tbuckley/cabot-search huggingface dataset:
Assessing the magnitude of antiemetic benefit with the addition of the NK1 receptor antagonist (NK1) aprepitant for all platinum agents: Analysis of 1,872 patients (pts) in prospective randomized clinical phase III trials (RCTs).
Authors: R. J. Gralla, B. L. Rapoport, K. Jordan, J. C. Street, A. Carides
Journal: Journal of Clinical Oncology (2010)

9057 Background: While improvements in the complete control of emesis with NK1s in pts receiving cisplatin (DDP) have been well demonstrated, efficacy reports of this antiemetic class in pts given carboplatin (carbo) or oxaliplatin (oxali) have only been anecdotal. Recent trials documented that emesis with oxali is greater than expected. Guideline groups support using NK1s as part of DDP regimens. Our question relates to the relative magnitude of improvement with aprepitant with newer platinum (PLT) agents in the context of known efficacy with DDP. Methods: We analyzed results of 4 RCTs in 1872 pts receiving chemotherapy. In all trials the control arm on Day 1 was ondansetron (ond) + dexamethasone (dex). The NK1 arms added aprepitant 125 mg on day 1 with 80 mg on days 2 and 3. Control arms for delayed emesis with DDP: dex 8 mg bid in two studies; ond 8 mg bid added in the third; in the aprepitant (investigative) arm only 8 mg of dex daily was given. For delayed emesis with carbo/oxali on the control arm, ond 8 mg bid was given versus the aprepitant dosing only on the investigative arm. 345 pts receiving carbo/oxali were randomized in the 4th study (Rapoport Supp Care Cancer 2009). Odds ratios (OR) and 95% confidence intervals (CI) were determined. A meta-analysis (MA) was conducted of the 3 DDP RCTs with Peto-Odds Ratio and the CI derived through fixed- and random-effect models. Results: The ORs in the carbo/oxali trial and in the DDP MA are in the Table. ORs show similar magnitude of effect with both carbo and DDP; the absolute benefit is greater with DDP given poorer control on the 2-drug regimen. Benefit occurs with aprepitant with oxali, but the magnitude is less than that seen with the other two PLTs. Conclusions: Benefit is documented with the addition of aprepitant to antiemetic regimens for all 3 PLT agents. Further analysis of demographic subgroups may suggest where control is greatest with aprepitant in pts receiving oxali. These results support broader use of NK1s in patients receiving platinum agents. N 5-day no emesis OR 95% CI p DDP 1,527 2.38 1.92, 2.93 <0.0001 CARBO 192 2.30 1.15, 4.63 0.019 OXALI 153 1.45 0.71, 3.34 0.274 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck Merck Merck
Abstract 315: The Role of Mixed Lineage Kinase 3 in Inflammatory Cell-Fibroblast Communication
Authors: Emily M Schulz, Allison E Dixon, Michael S Burhans, Michelle L Nieman, John N Lorenz, Val Goodfellow, Harris A Gelbard, Stephen Dewhurst, Burns C Blaxall
Journal: Circulation Research (2014)

Mixed lineage kinase 3 (MLK3) is a ubiquitously expressed pro-inflammatory, pro-apoptotic mitogen activated protein kinase kinase kinase (MAP3K). MLK3 is a key regulator of the p38 and c-jun terminal kinase (JNK) pathways and has been studied in cancer and neurodegenerative disease. Although the p38 and JNK pathways have been studied in the cardiac function and disease, little is known regarding the role of MLK3 in the heart. Studies in our laboratory have indicated that MLK3 RNA is highly expressed in macrophages, cardiomyocytes and cardiac fibroblasts, suggesting an important role in cardiac function. Recently published work has indicated that MLK3 plays an important role in inflammatory cell motility, leading us to hypothesize that MLK3 is involved in inflammatory cell-fibroblast communication during cardiac disease. Knockout (KO) or inhibition of MLK3 using the novel small molecule inhibitor URMC-099 does not significantly affect heart rate, mean arterial pressure, systolic pressure, minimum or maximum dp/dt compared to wild type (WT) controls as measured by invasive hemodynamics at 3 months of age. Echocardiographic analysis indicates that MLK3 KO or inhibition does not affect cardiac architecture or cardiac function, indicated by fractional shortening or ejection fraction. However, upon transaortic constriction (TAC), MLK3 KO and URMC-099 treatment results in decreases in Mac-3 positive staining at 3 and 7 days post-TAC as well as decreases in CD-45 staining 7 days post-TAC compared to WT TAC operated, vehicle treated controls, suggesting that MLK3 KO and drug treatment may attenuate the early inflammatory response after TAC. Studies examining the relationship between the MLK3 mediated inflammatory response and subsequent fibrosis and cardiac dysfunction post-TAC are currently ongoing.
Public Health England replies to Mike Rayner and colleagues
Authors: Alison Tedstone, Victoria Targett
Journal: BMJ (2015)

