tbuckley/cabot-search huggingface dataset:
A Phase II, Randomised, Open Label Study of Neoadjuvant Pembrolizumab with/without Dabrafenib and Trametinib (D+T) in BRAF V600 Mutant Resectable Stage IIIB/C/D Melanoma (NeoTrio Trial)
Authors: M. Gonzalez, A.M. Menzies, R. Saw, J.F. Thompson, A.J. Spillane, J. Howle, O. Nieweg, K. Shannon, S. Ch'Ng, J.F. Stretch, M.S. Carlino, A. Guminski, L. Emmett, H. Rizos, R.A. Scolyer, G.V. Long
Journal: Annals of Oncology (2017)
SELECT-2: a phase II, double-blind, randomized, placebo-controlled study to assess the efficacy of selumetinib plus docetaxel as a second-line treatment of patients with advanced or metastatic non-small-cell lung cancer
Authors: J.-C. Soria, A. Fülöp, C. Maciel, J.R. Fischer, G. Girotto, S. Lago, E. Smit, G. Ostoros, W.E.E. Eberhardt, P. Lishkovska, S. Lovick, G. Mariani, A. McKeown, E. Kilgour, P. Smith, K. Bowen, A. Kohlmann, D.J. Carlile, P.A. Jänne
Journal: Annals of Oncology (2017)

Combination of selumetinib plus docetaxel provided clinical benefit in a previous phase II trial for patients with KRAS-mutant advanced non-small-cell lung cancer (NSCLC). The phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC.Patients who had disease progression after first-line anti-cancer therapy were randomized (2 : 2 : 1) to selumetinib 75 mg b.i.d. plus docetaxel 60 or 75 mg/m2 (SEL + DOC 60; SEL + DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO + DOC 75). Patients were initially enrolled independently of KRAS mutation status, but the protocol was amended to include only patients with centrally confirmed KRAS wild-type NSCLC. Primary end point was progression-free survival (PFS; RECIST 1.1); statistical analyses compared each selumetinib group with PBO + DOC 75 for KRAS wild-type and overall (KRAS mutant or wild-type) populations.A total of 212 patients were randomized; 69% were KRAS wild-type. There were no statistically significant improvements in PFS or overall survival for overall or KRAS wild-type populations in either selumetinib group compared with PBO + DOC 75. Overall population median PFS for SEL + DOC 60, SEL + DOC 75 compared with PBO + DOC 75 was 3.0, 4.2, and 4.3 months, HRs: 1.12 (90% CI: 0.8, 1.61) and 0.92 (90% CI: 0.65, 1.31), respectively. In the overall population, a higher objective response rate (ORR; investigator assessed) was observed for SEL + DOC 75 (33%) compared with PBO + DOC 75 (14%); odds ratio: 3.26 (90% CI: 1.47, 7.95). Overall the tolerability profile of SEL + DOC was consistent with historical data, without new or unexpected safety concerns identified.The primary end point (PFS) was not met. The higher ORR with SEL + DOC 75 did not translate into prolonged PFS for the overall or KRAS wild-type patient populations. No clinical benefit was observed with SEL + DOC in KRAS wild-type patients compared with docetaxel alone. No unexpected safety concerns were reported.Clinicaltrials.gov NCT01750281.
Disruptive mutations in TP53 associate with survival benefit in a PARPi trial in ovarian cancer
Authors: A. Martinez Bueno, M.A. Molina, A. Fielding, J. Bertran-Alamillo, B.A. Dougherty, Z. Lai, D. Hodgson, C. Mayo de las Casas, P. Rowe, M. Gil, S. Spencer, S. Viteri, J. Lobera, R. Rosell, A. Gasco Hernandez
Journal: Annals of Oncology (2017)
Clinical features of squamous cell lung cancer with targetable gene alterations in a nationwide genomic screening network in Japan (LC-SCRUM-Japan).
Authors: Eri Sugiyama, Shingo Matsumoto, Nobuaki Kobayashi, Hiromi Aono, Masato Shingyoji, Katsuyuki Hotta, Akimasa Sekine, Satoshi Hara, Naoki Furuya, Taku Nakagawa, Hirofumi Nakazaki, Taishi Harada, Shunichi Sugawara, Saori Takata, Norio Okamoto, Kageaki Taima, Keisuke Tomii, Kiyotaka Yoh, Koichi Goto
Journal: Journal of Clinical Oncology (2017)

