Association between circulating levels of sex steroid hormones and esophageal adenocarcinoma in the FINBAR Study.

PLoS One. 2018;13(1):e0190325

Authors: Petrick JL, Falk RT, Hyland PL, Caron P, Pfeiffer RM, Wood SN, Dawsey SM, Abnet CC, Taylor PR, Guillemette C, Murray LJ, Anderson LA, Cook MB

Abstract
BACKGROUND: Esophageal adenocarcinoma (EA) is characterized by a strong male predominance. Sex steroid hormones have been hypothesized to underlie this sex disparity, but no population-based study to date has examined this potential association.
METHODS: Using mass spectrometry and ELISA, we quantitated sex steroid hormones and sex hormone binding globulin, respectively, in plasma from males- 172 EA cases and 185 controls-within the Factors Influencing the Barrett/Adenocarcinoma Relationship (FINBAR) Study, a case-control investigation conducted in Northern Ireland and Ireland. Multivariable adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between circulating hormones and EA.
RESULTS: Higher androgen:estrogen ratio metrics were associated with increased odds of EA (e.g., testosterone:estradiol ratio ORQ4 v. Q1 = 2.58, 95%CI = 1.23-5.43; Ptrend = 0.009). All estrogens and androgens were associated with significant decreased odds of EA. When restricted to individuals with minimal to no decrease in body mass index, the size of association for the androgen:estrogen ratio was not greatly altered.
CONCLUSIONS: This first study of sex steroid hormones and EA provides tentative evidence that androgen:estrogen balance may be a factor related to EA. Replication of these findings in prospective studies is needed to enhance confidence in the causality of this effect.

PMID: 29342161 [PubMed - indexed for MEDLINE]

High lncRNA H19 expression as prognostic indicator: data mining in female cancers and polling analysis in non-female cancers.

Oncotarget. 2017 Jan 03;8(1):1655-1667

Authors: Peng L, Yuan XQ, Liu ZY, Li WL, Zhang CY, Zhang YQ, Pan X, Chen J, Li YH, Li GC

Abstract
Upregulation of lncRNA H19 expression is associated with an unfavorable prognosis in some cancers. However, the prognostic value of H19 in female-specific cancers has remained uncharacterized. In this study, the prognostic power of high H19 expression in female cancer patients from the TCGA datasets was analyzed using Kaplan-Meier survival curves and Cox's proportional hazard modeling. In addition, in a meta-analysis of non-female cancer patients from TCGA datasets and 12 independent studies, hazard ratios (HRs) with 95% confidence interval (CI) for overall survival (OS) and disease-free survival (DFS)/relapse-free survival (RFS)/metastasis-free survival (MFS)/progression-free survival (PFS) were pooled to assess the prognostic value of high H19 expression. Kaplan-Meier analysis revealed that patients with uterine corpus cancer and higher H19 expression had a shorter OS (HR=2.710, p<0.05), while females with cervical cancer and increased H19 expression had a shorter RFS (HR=2.261, p<0.05). Multivariate Cox regression analysis showed that high H19 expression could independently predict a poorer prognosis in cervical cancer patients (HR=4.099, p<0.05). In the meta-analysis, patients with high H19 expression showed a poorer outcome in non-female cancer (p<0.05). These results suggest that high lncRNA H19 expression is predictive of an unfavorable prognosis in two female cancers (uterine corpus endometrioid cancer and cervical cancer) as well as in non-female cancer patients.

PMID: 27926484 [PubMed - indexed for MEDLINE]

A novel form of capsaicin-modified amygdala LTD mediated by TRPM1.

Neurobiol Learn Mem. 2016 Dec;136:1-12

Authors: Gebhardt C, von Bohlen Und Halbach O, Hadler MD, Harteneck C, Albrecht D

