Literature Watch
Detection of circulating tumour cell clusters in human glioblastoma.
Detection of circulating tumour cell clusters in human glioblastoma.
Br J Cancer. 2018 Aug 01;:
Authors: Krol I, Castro-Giner F, Maurer M, Gkountela S, Szczerba BM, Scherrer R, Coleman N, Carreira S, Bachmann F, Anderson S, Engelhardt M, Lane H, Evans TRJ, Plummer R, Kristeleit R, Lopez J, Aceto N
Abstract
Human glioblastoma (GBM) is a highly aggressive, invasive and hypervascularised malignant brain cancer. Individual circulating tumour cells (CTCs) are sporadically found in GBM patients, yet it is unclear whether multicellular CTC clusters are generated in this disease and whether they can bypass the physical hurdle of the blood-brain barrier. Here, we assessed CTC presence and composition at multiple time points in 13 patients with progressing GBM during an open-label phase 1/2a study with the microtubule inhibitor BAL101553. We observe CTC clusters ranging from 2 to 23 cells and present at multiple sampling time points in a GBM patient with pleomorphism and extensive necrosis, throughout disease progression. Exome sequencing of GBM CTC clusters highlights variants in 58 cancer-associated genes including ATM, PMS2, POLE, APC, XPO1, TFRC, JAK2, ERBB4 and ALK. Together, our findings represent the first evidence of the presence of CTC clusters in GBM.
PMID: 30065256 [PubMed - as supplied by publisher]
Clinicopathological features of He Shou Wu-Induced Liver Injury: This Ancient Anti-Aging Therapy Is Not Liver-Friendly.
Clinicopathological features of He Shou Wu-Induced Liver Injury: This Ancient Anti-Aging Therapy Is Not Liver-Friendly.
Liver Int. 2018 Aug 01;:
Authors: Wang Y, Wang L, Saxena R, Wee A, Yang R, Tian Q, Zhang J, Zhao X, Jia J
Abstract
BACKGROUND AND AIMS: Polygonum Multiflorum Thumb (PMT), an ancient anti-aging Chinese herb known traditionally as He Shou Wu, has side effects of liver toxicity. To determine the main clinical and pathological characteristics of liver toxicity induced by PMT and the clinical course after its cessation.
METHODS: Data of patients, diagnosed as drug-induced liver injury and hospitalized in Beijing Friendship Hospital from August 2005 to August 2017, were retrospectively reviewed. Clinical, pathological data and outcome after cessation of He Shou Wu were obtained and analyzed. Kruskal-Wallis and Chi-square (χ2 ) tests were performed.
RESULTS: Twenty-nine patients with He Shou Wu-induced liver injury were enrolled. The median age was 53 years (range 15-74) and 75.9% (22/29) were women. The most common symptom was jaundice (79.3%, 23/29). Of nine patients with liver biopsies, six showed acute cholestatic hepatitis, two acute and one chronic hepatocellular injury pattern. The latency, liver chemistries and outcomes were comparable between pure He Shou Wu (5 patients) and its compounds (24 patients). Twenty-five of 29 patients (86.2%) had normal serum alanine aminotransferase levels after 45 days (range: 10-138 days) and total bilirubin of 46 days (range: 0-551 days). One patient was rechallenged with He Shou Wu and two developed autoimmune features. One patient died of liver failure and three had chronic persistent liver injury.
CONCLUSIONS: The main clinicopathological injury pattern of He Shou Wu-induced liver injury is moderate to severe hepatitis with or without cholestasis. Most patients recover completely; however, chronic disease and death do occur. (249 words). This article is protected by copyright. All rights reserved.
PMID: 30066422 [PubMed - as supplied by publisher]
Dienogest Versus Leuprolide Acetate for Recurrent Pelvic Pain Following Laparoscopic Treatment of Endometriosis.
Dienogest Versus Leuprolide Acetate for Recurrent Pelvic Pain Following Laparoscopic Treatment of Endometriosis.
J Obstet Gynaecol India. 2018 Aug;68(4):306-313
Authors: Abdou AM, Ammar IMM, Alnemr AAA, Abdelrhman AA
Abstract
Objective: To compare the efficacy and safety of dienogest (DNG) with depot leuprolide acetate (LA) in patients with recurrent pelvic pain following laparoscopic surgery for endometriosis.
Design: Prospective randomized trial.
Setting: Zagazig University hospitals, Egypt.
