Glioblastoma multiforme (GBM) is the most lethal primary intracranial malignant neoplasm in adults and most resistant to treatment. Integration of gene therapy and chemotherapy, chemovirotherapy, has the potential to improve treatment. We have introduced an intravenous bacteriophage (phage) vector for dual targeting of therapeutic genes to glioblastoma. It is a hybrid AAV/phage, AAVP, designed to deliver a recombinant adeno‐associated virus genome (rAAV) by the capsid of M13 phage. In this vector, dual tumor targeting is first achieved by phage capsid display of the RGD4C ligand that binds the α v β 3 integrin receptor. Second, genes are expressed from a tumor‐activated and temozolomide (TMZ)‐induced promoter of the glucose‐regulated protein, Grp78 . Here, we investigated systemic combination therapy using TMZ and targeted suicide gene therapy by the RGD4C/AAVP‐ Grp78 . Firstly, in vitro we showed that TMZ increases endogenous Grp78 gene expression and boosts transgene expression from the RGD4C/AAVP‐ Grp78 in human GBM cells. Next, RGD4C/AAVP‐ Grp78 targets intracranial tumors in mice following intravenous administration. Finally, combination of TMZ and RGD4C/AAVP‐ Grp78 targeted gene therapy exerts a synergistic effect to suppress growth of orthotopic glioblastoma.

OBJECTIVESThe goal of this study was to characterize the complications and morbidity related to the surgical management of pediatric fourth ventricle tumors.METHODSAll patients referred to the authors’ institution with posterior fossa tumors from 2002 to 2018 inclusive were screened to include only true fourth ventricle tumors. Preoperative imaging and clinical notes were reviewed to extract data on presenting symptoms; surgical episodes, techniques, and adjuncts; tumor histology; and postoperative complications.RESULTSThree hundred fifty-four children with posterior fossa tumors were treated during the study period; of these, 185 tumors were in the fourth ventricle, and 167 fourth ventricle tumors with full data sets were included in this analysis. One hundred patients were male (mean age ± SD, 5.98 ± 4.12 years). The most common presenting symptom was vomiting (63.5%). The most common tumor types, in order, were medulloblastoma (94 cases) > pilocytic astrocytoma (30 cases) > ependymoma (30 cases) > choroid plexus neoplasms (5 cases) > atypical teratoid/rhabdoid tumor (4 cases), with 4 miscellaneous lesions. Of the 67.1% of patients who presented with hydrocephalus, 45.5% had an external ventricular drain inserted (66.7% of these prior to tumor surgery, 56.9% frontal); these patients were more likely to undergo ventriculoperitoneal shunt (VPS) placement at a later date (p = 0.00673). Twenty-two had an endoscopic third ventriculostomy, of whom 8 later underwent VPS placement. Overall, 19.7% of patients had a VPS sited during treatment.Across the whole series, the transvermian approach was more frequent than the telovelar approach (64.1% vs 33.0%); however, the telovelar approach was significantly more common in the latter half of the series (p < 0.001). Gross-total resection was achieved in 70.7%. The most common postoperative deficit was cerebellar mutism syndrome (CMS; 28.7%), followed by new weakness (24.0%), cranial neuropathy (18.0%), and new gait abnormality/ataxia (12.6%). Use of intraoperative ultrasonography significantly reduced the incidence of CMS (p = 0.0365). There was no significant difference in the rate of CMS between telovelar or transvermian approaches (p = 0.745), and multivariate logistic regression modeling did not reveal any statistically significant relationships between CMS and surgical approach.CONCLUSIONSSurgical management of pediatric fourth ventricle tumors continues to evolve, and resection is increasingly performed through the telovelar route. CMS is enduringly the major postoperative complication in this patient population.

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Background COVID-19 has impacted on the amount of formal theoretical and practical surgical teaching available for junior doctors and medical students. This added to an existing climate of variability in the undergraduate and foundation teaching curriculum. Junior doctors were subsequently reporting a lack in confidence when dealing with surgical patients. We aimed to assess the surgical learning needs of junior doctors and designed a quality improvement project that included implementing a surgical teaching programme to improve the quality of surgical education. Methods A baseline questionnaire was completed by foundation year one doctors to establish confidence levels in managing surgical patients and carrying out practical procedures. Two sequential improvement strategies were subsequently implemented and assessed using the Plan-Do-Study-Act methodology. Junior doctors participated in a local surgical workshop in limited numbers during cycle 1, and then attended four online webinar tutorials themed around general surgery for cycle 2. Results A total of 15 participants responded to the baseline questionnaire, 13 attended the workshop and a combined total of 572 viewed the four webinars. Mean confidence increase following the workshop was 113% (W = 91.0, p &lt; 0.001). Mean knowledge increase from the online webinars was 62.3% (t = 4.67, p = 0.009) and mean confidence increase was 66.67% (p &lt; 0.0001). Conclusion Junior doctors did not feel confident in assessing and managing surgically unwell patients. Implementing blended learning tools, such as online webinars, allowed the delivery of effective surgical teaching en masse and to continue the practice of social distancing during a viral pandemic.

Introduction: The recently updated FDA label for intravenous recombinant tissue plasminogen activator (IV-tPA) for stroke removed a history of intracranial hemorrhage (ICH) as a contraindication. The safety of IV-tPA in patients with prior ICH is not well-established, as only a few cases are described in the literature. We sought to determine (1) the proportion of patients treated with IV-tPA for stroke who have prior history of ICH and (2) whether this circumstance influences in-hospital mortality. Methods: Using administrative claims data on admissions to California hospitals between 2005-2011, we performed a cross-sectional study of adult patients admitted with acute ischemic stroke who received IV-tPA. ICD-9-CM codes were used to identify these patients and to ascertain prior diagnoses of (1) ICH, including intracerebral hemorrhage (IPH), subarachnoid hemorrhage (SAH), subdural hematoma (SDH), or epidural hematoma (EDH); and (2) existing comorbidities. We used multivariable logistic regression to model the odds of in-hospital mortality as a function of prior ICH, after adjusting for potential confounders. Results: Among 372,167 patients admitted with acute ischemic stroke during the study period, 10,882 (2.9%) received IV-tPA (mean age 70.6 [SD 14.6], female 5,614 [54.8%]). Among these, 268 (2.5%) patients had a diagnosis of prior ICH on admission, including IPH 194 (1.8%), SAH 81 (0.7%), SDH 9 (0.1%) and EDH 2 (0.0%). In-hospital mortality was 12.2% overall, 11.7% for patients without prior ICH, and 31.0% for patients with prior ICH (p<0.001). In adjusted analyses, prior ICH remained independently associated with in-hospital mortality (OR 3.48, 95% CI 2.63-4.56, p<0.001), as did most ICH subtypes, including IPH (OR 2.97, CI 2.12-4.09, P<0.001), SAH (OR 3.15, CI 1.89-5.12, P<0.001), and SDH (OR 4.27, CI 0.87-16.95, P=0.047). Conclusions: In California between 2005-2011, 2.5% of acute ischemic stroke patients who received thrombolysis had a prior diagnosis of ICH. In this population, a history of ICH was associated with mortality; this association held true for ICH subtypes IPH, SAH and SDH. Further observational and experimental studies are needed to confirm the observed associations.