9057 Background: Molecular-targeted therapies for precision medicine in squamous cell lung cancer (SqLC) have not yet been established. To identify precise patients for targeted therapies and to reveal their clinical characteristics, we have operated clinical sequencing of advanced SqLCs in our nationwide genomic screening project in Japan (LC-SCRUM-Japan) since March 2015. Methods: As of December 2016, 190 institutions across Japan were participating and 263 advanced SqLC patients had been enrolled in this project. Submitted tumor samples were subjected to a next-generation sequencing system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 cancer-related genes. Results: The median age of the 263 patients was 74 years (range, 27-87 years). Two hundred thirty (87%) were male and most patients (97%) were smokers. Among 211 available samples, potentially targetable gene alterations were detected in 58 (27%). Based on these gene alterations, the patients were subdivided into 4 groups, consisting of 25 (12%) with genetic alterations of FGFR family (FGFR type; 23 FGFR1 amplifications, 1 FGFR2 amplification and 1 FGFR3 fusion), 20 (9%) with genetic alterations of the PI3K pathway (PI3K type; 10 PIK3CA mutations, 8 PTEN mutations and 2 AKT mutations), 15 (7%) with other oncogene alterations (KRAS/EGFR/ALK type; 10 KRAS mutations, 3 EGFR mutations and 2 ALK fusions) and others. Comparative analyses of clinical characteristics between the 4 types showed that brain metastases were significantly more frequent in the FGFR type than the others (24% vs. 5%, p = 0.0007), and females (40% vs. 11%, p = 0.0009) and never-smokers (21% vs. 3%, p = 0.0004) were significantly frequent in the KRAS/EGFR/ALK type compared to the others. The prognostic significance of these genetic alterations has not yet been evaluated because of short follow-up time (median, 8.5 months). Conclusions: A series of potentially targetable gene alterations have been identified in SqLC patients. The SqLC patients had distinct clinical features according to the molecular subtypes, and genotype-directed therapeutic strategy should be developed for the individual subtypes.
A phase II study of capecitabine, oxaliplatin and irinotecan (XELOXIRI) as salvage therapy in patients with refractory metastatic colorectal cancer.
Authors: Gin Wai Kwok, Roland Ching-Yu Leung, Joanne Chiu, Vikki Tang, Thomas Cheung Yau
Journal: Journal of Clinical Oncology (2017)

e15049 Background: Advanced colorectal cancer (CRC) refractory to oxaliplatin, irinotecan, and fluoropyrimidines is associated with poor prognosis. The triplet combination of 5-fluorouracil, oxaliplatin, and irinotecan has shown efficacy and tolerability in treatment-naive disease. We investigated the efficacy and tolerability of salvage capecitabine, oxaliplatin and irinotecan (Xeloxiri) in patients who progressed on standard chemotherapy. Methods: This prospective phase 2 study with a primary endpoint of overall response rate (ORR) recruited patients with advanced CRC that have progressed on standard chemotherapy containing fluoropyrimidines, oxaliplatin, and irinotecan either as monotherapy or doublets. Prior use of anti-VEGF, and anti-EGFR agents were allowed. Patients received capecitabine 1250mg/m 2 twice daily on day 1-7, oxaliplatin 85mg/m 2 and irinotecan 165mg/m 2 on day 1 every 2 weeks until disease progression or intolerable toxicity. Secondary endpoints were progression free survival (PFS) and overall survival (OS). Results: Between July 2011 and May 2016, we recruited 32 patients. Median age was 57 and the median number of treatment cycles was 6. 16 patients (50%) were K-RAS wild-type (WT), of which 6 were also N-RAS WT. The ORR was 25% and the clinical benefit rate was 56%. 87.5% of patient received targeted therapy prior to study entry. 34% of patients had &gt; 3 previous lines of therapy. Median PFS and OS were 5.0 months (95% CI 3.2 - 7.1) and 10.4 months (95% CI 7.2 - 11.4) respectively. K-RAS mutation status, number of lines of previous therapy, and site of primary tumour were not predictive of ORR, PFS or OS on univariate testing. Treatment-related adverse events (AEs) occurred in all patients, with the majority being hematological. Dose reductions occurred in 87.5% of patients. 59% required dose delays, and 56% received granulocyte-colony stimulating factor. Grade 3/4 AEs included neutropenia (34%), anemia (16%), thrombocytopenia (12.5%), febrile neutropenia (9%), diarrhea (6%), and anorexia (3%). Conclusions: Xeloxiri is efficacious and safe in patients with chemo-refractory CRC and is a promising treatment strategy as salvage. Clinical trial information: in progress.
Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages
Authors: Inigo Ruiz de Azua, Giacomo Mancini, Raj Kamal Srivastava, Alejandro Aparisi Rey, Pierre Cardinal, Laura Tedesco, Cristina Maria Zingaretti, Antonia Sassmann, Carmelo Quarta, Claudia Schwitter, Andrea Conrad, Nina Wettschureck, V. Kiran Vemuri, Alexandros Makriyannis, Jens Hartwig, Maria Mendez-Lago, Laura Bindila, Krisztina Monory, Antonio Giordano, Saverio Cinti, Giovanni Marsicano, Stefan Offermanns, Enzo Nisoli, Uberto Pagotto, Daniela Cota, Beat Lutz
Journal: Journal of Clinical Investigation (2017)