We welcome the debate on our comprehensive evidence package informing the government’s thinking on sugar in the diet. However, Rayner and colleagues fail to grasp the detailed complexities at play in reducing sugar consumption.1 They seem not to understand the wider environmental drivers of UK diets and seem unaware that Public Health England (PHE) clearly prioritised actions for government consideration.

The report offers the most detailed analysis yet of how advertising, marketing, and fiscal measures influence our food choices, diet, and—where available—health outcomes. We also assess possible approaches to sugar reduction in foods and drinks. The methodologies are mixed to account for the different weights of primary evidence …
Cost-effectiveness of zoledronic acid (ZOL) for the treatment of bone loss in postmenopausal women with early-stage breast cancer receiving aromatase inhibitors in the United States (US).
Authors: S. J. Thurston, S. C. Zelt, M. Botteman
Journal: Journal of Clinical Oncology (2010)

e11007 Background: Treatment guidelines recommend the use of bisphosphonates in postmenopausal women with early-stage breast cancer receiving prolonged aromatase inhibitor therapy and who are at high risk of fractures (e.g., in patients whose bone loss has become clinically significant, e.g., with bone mineral density BMD T score < 2 SD below normal, or who have experienced a fragility fracture). This retrospective modeling analysis assessed the cost-effectiveness of ZOL therapy versus no therapy for the treatment of aromatase inhibitor induced bone loss in US postmenopausal women with breast cancer. Methods: A model was developed to project the lifetime fractures incidence as a function of BMD. In the model, patients were assumed to receive aromatase inhibitors (i.e., letrozole [Femara] 2.5 mg daily), for 5 years with a starting T score of -2 or more. In one arm, patients initiated ZOL (4 mg IV infusion q 6 months) when their BMD T-score decreased to more than 2 SD below normal or had nontraumatic fracture. Data regarding the efficacy of this treatment arm came from the results of the US- based Z-FAST trial. In the comparison group, patients were assumed to receive no ZOL therapy. The progression of bone loss and risk of fracture in the no treatment group were obtained from the published epidemiologic literature. The model simulated the impact of fractures on costs, quality of life and mortality. Results: Compared to the no treatment arm, patients on the ZOL arm experienced a gain of 0.032 quality-adjusted life-years (QALYs), at the incremental costs of $47,995 per QALY. In a sensitivity analysis in which a Medicare payer perspective was adopted, whereby only 80% of costs are included, the costs/QALY improved to $38,396. Conclusions: The use of ZOL for the treatment of aromatase inhibitor induced bone loss in postmenopausal women with breast cancer whose bone loss has become clinically significant or who have experienced a fragility fracture appears cost-effective in the US. These results might be conservative as they exclude the potential benefits of ZOL on disease progression. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis
Cetuximab, intensity-modulated radiotherapy (IMRT), and twice-weekly gemcitabine for pancreatic adenocarcinoma
Authors: J. M. Pipas, B. Zaki, A. A. Suriawinata, M. J. Tsapakos, G. H. Ripple, T. A. Colacchio, J. E. Sutton, S. R. Gordon, M. S. Kasibhatla, R. J. Barth
Journal: Journal of Clinical Oncology (2006)

