Scholarly Activity

Background: We determined the efficacy, safety, and tolerability of ND0612, an investigational, continuous 24-hours/day subcutaneous infusion of levodopa/carbidopa (LD/CD), versus oral immediate-release (IR) LD/CD in people with Parkinson’s disease (PwP) experiencing motor fluctuations.

Methods: This is a phase 3, double-blind, double-dummy (DBDD) trial (NCT04006210). PwP on ≥4 oral LD/CD doses/day (≥400mg/day LD) and experiencing ≥2.5h of daily OFF-time underwent 4-6 weeks of open-label IR-LD/CD dose adjustment followed by 4-6 weeks of open-label ND0612 conversion (+ IR-LD/CD as needed). Patients were randomized (1:1) to 12-week DBDD treatment with either their optimized ND0612 or IR-LD/CD regimens.

Results: In the open-label adjustment/conversion phases, mean ON-time without troublesome dyskinesia (OTwoTD) increased from 9.4h (both arms) at enrollment to 11.8h (ND0612) and 12.1h (IR-LD/CD) following optimization of the ND0612 regimen. During the 12-week DBDD treatment OTwoTD was maintained in the ND0612 group (11.5h at endpoint) but decreased in the IR-LD/CD group who had their ND0612 infusion withdrawn (9.8h at endpoint). The study met its primary endpoint, with the ND0612 regimen providing an additional 1.72h [95%CI: 1.08h, 2.36h] of OTwoTD compared with IR-LD/CD (p<0.0001). Significant treatment effects (TE) vs. IR-LD/CD were also seen in the hierarchical secondary endpoints: OFF-time (TE: -1.40 [-1.99, -0.80]h, p<0.0001), MDS-UPDRS Part II (TE: -3.05 [-4.28, -1.81], p<0.0001) and global impressions by patients (Odds ratio [OR] of improvement: 5.31 [2.67, 10.58], p<0.0001) and clinicians (OR: 7.23 [3.57, 14.64], p<0.0001). Infusion site reactions were the most reported adverse events (82.6% during open-label conversion to infusion, during the DBDD period the rates were 57.0% for ND0612 vs. 42.7% for IR-LD/CD). Discontinuation rates after randomization (DBDD phase; ND0612 vs IR-LD/CD) were 6.3% vs 6.1% overall, and 5.5% vs 3.1% due to adverse events.

Conclusions: ND0612 treatment led to clinically meaningful improvement in motor fluctuations and functional endpoints vs oral IR-LD/CD and was generally well tolerated.

Introduction: Salmonella subdural empyema is a rare but serious infection that impacts the brain and adjacent tissues. The condition develops when Salmonella bacterium spread from an infected site to the subdural space. Contaminated animal-derived food products, such as poultry and eggs, are a potential source of nontyphoidal Salmonella infection in humans. Timely detection and immediate treatment are critical to manage this disease and avoiding severe complications. Nevertheless, its rarity and non-specific symptoms make it challenging to diagnose. Description: An 83-year-old female with a history of lung cancer status post resection, hypertension, hyperlipidemia, and hypothyroidism, presented to the ER febrile with altered mentation, following a low impact fall sustained two weeks before her acute decline. On admission, the patient was aphasic and had RUE weakness. CT head showed acute on chronic subdural hematomas overlying the left and right cerebral convexities measuring 2 cm and 0.8 cm in thickness respectively, with associated mass effect on the left cerebral hemisphere with extensive sulcal effacement. The patient was admitted to the NICU, with plans for urgent neurosurgical hematoma evacuation later undergoing left frontal burr hole evacuation of subdural hematoma and insertion of a drain. Work-up revealed UA concerning for UTI and pulmonary infiltrate on CXR prompting initiation of empiric antibiotics. Surgical hematoma evacuation revealed a foul-smelling fluid with intra-operative cultures sent, later growing non-typhoidal Salmonella Enterica serotype Dublin. Patient was retaken to OR for reaccumulating left subdural hematoma and empyema, later medically stabilized and discharged after a 12-day admission. Discussion: The prevalence of Salmonella enterica, serotype Dublin has increased over the past few years in the US and been detected in animal products. This case presents a rare instance of subdural empyema with Salmonella Enterica and the only reported case with the serotype Dublin, presenting as a subdural hematoma in an adult.

