scholarly journals Molecular Testing for Hereditary Retinal Disease as Part of Clinical Care

2007 ◽  
Vol 125 (2) ◽  
pp. 252 ◽  
Author(s):  
Katy Downs
Keyword(s):  
Clinical Care ◽  
Retinal Disease ◽  
Molecular Testing ◽  
Hereditary Retinal Disease

Hereditary Retinal Disease-Related Retinal Detachment; Risk Factors, Pathogenesis, Clinic, and Management

2020 ◽  
pp. 193-200
Keyword(s):  
Risk Factors ◽  
Retinal Detachment ◽  
Cardiovascular System ◽  
Proliferative Vitreoretinopathy ◽  
Delayed Diagnosis ◽  
Retinal Disease ◽  
Skeletal System ◽  
Younger Age ◽  
Hereditary Retinal Disease

Hereditary retinal disease (HRD) is a group of pathologies characterized by histologically abnormally developing vitreous gel associated with peripheral retinal degenerative or proliferative changes. In HRD alterations in the structure of the vitreous with abnormal vitreoretinal adhesions can predispose to developing Retinal Detachment (RD). Many HRD is seen with a part of syndromes most of which have systemic abnormalities affecting the joints, skeletal system, and cardiovascular system.  Due to delayed diagnosis in younger age patients,  without prominent symptoms, most patients with HR presented with proliferative vitreoretinopathy PVR and macula-involving RD.

Comprehensive genomic profiling of advanced colorectal carcinoma in the course of clinical care to identify KRAS insertions not detected by focused molecular testing.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 497-497
Author(s):  
Andrew Rankin ◽  
Alexa Betzig Schrock ◽  
Julia Andrea Elvin ◽  
Juliann Chmielecki ◽  
Rachel Erlich ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
De Novo ◽  
Clinical Care ◽  
Molecular Testing ◽  
Large Set ◽  
Genomic Profiling ◽  
Kras Mutations ◽  
Exon 2 ◽  
Nccn Guidelines ◽  
Comprehensive Genomic Profiling

497 Background: As activating RAS mutations have been shown to predict lack of benefit from anti-EGFR therapies in advanced CRC, NCCN guidelines recommend testing for KRAS exon 2 and non-exon 2 mutations; however, these alterations are thought to explain only a subset of de novo resistance to targeted therapy. In a large set of CRC assayed with comprehensive genomic profiling (CGP) in the course of clinical care, we assessed the frequency of less common KRAS short insertions that may predict failure of anti-EGFR therapy. Methods: 4,422 CRC cases were assayed with CGP performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of > 650X for at least 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. All classes of genomic alterations (GA) were identified, including base pair substitutions, insertions/deletions, copy number alterations, and rearrangements. Pertinent available prior molecular testing results and clinical history was reviewed for selected cases. Results: Out of 4,422 CRC cases analyzed, KRAS short variants were identified in 50.9% of cases. A majority of cases contained a KRAS alteration at either codon G12 (35.5%) or G13 (9.1%), while alterations at codons Q61 or A146 were identified in 2.2% and 3.1% of cases, respectively. KRAS insertions were identified in 8 ( < 0.5%) cases. All KRAS insertions identified fell within codons 9-13, and 6/8 cases harbored V9_G10 insertions. Out of 6 patients with prior KRAS testing results available, 5 (83%) were negative by previous testing. Conclusions: CGP identifies KRAS insertions within or adjacent to hotspot regions in CRC cases which have previously tested negative for KRAS mutations. Given the importance of KRAS alterations in predicting lack of response to anti-EGFR therapies in CRC, accurate detection of these alterations in the course of clinical care is essential for effective treatment. CGP offers the possibility of identifying KRAS insertions that may impact efficacy of anti-EGFR targeted therapy and should be considered when previous focused testing for KRAS mutations is negative.

scholarly journals 2181. Yield and Impact of Molecular Diagnostics for Pathogen Detection in Pediatric Patients: 16/18S rRNA PCR and Noninvasive Assays

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S740-S741
Author(s):  
Angela Chun ◽  
Taylor Heald-Sargent ◽  
Michael Malczynski ◽  
William J Muller ◽  
Chao Qi ◽  
...  
Keyword(s):  
Molecular Diagnostics ◽  
18S Rrna ◽  
Pediatric Patients ◽  
Clinical Care ◽  
High Yield ◽  
Molecular Diagnostic ◽  
Clinical Samples ◽  
Molecular Testing ◽  
Rrna Gene ◽  
Fungal Culture

