Zoledronic Acid in a Mouse Model of Human Fibrous Dysplasia: Ineffectiveness on Tissue Pathology, Formation of "Giant Osteoclasts" and Pathogenetic Implications.

Calcif Tissue Int. 2020 Sep 01;:

Authors: Corsi A, Palmisano B, Spica E, Di Filippo A, Coletta I, Dello Spedale Venti M, Labella R, Fabretti F, Donsante S, Remoli C, Serafini M, Riminucci M

Abstract
We compared the effects of a nitrogen-containing bisphosphonate (N-BP), zoledronic acid (ZA), and an anti-mouse RANKL antibody (anti-mRANKL Ab) on the bone tissue pathology of a transgenic mouse model of human fibrous dysplasia (FD). For comparison, we also reviewed the histological samples of a child with McCune-Albright syndrome (MAS) treated with Pamidronate for 3 years. EF1α-GsαR201C mice with FD-like lesions in the tail vertebrae were treated with either 0.2 mg/kg of ZA at day 0, 7, and 14 or with 300 μg/mouse of anti-mRANKL Ab at day 0 and 21. All mice were monitored by Faxitron and histological analysis was performed at day 42. ZA did not affect the progression of the radiographic phenotype in EF1α-GsαR201C mice. FD-like lesions in the ZA group showed the persistence of osteoclasts, easily detectable osteoclast apoptotic activity and numerous "giant osteoclasts". In contrast, in the anti-mRANKL Ab-treated mice, osteoclasts were markedly reduced/absent, the radiographic phenotype reverted and the FD-like lesions were extensively replaced by newly formed bone. Numerous "giant osteoclasts" were also detected in the samples of the child with MAS. This study supports the hypothesis that osteoclasts per se, independently of their resorptive activity, are essential for development and expansion of FD lesions.

PMID: 32875378 [PubMed - as supplied by publisher]

Incidental sonographic detection of bladder cancer in a woman with large uterine fibroids: significance and lessons learned.

Clin Imaging. 2020 May;61:1-3

Authors: Soliman MM, Cornman-Homonoff J, Schiffman MH

Abstract
Uterine leiomyomas are the most common solid pelvic tumors in pre-menopausal women and typically present with abnormal uterine bleeding and/or symptoms of mass effect. A potential consequence of the space-occupying nature of these lesions is the decreased sensitivity for the detection of adjacent pelvic pathology, which can be particularly problematic given the overlap in symptoms between fibroids and other pelvic disease. We present the case of a woman with a large uterine fibroid who had multiple imaging evaluations before undergoing uterine fibroid embolization and on immediate follow-up sonography was discovered to have early-stage bladder cancer.

PMID: 31945687 [PubMed - indexed for MEDLINE]

Gastrointestinal: Diffuse esophageal lymphangiomatosis manifesting as multiple submucosal masses.

J Gastroenterol Hepatol. 2020 Feb;35(2):177

Authors: Cao D, Wang J, Guo L

PMID: 31257637 [PubMed - indexed for MEDLINE]

Small Data Challenges of Studying Rare Diseases.

JAMA Netw Open. 2020 03 02;3(3):e201965

Authors: Mitani AA, Haneuse S

PMID: 32202640 [PubMed - indexed for MEDLINE]

Transcript expression-aware annotation improves rare variant interpretation.

Nature. 2020 05;581(7809):452-458

Authors: Cummings BB, Karczewski KJ, Kosmicki JA, Seaby EG, Watts NA, Singer-Berk M, Mudge JM, Karjalainen J, Satterstrom FK, O'Donnell-Luria AH, Poterba T, Seed C, Solomonson M, Alföldi J, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Daly MJ, MacArthur DG

Abstract
The acceleration of DNA sequencing in samples from patients and population studies has resulted in extensive catalogues of human genetic variation, but the interpretation of rare genetic variants remains problematic. A notable example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Here, by manual curation of putative loss-of-function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD)1, we show that one explanation for this paradox involves alternative splicing of mRNA, which allows exons of a gene to be expressed at varying levels across different cell types. Currently, no existing annotation tool systematically incorporates information about exon expression into the interpretation of variants. We develop a transcript-level annotation metric known as the 'proportion expressed across transcripts', which quantifies isoform expression for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression (GTEx) project2 and show that it can differentiate between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expression-based annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder and intellectual disability or developmental disorders to show that pLoF variants in weakly expressed regions have similar effect sizes to those of synonymous variants, whereas pLoF variants in highly expressed exons are most strongly enriched among cases. Our annotation is fast, flexible and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for the genetic diagnosis of rare diseases, the analysis of rare variant burden in complex disorders, and the curation and prioritization of variants in recall-by-genotype studies.