Patients: Two hundred and forty-two patients with recurrent pelvic pain following laparoscopic surgery for endometriosis.
Intervention: Dienogest (2 mg/day, orally) or depot LA (3.75 mg/4 weeks, intramuscularly) for 12 weeks.
Main Outcome Measures: A visual analogue scale was used to test the intensity of pain before and after the end of treatment.
Results: There was highly significant reduction in pelvic pain, back pain and dyspareunia in both groups with mean of difference in dienogest group (28.7 ± 5.3, 19.0 ± 4.3 and 20.0 ± 3.08 mm, respectively) and in LA group (26.2 ± 3.01, 19.5 ± 3.01 and 17.9 ± 2.9 mm, respectively). The most frequent drug-related adverse effects in dienogest group were vaginal bleeding and weight gain (64.5 and 10.8%, respectively) which were significantly higher than LA group (21.5 and 3.3%, respectively). While the most frequent drug-related adverse effects in LA group were hot flushes and vaginal dryness (46.3 and 15.7%, respectively) which were significantly higher than dienogest group (15.7 and 3.3%, respectively).
Conclusion: Daily dienogest is as effective as depot LA for relieving endometriosis-associated pelvic pain, low back pain and dyspareunia. In addition, dienogest has acceptable safety, tolerability and lower incidence of hot flushes. Thus, it may offer an effective and well-tolerated treatment in endometriosis.
PMID: 30065547 [PubMed]
Predicting potential drug-drug interactions on topological and semantic similarity features using statistical learning.
Predicting potential drug-drug interactions on topological and semantic similarity features using statistical learning.
PLoS One. 2018;13(5):e0196865
Authors: Kastrin A, Ferk P, Leskošek B
Abstract
Drug-drug interaction (DDI) is a change in the effect of a drug when patient takes another drug. Characterizing DDIs is extremely important to avoid potential adverse drug reactions. We represent DDIs as a complex network in which nodes refer to drugs and links refer to their potential interactions. Recently, the problem of link prediction has attracted much consideration in scientific community. We represent the process of link prediction as a binary classification task on networks of potential DDIs. We use link prediction techniques for predicting unknown interactions between drugs in five arbitrary chosen large-scale DDI databases, namely DrugBank, KEGG, NDF-RT, SemMedDB, and Twosides. We estimated the performance of link prediction using a series of experiments on DDI networks. We performed link prediction using unsupervised and supervised approach including classification tree, k-nearest neighbors, support vector machine, random forest, and gradient boosting machine classifiers based on topological and semantic similarity features. Supervised approach clearly outperforms unsupervised approach. The Twosides network gained the best prediction performance regarding the area under the precision-recall curve (0.93 for both random forests and gradient boosting machine). The applied methodology can be used as a tool to help researchers to identify potential DDIs. The supervised link prediction approach proved to be promising for potential DDIs prediction and may facilitate the identification of potential DDIs in clinical research.
PMID: 29738537 [PubMed - indexed for MEDLINE]
Pharmacogenetic Analysis of the UK MRC (Medical Research Council) MAGIC Trial: Association of Polymorphisms with Toxicity and Survival in Patients Treated with Perioperative Epirubicin, Cisplatin, and 5-fluorouracil (ECF) Chemotherapy.
Pharmacogenetic Analysis of the UK MRC (Medical Research Council) MAGIC Trial: Association of Polymorphisms with Toxicity and Survival in Patients Treated with Perioperative Epirubicin, Cisplatin, and 5-fluorouracil (ECF) Chemotherapy.
