Operative planning for a functional precision medicine assay of recurrent high-grade glioma: illustrative case.

BACKGROUND: Functional precision medicine (FPM) represents a personalized and efficacious modality for treating malignant neoplasms. However, acquiring sufficient live tissue to perform FPM analyses is complicated by both difficult identification on imaging and radiation necrosis, particularly in cases of recurrence. The authors describe a case of planning biopsy trajectories for an FPM assay in a patient with recurrent high-grade glioma. OBSERVATIONS: A 25-year-old male with a history of recurrent high-grade glioma was scheduled for laser ablation and biopsy with ChemoID assaying after regions of potential recurrence were identified on follow-up imaging. Preoperative magnetic resonance (MR) spectroscopy of the regions showed areas of high choline/creatine ratios within lesions of radiation necrosis, which helped in planning the biopsy trajectories to selectively target malignancies for FPM analysis. ChemoID results showed high tumor susceptibility to lomustine, which was implemented as adjuvant therapy. LESSONS: FPM therapy in the setting of recurrence is complicated by radiation necrosis, which can present as malignancy on imaging and interfere with tissue acquisition during biopsy or resection. Thus, operative approaches should be carefully planned with the assistance of imaging modalities such as MR spectroscopy to better ensure effective tissue acquisition for accurate FPM analysis and to promote more definitive treatment of recurrence.

Belzutifan-induced regression of retinal capillary hemangioblastoma: A case-series.

Purpose: To report a series of three patients with von Hippel-Lindau (VHL) disease who demonstrated regression of their retinal hemangioblastomas (RH) using belzutifan in conjunction with photocoagulation therapy. Observations: Patient 1, a 23-year-old female, presented with multiple RHs in her right eye (OD) that were lasered. Her left eye (OS) revealed a large inferotemporal RH that measured approximately 2.1 mm2. Systemic belzutifan was administered. Four months after initiation of treatment, the lesion regressed to 1.4 mm2, but belzutifan was not well-tolerated and was discontinued due to side effects. At the date of belzutifan discontinuation, the lesion measured about 1.1 mm2. Focal laser photocoagulation was applied. The lesion regressed to around 0.6 mm2. Two additional laser treatments were applied one month later. On the most recent follow-up, the lesion was completely fibrosed.Patient 2, a 32-year-old male, presented with one RH OD and two RHs OS. Belzutifan was administered for one month before the patient began experiencing side effects of the medication. Consequently, the dose of belzutifan was decreased. After one month with the lowered dose, laser coagulation was applied to OS. In the most recent follow-up, five months after the initial presentation, the lesions remain less vascularized and reduced in size.Patient 3, is a 44-year-old male with a large RH OD. Following seven months of belzutifan daily, there was a significant reduction in the RH size. Conclusions: Belzutifan, a hypoxia-inducible factor inhibitor, is an FDA-approved medication for VHL disease associated with renal cell carcinoma, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors that do not require immediate surgical resection. Because of the high incidence of VHL-associated RHs, adjuvant laser photocoagulation therapy when belzutifan is suspended or withheld can allow for the regression of large lesions. In this case series, we also propose a reproducible and technically simple method to measure RH lesions size, using Optos fundus imaging.

Diffuse Leptomeningeal Glioneuronal Tumor: First Description of Metastasis to the Lung and Bone Marrow.

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare neoplasm of the central nervous system (CNS) that primarily affects the leptomeninges. However, it can also involve the brain parenchyma and spinal cord. We report the first case of metastasis of this primary CNS tumor to the lung and bone marrow. An 18-year-old male was diagnosed with DLGNT through meningeal biopsy after multiple events of transient neurologic signs and symptoms that included recurrent episodes of encephalopathy, seizures, cerebral vasospasms, cranial nerve palsy, and urinary dysfunction. Five months after diagnosis, the patient presented with pancytopenia and pulmonary effusion. At that time, he was being treated with temozolomide, after radiation treatment to the brain and spinal cord. Bone marrow biopsy and pleural cytology revealed systemic metastases from the primary CNS tumor. He was then treated with chemotherapy with carboplatin and vincristine which improved his condition for two and a half months. Unfortunately, the patient died of a high systemic metastatic burden. Primary CNS tumors rarely produce systemic metastases, and this is the first report of DLGNT with bone marrow and pulmonary metastases. Chemotherapy with carboplatin and vincristine should be considered as a treatment for patients with DLGNT, as the patient presented a systemic response with clinical and radiological improvement.

Prevalence of cerebrovascular accidents in patients with ulcerative colitis in a single academic health system.