PMID: 32461655 [PubMed - indexed for MEDLINE]

Development of a measure of genome sequencing knowledge for young people: The kids-KOGS.

Clin Genet. 2019 11;96(5):411-417

Authors: Lewis C, Loe BS, Sidey-Gibbons C, Patch C, Chitty LS, Sanderson SC

Abstract
Genome sequencing (GS) is increasingly being used to diagnose rare diseases in paediatric patients; however, no measures exist to evaluate their knowledge of this technology. We aimed to develop a robust measure of knowledge of GS (the kids-KOGS') suitable for use in the paediatric setting as well as for general public education. The target age was 11 to 15 year olds. An iterative process involving six sequential stages was conducted to develop a set of draft true/false items. These were then administered to 539 target-age school pupils (mean 12.8; SD ± 1.3), from the United Kingdom. Item-response theory was used to confirm the psychometric suitability of the candidate items. None of the Items was identified as misfits. All 10 items performed well under the two-parameter logistic model. The internal consistency of the test was 0.84 (Cronbach alpha value) indicating excellent reliability. The mean kids-KOGS score in the sample overall was 4.24 (SD; 2.49), where 0 = low knowledge and 10 = high knowledge. Age was positively associated with score in a multivariate linear regression. The kids-KOGS is a short and reliable tool that can be used by researchers and healthcare professionals offering GS to paediatric patients. Further validation in a clinical setting is required.

PMID: 31323115 [PubMed - indexed for MEDLINE]

The new genomic medicine service and implications for patients .

Clin Med (Lond). 2019 07;19(4):273-277

Authors: Barwell J, Snape K, Wedderburn S

Abstract
In January 2019, a new nationally commissioned Genomic Medicine Service (GMS) has now commenced in the NHS. Capitalising on the infrastructure developed through the 100,000 Genomes Project, the GMS is underpinned by seven supra-regional Genomic Laboratory Hubs (GLHs) delivering the new inherited rare disease and cancer somatic tissue genetic test directory. This replaces the UKGTN test directory, with the aim of standardising criteria for whole genome sequencing or targeted panel tests where applicable. The new test directory will define who can order specific genetic tests under prescribed eligibility criteria. In keeping with Dame Sally Davies' white paper Generation Genome, this will further democratise genetic testing and, in some situations, avoid the need to refer to clinical genetics to access testing. The aim is to simplify patient pathways and reduce regional or social inequalities. We will discuss the implications of whole genome sequencing and the potential impact of the new nationally commissioned GMS for both patients, their relatives and clinicians. We will also discuss the imminent challenges in implementing genomic medicine into the NHS, and the future impact of novel technologies on service delivery as genomic medicine becomes increasingly integrated into routine healthcare.

PMID: 31308102 [PubMed - indexed for MEDLINE]

A novel, hybrid, single- and multi-site clinical trial design for CLN3 disease, an ultra-rare lysosomal storage disorder.

Clin Trials. 2019 10;16(5):555-560

Authors: Adams HR, Defendorf S, Vierhile A, Mink JW, Marshall FJ, Augustine EF

Abstract
BACKGROUND: Travel burden often substantially limits the ability of individuals to participate in clinical trials. Wide geographic dispersion of individuals with rare diseases poses an additional key challenge in the conduct of clinical trials for rare diseases. Novel technologies and methods can improve access to research by connecting participants in their homes and local communities to a distant research site. For clinical trials, however, understanding of factors important for transition from traditional multi-center trial models to local participation models is limited. We sought to test a novel, hybrid, single- and multi-site clinical trial design in the context of a trial for Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease), a very rare pediatric neurodegenerative disorder.
METHODS: We created a "hub and spoke" model for implementing a 22-week crossover clinical trial of mycophenolate compared with placebo, with two 8-week study arms. A single central site, the "hub," conducted screening, consent, drug dispensing, and tolerability and efficacy assessments. Each participant identified a clinician to serve as a collaborating "spoke" site to perform local safety monitoring. Study participants traveled to the hub at the beginning and end of each study arm, and to their individual spoke site in the intervening weeks.
RESULTS: A total of 18 spoke sites were established for 19 enrolled study participants. One potential participant was unable to identify a collaborating local site and was thus unable to participate. Study start-up required a median 6.7 months (interquartile range = 4.6-9.2 months). Only 33.3% (n = 6 of 18) of spoke site investigators had prior clinical trial experience, thus close collaboration with respect to study startup, training, and oversight was an important requirement. All but one participant completed all study visits; no study visits were missed due to travel requirements.
CONCLUSIONS: This study represents a step toward local trial participation for patients with rare diseases. Even in the context of close oversight, local participation models may be best suited for studies of compounds with well-understood side-effect profiles, for those with straightforward modes of administration, or for studies requiring extended follow-up periods.