BACKGROUND: Most adults with ependymoma undergo tumor resection at the time of diagnosis, which may be followed by radiation. At recurrence, re-resection and/or (re)-irradiation may be given, however, there are few established chemotherapy treatments. A previous retrospective report of 8 patients treated with carboplatin and bevacizumab showed a high response rate with 6 patients demonstrating an imaging response (Green, Neurology 2009). We sought to further investigate this regimen with a prospective trial. MATERIAL AND METHODS: We performed a prospective phase 2 study in the CERN Adult Clinical Trials Network. Adult patients with recurrent or progressive ependymoma were enrolled to receive carboplatin (AUC =4-5) every 4 weeks for up to 6 cycles and bevacizumab at 10mg/kg every 2 weeks for one year, with the option to continue until progression or toxicity. The primary endpoint was 12-month PFS rate and >50% defined efficacy. Serial symptom burden measurement at baseline and at the time of disease evaluation using MD Anderson Symptom Inventory-brain tumor (MDASI-BT) or MDASI-Spine patient-reported outcomes (PROs) were used to evaluate the clinical impact of PFS. RESULTS: A total of 22 patients with median age of 45 years were accrued and treated; 11 were women. WHO grade was 3 in 13 patients and grade 2 in 9 patients (3 with myxopapillary ependymoma) Ten patients had only spinal cord disease, 3 had both spinal cord and brain involvement and 9 patients had brain involvement alone (6 supratentorial, 3 infratentorial). Previous treatments included radiotherapy in all 22 patients and alkylating chemotherapy in 9 patients. Treatment was well tolerated with expected myelotoxicities and hypertension. The Kaplan-Meier calculated 12-Month PFS rate was 76.4% (95%CI 52.2%, 89.4%), median PFS = 18 months (95%CI 12.2, +∞). There were 2 partial responses (9.1%). Brain tumor responders (objective response or stable disease) showed reduction while non-responders had an increase in both neurologic and cognitive symptoms but similar report of other symptoms. Spine tumor responders and non-responders both showed worsening disease-related symptoms; autonomic symptoms worsened in responders. Activity related interference worsened for all patients. CONCLUSION: This treatment regimen was safe and met the primary efficacy endpoint of 12-month PFS rate. The improvement in disease-related symptoms in brain tumor patients supports that the achieved disease stability was clinically meaningful, but the increased activity-related interference suggests that treatment-associated symptoms may impact work, general activity, and walking ability during treatment. Improvements in spine tumor disease-associated symptoms were not seen. A confirmatory trial is warranted to further investigate the findings and to determine if there are differences in response amongst ependymoma subtypes and tumor location.

BACKGROUND: GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. GBM AGILE is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed (ND) and recurrent GBM. METHODS: The primary objective of GBM AGILE is to identify therapies that effectively improve the overall survival in patients with ND or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. New experimental therapies are added as information about promising new drugs is identified, while therapies are removed as they complete their evaluation. GBM AGILE has screened over 1400 patients and enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/site/month. There are 41 active sites in the US, 4 active sites in Canada and 3 active sites in Europe with a total of 15 sites planned for Switzerland, France and Germany. Expansion to Australia is currently underway. GBM AGILE operates under a Master Protocol which allows multiple drugs from different pharmaceutical/ biotech companies to be evaluated simultaneously and/or over time against a common control. Along with an adaptive trial design, shared control arm and operational processes to serve the goal of helping patients receive optimal care in a fast and efficient manner, GBM AGILE incorporates new design and operational elements to enhance efficiencies, including more recently dose finding and enhanced safety management components. The dose finding phase allows for an initial evaluation of the experimental study drug in combination with radiotherapy and temozolomide, and/or lomustine in a limited number of patients at a select number of study sites within the trial in order to ensure that there are no critical safety signals before expansion to a larger subset of patients for enhanced safety monitoring followed by broader inclusion of the combination at all global study sites. The investigational drugs that have employed the dose finding phase and enhanced safety monitoring process have tolerable safety profile with toxicities that are monitorable, reversible, and not related to the control arm treatments. Through the use of improved and flexible processes, GBM AGILE continues to serve as a global trial that supports the efficient and rapid incorporation and evaluation of new experimental therapies for patients with GBM.

