tbuckley/cabot-search huggingface dataset:
Consequences of long-term oral corticosteroid therapy and its side-effects in severe asthma in adults: a focused review of the impact data in the literature
Authors: Timm Volmer, Timo Effenberger, Christoph Trautner, Roland Buhl
Journal: European Respiratory Journal (2018)

This review provides an overview of the role of long-term treatment of severe asthma with oral corticosteroids (OCS) and its associated side-effects in adults. It is based on a systematic literature search conducted in MEDLINE, Embase and the Cochrane Library to identify relevant studies. After a short overview of severe asthma and its treatment we present studies showing a dose-response relationship in asthmatic patients treated with OCS and then consider by organ systems the undesired effects demonstrated in clinical and epidemiological studies in patients with OCS-dependent asthma. It was found that the risk of developing various OCS-related complications, including infections, diabetes and osteoporosis as well as psychiatric disorders, was higher for patients with long-term exposure to OCS compared with control groups. In addition, studies showed a significant increase in healthcare resource utilisation due to OCS treatment. Therefore, it is incumbent on every clinician to carefully weigh the potential beneﬁt of preventing loss of asthma control against this risk before opting to prescribe long-term OCS therapy. Effective corticosteroid-sparing strategies must be used and should aim at short-term use with the lowest effective dose and start tapering as soon as possible until OCS therapy is terminated.
High levels of cell-free DNA (cfDNA) at baseline (BL) and increase of at least one mutation at day 14 (D14) as independent prognostic biomarkers for patients (pts) with advanced colorectal cancer (aCRC) under regorafenib.
Authors: Pashalina Kehagias, Caroline Vandeputte, Lieveke Ameye, Hakim El Housni, Amélie Deleporte, Karen Paula Geboes, Thierry Delaunoit, Marc Peeters, Gauthier Demolin, Lionel A. D'Hondt, Jozef Janssens, Javier Carrasco, Stephane Holbrechts, Jean-Charles Goeminne, Philippe Vergauwe, Jean-Luc Van Laethem, Ghanem Ghanem, Marianne Paesmans, Patrick Flamen, Alain Hendlisz
Journal: Journal of Clinical Oncology (2018)

3532 Background: BL-cfDNA combined with plasmatic changes in tumor-specific mutations after 14 days of therapy are explored as independent determinants of outcome in pts with aCRC. Methods: Archival tumor tissue and plasma samples at BL and D14 after regorafenib initiation were prospectively collected in aCRC pts (n=141) in a multicentric trial (NCT01929616). Tumor-specific mutations, selected on their allelic frequency on CRC-oriented targeted sequencing of tumor tissue, were analyzed for circulating tumor DNA (ctDNA) at BL and D14 via droplet digital PCR (Bio-Rad QX200 ddPCR system) using a 12 % cutoff to assess changes in ctDNA levels. Results: The cfDNA’s optimal cutoff at BL (Contal & O’Quigley method) is 1 µg/ml in 134/141 evaluable pts. Hazard ratio (HR) of cfDNA ≥1 vs <1 is 2.50 (95% CI, 1.73-3.63) P<0.001 for progression-free survival (mPFS) and 3.83 (95% CI, 2.57-5.71) P<001 for overall survival (mOS). The most common mutated genes (96 evaluable pts for ctDNA) are APC (73%), TP53 (72%), KRAS (66%), and PI3KCA (23%). On average 2 (1-4) mutations are followed per pt. An increase of ≥1 tumor-specific mutation as compared to none is associated with a significantly worse outcome: mPFS 1.3 vs 3.0 months (mo) (HR 1.88, P=0.002, 95% CI 1.24-2.85) and mOS 3.9 vs 8.5 mo (HR 2.04, P<0.001, 95% CI 1.33-3.12). BL cfDNA level and ctDNA changes between BL & D14 are not statistically correlated (P=0.23), and combined, define 4 subgroups with different prognosis. (Table 1) Conclusions: BL cfDNA and early (D14) changes in ctDNA during treatment with regorafenib are independent predictive markers for pts’ outcome and appear as potential robust tools for treatment personalization. Clinical trial information: NCT01929616. mPFS (mo) mOS (mo) 0 mut increase ≥ 1 mut increase 0 mut increase ≥ 1 mut increase BL cfDNA ≥1 1.3 (95% CI, 1.1 - 3.0) n=19 1.1 (95% CI, 0.4 - 1.3) n=30 6.1 (95% CI, 2.1 - 8.1) n=19 2.3 (95% CI, 1.3 - 3.0) n=30 HR 1.79 (95% CI, 0.99-3.23) P 0.05 2.43 (95% CI, 1.29-4.59) P 0.006 BL cfDNA<1 4.8 (95% CI, 1.6 - 5.1) n=24 2.2 (95%CI, 1.3 - 3.1) n=23 13.8 (95% CI, 8.2 - 19.1) n=24 6.6 (95% CI, 5.9 - 10.9) n=23 HR 1.85 (95% CI, 1.02 - 3.35) P 0.04 1.83 (95% CI, 0.99 - 3.37) P 0.05
Phase 1 study of an oxidative phosphorylation inhibitor IM156 in patients with advanced solid tumors.
Authors: Sun Young Rha, Seung-Hoon Beom, Minkyu Jung, Young Geun Shin, Jae-Ho Cheong, Hyo Song Kim, Gun Min Kim, Jong Hee Chang, Young Woo Lee, Yunseon Chong, Sanghee Yoo, Vincent O'Neil, Filip Janku
Journal: Journal of Clinical Oncology (2018)

