Assessing the Assessment-Developing and Deploying a Novel Tool for Evaluating Clinical Notes' Diagnostic Assessment Quality.

BACKGROUND: Ambulatory diagnostic errors are increasingly being recognized as an important quality and safety issue, and while measures of diagnostic quality have been sought, tools to evaluate diagnostic assessments in the medical record are lacking. OBJECTIVE: To develop and test a tool to measure diagnostic assessment note quality in primary care urgent encounters and identify common elements and areas for improvement in diagnostic assessment. DESIGN: Retrospective chart review of urgent care encounters at an urban academic setting. PARTICIPANTS: Primary care physicians. MAIN MEASURES: The Assessing the Assessment (ATA) instrument was evaluated for inter-rater reliability, internal consistency, and findings from its application to EHR notes. KEY RESULTS: ATA had reasonable performance characteristics (kappa 0.63, overall Cronbach's alpha 0.76). Variability in diagnostic assessment was seen in several domains. Two components of situational awareness tended to be well-documented ("Don't miss diagnoses" present in 84% of charts, red flag symptoms in 87%), while Psychosocial context was present only 18% of the time. CONCLUSIONS: The ATA tool is a promising framework for assessing and identifying areas for improvement in diagnostic assessments documented in clinical encounters.

Features of diffuse gliomas that are misdiagnosed on initial neuroimaging: a case control study.

PURPOSE: The neuroimaging diagnosis of diffuse gliomas can be challenging owing to their variable clinical and radiologic presentation. The purpose of this study was to identify factors that are associated with imaging errors in the diagnosis of diffuse gliomas. METHODS: A retrospective case-control analysis was undertaken. 18 misdiagnosed diffuse gliomas on initial neuroimaging (cases) and 108 accurately diagnosed diffuse gliomas on initial neuroimaging (controls) were collected. Clinical, pathological, and imaging metrics were tabulated for each patient. The tabulated metrics were compared between cases and controls to determine factors associated with misdiagnosis. RESULTS: Cases of misdiagnosed diffuse glioma (vs controls) were more likely to undergo initial triage as a stroke workup [OR 14.429 (95% CI 4.345, 47.915), p < 0.0001], were less likely to enhance [OR 0.283 (95% CI 0.098, 0.812), p = 0.02], were smaller (mean diameter 4.4 vs 6.0 cm, p = 0.0008), produced less midline shift (median midline shift 0.0 vs 2.0 mm, p = 0.003), were less likely to demonstrate necrosis [OR 0.156 (95% CI 0.034-0.713), p = 0.008], and were less likely to have IV contrast administered on the initial MRI [OR 0.100 (95% CI 0.020, 0.494), p = 0.008]. CONCLUSION: Several clinical and radiologic metrics are associated with diffuse gliomas that are missed or misdiagnosed on the initial neuroimaging study. Knowledge of these associations may aid in avoiding misinterpretation and accurately diagnosing such cases in clinical practice.

Primary CNS posttransplant lymphoproliferative disease (PTLD): an international report of 84 cases in the modern era.

We performed a multicenter, International analysis of solid organ transplant (SOT)-related primary central nervous system (PCNS) posttransplant lymphoproliferative disease (PTLD). Among 84 PCNS PTLD patients, median time of SOT-to-PTLD was 54 months, 79% had kidney SOT, histology was monomorphic in 83% and tumor was EBV+ in 94%. Further, 33% had deep brain involvement, 10% had CSF involvement, while none had ocular disease. Immunosuppression was reduced in 93%; additional first-line therapy included high-dose methotrexate (48%), high-dose cytarabine (33%), brain radiation (24%) and/or rituximab (44%). The overall response rate was 60%, while treatment-related mortality was 13%. With 42-month median follow-up, three-year progression-free survival (PFS) and overall survival (OS) were 32% and 43%, respectively. There was a trend on univariable analysis for improved PFS for patients who received rituximab and/or high-dose cytarabine. On multivariable Cox regression, poor performance status predicted inferior PFS (HR 2.61, 95% CI 1.32-5.17, p = 0.006), while increased LDH portended inferior OS (HR 4.16, 95% CI 1.29-13.46, p = 0.02). Moreover, lack of response to first-line therapy was the most dominant prognostic factor on multivariable analysis (HR 8.70, 95% CI 2.56-29.57, p = 0.0005). Altogether, PCNS PTLD appears to represent a distinct clinicopathologic entity within the PTLD spectrum that is associated with renal SOT, occurs late, is monomorphic and retains EBV positivity.

Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma.

Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway.

Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas.

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Prognostic Value of Preoperative MRI Metrics for Diffuse Lower-Grade Glioma Molecular Subtypes.

BACKGROUND AND PURPOSE: Despite the improved prognostic relevance of the 2016 WHO molecular-based classification of lower-grade gliomas, variability in clinical outcome persists within existing molecular subtypes. Our aim was to determine prognostically significant metrics on preoperative MR imaging for lower-grade gliomas within currently defined molecular categories. MATERIALS AND METHODS: We undertook a retrospective analysis of 306 patients with lower-grade gliomas accrued from an institutional data base and The Cancer Genome Atlas. Two neuroradiologists in consensus analyzed preoperative MRIs of each lower-grade glioma to determine the following: tumor size, tumor location, number of involved lobes, corpus callosum involvement, hydrocephalus, midline shift, eloquent cortex involvement, ependymal extension, margins, contrast enhancement, and necrosis. Adjusted hazard ratios determined the association between MR imaging metrics and overall survival per molecular subtype, after adjustment for patient age, patient sex, World Health Organization grade, and surgical resection status. RESULTS: For isocitrate dehydrogenase (IDH) wild-type lower-grade gliomas, tumor size (hazard ratio, 3.82; 95% CI, 1.94-7.75; P < .001), number of involved lobes (hazard ratio, 1.70; 95% CI, 1.28-2.27; P < .001), hydrocephalus (hazard ratio, 4.43; 95% CI, 1.12-17.54; P = .034), midline shift (hazard ratio, 1.16; 95% CI, 1.03-1.30; P = .013), margins (P = .031), and contrast enhancement (hazard ratio, 0.34; 95% CI, 0.13-0.90; P = .030) were associated with overall survival. For IDH-mutant 1p/19q-codeleted lower-grade gliomas, tumor size (hazard ratio, 2.85; 95% CI, 1.06-7.70; P = .039) and ependymal extension (hazard ratio, 6.34; 95% CI, 1.07-37.59; P = .042) were associated with overall survival. CONCLUSIONS: MR imaging metrics offers prognostic information for patients with lower-grade gliomas within molecularly defined classes, with the greatest prognostic value for IDH wild-type lower-grade gliomas.