14056 Background: Epidermal growth factor receptor (EGFR) is over expressed in pancreatic cancer. Cetuximab is an EGFR-antagonist which has synergy with gemcitabine (gem) and radiation. Gem is a potent radiosensitizer. We are conducting a Phase II trial of cetuximab with IMRT and twice-weekly gem. Eligibility includes stage I-III adenocarcinoma, with EGFR staining by immunohistochemistry. Pretreatment evaluation includes chest/abdomen CT scan and laparoscopy. Methods: Cetuximab 400 mg/m 2 IV load was given over two hours. One week later, treatment continued with weekly cetuximab 250mg/m 2 IV over one hour, and gem 50mg/m 2 IV twice-weekly for twelve doses, concurrent with IMRT given in 28 daily fractions to 54Gy. Cetuximab/gem was given prior to that day’s IMRT. GI prophylaxis was with a proton pump inhibitor. Patients were considered for resection 4–8 weeks following therapy. Results: Ten patients enrolled to date, median age 70 years (range 54–83). Ninety percent of tumors were EGFR positive (range 1+ to 3+). At presentation, three tumors were unresectable, three borderline resectable and four resectable. One patient was removed from study following cetuximab anaphylaxis. Eight patients experienced grade III-IV hematotoxicity. Two patients had ischemic stroke in the backdrop of infection, one from stent obstruction/cholangitis, the other during neutropenic fever. One of these patients (age 81) died. Autopsy revealed severe atherosclerotic disease and evidence of prior strokes. Eight patients were evaluable for response. No patient had local progression. One patient had liver metastases post treatment. Two patients (25%) exhibited partial response. All others had stable disease. EGFR over expression did not predict response. Six patients went on to margin (−) resection, including one patient each with borderline resectable and unresectable disease prior to therapy. At median follow up of 8.5 months, there were no recurrences. Conclusions: Therapy yields modest efficacy and high resectability rates in patients with pancreatic cancer. Downstaging of tumor can occur in some patients. Toxicity may in part reflect the elderly patient demographic. Planned accrual is 48 patients. [Table: see text]
Effect of a fully human anti-CD70 antibody on apoptosis and dephosphorylation of MAPK proteins in chronic lymphocytic leukemia
Authors: C. A. Llanos, J. A. Terrett, L. Cohen, T. J. Kipps, J. E. Castro
Journal: Journal of Clinical Oncology (2008)

3073 Background: CD70 is a member of the tumor necrosis factor receptor family and receptor for CD27, which is expressed on activated T cells. Both CD70 and CD27 are expressed in chronic lymphocytic leukemia (CLL). Ligation of CD70 on normal B or CLL cells may play a role in activation, suggesting co-expression of CD27 and CD70 might have pathophysiologic significance. MAbs specific for CD70 can induce apoptosis of CD70+ carcinoma cells in vitro and in vivo in xenograft models. As such, we investigated whether a novel fully human anti-CD70 antibody (h-anti-CD70) could induce apoptosis of CLL cells. Methods: Blood mononuclear cells from 12 patients with CLL and healthy volunteers were evaluated for expression of CD70 by flow cytometry. Also, CLL cells were treated with h-anti- CD70 (10–300 μg/ml) and evaluated after 24 hours culture by flow cytometry and immunoblot analysis. Results: CLL cells of each examined case expressed levels of CD70 that were significantly higher that noted on normal blood B cells. The levels of CD70 on CLL cells from patients with high risk vs. low risk CLL (IgVH mutation status or ZAP-70 level of expression) were comparable. CLL cells treated with h-anti-CD70 underwent apoptosis at rates that were significantly greater than that observed in control cultures. The CLL cells from each of the 12 cases studied underwent apoptosis when treated with h-anti-CD70. This was associated with apparent dephosphorylation of MAPK proteins that typically are phosphorylated in CLL cells and that have been associated with cellular activation. Conclusions: CLL cells express high levels of CD70 independent of whether they have features of high-risk disease. Ligation of CD70 with h-anti-CD70 induced specific apoptosis of CLL cells in all samples tested. Decreased viability was associated with loss of phosphorylated MAPK kinases. Our findings suggest that CD70 is a relevant target in CLL for therapeutic development and support the rationale for the use of h-anti-CD70 in future clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Medarex Medarex
Trc105 (Anti-Endoglin Antibody) in Combination with Bevacizumab (Bev) and As a Single Agent for Platinum Resistant Ovarian Cancer
Authors: A.A. Garcia, V. Makker, D.L. Spitz, D.E. Matei, A.M. Nick, C.N. Landen, E.A. Alvarez, D.S. Mendelson, R.M. Strother, B.K. Seon, D. Alvarez, B.J. Adams, C.P. Theuer, M. Gordon
Journal: Annals of Oncology (2014)
A Recombinant Bispecific CD20×CD95 Antibody With Superior Activity Against Normal and Malignant B-cells
Authors: Kristina Nalivaiko, Martin Hofmann, Karina Kober, Nadine Teichweyde, Peter H Krammer, Hans-Georg Rammensee, Ludger Grosse-Hovest, Gundram Jung
Journal: Molecular Therapy (2015)