TPS2620 Background: IM156 is a novel oral agent with a biguanide structure, which has anticancer activity through AMPK activation and reduction of oxidative phosphorylation. Inhibition of oxidative phosphorylation (OXPHOS) is detrimental to OXPHOS dependent drug resistant cancer cells which adapt metabolic shift upon cancer treatment or are intrinsically OXPHOS dependent cancer cells. OXPHOS dependent cancer cells are prone to energy stress such as OXPHOS inhibition that ultimately cause cancer cell death. Preclinical in vitro and in vivo experiments demonstrated that IM156 can be effective in glioblastoma, and other solid tumors. Therefore, a phase I dose-escalation study to determine safety and preliminary signals of activity of IM156 has been designed and activated (NCT03272256). Methods: This is an open label, single center, dose-escalation study using the 3+3 design to determine the maximum tolerated dose and/or recommended phase 2 dose, dose limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics and preliminary signals of anticancer efficacy of IM156 in patients with advanced solid tumors refractory to standard therapies. Eligible patients are adults with advanced solid tumors refractory to standard therapies with adequate performance status (ECOG ≤2) and organ function with measurable disease per RECIST 1.1 (or RANO for gliomas). IM156 is administered orally every other day starting on day 1 of each 28 days cycle. The study has total of 6 dose levels ranging from 100 mg to 1,800 mg and the dose escalation continues per 3+3 design as long as the proportion of DLTs < 33% ( < 2/6). DLTs are evaluated during the first 28 days of therapy (cycle 1). Efficacy per RECIST 1.1 (RANO for gliomas) is evaluated every two cycles. Pharmacokinetics studies have been designed to determine Cmax, AUC, T1/2 and other parameters. Pharmacodynamics studies include PET scans with FDG and acetate probes, tissue and blood biomarkers including lactate levels. As of 2/8/18 the study enrolled 6 patients into two dose levels (100mg and 200mg respectively) and enrollment continues. Clinical trial information: NCT03272256.
TCT-832 Resting Heart Rate at Discharge Predicts Adverse Cardiovascular Outcomes In Patients With Left Main Coronary Artery Disease Revascularized With PCI and CABG: Insights from the EXCEL trial
Authors: Ioanna Kosmidou, Aaron Crowley, Leon Gustavo Macedo, Ori Ben-Yehuda, Bernard Gersh, Ad van Boven, None Piet Willem Boonstra, A. Pieter Kappetein, Patrick Serruys, Joseph Sabik, Gregg Stone
Journal: Journal of the American College of Cardiology (2018)
TCT-426 Relationship Between Lesion Characteristics as Assesed by Intravascular Ultrasound and Clinical Outcomes ∼VAMPIRE 3 IVUS Substudy∼
Authors: Nobuhiko Maejima, Kiyoshi Hibi, Ken Kozuma, Akiyoshi Miyazawa, Naoki Nakayama, Shinjo Sonoda, Hiroyuki Tanaka, Hiroyuki Kyono, Ryoji Koshida, Takayuki Ishihara, Teruyoshi Kume, Kengo Tanabe, Yoshihiro Morino, Kengo Tsukahara, Yuji Ikari, Kenshi Fujii, Masao Yamasaki, Hideaki Yoshino, Tetsuya Sumiyoshi, Kazuo Kimura, Takaaki Isshiki
Journal: Journal of the American College of Cardiology (2018)
WINTHER: An international WIN Consortium precision medicine trial using genomic and transcriptomic analysis in patients with advanced malignancies.
Authors: Jordi Rodon, Jean-Charles Soria, Raanan Berger, Wilson H. Miller, Vladimir Lazar, Eitan Rubin, Apostolia Maria Tsimberidou, Pierre Saintigny, Aliza Ackerstein, Irene Brana, Yohann Loriot, Mohammad Afshar, Vincent A. Miller, Fanny Wunder, Catherine Bresson, Jean-Francois Martini, John Mendelsohn, Richard L. Schilsky, J. Jack Lee, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2018)