In general, IBD increases arteriovenous thromboembolic events, though the association between UC and cerebrovascular complications remains inconclusive. Some studies suggest young women with UC have an increased risk of cerebrovascular accidents (CVA). The focus of this study was to characterize the rates, anatomic distribution, and risk factors for CVA in patients with UC. We developed a retrospective cohort of patients with UC at a single health care system from June 2010 to June 2015. Neuroimaging was used to document presence, location and type of stroke and traditional risk factors were considered. Prevalence of CVAs in patients with UC was compared to that of the general population of Minnesota (MN) and the United States (U.S.). A total of 2,183 UC patients were identified (1088 females [f-UC], 1095 males [m-UC]). The prevalence of CVA in UC patients (4.7%, 95% CI 3.9-5.6) was higher than in the U.S. (2.5-2.7%, p < 0.0001) and in Minnesota (1.8% CI 1.5-2.2, p < 0.0001) . The prevalence increased in both sexes with a peak prevalence of 24.7% (95% CI 17.1-34.4) in women with UC over the age of 80. Older age, cancer and atrial fibrillation were risk factors for CVA in univariate analysis for both sexes. In multifactorial analysis, both age and atrial fibrillation were risk factors for CVA in the m-UC cohort, but only age was associated with CVA in f-UC. The most common type of CVA was ischemic stroke (77.7%). The most common locations for CVAs in UC patients were frontal and occipital lobes (19% and 18%, respectively). UC patients have an increased risk for CVA, with women over 80 demonstrating the highest risk. Providers should be aware of these risks in making treatment decisions for UC.

Neurotoxicity of antibodies in cancer therapy: A review.

The objective of this manuscript is to identify the neurological side effect profile associated with different classes of antibodies used in cancer pharmacotherapy and to estimate the frequency in which these neurotoxicity occurs. A systematic review of the literature was conducted using OVID MEDLINE and EMBASE databases for articles written between January of 2010 till August of 2018. The spectrum of neurotoxicity was searched using expanded terminology, medical subject headings, truncation, spelling variations and database specific controlled vocabulary. 2134 citations were retrieved that were narrowed down to 151 when SORT 1 or SORT 2 critical appraisal tool was applied to articles with human subjects. Meta-analysis using random effect model was done to estimate the prevalence of neurological symptoms per class of antibody described in SORT1 and SORT2 articles. It was found that the most common neurotoxicity per antibody class are as follows; Bi-specific T-cell engagers was headache 38% [35-40%; I2 0%]; anti-CD20, neuropathy, 16% [7-24%, I2 65%]; anti-CD30, neuropathy 57% [46-68%, I2 72%]; anti-CD52, neuropathy 5-15%; anti-CTL4, headache 12% [7-16%, I2 49%]; anti-EGFR, headache 25% [11-38%, I2 92%]; anti-Her2, neuropathy 33% [18-49%, I2 98%]; anti-PD1 and PDL1, headache 3% [2-5%, I2 85%]; and anti-VEGF, headache 25% [16-35%, I2 73%]. Therefore, all classes of antibodies used in cancer pharmacotherapy have associated neurotoxicity with a wide spectrum of effects afflicting the nervous system as a whole. The specific side effects and the frequency at which they occur differ per class of antibody. Broader and more severe symptoms were noted to effect patients with preexisting brain lesions.

Short myelitis lesions in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders.

IMPORTANCE: Short transverse myelitis (STM; <3 vertebral segments) is considered noncharacteristic of neuromyelitis optica (NMO) spectrum disorders (NMOSDs). Nonappreciation of the potential for STM to occur in NMOSD may lead to increased disability from delay in diagnosis and appropriate treatment. OBJECTIVES: To determine the frequency of short lesions at the initial myelitis manifestation of NMOSD and to compare the demographic, clinical, and radiological characteristics of aquaporin-4-IgG (AQP4-IgG) seropositive and seronegative STM. DESIGN, SETTING, AND PARTICIPANTS: We reviewed the records and images of patients at the Mayo Clinic who were identified as AQP4-IgG positive from 1996 to 2014. Inclusion criteria were first STM episode, magnetic resonance imaging performed 90 days or less from symptom onset, spinal cord T2-hyperintense lesion less than 3 vertebral segments, AQP4-IgG seropositivity, and a final diagnosis of NMO or NMOSD. Patients with an initial longitudinally extensive transverse myelitis were excluded (n = 151). Patients with STM who were seronegative for AQP4-IgG among an Olmsted County population-based cohort of inflammatory demyelinating disorders of the central nervous system were used as a control group. MAIN OUTCOMES AND MEASURES: Delay to diagnosis in months, clinical and radiological characteristics, and disability measured by ambulatory status. RESULTS: Twenty-five patients who were AQP4-IgG seropositive with an initial STM represented 14% of initial myelitis episodes among patients with NMOSD. The STM episode was defined as the first manifestation of NMOSD in 10 patients (40%) preceded by optic neuritis in 13 patients (52%) and preceded by a nausea and vomiting episode in 2 patients (8%). In comparison with the excluded patients with NMOSD who had an initial longitudinally extensive transverse myelitis, delay to diagnosis/treatment was greater when initial lesions were short (P = .02). In AQP4-IgG-positive STM cases, subsequent myelitis episodes were longitudinally extensive in 92%. Attributes more common in patients with AQP4-IgG-positive STM than in 27 population-based patients with AQP4-IgG-negative STM included the following: nonwhite race/ethnicity; tonic spasms; coexisting autoimmunity; magnetic resonance imaging (central cord lesions, T1 hypointensity, and a brain inconsistent with multiple sclerosis); and cerebrospinal fluid (oligoclonal bands lacking). CONCLUSIONS AND RELEVANCE: Short transverse myelitis is not uncommon in NMOSD and, when it is present, delays diagnosis and treatment. Clinical and radiological characteristics identified in this study may help select patients with STM who are at the highest risk for an NMOSD. Short transverse myelitis does not exclude consideration of AQP4-IgG testing or NMOSD diagnosis.

