tbuckley/cabot-search huggingface dataset:
Abstract 29: Biodegradable Elastomeric Polyurethane Scaffolds Mechanically Matching With Native Heart Muscle
Authors: Cancan Xu, Bryn Brazile, Kytai Nguyen, Jun Liao, Liping Tang, Yi Hong
Journal: Circulation Research (2015)

Introduction: Biodegradable cardiac patches need to be mechanically matching with native heart muscle, in order to provide appropriate mechanical support to rapidly restore heart functions and promote tissue remodeling for myocardial infarction (MI) management. Here, we utilized chemical molecular design to develop biodegradable elastomers with low initial modulus and then process them into porous scaffolds mechanically matching with native heart muscle. Methods and Results: We synthesized various amorphous copolymers including poly (δ-valerolactone-co-ε-caprolactone) (PVCL) and poly (ether ester) triblock copolymers with various molecular weights and poly(ethylene glycol) (PEG) molecular weights (PVCL-PEG-PVCL). The polyurethanes were then synthesized from PVCL or PVCL-PEG-PVCL as a soft segment, hexamethylene diisocyanate (HDI) as a hard segment and putrescine as a chain extender. The polyurethane products were presented as PU-PEGx-VCLy, where x and y refer to molecular weights of PEG and PVCL, respectively. Five polymers including PU-VCL 2k , PU-VCL 6K , PU-PEG 1K -VCL 1K , PU-PEG 1K -VCL 6K and PU-PEG 2K -VCL 6K were obtained. All polymers gradually degraded in phosphate buffer solution and enzyme solution. The 3T3 fibroblasts can grow and proliferate on all polymer film surface within 5 day culture, indicating the polymers have good cellular compatibility. PU-VCL 6K , PU-PEG 1K -VCL 6K and PU-PEG 2K -VCL 6K were further processed into porous scaffolds using thermally induced phase separation (TIPS). The PU-PEG 2K -VCL 6K scaffold at wet state had 0.19 ± 0.08 MPa initial modulus, which has no significant difference from initial modulus (0.19 ± 0.04 MPa) of the native porcine heart muscle. But the tensile strength of this scaffold is lower than that of heart muscle, which requies to be improved in the future. Conclusions: A new family of biodegradable elastic polyurethanes was synthesized and processed into porous scaffolds. The scaffolds showed promising mechanical match with heart muscle. These biodegradable polyurethane scaffolds would find opportunities to be used as a cardiac patch for heart infarction treatment.
Pharmacokinetic-driven phase I study of DCC-2618 a pan-KIT and PDGFR inhibitor in patients (pts) with gastrointestinal stromal tumor (GIST) and other solid tumors.
Authors: Filip Janku, Albiruni Ryan Abdul Razak, Michael S. Gordon, David Glenn Brooks, Daniel Lee Flynn, Michael Kaufman, Jama Pitman, Bryan Douglas Smith, Neeta Somaiah, John Frederick De Groot, Guo Chen, Julia Jennings, Samer Salah, Deb Westwood, Eric Gerstenberger, Oliver Rosen, Suzanne George
Journal: Journal of Clinical Oncology (2017)

