuroblastoma patients (pts) (2 males and 4 females), age at the diagnosis range 3 to 8 years from January 2005 to December 2006 were studied. All pts were previously treated with multiple regimens of chemotherapy, high-dose chemotherapy with autologous peripheral stem cells (PBSCs) rescue, salvage surgery, and local radiation ( table ). All these patients had relapsed or refractory disease at the time of I-131 MIBG treatment. The therapeutic dose of I-131 MIBG activity per course was given on the basis of weight, the hematological parameter, and tumor response assessment. The cycle of treatment was more 4 weeks apart. The treatment response was evaluated by imaging. and neuron-specific enolase (NSE) levels. Results: A total of 21 courses of I-131 MIBG were administered: one patient received one course, two received three courses, two received four courses and one received six courses. The median therapeutic dose of I-131 MIBG was 5.5 GBq (range; 1.1–5.5). Median duration of response was 10 months (range, 1–19). A partial response achieved in 1, and stable response in 5 patients. Pain relief was observed in 1/1 patients with bone pain. The most common side effect found was thrombocytopenia which became more severe with increasing number of course, grade 2 thrombocytopenia occurring in 4/6 patients over 3 courses of therapy. Three children died whereas three are still alive. There is no morbidity from the therapy. Conclusion: It can be concluded that MIBG treatment is effective and less toxic in patients with relapsed or refractory neuroblastoma and further studies of the role of I-131 MIBG treatment in advanced neuroblastoma in Thailand are needed. [Table: see text] No significant financial relationships to disclose.
Pretreatment (pre-tx) neutrophil to lymphocyte ratio (NLR) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with ketoconazole (keto): Association with outcome and predictive model.
Authors: Avishay Sella, Maya Ish-Shalom, Natalie Maimon, Maya Gottfried, Avivit Neumann, Avivit Peer, Eli Rosenbaum, Svetlana Kovel, Victoria J. Sinibaldi, Hans J. Hammers, Michael Anthony Carducci, Mario A. Eisenberger, Daniel Keizman
Journal: Journal of Clinical Oncology (2012)

4564 Background: The CYP17 inhibitor keto is active in mCRPC. The NLR, an index of systemic inflammation, is associated with prognosis in several types of cancer. We assessed the association between pre-tx NLR and outcome of mCRPC pts treated with keto. Methods: We performed an international multicenter retrospective study of pts with mCRPC, who were treated with keto. We analyzed the pre-tx NLR and previously described factors associated with keto tx outcome as prior response to hormonal tx, pre-tx PSADT, and extent of metastatic disease (limited vs extensive). Progression free survival (PFS) was determined by the Kaplan-Meier method. Multivariate analyses using Cox regression model were performed to determine their independent effect, and to form a predictive model. A survival tree analysis was used to find the best NLR cut-off value. Results: From 1999-2011, 156 mCRPR pts (median age 69) were treated with keto. 78/156 (50%) had ≥ 50% PSA decline. Overall median PFS was 8 months (mos) (range 1-144). Excluded from the analysis were 23 pts without available data on pre-tx NLR, and those with recent (≤1 mos) health event or tx (surgery, steroids, radiation) associated with a change of blood counts. 133 pts were included in the analysis. 62 (47%) had an elevated pre-tx NLR &gt;3. Risk factors associated with PFS (table) were pre-tx NLR &gt;3, prior response to GnRH-a &lt;24 mos and to antiandrogen (AA) &lt;6 mos, and pre-tx PSADT &lt;3 mos. The number of risk factors was used to categorize patients into three risk groups (table): favorable (0-1 factors), intermediate (2 factors), and poor (3-4 factors). Conclusions: In mCRPC pts treated with keto, pre-tx NLR, prior response to hormonal tx, and pre-tx PSADT are associated with PFS, and may be used to categorize pts into risk groups. [Table: see text]
Cytokines modulation and activity in non-small cell lung cancer (NSCLC) by chemotherapy and indinavir
Authors: A. Bearz, C. Simonelli, R. Talamini, C. Sgadari, P. Monini, B. Ensoli, S. Spazzapan, E. Vaccher, M. Berretta, U. Tirelli
Journal: Journal of Clinical Oncology (2006)

