tbuckley/cabot-search huggingface dataset:
Pharmacoeconomic analysis of dalteparin vs. vitamin k antagonists (VKA) for the prevention of recurrent venous thromboembolism (VTE) in cancer patients with renal insufficiency.
Authors: George Dranitsaris, Lesley Shane, Seth Woodruff, Laura Burgers
Journal: Journal of Clinical Oncology (2016)

e18238 Background: Patients with cancer who develop thrombosis are at increased risk for recurrent VTE. To reduce this risk, prolonged prophylaxis with VKA may be offered. However in a randomized trial (i.e. CLOT) which evaluated secondary prophylaxis of recurrent VTE in cancer patients (Lee et al, 2003), extended duration dalteparin reduced the relative risk of recurrent VTE by 52% compared to oral VKA therapy (P = 0.002). A recent subgroup analysis in patients with moderate to severe renal impairment at randomization also revealed lower absolute VTE rates with dalteparin (3% vs. 17%; p = 0.011) (Woodruff et al, 2015). To measure the economic value of dalteparin in these populations, a pharmacoeconomic analysis was conducted from the Dutch health care system perspective. Methods: Resource utilization data contained within the CLOT trial database was extracted and converted into Dutch cost estimates. Univariate and multivariate quantile regression analysis was conducted to compare the total direct cost of therapy between patients randomized to dalteparin or VKA therapy. Health state utilities and treatment preferences were measured in 24 members of the general public using the Time Trade-Off technique. Results: When all of the cost components were combined for the full CLOT trial population (n = 676), the dalteparin group had significantly higher mean costs than the control group (dalteparin = €2,375 vs. VKA = €1,724; p < 0.001). However, the preference assessment revealed that 21 of 24 respondents (88%) selected dalteparin over VKA with an associated gain of 0.14 (95%CI: 0.10 to 0.18) QALYs. When the incremental cost of dalteparin was combined with the QALY gain, dalteparin was associated with a cost of €4,697 (95%CI: €3,824 to €4,951) per QALY gained. The analysis in patients with moderate to severe renal impairment suggested an even better economic profile with the cost per QALY gained being < €2,000. Conclusions: Secondary prophylaxis with dalteparin is a clinically and economically attractive alternative to VKA for the prevention of recurrent VTE in patients with cancer, and especially in those with moderate to severe renal impairment.
Hierarchical structured and programmed vehicles deliver drugs locally to inflamed sites of intestine
Authors: Wei Li, Yunzhan Li, Zehua Liu, Nattha Kerdsakundee, Ming Zhang, Feng Zhang, Xueyan Liu, Tomás Bauleth-Ramos, Wenhua Lian, Ermei Mäkilä, Marianna Kemell, Yaping Ding, Bruno Sarmento, Ruedeekorn Wiwattanapatapee, Jarno Salonen, Hongbo Zhang, Jouni T. Hirvonen, Dongfei Liu, Xianming Deng, Hélder A. Santos
Journal: Biomaterials (2018)

Orally administrable drug delivery vehicles are developed to manage incurable inflammatory bowel disease (IBD), however, their therapeutic outcomes are compromised by the side effects of systemic drug exposure. Herein, we use hyaluronic acid functionalized porous silicon nanoparticle to bridge enzyme-responsive hydrogel and pH-responsive polymer, generating a hierarchical structured (nano-in-nano-in-micro) vehicle with programmed properties to fully and sequentially overcome the multiple obstacles for efficiently delivering drugs locally to inflamed sites of intestine. After oral administration, the pH-responsive matrix protects the embedded hybrid nanoparticles containing drug loaded hydrogels against the spatially variable physiological environments of the gastrointestinal tract until they reach the inflamed sites of intestine, preventing premature drug release. The negatively charged hybrid nanoparticles selectively target the inflamed sites of intestine, and gradually release drug in response to the microenvironment of inflamed intestine. Overall, the developed hierarchical structured and programmed vehicles load, protect, transport and release drugs locally to inflamed sites of intestine, contributing to superior therapeutic outcomes. Such strategy could also inspire the development of numerous hierarchical structured vehicles by other porous nanoparticles and stimuli-responsive materials for the local delivery of various drugs to treat plenty of inflammatory gastrointestinal diseases, including IBD, gastrointestinal cancers and viral infections.
An app to increase cross-referral and recruitment to melanoma clinical trials.
Authors: Maria Gonzalez, Matteo S. Carlino, Robert Richard Zielinski, Joel Smith, Robyn Saw, Angela Hong, Monika Keczkowska, Roslyn Ristuccia, Jim McBride, Alexander M. Menzies, Georgina V. Long
Journal: Journal of Clinical Oncology (2016)

