Zimmerman, Richard S.

Abstract INTRODUCTION The quantification of intratumoral heterogeneity – through radiomics-based approaches - can help resolve the regionally distinct genetic drug targets that may co-exist within a single Glioblastoma (GBM) tumor. While this offers potential diagnostic value under the paradigm of individualized oncology, clinical decision-making must also consider the degree of uncertainty associated with each model. In this study, we evaluate the performance of a novel machine-learning (ML) algorithm, called Gaussian Process (GP) modeling, that can quantify the impact of multiple sources of uncertainty in ML model development and prediction accuracy, including variabilities in the copy number measurement, radiomics features, training sample characteristics, and training sample size. METHOD We collected 95 image-localized biopsies from 25 primary GBM patients. We coregistered stereotactic locations with preoperative multi-parametric MRI features (conventional MRI, DSC perfusion, Diffusion Tensor Imaging) to generate spatially matched pairs of MRI and copy number variants (CNV) for for each biopsy. We developed a Gaussian Process (GP) model to predict CNV for Epidermal Growth Factor Receptor (EGFR) based on MRI radiomic features in each patient. We used leave-one-patient-out cross validation to quantify prediction accuracy and model uncertainty. Spatial prediction and uncertainty (p-value) maps were overlaid to help visualize regional genetic variation of EGFR and uncertainty of the radiomic predictions. RESULT: The initial GP radiomics model for EGFR amplification (CNV > 3.5) produced a sensitivity of 0.8 and specificity of 0.8. Samples/regions associated with high uncertainty (p-value >0.05) correlated with either 1) extrapolation of radiomic features from the training set-defined feature space or 2) insufficient training samples in the feature space. CONCLUSION We present a ML-based model that quantifies spatial genetic heterogeneity in GBM, while also estimating model uncertainties that result from multi-source data variabilities. This approach lays the groundwork for prospective clinical integration of modeling-based diagnostic approaches in the paradigm of individualized medicine.

Abstract BACKGROUND Radiation is an integral component of the multidisciplinary treatment of patients with intracranial metastasis (ICM) from melanoma. The risk of radiation necrosis (RN) post-treatment can range from 5–25%. We retrospectively evaluated pre- and post-radiation clinical and radiographical characteristics in patients with ICM from melanoma to identify potential risk factors for RN. METHODS After IRB approval, patients with ICM from melanoma who received radiation at our institution between 2013 and 2018 were retrospectively reviewed. We recorded demographics, intracranial metastasis (burden and location), systemic therapy, resection, stereotactic radiosurgery versus whole brain radiation, and outcomes. Brain MRI was evaluated using the Response Assessment in Neuro-Oncology criteria (RANO). RESULTS A total of 27 patients were included in the study. RN was diagnosed in 14 patients (52%) at one month to three years following radiation. Cerebellar location (n=7) was significantly associated with RN (p=0.0058). Metastasis-associated hemorrhage was present in 7 patients, 6 of which developed RN (43% vs 8%, p=0.08). Surgical resection prior to radiation was performed in 9 patients, 7 of which developed RN (50% vs 15%, p=0.1). RN appeared to be less often diagnosed when ICM were treated with higher doses of radiation (24 Gy vs 20 Gy, p=0.07). Systemic treatment was administered prior to radiation in 25 patients and we found no relationship with systemic therapy type and RN. Presumed RN was treated in 12 of 14 patients (86%). Steroids or surgical resection were the primary treatment modalities, with laser ablation used in 1 case. Following treatment, improvement was noted in 3 patients radiographically and in 1 of these clinically. CONCLUSIONS This series of patients with radiotherapy-treated brain metastases from melanoma reveals cerebellar involvement, hemorrhage, and prior surgical resection as potential risk factors for radiation necrosis. Neoadjuvant systemic treatment did not appear to be a risk factor in our review.

OBJECTIVEGeniculate neuralgia (GN) is an uncommon craniofacial pain syndrome attributable to nervus intermedius (NI) dysfunction. Diagnosis and treatment can be challenging, due to the complex nature of ear sensory innervation, resulting in clinical overlap with trigeminal neuralgia (TN) and glossopharyngeal neuralgia (GPN).METHODSA retrospective review of a prospective neurosurgical database at our institution was performed, 2000–2017, with a corresponding systematic literature review. Pain outcomes were dichotomized as unfavorable for unchanged/worsened symptoms versus favorable if improved/resolved. Eight formalin-fixed brains were examined to describe NI at the brainstem.RESULTSEleven patients were surgically treated for GN—9 primary, 2 reoperations. The median age was 48, 7 patients were female, and the median follow-up was 11 months (range 3–143). Seven had ≥ 2 probable cranial neuralgias. NI was sectioned in 9 and treated via microvascular decompression (MVD) in 2. Five patients underwent simultaneous treatment for TN (4 MVD; 1 rhizotomy) and 5 for GPN (3 MVD; 2 rhizotomy). Eleven reported symptomatic improvement (100%); 8 initially reported complete resolution (73%). Pain outcomes at last contact were favorable in 8 (73%)—all among the 9 primary operations (89% vs 0%, p = 0.054). Six prior series reported outcomes in 111 patients.CONCLUSIONSGN is rare, and diagnosis is confounded by symptomatic overlap with TN/GPN. Directed treatment of all possible neuralgias improved pain control in almost all primary operations. Repeat surgery seems a risk factor for an unfavorable outcome. NI is adherent to superomedial VIII at the brainstem; the intermediate/cisternal portion is optimal for visualization and sectioning.