Objectives: Chromobox protein homolog 7 (CBX7), a member of the Polycomb repressor complex, is a potent epigenetic regulator and gene silencer. Our group previously reported that CBX7 functions as a tumor suppressor in ovarian cancer cells, and its loss accelerated the formation of carcinomatosis and drove tumor progression in an ovarian cancer mouse model. The goal of this study was to identify specific signaling pathways in the ovarian tumor microenvironment that can downregulate CBX7. Adipocytes are an integral component of the peritoneal cavity and the ovarian tumor microenvironment. Given its known pro-tumor functions, we hypothesized that the adipose microenvironment might be a main regulator of CBX7 expression. We report the characterization of exosomes derived from adiposities that regulate OC cell differentiation by releasing mir-421, a major regulator of CBX7 expression. Methods: Normal omentum was collected from female patients undergoing surgery for either benign or malignant conditions (age range: 30–80), and adipose-conditioned media (ACM) were obtained from these organ cultures. Human ovarian cancer cells used in this study include ATCC ovarian cancer (A2780, OVCA432, OVCAR3) and in-house cell lines (R182). Exosomes were isolated by serial centrifugation. Size and granularity were characterized using Nanosight, and cellular origin was determined using Exoview. mRNA and protein levels were determined by qPCR and western blot, respectively. Transfections were performed using a Lipofectamine transfection reagent. Results: Exosomes isolated from ACM decrease CBX7 protein levels without affecting its mRNA. These exosomes were characterized by higher expression of CD36 (adipocyte marker) compared to CD11b (macrophage marker) and showed a characteristic pattern of higher granularity suggesting a more complex cargo. Furthermore, they showed high levels of mir-421. Pre-treatment of ovarian cancer cells with the endocytosis inhibitor, nystatin, before culturing with ACM or exosomes, abolished the effect on CBX7. Furthermore, treatment of OC cells with anti-mir-421, but not control anti-mir, prior to the addition of adipose-derived exosomes abolished the effect on CBX7 expression. The direct binding of mir-421 to CBX7 3’ UTR was demonstrated by a significant decrease in luciferase activity when CBX7 3’ UTR plasmid was co-transfected with mir-421 (P = 0.0005, compared to control miRNA). Conclusions: We identified adipose-derived exosomal mir-421 as a specific signaling pathway in the ovarian tumor microenvironment that can downregulate CBX7 and induce an epigenetic change in ovarian cancer cells, which can drive disease progression. These findings open new venues to determine the value of targeting mir-421 to curtail ovarian cancer progression.

Background & Purpose Critics of brain death allege that up to 50% of brain dead (BD) patients have residual brain function based on the absence of central diabetes insipidus (Dl), which suggests remaining hypothalamic/pituitary function. We hypothesized that different degrees of renal dysfunction may impact the presence of Dl in BD patients. Methods All adult patients declared BD over 12 years at Henry Ford Hospital were evaluated. Dl was diagnosed by polyuria (>300 ml urine output for 2 or more consecutive hours), low urine specific gravity (< 1.005) and increasing serum sodium. Renal function was assessed by the estimated glomerular filtration rate (eGFR), calculated using the simplified Modification of Diet in Renal Disease (sMDRD) equation (validated for ages > 18). 192/266 BD patients were included in the analysis after excluding those with missing data, < 18-years-old or on vasopressin infusions (for hypotension). 122 (63.5%) developed Dl. The proportion with Dl decreased significantly with decreasing eGFR: for eGFR > 60ml/min, Dl was present in 77.2%; for eGFR 15-60ml/min in 54.5%, and for eGFR < 15ml/min in 32% (p < 0.001). There were 14 patients with eGFR <9.7 ml/min (all with serum creatinine > 7.1 mg/dL); none experienced Dl. Using logistic regression, for every 10 ml/min increase in eGFR the odds of Dl increased by 1.2 times (95% CI: 1.10 to 1.32, p < 0.001) Conclusion Presence of hypothalamic/pituitary function (based on the absence of Dl) is less common than previously thought in BD patients, as kidney dysfunction significantly impacts Dl development. Dl is observed less frequently in BD patients who have renal injury, and some patients with severe renal dysfunction never develop Dl. Renal dysfunction should be accounted for when considering the presence or absence of Dl in brain death.

