Citations

OBJECTIVE The goal of microsurgical resection of vestibular schwannoma (VS) is gross-total resection (GTR) to provide oncological cure. However, a popular strategy is to halt the resection if the surgical team feels the risk of cranial nerve injury is imminent, achieving a maximally safe subtotal resection (STR) instead. The tumor remnant can then be treated with stereotactic radiosurgery (SRS) once the patient has recovered from the immediate postoperative period, or it can be followed with serial imaging and treated with SRS in a delayed fashion if residual tumor growth is seen. In this study, the authors evaluated the efficacy of this multimodality approach, particularly the influence of timing and dose of SRS on radiological tumor control, need for salvage treatment, and cranial nerve function. METHODS VS patients treated with initial microsurgery and subsequent radiosurgery were retrospectively included from two tertiary treatment centers and dichotomized depending on whether SRS was given upfront (defined as before 12 months) or later. Radiological tumor control was defined as less than 20% tumor volume expansion and oncological tumor control as an absence of salvage treatment. Facial and cochlear nerve functions were assessed after surgery, at the time of SRS, and at last follow-up. Finally, a systematic literature review was conducted according to PRISMA guidelines. RESULTS A total of 110 VS patients underwent SRS following microsurgical resection, with a mean preradiosurgical tumor volume of 2.2 cm3 (SD 2.5 cm3) and mean post-SRS follow-up time of 5.8 years (SD 4.1 years). The overall radiological tumor control and oncological tumor control were 77.3% and 90.9%, respectively. Thirty-five patients (31.8%) received upfront SRS, while 75 patients (68.2%) were observed for a minimum of 12 months prior to SRS. The timing of SRS did not influence the radiological tumor control (p = 0.869), the oncological tumor control (p = 0.560), or facial nerve (p = 0.413) or cochlear nerve (p = 0.954) function. An escalated marginal dose (> 12 Gy) was associated with greater tumor shrinkage (p = 0.020) and superior radiological tumor control (p = 0.020), but it did not influence the risk of salvage treatment (p = 0.904) or facial (p = 0.351) or cochlear (p = 0.601) nerve deterioration. CONCLUSIONS Delayed SRS after close observation of residuals following STR is a safe alternative to upfront SRS regarding tumor control and cranial nerve preservation in selected patients.

AbstractThe temporal evolutions and relative orderings of Alzheimer disease biomarkers, including CSF amyloid-β42 (Aβ42), Aβ40, total tau (Tau) and phosphorylated tau181 (pTau181), standardized uptake value ratio (SUVR) from the molecular imaging of cerebral fibrillar amyloid-β with PET using the 11C-Pittsburgh Compound-B (PiB), MRI-based hippocampal volume and cortical thickness and cognition have been hypothesized but not yet fully tested with longitudinal data for all major biomarker modalities among cognitively normal individuals across the adult lifespan starting from 18 years. By leveraging a large harmonized database from 8 biomarker studies with longitudinal data from 2609 participants in cognition, 873 in MRI biomarkers, 519 in PET PiB imaging and 475 in CSF biomarkers for a median follow-up of 5–6 years, we estimated the longitudinal trajectories of all major Alzheimer disease biomarkers as functions of baseline age that spanned from 18 to 103 years, located the baseline age window at which the longitudinal rates of change accelerated and further examined possible modifying effects of apolipoprotein E (APOE) genotype. We observed that participants 18–45 years at baseline exhibited learning effects on cognition and unexpected directions of change on CSF and PiB biomarkers. The earliest acceleration of longitudinal change occurred for CSF Aβ42 and Aβ42/Aβ40 ratio (with an increase) and for Tau, and pTau181 (with a decrease) at the next baseline age interval of 45–50 years, followed by an accelerated increase for PiB SUVR at the baseline age of 50–55 years and an accelerated decrease for hippocampal volume at the baseline age of 55–60 years and finally by an accelerated decline for cortical thickness and cognition at the baseline age of 65–70 years. Another acceleration in the rate of change occurred at the baseline age of 65–70 years for Aβ42/Aβ40 ratio, Tau, pTau181, PiB SUVR and hippocampal volume. Accelerated declines in hippocampal volume and cognition continued after 70 years. For participants 18–45 years at baseline, significant increases in Aβ42 and Aβ42/Aβ40 ratio and decreases in PiB SUVR occurred in APOE ɛ4 non-carriers but not carriers. After age 45 years, APOE ɛ4 carriers had greater magnitudes than non-carriers in the rates of change for all CSF biomarkers, PiB SUVR and cognition. Our results characterize the temporal evolutions and relative orderings of Alzheimer disease biomarkers across the adult lifespan and the modification effect of APOE ɛ4. These findings may better inform the design of prevention trials on Alzheimer disease.