Abstract
Recently we have shown that capsaicin attenuates the strength of LTP in the lateral amygdala (LA) and demonstrated that this effect is mediated by the transient receptor potential (TRP) channel TRPV1. Here we further show that capsaicin, which is thought to act primarily through TRPV1, modifies long term depression (LTD) in the LA. Yet the application of various TRPV1 antagonists does not reverse this effect and it remains in TRPV1-deficient mice. In addition, voltage gated calcium channels, nitric oxide and CB1 receptors are not involved. Using pharmacology and TRPM1-/- mice, our electrophysiological data indicate that capsaicin-induced activation of TRPM1 channels contribute to the induction of LA-LTD. Whereas LA-LTD in general depends on the acitvation of NMDA receptors- and group II metabotropic glutamate receptors (mGluR), the modifying effect of capsaicin on LA-LTD via TRPM1 appears to be specifically mediated by group I mGluRs and in interaction with another member of the TRP family, TRPC5. Additionally, intact GABAergic transmission is required for the capsaicin-effect to take place. This is the first documentation that beside their function in the retina TRPM1 proteins are expressed in the brain and have a functional relevance in modifying synaptic plasticity.

PMID: 27633915 [PubMed - indexed for MEDLINE]

BART miRNAs: an unimaginable force in the development of nasopharyngeal carcinoma.

Eur J Cancer Prev. 2017 Mar;26(2):144-150

Authors: Wang Y, Guo Z, Shu Y, Zhou H, Wang H, Zhang W

Abstract
Nasopharyngeal carcinoma (NPC) is a head and neck cancer that represents a major health burden in Southern China and Southeast Asia. Although the close association of NPC with Epstein-Barr virus (EBV) infection has been demonstrated, its exact role in the pathogenesis of this malignancy is still unclear. The expression of EBV-encoded microRNAs, especially BART miRNAs, which are encoded from the BamHI-A region of the viral genome, is detected at a high level in NPC. miRNAs are small noncoding mRNAs that can positively regulate the virus to ensure accurate expression of viral genomes and to modify the gene expression of host cells by negative regulation. Accumulating evidence suggests that ebv-mir-BARTs play a critical role in host cell survival, immune escape, cell proliferation, cell apoptosis, and cancer metabolism, promoting the generation of NPC. This review will summarize our current understanding of the nature and function of ebv-mir-BARTs in NPC.

PMID: 26909566 [PubMed - indexed for MEDLINE]

Elastase as a potential biomarker for radiation-induced gut wall injury of the distal bowel in an experimental mouse model.

Acta Oncol. 2018 Feb 15;:1-6

Authors: Sjöberg F, Malipatlolla DK, Patel P, Wilderäng U, Kalm M, Steineck G, Bull C

Abstract
BACKGROUND AND PURPOSE: Traditionally, elastase has been used to study exocrine activity of the pancreas in patients with chronic pancreatitis and cystic fibrosis, and calprotectin as a marker for gut-wall inflammation in patients with inflammatory bowel disease. The aim of the study was to find out whether elastase and calprotectin could be used as inflammatory markers for radiation-induced gut wall injury of the distal bowel.
MATERIAL AND METHODS: Adult male mice were exposed to two, three, or four fractions of 6 Gy or 8 Gy irradiation to the sigmoid and rectum of the large bowel, using a linear accelerator. Fecal samples were collected from mice at 1, 3, and 6 weeks post-irradiation. The fecal levels of elastase and calprotectin were analyzed using ELISA.
RESULTS: Three and 6 weeks after irradiation, we found a dose-effect relationship between dose of ionizing radiation and the fecal level of elastase; that is significantly higher levels of elastase were observed in mice that had received a high irradiation dose. We also found that irradiated mice hosted in the same cage had a comparable level (either high or low) of elastase. No significant differences were observed from the calprotectin data.
CONCLUSIONS: We found a clear association between the dose of ionizing radiation to the distal colon and the level of elastase in the fecal samples.

PMID: 29447028 [PubMed - as supplied by publisher]

Phytomedicines (medicines derived from plants) for sickle cell disease.