Neural autoantibody clusters aid diagnosis of cancer.

PURPOSE: Clustering of neural autoantibodies in patients with paraneoplastic neurologic disorders may predict tumor type. A mathematical analysis of neural autoantibody clusters was performed in 78,889 patients undergoing evaluation for a suspected paraneoplastic autoimmune neurologic disorder. Tumor predictive autoantibody profiles were confirmed in sera from patients with histologically proven tonsillar cancer, thymoma, and lung cancer. PATIENTS AND METHODS: Of note, 78,889 patient sera were tested for 15 defined neural autoantibodies (1.2 million tests). The observed and hypothesized frequencies of autoantibody clusters were compared and their tumor associations defined. A tumor validation study comprised serum from 368 patients with a variety of tumors (thymoma, lung, or tonsil). RESULTS: Informative oncological associations included (i) thymoma in 85% of patients with muscle striational, acetylcholine receptor antibodies plus CRMP5 autoantibodies; (ii) lung carcinoma in 80% with both P/Q-type and N-type calcium channel antibodies plus SOX1-IgG; and (iii) in men, prostate carcinoma frequency more than doubled when striational and muscle AChR specificities were accompanied by ganglionic AChR antibody. In women, amphiphysin-IgG alone was associated commonly with breast carcinoma, but amphiphysin-IgG, coexisting with antineuronal nuclear autoantibody-type 1 or CRMP5-IgG, was associated with lung cancer (P < 0.0001). In the validation cohorts, many tumor-associated profiles were encountered that matched the clusters identified in the screening study (e.g., 15% of thymoma patients had striational, acetylcholine receptor antibodies plus collapsin response-mediator protein-5 autoantibodies). CONCLUSIONS: Neural autoantibodies commonly coexist in specific clusters that are identifiable by comprehensive screening. Signature autoantibody clusters may predict a patient's cancer risk and type.

Diagnostic utility of NMO/AQP4-IgG in evaluating CNS inflammatory disease in Thai patients.

Epidemiological studies in Thailand have reported that inflammatory demyelinating diseases (IDDs) commonly affect the optic nerve and spinal cord. We investigated the diagnostic utility of aquaporin (AQP)-4-IgG testing in 31 consecutive patients evaluated for CNS IDDs in 3 academic Thai hospital neurology clinics between February 2008 and January 2009. Patients were classified into 3 clinical diagnostic groups: Neuromyelitis optica (NMO, n=10) multiple sclerosis (MS, n=5) and unclassified IDD (n=16). All sera were tested blindly by cell binding (Euroimmun) assay (CBA). Sera were also tested by indirect immunofluorescence assay (IFA) and ELISA (RSR/Kronus). After initial screening by CBA, AQP4-IgG was detected in 6 NMO patients (60%); 3 of the 4 seronegative cases were receiving immunosuppressants. AQP4-IgG was detected in 13 unclassified IDD cases (81%), but in no MS cases. Cell binding assay and ELISA were more sensitive than IFA (p=0.0004). The 81% seropositivity rate in "unclassified" patients suggests that AQP4 autoimmunity accounts for a significant proportion of Thai CNS inflammatory demyelinating disease, especially those with optic neuritis or transverse myelitis, with or without abnormal brain MRI, in whom a specific diagnosis or clear-cut treatment approach is unclear.