PMID: 31184505 [PubMed - indexed for MEDLINE]

Wolfram Syndrome: a Monogenic Model to Study Diabetes Mellitus and Neurodegeneration.

Curr Opin Physiol. 2020 Oct;17:115-123

Authors: Fischer TT, Ehrlich BE

Abstract
Wolfram syndrome (WS) is a rare, progressive disorder characterized by childhood-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and neurodegeneration. Currently, there is no effective treatment for WS, and patients typically die between 30 and 40 years of age. WS is primarily caused by autosomal recessive mutations in the Wolfram syndrome 1 (WFS1) gene (OMIM 222300), which encodes for wolframin (WFS1). This disorder is therefore a valuable monogenic model for prevalent diseases, particularly diabetes mellitus and neurodegeneration. Whereas reduced survival and secretion are known cellular impairments causing WS, the underlying molecular pathways and the physiological function of WFS1 remain incompletely described. Here, we characterize WFS1 as a regulator of intracellular calcium homeostasis, review our current understanding of the disease mechanism of WS, and discuss candidate treatment approaches. These insights will facilitate identification of new therapeutic strategies not only for WS but also for diabetes mellitus and neurodegeneration.

PMID: 32864536 [PubMed]

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/08/29

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.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/08/28

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.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/08/28

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.

[Interstitial cystitis/bladder pain syndrome (IC/BPS)].

Urologe A. 2020 Aug 25;:

Authors: Bschleipfer T

Abstract
As an orphan disease interstitial cystitis/bladder pain syndrome (IC/BPS) is a frequently underdiagnosed and inadequately treated disease of the urinary bladder, often after years of symptoms. Caused by an unknown etiology, a high variability of symptoms, a lack of biomarkers and a gradual onset, IC/BPS is a diagnosis by exclusion and poses a special challenge to doctors and patients. In addition to conventional and complementary medical treatment, oral medication, intravesical and transurethral procedures are available as treatment options. Due to the invasiveness or irreversibility, however, interventional surgical procedures should only be used after careful consideration or as a last resort. In order to find a suitable individualized treatment, a classification of the patients according to the severity and type of symptoms can be advantageous.

PMID: 32840644 [PubMed - as supplied by publisher]

The Status Quo of Rare Diseases Centres for the Development of a Clinical Decision Support System - A Cross-Sectional Study.

Stud Health Technol Inform. 2020 Jun 23;271:176-183

Authors: Schaaf J, Sedlmayr M, Prokosch HU, Ganslandt T, Schade-Brittinger C, von Wagner M, Kadioglu D, Schubert K, Lee-Kirsch MA, Kraemer BK, Winner B, Mueller T, Schaefer JR, Wagner TOF, Bruckner-Tuderman L, Tuescher O, Boeker M, Storf H

Abstract
Clinical decision support systems (CDSS) help to improve the diagnostics and treatment of rare diseases (RD). As one of four funded consortia of the Medical Informatics Initiative supported by the Federal Ministry of Education and Research (BMBF, Germany), MIRACUM develops a clinical decision support system (CDSS) for RD based on distributed data of ten university hospitals. The CDSS will be developed at the Rare Diseases Centres (RDC) of the MIRACUM consortium. Since it is essential to deliver decision support at the right time and place in the clinician's workflow, this study aimed to capture relevant information of the RDCs regarding patient admission and diagnostic process. Additionally, we investigated how patient documentation and digitalisation is performed at the centres. Therefore, we conducted a cross-sectional survey involving experts in the RDs domain to capture relevant information for the further development of a CDSS in RD. For each centre, one expert on RDs participated in the study (n=8). The survey identified several challenges regarding the reuse of patient data, e.g. the paper-based documentation of a patientâĂŹs medical history and coding of diagnoses using ICD-10. However, we noticed a relevant use of current software diagnosis support and a similarly performed diagnostic process in all RDC. Further studies are needed to get more detailed insights and to define specific requirements.

PMID: 32578561 [PubMed - indexed for MEDLINE]

Applying the FAIR Data Principles to the Registry of Vascular Anomalies (VASCA).

Stud Health Technol Inform. 2020 Jun 23;271:115-116

Authors: Dos Santos Vieira B, Groenen K, 't Hoen PAC, Jacobsen A, Roos M, Kaliyaperumal R, Kersloot M, Cornet R, Schultze Kool L

Abstract
BACKGROUND: Connecting currently existing, heterogeneous rare disease (RD) registries would greatly facilitate epidemiological and clinical research. To increase their interoperability, the European Union developed a set of Common Data Elements (CDEs) for RD registries.
OBJECTIVES: To implement the CDEs and the FAIR data principles in the Registry of Vascular Anomalies (VASCA).
METHODS: We created a semantic model for the CDE and transformed this into a Resource Description Framework (RDF) template. The electronic case report forms (eCRF) were mapped to the RDF template and published in a FAIR Data Point (FDP).
RESULTS: The FAIR VASCA registry was successfully implemented using Castor EDC (Electronic Data Capture) software.
CONCLUSION: FAIR technology allows researchers to query and combine data from different registries in real-time.

