Sean P. Polster

Unlocking the promise of oncolytic virotherapy in glioma: combination with chemotherapy to enhance efficacy

Malignant glioma is a relentless burden to both patients and clinicians, and calls for innovation to overcome the limitations in current management. Glioma therapy using viruses has been investigated to accentuate the nature of a virus, killing a host tumor cell during its replication. As virus mediated approaches progress with promising therapeutic advantages, combination therapy with chemotherapy and oncolytic viruses has emerged as a more synergistic and possibly efficacious therapy. Here, we will review malignant glioma as well as prior experience with oncolytic viruses, chemotherapy and combination of the two, examining how the combination can be optimized in the future.

Plasma Biomarkers of Inflammation Reflect Seizures and Hemorrhagic Activity of Cerebral Cavernous Malformations

The clinical course of cerebral cavernous malformations (CCMs) is highly variable. Based on recent discoveries implicating angiogenic and inflammatory mechanisms, we hypothesized that serum biomarkers might reflect chronic or acute disease activity. This single-site prospective observational cohort study included 85 CCM patients, in whom 24 a priori chosen plasma biomarkers were quantified and analyzed in relation to established clinical and imaging parameters of disease categorization and severity. We subsequently validated the positive correlations in longitudinal follow-up of 49 subjects. Plasma levels of matrix metalloproteinase-2 and intercellular adhesion molecule 1 were significantly higher (Pxa0=xa00.02 and Pxa0=xa00.04, respectively, FDR corrected), and matrix metalloproteinase-9 was lower (Pxa0=xa00.04, FDR corrected) in patients with seizure activity at any time in the past. Vascular endothelial growth factor and endoglin (both Pxa0=xa00.04, FDR corrected) plasma levels were lower in patients who had suffered a symptomatic bleed in the prior 3xa0months. The hierarchical clustering analysis revealed a cluster of four plasma inflammatory cytokines (interleukin 2, interferon gamma, tumor necrosis factor alpha, and interleukin 1 beta) separating patients into what we designated “high” and “low” inflammatory states. The “high” inflammatory state was associated with seizure activity (Pxa0=xa00.02) and more than one hemorrhagic event during a patient’s lifetime (Pxa0=xa00.04) and with a higher rate of new hemorrhage, lesion growth, or new lesion formation (Pxa0<xa00.05) during prospective follow-up. Peripheral plasma biomarkers reflect seizure and recent hemorrhagic activity in CCM patients. In addition, four clustered inflammatory biomarkers correlate with cumulative disease aggressiveness and predict future clinical activity.

Convection-Enhanced Delivery of Polymeric Nanoparticles Encapsulating Chemotherapy in Canines with Spontaneous Supratentorial Tumors

BACKGROUNDnDespite aggressive multimodal treatment, survival for patients with glioblastoma remains dismal. One obstacle to improving patient outcomes is the difficulty in delivering adequate therapeutic to the central nervous system due to the presence of the blood-brain barrier. Although direct drug infusion by convection-enhanced delivery (CED) can bypass the blood-brain barrier and facilitate delivery to intracranial tumors, determining the distribution of delivered therapeutic remains problematic. Image guidance is a strategy that can optimize the accuracy of therapeutic delivery.nnnMETHODSnHere we performed an open-label clinical trial in 10 pet dogs with spontaneous intracranial tumors to examine the target coverage accuracy of delivering polymeric magnetite nanoparticles (PMNPs) encapsulating temozolomide (TMZ). A modified small animal frame was applied to the head of each subject, and PMNPs were delivered stereotactically to the center of the tumor. Magnetic resonance imaging (MRI) was performed immediately postoperatively to examine PMNP distribution, and the animals were followed until death.nnnRESULTSnNine of the 10 dogs underwent PMNP infusion without complications. No infusate backflow was observed during any procedure. In 70% of the cases, the infusion accurately targeted the tumor mass, as determined by the presence of PMNP signal in the tumor on immediate postoperative MRI.nnnCONCLUSIONSnThese data suggest that CED of PMNPs carrying TMZ is safe in dogs with intracranial tumors and can lead to nanoparticle distribution in the region of the target. Image guidance is an important adjunct to CED, because distribution is unpredictable, with the potential for missed target delivery.

