Refining the predictive value of preoperative apparent diffusion coefficient (ADC) by whole-tumor analysis for facial nerve outcomes in vestibular schwannomas.

BACKGROUND: Apparent diffusion coefficient (ADC) in MRI has been shown to correlate with postoperative House-Brackmann (HB) scores in patients with vestibular schwannoma despite limited methodology. To rectify limitations of single region of interest (ROI) sampling, we hypothesize that whole-tumor ADC histogram analysis will refine the predictive value of this preoperative biomarker related to postoperative facial nerve function. METHODS: Of 155 patients who underwent resection of vestibular schwannoma (2014-2020), 125 patients were included with requisite clinical and radiographic data. After volumetric analysis and whole-tumor ADC histogram, regression tree analysis identified ADC cutoff for significant differences in HB grade. Outcomes were extent of resection, facial nerve function, hospital length of stay (LOS), and complications. RESULTS: Regression tree analysis defined three quantitative ADC groups (× 10-6 mm2/s) as high (> 2248.77; HB 1.7), mid (1468.44-2248.77; HB 3.1), and low (< 1468.44; HB 2.3) range (p 0.04). The mid-range ADC group had significantly worse postoperative HB scores and longer hospital LOS. Large tumor volume was independently predictive of lower rates of gross total resection (p <0.0001), higher postoperative HB score (p 0.002), higher rate of complications (p 0.04), and longer LOS (p 0.003). CONCLUSIONS: Whole-tumor histogram yielded a robust regression tree analysis that defined three ADC groups with significantly different facial nerve outcomes. This likely reflects tumor heterogeneity better than solid-tumor ROI sampling. Whole-tumor ADC warrants further study as a useful radiographic biomarker in patients with vestibular schwannoma who are considering surgical resection.

Surgical outcomes in large vestibular schwannomas: should cerebellopontine edema be considered in the grading systems?

PURPOSE: Large (> 3 cm) vestibular schwannomas pose complexity in surgical management because of narrow working corridors and proximity to the cranial nerves, brainstem, and inner ear structures. With current vestibular schwannoma classifications limited in information regarding cerebellopontine edema, our retrospective series examined this radiographic feature relative to clinical outcomes and its possible role in preoperative scoring. METHODS: Of 230 patients who underwent surgical resection of vestibular schwannoma (2014-2020), we identified 107 patients with Koos grades 3 or 4 tumors for radiographic assessment of edema in the middle cerebellar peduncle (MCP), brainstem, or both. Radiographic images were graded and patients grouped into Koos grades 3 or 4 or our proposed grade 5 with edema. Tumor volumes, radiographic features, clinical presentations, and clinical outcomes were evaluated. RESULTS: The 107 patients included 22 patients with grade 3 tumors, 39 with grade 4, and 46 with grade 5. No statistical differences were noted among groups for demographic data or complication rates. Unlike grades 3 and 4 patients, grade 5 patients presented with worse hearing (p < 0.001), larger tumors (p < 0.001), lower rates of gross total resection (GTR), longer hospital stays, and higher rates of balance dysfunction. CONCLUSION: With edema detected in 43% of this cohort, special considerations are warranted for grade 5 vestibular schwannomas given the preoperative findings of worse hearing, lower GTR rates, longer hospital stays, and 96% who pursued postoperative balance therapy. We propose that grade 5 with edema offers a more nuanced interpretation of a radiographic feature that holds relevance to treatment selection and patient outcomes.

Ordering Characteristics Predictive of Noncontrast CT Head Positivity in the Emergency Department.

RATIONALE AND OBJECTIVES: Recent decades have seen a steady increase in noncontrast head CT utilization in the emergency department with a concurrent rise in the practice of physician assistants (PAs) and nurse practitioners (NPs). The goal of this study was to identify ordering and patient characteristics predictive of positive noncontrast head CTs in the ED. We hypothesized NP/PAs would have lower positivity rates compared to physicians, suggestive of relative overutilization. MATERIALS AND METHODS: We retrospectively identified ED patients who underwent noncontrast head CTs at a single institution: a nonlevel 1 trauma center, during a 7-year period, recording examination positivity, ordering provider training/experience, and multiple additional ordering/patient attributes. Exam positivity was defined as any intracranial abnormality necessitating a change in acute management, such as acute hemorrhage, hydrocephalus, herniation, or worsening prior findings. RESULTS: 6624 patients met inclusion criteria. 4.6% (280/6107) of physician exams were positive while 3.7% (19/517) of NP/PA exams were positive; however, differences were not significant. Increasing provider experience was not associated with positivity. Attributes with increased positivity were patient age (p < 0.001), daytime exam (p < 0.05), and indications regarding malignancy (p < 0.001) or focal neurologic deficit (p = 0.001). Attributes with decreased positivity were indications of trauma (p < 0.001) or vertigo/dizziness (p < 0.05). CONCLUSION: We found no significant difference in rates of exam positivity between physicians and NP/PAs, even accounting for years of experience. This suggests increasing utilization of head CTs in the ED is not due to the increasing presence of NP/PAs, and may be reflective of general practice trends and clear diagnostic algorithms leading to head CT.