Monoclonal antibodies directed to the B-cell-specific CD20-antigen are successfully used for the treatment of lymphomas and autoimmune diseases. Here, we compare the anti-B-cell activity of three different antibodies directed to CD20: (i) a chimeric, monospecific antibody, (ii) an Fc-optimized variant thereof, and (iii) a bispecific CD20×CD95-antibody in a newly developed recombinant format, termed Fabsc. The bispecific antibody specifically triggers the CD95 death receptor on malignant, as well as activated, normal B-cells. We found that the capability of this antibody to suppress the growth of malignant B-cells in vitro and in vivo and to specifically deplete normal, activated B-cells from peripheral blood mononuclear cell (PBMC) cultures was superior to that of the Fc-optimized monospecific antibody. This antibody in turn was more effective than its nonoptimized variant. Moreover, the bispecific antibody was the only reagent capable of significantly suppressing antibody production in vitro. Our findings imply that the bispecific CD20×CD95-antibody might become a new, prototypical reagent for the treatment of B-cell-mediated autoimmune disease.
Fraction of exhaled nitric oxide in children aged 4 to 11 years
Authors: Jana Kivastik, Tiina Rebane, Maire Vasar
Journal: European Respiratory Journal (2012)

Introduction: Fraction of exhaled nitric oxide (FENO) is a useful marker of allergic airway inflammation and can measure the response to anti-inflammatory therapy. Availability of commercial portable FENO analyzers has made the measurement more wide-spread in clinical care of children.

Aim: To study FENO in relation to current respiratory symptoms and medication in patients of Tartu Children's Clinic and in healthy children.

Methods: We measured fraction of exhaled NO with the hand-held device (NIOX MINO; Aerocrine AB, Sweden) in 242 children aged 4-11 years. Children were classified as wheezers (wheeze during the last 12 months), coughers or healthy (groups W, C and H, resp.) according to the questionnaires about respiratory and atopic problems. 79 out of 207 symptomatic children had been treated with inhaled corticosteroids (ICS) during the last month. We defined FENO values >20 ppb as abnormal, the limit suggested for children aged 12 or less by Taylor, D.R. et al. (Thorax 2006;6:817-827).

Results: Measured FENO values and the amount of abnormal values by groups are presented in Table 1. FeNO levels were significantly higher in wheezers compared to healthy children (p<0.05).

View this table:

Table 1. Data by groups.





Conclusions: Measurement of FENO by a portable device is feasible for children over 4 years, and can provide an objective measure of airway inflammation for monitoring of asthma in Tartu Children's Clinic.
Abstract P074: Substituting Homemade Fruit Juice for Sugar-Sweetened Beverages is Associated with Lower Odds of Metabolic Syndrome among Hispanic Adults
Authors: Josiemer Mattei, Vasanti Malik, Frank B Hu, Hannia Campos
Journal: Circulation (2012)

Introduction: Consumption of sugar sweetened beverages (SSB) has been consistently associated with metabolic syndrome (MetS), while results on the role of fruit juice intake are conflicting. Hispanics consume both SSB and traditional fruit-based beverages; however, studies conducted on such ethnic group are scarce. Given the high prevalence of MetS among Hispanics, describing putative contributors to this condition is essential in proposing approaches that may successfully reduce its prevalence and avoid further complications. Hypothesis: We assessed the hypothesis that substituting fruit-based beverages traditionally consumed by Hispanics for SSB may be associated with lower odds of MetS. Methods: To determine the cross-sectional association between beverages consumed by Hispanics, and MetS and its components, data were analyzed in 1,872 Costa Rican adults who served as controls of a population-based case-control study of coronary heart disease. Multivariate adjusted means were calculated for components of MetS by servings (never, &lt;1/week, 2–6/week, ≥1/day) of two traditional fruit-based beverages (‘fresco’ and homemade fruit juice, separately) and two SSB (instant drinks and regular sodas, separately and combined). Prevalence ratio (PR) of MetS was calculated for each beverage, and odds ratio (OR) was calculated by substituting one serving of homemade fruit juice or water for one of SSB. Results: Significant positive trends were observed for increasing servings of instant drinks and combined SSB with plasma triglyceride and waist circumference, and for regular soda with waist circumference (all P -trend&lt;0.001). Increasing servings of homemade fruit juice were associated positively with HDL-C ( P -trend=0.033). Consuming ≥1 serving/day of instant drinks was associated with higher PR of MetS (1.42, 95%CI: 1.11, 1.83) compared to no consumption; similar results were obtained for combined SSB. Substituting one serving of homemade fruit juice for instant drink was associated with 29% (95% CI=7, 47%) lower odds of MetS, and for regular soda with 30% (1, 50%) lower odds. Substituting water for combined SSB was marginally significant (OR=0.86 (0.74, 1.00). Conclusion: In conclusion, reducing consumption of SSB and substituting them with homemade fruit juices in moderation, may be a culturally-appropriate approach to lower metabolic syndrome among Hispanics. Our study provides the groundwork for interventions on beverage intake that aim to prevent MetS and type 2 diabetes in Hispanic ethnic subgroups, and may support current public health efforts on limiting availability and intake of SSB, while substituting with a healthy beverage.
Efficacy and Safety of Single-Agent Ibrutinib in Patients with Mantle Cell Lymphoma Who Progressed after Bortezomib Therapy
Authors: Michael Wang, Andre Goy, Peter Martin, Rod Ramchandren, Julia Alexeeva, Rakesh Popat, Irit Avivi, Ranjana Advani, Steven Le Gouill, Netanel Horowitz, Zhilong Yuan, Britte Kranenburg, Aleksandra Rizo, Sen Hong Zhuang, William Deraedt, Simon Rule
Journal: Blood (2014)
Phase II study of continuous infusion fluorouracil and interferon alfa-2b in the palliation of malignant neuroendocrine tumors.
Authors: H J Andreyev, P Scott-Mackie, D Cunningham, V Nicolson, A R Norman, S S Badve, A Iveson, M C Nicolson
Journal: Journal of Clinical Oncology (1995)