Clin Cancer Res. 2017 Dec 15;23(24):7543-7549
Authors: Smyth E, Zhang S, Cunningham D, Wotherspoon A, Soong R, Peckitt C, Valeri N, Fassan M, Rugge M, Okines A, Allum W, Stenning S, Nankivell M, Langley R, Tan P
Abstract
Purpose: Germline polymorphisms may affect chemotherapy efficacy and toxicity. We examined the effect of polymorphisms in drug metabolism and DNA repair genes on pathologic response rates, survival, and toxicity for patients randomized to surgery alone or perioperative ECF chemotherapy in the MRC MAGIC trial.Experimental Design: DNA was extracted from nontumor resection formalin-fixed paraffin-embedded (FFPE) blocks. ERCC1, ERCC2, XRCC1, DYPD, and OPRT SNPs were evaluated using Sequenom, GSTP1, GSTT1 deletion, and TYMS (TS) 5' 2R/3R using multiplex PCR. Post PCR amplification, TS 2R/3R and GSTT1 samples underwent gel electrophoresis.Results: Polymorphism data were available for 289 of 456 (63.4%) operated patients. No polymorphism was statistically significantly associated with pathologic response to chemotherapy. Median overall survival (OS) for patients treated with surgery alone with any TS genotype was not different (1.76 years 2R/2R, 1.68 years 2R/3R, 2.09 years 3R/3R). Median OS for patients with a TS 2R/2R genotype treated with chemotherapy was not reached, whereas median OS for 2R/3R and 3R/3R patients were 1.44 and 1.60 years, respectively (log rank P value = 0.0053). The P value for the interaction between treatment arm and genotype (3R/3R and 3R/2R vs. 2R/2R) was 0.029. No polymorphism was statistically significantly associated with chemotherapy toxicity.Conclusions: In MAGIC, patients with a TS 2R/2R genotype appeared to derive a larger benefit from perioperative ECF chemotherapy than patients with 3R containing genotypes. Further exploration of this potential predictive biomarker in this patient population is warranted. Clin Cancer Res; 23(24); 7543-9. ©2017 AACR.
PMID: 28972045 [PubMed - indexed for MEDLINE]
A First-in-Human Phase I Study of the Anticancer Stem Cell Agent Ipafricept (OMP-54F28), a Decoy Receptor for Wnt Ligands, in Patients with Advanced Solid Tumors.
A First-in-Human Phase I Study of the Anticancer Stem Cell Agent Ipafricept (OMP-54F28), a Decoy Receptor for Wnt Ligands, in Patients with Advanced Solid Tumors.
Clin Cancer Res. 2017 Dec 15;23(24):7490-7497
Authors: Jimeno A, Gordon M, Chugh R, Messersmith W, Mendelson D, Dupont J, Stagg R, Kapoun AM, Xu L, Uttamsingh S, Brachmann RK, Smith DC
Abstract
Purpose: Wnt signaling is implicated in tumor cell dedifferentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors.Experimental design: A 3+3 design was used; ipafricept was given intravenously every 3 weeks. The objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy.Results: 26 patients were treated in seven dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15, and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related grade 1 and 2 adverse events (AEs; ≥20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ∼4 days and had low incidence of antidrug antibody formation (7.69%) with no impact on drug exposure. Six patients had β-C-terminal telopeptide (β-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for >6 months.Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients. Clin Cancer Res; 23(24); 7490-7. ©2017 AACR.
PMID: 28954784 [PubMed - indexed for MEDLINE]
Safety and efficacy of glycerol phenylbutyrate for management of urea cycle disorders in patients aged 2months to 2years.
Safety and efficacy of glycerol phenylbutyrate for management of urea cycle disorders in patients aged 2months to 2years.
Mol Genet Metab. 2017 Nov;122(3):46-53
Authors: Berry SA, Longo N, Diaz GA, McCandless SE, Smith WE, Harding CO, Zori R, Ficicioglu C, Lichter-Konecki U, Robinson B, Vockley J
Abstract
INTRODUCTION: Glycerol phenylbutyrate (GPB) is approved in the US for the management of patients 2months of age and older with urea cycle disorders (UCDs) that cannot be managed with protein restriction and/or amino acid supplementation alone. Limited data exist on the use of nitrogen conjugation agents in very young patients.
METHODS: Seventeen patients (15 previously on other nitrogen scavengers) with all types of UCDs aged 2months to 2years were switched to, or started, GPB. Retrospective data up to 12months pre-switch and prospective data during initiation of therapy were used as baseline measures. The primary efficacy endpoint of the integrated analysis was the successful transition to GPB with controlled ammonia (<100μmol/L and no clinical symptoms). Secondary endpoints included glutamine and levels of other amino acids. Safety endpoints included adverse events, hyperammonemic crises (HACs), and growth and development.
RESULTS: 82% and 53% of patients completed 3 and 6months of therapy, respectively (mean 8.85months, range 6days-18.4months). Patients transitioned to GPB maintained excellent control of ammonia and glutamine levels. There were 36 HACs in 11 patients before GPB and 11 in 7 patients while on GPB, with a reduction from 2.98 to 0.88 episodes per year. Adverse events occurring in at least 10% of patients while on GPB were neutropenia, vomiting, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash/papule.