9590 Background: Melanoma Institute Australia (MIA) is a major referral centre providing melanoma pts with specialist multidisciplinary care including access to clinical trials. In the current environment of rapid therapeutic progress and recent drug approvals, maintaining up to date knowledge of current recruiting trials will ensure melanoma clinical trials remain an accessible treatment avenue for pts and referrers. We sought to create a free smart phone application (app) to provide any clinician and research team with reliable and instantaneous information regarding open trials in melanoma at MIA and to increase referrals of pts for trials. Methods: An existing clinical trial app platform (Haematology Clinical Research Network) was modified to meet melanoma specifications. An iOS and Android app was developed enabling searches of open trials filtered by disease stage, mutation and intracranial disease status. Other features include inclusion/exclusion criteria and direct links to Clinicaltrials.gov. Locally managed real-time back-end database entry ensured app content accuracy. User uptake was examined using Google Analytics. MIA patient cross-referral figures, recruitment and staffing data were obtained for 2015 and compared with 2014 activity. Results: Since launching ‘CinTrial Refer Melanoma’ in December 2014, there were 4140 users and over 6920 sessions lasting an average of 35 sec. 38% of users were in Australia, 62% elsewhere (20% USA). Trial recruitment increased from 97 to 220 pts (127%) and a 2.0 full time equivalent increase in coordinators during 2015 compared with the preceding year. Analysis of medical oncology referrals showed an increase of 23% during the same period. This may also be attributed to other MIA profiling activities and an overall increase in the number of new trials during 2015. Conclusions: ClinTrial Refer Melanoma is a powerful real-time networking resource and an innovative instrument for enhancing awareness of open trials. User uptake is high and was associated with increased referrals. Further efforts to augment and monitor user uptake continues and work is underway to extend participation to other trial sites in Australia. Findings support the use of app technology for all solid tumours.
Preliminary results of a phase Ib study of GS-4059 in combination with entospletinib in patients with B-cell malignancies.
Authors: Christopher Fegan, Alexey Valeryevich Danilov, Daniel Hodson, Gilles A. Salles, Alexander Starodub, Siddhartha Mitra, Yingsi Yang, Harriet Walter, Franck Morschhauser
Journal: Journal of Clinical Oncology (2017)

7518 Background: GS-4059 (ONO-4059) selectively and irreversibly inhibits Bruton’s tyrosine kinase (BTK) and entospletinib selectively inhibits spleen tyrosine kinase (SYK). Methods: This ongoing phase 1b study is evaluating the safety and tolerability of GS-4059 combined with entospletinib in patients with previously treated CLL, FL, SLL, MCL, MZL, WM, or non-GCB DLBCL. The study design uses 3+3 dose escalation (Table) withexpansion cohorts at potential phase 2 doses. Results: With a median duration of treatment of 22 weeks (range 3-56), 26/32 enrolled patients continue on treatment. The median age was 70 (43–85) years and 59% were men. Patients had the following diseases: CLL (n = 9), non-GCB DLBCL (7), FL (6), WM (5), MCL (2), SLL (2), and MZL (1). The median number of prior therapies was 2 (1–5). Five patients discontinued all study treatment, 4 due to disease progression (DLBCL x 2, MCL, MZL) and one due to withdrawal of consent. There has been 1 death on study due to progressive disease. The maximum tolerated dose was not reached. 90% of patients treated reported a treatment-emergent AE (TEAE) of which 48% were grade ≥3. Grade ≥3 TEAEs that were present in more than 1 patient were neutropenia (4), anemia, thrombocytopenia, pneumonia and AST/ALT elevation (2 each). The TEAEs present in &gt;10% of patients were fatigue (7), petechiae (5), asthenia, constipation, contusion, dyspepsia, neutropenia and rash (4 each). No patients discontinued treatment due to AEs and all 5 patients with interruption of treatment for an AE successfully re-initiated therapy. 17 patients were evaluable for best overall response with the results as follows: 11 with partial responses (2 each with CLL, DLBCL, FL, SLL, WM, 1 with MCL); 4 with stable disease; 2 with progressive disease. Conclusions: GS-4059 at up to 160 mg in combination with entospletinib up to 400 mg daily was safe and well tolerated, supporting the continued clinical evaluation of the combination for the treatment of B-cell malignancies. Clinical trial information: NCT02457598 Clinical trial information: NCT02457598. [Table: see text]
Sunitinib (SM) in advanced extraskeletal myxoid chondrosarcoma (EMC): Updated analysis in 11 patients (pts).
Authors: Salvatore Provenzano, Roberta Maestro, Gianpaolo Dagrada, Paola Collini, Maria A. Pantaleo, Annalisa Astolfi, Tiziana Negri, Alessandro Gronchi, Chiara Colombo, Carlo Morosi, Angelo Paolo Dei Tos, Monica Brenca, Maurizio Polano, Silvana Pilotti, Paolo Giovanni Casali, Silvia Stacchiotti
Journal: Journal of Clinical Oncology (2016)

