tbuckley/cabot-search huggingface dataset:
The safety of incretin based drug treatments for type 2 diabetes
Authors: Shari D Bolen, Nisa M Maruthur
Journal: BMJ (2016)

Latest data are reassuring about pancreatic cancer, less so about heart failure

The incretin based drugs (dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists) are one of several options for glucose lowering in people with type 2 diabetes who are already taking (or unable to take) metformin.1 As with other antidiabetic drugs, the long term safety of these drugs remains unclear. Studies by Azoulay and colleagues (doi:10.1136/bmj.i581) and Li and colleagues (doi:10.1136/bmj.i610) in this issue provide updated evidence about incretin based treatments and the risk of pancreatic cancer and heart failure.2 3

In 2013 the Food and Drug Administration and European Medicines Agency undertook investigations of the possible link between incretin based treatments and pancreatic cancer owing to post-marketing reports suggesting higher rates of pancreatic cancer with these drugs,4 and a study suggesting abnormal pancreatic histology among users of incretin drugs versus non-users.5 These investigations revealed no clear causal role …
Necessity for including quality of life diagnostics and therapy in routine oncological care: Evaluation by methods of clinical guideline implementation
Authors: M. Klinkhammer-Schalke, M. Koller, C. Ehret, B. Steinger, B. Ernst, F. Hofstädter, W. Lorenz
Journal: Journal of Clinical Oncology (2006)

18594 Background: Application of quality of life assessment has become an important topic in oncology. Current approaches, however, have focused on technical issues within single center settings overlooking the requirements of routine care. We report on implementing of structural elements of a quality of life diagnostics and therapy system (QoL system). It was designed as integral part of the health care program for breast cancer patients in a regional tumor center. Methods: The QoL system was implemented by a systematic approach (Med. Care, 39, Suppl.2, 2(2001). Its elements comprised (a) coordinating practitioners (CPs) who functioned as gate keepers for QoL related therapies, (b) experts in the QoL unit who provided QoL reports and specific therapeutic recommendations based on patients’ responses to the EORTC questionnaire, (c) professional health care providers in psychotherapy, pain therapy, social support, physiotherapy/lymph drainage, and fitness (nutrition, sports), (d) clinicians (gynecologists) for patient recruitment and (e) opinion leaders for educational influence on the CPs to keep the QoL system in daily practice. Success of implementation (as indicated by CPs’ QoL-related changes in knowledge, attitude and behavior) was evaluated in a prospective study with breast cancer patients. Results: The QoL system was applicable in all of 170 patients recruited between Dec. 2002-June 2004 (age 34–86yrs, UICC 0–4, breast conserving surgery 67%). From 75 CPs (mostly gynecologists) in the area only 39 fulfilled criteria for the QoL system, 1 refused to participate. 38 CPs showed knowledge about QoL following educational outreach visits. Concerning attitudes and behavior, 64% of CPs found the experts’ reports comprehensible, 56% followed their recommendations, 20% made additional actions. Follow-up 4 months after first QoL measurement revealed improvements in pain, body image and social life (p &lt; .05). Conclusion: The study—in combining doctor’s approach and patient’s demands—showed success using methods of guideline implementation by improving QoL deficits within a routine oncological care. Effectiveness will be analyzed in an ongoing randomized trial. No significant financial relationships to disclose.
Kinetics of response to ipilimumab (MDX-010) in patients with stage III/IV melanoma
Authors: O. Hamid, W. J. Urba, M. Yellin, G. M. Nichol, J. Weber, E. M. Hersh, S. Tchekmedyian, F. S. Hodi, R. Weber, S. O'Day
Journal: Journal of Clinical Oncology (2007)