Cochrane Database Syst Rev. 2018 Feb 15;2:CD004448

Authors: Oniyangi O, Cohall DH

Abstract
BACKGROUND: Sickle cell disease, a common recessively inherited haemoglobin disorder, affects people from sub-Saharan Africa, the Middle East, Mediterranean basin, Indian subcontinent, Caribbean and South America. It is associated with complications and a reduced life expectancy. Phytomedicines (medicine derived from plants in their original state) encompass many of the plant remedies from traditional healers which the populations most affected would encounter. Laboratory research and limited clinical trials have suggested positive effects of phytomedicines both in vivo and in vitro. However, there has been little systematic appraisal of their benefits. This is an update of a Cochrane Review first published in 2004, and updated in 2010, 2013, and 2015.
OBJECTIVES: To assess the benefits and risks of phytomedicines in people with sickle cell disease of all types, of any age, in any setting.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, the International Standard Randomised Controlled Trial Number Register (ISRCTN), the Allied and Complimentary Medicine Database (AMED), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP).Dates of most recent searches: Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Trials Register: 10 April 2017; ISRCTN: 26 July 2017; AMED: 24 August 2017; ClinicalTrials.gov: 02 August 2017; and the WHO ICTRP: 27 July 2017.
SELECTION CRITERIA: Randomised or quasi-randomised trials with participants of all ages with sickle cell disease, in all settings, comparing the administration of phytomedicines, by any mode to placebo or conventional treatment, including blood transfusion and hydroxyurea.
DATA COLLECTION AND ANALYSIS: Both authors independently assessed trial quality and extracted data.
MAIN RESULTS: Two trials (182 participants) and two phytomedicines Niprisan® (also known as Nicosan®) and Ciklavit® were included. The Phase IIB (pivotal) trial suggests that Niprisan® was effective in reducing episodes of severe painful sickle cell disease crisis over a six-month period (low-quality evidence). It did not affect the risk of severe complications or the level of anaemia (low-quality evidence). No serious adverse effects were reported. The single trial of Cajanus cajan (Ciklavit®) reported a possible benefit to individuals with painful crises (low-quality evidence), and a possible adverse effect (non-significant) on the level of anaemia (low-quality evidence).
AUTHORS' CONCLUSIONS: While Niprisan® appeared to be safe and effective in reducing severe painful crises over a six-month follow-up period, further trials are required to assess its role in the management of people with sickle cell disease and the results of its multicentre trials are awaited. Currently no conclusions can be made regarding the efficacy of Ciklavit®. Based on the published results for Niprisan® and in view of the limitations in data collection and analysis of both trials, phytomedicines may have a potential beneficial effect in reducing painful crises in sickle cell disease. This needs to be further validated in future trials. More trials are required on the safety and efficacy of phytomedicines used in managing sickle cell disease.

PMID: 29446825 [PubMed - as supplied by publisher]

Making a (cautious) case for expanding reproductive genetic carrier screens: Australian researchers report success, and caveats, with a simultaneous panel of cystic fibrosis, fragile X syndrome, and spinal muscular atrophy.

Am J Med Genet A. 2018 Mar;176(3):510-512

Authors:

PMID: 29446568 [PubMed - in process]

Comparison of Oropharyngeal Microbiota from Children with Asthma and Cystic Fibrosis.

Mediators Inflamm. 2017;2017:5047403

Authors: Boutin S, Depner M, Stahl M, Graeber SY, Dittrich SA, Legatzki A, von Mutius E, Mall M, Dalpke AH

Abstract
A genuine microbiota resides in the lungs which emanates from the colonization by the oropharyngeal microbiota. Changes in the oropharyngeal microbiota might be the source of dysbiosis observed in the lower airways in patients suffering from asthma or cystic fibrosis (CF). To examine this hypothesis, we compared the throat microbiota from healthy children (n = 62) and that from children with asthma (n = 27) and CF (n = 57) aged 6 to 12 years using 16S rRNA amplicon sequencing. Our results show high levels of similarities between healthy controls and children with asthma and CF revealing the existence of a core microbiome represented by Prevotella, Streptococcus, Neisseria, Veillonella, and Haemophilus. However, in CF, the global diversity, the bacterial load, and abundances of 53 OTUs were significantly reduced, whereas abundances of 6 OTUs representing opportunistic pathogens such as Pseudomonas, Staphylococcus, and Streptococcus were increased compared to those in healthy controls controls and asthmatics. Our data reveal a core microbiome in the throat of healthy children that persists in asthma and CF indicating shared host regulation favoring growth of commensals. Furthermore, we provide evidence for dysbiosis with a decrease in diversity and biomass associated with the presence of known pathogens consistent with impaired host defense in children with CF.

PMID: 29445257 [PubMed - in process]

Chronic infection sustained by a Pseudomonas aeruginosa High-Risk clone producing the VIM-1 metallo-β-lactamase in a cystic fibrosis patient after lung transplantation.