Abstract Background Molecular diagnostic tests can identify bacterial and fungal pathogens from clinical samples. Nucleic acid detection tests include 16S and 18S rRNA gene PCR (16/18S PCR) and plasma next-generation sequencing (NGS). Other assays (fungal galactomannan and 1,3-β-d-glucan) detect structural factors. Our objective was to assess the utilization, yield, and impact of molecular diagnostics in pediatric patients who had samples sent for 16/18S PCR. Methods Sterile site fluid or tissue specimens were collected as part of standard care at Lurie Children’s Hospital, cultured, and sent to Northwestern Memorial Hospital for 16/18S PCR as clinically indicated. Medical records were reviewed for diagnostics, antibiotics, and clinical course. Results From 1/2016–8/2018, 236 samples were sent for 16 and/or 18S PCR from 183 patients. 83% had a concurrent ID consult. 16S PCR was done on 215 samples, 42 (20%) were positive, and 36 yielded species identification (Table 1). Antibacterial agents were administered prior to specimen collection in 73% and did not affect likelihood of positive 16S PCR. 18S PCR was sent on 163 samples; 12 (7.4%) were positive (Table 2) of which 10 were from immunocompromised hosts. 40% of patients were on antifungals prior to sample acquisition. 16/18S PCR impacted antimicrobial decision-making in 70 cases (30%). A pathogenic fungus was detected by PCR but not culture in 2 cases. Time to positivity of fungal culture was 1–15 days. Fungal culture was positive in 5 cases with-negative 18S PCR. Seventeen patients had positive serum 1,3-ß-D-glucan and/or galactomannan: 3 of which had positive 18S PCR, 5 with fungal growth, 5 presumed infection based on imaging, 1 Nocardia, and 3 noninfectious etiology. Plasma NGS was sent on 45 cases, was positive in 34, and affected clinical management in 10. Conclusion 16S PCR can identify bacterial pathogens in the setting of negative culture and impact clinical care. Abscess, bronchial/pleural fluid, and brain/organ tissue were high yield specimens. 18S PCR can provide expeditious fungal identification in cases of suspected invasive disease, but fungal culture and serum molecular testing increase diagnostic yield. No single fungal test is comprehensive. Plasma NGS had relatively high yield and clinical impact in selected patients. Disclosures All authors: No reported disclosures.

Optimizing management of glioblastoma: Educational impact on clinicians.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11026-11026
Author(s):  
Michelle Arielle Worst ◽  
Ann Carothers ◽  
Kinjal Parikh ◽  
Lisa Brauer ◽  
Giuseppe Lombardi ◽  
...  
Keyword(s):  
Clinical Care ◽  
Statistical Significance ◽  
Treatment Options ◽  
Educational Activity ◽  
Molecular Testing ◽  
Chi Square ◽  
Assessment Scores ◽  
Confidence Assessment ◽  
Investigational Agents ◽  
Post Assessment

11026 Background: Glioblastoma multiforme (GBM) is a rare, malignant tumor of the central nervous system (CNS) with poor prognosis. Nearly all patients experience recurrence due to GBM’s heterogeneity and there is currently no standard approach to treatment. Despite having few targeted agents with demonstrated efficacy, molecular testing is utilized due to its value in improving diagnostic accuracy and prognostic stratification. Moreover, recent data has shown an increase in promising data with regards to treating GBM using various mechanisms. Because of the clinical conundrum GBM poses and the lack of available treatment options, clinicians are challenged to stay current with new data and how best to integrate new agents into treatment paradigms. The objective of this study was to assess the changes in oncologists’ and pathologists’ knowledge through participation in education regarding optimal GBM treatment. Methods: The educational activity was a 30-minute online, video discussion segmented into 3 parts with synchronized slides and 2 faculty. Educational effect was assessed with a repeated pairs pre-/post-assessment study with a 3-item, multiple choice, knowledge questionnaire and one confidence assessment question. For all questions, each participant served as his/her own control. Pre- and post-assessment scores were compared to determine the relative changes in the proportion of correct responses. A chi-square test assessed statistical significance at the P < 0.05 level. The activity launched 26th June 2019; data were collected until 19th August 2019. Results: Overall significant improvements were seen after education for oncologists (N = 62, P < .001) and pathologists (N = 67, P < .01). The relative improvement was 67% for oncologists and 45% for pathologists (pre-/post-assessment average correct response rates were 30%/50% and 29%/42%, respectively). Following the activity, 55% of oncologists and 51% of pathologists had a measurable improvement in confidence in their ability to differentiate among late-stage investigational agents for GBM based on mechanism of action. Conclusions: Participation in an online, CME intervention consisting of a series of video discussions, totaling 30-minutes, resulted in statistically significant improvements in knowledge and confidence of oncologists and pathologists, that may lead to improvements in clinical care. As new data and agents emerge, new educational activities are necessary to reinforce knowledge, close persistent gaps, and increase oncologists’ and pathologists’ confidence in this clinical setting.