12011 Background: Precision medicine has focused mainly on matching drugs to tumor DNA alterations. However, not all individuals have tractable genomic alterations.We initiated the WINTHER trial to navigate patients to therapy based on either next generation sequencing (NGS) or transcriptomic analysis that compared tumor to normal tissue. Methods: Genomics (Arm A) was performed by NGS (N = 236 genes) (Foundation Medicine); transcriptomics (Arm B), by Agilent oligo-arrays (from fresh biopsies). A matching score was calculated for each patient (based on drugs received): for Arm A, number of alterations matched/total number of alterations; for RNA, by adding the reciprocals of the ranks of expression-matched drugs (using a transcriptomic algorithm). The clinical management committee (CMC) (lead investigators from the participating centers in 5 countries) suggested therapies, prioritizing genomic matches if available. The treating physician determined therapy given. Results: Overall, 303 patients consented; 107 (35%) received therapy consistent with CMC recommendations: 69 patients (64.5%) on Arm A (DNA-guided); 38 (35.5%), Arm B (RNA-guided). The median number of prior therapies was 3; median age = 59; median performance status = 1 (did not differ between arms). The most common diagnoses were colon, head/neck, and lung cancers. Adverse events after biopsy occurred in 1.2% of patients (1, (unrelated) convulsion; 2, pneumothorax). The rate of stable disease (SD) ≥ 6 months plus partial and complete response was 26.2%: Arm A, 23.2%; Arm B, 31.6%. Median progression-free survival (PFS) was 2.1 months (Arm A, 1.9; Arm B, 2.4). In multivariate analysis (hazard ratio (HR), 95% confidence interval (CI)), fewer prior therapies (0.63, 0.40-1.00, p = 0.048), better performance status (0.59, 0.37-0.92, p = 0.020) and a higher matching score (0.52, 0.33-0.82, p = 0.005) correlated with PFS. Higher matching score was also significantly associated with better overall survival (OS). (p = 0.012). Conclusions: Genomic and transcriptomic analysis were both useful for therapy selection. Higher degrees of DNA and RNA matching independently associated with longer PFS and OS. Clinical trial information: NCT01856296.
Barriers and solutions of long-term follow up of childhood cancer survivors in Turkey: A questionaire survey.
Authors: Nurdan Tacyildiz, Sonay incesoy Ozdemir, Emel Cabi Unal, Handan Dincaslan, Gulsan Yavuz
Journal: Journal of Clinical Oncology (2017)

e22020 Background: The population of childhood cancer survivors has grown with 80 % cure rates. Our aim was to establish the barriers of longterm followup (LTFU) in Turkey. Methods: An e-mail questionnaire survey has been sent to 33 pediatric oncology centers (POC). Questionnaire compossed of 3 sections: 1- Description of the center; yearly new patients number, follow-up period, etc. 2- Methods for follow-up of late effects Content of provided information to the families related cancer treatment &amp; side effects &amp; healthy life style, missing parts of LTFU 3- Transition problems of survivors to adult survivorship programs. Educational problems of Hematology/Oncology Fellows (HOF) Suggestions for improvement of LTFU. Results: 21 of 33 centers (63%) responded the questionnaire. Experience as POC: 2-50 years (median: 23). New patients / each year: 8 - 300 (median: 68). Most of the centers accepting patients up to 18 years, only 4 center providing lifelong LTFU. No Available Risk Adapted LTFU guideline at 21 center. LTFU provided by pediatric oncologist at the pediatric oncology outpatient clinic with transition problems to adult clinic. All centers were following Cardiotoxicity, Secondary cancer,and Kidney toxicity with no problem Barriers of Turkish POC for LTFU of Pediatric Cancer Survivors were: Lack of enough care providers 66%, lack of time 57%, transportation problems 57 % ,lack of providing knowledge to patients 38 %. Although 80 % of the centers have fellows for HOF, not enough edication on survivorship 66%, due to lack of survivorship clinic ( 80%), busy working schedules. Conclusions: Questionnaire survey was able to reach 2/3 the pediatric oncology centers that were located in 8 cities and following most of the pediatric oncology patients in Turkey Mostly POCs do not provide enough LTFU. All centers agree on national guidelines for LTFU. [Table: see text]
A phase II study of oral S-1 with concurrent hypofractionated simultaneous integrated boost radiotherapy for metastatic pancreatic cancer with helical tomotherapy.
Authors: Gang Ren, Feng Zhu, Yingjie Wang, Tingyi Xia
Journal: Journal of Clinical Oncology (2017)