11059 Background: EMC is a rare sarcoma, marked by a specific rearrangement involving NR4A3. We reported on the activity of SM in 10 EMC pts (Eur J Cancer 2014;50:1657). We update herein this series with a longer follow-up and provide clues on the molecular bases of response. Methods: All pts with a confirmed diagnosis of progressive, advanced EMC treated since July 2007 with SM 37.5 mg/day on a named-used program were considered. Pts were treated until unacceptable toxicity or progression. SM dose was increased to 50 mg/day in pts with primary PD and acceptable toxicity while on SM 37.5 mg. Diagnosis was confirmed by the presence of NR4A3 fusion. Response was assessed by RECIST, considering treatment failure those cases who progressed while on therapy and after escalating SM to 50 mg/day. The pretreatment transcriptional profiles of 4 responsive and 2 non-responsive pts were compared. Results: Eleven pts with progressive, metastatic EMC were identified (mean age: 62 yrs - prior chemotherapy: 10). All pts were evaluable for response. Six pts stopped SM (toxicity: 3; PD: 3, of which 2 were primary, 1 secondary), while 5 pts are currently on therapy (range of time on treatment: 1-54+ mos). Best responses were: 6 PR, 3 SD, 2 PD. PR was achieved at the dose of 37.5 and 50 mg/day in 4 and 2 cases, respectively, while 2 pts progressed despite of dose escalation. One pt had a response to SM after PD while on pazopanib. Interval PD were observed in 4 pts and response was restored in all after SM rechallenge. Among pts with a PR to SM, no secondary resistance has been detected as of today, while in one pt a PD was observed after an initial SD. At a median FU of 32 mos, median PFS is 34 mos, while median OS is not reached. Unsupervised cluster analysis divided EMC into 2 major groups corresponding to responsive/EWSR1-NR4A3+ and non-responsive/TAF15-NR4A3+ cases. Conclusions: We confirm that SM is active in EMC, with responsive pts reaching prolonged progression-free intervals. We already reported that all responsive pts had the EWSR1-NR4A3 fusion variant and RNAseq analysis suggests that SM response correlates with a distinctive expression profile. The specific mechanism of action is under evaluation. A European phase II study on pazopanib in EMC is ongoing.
Folate gene prediction of treatment response to 5-FU and leucovorin in advanced colorectal cancer.
Authors: Bengt Gustavsson, Elisabeth Odin, Pushpa Saksena, Hans Wedel, Anders Edsjo, Goran Ulf Carlsson, Helena Anna Taflin, Elinor Bexe Lindskog, Karin M E Ganlov, Anders Vedin, Yvonne Wettergren
Journal: Journal of Clinical Oncology (2018)