8525 Background: Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), enhances immune responses to tumor-associated antigens resulting in durable objective responses (OR). This abstract describes the kinetics of response after ipilimumab treatment. Methods: 5 studies (2 complete; 3 ongoing) in 269 treated patients with stage III/IV melanoma were reviewed and analyzed to determine the kinetics and duration of response after ipilimumab. Patients received ipilimumab alone or with dacarbazine, IL-2 or gp100 peptide vaccine. Ipilimumab doses ranged from 0.3–10mg/kg/dose (single or multiple). Complete and partial response (CR, PR), stable and progressive disease (SD, PD) were evaluated. Results: 41 patients (15%) had a confirmed OR at analysis. CR and PR was of late onset in some patients and occurred from ∼10–106 and ∼5–62 weeks (w) post-treatment initiation, respectively. In 28 patients onset of CR or PR occurred after &gt;∼12w of treatment. PD preceded OR (without additional therapy) in 4 patients. In 2 patients, PD measured at ∼6w post-treatment initiation was followed by a PR at ∼12w. In 1 patient the PR changed to a CR at ∼24w and lasted for ∼188w+; the other patient maintained a PR for ∼17w. In the other 2 patients, PD at ∼12w was followed by SD at ∼17–20w and a PR after ∼30 and 62w; PRs in both patients lasted for ∼17 and 40w+, respectively. Duration of OR ranged from ∼6–187w+; ORs are ongoing in 25 patients. Late onset occurred irrespective of dose, regimen and therapeutic partner. Conclusions: Preliminary results suggest that ORs with ipilimumab may be later in onset and more durable than with traditional chemotherapy and may occur after progression. This late onset of effect likely reflects the immune-related mechanism of action of ipilimumab, and suggests that continued treatment/observation may be beneficial despite initial PD or SD. Acknowledgement: Dr. S. Rosenberg [Table: see text]
A Phase I/II Trial Of Pomalidomide, Bortezomib and Dexamethasone In Patients With Relpased Or Refractory Multiple Myeloma
Authors: Joseph R. Mikhael, Vivek Roy, Paul G. Richardson, Andrzej Jakubowiak, Kristina Laumann, Betsy R. LaPlant, Angela Dispenzieri, S. Vincent Rajkumar, Rafael Fonseca, Nelson Leung, Francis Buadi, P. Leif Bergsagel, Robert Kyle, Macp Macp, Thomas E. Witzig, Craig Reeder, John A Lust, Stephen Russell, Suzanne R Hayman, Shaji K Kumar, David Dingli, Stephen M Ansell, Robert Dalton, Yi Lin, MDPhD MDPhD, Taimur Sher, Prashant Kapoor, Arleigh McCurdy, Asher Chanan-Khan, A. Keith Stewart, Chb Chb, Morie A Gertz, Martha Q Lacy
Journal: Blood (2013)
Rational design for enhancing inflammation-responsive in vivo chemiluminescence via nanophotonic energy relay to near-infrared AIE-active conjugated polymer
Authors: Young Hun Seo, Ajay Singh, Hong-Jun Cho, Youngsun Kim, Jeongyun Heo, Chang-Keun Lim, Soo Young Park, Woo-Dong Jang, Sehoon Kim
Journal: Biomaterials (2016)
Phase II of trastuzumab and cisplatin in patients (pts) with advanced gastric cancer (AGC) with HER2/neu overexpression/amplification
Authors: H. Cortés-Funes, F. Rivera, I. Alés, A. Márquez, A. Velasco, R. Colomer, R. García-Carbonero, J. Sastre, J. Guerra, C. Grávalos
Journal: Journal of Clinical Oncology (2007)

4613 Background: Trastuzumab(T) exhibits activity in human gastric cancer cells that overexpress HER2/neu. We previously reported a 13.5% HER2/neu overexpression/amplification in AGC or gastroesofageal junction (GEJ) cancers (Grávalos C, et al. J Clin Oncol 24, 18S, 200s, abstr # 4089). We designed a phase II trial to determine the efficacy and tolerability of T and cisplatin(C) in pts with ACG with HER2/neu overexpression/amplification. Exploratory objectives include analysis of c-erbB-2 extracellular domain and correlation of the results with histological erB-2/neu overexpression and with clinical response Methods: Chemo-naïve pts with adenocarcinoma histopatologically confirmed, HER2/neu overexpression/amplification, measurable, no operable, locally advanced or metastatic AGC, age ≥ 18, ECOG ≤ 2, FEVI ≥ 50% and adequate organ function were eligible. Prior adjuvant radiotherapy or/and chemotherapy were allowed. Immunohistochemistry (IHC) was performed using herceptest. A fluorescence in situ hybridization (FISH) assay was done when IHQ was = 2. HER2/neu expression was considered negative if IHC= 0, 1 or IHC=2 and FISH -; and positive if IHC=2 and FISH + or IHC=3. T 8 mg/kg d1 (loading dose in first cycle) and 6 mg/kg (maintenance doses) and C 75 mg/m 2 d1 were administered every 21 days until progression, unacceptable toxicity or withdrawal inform consent Results: 21 pts has been included. 17 are evaluable. 16 were men. Median age 66 (50–78). ECOG 0/1: 5/12. Histological subtypes were: 50% intestinal, 25% diffuse and 25% unknown. 56% had gastric localization and 44% GEJ. 16 pts had metastases (59% liver, 47% lymph nodes, 23% peritoneum, 17% lung, and 24% others). Prior treatment: 5 pts underwent surgery and 2 had adjuvant chemotherapy. Median cycles 2 (1–14). Efficacy: 6 (35%) pts achieved response (1/5 CR/PR), 3 (17%) stabilization (52% control disease = RC + PR+SD), 4 pts with progression disease, 4 pts too early Tolerance: There was no grade 4 toxicity. Main grade 3 adverse events included: asthenia (3 pts), nauseas/vomiting (3), diarrhea (2), hiporexia (2) and neutropenia (1) Conclusions: Trastuzumab and cisplatin is a well tolerated regimen with a promising activity. The study is ongoing and an update will be presented at the meeting. No significant financial relationships to disclose.
Abstract 354: Haploinsufficiency Of Sam68 Attenuates Vascular Inflammation And Atherosclerosis In Apoe-deficient Mice
Authors: Shuling Han, Junlan Zhou, Gangjian Qin
Journal: Circulation Research (2014)