The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation

Epithelial barrier maintenance and regulation requires an intact perijunctional actomyosin ring underneath the cell‐cell junctions. By searching for known factors affecting the actin cytoskeleton, we identified Krev interaction trapped protein 1 (KRIT1) as a major regulator for epithelial barrier function through multiple mechanisms. KRIT1 is expressed in both small intestinal and colonic epithelium, and KRIT1 knockdown in differentiated Caco‐2 intestinal epithelium decreases epithelial barrier function and increases cation selectivity. KRIT1 knockdown abolished Rho‐associated protein kinase‐induced and myosin II motor inhibitor–induced barrier loss by limiting both small and large molecule permeability but did not affect myosin light chain kinase–induced increases in epithelial barrier function. These data suggest that KRIT1 participates in Rho‐associated protein kinase‐ and myosin II motor–dependent (but not myosin light chain kinase–dependent) epithelial barrier regulation. KRIT1 knockdown exacerbated low‐dose TNF‐induced barrier loss, along with increased cleaved casρase‐3 production. Both events are blocked by pan‐caspase inhibition, indicating that KRIT1 regulates TNF‐induced barrier loss through limiting epithelial apoptosis. These data indicate that KRIT1 controls epithelial barrier maintenance and regulation through multiple pathways, suggesting that KRIT1 mutation in cerebral cavernous malformation disease may alter epithelial function and affect human health.—Wang, Y., Li, Y., Zou, J., Polster, S. P., Lightle, R., Moore, T., Dimaano, M., He, T.‐C., Weber, C. R., Awad, I. A., Shen, L. The cerebral cavernous malformation disease causing gene KRITl participates in intestinal epithelial barrier maintenance and regulation. FASEB J. 33, 2132–2143 (2019). www.fasebj.org

A Report of 2 Cases of Brainstem Hemorrhage After Suboccipital Craniectomy for Chiari Decompression

BACKGROUND AND IMPORTANCEnDecompression surgery for Chiari malformation is known to have very low procedure-related complications. There has been no report of post-Chiari malformation decompression surgery development of brainstem hemorrhage. We report 2 post-Chiari decompression surgery brainstem hemorrhage cases with 2-yr follow-up.nnnCLINICAL PRESENTATIONnTwo cases were reviewed in which patients underwent uncomplicated suboccipital craniectomy with expansive autologous pericranium duraplasty for Chiari decompression. Postoperatively, both patients awoke with hemibody sensory and motor deficits. Immediate postoperative magnetic resonance imaging revealed a small hemorrhage within the dorsal medulla in both cases. Follow-up imaging shows resolution along with near complete clinical recovery of deficits.nnnCONCLUSIONnThese cases demonstrate a rare postdecompression surgery-related complication in Chiari malformation. We hypothesize that these hemorrhages may occur from the rapid drainage of cerebrospinal fluid resulting in a loss of positive pressure, allowing a low-pressure hemorrhage to occur. Given that these hemorrhages are of low pressure, recovery is excellent.

Trial Readiness in Cavernous Angiomas With Symptomatic Hemorrhage (CASH)

BACKGROUNDnBrain cavernous angiomas with symptomatic hemorrhage (CASH) are uncommon but exact a heavy burden of neurological disability from recurrent bleeding, for which there is no proven therapy. Candidate drugs to stabilize the CASH lesion and prevent rebleeding will ultimately require testing of safety and efficacy in multisite clinical trials. Much progress has been made in understanding the epidemiology of CASH, and novel biomarkers have been linked to the biological mechanisms and clinical activity in lesions. Yet, the ability to enroll and risk-stratify CASH subjects has never been assessed prospectively at multiple sites. Biomarkers and other outcomes have not been evaluated for their sensitivity and reliability, nor have they been harmonized across sites.nnnOBJECTIVEnTo address knowledge gaps and establish a research network as infrastructure for future clinical trials, through the Trial Readiness grant mechanism, funded by National Institute of Neurological Disorders and Stroke/National Institutes of Health.nnnMETHODSnThis project includes an observational cohort study to assess (1) the feasibility of screening, enrollment rates, baseline disease categorization, and follow-up of CASH using common data elements at multiple sites, (2) the reliability of imaging biomarkers including quantitative susceptibility mapping and permeability measures that have been shown to correlate with lesion activity, and (3) the rates of recurrent hemorrhage and change in functional status and biomarker measurements during prospective follow-up.nnnEXPECTED OUTCOMESnWe propose a harmonized multisite assessment of enrollment rates of CASH, baseline features relevant to stratification in clinical trials, and follow-up assessments of functional outcomes in relation to clinical bleeds. We introduce novel biomarkers of vascular leak and hemorrhage, with firm mechanistic foundations, which have been linked to clinical disease activity. We shall test their reliability and validity at multiple sites, and assess their changes over time, with and without clinical rebleeds, hence their fitness as outcome instruments in clinical trials.nnnDISCUSSIONnThe timing cannot be more opportune, with therapeutic targets identified, exceptional collaboration among researchers and the patient community, along with several drugs ready to benefit from development of a path to clinical testing using this network in the next 5 years.

