tbuckley/cabot-search huggingface dataset:
Assessing the effectiveness of adjuvant chemoradiotherapy after cholecystectomy in patients with gallbladder cancer.
Authors: Grant McLeod Van der Voort, Brendan Martin, Tarita Thomas
Journal: Journal of Clinical Oncology (2018)

455 Background: The study was conducted to compare the overall survival for patients receiving concurrent chemoradiotherapy (CCRT) versus radiotherapy (RT) or chemotherapy (CT) alone after cholecystectomy in patients with gallbladder cancer. Methods: Patients with gallbladder cancer who had surgical resection from 2004 to 2015 were identified in the National Cancer Database. The proportional hazards assumption for each predictor was assessed using Martingale residuals. Significance was then determined using univariable and multivariable Cox proportional hazards frailty models that allow for clustering of patients within their treatment facility type. Results: A total of 7,258 gallbladder cancer patients who had undergone cholecystectomy met eligibility criteria: 1,509 (20.8%) received CCRT, 283 (3.9%) received RT alone, 1,368 (18.9%) received CT alone, and 4,098 (56.5%) received no adjuvant therapy. The median survival for this patient sample was 29.11 months with median follow-up of 59.10 months. On multivariable analysis, the hazard of death at any given time for patients who received adjuvant CCRT following surgery was 20% (HR = 0.80, 95 CI: 0.73-0.87) lower than those who only underwent surgery alone (p &lt; .0001). By contrast, the hazard of death at any given time for patients who received CT following surgery was 33% (HR = 1.33, 95 CI: 1.22-1.44) higher than those who only underwent surgery (p &lt;.0001). Conclusions: CCRT is associated with improved OS compared with CT or RT alone after cholecystectomy in patients with gallbladder cancer, suggesting that adjuvant CCRT should be used in this population although prospective data is needed to validate these findings.
A Survey on Data Reproducibility and the Effect of Publication Process on the Ethical Reporting of Laboratory Research
Authors: Delphine R. Boulbes, Tracy Costello, Keith Baggerly, Fan Fan, Rui Wang, Rajat Bhattacharya, Xiangcang Ye, Lee M. Ellis
Journal: Clinical Cancer Research (2018)

Purpose: The successful translation of laboratory research into effective therapies is dependent upon the validity of peer-reviewed publications. However, several publications in recent years suggested that published scientific findings could be reproduced only 11% to 45% of the time. Multiple surveys attempted to elucidate the fundamental causes of data irreproducibility and underscored potential solutions, more robust experimental designs, better statistics, and better mentorship. However, no prior survey has addressed the role of the review and publication process on honest reporting.Experimental Design: We developed an anonymous online survey intended for trainees involved in bench research. The survey included questions related to mentoring/career development, research practice, integrity, and transparency, and how the pressure to publish and the publication process itself influence their reporting practices.Results: Responses to questions related to mentoring and training practices were largely positive, although an average of approximately 25% did not seem to receive optimal mentoring. A total of 39.2% revealed having been pressured by a principle investigator or collaborator to produce "positive" data. About 62.8% admitted that the pressure to publish influences the way they report data. The majority of respondents did not believe that extensive revisions significantly improved the manuscript while adding to the cost and time invested.Conclusions: This survey indicates that trainees believe that the pressure to publish affects honest reporting, mostly emanating from our system of rewards and advancement. The publication process itself affects faculty and trainees and appears to influence a shift in their ethics from honest reporting ("negative data") to selective reporting, data falsification, or even fabrication. Clin Cancer Res; 24(14); 3447-55. ©2018 AACR.
Dose escalation study of ODM-203, a selective dual FGFR/VEGFR inhibitor, in patients with advanced solid tumours.
Authors: Jordi Rodon Ahnert, Chris Garratt, Kaisa Laapas, Hanna Leskinen, Harry Bjorklund, Angela Ruck, Katriina Peltola, Analia Azaro, Eduardo Castanon-Alvarez, Christophe Massard, Petri Bono
Journal: Journal of Clinical Oncology (2016)