Background: Chronic inflammation in the arterial wall is a major drive of atherosclerosis and is largely mediated by the NF-kappaB signaling pathway in the vascular and pro-inflammatory cells, notably macrophages. Recently, Sam68, an adaptor protein and Src kinase substrate, has been shown to promote NF-kappaB signaling in mouse embryonic fibroblasts (MEFs). However, whether Sam68 plays a role in the development of atherosclerosis is currently unknown. Methods and Results: To evaluate the role of Sam68 in atherosclerosis, we crossed Sam68(+/-)mice (Sam68-/- mice are sterile) with ApoE(-/-)mice and obtained ApoE(-/-)Sam68(+/-)and ApoE(-/-)sam68(+/+)mice, which are both grossly normal. Fed on a regular chow, time-course analyses of atherosclerotic lesions were performed histologically throughout the aortas in these mice. ApoE(-/-)Sam68(+/-) mice displayed a significantly delayed development of atheromatous plaques as compared to ApoE(-/-)sam68(+/+)mice at 5, 7, and 10 months of age. The expression levels of pro-inflammatory factors, including TNFalpha, IL-1beta, and IL-6, in the aortas were significantly lower in ApoE(-/-)Sam68(+/-)mice than in ApoE(-/-)Sam68(+/+) mice. Consistently, in the cultured Raw264.7 macrophages, knockdown of Sam68 resulted in a significant reduction in the TNFalpha-induced expression of these pro-inflammatory genes and also in the level of nuclear phospho-p65, indicating an attenuated NF-kappaB activity. Similar results were reproduced in primary macrophages that were isolated from peritoneum or differentiated from bone-marrow mononuclear cells of Sam68(-/-) mice vs. wild-type mice. Conclusions: Our results for the first time suggest that Sam68 is a critical component of the pro-inflammatory NF-kappaB signaling pathway in macrophages and modulates the course of atherosclerosis at least in ApoE(-/-) mice. Additionally, we have performed Sam68 co-immunoprecipitation and identified by mass spectrometry a panel of new Sam68-interacting proteins. Further experiments are under way to validate those Sam68-interacting proteins that contribute to the NF-kappaB signaling pathway.
Editorial
Authors: S M Krause
Journal: Cardiovascular Research (1999)

See article by Prestle et al. [17] ( pages 323 -331) in thisof active sarcomeres, this can occur at the expense of issue.metabolism, is only temporary and eventually decompensates.Similarly, ischemic cardiomyopathy can be associ-The realization that a non-uniform distribution of wall ated with wall thinning and dilation resulting from loss of stress across the ventricular wall can have transmural contractile sarcomeres.As wall stress increases with effects on cardiac function has been of intense interest to dilation, the time allowed for endocardial perfusion dephysiologists, cardiologists and engineers since Woods creases.This is complicated by the increase in myocardial published his application of the law of LaPlace [11] over a oxygen consumption, which is directly related to the century ago [25].Using the simplified model, LaPlace [11] increase in wall stress [19].Thus, the dilated heart is in a found that, in a thin vessel, tension (stress in a structure higher energy-consuming state than the normal heart.with minimum thickness) is directly related to the internal Consequently, the endocardium may be in a constant state pressure and the radius of the vessel (T5P3r).When this of energy supply / demand imbalance in the failing heart.relationship is applied to a simplified model of the heart,The vulnerability of the endocardium to mismatched either a sphere or an ellipsoid shape, the wall thickness can energy supply / demand may be magnified by an alteration 21
Kidney-Failure Risk Projection for the Living Kidney-Donor Candidate
Authors: Morgan E. Grams, Yingying Sang, Andrew S. Levey, Kunihiro Matsushita, Shoshana Ballew, Alex R. Chang, Eric K.H. Chow, Bertram L. Kasiske, Csaba P. Kovesdy, Girish N. Nadkarni, Varda Shalev, Dorry L. Segev, Josef Coresh, Krista L. Lentine, Amit X. Garg
Journal: New England Journal of Medicine (2015)