A phase I/Ib trial and biological correlate analysis of neoadjuvant SBRT with single-dose durvalumab in HPV-unrelated locally advanced HNSCC.

Five-year survival for human papilloma virus-unrelated head and neck squamous cell carcinomas remain below 50%. We assessed the safety of administering combination hypofractionated stereotactic body radiation therapy with single-dose durvalumab (anti-PD-L1) neoadjuvantly (n = 21) ( NCT03635164 ). The primary endpoint of the study was safety, which was met. Secondary endpoints included radiographic, pathologic and objective response; locoregional control; progression-free survival; and overall survival. Among evaluable patients at an early median follow-up of 16 months (448 d or 64 weeks), overall survival was 80.1% with 95% confidence interval (95% CI) (62.0%, 100.0%), locoregional control and progression-free survival were 75.8% with 95% CI (57.5%, 99.8%), and major pathological response or complete response was 75% with 95% exact CI (51.6%, 100.0%). For patients treated with 24 Gy, 89% with 95% CI (57.1%, 100.0%) had MPR or CR. Using high-dimensional multi-omics and spatial data as well as biological correlatives, we show that responders had: (1) an increase in effector T cells; (2) a decrease in immunosuppressive cells; and (3) an increase in antigen presentation post-treatment.

New-onset seizures in adults: Low diagnostic yield of gadolinium contrast in initial brain MRI evaluation.

BACKGROUND AND PURPOSE: The diagnostic utility of contrast MR-imaging in adult new-onset seizures without clinically suspected neoplasia or infection is not well defined in the literature. Imaging guidelines consider both contrast and noncontrast MR-imaging examinations appropriate in this clinical scenario. The purpose of this study was to evaluate the utility of contrast MR-sequences in evaluation of seizure in patients without suspicion for neoplasia or infection. METHODS: Imaging and clinical data were reviewed for 103 consecutive patients admitted for phase-1 seizure monitoring with the following criteria: (1) MRI-brain performed with/without intravenous contrast; (2) no clinical suspicion for central nervous system (CNS) infection; and (3) no history of CNS neoplasia, or suspected metastatic disease. Readers designated cases as lesional or nonlesional. Lesional cases were further categorized as either visualized on noncontrast sequences only, contrast sequences only, or both. RESULTS: 29/103 (28%) patients had epileptogenic lesions, 74/103 (72%) were nonlesional studies. 29/29 (100%) lesional abnormalities were detected on noncontrast sequences (sensitivity 100% [95 confidence interval (CI): 88-100], specificity 100% [95 CI: 95-100]). 23/29 (79.3%) lesional cases were visualized on both noncontrast and postcontrast sequences. 6/29 (20.7%) were visualized only on noncontrast sequences. No lesional cases were detected exclusively on postcontrast MR sequences. With an observed nonlesional extraneous contrast MR-imaging rate of 72%, estimated excess cost of contrast MR-imaging per 1000 patients using Medicare data was $103,680 USD. CONCLUSIONS: Contrast MR-imaging has limited diagnostic utility in initial screening of adult new-onset seizure patients without clinically suspected neoplasia or infection. More judicious use of contrast MR-imaging in this patient population may reduce unnecessary exposure to gadolinium and lower associated healthcare costs.

Safety and efficacy of sargramostim (GM-CSF) in the treatment of Alzheimer's disease.