Dysregulated adipocyte physiology leads to imbalanced energy storage, obesity, and associated diseases, imposing a costly burden on current health care. Cannabinoid receptor type-1 (CB1) plays a crucial role in controlling energy metabolism through central and peripheral mechanisms. In this work, adipocyte-specific inducible deletion of the CB1 gene (Ati-CB1–KO) was sufficient to protect adult mice from diet-induced obesity and associated metabolic alterations and to reverse the phenotype in already obese mice. Compared with controls, Ati-CB1–KO mice showed decreased body weight, reduced total adiposity, improved insulin sensitivity, enhanced energy expenditure, and fat depot–specific cellular remodeling toward lowered energy storage capacity and browning of white adipocytes. These changes were associated with an increase in alternatively activated macrophages concomitant with enhanced sympathetic tone in adipose tissue. Remarkably, these alterations preceded the appearance of differences in body weight, highlighting the causal relation between the loss of CB1 and the triggering of metabolic reprogramming in adipose tissues. Finally, the lean phenotype of Ati-CB1–KO mice and the increase in alternatively activated macrophages in adipose tissue were also present at thermoneutral conditions. Our data provide compelling evidence for a crosstalk among adipocytes, immune cells, and the sympathetic nervous system (SNS), wherein CB1 plays a key regulatory role.
Formulation of self-nanoemulsifying drug delivery systems containing monoacyl phosphatidylcholine and Kolliphor® RH40 using experimental design
Authors: Thuy Tran, Thomas Rades, Anette Müllertz
Journal: Asian Journal of Pharmaceutical Sciences (2017)

The development of self-nanoemulsifying drug delivery systems (SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be inadequate to analyse the effect of each excipient and their potential interactions on the emulsion droplet size formed when dispersing the SNEDDS in an aqueous environment. The current study investigates the emulsion droplet sizes formed from SNEDDS containing different levels of the natural surfactant monoacyl phosphatidylcholine to reduce the concentration of the synthetic surfactant polyoxyl 40 hydrogenated castor oil (Kolliphor® RH40). Monoacyl phosphatidylcholine was used in the form of Lipoid S LPC 80 (LPC, containing approximately 80% monoacyl phosphatidylcholine, 13% phosphatidylcholine and 4% concomitant components). The investigated SNEDDS comprised of long-chain or medium-chain glycerides (40% to 75%), Kolliphor® RH40 (5% to 55%), LPC (0 to 40%) and ethanol (0 to 10%). D-optimal design, multiple linear regression, and partial least square regression were used to screen different SNEDDS within the investigated excipient ranges and to analyse the effect of each excipient on the resulting droplet size of the dispersed SNEDDS measured by dynamic light scattering. All investigated formulations formed nano-emulsions with droplet sizes from about 20 to 200 nm. The use of medium-chain glycerides was more likely to result in smaller and more monodisperse droplet sizes compared to the use of long-chain glycerides. Kolliphor® RH40 exhibited the most significant effect on reducing the emulsion droplet sizes. Increasing LPC concentration increased the emulsion droplet sizes, possibly because of the reduction of Kolliphor® RH40 concentration. A higher concentration of ethanol resulted in an insignificant reduction of the emulsion droplet size. The study provides different ternary diagrams of SNEDDS containing LPC and Kolliphor® RH40 as a reference for formulation developers.
Mapping global cancer research and control in areas of low and middle income: The need for shared data on a single, interactive platform.
Authors: Ali Chisti, Nour Sharara, Manaswi Gupta, Ilyana Rosenberg, Rachel Abudu, Camille Morgan, Kalina Duncan, Shannon Silkensen, Jane Craycroft, Jennifer Silva, Billy Andre, Edward Lloyd Trimble, Ami Siddharth Bhatt, Franklin W. Huang
Journal: Journal of Clinical Oncology (2016)