Evaluation of candidates to serve as living kidney donors relies on screening for individual risk factors for end-stage renal disease (ESRD). To support an empirical approach to donor selection, we developed a tool that simultaneously incorporates multiple health characteristics to estimate a person's probable long-term risk of ESRD if that person does not donate a kidney.We used risk associations from a meta-analysis of seven general population cohorts, calibrated to the population-level incidence of ESRD and mortality in the United States, to project the estimated long-term incidence of ESRD among persons who do not donate a kidney, according to 10 demographic and health characteristics. We then compared 15-year projections with the observed risk among 52,998 living kidney donors in the United States.A total of 4,933,314 participants from seven cohorts were followed for a median of 4 to 16 years. For a 40-year-old person with health characteristics that were similar to those of age-matched kidney donors, the 15-year projections of the risk of ESRD in the absence of donation varied according to race and sex; the risk was 0.24% among black men, 0.15% among black women, 0.06% among white men, and 0.04% among white women. Risk projections were higher in the presence of a lower estimated glomerular filtration rate, higher albuminuria, hypertension, current or former smoking, diabetes, and obesity. In the model-based lifetime projections, the risk of ESRD was highest among persons in the youngest age group, particularly among young blacks. The 15-year observed risks after donation among kidney donors in the United States were 3.5 to 5.3 times as high as the projected risks in the absence of donation.Multiple demographic and health characteristics may be used together to estimate the projected long-term risk of ESRD among living kidney-donor candidates and to inform acceptance criteria for kidney donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).
Evaluating quality and quantity of life in breast cancer adjuvant trials.
Authors: J H Fetting
Journal: Journal of Clinical Oncology (1988)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1988.6.12.1795 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 3058873 Evaluating quality and quantity of life in breast cancer adjuvant trials. J H FettingxJ H FettingSearch for articles by this author https://doi.org/10.1200/JCO.1988.6.12.1795 First Page PDF © 1988 by American Society of Clinical Oncology
Prognostic factors for stage IV gastric cancer.
Authors: K. Chu, S. Chan
Journal: Journal of Clinical Oncology (2011)

23 Background: In general, the most significant prognostic factor for gastric cancer is tumor stage. In a patient with stage IV gastric cancer, other prognostic factors would be helpful to guide appropriate therapy and to avoid unnecessary suffering as well as fruitless and expensive therapy. Methods: Data of all patients with gastric cancer managed at the Department of Surgery of The University of Hong Kong are entered prospectively into a computer database. Between January 1996 and December 2007, 1,109 patients who have not received prior treatment for their gastric cancer are included in the present study. Factors correlated with tumor stage as well as factors associated with survival are studied with univariate analysis. Significant factors are then subjected to multivariate analysis. In patients with stage IV disease, significant factors associated with survival are then studied with univariate and multivariate Cox regression analysis. Results: 1,109 patients with age of 66 ± 14 years were included. There was a male predominance (M:F = 705:404). 18.1%, 10.3%, 28.3%, and 43.2% have stage I, II, III, and IV diseases, respectively. Spearman's rank correlation analysis identified haemoglobin, lymphocyte/WCC ratio (LWR), platelet count, albumin, CEA, CA19-9, and C-reactive protein (CRP) to be significantly correlated with tumor stage. Multivariate analysis identified LWR, platelet count, albumin, CA 19-9 and CRP as independent factors associated with tumor stage. On the other hand, CA19-9, CRP, LWR and tumor stage were found to be independent prognostic factors associated with overall survival. Among the group of patients with stage IV disease, ECOG status (OR 1.265, 95% CI 1.025 – 1.562), CA 19-9 (OR 1.0, 95% CI 1.0 – 1.0), CRP (OR 1.050, 95% CI 1.021 – 1.081) as well as LWR (OR 0.076, 95% CI 0.011 – 0.552) were found to be independent prognostic factors for survival. Conclusions: Within the group of patients with stage IV gastric cancer, ECOG status, lymphocyte/ WCC ratio, serum CA19.9 and C-reactive protein level were found to be independent prognostic factors for survival. No significant financial relationships to disclose.
Supporting meaningful advance care planning: A quality-improvement initiative to enhance number and preparedness of individuals selected as medical power of attorney.
Authors: Donna S. Zhukovsky, Maria Susan Gaeta, Karen Stepan, Margaret W. Meyer
Journal: Journal of Clinical Oncology (2014)