INTRODUCTION: Inflammatory markers have long been observed in the brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients, suggesting that inflammation contributes to AD and might be a therapeutic target. However, non-steroidal anti-inflammatory drug trials in AD and mild cognitive impairment (MCI) failed to show benefit. Our previous work seeking to understand why people with the inflammatory disease rheumatoid arthritis are protected from AD found that short-term treatment of transgenic AD mice with the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) led to an increase in activated microglia, a 50% reduction in amyloid load, an increase in synaptic area, and improvement in spatial memory to normal. These results called into question the consensus view that inflammation is solely detrimental in AD. Here, we tested our hypothesis that modulation of the innate immune system might similarly be used to treat AD in humans by investigating the ability of GM-CSF/sargramostim to safely ameliorate AD symptoms/pathology. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in mild-to-moderate AD participants (NCT01409915). Treatments (20 participants/group) occurred 5 days/week for 3 weeks plus two follow-up (FU) visits (FU1 at 45 days and FU2 at 90 days) with neurological, neuropsychological, blood biomarker, and imaging assessments. RESULTS: Sargramostim treatment expectedly changed innate immune system markers, with no drug-related serious adverse events or amyloid-related imaging abnormalities. At end of treatment (EOT), the Mini-Mental State Examination score of the sargramostim group increased compared to baseline (P = .0074) and compared to placebo (P = .0370); the treatment effect persisted at FU1 (P = .0272). Plasma markers of amyloid beta (Aß40 [decreased in AD]) increased 10% (P = .0105); plasma markers of neurodegeneration (total tau and UCH-L1) decreased 24% (P = .0174) and 42% (P = .0019), respectively, after sargramostim treatment compared to placebo. DISCUSSION: The innate immune system is a viable target for therapeutic intervention in AD. An extended treatment trial testing the long-term safety and efficacy of GM-CSF/sargramostim in AD is warranted.

Quantitative [18]FDG PET asymmetry features predict long-term seizure recurrence in refractory epilepsy.

OBJECTIVE: Fluorodeoxyglucose-positron emission tomography (FDG-PET) is an established, independent, strong predictor of surgical outcome in refractory epilepsy. In this study, we explored the added value of quantitative [18F]FDG-PET features combined with clinical variables, including electroencephalography (EEG), [18F]FDG-PET, and magnetic resonance imaging (MRI) qualitative interpretations, to predict long-term seizure recurrence (mean post-op follow-up of 5.85 ±â€¯3.77 years). METHODS: Machine learning predictive models of surgical outcome were created using a random forest classifier trained on quantitative features in 89 patients with drug-refractory temporal lobe epilepsy evaluated at the Hospital of the University of Pennsylvania epilepsy surgery program (2003-2016). Quantitative features were calculated from asymmetry features derived from image processing using Advanced Normalization Tools (ANTs). RESULTS: The best-performing model used quantification and had an out-of-bag accuracy of 0.71 in identifying patients with seizure recurrence (Engel IB or worse) which outperformed that using qualitative clinical data by 10%. This model is shared through open-source software for research use. In addition, several asymmetry features in temporal and extratemporal regions that were significantly associated with seizure freedom are identified for future study. SIGNIFICANCE: Complex quantitative [18F]FDG-PET imaging features can predict seizure recurrence in patients with refractory temporal lobe epilepsy. These initial retrospective results in a cohort with long-term follow-up suggest that using quantitative imaging features from regions in the epileptogenic network can inform the clinical decision-making process.

The predictive value of preoperative apparent diffusion coefficient (ADC) for facial nerve outcomes after vestibular schwannoma resection: clinical study.

OBJECT: Diffusion MRI has been used to predict intraoperative consistency of tumors. Apparent diffusion coefficient (ADC) has shown predictive value as an imaging biomarker in many CNS tumors but has not been studied in a large cohort of patients with vestibular schwannoma. In this study, we examine the utility of ADC as a predictive biomarker for intraoperative tumor characteristics and postoperative facial nerve outcome. METHODS: A retrospective review of patients who underwent vestibular schwannoma resection at our institution from 2008 to 2018 yielded 87 patients, of which 72 met inclusion criteria. Operative reports and clinical records were reviewed for clinical data; MRI data were interpreted in a blinded fashion for qualitative and quantitative biomarkers, including tumor ADC. RESULTS: Mean tumor ADC values did not predict intraoperative consistency or adherence (p = 0.63). Adherent tumors were associated with worse facial nerve outcomes (p = 0.003). Regression tree analysis identified 3 ADC categories with statistically different facial nerve outcomes. The categories identified were ADC < 1006.04 × 10-6 mm2/s; ADC 1006.04-1563.93 × 10-6 mm2/s and ADC ≥ 1563.94 × 10-6 mm2/s. Postoperative and final House-Brackmann (HB) scores were significantly higher in the intermediate ADC group (2.3, p = 0.0038). HB outcomes were similar between the group with ADC < 1006.04 × 10-6 mm2/s and ≥ 1563.94 × 10-6 mm2/s (1.3 vs 1.3). CONCLUSIONS: Middle-range preoperative ADC in vestibular schwannoma suggests a less favorable postoperative HB score. Preoperative measurement of ADC in vestibular schwannoma may provide additional information regarding prognostication of facial nerve outcomes.