17094 Background: Our aim was to evaluate the activity of chemotherapy (CT) and indinavir, a protease inhibitor affecting matrix metalloproteases (mmps) of tumors, according to in-vitro studies (Sgadari, Nat Med 2002), in NSCLC patients (pts). Methods: All consecutive pts with NSCLC, IIIB and IV, underwent a platin-gemcitabine treatment. All pts with stable disease or partial remission after 3 courses were given 3 more courses plus indinavir 800 mg tid p.o, till progression. For each pt serum samples were collected before CT and every month till end of the study. Results: We enrolled 24 pts, with the same prognostic factors (age &lt;70 years; PS 0 and IV stage disease). Clinical data are available for 18 pts. Up to now we did not find any clinical benefit with indinavir as maintenance therapy: median time to treatment failure (TTF) is 2.75 mos (±1.0) and median overall survival (OS) is 16 mos (±4.5), not significantly different from literature data. For 11 pts, biological data are available. Using a paired T-test to compare differences at different times, we did not find any variation in VEGF, TNF-α, ICAM, neopterine, γ-IFN, mmps by CT. VEGF decreases in comparison with basal time, but not significantly, mean value 326 pg/mL (±79). Indinavir induces an increase of mmp2, before Indinavir 68.8 pg/mL (±9.18), after 97.09 (±10.21), p = 0,04. Analyzing by response, all pts with a RP at CT had a progressive decrease of serological VEGF; pts with SD or PD had an increase of VEGF. Pts with longer OS had a decrease of TNF-α, even at the time of progression. Conclusion: In our pts TNF-α and VEGF seem to have different pathways. TNF-α is related with OS, while VEGF is related with response to treatment. VEGF is a good marker to follow the clinical response and TNF-α is a better prognostical marker for OS. All our pts showed mean serum VEGF values lower than the previously reported values as cut-off level for prognostic value (Laack E. Lung Cancer 2005); in fact we selected pts in SD or RP after the third course of CT. In our pts VEGF is related with tumor response to therapy (i.e. tumor volume) while TNF-α drives their outcome. Modulation of TNF-α and his pathway may improve pts outcome. No significant financial relationships to disclose.
Abstract 16255: Wearable Cardioverter Defibrillator Treatment Characteristics and Outcomes in Recent Myocardial Infarction Patients With Heart Failure
Authors: Ramu Perumal, Jackie Sun, Steven J Szymkiewicz
Journal: Circulation (2014)

