Monitoring long-term opioid therapy and chronic noncancer pain in primary care: Whole Health Primary Care Pain Education and Opioid Monitoring Program (PC-POP).

OBJECTIVE: To replicate and extend previous research by examining, among a larger sample, the effectiveness of a Whole Health Primary Care Pain Education and Opioid Monitoring Program (PC-POP) at increasing adherence to the Veteran Affairs/Department of Defense (VA/DoD) recommended guidelines for long-term opioid therapy among chronic noncancer patients seen in primary care-medications, hospitalization, monitoring/safety, assessment, and nonpharmacological pain treatment referrals. DESIGN/METHODS: Using data collected from medical records, a between-subjects comparison (PC-POP enrollees vs nonenrollees) was conducted to determine if there were differences between the groups 12 months post-enrollment in PC-POP (12 months post-index date for nonenrollees). Additionally, a within-subjects comparison of outcomes was also conducted with PC-POP enrollees, ie, 12 months pre-enrollment to 12 months post-enrollment. SUBJECTS: A convenience sample of adult Veterans with chronic noncancer pain receiving opioid therapy consecutively for ≥3 months in primary care. RESULTS: A total of 734 Veterans (423 PC-POP enrollees and 311 nonenrollees) were included in the analyses. Results showed increased concordance with VA/DoD guidelines among those enrolled in PC-POP, characterized by increased documentation of urine drug screens, Stratification Tool for Opioid Risk Mitigation reports, Narcan education/prescriptions, assessment measures for mental health/substance use/physical function, and referrals for nonpharmacological pain treatment. A decrease in morphine equivalent daily dose among patients enrolled in PC-POP across a 2-year timeframe was also found. CONCLUSIONS: PC-POP increases guideline concordant care for providers working in primary care.

Genome-wide association analysis identifies a susceptibility locus for sporadic vestibular schwannoma at 9p21.

Vestibular schwannomas are benign nerve sheath tumours that arise on the vestibulocochlear nerves. Vestibular schwannomas are known to occur in the context of tumour predisposition syndromes NF2-related and LZTR1-related schwannomatosis. However, the majority of vestibular schwannomas present sporadically without identification of germline pathogenic variants. To identify novel genetic associations with risk of vestibular schwannoma development, we conducted a genome-wide association study in a cohort of 911 sporadic vestibular schwannoma cases collated from the neurofibromatosis type 2 genetic testing service in the north-west of England, UK and 5500 control samples from the UK Biobank resource. One risk locus reached genome-wide significance in our association analysis (9p21.3, rs1556516, P = 1.47 × 10-13, odds ratio = 0.67, allele frequency = 0.52). 9p21.3 is a genome-wide association study association hotspot, and a number of genes are localized to this region, notably CDKN2B-AS1 and CDKN2A/B, also referred to as the INK4 locus. Dysregulation of gene products within the INK4 locus have been associated with multiple pathologies and the genes in this region have been observed to directly impact the expression of one another. Recurrent associations of the INK4 locus with components of well-described oncogenic pathways provides compelling evidence that the 9p21.3 region is truly associated with risk of vestibular schwannoma tumorigenesis.

Re-evaluation of missense variant classifications in NF2.

Missense variants in the NF2 gene result in variable NF2 disease presentation. Clinical classification of missense variants often represents a challenge, due to lack of evidence for pathogenicity and function. This study provides a summary of NF2 missense variants, with variant classifications based on currently available evidence. NF2 missense variants were collated from pathology-associated databases and existing literature. Association for Clinical Genomic Sciences Best Practice Guidelines (2020) were followed in the application of evidence for variant interpretation and classification. The majority of NF2 missense variants remain classified as variants of uncertain significance. However, NF2 missense variants identified in gnomAD occurred at a consistent rate across the gene, while variants compiled from pathology-associated databases displayed differing rates of variation by exon of NF2. The highest rate of NF2 disease-associated variants was observed in exon 7, while lower rates were observed toward the C-terminus of the NF2 protein, merlin. Further phenotypic information associated with variants, alongside variant-specific functional analysis, is necessary for more definitive variant interpretation. Our data identified differences in frequency of NF2 missense variants by exon between gnomAD population data and NF2 disease-associated variants, suggesting a potential genotype-phenotype correlation; further work is necessary to substantiate this.

Examining the relationship between pain interference, pain intensity, and mental health symptoms among veterans receiv-ing long-term opioid therapy for chronic noncancer pain in primary care.