e18048 Background: In response to the growing global burden of cancer, Global Oncology, Inc., and NCI’s Center for Global Health propose a call to action to populate work in low- and middle-income areas onto an online platform to catalyze collaboration in cancer research and clinical care, while also informing research and care gaps. The platform, the Global Cancer Project Map (GCPM) [http://gcpm.globalonc.org], launched as a free, interactive map to fill this void. Methods: Currently, the GCPM displays projects with international collaborators collated from the NCI, NCI-Designated Cancer Centers, UICC and ASCO. In addition to search options by project attributes, the GCPM provides overlays of epidemiological measures using cancer-specific estimates of incidence, prevalence, and mortality, as well as disability-adjusted life-years, and Human Development Index country values. An online submission form is available for individuals and organizations working in this field to contribute, index their work, and build partnerships. Results: Of the 1479 currently-mapped projects, 44.8% have investigators or collaborators in less-developed countries (LDCs) (as defined by the UN by low gross national income, human asset index, and economic vulnerability index). Of the 1218 with a project type classification, 104 relate to capacity building and/or training, with 69 of these projects (66.3%) occurring in LDCs. Utilizing the cancer type search options, the GCPM currently displays 54 cervical cancer projects with LDC collaborators, where the cervical cancer mortality age-standardized risk is more than 2.5 times higher for LDCs than more-developed countries. Conclusions: The GCPM visualizes international efforts in cancer control and links need to action. To better address the growing burden of cancer, the partnership is actively seeking additional project submissions. Utilized with cancer statistic overlays, the GCPM can help develop regional priorities in cancer research and control.
Children seen by GP in emergency department less likely to be admitted, study found
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

Having a GP in the emergency department of a paediatric hospital reduced waiting times and admissions but led to more antibiotic prescribing, a study has found.

Visits to accident and emergency departments in England have risen by a third in the past decade, reaching 22 million in 2014-15. But there is evidence that about a third of visits could be managed in primary care. About two thirds of emergency departments in England have GP services co-located within them, but evidence of the benefits is lacking.

In 2014 a GP service was co-located in …
Dual targeting of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) by miR-4317 displays a synergistic efficacy in repressing breast cancer progression
Authors: R.A. Youness, R.A. Assal, E. Khallaf, H.M. Hafez, A.A. Abdelmotaal, M.Z. Gad
Journal: Annals of Oncology (2017)
Evaluation of dose intensification of cytarabine in postremission therapy in older AML patients within the prospective phase II AMLSG 06-04 study
Authors: L. Häcker, M. Tassara, P. Brossart, G. Held, H.A. Horst, M. Ringhoffer, C-H. Köhne, S. Kremers, A. Raghavachar, G. Wulf, H. Kirchen, D. Nachbaur, M. Wattad, A. Benner, D. Weber, V.I. Gaidzik, P. Paschka, K. Döhner, H. Döhner, R. Schlenk
Journal: Annals of Oncology (2017)

Background: Progress in the treatment of acute myeloid leukemia (AML) in older patients (pts) is still limited. In the randomized part of the AMLSG 06-04 trial, valproic acid (VPA) was evaluated in combination with intensive therapy plus all-trans retinoic acid (ATRA) in older pts (>60 years) with newly diagnosed AML. The randomized part of the study (cohort-1) was terminated due to excessive VPA-induced toxicity (Tassara et al, Blood 2014;123:4027-36.). The study was amended thereafter (cohort-2) to evaluate a cytarabine dose-intensifcation in first consolidation therapy. Here we report on the comparison of the two cohorts. Methods: Between 2004 and 2008, patients were treated in cohort-1 (n = 186) and cohort-2 (n = 376). 2 cycles of induction therapy (ATRA, idarubicin, cytarabine, n = 93 with VPA) were followed by consolidation-1 (mitoxantrone, ATRA, cytarabine [cohort-1, 0.5g/m2; cohort-2, 1g/m2] bid, days 1-3) and consoldation-2 (idarubicin, etoposide, ATRA). Results: Median age was 68 (range, 60-84) years without difference between the cohorts (p = 0.49). Complete remission (CR) rates after induction therapy were 45% and 48% (p = 0.59) in cohort-1 and -2, respectively. There were no significant differences in the cumulative incidences of relapse (CIR, p = 0.26) and death (p = 0.51) between cohort-1 and -2 with CIR of 63% (SE, 4.8%) in cohort-1 compared to 51% (SE, 6.3%) in cohort-2. A Cox regression model on overall survival revealed older age (hazard ratio (HR) for a 10 years difference, 1.97, p < 0.0001), 2010 European LeukemiaNet (ELN) unfavorable risk (HR, 1.57, p = 0.0003) as well as cohort-1 (HR, 1.31, p = 0.02) as unfavorable parameters and ELN favorable risk (HR 0.55, p < 0.0001) as favorable prognostic parameter. Survival was inferior (p = 0.03) in cohort-1 with 21% (95%-CI, 16-28%) compared to cohort-2 with 28% (95%-CI, 23-33%) at 2 years. In an age-adjusted analysis the molecular marker FLT3-ITD was associated with an unfavorable prognosis. Conclusions: Although evaluated in a cohort- rather than a randomized study, intensification of cytarabine dosage in consolidation therapy seems to improve survival. Clinical trial identification: NCT00151255 Legal entity responsible for the study: University Hospital Ulm Funding: University Ulm, Pfizer Disclosure: R. Schlenk: Research funding: Novartis, Pfizer, Amgen, AstraZeneca, PharmaMar; Speakers bureau: Novartis, Pfizer; Advisory board: Daiichi Sankyo, Novartis, Pfizer. All other authors have declared no conflicts of interest.
Abstract 12918: Comparison between Standard and Reduced Doses of Direct Oral Anticoagulants for Periprocedural Anticoagulation in Truly Low Thromboembolic Risk Patients Undergoing Catheter Ablation of Atrial Fibrillation
Authors: Kohki Nakamura, Shigeto Naito, Kentaro Minami, Takehito Sasaki, Koji Kumagai, Nobusada Funabashi, Yoshio Kobayashi, Shigeru Oshima
Journal: Circulation (2016)