2515 Background: DCC-2618 is a potent switch control inhibitor of KIT and PDGFR kinases active in a broad range of mutations. GIST is an important disease to achieve a proof-of-concept due to the heterogeneity of KIT resistance mutations, which emerge on treatment with approved KIT inhibitors. Methods: This was a PK-guided dose escalation study of oral DCC-2618 (QD or BID q28 days) in advanced solid tumors. FDG-PET scans were used to assess changes in FDG uptake in GIST pts after 3 wks of therapy. Next generation sequencing (NGS) of plasma cell-free (cf) DNA was performed throughout the study to assess and quantify KIT and other molecular alterations in drug targets and potential mechanisms of resistance. Results: 38 pts were enrolled (30 GIST; 4 glioma; 1 mastocytosis, 3 other carcinoma) to 8 dose levels: BID doses: 20 (4 pts), 30 (4), 50 (5), 100 (6), 150 (6) and 200 mg (3); QD doses: 100 (5) and 150 mg (4). Safety of evaluable pts is as follows: G3 or G4 adverse effects (regardless of attribution and occurring in &gt; 1 pt) included anemia (5), lipase increase (4), hypertension (2). Two of the G3/4 lipase increase at 100 mg BID and 200 mg BID were DLTs. All G3/4 lipase increase were asymptomatic. G1/2 AEs (considered at least possibly related to DCC-2618) and occurring in ≥15% (n &gt; 5) of pts include fatigue (12), alopecia &amp; lipase increase (7), weight decrease (6). Starting with 50 mg BID dose level, trough concentrations of total drug exceeded the IC90 of the least sentivitive KIT mutations. Plasma concentrations &gt; 5μM were achieved starting at 100 mg BID and the selection of the expansion phase dose is being finalized. Of 18 pts with KIT mutant GIST assessed by FDG PET, 14 (78%) had partial metabolic response per EORTC criteria. RANO/RECIST partial responses (PRs) were reported in 3 patients (1 GBM with PDGFRA/KIT amplifications and 2 GIST with Ex 11 &amp; 17 / Ex 11 &amp; 18 mutations, respectively). NGS of plasma cfDNA revealed 44 KIT mutations in baseline samples from 19 of 21 pts with GIST. Conclusions: DCC-2618 is well tolerated with encouraging preliminary activity in GIST pts with a broad spectrum of mutations and prior therapies. PR was also seen in a pt with GBM with PDGFRA/KIT amplifications. Clinical trial information: NCT02571036.
Mars therapy as a bridge to liver transplantation
Authors: J Sultan, A Qasim, M Cullen, J Hegarty, PA McCormick
Journal: Endoscopy (2006)

Background: Different artificial liver support systems are being developed for use in patients with acute decompensation of chronic liver disease or acute liver failure. Molecular adsorbents recalculating system (MARS) is a liver support system based on albumin dialysis.
Phase Ib study of BGJ398 in combination with BYL719 in patients (pts) with select advanced solid tumors.
Authors: David Michael Hyman, Ben Tran, Jesus Corral Jaime, Elena Garralda, Jean-Pascal H. Machiels, Jan H. M. Schellens, Phillipe Bedard, Mario Campone, Philippe Cassier, John Sarantopoulos, Ulka N. Vaishampayan, Rashmi Chugh, Amit Mahipal, Albert C. Lockhart, Cristiana Sessa, Thomas Zander, Matthew Ng, Giuseppe Curigliano, Jennifer Bendiske, Jose Manuel Perez-Garcia
Journal: Journal of Clinical Oncology (2016)

2500 Background: Phosphatidylinositol-3-kinase (PI3K) and fibroblast growth factor receptor (FGFR) pathway dysregulation can co-occur in tumors. In this study (NCT01928459), safety, tolerability, and preliminary activity of the pan-FGFR (BGJ398) + α-specific PI3K (BYL719) inhibitors were evaluated and maximum tolerated dose (MTD) was established in pts w/ advanced solid tumors w/ PI3K catalytic subunit (PIK3CA) mutations ± FGFR alterations. Methods: Pts w/ solid tumors received once-daily (QD) BGJ on D1-D21 of each 28-D cycle (C) and BYL continuously during escalation (PIK3CA-mutant ± FGFR-altered) and expansion (arm 1, PIK3CA-mutant [n = 15]; arm 2, PIK3CA-mutant + FGFR-altered [n = 10]; arm 3, PIK3CA-mutant + FGFR-altered breast cancer [n = 10]). Results: Of 62 pts enrolled, 44% had ≥ 4 prior therapies. The MTD, 125 BGJ + 300 BYL, was determined based on 32 evaluable pts' data during escalation. C1 dose-limiting toxicities (DLTs) occurred in 4 pts (table). During expansion, 24 pts in arms 1 (n = 12), 2 (n = 6), and 3 (n = 6) received the MTD. At data cutoff (Nov 6, 2015), 4 pts were ongoing; median treatment duration was 64 D (range, 7-456 D). Common adverse events (AEs) included diarrhea (60%), fatigue (53%), nausea (48%), and on-target AEs (hyperphosphatemia [37%], hyperglycemia [36%]); most were G1/2. At the MTD, 61% of pts had ≥ 1 BGJ dose reduction; 61% of pts had ≥ 1 BYL dose reduction. Eight pts had partial responses (PRs), w/ 4 confirmed in urothelial, head and neck, melanoma, and anal cancer. One pt w/ FGFR3-TACC3 fusion urothelial carcinoma w/ PR had a complete shrinkage in target lesions lasting 4 mo. Conclusions: The MTD for BGJ + BYL was determined as QD 125 BGJ on D1-D21 of each C + 300 BYL continuously. Given the high number of reductions w/ chronic treatment, lower starting doses may be warranted in future studies. Responses were observed in tumors w/ specific genetic alterations; however, it is not known if BGJ + BYL in combination offers improved efficacy over single agents. Clinical trial information: NCT01928459.Dose-escalation DLTs. Dose, mg Pts Evaluable/Enrolled, n/N DLTs BGJ BYL 20 300 3/4 20 400 4/4 40 300 5/6 G4 hyperglycemia, n = 1 75 300 5/6 G3 stomatitis, n = 1 90 300 4/5 100 300 5/6 G3 stomatitis, n = 1; pt received < 50% of doses due to non-DLT AEs, n = 1 125 300 6/7
Circulating tumor cells and genomic profiling of patients with ERBB2 mutant, HER2 non-amplified metastatic breast cancer treated with neratinib.
Authors: Anishka D'souza, Stephanie Shishedo, Darcy V. Spicer, Lisa Welter, Yuanfei Jiang, David Michael Hyman, David B. Solit, Cynthia X. Ma, Ron Bose, Richard E. Cutler, Lisa Eli, James B Hicks, Peter Kuhn, Janice M. Lu
Journal: Journal of Clinical Oncology (2017)