Introduction: Previous studies report patients (pts) with acute myocardial infarction (MI) complicated by heart failure (HF) have poorer outcomes than non-ischemic HF pts. We determined the clinical and arrhythmia characteristics and outcomes in recent (&lt; 40 days) MI pts with HF versus non-ischemic (NICM) HF pts treated by the wearable cardioverter defibrillator (WCD). Methods: WCD pts with a medical history of HF treated for VT or VF between 1/2007 and 11/2013 were identified from the manufacturer-maintained registry. Pts were classified as recent MI if they were identified as having a “recent MI with ejection fraction (EF) ≤ 35%” or given an ICD-9 diagnostic code of 410.xx (acute MI). Pts were classified as non-ischemic if they had no epicardial coronary vessels with ≥ 75% stenosis, no history of myocardial infarction, and no coronary revascularization. Data were reviewed for demographics, ECG recordings, and 24-hour survival. Electrical storm was defined as 3 or more unique VT/VF events requiring WCD therapy over a 24-hour time period. Results: Total of 346 pts met the study criteria, with 56% classified as recent MI with HF (MI-HF). MI-HF group was more likely to have risk factors for ischemic disease such as being older, male, hypertensive, diabetic, etc. (Table). The mean difference in EF between the two groups was less than 5%. MI-HF pts were 1.7 times more likely to be in VT versus VF at initial shock and 2.1 times more likely to have an electrical storm. Conversion of VT/VF events to slower rhythms by WCD treatment shock was 98% or greater in both groups. 24-hour post-treatment survival was 92% for all pts, with no difference between the two groups. CONCLUSIONS: Recent MI pts with HF who were treated by the WCD were likely to be older and male, with risk factors for ischemic disease. In addition, MI-HF pts exhibited increased incidence of VT versus VF events and electrical storm. The WCD was effective in terminating arrhythmic events with a high post-treatment survival in both groups.
Innate and adaptive immunity contribute to the anti-tumor mechanisms of action of OncoVEXmGM-CSF
Authors: Keegan Cooke, Karen Fitzgerald, Becky Yang, Petia Mitchell, Juan Estrada, Beltran Pedro, Achim K Moesta
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Talimogene laherparepvec, an investigational oncolytic immunotherapy, is a modified herpes simplex virus type-1 (HSV-1) designed to selectively replicate in tumors and to initiate a systemic immune response to target cancer cells. Intralesional administration of talimogene
Data Sharing as Part of the Normal Scientific Process: A View from the Pharmaceutical Industry
Authors: Patrick Vallance, Andrew Freeman, Murray Stewart
Journal: PLoS Medicine (2016)

In this week’s PLOS Medicine, Modjarrad and colleagues report the outcome of a World Health Organisation (WHO) consultation on developing global norms for sharing data and results during public health emergencies, with a focus on clinical, epidemiologic, and genetic features of emerging infectious diseases as well as experimental diagnostics, therapeutics, and vaccines [1]. There can be little doubt that the need to find effective health care solutions as quickly as possible to prevent or stop the spread of infectious disease in an emergency makes rapid data sharing the right thing to do for patients and society. Many of the barriers to data sharing in public health emergencies identified in the paper by Modjarrad et al. have been highlighted as areas for change to enable data sharing more generally [2,3]. We are perpetually in the midst of several health care crises, including those of neglected tropical diseases and other chronic diseases, for which data sharing has the potential to lead to faster and better solutions. As a matter of principle, we should be willing to share data without regards to which disease is being studied. So, which data and when?
Effect of infliximab treatment on colonic mucosal gene expression profiles in patients with inflammatory bowel disease
Authors: I. Arijs, R. Quintens, L. Van Lommel, Kristel Van Steen, G. De Hertogh, G. Van Assche, S. Vermeire, K. Geboes, F. Schuit, P. Rutgeerts
Journal: Gut (2008)
Parkinson’s disease: fetal cell or stem cell derived treatments
Authors: Arnar Astradsson, Tipu Aziz
Journal: BMJ (2016)

Butyrylcholinesterase (BuChE) was examined as an in vivo exogenous scavenger for highly toxic organophosphorus (OP) poisons. Protection studies with equine BuChE were carried out in rhesus monkeys trained to perform a Serial Probe Recognition task. The pharmacokinetics of equine BuChE administered i.v. in rhesus monkeys revealed an elimination T1/2 of approximately 620 hr. Animals given 503 nmol of BuChE i.v. and then challenged with 220 to 260 nmol of soman (two LD50; a lethal dose in untreated animals) all survived with no clinical signs of OP poisoning. Serial Probe Recognition performance was depressed after enzyme administration and at 1 hr postsoman. However, all monkeys performed the task at base-line levels at 8 hr after soman and throughout the remainder of the experimental period. Two different monkeys each were given two doses of sarin, 183 nmol/dose (one LD50) after 460 nmol of BuChE. No signs were observed. A third group of monkeys given 253 or 340 nmol (three and four LD50, respectively) of soman after 460 nmol of BuChE required 1 mg/kg of atropine i.v. 10 min postsoman, but recovered completely within 24 hr. Our results indicate that BuChE has the required properties to function as a biological scavenger to protect against the pharmacological and behavioral toxicity of OP poisons.