201 Background: Few health care organizations have successfully implemented a systematic process for meaningful advance care planning (ACP). An available and capable medical power of attorney (MPOA) allows early engagement in the process and is a foundation for successful ACP. As a first step, we implemented a quality improvement (QI) initiative to systematically offer patients (pts) an opportunity to select a MPOA that is valid*, incorporating quality measures to better prepare selected individuals for medical decision-making in a manner that supports the patient’s values and goals. Here we report on yield of valid MPOA documents (MPOAD) obtained. Methods: After QI Assessment Board approval was obtained, baseline data were collected for all head and neck medical oncologists (HNMO) over a 2-week period. In cycle 1, electronic health records (EHR) of pts seen by 2 HNMO were screened by clinic RN for MPOA. Those with MPOAD that were not available in EHR underwent RN follow up. All others were referred to social work (SW) for education regarding value of MPOA and factors important to preparation of decision maker. In cycle 2, revisions made to process included limiting targeted pts to new pts and consults (NPC). Results: See Table. Conclusions: Systematic SW contact and counseling increases the yield of valid MPOA, but is still insufficient for optimal results. Additional measures to be evaluated in future cycles include scheduled appointments for all NPC to increase SW contact, tighter follow up after initial SW contact and MD discussion with NPC to indicate importance of selecting a prepared MPOA. [Table: see text]
Inhibition and flare patterns of metabolic response to the heat shock protein 90 (Hsp90) inhibitor IPI-504 visualized by FDG-PET in patients (pts) with advanced gastrointestinal stromal tumors (GIST) resistant to tyrosine kinase inhibitor (TKI) therapy
Authors: A. D. Van den Abbeele, J. T. Yap, D. S. Grayzel, J. Walker, G. D. Demetri
Journal: Journal of Clinical Oncology (2007)

3530 Background: We have previously demonstrated the inhibition and rebound of GIST glycolytic metabolism with FDG-PET while pts were on or off TKI in prior trials of imatinib and sunitinib. We tested the same principle in a phase I trial of IPI-504, a novel potent inhibitor of Hsp90 (a chaperone for protein homeostasis) that results in selective destruction of the mutated KIT kinase in human GIST cell lines regardless of TKI-resistance mutations. Methods: Twenty-one patients with metatastic and/or unresectable GIST following failure of prior therapy with TKI were treated with IPI-504. Serial FDG-PET imaging was performed at baseline, during the 1st cycle after at least 2 doses (C1, days 4–11, “ON”, n = 18), and at the end of the 10-day off-treatment period prior to the start of the 2nd cycle (C1, “OFF”, n = 20). A subset of 5 pts also had FDG-PET at the end of the 3rd cycle (C3, day 11, “ON”). Maximum standardized uptake values (SUVmax) were measured in up to 3 lesions/pt with the greatest FDG uptake, and the SUVmax of all lesions was summed at each time point. Percent change in the summed mean SUVmax was calculated at each time point relative to the previous scan. Temporal changes were evaluated in those pts showing more than a 10% decrease in SUVmax during C1 “ON” compared to baseline. Results: We observed a &gt;10% reduction in SUVmax (mean = - 28%) during the 1st cycle (C1, “ON”) in 8/18 pts. All these pts showed an increase in SUVmax (mean = +29%) when off therapy (C1, “OFF”). Three of these 8 pts had a scan during cycle 3. All demonstrated a decrease in SUVmax (mean = -30%) while on the drug (C3, “ON”). Conclusion: These preliminary findings suggest that: (1) tumor metabolic response as measured with FDG-PET parallels the intermittent pattern of IPI-504 administration in this study as early as after the 2nd dose administration; and, (2) IPI-504 has a rapid downstream effect on glucose metabolism similar to that observed with TKIs despite the very different mechanism of action of IPI-504. The pattern of response to Hsp90 inhibition seen in this heavily pretreated population strongly supports further clinical investigation. No significant financial relationships to disclose.