e12554 Background: ERBB2 mutations in the absence of gene amplification are rare, with an incidence of 2-4%. Neratinib is a HER2/EGFR tyrosine kinase inhibitor being evaluated for use in ERBB2 mutated breast cancer. Neratinib has been found to have clinical activity on heavily pre-treated ERBB2 mutant breast cancer patients. We are evaluating the response and genomic profiles of 3 postmenopausal patients with metastatic ERBB2 mutant/non-amplified breast cancer receiving neratinib and fulvestrant NCT01953926, NCT01670877. Methods: Samples were collected at different points during treatment and CTCs were identified. Other representative cells were tracked but not classified as CTCs. CD45-CK+ cells with cytoplasmic and/or nuclear apoptosis were defined as CTC-Apoptotic. CD45- cells expressing little to no CK but otherwise meeting morphological criteria for CTCs are CTC-LowCK. CD45-CK+ cells with small nuclear size are CTC-SmallCK. Single CTCs will be analyzed using whole genome copy number variation to determine chromosomal alterations. Results: The patients had an average of 4.7 lines of therapy for metastatic disease before neratinib. Two had stable disease and one had progression. The patient who progressed had a rise in the number of CTCs from 37 to 52 cells/ml and drop in apoptotic cells from 5 to 0 cells/ml. Conclusions: The high CTC count of the patient who progressed may suggest more aggressive disease. The drop in the apoptotic cell count may correlate with a failure to respond to therapy. Samples have been sent for copy number variation profiling. The goal is to identify any genomic amplifications or deletions associated with clinical response and progression after targeted therapy. We hope to demonstrate the timeframe of tumor evolution in response to therapy and provide a framework for the use of fluid biopsies to monitor disease progression. [Table: see text]
Activity and safety of CPBev regimen (cisplatinum, pemetrexed, and bevacizumab) as first-line therapy for locally advanced or metastatic adenocarcinoma of the lung: Final results of a phase II study.
Authors: Roberto Bordonaro, Hector Soto-parra, Carmelo Giannitto-Giorgio, Saverio Cinieri, Fiorenza Latteri, Concetta Sergi, Giovanni L. Pappagallo, Stefano Sergio Cordio, Placida Salice, Daniela Sambataro, Enrico Potenza
Journal: Journal of Clinical Oncology (2012)