CONCLUSION: GPB was safe and effective in UCD patients aged 2months to 2years. GPB use was associated with good short- and long-term control of ammonia and glutamine levels, and the annualized frequency of hyperammonemic crises was lower during the study than before the study. There was no evidence for any previously unknown toxicity of GPB.
PMID: 28916119 [PubMed - indexed for MEDLINE]
FDA Approval Summary: Trabectedin for Unresectable or Metastatic Liposarcoma or Leiomyosarcoma Following an Anthracycline-Containing Regimen.
FDA Approval Summary: Trabectedin for Unresectable or Metastatic Liposarcoma or Leiomyosarcoma Following an Anthracycline-Containing Regimen.
Clin Cancer Res. 2017 Dec 15;23(24):7448-7453
Authors: Barone A, Chi DC, Theoret MR, Chen H, He K, Kufrin D, Helms WS, Subramaniam S, Zhao H, Patel A, Goldberg KB, Keegan P, Pazdur R
Abstract
On October 23, 2015, the FDA approved trabectedin, a new molecular entity for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Approval was based on results of a single, randomized, active-controlled, 518-patient, multicenter study comparing the safety and efficacy of trabectedin 1.5 mg/m2 as a 24-hour continuous intravenous (i.v.) infusion once every 3 weeks with dacarbazine 1,000 mg/m2 i.v. once every 3 weeks. Treatment with trabectedin resulted in a statistically significant improvement in progression-free survival (PFS), with a PFS of 4.2 months and 1.5 months for trabectedin and dacarbazine, respectively (HR, 0.55; 95% confidence interval, 0.44-0.70; unstratified log-rank test, P < 0.001). The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. Serious adverse reactions included anaphylaxis, neutropenic sepsis, rhabdomyolysis, hepatotoxicity, cardiomyopathy, and extravasation resulting in tissue necrosis. A postmarketing trial was required to evaluate the serious risk of cardiomyopathy. This approval provides another treatment option in a setting where no drug has been shown to improve overall survival. A key regulatory consideration during review of this application was the use of PFS as an endpoint to support regular approval of trabectedin. Clin Cancer Res; 23(24); 7448-53. ©2017 AACR.
PMID: 28774898 [PubMed - indexed for MEDLINE]
Dose Transition Pathways: The Missing Link Between Complex Dose-Finding Designs and Simple Decision-Making.
Dose Transition Pathways: The Missing Link Between Complex Dose-Finding Designs and Simple Decision-Making.
Clin Cancer Res. 2017 Dec 15;23(24):7440-7447
Authors: Yap C, Billingham LJ, Cheung YK, Craddock C, O'Quigley J
Abstract
The ever-increasing pace of development of novel therapies mandates efficient methodologies for assessment of their tolerability and activity. Evidence increasingly support the merits of model-based dose-finding designs in identifying the recommended phase II dose compared with conventional rule-based designs such as the 3 + 3 but despite this, their use remains limited. Here, we propose a useful tool, dose transition pathways (DTP), which helps overcome several commonly faced practical and methodologic challenges in the implementation of model-based designs. DTP projects in advance the doses recommended by a model-based design for subsequent patients (stay, escalate, de-escalate, or stop early), using all the accumulated information. After specifying a model with favorable statistical properties, we utilize the DTP to fine-tune the model to tailor it to the trial's specific requirements that reflect important clinical judgments. In particular, it can help to determine how stringent the stopping rules should be if the investigated therapy is too toxic. Its use to design and implement a modified continual reassessment method is illustrated in an acute myeloid leukemia trial. DTP removes the fears of model-based designs as unknown, complex systems and can serve as a handbook, guiding decision-making for each dose update. In the illustrated trial, the seamless, clear transition for each dose recommendation aided the investigators' understanding of the design and facilitated decision-making to enable finer calibration of a tailored model. We advocate the use of the DTP as an integral procedure in the co-development and successful implementation of practical model-based designs by statisticians and investigators. Clin Cancer Res; 23(24); 7440-7. ©2017 AACR.
PMID: 28733440 [PubMed - indexed for MEDLINE]
Registries in European post-marketing surveillance: a retrospective analysis of centrally approved products, 2005-2013.
Registries in European post-marketing surveillance: a retrospective analysis of centrally approved products, 2005-2013.