OBJECTIVE: As part of the evaluation of the Whole Health Primary Care Pain Education and Opioid Monitoring Program (PC-POP), we examined the relationship between pain intensity, pain interference, and mental health symptoms among PC-POP enrollees. DESIGN/METHODS: Retrospective cohort study examining self-reported symptoms of pain intensity, pain interference, anxiety, depression, substance use, and quality of life. Data were retrieved through a combination of chart review and data extracted from the VA Informatics and Computing Infrastructure. SETTING: Veterans Health Administration Health Care System Primary Care -service. SUBJECTS: Adult veterans with chronic noncancer pain receiving opioid therapy >3 months being managed in primary care and enrolled in PC-POP between August 1, 2018 and April 1, 2019. RESULTS: A total of 439 participants were included in the final analysis. Results showed that anxiety has a unique relationship to pain intensity and that depression and quality of life have unique relationships to pain interference when relevant covariates, eg, gender, age, pain diagnosis, and predictors are examined among this unique sample of veterans enrolled in a pain and opioid education and monitoring program. CONCLUSIONS: Given that primary care is the dominant healthcare setting in which opioids are prescribed for chronic noncancer pain, further research is needed to examine factors that influence pain management in this setting. This study examined the role mental health factors have on pain intensity and pain interference among patients enrolled in an opioid monitoring program and found that anxiety and depression appear to uniquely predict how intensely and impactful these veterans experience their pain. This study extends the literature by examining such factors among a unique population that has yet to be studied and offers some recommendations for monitoring and practice.

Sporadic vestibular schwannoma: a molecular testing summary.

OBJECTIVES: Cases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis. METHODS: Cases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in NF2 on blood samples for all patients, and tumour DNA samples when available. LZTR1 and SMARCB1 screening was also performed in patient subgroups. RESULTS: Age at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline NF2 variants were confirmed in 2% of patients. Pathogenic germline variants in LZTR1 were found in 3% of all tested patients, with a higher rate of 5% in patients <30 years. No pathogenic SMARCB1 variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic NF2 variants, including those with germline LZTR1 pathogenic variants. CONCLUSIONS: Undiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of NF2 function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of LZTR1-associated VS tumourigenesis.

Association of Genetic Predisposition With Solitary Schwannoma or Meningioma in Children and Young Adults.

Importance: Meningiomas and schwannomas are usually sporadic, isolated tumors occurring in adults older than 60 years and are rare in children and young adults. Multiple schwannomas and/or meningiomas are more frequently associated with a tumor suppressor syndrome and, accordingly, trigger genetic testing, whereas solitary tumors do not. Nevertheless, apparently sporadic tumors in young patients may herald a genetic syndrome. Objective: To determine the frequency of the known heritable meningioma- or schwannoma-predisposing mutations in children and young adults presenting with a solitary meningioma or schwannoma. Design, Setting, and Participants: Using the database of the Manchester Centre for Genomic Medicine, this cohort study analyzed lymphocyte DNA from young individuals prospectively referred to the clinic for genetic testing between January 1, 1990, and December 31, 2016, on presentation with a single meningioma (n = 42) or schwannoma (n = 135) before age 25 years. Sequencing data were also examined from an additional 39 patients with neurofibromatosis type 2 who were retrospectively identified as having a solitary tumor before age 25 years. Patients with schwannoma were screened for NF2, SMARCB1, and LZTR1 gene mutations, while patients with meningioma were screened for NF2, SMARCB1, SMARCE1, and SUFU. Main Outcomes and Measures: The type of underlying genetic mutation, or lack of a predisposing mutation, was associated with the presenting tumor type and subsequent development of additional tumors or other features of known schwannoma- and meningioma-predisposing syndromes. Results: In 2 cohorts of patients who presented with an isolated meningioma (n = 42; median [range] age, 11 [1-24] years; 22 female) or schwannoma (n = 135; median [range] age, 18 [0.2-24] years; 60 female) before age 25 years, 16 of 42 patients (38%) had a predisposing mutation to meningioma and 27 of 135 patients (20%) to schwannoma, respectively. In the solitary meningioma cohort, 34 of 63 patients (54%) had a constitutional mutation in a known meningioma predisposition gene. Twenty-five of 63 patients (40%) had a constitutional NF2 mutation, and 9 (14%) had a constitutional SMARCE1 mutation. In the cohort of those who developed a solitary schwannoma before age 25 years, 44 of 153 patients (29%) had an identifiable genetic predisposition. Twenty-four patients (55%) with a spinal schwannoma had a constitutional mutation, while only 20 (18%) with a cranial schwannoma had a constitutional predisposition (P < .001). Of 109 cranial schwannomas, 106 (97.2%) were vestibular. Four of 106 people (3.8%) with a cranial schwannoma had an LZTR1 mutation (3 were vestibular schwannomas and 1 was a nonvestibular schwannoma), and 9 (8.5%) had an NF2 mutation. Conclusions and Relevance: A significant proportion of young people with an apparently sporadic solitary meningioma or schwannoma had a causative predisposition mutation. This finding has important clinical implications because of the risk of additional tumors and the possibility of familial disease. Young patients presenting with a solitary meningioma or schwannoma should be referred for genetic testing.