J Cyst Fibros. 2018 Feb 12;:

Authors: Pollini S, Mugnaioli C, Dolce D, Campana S, Neri AS, Taccetti G, Rossolini GM

Abstract
BACKGROUND: The significance of chronic lung infection by multidrug-resistant (MDR) pathogens in Cystic Fibrosis (CF) transplanted patients remains controversial, and the available information is overall limited. Here we describe the case of a chronic infection, sustained by a metallo-β-lactamase (MBL)-producing P. aeruginosa strain, in a CF patient following lung transplantation.
METHODS: Twelve P. aeruginosa isolates collected from a CF patient over a 15-years follow-up period after lung transplantation were analysed for their antibiotic susceptibility profile, MBL production and clonal relatedness. Available clinical and microbiological records were reviewed.
RESULTS: The transplanted CF patient was chronically infected by an MBL-producing P. aeruginosa strain which harboured a blaVIM-1 determinant inserted into a novel class 1 integron. The strain exhibited an MDR phenotype and belonged to the globally widespread ST235 epidemic clonal lineage, which however is not a typical CF-associated epidemic clone. Despite the chronic infection, the long-term outcome of this patient during the post-transplant period was characterized by the absence of acute exacerbations and by a mostly stable pulmonary function.
CONCLUSIONS: This report provides one of the few descriptions of MBL-producing P. aeruginosa infections in CF patients, and the first description of such an infection after lung transplantation in these patients. Infection with the MBL-producing strain apparently did not significantly affect the patient pulmonary function.

PMID: 29444761 [PubMed - as supplied by publisher]

Risk factors for persistent Aspergillus respiratory isolation in cystic fibrosis.

J Cyst Fibros. 2018 Feb 12;:

Authors: Hong G, Psoter KJ, Jennings MT, Merlo CA, Boyle MP, Hadjiliadis D, Kawut SM, Lechtzin N

Abstract
BACKGROUND: Aspergillus species are increasingly detected in the respiratory tracts of individuals with cystic fibrosis (CF), and chronic Aspergillus fumigatus is associated with more frequent hospitalizations for pulmonary exacerbations. However, patient and clinical factors that may contribute to the acquisition of persistent Aspergillus infection have yet to be identified. The objective of this study was to identify risk factors for development of Aspergillus respiratory isolation in CF.
METHODS: A retrospective cohort study of participants in the CF Foundation Patient Registry between 2006 and 2012 was conducted. Generalized estimating equation models were used to evaluate the association between the development of persistent Aspergillus respiratory isolation and individual level demographic and clinical characteristics.
RESULTS: Among 16,095 individuals with CF followed from 2006 to 2012, 1541 (9.6%) subjects developed persistent Aspergillus isolation. White race (Odds Ratio [OR] 1.74, 95% confidence interval 1.23, 2.48, p<0.001) and pancreatic insufficiency (OR 1.50, 95% CI 1.09, 2.06, p<0.001) were found to be risk factors for persistent Aspergillus isolation. Chronic therapies, including inhaled antibiotics (OR 1.33; 95% CI 1.21, 1.46), macrolides (OR 1.23, 95% CI 1.14, 1.32, p<0.001), and inhaled corticosteroids (OR 1.13, 95% CI 1.04, 1.20, p<0.001) were also independently associated with an increased risk for persistent Aspergillus isolation.
CONCLUSIONS: We identified macrolides and inhaled antibiotics, which individually have been shown to improve CF outcomes, and inhaled corticosteroids as risk factors for developing persistent Aspergillus isolation. Further work is needed to determine whether these associations are causal or due to confounding by other factors.

PMID: 29444760 [PubMed - as supplied by publisher]

Implementation of a successful eradication protocol for Burkholderia Cepacia complex in cystic fibrosis patients.