e18026 Background: During the past five years the paradigms of advanced lung cancer therapy dramatically changed; Bevacizumab and Pemetrexed, when administered separately in association with platinum salts, demonstrated to improve survival in patients with non-squamous histologies. In the aim to investigate activity and safety of a three-drugs-regimen containing both these agents and cis-platinum, we conducted a multi-institutional phase II study started on november 2007. Methods: chemonaive patients with non-squamous non-small cell lung cancer were considered eligible We adopt the two-stage of Simon model as statistical design of the study; activity of the regime, expressed as overall response rate and safety were the main end-points. Administered doses were 75 and 500 mg/p.s.m for cis-platinum and pemetrexed respectively and 7.5 mg./kg for Bevacizumab, for 3 - 6 cycles. G-CSF were administered only after the first cycle of therapy, whereas vitamin supplementation started from day 1 of the first cycle. No maintenance therapy was allowed. Results: We registered 9 partial responses among the first 15 patients treated so, accordingly with the design of the study, we completed the enrollment up to 32 patients. Patients characteristics are: male/female: 20/12, median age (years): 59 (r. 36 - 77), ECOG-WHO/PS 0/1: 21/11. One hundred eighty-three cycles of CPBev were administered: we registered only 13 cases of grade 3 adverse events. No grade 4 toxicities were observed. One case of allergic reaction to cis-platinum were observed. In terms of response rate, we registered 20/32 (62.5%) partial responses, 8/32 (25%) stable diseases and 4/32 (12.5%) progressive diseases, with a clinical benefit rate of 28/32 (87.5%). Results in terms of outcome parameters expressed by progression-free and overall survival will be presented at the meeting. Conclusions: On the basis of our data, CPBev have a good toxicity profile and seems to be extremely active in advanced non-squamous lung carcinomas.
Soundings: Slugs and snails and puppy dog tails
Authors: Trisha Greenhalgh
Journal: BMJ (2006)

Fancy making a battery? You will need (a) 10 two-pence pieces; (b) kitchen foil; (c) blotting paper; (d) two pieces of copper wire (taken from any electric wire or flex); (e) malt vinegar; (f) salt; (g) bowl; (h) light emitting diode (available from hardware and model shops); (i) masking tape. Mix vinegar and salt together in the bowl. Soak blotting paper. Stack alternate layers of coin/paper/foil. Attach copper wire to each end of the stack with masking tape. Fix other ends of wires to diode. The light should go on.

My parents lived unashamedly gendered lives. Their marriage probably only lasted as long as it did because within a year of her wedding day my mother produced a son, with whom my father planned to spend happy hours building transistor radios, fishing, and playing cricket. But his firstborn showed neither interest nor aptitude in such pleasures—nor did the next son, or the next. When Mum and the boys started baking, Dad and I would retreat to the shed to repair the vacuum cleaner, filter the newts out of pond water, or send messages to each other in Morse code.

Simone de Beauvoir observed in The Second Sex that the widespread interest of girls in “male” pursuits does not need a psychoanalytic explanation. Climbing trees is simply fun, as is stringing conkers or making stink bombs. But everyone knows this is boys' stuff, so no self respecting tomboy is going to be put off by chapter titles like “The five knots every boy should know” or “Advice about girls.” Conversely, if grubs and gadgets never turned you on, you won't assume that having a Y chromosome makes The Dangerous Book for Boys compulsory reading for you.

Audacious political incorrectness and the absence of risk assessment in any activity is, of course, why this book has shot straight to the top of the bestseller list. I was enthralled by the lists of trivia (the laws of rugby, the history of artillery) and by step-by-step instructions on everything from skinning a rabbit to making a tree house. But my own sons were unimpressed—at least until their friends went off line. I'll encourage them to take another look. As the authors comment: “In the long run it's a lot safer than having them grow fat and irritable in front of the TV.”
Clearance of circulating leukemic blasts during induction therapy to predict treatment response regardless of cytogenetic risk or age in adult acute myeloid leukemia.
Authors: Zhou Yu, Leann Blankenship, Ishmael A. Jaiyesimi, James Huang
Journal: Journal of Clinical Oncology (2016)