Phenotypic characterization of murine models of cerebral cavernous malformations

Cerebral cavernous malformations (CCMs) are clusters of dilated capillaries that affect around 0.5% of the population. CCMs exist in two forms, sporadic and familial. Mutations in three documented genes, KRIT1(CCM1), CCM2, and PDCD10(CCM3), cause the autosomal dominant form of the disease, and somatic mutations in these same genes underlie lesion development in the brain. Murine models with constitutive or induced loss of respective genes have been applied to study disease pathobiology and therapeutic manipulations. We aimed to analyze the phenotypic characteristic of two main groups of models, the chronic heterozygous models with sensitizers promoting genetic instability, and the acute neonatal induced homozygous knockout model. Acute model mice harbored a higher lesion burden than chronic models, more localized in the hindbrain, and largely lacking iron deposition and inflammatory cell infiltrate. The chronic model mice showed a lower lesion burden localized throughout the brain, with significantly greater perilesional iron deposition, immune B- and T-cell infiltration, and less frequent junctional protein immunopositive endothelial cells. Lesional endothelial cells in both models expressed similar phosphorylated myosin light chain immunopositivity indicating Rho-associated protein kinase activity. These data suggest that acute models are better suited to study the initial formation of the lesion, while the chronic models better reflect lesion maturation, hemorrhage, and inflammatory response, relevant pathobiologic features of the human disease.Cerebral cavernous malformations (CCMs) are clusters of dilated capillaries affecting around 0.5% of the population. The authors analyzed the phenotypic characteristics of chronic and acute murine models of CCM. The acute model harbored higher lesion burden while the chronic model showed more inflammation and lesional iron deposition.

Plasma Biomarkers of Inflammation and Angiogenesis Predict Cerebral Cavernous Malformation Symptomatic Hemorrhage or Lesional Growth

Rationale: The clinical course of cerebral cavernous malformations is highly unpredictable, with few cross-sectional studies correlating proinflammatory genotypes and plasma biomarkers with prior disease severity. Objective: We hypothesize that a panel of 24 candidate plasma biomarkers, with a reported role in the physiopathology of cerebral cavernous malformations, may predict subsequent clinically relevant disease activity. Methods and Results: Plasma biomarkers were assessed in nonfasting peripheral venous blood collected from consecutive cerebral cavernous malformation subjects followed for 1 year after initial sample collection. A first cohort (N=49) was used to define the best model of biomarker level combinations to predict a subsequent symptomatic lesional hemorrhagic expansion within a year after the blood sample. We generated the receiver operating characteristic curves and area under the curve for each biomarker individually and each weighted linear combination of relevant biomarkers. The best model to predict lesional activity was selected as that minimizing the Akaike information criterion. In this cohort, 11 subjects experienced symptomatic lesional hemorrhagic expansion (5 bleeds and 10 lesional growths) within a year after the blood draw. Subjects had lower soluble CD14 (cluster of differentiation 14; P=0.05), IL (interleukin)-6 (P=0.04), and VEGF (vascular endothelial growth factor; P=0.0003) levels along with higher plasma levels of IL-1&bgr; (P=0.008) and soluble ROBO4 (roundabout guidance receptor 4; P=0.03). Among the 31 weighted linear combinations of these 5 biomarkers, the best model (with the lowest Akaike information criterion value, 25.3) was the weighted linear combination including soluble CD14, IL-1&bgr;, VEGF, and soluble ROBO4, predicting a symptomatic hemorrhagic expansion with a sensitivity of 86% and specificity of 88% (area under the curve, 0.90; P<0.0001). We then validated our best model in the second sequential independent cohort (N=28). Conclusions: This is the first study reporting a predictive association between plasma biomarkers and subsequent cerebral cavernous malformation disease clinical activity. This may be applied in clinical prognostication and stratification of cases in clinical trials.

Patients with cranial dural arteriovenous fistulas may benefit from expanded hypercoagulability and cancer screening

OBJECTIVEnCranial dural arteriovenous fistulas (DAVFs) have been associated with dural sinus occlusion, and previous reports have suggested the association of hypercoagulability with some cases. But the prevalence of a hypercoagulable state has not been systematically analyzed in conjunction with laboratory markers and clinical manifestations, including history of thromboembolism or systemic malignancy. The authors hypothesize that laboratory or clinical evidence of a hypercoagulable state, including cancer, is commonly identifiable in consecutively identified patients with DAVFs, with implications for clinical management.nnnMETHODSnThe retrospective cohort study included all patients older than 17 years with cranial DAVFs diagnosed at University of Chicago Medicine during a 6-year period, whose medical records and imaging results were reviewed for objective laboratory or clinical evidence of a hypercoagulable state, including malignancy. Each case was analyzed for implications on clinical management. Data were analyzed in relation to a systematic review of the literature on this association.nnnRESULTSnFifteen (88%) of 17 cases of DAVFs had laboratory (n = 8) or clinical evidence of a hypercoagulable state (thromboembolism [n = 8] or cancer [n = 6]). This hypercoagulability or cancer impacted clinical care in all 15 cases.nnnCONCLUSIONSnAn underlying hypercoagulable state manifested by laboratory testing or clinically, including cancer, is staggeringly common. It is important to recognize this association, along with its impact on the management of the DAVFs and systemic diseases.