BMC Pulm Med. 2018 Feb 14;18(1):35

Authors: Garcia BA, Carden JL, Goodwin DL, Smith TA, Gaggar A, Leon K, Antony VB, Rowe SM, Solomon GM

Abstract
BACKGROUND: Infection with Burkholderia cepacia complex (Bcc) results in a heterogeneous clinical course ranging from asymptomatic colonization of the airways to fulminant respiratory failure in patients with cystic fibrosis (CF). Early eradication of Pseudomonas aeruginosa improves clinical outcomes. The efficacy and clinical outcomes following implementation of an eradication protocol for Bcc are less well understood.
METHODS: We developed and implemented a single center Bcc eradication protocol that included an intensive combination of intravenous, inhaled, and oral antibiotic therapies based on in vitro sensitivities. We conducted a retrospective cohort analysis of clinical outcomes compared to patients with chronic Bcc infection.
RESULTS: Six patients were identified as having a newly acquired Bcc colonization and were placed on the eradication protocol. Sequential sputum samples after completion of the protocol demonstrated sustained clearance of Bcc in all patients. Lung function and nutritional status remained stable in the year following eradication.
CONCLUSION: Clearance of Bcc from sputum cultures using a standardized protocol was successful at one year and was associated with clinical stability.

PMID: 29444656 [PubMed - in process]

Towards a 21st-century roadmap for biomedical research and drug discovery: consensus report and recommendations.

Drug Discov Today. 2017 Feb;22(2):327-339

Authors: Langley GR, Adcock IM, Busquet F, Crofton KM, Csernok E, Giese C, Heinonen T, Herrmann K, Hofmann-Apitius M, Landesmann B, Marshall LJ, McIvor E, Muotri AR, Noor F, Schutte K, Seidle T, van de Stolpe A, Van Esch H, Willett C, Woszczek G

Abstract
Decades of costly failures in translating drug candidates from preclinical disease models to human therapeutic use warrant reconsideration of the priority placed on animal models in biomedical research. Following an international workshop attended by experts from academia, government institutions, research funding bodies, and the corporate and non-governmental organisation (NGO) sectors, in this consensus report, we analyse, as case studies, five disease areas with major unmet needs for new treatments. In view of the scientifically driven transition towards a human pathways-based paradigm in toxicology, a similar paradigm shift appears to be justified in biomedical research. There is a pressing need for an approach that strategically implements advanced, human biology-based models and tools to understand disease pathways at multiple biological scales. We present recommendations to help achieve this.

PMID: 27989722 [PubMed - indexed for MEDLINE]

Gratitude, protective buffering, and cognitive dissonance: How families respond to pediatric whole exome sequencing in the absence of actionable results.

Am J Med Genet A. 2018 Mar;176(3):578-588

Authors: Werner-Lin A, Zaspel L, Carlson M, Mueller R, Walser SA, Desai R, Bernhardt BA

Abstract
Clinical genome and exome sequencing (CGES) may identify variants leading to targeted management of existing conditions. Yet, CGES often fails to identify pathogenic diagnostic variants and introduces uncertainties by detecting variants of uncertain significance (VUS) and secondary findings. This study investigated how families understand findings and adjust their perspectives on CGES. As part of NIH's Clinical Sequencing Exploratory Research Consortium, children were recruited from clinics at the Children's Hospital of Pennsylvania (CHOP) and offered exome sequencing. Primary pathogenic and possibly pathogenic, and some secondary findings were returned. Investigators digitally recorded results disclosure sessions and conducted 3-month follow up interviews with 10 adolescents and a parent. An interdisciplinary team coded all transcripts. Participants were initially disappointed with findings, yet reactions evolved within disclosure sessions and at 3-month interviews toward acceptance and satisfaction. Families erroneously expected, and prepared extensively, to learn about risk for common conditions. During disclosure sessions, parents and adolescents varied in how they monitored and responded to each others reactions. Several misinterpreted, or overestimated, the utility of findings to attribute meaning and achieve closure for the CGES experience. Participants perceived testing as an opportunity to improve disease management despite results that did not introduce new treatments or diagnoses. Future research may examine whether families experience cognitive dissonance regarding discrepancies between expectations and findings, and how protective buffering minimizes the burden of disappointment on loved ones. As CGES is increasingly integrated into clinical care providers must contend with tempering family expectations and interpretations of findings while managing complex medical care.

PMID: 29446570 [PubMed - in process]

De novo variants in Myelin regulatory factor (MYRF) as candidates of a new syndrome of cardiac and urogenital anomalies.