OBJECTIVE Although it is still early in its application, laser interstitial thermal therapy (LiTT) has increasingly been employed as a surgical option for patients with mesial temporal lobe epilepsy. This study aimed to describe mesial temporal lobe ablation volumes and seizure outcomes following LiTT across the Mayo Clinic’s 3 epilepsy surgery centers. METHODS This was a multi-site, single-institution, retrospective review of seizure outcomes and ablation volumes following LiTT for medically intractable mesial temporal lobe epilepsy between October 2011 and October 2015. Pre-ablation and post-ablation follow-up volumes of the hippocampus were measured using FreeSurfer, and the volume of ablated tissue was also measured on intraoperative MRI using a supervised spline-based edge detection algorithm. To determine seizure outcomes, results were compared between those patients who were seizure free and those who continued to experience seizures. RESULTS There were 23 patients who underwent mesial temporal LiTT within the study period. Fifteen patients (65%) had left-sided procedures. The median follow-up was 34 months (range 12–70 months). The mean ablation volume was 6888 mm 3 . Median hippocampal ablation was 65%, with a median amygdala ablation of 43%. At last follow-up, 11 (48%) of these patients were seizure free. There was no correlation between ablation volume and seizure freedom (p = 0.69). There was also no correlation between percent ablation of the amygdala (p = 0.28) or hippocampus (p = 0.82) and seizure outcomes. Twelve patients underwent formal testing with computational visual fields. Visual field changes were seen in 67% of patients who underwent testing. Comparing the 5 patients with clinically noticeable visual field deficits to the rest of the cohort showed no significant difference in ablation volume between those patients with visual field deficits and those without (p = 0.94). There were 11 patients with follow-up neuropsychological testing. Within this group, verbal learning retention was 76% in the patients with left-sided procedures and 89% in those with right-sided procedures. CONCLUSIONS In this study, there was no significant correlation between the ablation volume after LiTT and seizure outcomes. Visual field deficits were common in formally tested patients, much as in patients treated with open temporal lobectomy. Further studies are required to determine the role of amygdalohippocampal ablation.

SummaryObjectiveEvaluate the seizure‐reduction response and safety of mesial temporal lobe (MTL) brain‐responsive stimulation in adults with medically intractable partial‐onset seizures of mesial temporal lobe origin.MethodsSubjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain‐responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2–6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events.ResultsThere were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy‐six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow‐up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty‐nine percent of subjects experienced at least one seizure‐free period of 6 months or longer, and 15% experienced at least one seizure‐free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device‐related adverse event was soft tissue implant‐site infection (overall rate, including events categorized as device‐related, uncertain, or not device‐related: 0.03 per implant year, which is not greater than with other neurostimulation devices).SignificanceBrain‐responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

SummaryObjectiveEvaluate the seizure‐reduction response and safety of brain‐responsive stimulation in adults with medically intractable partial‐onset seizures of neocortical origin.MethodsPatients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain‐responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2–6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset.ResultsThere were 126 patients with seizures of neocortical onset. The average follow‐up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty‐six percent of patients experienced at least one seizure‐free period of 6 months or longer and 14% experienced at least one seizure‐free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices.SignificanceBrain‐responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Summary Objective To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. Methods Randomized multicenter double‐blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period ( OLP ) to complete 2 years of postimplant follow‐up. Results All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was −37.9% in the active and −17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. Significance Responsive stimulation to the seizure focus reduced the frequency of partial‐onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial‐onset seizures.

We present an overview of strategies our institution has taken to understand the state of its inpatient diabetes management. We first describe how we utilized information systems to assess inpatient glycemic control and insulin management in noncritically ill patients and discuss our findings regarding mean bedside glucose levels, the prevalence and frequency hypoglycemic and hyperglycemic events, the patterns of insulin therapy, and evidence of inpatient clinical inertia. We also review the development of a survey to determine practitioner attitudes and beliefs about inpatient diabetes. Results of this survey study found that, in general, practitioners believed in the importance of controlling hyperglycemia but were not comfortable with many aspects of inpatient diabetes care, particularly with the use of insulin. Finally, we suggest steps to follow in developing a quality-improvement program for hospitals.

Purpose Individuals whose diabetes is being treated in the outpatient setting via an insulin pump often wish to maintain this therapy during hospitalization. The authors propose guidelines for management of patients on insulin pumps who require a hospital admission. Methods A collaborative interinstitutional task force reviewed current available information regarding the use of insulin pumps in the hospital. Results There was little information in the medical literature on how to manage individuals on established insulin pump therapy during a hospital stay. The task force believed that a policy that promotes patient independence through continuation of insulin pump therapy while ensuring patient safety was possible. A set of contraindications for continued use of pump therapy in the hospital are proposed. A sample patient consent form and order set are presented. Finally, measures that can be used to assess effectiveness of an inpatient insulin pump policy are outlined. Conclusions Patients on established insulin pump therapy do not necessarily have to discontinue treatment while hospitalized. However, clear policies and procedures should be established at the institutional level to guide continued use of the technology in the acute care setting.