2576 Background: Inhibitors of fibroblast growth factor receptors (FGFR) are being developed for treatment of solid tumours with FGFR genetic alterations. ODM-203 is a small molecule with balanced inhibitory effects on both FGFR 1-4 and VEGFR 1-3 subtypes. We present the results of the first-in-man study. Methods: ODM-203 was evaluated in a 3+3 dose escalation design to identify the maximum tolerated dose (MTD), dosed daily in a 4 week cycle. PK profiles were taken on days 1 and 8, and safety labs, ECG, vital signs and adverse events were recorded on days 1, 4, 8, 15, 22, 29, week (wk) 6 and wk 8. Plasma markers of FGFR and VEGFR inhibition were measured at baseline, day 8 and day 29 and tumour response by RECIST criteria every 8 weeks. Patients continued ODM-203 treatment until disease progression or dose limiting toxicity (DLT). Results: 24 patients (median age 55, range 28-80 years) with advanced solid tumours received ODM-203 in doses between 50-800mg once/day. The longest treatment period so far is 40 wks (cholangiocarcinoma with FGFR fusion). Patients had various primary tumours, some having FGFR alterations. One DLT (corneal keratopathy) was recorded at 800mg/day but MTD was not identified. A single grade 4 AE (lipase increase) was reported. Most AE’s reported were G1-2, the most common being increased bilirubin (63%, G3 in 11 (46%) pts), diarrhoea (46%, G3 in 2 (8%) pts), alopecia (33%), jaundice (33%, G3 in 1 (4%) pt), stomatitis (29%) and increased phosphate (25%). Increased bilirubin was due to UGT1A1 inhibition by ODM-203 and resolved upon dose reduction/discontinuation. After repeated dosing ODM-203 exposure increased more than dose-proportionally. Steady state was generally not reached by day 8. There were 2 partial responses (RCC and FGFR mutated salivary gland cancer) and 5 further patients achieved stable disease for at least 16 wks. Conclusions: ODM-203 elicited on-target adverse effects in addition to bilirubin changes. There was preliminary evidence of promising anti-tumour activity although FGFR-aberrant tumours were not specified. Further evaluation is ongoing at 600mg/day and will continue in an expansion study in patients with FGFR-aberrant tumours. Clinical trial information: NCT02264418.
Abstract 861: Angiopoietin-2 blocking antibodies improve tumor growth inhibition and survival in mice treated with low doses of radiation
Authors: Pauliina Kallio, Elina Jokinen, Suvendu Das, Jenny Högström, Sarika Heino, Marianne Lähde, Kari Alitalo
Journal: Cancer Research (2018)

Abstract Almost 50 % of all cancer patients receive radiation therapy during their treatment, yet several tumor types show radiation therapy resistance that compromises treatment efficacy. Many radiation sensitizers have been tested for improvement of the outcome of radiation therapy. For example, inhibitors of VEGF and VEGF receptors were tested in attempt to normalize the tumor vasculature and to improve the outcome of radiation therapy. Here, we have analysed if antibodies blocking the angiogenic factor angiopoietin-2 could improve radiation therapy of mouse tumor isografts and human tumor xenografts in mice. To test if the anti-tumor effect of small doses of radiation can be increased by Ang2 blocking antibodies, we analysed the radiation sensitivity of subcutaneous tumor isografts in C57bl/6JRj mice, and human xenografts in NOD scid gamma mice. In several models, the combination treatment with anti-Ang2 plus radiation was superior to the monotherapies in decreasing tumor growth and increasing the lifespan of the tumor-bearing mice both in immunocompetent and immunocompromised mice. Based on our results, the anti-Ang2 blocking antibody treatment could be tested in the clinics to improve the effect of radiation therapy, especially in those cases in which an optimal radiation dose cannot be given because of the radiation sensitivity of the surrounding tissues. Citation Format: Pauliina Kallio, Elina Jokinen, Suvendu Das, Jenny Högström, Sarika Heino, Marianne Lähde, Kari Alitalo. Angiopoietin-2 blocking antibodies improve tumor growth inhibition and survival in mice treated with low doses of radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 861.
In situ vaccination with local radiation and intratumoral immunocytokine to elicit a tumor-specific memory B-cell response.
Authors: Claire Baniel, Jacquelyn A Hank, Emily I. Guy, Stephen D Gillies, Alan J. Korman, Hans Loibner, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel, Zachary Scott Morris
Journal: Journal of Clinical Oncology (2017)

