tbuckley/cabot-search huggingface dataset:
Abstract 3588: Emergence of multiple EGFR extracellular mutations during cetuximab treatment in colorectal cancer
Authors: Luca Lazzari, Sabrina Arena, Beatriz Bellosillo, Giulia Siravegna, Alejandro Martínez, Israel Cañadas, Noelia Ferruz, Mariangela Russo, Sandra Misale, Iria González, Mar Iglesias, Elena Gavilan, Giorgio Corti, Sebastijan Hobor, Giovanni Crisafulli, Marta Salido, Juan Sánchez, Alba Dalmases, Joaquim Bellmunt, Gianni De Fabritiis, Ana Rovira, Federica Di Nicolantonio, Joan Albanell, Alberto Bardelli, Clara Montagut
Journal: Cancer Research (2015)

Abstract Colorectal cancer (CRC) patients who respond to the anti-EGFR antibody cetuximab often develop resistance within several months of initiating therapy. To design new lines of treatment the molecular landscape of resistant tumors must be ascertained. We investigated the role of mutations in the EGFR signalling axis on the acquisition of resistance to cetuximab in patients and cellular models. Mutational profiling was performed on both biopsies collected from 37 CRC patients who became refractory to cetuximab and on a collection of cetuximab-resistant derivatives obtained from CRC cells sensitive to EGFR blockade. The genetic profile of tumor specimens obtained after cetuximab treatment revealed the emergence of a complex pattern of mutations in EGFR, KRAS, NRAS, BRAF and PIK3CA genes, including two novel EGFR ectodomain mutations. Mutational profiling of cetuximab resistant cells recapitulated the molecular landscape observed in clinical samples and revealed three additional EGFR ectodomain alleles. Structural modelling showed that these mutations are located in the cetuximab-binding region, except for one mutant. Functionally, EGFR ectodomain mutations prevent binding to cetuximab but a subset is permissive for interaction with panitumumab. In conclusion, we reported that colorectal tumors evade EGFR blockade by constitutive activation of downstream signalling effectors and through mutations affecting receptor-antibody binding. Both mechanisms of resistance may occur concomitantly. Our data have implications for designing additional lines of therapy for CRC patients who relapse upon treatment with anti-EGFR antibodies. Citation Format: Luca Lazzari, Sabrina Arena, Beatriz Bellosillo, Giulia Siravegna, Alejandro Martínez, Israel Cañadas, Noelia Ferruz, Mariangela Russo, Sandra Misale, Iria González, Mar Iglesias, Elena Gavilan, Giorgio Corti, Sebastijan Hobor, Giovanni Crisafulli, Marta Salido, Juan Sánchez, Alba Dalmases, Joaquim Bellmunt, Gianni De Fabritiis, Ana Rovira, Federica Di Nicolantonio, Joan Albanell, Alberto Bardelli, Clara Montagut. Emergence of multiple EGFR extracellular mutations during cetuximab treatment in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3588. doi:10.1158/1538-7445.AM2015-3588
Clinical and Biological Features in Patients with Ph-Negative Chronic Myeloproliferative Neoplasm Showing Different Molecular Pattern. Comparative Study in 596 Patients of the Registro Italiano Trombocitemie (RIT)
Authors: Luigi Gugliotta, Alessandra Iurlo, Gabriele Gugliotta, Alessia Tieghi, Giorgina Specchia, Gianluca Gaidano, Anna Candoni, Maria Luigia Randi, Potito Rosario Scalzulli, Alfredo Dragani, Vincenzo Martinelli, Giuseppe Tagariello, Elisabetta Antonioli, Anna Marina Liberati, Raffaele Palmieri, Maria Langella, Angela Rago, Rossella R Cacciola, Ivana Pierri, Alessandra Ricco, Daniele Cattaneo, Umberto Santoro, Serena Rupoli, Cristina Santoro, Lucia Mastrullo, Bruno Martino, Maria Gabriella Mazzucconi, Nicola Vianelli, Valerio De Stefano, Francesco Passamonti, Alessandro M. Vannucchi
Journal: Blood (2015)
BRD4 Degradation By Protacs Represents a More Effective Therapeutic Strategy Than BRD4 Inhibitors in DLBCL
Authors: Jing Lu, Yimin Qian, Kanak Raina, Martha Altieri, Hanqing Dong, Jing Wang, Xin Chen, Andrew Crew, Kevin Coleman, Craig Crews, James Winkler
Journal: Blood (2015)
Evaluating the value of continuing docetaxel and prednisone (DP) beyond 10 cycles in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: G. R. Pond, A. J. Armstrong, B. A. Wood, M. Brookes, L. H. Leopold, W. R. Berry, R. De Wit, M. A. Eisenberger, I. Tannock, G. Sonpavde
Journal: Journal of Clinical Oncology (2011)