Introduction: The BouNDless study (NCT04006210) compared the efficacy, safety, and tolerability of subcutaneous levodopa/carbidopa (LD/CD) as an investigational ND0612 24-hour infusion versus oral immediate-release (IR)-LD/CD in patients with Parkinson's disease (PwP) experiencing motor fluctuations. Here we report patient enrollment characteristics; primary results will be available in 2023. Methods: Following screening, PwP on ≥4 doses/day of oral LD/dopa-decarboxylase inhibitor (LD ≥400mg/day) and experiencing ≥2.5h daily OFF-time were consented and enrolled. They entered a 4-6 week open-label adjustment period during which oral LD formulations and COMT inhibitor doses were converted to equivalent doses of IR-LD/CD and then adjusted to optimal clinical effect. Patients then entered an 4-6 week open-label ND0612 conversion period in which IR-LD/CD was replaced by ND0612 (LD/CD dose up to 720/90mg/day) with adjunct IR-LD/CD, as required, and adjusted until this combination regimen was optimal. Patients then entered a 12-week, double-blind, double-dummy period, during which they were randomized (1:1) either to their optimized regimen of ND0612 infusion (plus IR-LD/CD), or to the optimized IR-LD/CD-only regimen. Results: Enrollment characteristics of randomized patients (N=259) were similar to other clinical trials in PwP experiencing motor fluctuations refractory (mean±SD age: 63.5±9.0y; 63.7% male; diagnosed 9.6±4.3y; motor fluctuations 4.5±3.3y, mean OFF time 6.1±1.7h). Levodopa equivalent daily doses at enrollment were 1029mg; 86% patient were receiving adjunct Parkinson's medications, mainly dopamine agonists (63%). Conclusions: Enrollment characteristics of patients randomized in the BouNDless trial are consistent with those observed in other clinical studies in PwP experiencing motor fluctuations.

Objectives: Opicapone is an oral, once-daily, selective catechol-O-methyltransferase (COMT) inhibitor, approved as an adjunctive treatment to levodopa/carbidopa (LD/CD) in patients with Parkinson’s disease (PD) experiencing “OFF” episodes. OPTI-ON (OPicapone Treatment Initiation OpeN-Label Study) was a “real-world” study of opicapone use in the US that evaluated the characteristics, treatment patterns, and safety/tolerability of patients initiating opicapone treatment.

Methods: OPTI-ON was a 6-month, prospective, single-arm, multicenter, observational, longitudinal study that included patients with PD experiencing “OFF” episodes who were newly prescribed opicapone adjunctive to LD/CD. Patient-reported outcomes including the Patient Global Impression of Severity in the “OFF” state (PGI-S OFF), Patient Global Impression of Change (PGI-C), Non-Motor Fluctuations PGI-S (NMFs PGI-S), and Medication Satisfaction Questionnaire (MSQ) were obtained at baseline and throughout follow-up.

Results: Overall, 164 participants completed the study. On the PGI-S OFF, more participants rated their “OFF”-time symptom severity as “none” or “very mild” at 6 months versus baseline (20.4% vs. 10.3%). Fewer rated their “OFF”-time as “moderately severe” to “extremely severe” at 6 months versus baseline (17.3% vs. 26.5%). For the PGI-C, 23.5% of patients were “much improved” or “very much improved” at 6 months. On the NMFs PGI-S, fewer participants self-rated themselves as “markedly affected” to “most extremely affected” with non-motor fluctuations at 6 months versus baseline (3.2% vs. 11.9%). On the MSQ, 42.3% of participants were “very satisfied” or “extremely satisfied” with opicapone at 6 months; in contrast, only 14.1% were very or extremely satisfied with their LD/CD-only regimen at baseline.

Conclusions: Results from the OPTI-ON study, along with the efficacy demonstrated in Phase 3 studies, demonstrated that once-daily opicapone may improve the quality of “OFF”-time, more effectively manage motor and non-motor fluctuations, and increase patients’ satisfaction with their PD treatment regimen.