Abstract Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer’s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. We evaluated plasma, serum, and CSF GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Plasma GFAP elevations appear a decade before expected symptom onset, after β-amyloid accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished β-amyloid-positive from β-amyloid-negative ADAD participants and showed a stronger relationship with β-amyloid load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Our findings support a role for plasma GFAP as a clinical biomarker for β-amyloid-associated cognitive deterioration in AD.

Abstract Case reports of patients infected with COVID-19 and influenza virus (“flurona”) have raised questions around the prevalence and severity of coinfection. Using data from HHS Protect Public Data Hub, NCBI Virus, and CDC FluView, we analyzed trends in SARS-CoV-2 and influenza hospitalized coinfection cases and strain prevalences. We also characterized coinfection cases across the Mayo Clinic Enterprise from January 2020 to April 2022. We compared expected and observed coinfection case counts across different waves of the pandemic and assessed symptoms and outcomes of coinfection and COVID-19 monoinfection cases after propensity score matching on clinically relevant baseline characteristics. From both the Mayo Clinic and nationwide datasets, the observed coinfection rate for SARS-CoV-2 and influenza has been higher during the Omicron era (2021 December 14 to 2022 April 2) compared to previous waves, but no higher than expected assuming infection rates are independent. At the Mayo Clinic, only 120 coinfection cases were observed among 197,364 SARS-CoV-2 cases. Coinfected patients were relatively young (mean age: 26.7 years) and had fewer serious comorbidities compared to monoinfected patients. While there were no significant differences in 30-day hospitalization, ICU admission, or mortality rates between coinfected and matched COVID-19 monoinfection cases, coinfection cases reported higher rates of symptoms including congestion, cough, fever/chills, headache, myalgia/arthralgia, pharyngitis, and rhinitis. While most coinfection cases observed at the Mayo Clinic occurred among relatively healthy individuals, further observation is needed to assess outcomes among subpopulations with risk factors for severe COVID-19 such as older age, obesity, and immunocompromised status.

Abstract Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer’s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. We evaluated plasma, serum, and CSF GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Plasma GFAP elevations appear a decade before expected symptom onset, after β-amyloid accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished β-amyloid-positive from β-amyloid-negative ADAD participants and showed a stronger relationship with β-amyloid load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Our findings support a role for plasma GFAP as a clinical biomarker for β-amyloid-associated cognitive deterioration in AD.

Abstract Precision oncology is the practice of interpreting the clinical significance of observed molecular changes in patient neoplasms, potentially impacting medical decision making and care. This process is labor-intensive and (among other challenges) involves accurately translating between variation representation conventions from one resource to the next. For example, differences in representations of Copy Number Variation (CNV) from genomic regions, cytogenomic bands, or gene features create challenges in knowledge matching due to lack of standards covering all of these modalities of observed variation.The Global Alliance for Genomics and Health (GA4GH; ga4gh.org) is an international collaborative of genomic data sharing initiatives (Driver Projects) developing genomic data sharing standards within a human rights framework. GA4GH recently published the Variation Representation Specification (VRS; pronounced “verse”), a standard for the computational representation of biomolecular variation. VRS is a terminology, schema, and associated conventions for creating uniquely identifiable and federatable representations of molecular variation. VRS has formal data classes well-suited to differentiating between variation on a single molecule (e.g. tandem duplications) from variation measured at a systemic level (e.g. genome-wide copy number variation). In addition to molecular sequence variation, VRS also supports variation on cytogenetic coordinate systems and genes, making it well-suited to representing variation associated with cancer biomarkers.We demonstrate the use of VRS to model reported gene-associated CNVs from the AACR Project GENIE cohort, to aid in the computational discovery of evidence from clinico-genomic knowledgebases with genomic or cytogenomic CNV representations. We highlight the use case of knowledge matching to the Atlas of Genetics and Cytogenetics in Oncology and Haematology (“the Atlas”; atlasgeneticsoncology.org), a cytogenetics resource historically driven by user website navigation. Using VRS search tools we developed for the Variant Interpretation for Cancer Consortium (VICC; cancervariants.org) GA4GH Driver Project, we found that 64% of GENIE samples with reported CNVs matched clinically relevant knowledge in the Atlas. This work was enabled by programmatic search tools leveraging standard VRS object structures, demonstrating how VRS enables collection of real-world evidence across more resources without manual interpretation or custom normalization methods. We conclude with a survey of open-source tools supporting this analysis as well as search of other clinico-genomic knowledgebases with VRS, including CIViC (civicdb.org), BRCA Exchange (brcaexchange.org), and the Molecular Oncology Almanac (moalmanac.org). Citation Format: Matthew Cannon, Kori Kuzma, James Stevenson, Jiachen Liu, Colin O'Sullivan, Bimal P. Chaudhari, Matthew Brush, Robert R. Freimuth, Tristan Nelson, Michael Baudis, Obi L. Griffith, Malachi Griffith, Lawrence Babb, Melissa S. Cline, Xuelu Liu, Brian Walsh, Alex H. Wagner. Introduction of the GA4GH Variation Representation Specification (VRS) and supporting tools for discovery and exchange of clinical genomic and cytogenomic knowledge in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1177.