Pharmacological studies of the mouse cone electroretinogram

2005 ◽  
Vol 22 (5) ◽  
pp. 631-636 ◽  
Author(s):  
SUMIT SHARMA ◽  
SHERRY L. BALL ◽  
NEAL S. PEACHEY
Keyword(s):  
Cell Activity ◽  
Retinal Disease ◽  
Experimental Treatment ◽  
Receptor Activation ◽  
Bipolar Cells ◽  
Small Contribution ◽  
Hereditary Retinal Disease ◽  
Cone Pathway ◽  
Pharmacological Studies ◽  
Species Activity

Electroretinography provides a useful noninvasive approach to evaluate cone pathway activity. Despite wide application of the cone ERG to characterize retinal function in transgenic mice and mouse models of human hereditary retinal disease, the cellular origins of the mouse cone ERG have not been well defined. Here, we address this issue using a pharmacological approach that has been previously applied to other species. Agents that block receptor activation at well-defined retinal loci were dissolved in saline and injected into the vitreous of anesthetized adult BALBc/ByJ mice; cone ERGs were recorded 1–2 h later. Analysis of the resulting waveforms indicated that the mouse cone ERG includes a cornea-negative component that is derived from the activity of cone photoreceptors and retinal glial (Müller) cells. Similar to other species, activity of cone depolarizing bipolar cells contributes a large amplitude cornea-positive potential to the mouse cone ERG. In contrast to primate but similar to rat, the mouse cone ERG includes only a small contribution from hyperpolarizing bipolar cell activity. The inner retina appears to contribute to both thea- andb-waves of the mouse cone ERG. These results provide a foundation for interpreting changes in the waveform of the mouse cone ERG that may be observed following genetic alteration or other experimental treatment.

scholarly journals Clinically-guided mutation screening of two families with hereditary retinal disease

2017 ◽  
Author(s):  
Jian Li ◽  
Aierken Yiming ◽  
Ping Wang
Keyword(s):  
Molecular Diagnosis ◽  
Large Scale ◽  
Direct Sequencing ◽  
Mutation Screening ◽  
Retinal Disease ◽  
Cost Effective ◽  
Mendelian Disease ◽  
Cost Effective Approach ◽  
Hereditary Retinal Disease ◽  
The Cost

AbstractHereditary retinal disease (HRD) is a series of Mendelian diseases affecting the retina in the eye. The genetic basis of HRD is very complicated, with more than 100 disease-causing genes being identified. Though NGS has allowed rapid and large-scale mutation screening of Mendelian disease, the cost of NGS still prevents its universal application all over the world, for an accurate molecular diagnosis. Here, by clinical guidance from patient phenotypes, we performed targeted molecular diagnosis by direct Sanger sequencing of the most likely candidate gene in two families diagnosed with HRD. Then we identified two novel protein-truncating variants in the gene CRB1. Our results demonstrated the notion that molecular diagnosis and clinical diagnosis can be mutually supplemented and clinically guided direct sequencing is a cost-effective approach for molecular diagnosis and subsequent genetic counseling.

scholarly journals Identifying potential germline variants from sequencing hematopoietic malignancies

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 219-227
Author(s):  
Ira L. Kraft ◽  
Lucy A. Godley
Keyword(s):  
Clinical Care ◽  
Copy Number Variations ◽  
Molecular Testing ◽  
Single Nucleotide Variants ◽  
Germline Variants ◽  
Hematopoietic Malignancy ◽  
Risk Alleles ◽  
Dna Alterations ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data

Abstract Next-generation sequencing (NGS) of bone marrow and peripheral blood increasingly guides clinical care in hematological malignancies. NGS data may help to identify single nucleotide variants, insertions/deletions, copy number variations, and translocations at a single time point, and repeated NGS testing allows tracking of dynamic changes in variants during the course of a patient’s disease. Tumor cells used for NGS may contain germline, somatic, and clonal hematopoietic DNA alterations, and distinguishing the etiology of a variant may be challenging. We describe an approach using patient history, individual variant characteristics, and sequential NGS assays to identify potential germline variants. Our current criteria for identifying an individual likely to have a deleterious germline variant include a strong family history or multiple cancers in a single patient, diagnosis of a hematopoietic malignancy at a younger age than seen in the general population, variant allele frequency &gt; 0.3 of a deleterious allele in a known germline predisposition gene, and variant persistence identified on clinical NGS panels, despite a change in disease state. Sequential molecular testing of hematopoietic specimens may provide insight into disease pathology, impact patient and family members’ care, and potentially identify new cancer-predisposing risk alleles. Ideally, individuals should give consent at the time of NGS testing to receive information about potential germline variants and to allow future contact as research advances.