4582 Background: The optimal number of cycles of 3-weekly DP therapy for mCRPC has not been ascertained. An exploratory analysis was conducted comparing results of 335 men on the DP arm of the TAX-327 study, which limited chemotherapy to 10 cycles, and a recently completed randomized clinical trial of 221 men allocated to either DP+AT-101 (bcl-2 inhibitor) versus DP+placebo, which allowed up to 17 cycles of DP. Methods: Patients who initiated cycle 10 of therapy without progression in both studies were included. Per protocol, men on the TAX-327 study received 1 additional cycle, while men on the AT-101 study received up to cycle 17. Men in both arms of the AT-101 study were combined for analysis, as no significant differences in outcomes were observed. Overall survival (OS) was estimated from the cycle 10 D infusion date, using the Kaplan-Meier method. Results: The number of men receiving cycle 10 cycle was similar (Fisher's exact test p-value=0.60) between the two studies (166 or 49.6% in the TAX-327 study versus 99 or 44.8% in the AT-101 study), though of these men, death date information was more complete due to longer follow-up in TAX-327 (79.5% versus 34.4%). Six- and 12-month estimated survival from cycle 10 was 92.2% (95% CI: 86.9-95.4%) and 74.6% (CI: 67.2-80.5%) for TAX-327 patients, compared with 92.8% (CI: 85.5-96.5) and 63.4% (CI: 51.8-72.9%) for those on AT-101. Survival statistics were similar beyond cycle 10 within good, intermediate and poor risk groups. 38 (38.4%) men on the AT-101 study completed all 17 cycles. Of men on the AT-101 study, 24 and 13 had consistently declining PSA through cycles 13 and 17. Conclusions: A survival benefit was not detected with more than 10 cycles of DP chemotherapy in men with mCRPC in this hypothesis-generating exploratory analysis. A subset of men with mCRPC continue to have declines in PSA up to cycle 17 and thus may have ongoing benefit to continued chemotherapy administration. However, a randomized clinical trial is necessary to establish the optimal duration of therapy.
534. Preparation for a First-in-Man Lentivirus Trial in Cystic Fibrosis Patients
Authors: Uta Griesenbach, Eric W. F.W. Alton, Jeffery M. Beekman, Christopher A. Boyd, Jane C. Davies, Lee A. Davies, Johanna F. Dekkers, Deborah R. Gill, Mamoru Hasegawa, Tracy E. Higgins, Takashi Hironaka, Makoto Inoue, Stephen C. Hyde, Alastair J. Innes, Ian A. Pringle, Kamila M. Pytel, Stephanie G. Sumner-Jones, Shu Tsugumine, Marguerite W. Wasowicz
Journal: Molecular Therapy (2016)

Background: We have recently shown that non-viral gene therapy can stabilise the decline of lung function in cystic fibrosis (CF) patients. However, the effect was modest, and it is important to develop more potent gene transfer agents in parallel. F/HN-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in pre-clinical models. In preparation for a first-in-man CF trial using the lentiviral vector we have undertaken key translational pre-clinical studies. Methods: Regulatory-compliant vectors carrying a range of promoter/enhancer elements were assessed in mice and human air liquid interface cultures to select the lead candidate; CFTR expression and function were assessed in CF models (knockout mice and human intestinal organoids) using this lead candidate vector. Toxicity was assessed and "benchmarked" against the leading non-viral formulation recently used in a Phase IIb clinical trial. Integration site profiles were mapped and transduction efficiency determined to inform clinical trial dose-ranging. The impact of pre-existing and acquired immunity against the vector and vector stability in several clinically relevant delivery devices was assessed. Results: A hybrid promoter consisting of the elongation factor 1α promoter and the CMV enhancer was most efficacious in both murine lungs and human air liquid interface cultures. The efficacy, toxicity and integration site profile supports further progression towards clinical trial and pre-existing and acquired immune responses do not interfere with vector efficacy. The lead rSIV.F/HN candidate expresses functional CFTR and the vector is stable in clinically relevant delivery devices. Conclusions: The data support progression of the F/HN pseudotyped lentiviral vector into a first-in-man CF trial due to start in Q2 2017. Regulatory-compliant toxicology studies are currently being performed.
Abstract 4813: High-depth sequencing of 800 cancer-associated genes in 48 matched tumor-normal tissues to identify somatic alterations including low-frequency variants in colorectal cancer
Authors: Clarinda Chua, Dan Liang Ho, Yuka Suzuki, Simeen Malik, John McPherson, Anna Gan, Dennis Koh, Choon Leong Tang, Sarah Boon Hsi Ng, Patrick Tan, Steve Rozen, Iain Beehuat Tan
Journal: Cancer Research (2015)