Am J Med Genet A. 2018 Feb 15;:

Authors: Pinz H, Pyle LC, Li D, Izumi K, Skraban C, Tarpinian J, Braddock SR, Telegrafi A, Monaghan KG, Zackai E, Bhoj EJ

Abstract
Myelin Regulatory Factor (MYRF) is a transcription factor that has previously been associated with the control of the expression of myelin-related genes. However, it is highly expressed in human tissues and mouse embryonic tissues outside the nervous system such as the stomach, lung, and small intestine. It has not previously been reported as a cause of any Mendelian disease. We report here two males with Scimitar syndrome [MIM 106700], and other features including penoscrotal hypospadias, cryptorchidism, pulmonary hypoplasia, tracheal anomalies, congenital diaphragmatic hernia, cleft spleen, thymic involution, and thyroid fibrosis. Gross neurologic functioning appears to be within normal limits. In both individuals a de novo variant in MYRF was identified using exome sequencing. Neither variant is found in gnomAD. Heterozygous variants in MYRF should be considered in patients with variants of Scimitar syndrome and urogenital anomalies.

PMID: 29446546 [PubMed - as supplied by publisher]

The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines.

Endocr Relat Cancer. 2018 Mar;25(3):367-380

Authors: Hofving T, Arvidsson Y, Almobarak B, Inge L, Pfragner R, Persson M, Stenman G, Kristiansson E, Johanson V, Nilsson O

Abstract
Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number profiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2 Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors.

PMID: 29444910 [PubMed - in process]

Diagnostic outcomes of exome sequencing in patients with syndromic or non-syndromic hearing loss.

PLoS One. 2018;13(1):e0188578

Authors: Likar T, Hasanhodžić M, Teran N, Maver A, Peterlin B, Writzl K

Abstract
Hereditary hearing loss (HL) is a common sensory disorder, with an incidence of 1-2 per 1000 newborns, and has a genetic etiology in over 50% of cases. It occurs either as part of a syndrome or in isolation and is genetically very heterogeneous which poses a challenge for clinical and molecular diagnosis. We used exome sequencing to seek a genetic cause in a group of 56 subjects (49 probands) with HL: 32 with non-syndromic non-GJB2 HL and 17 with syndromic HL. Following clinical examination and clinical exome sequencing, an etiological diagnosis was established in 15 probands (15/49; 30%); eight (8/17;47%) from the syndromic group and seven (7/32; 21%) from the non-syndromic non-GJB2 subgroup. Fourteen different (half of them novel) non-GJB2 variants causing HL were found in 10 genes (CHD7, HDAC8, MITF, NEFL, OTOF, SF3B4, SLC26A4, TECTA, TMPRSS3, USH2A) among 13 probands, confirming the genetic heterogeneity of hereditary HL. Different genetic causes for HL were found in a single family while three probands with apparent syndromic HL were found to have HL as a separate clinical feature, distinct from the complex phenotype. Clinical exome sequencing proved to be an effective tool used to comprehensively address the genetic heterogeneity of HL, to detect clinically unrecognized HL syndromes, and to decipher complex phenotypes in which HL is a separate feature and not part of a syndrome.

PMID: 29293505 [PubMed - indexed for MEDLINE]

Preventable ADRs leading to hospitalization - results of a long-term prospective safety study with 6,427 ADR cases focusing on elderly patients.

Expert Opin Drug Saf. 2018 Feb;17(2):125-137

Authors: Schmiedl S, Rottenkolber M, Szymanski J, Drewelow B, Siegmund W, Hippius M, Farker K, Guenther IR, Hasford J, Thuermann PA, German Net of Regional Pharmacovigilance Centers (NRPC)

Abstract
BACKGROUND: Studies evaluating the impact of age and potentially inappropriate medication (PIM) on avoidable adverse drug reactions (ADRs) are scarce.
METHODS: In this prospective, multi-center, long-term (8.5 years) observational study, we analysed ADRs leading to hospitalization in departments of internal medicine. ADRs causality and preventability were assessed using standardised algorithms. PIM was defined based on the PRISCUS-list. Multivariate analyses and estimation of ADR incidence rates were conducted.
RESULTS: Of all 6,427 ADR patients, a preventable ADR was present in 1,253 (19.5%) patients (elderly patients ≥70 years: 828). Risk factors for preventable ADRs in elderly patients were multimorbidity, two to four ADR-causative drugs, and intake of particular compounds (e.g. spironolactone) but not sex, PIM usage, or the total number of drugs. Regarding particular compounds associated with preventable ADRs, highest incidence rates for preventable ADRs were found for patients aged ≥70 years for spironolactone (3.3 per 1,000 exposed persons (95% CI: 1.4-6.6)) and intermediate-acting insulin (3.3 per 1,000 exposed persons (95% CI: 1.6-6.1)).
CONCLUSION: Avoiding PIM usage seems to be of limited value in increasing safety in elderly patients whereas our results underline the importance of an individualized medication review of the most commonly implicated drugs in preventable ADRs (supported by BfArM FoNr: V-11337/68605/2008-2010).