69 Background: In a murine melanoma (MEL) model, we reported an in situ vaccination response to combined radiation (RT) and intra-tumor (IT) injection of anti-GD2 hu14.18-IL2 immunocytokine (IC). This treatment resulted in 71% complete regression of 5-week (~ 200mm 3 ) tumors, a memory T cell response, and augmented response to systemic anti-CTLA-4 antibody (mAb) checkpoint blockade. We hypothesized that mice rendered disease-free (DF) by RT, IT-IC, and anti-CTLA-4 mAb might also exhibit a memory B cell response. Methods: C57BL/6 mice were implanted with 2x10 6 syngeneic, GD2+ B78 MEL cells and tumors developed for 5 weeks. Mice were treated with 12 Gy RT to this tumor followed by 5 daily IT injections of hu14.18-IL2 d6-10 after RT and IP injection of anti-CTLA-4 d3, 6, and 9 after RT. DF mice and naïve controls were challenged by subcutaneous implantation with 2x10 6 B78 MEL cells. Peripheral blood was collected from mice before and after B78 challenge and serum was evaluated for presence of tumor-specific mAbs using flow cytometry and ELISA. Results: Seventy-three percent of mice were rendered DF by treatment with RT, IT-hu14.18-IL2, and anti-CTLA-4. All of these (13/13) rejected a rechallange B78 implantation &gt; 1 year later (range d378 – 511), whereas no naïve mice rejected B78 implantation (0/66). IgG from serum of DF mice bound selectively to B78 and parental GD2- B16 MEL cells and the level of this mAb response appeared to increase modestly d14 after B78 challenge. In naïve mice, a modest increase in tumor-specific mAb was identified between non-tumor implanted mice and d35 post-implantation mice (bearing tumors &gt; 200mm 3 ), however this level remained ~ 5 fold below that observed in DF mice prior to B78 rechallenge. In contrast, no appreciable mAb response was observed for unrelated syngeneic GD2+ Panc02 pancreatic tumor cells in serum of DF or naïve mice. Conclusions: We report an endogenous anti-tumor IgG humoral response in DF mice &gt; 1 year after treatment with RT, IT-IC, and anti-CTLA-4 mAb, concurrent with demonstration of long lasting immune protection from re-challenge. Studies are underway to determine whether this response is involved in the therapeutic efficacy of this in situ vaccination regimen.
Evaluation of whole genome sequencing and software tools for drug susceptibility testing of Mycobacterium tuberculosis
Authors: J. van Beek, M. Haanperä, P.W. Smit, S. Mentula, H. Soini
Journal: Clinical Microbiology and Infection (2018)

ObjectivesCulture-based assays are currently the reference standard for drug susceptibility testing for Mycobacterium tuberculosis. They provide good sensitivity and specificity but are time consuming. The objective of this study was to evaluate whether whole genome sequencing (WGS), combined with software tools for data analysis, can replace routine culture-based assays for drug susceptibility testing of M. tuberculosis.MethodsM. tuberculosis cultures sent to the Finnish mycobacterial reference laboratory in 2014 (n = 211) were phenotypically tested by Mycobacteria Growth Indicator Tube (MGIT) for first-line drug susceptibilities. WGS was performed for all isolates using the Illumina MiSeq system, and data were analysed using five software tools (PhyResSE, Mykrobe Predictor, TB Profiler, TGS-TB and KvarQ). Diagnostic time and reagent costs were estimated for both methods.ResultsThe sensitivity of the five software tools to predict any resistance among strains was almost identical, ranging from 74% to 80%, and specificity was more than 95% for all software tools except for TGS-TB. The sensitivity and specificity to predict resistance to individual drugs varied considerably among the software tools. Reagent costs for MGIT and WGS were €26 and €143 per isolate respectively. Turnaround time for MGIT was 19 days (range 10–50 days) for first-line drugs, and turnaround time for WGS was estimated to be 5 days (range 3–7 days).ConclusionsWGS could be used as a prescreening assay for drug susceptibility testing with confirmation of resistant strains by MGIT. The functionality and ease of use of the software tools need to be improved.
FDA places “unique” restrictions on contraceptive implant Essure
Authors: Owen Dyer
Journal: BMJ (2018)