Enhanced distress vocalization through selective reinforcement.

Eighteen Peking ducklings were imprinted and tested for their tendency to emit distress calls during the presentation and withdrawal of the imprinted stimulus. A subsequent arrangement in which each distress vocalization led to a 5-second presentation of the imprinted stimulus resulted in an enhanced tendency to emit distress calls.

Molecular Subtype Classification in Lower-Grade Glioma with Accelerated DTI.

BACKGROUND AND PURPOSE: Image-based classification of lower-grade glioma molecular subtypes has substantial prognostic value. Diffusion tensor imaging has shown promise in lower-grade glioma subtyping but currently requires lengthy, nonstandard acquisitions. Our goal was to investigate lower-grade glioma classification using a machine learning technique that estimates fractional anisotropy from accelerated diffusion MR imaging scans containing only 3 diffusion-encoding directions. MATERIALS AND METHODS: Patients with lower-grade gliomas (n = 41) (World Health Organization grades II and III) with known isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion status were imaged preoperatively with DTI. Whole-tumor volumes were autodelineated using conventional anatomic MR imaging sequences. In addition to conventional ADC and fractional anisotropy reconstructions, fractional anisotropy estimates were computed from 3-direction DTI subsets using DiffNet, a neural network that directly computes fractional anisotropy from raw DTI data. Differences in whole-tumor ADC, fractional anisotropy, and estimated fractional anisotropy were assessed between IDH-wild-type and IDH-mutant lower-grade gliomas with and without 1p/19q codeletion. Multivariate classification models were developed using whole-tumor histogram and texture features from ADC, ADC + fractional anisotropy, and ADC + estimated fractional anisotropy to identify the added value provided by fractional anisotropy and estimated fractional anisotropy. RESULTS: ADC (P = .008), fractional anisotropy (P < .001), and estimated fractional anisotropy (P < .001) significantly differed between IDH-wild-type and IDH-mutant lower-grade gliomas. ADC (P < .001) significantly differed between IDH-mutant gliomas with and without codeletion. ADC-only multivariate classification predicted IDH mutation status with an area under the curve of 0.81 and codeletion status with an area under the curve of 0.83. Performance improved to area under the curve = 0.90/0.94 for the ADC + fractional anisotropy classification and to area under the curve = 0.89/0.89 for the ADC + estimated fractional anisotropy classification. CONCLUSIONS: Fractional anisotropy estimates made from accelerated 3-direction DTI scans add value in classifying lower-grade glioma molecular status.

Extent of Surgical Resection in Lower-Grade Gliomas: Differential Impact Based on Molecular Subtype.

BACKGROUND AND PURPOSE: Diffuse lower-grade gliomas are classified into prognostically meaningful molecular subtypes. We aimed to determine the impact of surgical resection on overall survival in lower-grade glioma molecular subtypes. MATERIALS AND METHODS: For 172 patients with lower-grade gliomas (World Health Organization grade II or III), pre- and postsurgical glioma volumes were determined using a semiautomated segmentation software based on FLAIR or T2-weighted MR imaging sequences. The association of pre- and postsurgical glioma volume and the percentage of glioma resection with overall survival was determined for the entire cohort and separately for lower-grade glioma molecular subtypes based on isocitrate dehydrogenase (IDH) and 1p/19q status, after adjustment for age, sex, World Health Organization grade, chemotherapy administration, and radiation therapy administration. RESULTS: For the entire cohort, postsurgical glioma volume (hazard ratio, 1.80; 95% CI, 1.18-2.75; P = .006) and the percentage of resection (hazard ratio, 3.22; 95% CI, 1.79-5.82; P < .001) were associated with overall survival. For IDH-mutant 1p/19q-codeleted oligodendrogliomas, the percentage of resection (hazard ratio, 6.69; 95% CI, 1.57-28.46; P = .01) was associated with overall survival. For IDH-mutant 1p/19q-noncodeleted astrocytomas, presurgical glioma volume (hazard ratio, 3.20; 95% CI, 1.22-8.39; P = .018), postsurgical glioma volume (hazard ratio, 2.33; 95% CI, 1.32-4.12; P = .004), and percentage of resection (hazard ratio, 4.34; 95% CI, 1.74-10.81; P = .002) were associated with overall survival. For IDH-wild-type lower-grade gliomas, pre-/postsurgical glioma volume and percentage of resection were not associated with overall survival. CONCLUSIONS: The extent of surgical resection has a differential survival impact in patients with lower-grade gliomas based on their molecular subtype. IDH-mutant lower-grade gliomas benefit from a greater extent of surgical resection, with the strongest impact observed for IDH-mutant 1p/19q-noncodeleted astrocytomas.