Abstract Purpose: Colorectal cancer is the 3rd most common cancer globally accounting for 10% of the global cancer burden. Catalogues of somatic mutations in cancer (e.g. The Cancer Genome Atlas (TCGA)) are based upon exome sequencing, typically performed at depths of ∼ 80x, which will miss sub-clonal low-frequency somatic variants. We performed high depth sequencing of 800 cancer-associated genes across 48 tumor/normal pairs of CRC to catalogue somatic variants including those present at low variant allele frequencies. Method: We used the Agilent SureSelect Target Enrichment system to design a customized enrichment panel comprising all coding exons of ∼800 cancer-associated genes. From genomic DNA extracted from frozen tissue specimens (matched primary tumor and adjacent normal), we performed library construction, target enrichment and illumina next generation sequencing. We used 3 variant-calling algorithms - a Genome Analyzer Toolkit (GATK) based pipeline, LoFreq and MuTect to identify somatic variants including sub-clonal variants present at low variant allele frequencies. Results: Sequencing was performed to a median of 302-fold and 310-fold coverage across target regions in the tumor tissues and normal tissues respectively. The use of 3 bioinformatics variant-calling algorithm allowed sensitive and comprehensive identification of variants down to a variant allele frequency of 2.5%; selected variants were validated by an orthogonal sequencing platform (Ion Torrent). The validation rate was &amp;gt; 97%. Each patient had a variant in a median of 19 genes (range 8-100) with a different complement of clonal and sub-clonal variants. Recurrent alterations (e.g. APC, KRAS, TP53) tended to be clonal. Broad regions of allelic imbalance (based on heterozygous SNPs identified in each patient's normal tissue) could also be mapped in each patient. Conclusion: High Depth sequencing of 800 cancer-associated genes in 48 matched tumor normal tissues permits identification of somatic alterations including low-frequency variants and sub-clonal alterations in patients with colorectal cancer. Citation Format: Clarinda Chua, Dan Liang Ho, Yuka Suzuki, Simeen Malik, John McPherson, Anna Gan, Dennis Koh, Choon Leong Tang, Sarah Boon Hsi Ng, Patrick Tan, Steve Rozen, Iain Beehuat Tan. High-depth sequencing of 800 cancer-associated genes in 48 matched tumor-normal tissues to identify somatic alterations including low-frequency variants in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4813. doi:10.1158/1538-7445.AM2015-4813
A phase II randomized study of cixutumumab (IMC-A12: CIX) or ramucirumab (IMC‐1121B: RAM) plus mitoxantrone (M) and prednisone (P) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following disease progression (PD) on docetaxel (DCT) therapy.
Authors: Maha Hussain, Dana E. Rathkopf, Glenn Liu, Andrew J. Armstrong, William Kevin Kelly, Anna C. Ferrari, John D. Hainsworth, Ling Yang, Jonathan D. Schwartz, Celestia S. Higano
Journal: Journal of Clinical Oncology (2012)