PMID: 32578552 [PubMed - indexed for MEDLINE]

Salivary Carcinosarcoma: An Extremely Rare and Highly Aggressive Malignancy.

Laryngoscope. 2020 05;130(5):E335-E339

Authors: Gupta A, Koochakzadeh S, Neskey DM, Nguyen SA, Lentsch EJ

Abstract
OBJECTIVES/HYPOTHESIS: Carcinosarcomas represent a rare entity of mixed malignant tumors of the salivary gland with limited evidence regarding management strategies. We aim to demonstrate the incidence, prognostic factors, and conduct a survival analysis for this aggressive malignancy.
STUDY DESIGN: Retrospective database review.
METHODS: The Surveillance, Epidemiology, and End Results database was queried for all cases of major salivary carcinosarcoma and its incidence from 1973 to 2015 to identify 66 patients.
RESULTS: The incidence of this tumor was 0.02 cases per 1 million, with a rising number of absolute cases in the past 2 decades. The parotid gland was the most common site (78.8%) of involvement. The 5-year overall survival was 37% and 5-year disease-specific survival was 62%. Surgery was most common management strategy (95.5%), with total parotidectomy and facial nerve sacrifice procedures for those with parotid disease. Radiotherapy was commonly performed (75.8%) and chemotherapy use was rare (18.2%). Patients with distant metastasis had a greater than threefold increase in mortality, and those with total parotidectomy surgery had decreased mortality.
CONCLUSIONS: Carcinosarcomas of major salivary glands are extremely rare and highly aggressive tumors. We recommend prompt surgical management and postoperative radiation for this tumor with a poor prognosis.
LEVEL OF EVIDENCE: NA Laryngoscope, 130:E335-E339, 2020.

PMID: 31291005 [PubMed - indexed for MEDLINE]

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/08/25

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.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/08/22

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.

Evolution of genomic and T cell repertoire heterogeneity of malignant pleural mesothelioma under dasatinib treatment.

Clin Cancer Res. 2020 Aug 14;:

Authors: Chen R, Lee WC, Fujimoto J, Li J, Hu X, Mehran R, Rice D, Swisher SG, Sepesi B, Tran HT, Chow CW, Little LD, Gumbs C, Haymaker C, Heymach JV, Wistuba II, Lee JJ, Futreal PA, Zhang J, Reuben A, Tsao AS, Zhang J

Abstract
PURPOSE: Malignant pleural mesothelioma (MPM) is considered an orphan disease with few treatment options. Despite multimodality therapy, the majority of MPM recur and eventually become refractory to any systemic treatment. One potential mechanism underlying therapeutic resistance may be intratumor heterogeneity (ITH), making MPM challenging to eradicate. However, the ITH architecture of MPM and its clinical impact have not been well studied.
EXPERIMENTAL DESIGN: We delineated the immunogenomic ITH by multi-region whole exome sequencing (WES) and T cell receptor (TCR) sequencing of 69 longitudinal MPM specimens from 9 patients with resectable MPM, who were treated with dasatinib.
RESULTS: The median total mutation burden (TMB) before dasatinib treatment was 0.65/Mb, similar with that of post-dasatinib treatment (0.62/Mb). The median proportion of mutations shared by any given pair of two tumor regions within the same tumors was 80% prior to and 83% post-dasatinib treatment indicating a relatively homogenous genomic landscape. T cell clonality, a parameter indicating T cell expansion and reactivity was significantly increased in tumors after dasatinib treatment. Furthermore, on average, 82% of T cell clones were restricted to individual tumor regions, with merely 6% of T cell clones shared by all regions from the same tumors indicating profound TCR heterogeneity. Interestingly, patients with higher T cell clonality and higher portion of T cells present across all tumor regions in post-dasatinib treated tumors had significantly longer survival.
CONCLUSIONS: Despite the homogeneous genomic landscape, the TCR repertoire is extremely heterogeneous in MPM. Dasatinib may potentially induce T cell response leading to improved survival.

PMID: 32816946 [PubMed - as supplied by publisher]

APP gene copy number changes reflect exogenous contamination.

Nature. 2020 Aug;584(7821):E20-E28

Authors: Kim J, Zhao B, Huang AY, Miller MB, Lodato MA, Walsh CA, Lee EA

PMID: 32814883 [PubMed - in process]