Twenty-four patients with rapidly progressive neuroendocrine tumors were treated with a new regimen of continuous infusion fluorouracil for 20 weeks (200 mg/m2/d) together with interferon alfa-2b (5 MU three times per week). Maintenance interferon alfa at the same dose was continued after the initial 20-week period.Of 15 patients with carcinoid tumors, seven (47%) had an objective response, with a median duration of 20.5 months (range, 8.5 to 41), and five (33%) had stabilization of disease for between 3.5 and 42 months. Improvement in symptoms was reported by 10 patients (67%). Three early deaths occurred, all in patients with advanced disease. Of nine patients with neuroendocrine tumors other than carcinoid, three (33%) had an objective response that lasted 2.5 to 24.5 months, and five had disease stabilization for between 2.5 and 16 months.These data, particularly in respect to carcinoid tumors, are encouraging, especially since serious complications from treatment were limited. This regimen is not generally toxic, is well tolerated, and offers useful palliation and symptom control in patients with disease that does not respond to simple pharmacologic manipulations.
Induction of Changes in the Pepsinogen Content and the Pepsinogen Isoenzyme Pattern of the Pyloric Mucosa of the Rat Stomach by Short-Term Administration of Stomach Carcinogens&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: C Furihata, K Kodama, T Matsushima
Journal: JNCI Journal of the National Cancer Institute (1981)

Changes in pepsinogen isoenzyme patterns were examined in the pyloric mucosae of the stomachs of noninbred male Wistar rats after short-term administration of gastric carcinogens. N-Methyl-N-nitro-N-nitrosoquanidine, N-ethyl-N1-nitro-N-nitrosoguanidine, and N-propyl-N-nitro-N-nitrosoguanidine, which induce stomach cancer in rats, decreased the content of pepsinogen isoenzyme 1 )Pg 1), which was separated by poly-acrylamide gel electrophoresis. They also decreased the pepsingoen content of the pyloric mucosa. 4-Nitroguinoline 1-oxide, which induces a low incidence of stomach cancer in rats, rarely decreased the Pg 1 content or the pepsinogen content of the pyloric mucosa, and the incidence of such decreases was not statistically significant. However, diethylnitrosamine and dimethylnitrosamine, which do not induce stomach cancer in rats, did not cause any decrease in pepsinogen content. Ethyl methanesulfonate, a direct-acting carcinogen used as a control, also did not decrease the pepsinogen content.
Myeloma Patient-Derived Mesenchymal Stem Cells Grown In 3-D Culture Induce Primary Myeloma Cell Proliferation and Resistance To Therapy
Authors: Jana Jakubikova, Richard W.J. Groen, Teru Hideshima, Danka Cholujova, Jan Sedlak, Constantine S. Mitsiades, Jacob P. Laubach, Nikhil C. Munshi, Paul G. Richardson, Kenneth C. Anderson
Journal: Blood (2013)