97 Background: Vascular endothelial growth factor (VEGF)-mediated angiogenesis and insulin-like growth factor (IGF-IR)-mediated signaling contribute to mCRPC growth. CIX and RAM are fully human IgG1 human monoclonal antibodies targeting IGF‐IR and VEGF receptor-2 (VEGFR-2) respectively. We investigated the safety and efficacy of CIX or RAM in combination with M + P in mCRPC pts with PD on DCT. Methods: Eligible pts had mCRPC and PD during/within 120 days of DCT, ECOG PS 0-2, PSA ≥ 2 ng/mL, and adequate organ function. All pts received M 12 mg/m 2 IV every 3 weeks (w) + P 5 mg PO BID for up to 12 cycles and were randomized to either CIX 6 mg/kg or RAM 6 mg/kg IV q w. Tumor assessments were after the first 3 cycles and then q6w. Primary endpoint was composite progression-free survival (cPFS: either RECIST PD, bone scan PD or new skeletal events). Other endpoints included safety, response and overall survival (OS). Sample size was based on a targeted 50% increase in median (mdn) cPFS from 2.6 months (m) to 3.9 m. Results: 132 pts were treated; 66 each to CIX or RAM. Mdn age and baseline PSA was 65 yr and 129 ng/mL for pts treated with CIX and 68 yr and 111 ng/mL for RAM. Involvement of sites other than bone was CIX: 79% and RAM: 70%. The most frequent Grade ≥3 related adverse events for CIX/M/P: fatigue 17%, leukopenia 12%, and neutropenia 8%, and for RAM/M/P: leukopenia 8%, neutropenia 8% and hypertension 8%. Left ventricular dysfunction/CHF: 12% for CIX (0% G3) and 23% for RAM (8% G3). Mdn number of Rx cycles were 5 for CIX and 6 for RAM. Mdn follow-up was 22.7 m for CIX and 21.8 m for RAM. PSA response was 18.4% (8.8-32% 95% CI) on CIX and 22.0% (11.5-36% 95% CI) on RAM. Mdn cPFS and OS were 4.1 m (3.0-5.6 m 95% CI) and 10.8 m (6.5-13.0 m 95% CI) for CIX and 6.7 m (4.5-8.3 m 95% CI) and 13.0 m (9.5-16.0 m 95% CI) for RAM. Conclusions: CIX/M/P and RAM/M/P were reasonably tolerated and achieved the primary endpoint. Preliminary cPFS and OS of RAM/M/P appear encouraging; sustained disease control was observed in pts on both rx arms. Correlation of serum markers of IGF and VEGF activity with clinical endpoints is planned.
Abstract 15077: Left Atrial Endocardial Surface Area Strain Assessed by 3-Dimensional Speckle Tracking Imaging is a Useful Method in Assessing Left Ventricular End-Diastolic Pressure
Authors: Nobukatsu Akita, Nobuyuki Ohte, Kazuaki Wakami, Shohei Kikuchi, Noriyuki Ikehara, Hiroshi Fujita, Toshihiko Goto, Hidekatsu Fukuta, Tomomitsu Tani, Genjiro Kimura
Journal: Circulation (2011)

Background: Some previous studies reported that elevated left atrial (LA) pressure deteriorates LA wall distensibility. A novel 3-dimensional ultrasound speckle tracking imaging (3D-STI) technique ...
PTCT-01INTERCONTINENTAL MULTIDISCIPLINARY DATA COLLECTION AND TREATMENT OPTIMIZATION STUDY FOR PATIENTS WITH CHOROID PLEXUS TUMORS
Authors: Michal Bahar, Aditi Dhir, Uwe Kordes, Johannes Wolff
Journal: Neuro-Oncology (2015)

BACKGROUND: Choroid plexus tumors (CPTs) are rare pediatric tumors. They are classified by the World Health Organization as Choroid plexus papillomas (CPP), Atypical choroid plexus papillomas (APP) and Choroid plexus carcinomas (CPC). Current recommendations for the treatment of CPTs include surgical resection followed by adjuvant chemotherapy and or radiation therapy. The CPT-SIOP 2009 protocol compared four different chemotherapy treatment arms (standard arm A-Cyclophosphamide/VP16/VCR (CycEV) alternating with Carboplatin/VP16/VCR CarbEV) blocks, arm B-Doxorubicin/Cisplatinum/Actinomycin-D/VCR, arm C-high dose Methotrexate and arm D-Temozolomide/Irinotecan). The study closed due to insufficient enrollment of formally randomized patients. Our study reviews the patient data registry, which includes non-randomized patients. METHODS: Clinical course was evaluated amongst patients enrolled in the CPT-SIOP 2009 protocol. Data was obtained from international institutions including Australia, New Zealand, Germany, Lebanon, Turkey, Switzerland and USA. Qualitative parameters included age, sex, presenting symptoms and adjuvant therapy. Overall survival and event free survival were analyzed. RESULTS: We identified 27 cases with CPTs (APP 5, CPP 5, CPC 17), 9 females and 15 males, (2 unknown). The mean age at presentation was 7 years with a median age of 2.4 years (range 0.16 to 58 years). Twelve patients were treated under arm A, (1 B, 4 C, 1 D, 3 in observation and 6 unknown). 2y overall survival/2y EFS for n = 12 CPC patients on arm A was 78%/ 35% with a median follow up of 1.7 years, compared to 76%/ 63% for n = 41 CPC patients treated with non-alternating blocks of CarbEV or CycEV in the SIOP-CPT database. CONCLUSION: The outcome of alternating CarbEV/CycEV appears inferior to non-alternating cycles of either CarbEV or CycEV and is no longer recommended as a guidance in the SIOP-CPT registry. Our aim is to continue following these patients over time to monitor overall and event free survival.
498. Prolonged Benefit from Systemic rAAV8 in a Canine Model of Myotubular Myopathy
Authors: Matthew Elverman, David Mack, Melissa Goddard, Jessica Snyder, Robert Grange, Karine Poulard, Virginie Latournerie, Philippe Veron, Laurine Buscara, Christine Le Bec, Samia Martin, Fulvio Mavilio, Federico Mingozzi, Hui Meng, Michael Lawlor, Alan Beggs, Anna Buj-Bello, Martin Childers
Journal: Molecular Therapy (2016)