Introduction: Direct oral anticoagulants (DOACs) are generally administered in truly low thromboembolic risk patients undergoing atrial fibrillation (AF) ablation. All DOACs have two dose settings, but reduced doses are commonly used in patients for whom a DOAC dose reduction is not necessary according to the dose reduction criteria in the real world. Purpose: This study aimed to evaluate the safety and efficacy of periprocedural DOACs in AF patients with a CHA 2 DS 2 -VASc score of 0 (male) or 1 (female), and compare that between standard and reduced DOAC doses. Methods: We retrospectively enrolled 1013 consecutive patients receiving periprocedural DOACs, and 232 patients (median, 54 years) with a CHA 2 DS 2 -VASc score of 0 (190 males) or 1 (42 females) were analyzed (dabigatran, n=36; rivaroxaban, n=121; apixaban, n=59; edoxaban, n=16). Standard and reduced doses were administered in 149 and 83 patients, respectively, but essentially a dose reduction was not necessary in 95.2% of the reduced dose patients. All DOACs were discontinued on the day of the procedure and no pre-ablation heparin bridging was performed. Results: The standard and reduced dose patients required a similar heparin dosage (median, 13630 vs. 13330 units, P=0.671), and the mean and maximum activated clotting times were 303 and 329 seconds with the standard doses, and 310 and 333 seconds with the reduced doses, respectively (P=0.012 and 0.076). No symptomatic thromboembolisms occurred. The incidence of major and minor bleeding and silent cerebral ischemic lesions on magnetic resonance imaging was 0.7%, 5.4%, and 10.0% with the standard doses and 0%, 1.2%, and 12.5% with the reduced doses, respectively (P=0.642, 0.107, and 0.558). The standard and reduced doses revealed a similar bleeding risk (2 with minor bleeding vs. 0; P=0.305) during the post-ablation oral anticoagulation (median, 106 days vs. 92 days; P=0.627). Conclusions: Standard and reduced DOAC doses for periprocedural anticoagulation revealed a similar thromboembolic and hemorrhagic risk in CHA 2 DS 2 -VASc low-risk patients undergoing AF ablation. A reduced dose use, if not according to the dose reduction criteria, may not contribute to either a reduction in bleeding or an increase in thromboembolisms associated with AF ablation.
Re-education of tumor-associated macrophages by CXCR2 blockade drives senescence enhancement and tumor inhibition in advanced prostate cancer
Authors: D. Di Mitri, J. Vasilevska, A. Calcinotto, V. Gil, G. Boysen, A. Revandkar, D. Waugh, S. Barry, J. de Bono, A. Alimonti
Journal: Annals of Oncology (2017)
Efficacy and safety profile of the adriamycin/cyclophosphamide (AC) followed by docetaxel/cisplatin (DC) in locally advanced breast cancer
Authors: T. Abdelhamid, M. Saber, A. Abdel-Samie Gaber, M. Selim, O. Youssef, A. Salama, N. Aly Eldin
Journal: Annals of Oncology (2017)