e18522 Background: Despite the development of prognostic factors for stratification models in AML patients, treatment response in individual patient has not been predicted accurately. Early assessment of individual response is of great practical significance in determining the timing of interim bone marrow biopsy and guide further chemotherapy. Our study investigates whether the timing of circulating blasts (CBs) clearance during induction therapy can predict treatment response in AML patients. Methods: We retrospectively reviewed the charts of 59 AML patients who received standard cytarabine and anthracycline regimen during induction between January, 2000- 2011 at William Beaumont Health System. Patients with acute promyelocytic leukemia or history of myelodysplastic syndrome were excluded. AML is considered refractory if morphological evaluation, flow cytometry or cytogenetic study was positive in the post induction bone marrow results. Response to induction therapy was assessed according to Cancer and Leukemia Group B criteria as complete remission versus treatment failure. Results: We noted that 46 of 59 patients (77.9%) showed CBs at the time of diagnosis. During the induction therapy, CBs clearance occurred within 7 days (early clearance) in 31 among these 46 patients. The remaining 13 patients had CBs persistent more than 7 days (delayed clearance). The frequency of treatment failure was significant higher in patients with delayed clearance comparing to those with early clearance (93.3% vs 48.3%, p = 0.0033). There were no statistically significant difference in treatment response among cytogentic risk groups, nor among age groups (60 years and older vs. younger than 60). Absence of peripheral blasts at diagnosis was not associated with superior complete remission rate comparing to group with early blast clearance (53.8% vs 51.6%, p > 0.05). Conclusions: Persistent peripheral blasts more than 7 days during standard induction therapy is associated with higher induction failure rates, regardless of cytogenetic risks and age. Clearance of CBs can be used as an independant predictor of treatment response to induction chemotherapy.
A phase I dose escalation study of SCB01A, a micro-tubular inhibitor with vascular disrupting activity, in patients with advanced solid tumors refractory to standard therapy.
Authors: Nai-Jung Chiang, Her-Shyong Shiah, Chia-Chi Lin, Chia-Jui Yen, Hui-Jen Tsai, Shang-Yin Wu, Wu-Chou Su, Kwang-Yu Chang, Li-Tzong Chen
Journal: Journal of Clinical Oncology (2017)

2531 Background: SCB01A is a novel anti-microtubular agent with vascular disrupting activity. The Phase I study aimed to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), safety, and pharmacokinetic (PK) profiles of SCB01A in patients with advanced solid tumor. Methods: This was an open-label, phase I clinical trial with a rapid titration followed by a 3 x 3 study design. Eligible patients would receive a 3-hr intravenous infusion of SCB01A, every 21 days as one cycle. All adverse events were classified according to the CTCAE V4.0. DLT was defined as the occurrence of grade 3 with complications and grade 4 hematoloigcal, or ≥grade 3 non-hematological toxicities. Results: From June 2011 to November 2015, a total of 33 eligible patients were enrolled to eight dose levels: 2 mg/m 2 (n = 1), 3 mg/m 2 (n = 1), 4 mg/m 2 (n = 6), 6.5 mg/m 2 (n = 9, with 3 additional subjects were recruited for safety concern), 10 mg/m 2 (n = 3), 16 mg/m 2 (n = 3), 24 mg/m 2 (n = 6) and 32 mg/m 2 (n = 4). Six episodes of DLTs were observed in 5 patients (each one in dose levels of 4/6.5/24 mg/m 2 and two in dose level of 32 mg/m 2 ), including grade 4 blood creatine phosphokinase elevation (4 mg/m 2 ), grade 3 gastric hemorrhage (6.5 mg/m 2 ), grade 2 venous thrombosis (24 mg/m 2 ), grade 3 peripheral neuropathy manifested as weakness of lower limbs, grade 3 aspartate aminotransferase elevation, and grade 3 hypertension (32 mg/m 2 ). The MTD was determined to be 24 mg/m 2 . Pharmacokinetic profiles revealed a linear AUC-dose response with an average elimination half-life (t 1/2 ) of 2.5 hours. Partial response was observed in one subject with buccal cancer. A total of 57.6% (19/33) subjects had stable disease for at least 2 cycles. Conclusions: SCB01A is safe and tolerable in patients with solid tumor. The MTD of SCB01A is 24 mg/m 2 every 21 days, which deserves further development. Clinical trial information: NCT011159522.
Antiplatelet Therapy in Patients With Coronary Stents Undergoing Elective Noncardiac Surgery
Authors: Christopher P. Childers, Melinda Maggard-Gibbons, Paul G. Shekelle
Journal: JAMA (2017)

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Kinetics of Immune Reconstitution in Event-Free Patients: Establishing Reference Values for Immune Recovery of Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Xu-Ying Pei, Yu Wang, Lan-Ping Xu, Xiao-Hui Zhang, Xiang-Yu Zhao, Ying-Jun Chang, Xiao-Jun Huang
Journal: Blood (2016)