Body: Mutations in MTM1 result in X-linked myotubular myopathy (XLMTM), a rare neuromuscular disease that causes devastating muscular weakness in affected children, often fatal in the first years of life. A naturally occurring MTM1 mutation in Labrador retrievers provides unprecedented opportunity to assess MTM1 gene replacement strategies. Here, we report clinical and physiological outcomes more than 3 years after a single intravenous infusion of AAV8-MTM1 in two dogs. Readouts include neurological assessment, limb strength, gait, respiratory function, and histology. Results (Fig 1) are shown in comparison to age-matched littermates, and indicate that a single infusion of AAV8-MTM1 can markedly prolong life and achieve near normal levels of neurological function, strength, gait, and respiratory function for more than 3 years in MTM1 mutant dogs.
Improving uptake of flexible sigmoidoscopy screening: a randomized trial of nonparticipant reminders in the English Screening Programme
Authors: Robert Kerrison, Lesley McGregor, Sarah Marshall, John Isitt, Nicholas Counsell, Colin Rees, Christian von Wagner
Journal: Endoscopy (2016)

<b>Background and study aims</b> Uptake of flexible sigmoidoscopy screening in the English Bowel Scope Screening (BSS) Programme is low. The aim of this study was to test the impact of a nonparticipant reminder and theory-based leaflet to promote uptake among former nonresponders (previously did not confirm their appointment) and nonattenders (previously confirmed their appointment but did not attend). <b>Patients and methods</b> Eligible adults were men and women in London who had not attended a BSS appointment within 12 months of their invitation. Individuals were randomized (1:1:1) to receive no reminder (control), a 12-month reminder plus standard information booklet (TMR-SIB), or a 12-month reminder plus bespoke theory-based leaflet (TMR-TBL) designed to address barriers to screening. The primary outcome of the study was the proportion of individuals screened within each group 12 weeks after the delivery of the reminder. <b>Results</b> A total of 1383 men and women were randomized and analyzed as allocated (n = 461 per trial arm). Uptake was 0.2 % (n = 1), 10.4 % (n = 48), and 15.2 % (n = 70) in the control, TMR-SIB, and TMR-TBL groups, respectively. Individuals in the TMR-SIB and TMR-TBL groups were significantly more likely to attend screening than individuals in the control group (adjusted odds ratio [OR] 53.7, 95 % confidence interval [CI] 7.4 – 391.4, <i>P</i> < 0.001 and OR 89.0, 95 %CIs 12.3 – 645.4, <i>P</i> < 0.01, respectively). Individuals in the TMR-TBL group were also significantly more likely to attend screening than individuals in the TMR-SIB group (OR 1.7, 95 %CIs 1.1 – 2.5, <i>P</i> = 0.01). Across all groups, former nonattenders were more likely to participate in screening than former nonresponders (uptake was 14.2 % and 8.0 %, respectively; OR 2.5, 95 %CIs 1.4 – 4.4, <i>P</i> < 0.01). The adenoma detection rate among screened adults was 7.6 %, which is comparable to the rate in initial attenders. <b>Conclusions</b> Reminders targeting former nonparticipants can improve uptake and are effective for both former nonresponders and nonattenders. Theory-based information designed to target barriers to screening added significantly to this strategy.
Leucotriene receptor antagonists for asthma can save millions, says NICE
Authors: Jacqui Wise
Journal: BMJ (2016)

A leucotriene receptor antagonist should be offered before a combination inhaler in patients with poorly controlled asthma, draft guidance from the National Institute for Health and Care Excellence (NICE) recommends.1

The generic leucotriene receptor antagonist montelukast costs just 7p (€0.08; $0.09) a day, and NICE estimates that the shift in practice would save £3m a year among every 10 000 people who take up the new recommendation. Leucotriene receptor …
The Impact of Allogeneic Hematopoietic Cell Transplantation (HCT) and Treatment with Ruxolitinib on Survival in Patients with Myelofibrosis
Authors: Nadja Jaekel, Song-Yau Wang, Rainer Krahl, Karolin Hubert, Susann Schulze, Rayk Stengel, Melanie Schneider, Martin Roskos, Dietger Niederwieser, Haifa Kathrin Al-Ali
Journal: Blood (2015)