3550 Background: 5-fluorouracil (5-FU) with the folate pro-drug leucovorin (LV) has long been backbone of chemotherapy for colorectal cancer (CRC). Low expression of folate-related genes may lead to poor response to 5-FU + LV (FLV) since poor transport and metabolization of LV yield insufficient co-factor ([6R]-5,10-methylenetetrahydrofolate) and weak inhibition of the target gene thymidylate synthase (TYMS). We have previously found a positive correlation between survival and expression of folate pathway genes in stage III CRC treated with adjuvant FLV. The aim of the present study was to relate progression-free survival (PFS) with gene expression in tumors from patients with metastasizing CRC (mCRC). Methods: Tissue samples of primary tumors were obtained at surgery from patients with mCRC (n = 143) prior to FLV-based chemotherapy. Outcome data were extracted from the Sahlgrenska University Hospital data base. Gene expression was determined with qPCR. Results: Significant positive correlations between PFS and expression of several folate relevant genes were found. After adjustment in a multiple Cox analysis of all analyzed genes, only ABCC3 remained significant (p < 0.0002). The ABCC3 protein is involved in outward transport of folates, and has preference for 10-formyltetrahydrofolate. This folate inhibits the first conversion step of LV to active co-factor. High expression of ABCC3 may therefore cause a high conversion rate of LV to co-factor, and enhanced inhibition of TYMS. After Cox analysis, ABCC3 expression levels were divided into tertiles; the low, intermediate and high levels. The intermediate and low tertiles had near identical outcomes and were combined. The high expression group had a median PFS of 10.1 months compared to 6.5 months among patients in the low expression group. Conclusions: Folate-related genes predict response to treatment with FLV in stage III and IV CRC. Outcome study after direct treatment with the direct co-factor diastereoisomer is warranted.
2017 ACC/AHA Blood Pressure Treatment Guideline Recommendations and Cardiovascular Risk
Authors: Lisandro D. Colantonio, John N. Booth, Adam P. Bress, Paul K. Whelton, Daichi Shimbo, Emily B. Levitan, George Howard, Monika M. Safford, Paul Muntner
Journal: Journal of the American College of Cardiology (2018)
Abstract 16120: Development of a Transplant Injection Device for the Optimal Distribution and Retention of iPS Cell-Derived Cardiomyocytes
Authors: Ryota Tabei, Hideaki Kanazawa, Jun Fujita, Shugo Tohyama, Akinori Hirano, Shinji Kawaguchi, Kazuaki Nakajima, Tomohisa Seki, Yoshikazu Kishino, Marina Okada, Hideyuki Shimizu, Eiji Kobayashi, Yasuhiko Tabata, Keiichi Fukuda
Journal: Circulation (2017)

Introduction: Induced pluripotent stem cell (iPSC)-based regenerative therapies are a promising strategy to treat several cardiovascular diseases; however, difficulties present from the limited myo...
P05.01 New techniques in Radiotherapy for brain tumors and brain metastasis, VMAT (volumetric modulated arc therapy) and SIB technique (simultaneous integrated boost), Neuroaxis radiotherapy, pediatric gliomas
Authors: M Theodorou, M Theodorou
Journal: Neuro-Oncology (2018)

With the VAMT technique we radiated the brain tumors such as Glioblastomas, Astrocytomas, low grade Gliomas, Gliomas -Recurrence, meningiomas, acustic neurinomas, pituitary adenomas, brain metastasis and pediatric gliomas and Neuroaxisradiation for PNET and Medulloblastoma. With the VMAT plan the PTV coverage is higher compared the 3D conformal technique and the radiation for the OAR (organs at risk) is less so the safety for the organ at risk is a significant factor to choose the VMAT technique. Due to the lower dose in the organ at risks the rate for acute side effects and late side effects is lower such as the radionecrosis risk. The Neuroaxis Radiation (Brain and whole spine) in VMAT technique delivers high coverage in the target and a good toleration of the treatment without significant side effects such as gastrointestinal symptoms. Mild fatigue and nausea is mentioned and alopecia at the end of radiation. The simultaneous integrated boost (SIB) delivers higher dose for the macroscopic tumor daily and at the same time the whole target inclusive safe margin takes lower dose. The toleration is also good without significant side effects. In conclusion we can suggest the New techniques in Radiotherapy using the VMAT technique for brain tumor due to the high coverage of the targets, the safety for the OAR and the short time radiation especially for little children in order to avoid sedation.
Patterns of care and outcomes with the addition of radiotherapy to surgery for stage I rectal adenocarcinoma.
Authors: Nan Zhao, Chi Lin
Journal: Journal of Clinical Oncology (2018)