Effectiveness of Policies on Reducing Exposure to Ionizing Radiation From Medical Imaging: A Systematic Review.

PURPOSE: The use of medical imaging has expanded greatly in the past three decades, raising concern about potential unwanted carcinogenic harms associated with exposure to ionizing radiation among patients. This study summarizes evidence of efficacy of interventions that have prompted policies, and structural-level interventions aimed at reducing radiation dose and risk of cancer, especially among women. METHODS: Using standard terms, we conducted searches in MEDLINE, Scopus, and Web of Science, and de-duplicated retrieved citations. We hand-searched the reference section of eligible studies and contacted radiology experts to identify studies missed from electronic searches. Two reviewers screened retrieved citations based on predefined eligibility criteria, to identify relevant studies, extract key information from each, rate the quality of evidence, and summarize data in tabular and graphical format. RESULTS: From a total of 1,543 unique citations identified from all sources, 16 were included for data extraction. Half of the studies focused on reduction of ionizing exposure from CT, and half on x-ray or fluoroscopy. Identified interventions were broadly categorized as: policy or structural intervention (two; 13%); multipronged (four; 25%); dose-feedback system (five; 31%); provision of training (four; 25%); and quality-control audit (one; 6%). In general, multipronged programs had a higher range for dose reduction (22%-74%), followed by policy/structural interventions (37%-50%). CONCLUSIONS: Existing evidence on the effectiveness of policies aimed at reducing patient radiation dose is disperse and low in quality. Compared with other approaches, multipronged efforts may offer more patient protection.

Natalizumab-induced progressive multifocal leukoencephalopathy.

A 55-year-old woman with known relapsing-remitting multiple sclerosis (RRMS) on natalizumab (Tysabri®) for 3 years was admitted to the hospital with worsening word-finding difficulties and gait instability. Neurologic examination revealed right hemianopia, right arm hemiplegia, right-sided sensory loss, and global aphasia. The patient underwent MRI and PET imaging with concurrent electroencephalogram. She was subsequently diagnosed with natalizumab-induced progressive multifocal leukoencephalopathy (PML) and treated with plasmapheresis, intravenous immunoglobulin, and high-dose intravenous steroids. Steroids were continued over a 3-month hospital course and tapered upon discharge. Speech, arm strength, and ambulation have since improved.

Combination therapy of radiofrequency ablation and bevacizumab monitored with power Doppler ultrasound in a murine model of hepatocellular carcinoma.

PURPOSE: The purpose of this study was to monitor tumour blood flow with power Doppler ultrasound following antiangiogenic therapy with bevacizumab in order to optimally time the application of radiofrequency (RF) ablation to increase ablation diameter. MATERIALS AND METHODS: Athymic nude mice bearing human hepatocellular carcinoma xenografts were treated with bevacizumab and imaged daily with power Doppler ultrasound to quantify tumour blood flow. Mice were treated with RF ablation alone or in combination with bevacizumab at the optimal time, as determined by ultrasound. Ablation diameter was measured with histology and tumour microvascular density was calculated with immunohistochemistry. A computational thermal model of RF ablation was used to estimate ablation volume. RESULTS: A maximum reduction of 27.8 ± 8.6% in tumour blood flow occurred on day 2 following antiangiogenic therapy, while control tumours increased 29.3 ± 17.1% (p < 0.05). Tumour microvascular density was similarly reduced by 45.1 ± 5.9% on day 2 following antiangiogenic therapy. Histology demonstrated a 13.6 ± 5.6% increase in ablation diameter (40 ± 21% increase in volume) consistent with a computational model. CONCLUSION: Quantitative power Doppler ultrasound is a useful biomarker to monitor tumour blood flow following antiangiogenic treatment and to guide the application of RF ablation as a drug plus device combination therapy.

Ectopic functioning adrenocortical oncocytic adenoma (oncocytoma) with myelolipoma causing virilization.

Functioning adrenal adenomas are well-described entities that can rarely occur outside the adrenal gland in the ectopic adrenal tissue. Similarly, myelolipoma is an another benign lesion of the adrenal tissue which can rarely occur outside the adrenal gland. We report the first case of a testosterone producing an extra-adrenal adrenocortical oncocytoma accompanied by a myelolipoma. The patient presented with virilization and elevated androgen levels. Imaging revealed a retroperitoneal mass, which histologically consisted of oncocytes and intermingled myelolipoma. Postoperative androgen levels decreased to normal. The tumor cells were strongly positive for inhibin and Melan-A, supporting the adrenal origin. This case demonstrates a diagnostic challenge in which correlation with histology, immunohistochemistry, and serum endocrine studies led to the final diagnosis.