PMID: 29258401 [PubMed - indexed for MEDLINE]

New and incremental FDA black box warnings from 2008 to 2015.

Expert Opin Drug Saf. 2018 Feb;17(2):117-123

Authors: Solotke MT, Dhruva SS, Downing NS, Shah ND, Ross JS

Abstract
BACKGROUND: The boxed warning (also known as 'black box warning [BBW]') is one of the strongest drug safety actions that the U.S. Food & Drug Administration (FDA) can implement, and often warns of serious risks. The objective of this study was to comprehensively characterize BBWs issued for drugs after FDA approval.
METHODS: We identified all post-marketing BBWs from January 2008 through June 2015 listed on FDA's MedWatch and Drug Safety Communications websites. We used each drug's prescribing information to classify its BBW as new, major update to a preexisting BBW, or minor update. We then characterized these BBWs with respect to pre-specified BBW-specific and drug-specific features.
RESULTS: There were 111 BBWs issued to drugs on the US market, of which 29% (n = 32) were new BBWs, 32% (n = 35) were major updates, and 40% (n = 44) were minor updates. New BBWs and major updates were most commonly issued for death (51%) and cardiovascular risk (27%). The new BBWs and major updates impacted 200 drug formulations over the study period, of which 64% were expected to be used chronically and 58% had available alternatives without a BBW.
CONCLUSIONS: New BBWs and incremental updates to existing BBWs are frequently added to drug labels after regulatory approval.

PMID: 29215916 [PubMed - indexed for MEDLINE]

First experiences with a tool to measure the level of clinical information present in adverse drug reaction reports.

Expert Opin Drug Saf. 2018 Feb;17(2):111-115

Authors: Oosterhuis I, Rolfes L, Ekhart C, Muller-Hansma A, Härmark L

Abstract
BACKGROUND: To make a proper causality assessment of an adverse drug reaction (ADR) report, a certain level of clinical information is necessary. A tool was developed to measure the level of clinical information present in ADR reports. The aim of this study was to test the validity and reliability of the clinical documentation tool (ClinDoc) in an international setting.
METHODS: The tool was developed by a panel of pharmacovigilance experts. It includes four domains: ADR, chronology of the ADR, suspected drug and patient characteristics. The final score categorizes reports into: excellent, well, moderately or poorly documented. In two rounds, eight pharmacovigilance assessors of different countries made a total of 224 assessments using the tool, with the expert panels judgement as a standard. Sensitivity and specificity were calculated.
RESULTS: The tool with four outcome-categories demonstrated low sensitivity. A lack of distinctiveness was demonstrated between the categories moderate and well. Results for the second round were re-analysed using three categories. This demonstrated a better validity.
CONCLUSION: This is the first tool to give insight in the level of relevant clinical information present in ADR reports. It can be used internationally to compare reports coming from different reporting methods and different types of reporters in pharmacovigilance.

PMID: 29157026 [PubMed - indexed for MEDLINE]

Immunotherapeutic strategies in non-small-cell lung cancer: the present and the future.

Immunotherapy. 2017 05;9(6):507-520

Authors: Steendam CM, Dammeijer F, Aerts JGJV, Cornelissen R

Abstract
Non-small cell lung cancer (NSCLC) is still the leading cause of cancer death worldwide, with a poor prognosis. In the era of immunotherapies, the field is rapidly changing, and the clinician needs to be aware of the current state and future perspectives of immunotherapeutic strategies. In this review, we discuss the current status of immune checkpoint inhibitors, cancer vaccines and cellular therapies specifically in NSCLC. Last but not least, we will discuss rational combination strategies that are promising for the near future.

PMID: 28472903 [PubMed - indexed for MEDLINE]