e15687 Background: The standard of care for stage I (T1/2N0M0) rectal adenocarcinoma (RA) is surgery alone. We investigated practice patterns and outcomes associated with administration of radiotherapy (RT) to surgery for stage I RA. Methods: Using National Cancer Database from 2004 to 2015, 11030 patients with clinical stage T1-2N0M0 RA who had definitive surgery were analyzed (7448, definitive surgery alone; 3582, definitive surgery with preoperative or postoperative RT). Between groups, demographic, tumor, and treatment characteristics were compared. Multivariate logistics regression was used to examine factors associated with the receipt of RT. Overall survival (OS) were estimated by Kaplan-Meier method, the log-rank test, Cox proportional hazards models, and propensity score-matched analysis. Results: Of 11030 patients, 33% received RT (58% preoperative, 42% postoperative (only 11 (0.7%) had pathological stage III)); among them, 94.1% received chemotherapy (CT). Patients who received RT tended to be younger, male, diagnosed in early years, covered by Medicare/Not Insured, treated at community cancer program, a lower Charlson score, a T2 clinical stage, a poorly differentiated or a larger tumor. Survival analysis revealed no difference in patients with or without RT (Median survival of 148 vs. 147 months and 5 year OS of 77 vs. 78%, p = 0.12). Multivariate Cox models showed that variables significantly associated with increased hazard of death (p < 0.05) were older age (HR = 1.06), Charlson score 1 (HR = 1.46)/ Charlson score ≥ 2 (HR = 2.14) (vs. Clarlson score 0), pathological III/IV stage (HR = 4.06), Medicaid (HR = 1.68) /Medicare (HR = 1.26)(vs. private insurance), black (HR = 1.28), clinical T2 stage (HR = 1.14) (vs. clinical T1 stage), poor differentiated (HR = 1.32), community cancer program (HR = 1.14) and with larger tumor (HR = 1.001). Propensity score-matched analysis demonstrated a similar 5 year OS (77 vs.76%) in patients with RT or without RT (p = 0.079). Conclusions: One third of stage I RA patients had either preoperative or postoperative RT although addition of RT ± CT did not have a survival advantage and was not recommended. Further studies are warranted to explore reasons for these patterns of care.
TCT-242 Residual Shunt after Patent Foramen Ovale Device Closure in Patients With Cryptogenic Stroke: Serial Bubble Contrast Transesophageal Echocardiography Data
Authors: Pyung Chun Oh, Woong Chol Kang, Jeonggeun Moon, Minsu Kim, Jongwook Yu
Journal: Journal of the American College of Cardiology (2018)
Relapse prevention with second generation tyrosine kinase inhibitors for Ph+ve acute leukemia after allogenic stem cell transplantation.
Authors: Faiz K. Anwer, Zabih Warraich, Atif Sohail, Theresa Thai, Azka Latif, Vikas Kapoor, Keri Renee Maher, Faiza Hassan Warraich, Sami Warraich, Zeeshan Baig, Adeela Mushtaq, Pavan Tenneti, Ali McBride
Journal: Journal of Clinical Oncology (2018)

7050 Background: Relapse after allogeneic hematopoietic stem cell transplantation (AlloHSCT) for Ph+ve acute lymphoblastic leukemia (Ph+ ALL) remains the major cause of treatment failure. Use of tyrosine kinase inhibitors (TKIs) for post-transplant maintenance is not well defined. Methods: Database search using PubMed, Cochrane library, and Embase was performed on 08/10/2017 yielding 861 articles, 17 articles met inclusion criteria (n = 502). Results: Patients in seven prospective trials (n = 224) received imatinib post-transplant (PT) either prophylactically or pre-emptively for median duration of 3-12 months, at dose of 200–600 mg. Imatinib yielded a better overall survival (OS) (1.7 to 5-year OS was 30-86.7%), disease free survival (DFS) (30–81.5%) and low relapse rate (13 – 31.5%). Chen et al, in 2012 reported 52.4% higher OS (p = 0.0) with imatinib. Five retrospective trial patients (n = 221) received TKI PT either prophylactically or pre-emptively for median duration of 1-11 months, at dose of 300–800mg. TKI prophylactically led to better OS (1-year OS-100%, 2-year OS-66.7%), DFS (20-100%) and with the 3-year relapse rate of 63.6%. Three prospective trial patients (n = 28) received nilotinib PT prophylactically for a median duration of 0-20 month, at dose of 200-300 mg. Nilotinib prophylactically had a better OS (2-year OS was 69%, and mOS was 35.5 months) and DFS (56% in one study and median 34.1 months in another). Two retrospective trial patients (n = 29) received post-AlloHSCT dasatinib for median duration of 11-15 months, at dose of 50-100 mg. Patients who received dasatinib had a better OS (3-year 87% in one study, and median OS was 22 months in another study) and DFS (88%). Conclusions: Post-transplant prophylactic or maintenance TKIs in Ph+ ALL showed increase in OS, DFS and decrease in relapse rates. Limited data appears to favor a prophylactic rather than a pre-emptive strategy. In retrospective trials, use of dasatinib reported increase 3-year OS-87% whereas imatinib 3-year OS was 40% is post-transplant patients. The second generation TKIs have better outcomes in comparison to imatinib although further studies are needed to assess this fact definitively.