The US Food and Drug Administration will apply unprecedented restrictions on the use of Bayer’s contraceptive implant Essure after finding that previous warnings did not do enough to inform patients about the device’s potential risks.

Effective immediately, the only healthcare facilities allowed to implant the device will be those that agree that, in every case, a healthcare professional will guide prospective recipients through a 20 page, FDA approved brochure laying out potential adverse effects.1

Informed …
A novel cancer vaccine platform utilizing autologous tumor lysate loaded into capped yeast cell wall particles.
Authors: Kaitlin M. Peace, Timothy J Vreeland, Diane F Hale, Doreen O Jackson, Julia M Greene, Alfred F Trappey, John S Berry, Guy T Clifton, Garth S Herbert, George Yu, Tom Wagner, George Earl Peoples
Journal: Journal of Clinical Oncology (2017)

169 Background: Our current tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine employs yeast cell wall particles (YCWP) to deliver antigen to DC ex vivo and is being tested in a randomized phase IIb trial. This strategy may be improved by injecting TL-loaded YCWP as an intradermal vaccine, with in vivo DC uptake. Silicate capping should allow YCWP to retain TL longer and stimulate DC uptake. Here, we present preclinical data on the tumor lysate, particle only (TLPO) vaccine concept vs. TLPLDC. Methods: To test the TLPO concept, YCWP were loaded with fluorescence (flr) labeled albumin and capped (cp) vs. uncapped (ucp) particles were compared for flr leak. Next, YCWP were added to cultured macrophages to evaluate DC uptake. Cells were then lysed, centrifuged, and flr in the cytoplasm vs. organelles measured. 3 C57B mice were then injected with 100ml NaCl, 10 6 empty cp YCWP, or 1mcg GM-CSF. 5 hours (hr) post-injection, 100ml NaCl was injected into the same site, withdrawn, and examined via microscope to count monocytes. TLPO was compared to TLPLDC in a B16 murine melanoma survival model. Finally, 4 grey horses with equine melanoma were treated with autologous TLPO, injected biweekly for 4 vaccinations. Target lesions were assessed over 6 months. Results: Compared to ucp YCWP, cp had decreased flr leak at 1 (15.8% vs. 24.7%) and 2 hr (6.7% vs. 16.6%), increased uptake by DC (2hr flr readings 11065 vs. 3928) and higher delivery to DC cytoplasm (68.9% vs. 48.8%). Empty cp YCWP showed increased recruitment of monocytes (276/hpf) vs. GM-CSF (55/hpf) or NaCl alone (18/hpf). In the B16 murine melanoma model, the median survival time in days was 21 for controls (n=5), 42 for TLPLDC (n=10), and 56 for TLPO (n=20). At 6 months, the equine model revealed 1 complete and 3 partial responses (50%, 68%, and 45% tumor reduction). Conclusions: Silicate capping of the YCWP effectively limits leakage of contents, improves uptake by DC and delivery to the cytoplasm without the need for GM-CSF. In early animal studies, TLPO appears to have equivalent efficacy to TLPLDC, but eliminates the need for in vitro DC loading. We plan to perform a bridging study comparing TLPO to TLPLDC after enrollment is complete in our phase IIb TLPLDC melanoma trial.
Treatment Approaches for Malignant Pleural Effusion
Authors: Rajesh Thomas, Kevin Murray, Y. C. Gary Lee
Journal: JAMA (2018)

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Roger Gilbert Bannister: innovative neurologist and the first athlete to run a mile in less than four minutes
Authors: Matt Limb
Journal: BMJ (2018)

Credit: PA

Sir Roger Bannister was a towering figure in the history of British sport and medicine. He was the first athlete to run a mile in less than four minutes, a feat some thought impossible in 1954, when Bannister was a 25 year old medical student, training mostly between lectures. But subsequent achievements would matter to him more.