Clinical actionability of germline testing in patients with limited colorectal polyps.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13027-e13027
Author(s):  
Mersedeh Rohanizadegan ◽  
Saud H Aldubayan ◽  
Marios Giannakis ◽  
Xinmeng Jasmine Mu ◽  
Reiko Nishihara ◽  
...  
Keyword(s):  
Pilot Study ◽  
Family History ◽  
Diagnostic Yield ◽  
Clinical Care ◽  
Colorectal Adenomas ◽  
Molecular Testing ◽  
Main Process ◽  
Colon Polyps ◽  
Truncating Mutation ◽  
Germline Testing

e13027 Background: As classic adenoma-carcinoma sequence is the main process underlying most colorectal cancer (CRC), early detection and removal of colorectal adenomas is crucial in preventing CRC. Although adenomatous polyps are usually sporadic, several inherited CRC syndromes such as Familial adenomatous polyposis, MUTYH-associated polyposis and Lynch syndrome can present initially with colon polyps. The identification of germline defects in patients with colon polyps is thus critical for proper cancer risk counseling and CRC prevention. Current guidelines recommend germline testing for patients with more than 20 polyps or those with more than 10 polyps and a family history of CRC. However, the diagnostic yield of germline testing on otherwise healthy individuals with 10 or fewer colon polyps has not been well studied. Here, we performed a pilot study to evaluate the clinical actionability of germline genetic testing on these patients. Methods: A total of 13 cancer-free adults, who presented with colon polyps (n < 10) and who otherwise were not selected based on age of onset or family history underwent germline Exome Sequencing. Variants in 13 well-established CRC risk genes ( APC, CHEK2, MYH, MLH1, MSH2, MSH6, PMS2, NTHL1, BMPR1A, SMAD4, PTEN, STK11, TP53) were evaluated for pathogenicity. Results: A total of 13 patients (12 male, 1 female) were evaluated. The median age of presentation was 69 (range 49 to 88). The median number of adenomatous colon polyps was 1 (range 1 to 8). Two (15.4%, 95% CI = 1.9 - 45.4, Binomial Exact) patients had at least one disruptive mutation in the examined genes. One of these patients had a truncating mutation in APC (p.Arg216*) and presented with two tubulovillous adenomas at age 49. The second patient had 8 adenomas in distal colon and rectum at age 64, and harbored a known pathogenic mutation in MSH6(p.Arg1035*). Conclusions: This pilot study provides evidence that a relatively high percentage of patients presenting with a few colon polyps may have inherited defects in highly actionable genes. If validated in larger cohorts with appropriate population controls, these findings may influence the clinical care of such patients and their families and suggest germline molecular testing in those patients.

scholarly journals The medical necessity of advanced molecular testing in the diagnosis and treatment of brain tumor patients

2019 ◽  
Vol 21 (12) ◽  
pp. 1498-1508 ◽  
Author(s):  
Craig Horbinski ◽  
Keith L Ligon ◽  
Priscilla Brastianos ◽  
Jason T Huse ◽  
Monica Venere ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Clinical Care ◽  
Pediatric Brain Tumor ◽  
Molecular Data ◽  
World Health ◽  
Molecular Testing ◽  
Medical Necessity ◽  
Health Organization ◽  
Cancer Network

Abstract Accurate pathologic diagnoses and molecularly informed treatment decisions for a wide variety of cancers depend on robust clinical molecular testing that uses genomic, epigenomic, and transcriptomic-based tools. Nowhere is this more essential than in the workup of brain tumors, as emphasized by the incorporation of molecular criteria into the 2016 World Health Organization classification of central nervous system tumors and the updated official guidelines of the National Comprehensive Cancer Network. Despite the medical necessity of molecular testing in brain tumors, access to and utilization of molecular diagnostics is still highly variable across institutions, and a lack of reimbursement for such testing remains a significant obstacle. The objectives of this review are (i) to identify barriers to adoption of molecular testing in brain tumors, (ii) to describe the current molecular tools recommended for the clinical evaluation of brain tumors, and (iii) to summarize how molecular data are interpreted to guide clinical care, so as to improve understanding and justification for their coverage in the routine workup of adult and pediatric brain tumor cases.

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