BACKGROUND: Selection of skull base approaches is a critical skill for complex cranial surgery, which demands nuanced understanding of neuroanatomy and pathology. OBJECTIVE: To develop novel pedagogical resources for approach selection education and assessment. METHODS: A prospectively maintained skull base registry was screened for posterior fossa tumors amenable to 3-dimensional (3D) modeling of multiple operative approaches. Inclusion criteria were high-resolution preoperative and postoperative computed tomography and MRI studies (≤1 mm) and consensus that at least 3 posterior fossa craniotomies would provide feasible access. Cases were segmented using Mimics and modeled using 3-Matic. Clinical Vignettes, Approach Selection Questionnaire, and Clinical Application Questionnaire were compiled for implementation as a teaching/testing tool. RESULTS: Seven cases were selected, each representing a major posterior fossa approach group. 3D models were rendered using clinical imaging for the primary operative approach, as well as a combination of laboratory neuroanatomic data and extrapolation from comparable craniotomies to generate 2 alternative approaches in each patient. Modeling data for 3D figures were uploaded to an open-sourced database in a platform-neutral fashion (.x3d) for virtual/augmented reality and 3D printing applications. A semitransparent model of each approach without pathology and with key deep structures visualized was also modeled and included for comprehensive understanding. CONCLUSION: We report a novel series of open-source 3D models for skull base approach selection training, with supplemental resources. To the best of our knowledge, this is the first such series designed for pedagogical purposes in skull base surgery or centered on open-source principles.

Abstract COVID-19 vaccines are effective, but breakthrough infections have been increasingly reported. We conducted a test-negative case-control study to assess the durability of protection after full vaccination with BNT162b2 against polymerase chain reaction (PCR)-confirmed symptomatic SARS-CoV-2 infection, in a national medical practice from January 2021 through January 2022. We fit conditional logistic regression (CLR) models stratified on residential county and calendar time of testing to assess the association between time elapsed since vaccination and the odds of symptomatic infection or non-COVID-19 hospitalization (negative control), adjusted for several covariates. There were 5,985 symptomatic individuals with a positive test after full vaccination with BNT162b2 (cases) and 32,728 negative tests contributed by 27,753 symptomatic individuals after full vaccination (controls). The adjusted odds of symptomatic infection were higher 250 days after full vaccination versus at the date of full vaccination (Odds Ratio [OR]: 3.62, 95% CI: 2.52 to 5.20). The odds of infection were still lower 285 days after the first BNT162b2 dose as compared to 4 days after the first dose (OR: 0.50, 95% CI: 0.37 to 0.67), when immune protection approximates the unvaccinated status. Low rates of COVID-19 associated hospitalization or death in this cohort precluded analyses of these severe outcomes. The odds of non-COVID-19 associated hospitalization (negative control) decreased with time since vaccination, suggesting a possible underestimation of waning protection by this approach due to confounding factors. In summary, BNT162b2 strongly protected against symptomatic SARS-CoV-2 infection for at least 8 months after full vaccination, but the degree of protection waned significantly over this period.