He became a consultant at 34, was a groundbreaking neurologist, and in the 1970s led the fight against drugs in sport, developing tests for anabolic steroids as head of the Sports Council. He was knighted in 1975 and made a Companion of Honour in the 2017 New Year’s Honours. But he was never spoilt by fame, say those who knew and worked with him over many years. “He was a lovely man with many friends. Many of us have been greatly enriched by having known him and will be forever grateful,” says neurologist Dafydd Thomas.

Bannister specialised in understanding and treating disorders of the autonomic nervous system, which controls all the automatic functions of the body—such as heartbeat, blood pressure, and digestion. Patients with autonomic failure can experience debilitating problems, including fainting caused by inability to maintain blood pressure to the brain.



Credit: Anne Katrin Purkiss/REX/Shutterstock

Christopher Mathias, who began collaborating with Bannister at St Mary’s Hospital in 1981, and at times struggled to keep up with his long stride on ward rounds, says, “Roger was a pioneer in clinical autonomic work. Before then, the science hadn’t really been applied to patients.

“These were the patients who felt faint when they stood up, they had what’s called postural hypotension. It was grossly under-recognised because very few were having blood pressure taken lying and standing,” says Mathias, who is emeritus professor at University College London.

Bannister developed autonomic investigation units in London at both the National Hospital for …
209P The management of brain disease (BD) in ALK-rearranged non-small cell lung cancer (ALK NSCLC): Can systemic treatment delay the initiation of local treatments? Experience of the Ramón y Cajal University Hospital (RyCUH, Madrid)
Authors: R. Martin Huertas, I. Ciscar Garcia, C. Saavedra Serrano, J.J. Serrano Domingo, E. Corral de la Fuente, J.J. Soto Castillo, A. Gomez Rueda, M.E. Olmedo Garcia, P. Garrido Lopez
Journal: Journal of Thoracic Oncology (2018)
Immunomodulatory pathways in both breast cancer and placental tissues: Insights from a unique clinical and genomic case report.
Authors: Miguel Hernandez Bronchud
Journal: Journal of Clinical Oncology (2017)

13 Background: some cancers might partially ectopically express intrinsic immune escape gene programs naturally developed during mammalian evolution to allow for materno-fetal immune tolerance. Methods: Genomic analysis (Nanostring Inc, Seattle, WA, USA) was carried out in primary breast cancer with metastatic homolateral axillary lymph nodes as well as placenta tissue (both uterine decidual tissue and term placenta tissue) from a pregnant woman (same patient). Gene expression profiling of paired non-self and self tissues (i.e. placenta/uterus; breast cancer/normal breast tissue; metastatic lymphnode/normal lymphnode tissue) was performed using the PanCancer Immune gene panel, a 770 Nanostring gene expression panel. Results: Our findings reveal overlapping in specific immune gene expression in placenta and cancer tissue, suggesting that these genes might play an important role in maintaining immune tolerance both physiologically (placenta) and pathologically ( cancer). Placenta and uterus, breast tissues (tumor and normal) and lymph node tissues (tumor and normal) formed their own RNA transcription cluster, suggesting that tissue specific gene expression patterns were well preserved during experimental procedures . We analyzed differential expression within each tissue type (i.e. matching for the analysis placenta with uterus, breast cancer with normal breast tissue and node positive with node negative tissue). Among the 583 genes analyzed, 103 genes were upregulated &gt; 1.5 fold in placenta versus uterus, while 258 genes were downregulated at least 1.5 fold. Using the same cut-off, 258 genes were upregulated and 44 genes downregulated in breast tumor versus normal breast tissue, and 178 genes were upregulated while 146 genes downregulated in tumor bearing lymph node versus non-involved lymph node. Conclusions: A variety of complex immune regulation mechanisms seem to be shared by both placental tissues and cancer.