Background: Multiple sclerosis (MS) is one of the most common inflammatory and neurodegenerative diseases in young adults leading to a build-up of neurological defects with an irreversible disability. Unresolved inflammation represents the pathological hallmark of MS and several other autoimmune diseases, however current therapeutic options fail to adequately suppress the ongoing inflammation, resulting in inflammatory attacks that gradually increase in severity. Studies suggest that the endogenous mechanisms to resolve inflammation are intact but become defective in patients which result in deficiency of downstream metabolites, pro-resolving lipid mediators, leading to unresolved inflammation and a delay in the healing/repair process, thus resulting in disease progression and continued neuronal damage. Objectives: Docosahexaenoic acid (DHA) metabolism being defective in MS, we hypothesize that supplementation of downstream metabolite of DHA, maresin 1 (MaR1) will resolve inflammation and demyelination in preclinical animal model of MS, experimental allergic encephalomyelitis (EAE). Methods: We performed a comparative metabolite profiling using targeted metabolipidomics in serum samples from 29 relapsing-remitting (RRMS) patients and 29 age and gendermatched healthy controls (HC). For therapeutic effect of MaR1, we induced EAE in SJL mice, followed by intraperitoneal treatment with 300ng of MaR1 from day1 post-disease induction. We evaluated the effect on disease severity and inflammation by monitoring disease course of EAE, recall response by ELISA, cytokine expression analysis by qPCR and western blotting, and immune profiling by flow cytometry. Also, the neuroprotective effect of MaR1 through myelination was assessed by single molecule array (SIMOA) assay and histopathology. Statistical analysis was done using Graph-Pad Prism. Results: Metabolite profiling revealed significant imbalance (p<0.05) between inflammatory response and resolution process in MS, confirming the metabolic dysfunction of lipid mediators including MaR1. Restoration of MaR1 prevented disease progression and reduced disease severity in EAE by inhibiting the infiltration of immune cells (CD4+IL17+ and CD4+FNγ+) in CNS as shown by intracellular staining (P<0.001). Recall response showed that MaR1 significantly inhibited pro-inflammatory cytokine IL17 (P<0.01) and promoted IL10 and IL4 production (P<0.001). Also, MaR1 exerted neuroprotective effects as we found lower levels of NFL (P<0.01) in the serum of treated mice compared to untreated which was further confirmed by higher expression of MBP in brain from MaR1 treated group. Conclusions: Overall, our targeted metabolipidomics in MS patients identified MaR1 deficiency, whose supplementation exerts anti-inflammatory and neuroprotective effects in preclinical animal model, suggesting MaR1 could be a new therapeutic molecule in MS.

Background and aims: Randomized trials proved the benefits of mechanical thrombectomy (MT) for select patients with large vessel occlusion (LVO) within 24-hours of last-known-well (LKW). Recent data suggest that LVO patients may benefit from MT beyond 24-hours. This study reports the safety and outcomes of MT beyond 24-hours of LKW compared to standard medical therapy (SMT). Methods: This is a retrospective analysis of LVO patients presented to eleven comprehensive stroke centers in the US beyond 24-hours from LKW between 01/2015-12/2021.We assessed 90-days outcomes using the modified Rankin Scale (mRS). Results: Of 334 patients presented with LVO beyond 24-hours, 64% received MT and 36% received SMT only. Patients who received MT were older (66±15 vs. 62±55 years, p= 0.047) and had a higher baseline NIHSS (16±7 vs.10±9, p=<0.001). Successful recanalization (TICI 2b-3) was achieved in 83%, and 5.6% had symptomatic ICH compared to 2.5% in the SMT group (p=0.19). MT was associated with mRS (0-2) at 90-days (aOR 5.73, p=0.02), less mortality 34 vs. 63% (p<0.001), and better discharge NIHSS (p=0.001) compared to SMT in patients with baseline NIHSS≥6. This treatment benefit remained after matching both groups. Age (aOR 0.94, p<0.001), baseline NIHSS (aOR 0.91, p 0.01), ASPECTS score ≥8 (aOR 3.06, p=0.04) and collaterals scores aOR (1.41, p=0.027) were associated with 90-day functional independence. Conclusions: MT for LVO beyond 24-hours appears to improve outcomes compared to SMT, especially in patients with severe strokes. Patients' age, ASPECTS, collaterals, and baseline NIHSS score should be considered before discounting MT merely based on LKW.