Pharmacoepidemiol Drug Saf. 2017 Dec;26(12):1442-1450
Authors: Bouvy JC, Blake K, Slattery J, De Bruin ML, Arlett P, Kurz X
Abstract
PURPOSE: Regulatory agencies and other stakeholders increasingly rely on data collected through registries to support their decision-making. Data from registries are a cornerstone of post-marketing surveillance for monitoring the use of medicines in clinical practice. This study was aimed at gaining further insight into the European Medicines Agency's (EMA) requests for new registries and registry studies using existing registries and to review the experience gained in their conduct.
METHODS: European Public Assessment Reports were consulted to identify products for which a request for a registry was made as a condition of the marketing authorisation. All centrally authorised products that received a positive opinion of the EMA Committee for Medicinal Products for Human Use between 1 January 2005 and 31 December 2013 were included. Data regarding registry design and experiences were collected from EMA electronic record keeping systems.
RESULTS: Of 392 products that received a positive Committee for Medicinal Products for Human Use opinion during 2005-2013, 31 registries were requested for 30 products in total. Sixty-five percent were product registries whereas 35% were disease registries and 71% of the registries had a primary safety objective. Most commonly reported issues with registries were delayed time to start and low patient accrual rates.
CONCLUSIONS: The delays found in getting new registries up and running support the need to improve the timeliness of data collection in the post-marketing setting. Methodological challenges met in conducting this study highlighted the need for a clarification of definitions and epidemiological concepts around patient registries. The results will inform the EMA Patient Registry initiative to support use of existing patient registries for the post-authorisation benefit-risk monitoring of medicinal products. © 2017 Commonwealth of Australia. Pharmacoepidemiology & Drug Safety © 2017 John Wiley & Sons, Ltd.
PMID: 28345151 [PubMed - indexed for MEDLINE]
"systems biology"; +19 new citations
19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
These pubmed results were generated on 2018/08/01
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
Innovations for Healthy Living - Improving Minority Health and Eliminating Health Disparities (R43/R44 - Clinical Trial Optional)
Technologies for Improving Minority Health and Eliminating Health Disparities (R41/R42- Clinical Trial Optional)
Novel Approaches to Safe, Non-Invasive, Real Time Assessment of Human Placenta Development and Function Across Pregnancy (R21 - Clinical Trial Not Allowed)
Novel Approaches to Safe, Non-Invasive, Real Time Assessment of Human Placenta Development and Function Across Pregnancy (R01 - Clinical Trial Not Allowed)
Notice of Pre-Application Webinar for the NIH Common Fund Somatic Cell Genome Editing program
Notice of Correction of Peer Review and Council Dates in RFA-DC-19-001 NIDCD Hearing Healthcare for Adults: Improving Access and Affordability (R21/R33 Clinical Trials Optional)
Notice of Clarification of Application Types Allowed for RFA-DK-18-012, Human Islet Research Enhancement Center for the Human Islet Research Network (U24 Clinical Trial Not Allowed)
("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects"); +15 new citations
15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")
These pubmed results were generated on 2018/08/01
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
An Ontology-Based Knowledge Methodology in the Medical Domain in the Latin America: the Study Case of Republic of Panama.
An Ontology-Based Knowledge Methodology in the Medical Domain in the Latin America: the Study Case of Republic of Panama.
Acta Inform Med. 2018 Jun;26(2):98-101
Authors: Cedeno-Moreno D, Vargas-Lombardo M
Abstract
Introduction: Nowadays in Panama, there is a lot of patient information stored in textual form which cannot be manipulated to manage adequate knowledge. There are multiple resources created to represent knowledge, including specialized glossaries, ontologies, among others. The ontologies are an important part within the scope of the recovery and organization of the information and the semantic web. Also in recent works they are used in applications of natural language processing (NLP), as a knowledge base.
Aim: This research was conducted with the aim of creating a methodology that allows from a text written in NL, extract the necessary elements using NLP tools and with them create a knowledge base represented by one domain ontology and extract knowledge to help medical specialists.
Material and Methods: In this study we carried out a methodology that allows the extraction of knowledge of patient clinical records, general medicine and palliative care, in order to show relevant knowledge elements to specialists. The methodology was validated with a data corpus of approximately 200 patient records.
Conclusion: We have created a knowledge representation methodology, combining NLP techniques and tools and the automatic instantiation of an ontology, which can serve as a software agent for other applications or used to visualize the patient's clinical information. The study was validated using the traditional metrics of information retrieval systems precision, recall, F-measure obtaining excellent results, and can be used as a software agent or methodology for the development of information extraction software systems in the medical domain.
PMID: 30061779 [PubMed]
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