e15720 Background: This study was conducted to evaluate the efficacy as well as toxicity of oral S-1 with concurrent hypofractionated simultaneous integrated boost radiotherapy for metastatic pancreatic cancer using helical Tomotherapy. Methods: Patients with metastatic pancreatic cancer, adequate organ and marrow function and no prior anticancer therapy were enrolled in our study. S-1 was administered orally at a day of 40mg/m2 twice daily from day for 2 weeks, repeated every 3 weeks. Dose to the primary lesion was delivered as PTV for 50Gy, CTV for 60Gy and GTV for 70Gy in 15 to 20 fractions. Radiation induced toxicities were evaluated with the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.02. The overall survival (OS), progressive-free survival (PFS) and freedom from local progression (FFLP) were estimated using the Kaplan-Meier survival curve. Results: 45 patients were enrolled in this prospective clinical study. Pain relief rate was 91.7% (33/36). 1 year FFLP rate of the pancreatic lesion was 92.5%. 1 year OS rate was 17.6%. 1 year PFS was 4.2%. Median OS was 6 months. Grade 3 gastrointestinal reaction and blood reaction both appeared in 3 cases (13.3%). Conclusions: S-1 with concurrent hypofractionated simultaneous integrated boost radiotherapy using helical Tomotherapy resulted in high pain relief rate for patient with metastatic pancreatic cancer, with a tolerable side effect.
Letter To Editor: Terlipressin is Superior to Noradrenaline in the Management of Acute Kidney Injury in Acute On Chronic Liver Failure
Authors: Sapana Verma, Shaleen Agarwal, Shweta Singh, Nivedita Pandey, Subhash Gupta
Journal: Hepatology (2018)

To the Editor: The article by Arora et al.1 compared the use of two vasoconstrictors, terlipressin and noradrenaline, in the management of acute kidney injury in patients with acute on chronic liver failure (ACLF). Numerous other trials have shown no difference between the two when hepatorenal syndrome (HRS) occurred in decompensated cirrhosis.2 However, the authors claim that the pathophysiology of HRS in ACLF is different and, therefore, that these two vasoconstrictors may have different outcomes in this situation. First of all, it would be interesting to know whether or not these patients were managed in an intensive care unit as the article does not mention anything about their critical care management. Furthermore, we noted some inconsistencies in the presented data. The serum creatinine (sCr) compared between the two groups at the time of admission and at randomization looks inappropriate to us. The delta creatinine, i.e., peak creatinine – baseline creatinine, seems to be higher in the noradrenaline group at the time of randomization compared to that of the terlipressin group. This shows that more of the patients in the noradrenaline group might have been in a more severe stage of acute kidney injury when the treatment was started according to the definition the authors used. This difference might influence the outcome and treatment response in these patients irrespective of what vasoconstrictor was given. Moreover, the authors were not consistent in analyzing sCr data as they presented it as median (interquartile range) despite the fact that these are symmetrical variables and if presented as mean ± SD, the significance might differ between the two groups. Terlipressin is a much more expensive drug and showing its benefit with inconsistent data might increase the cost of care for these patients. While giving terlipressin in a divided dose is an advantage, it continues to be associated with a higher incidence of severe adverse effects, whereas noradrenaline has been found to be equally efficacious in a low dose as an infusion for the management of HRS.2 Thus, it is a cheaper and effective alternative. We do hope that noradrenaline continues to be used in HRS after decompensated cirrhosis as well as ACLF. Potential conflict of interest Nothing to report.
Evolocumab in Patients with Cardiovascular Disease
Authors: Jaime García de Tena, Alejandro Morales-Ortega, Gloria Pindao-Quesada
Journal: New England Journal of Medicine (2017)

CardiovascularOutcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial.The addition of evolocumab to standard therapy was associated with an absolute risk reduction of 2 percentage points in both the primary and secondary end points after a median duration of follow-up of 26 months.The fact that approximately 30% of the patients were receiving moderate-intensity statin therapy and the lack of clinical efficacy of evolocumab in the small group of patients receiving ezetimibe (presumably combined with a statin) arouse concern about the desirability of achieving such a marginal absolute risk reduction by inhibiting proprotein convertase subtilisin-kexin type 9 (PCSK9) in patients receiving high-intensity statin therapy, combined with ezetimibe, as appropriate.The results of trials that show a cardiovascular benefit of the addition of ezetimibe to statins 2,3 support the role of this combination as an initial lipid-lowering strategy in patients at high cardiovascular risk.Given the findings of the FOURIER trial, in patients at high cardiovascular risk in whom low-density lipoprotein (LDL) cholesterol goals cannot be achieved despite the use of lipid-lowering treatment, it would be more cost-effective to add evolocumab to a high-intensity statin combined with ezetimibe, as needed and if this combination has an acceptable side-effect profile.These recommendations are consistent with current guidelines that were published after PCSK9 inhibitors became available.
AUM voice prosthesis: A $1 novel modified tracheo-esophageal voice prosthesis for total laryngectomy patients (TEP).
Authors: Vishal Uchila Shishir Rao, Sataksi Chatterjee
Journal: Journal of Clinical Oncology (2017)

e17549 Background: Patients undergoing total laryngectomy require subsequent voice rehabilitation, which can be done by different modalities. The tracheo-esophageal voice prosthesis provides the clarity of speech and has a high rate of success in terms of acquisition of post laryngectomy speech.In this pilot study we evaluate the functionality of a modified trachea- oesophageal prosthesis to be used in primary and secondary trachea- esophageal puncture in 30 patients of total laryngectomy. Methods: This study was conducted at Health care Global Cancer Centre to evaluate the role of a novel trachea-oesophageal prosthesis for total laryngectomy +/- partial pharyngectomy patients from 2015-2016. 30 patients will be enrolled as an inpatient or outpatient. Post TEP insertion evaluation: Patients, who are undergoing primary TEP insertion, will be evaluated for speech/ voice interval of 6weeks, 12 weeks and 6 months. Objective assessment of speech Assessment of the incidence of TEP leak clinically after a test fluid feed. Through the prosthesis (intra TEP leak) Around the TEP leak (peri TEP leak) Assessment of the extrusion rate of the TEP device Assessment of the complication rate associated with the procedure/TEP Results: On objective assemsmsent of speech, all patients (100%) used prosthesis were able able to phonate and communicate using intelligible speech. 10% patients developed intra TEP leak immediately after insertion of prosthesis, 6% within 3 months of insertion, &amp; 3% developed peri tep leak. All patients were immedaitely given a repalcement prosthesis and leaks corrected. Extrusion was seen in 3% of the patients. None reported any complications. Conclusions: Aum voice prosthesis is a excellent and affrodable tracheo oesophageal prosthetic device to enable and empower patients speeech rehabilitation. Clinical trial information: NCT03039465.
GMC is told to use restraint in appealing against tribunal findings
Authors: Clare Dyer
Journal: BMJ (2018)

Three Court of Appeal judges have overturned a High Court judge’s ruling that a doctor acted dishonestly and have urged the General Medical Council (GMC) to show restraint in appealing against findings of fact in favour of doctors in regulatory cases.1

A medical practitioners tribunal decided in February 2017 that Hemmay Raychaudhuri, a locum paediatric registrar, had not been dishonest and that his fitness to practise was not impaired. It gave him a formal written warning.

The GMC appealed, and a High Court judge substituted a finding that he had been dishonest. Backed by the Medical Defence Union, Raychaudhuri appealed against that decision, and the Court of Appeal has now ruled that the tribunal was right in the first place to find no dishonesty.

Lord Justice Bean expressed “regret” that …
Bcl2-like protein 12 plays a critical role in development of airway allergy through inducing aberrant TH2 polarization
Authors: Zhi-Qiang Liu, Ying Feng, Li-Hua Mo, Xian-Hai Zeng, Jiang-Qi Liu, Rui-Di Xie, Zhi-Gang Liu, Ping-Chang Yang, Guang-Ji Zhang, Shan-Dong Wu
Journal: Journal of Allergy and Clinical Immunology (2018)