OBJECTIVES: The worldwide elderly population is steadily increasing. It has been recommended that age-appropriate information should be available for older patients, but little exists in neurosurgery. We aim to better understand the clinical characteristics, bed occupancy and outcomes of elderly patients admitted to a UK neurosurgical unit. METHODS: Retrospective review of medical records of all patients aged 75 years and older admitted for at least 1 night to the Southwest Neurosurgery Centre from 2007 to 2010. Mortality data up to 31 December 2012 were obtained from a national registry. RESULTS: Eight hundred and eighty-six elderly patients were admitted, for whom 877 records were available. Three hundred and eighty-nine patients were admitted electively; 488 were emergency or urgent; 48.8% had cranial pathology and 50.7% had spinal disease. Emergency cases were significantly older and more likely to be male than elective patients. The median length of stay for emergency patients was significantly longer than that of elective patients (P < 0.0001, 3 vs. 8 days). One elective patient died as an inpatient, compared with 46 emergency patients. Of emergency and elective patients, 25.6% and 3.6%, respectively, had died by 6 months after discharge. Age and length of stay were not associated with early death. CONCLUSIONS: The demographics and outcomes of the elderly admitted to a UK neurosurgical center are discussed. Differences between elective and emergency groups are attributable to both the pathologic processes and case selection. Neurosurgical treatment should not be denied based on age, however the high risks of emergency surgery in this age group should be acknowledged.
\n \n\n \n \nGlioblastoma (World Health Organization grade IV) is an aggressive adult brain tumor that is inevitably fatal despite surgery, radiation, and chemotherapy. Treatment failures are attributed to combinations of cellular heterogeneity, including a subpopulation of often-resistant cancer stem cells, aberrant vasculature, and noteworthy immune suppression. Current preclinical models and treatment strategies do not incorporate or address all these features satisfactorily. Herein, we describe a murine glioblastoma stem cell (GSC) model that recapitulates tumor heterogeneity, invasiveness, vascularity, and immunosuppressive microenvironment in syngeneic immunocompetent mice and should prove useful for a range of therapeutic studies. Using this model, we tested a genetically engineered oncolytic herpes simplex virus that is armed with an immunomodulatory cytokine, interleukin 12 (G47-mIL12). G47\u0394-mIL12 infects and replicates similarly to its unarmed oncolytic herpes simplex virus counterpart in mouse 005 GSCs in vitro, whereas in vivo, it significantly enhances survival in syngeneic mice bearing intracerebral 005 tumors. Mechanistically, G47-mIL12 targets not only GSCs but also increases IFN-\u03b3 release, inhibits angiogenesis, and reduces the number of regulatory T cells in the tumor. The increased efficacy is dependent upon T cells, but not natural killer cells. Taken together, our findings demonstrate that G47\u0394-mIL12 provides a multifaceted approach to targeting GSCs, tumor microenvironment, and the immune system, with resultant therapeutic benefit in a stringent glioblastoma model.
\n \n\n \n \nOncolytic herpes simplex virus (oHSV) can potentially spread throughout the tumor, reach isolated infiltrating cells, kill them, and deliver anticancer agents. However, the host responds to oHSV by inducing intratumoral infiltration of macrophages that can engulf the virus, limiting the potential of this therapeutic strategy. Hypervascularity is a pathognomonic feature of glioblastoma (GBM) and is a promising therapeutic target. Antiangiogenic treatments have multiple benefits, including the capacity to increase oHSV efficacy by suppressing macrophage extravasation and infiltration into the tumor. Angiostatin is an antiangiogenic polypeptide, and interleukin-12 (IL-12) is an immunostimulatory cytokine with strong antiangiogenic effects. Clinical use of each has been limited by delivery issues and systemic toxicity. We tested a combination treatment strategy using oHSVs expressing angiostatin (G47\u0394-mAngio) and IL-12 (G47\u0394-mIL12) in two orthotopic human GBM models. Intratumoral injection of G47\u0394-mAngio and G47\u0394-mIL12 in mice bearing intracranial U87 or tumors derived from glioblastoma stem cells significantly prolonged survival compared to each armed oHSV alone. This was associated with increased antiangiogenesis and virus spread and decreased macrophages. These data support the paradigm of using oHSV expressing different antiangiogenic agents and show for the first time that oHSVs expressing angiostatin and IL-12 can improve efficacy in human GBM models.
\n \n\n \n \nWe report the case of a seventy-five year old woman with a sporadic primary malignant intracerebral nerve sheath tumor (MINST). These tumors fall within the spectrum of malignant peripheral nerve sheath tumors (MPNST) but confirming the diagnosis of a MINST can be difficult due to its rarity and unusual intraparenchymal location. Radiographically, MINST's mimic malignant glioma and should be considered in the differential diagnosis of enhancing cerebral lesions. In this report, we present a comprehensive panel of histological, immunohistochemical, ultrastructural, and genetic considerations that may be used to diagnosis MINST based on their similarities to MPNSTs and brain parenchyma location.
\n \n\n \n \nThis study describes our experience in the surgical treatment of neuralgia of the glossopharyngeal and vagal nerves. Over the last 19 years, 21 patients underwent surgery. Their case notes were reviewed to obtain demographic information, clinical presentation, surgical findings and early results. All patients were then contacted by telephone for long-term results and complications. Independent analysis of results was carried out by a Neurology team. Ten patients had microvascular decompression (MVD). Four patients had MVD and nerve section. In the remaining seven patients, the glossopharyngeal and first two rootlets of the vagal nerve were sectioned. Nineteen (90%) of 21 patients experienced complete relief of pain immediately after surgery. The remaining patients reported an improvement in their symptoms. There were no mortalities. Four patients experienced short-term complications, which resolved. Two patients were left with a persistent hoarse voice. At follow-up (mean duration of 4 years), there was no recurrence in symptoms. In our experience, surgery is safe and effective for the treatment of vago-glossopharyngeal neuralgia.
\n \n\n \n \nGlioblastoma, the most malignant type of primary brain tumor, is one of the solid cancers where cancer stem cells have been isolated, and studies have suggested resistance of those cells to chemotherapy and radiotherapy. Here, we report the establishment of CSC-enriched cultures derived from human glioblastoma specimens. They grew as neurospheres in serum-free medium with epidermal growth factor and fibroblast growth factor 2, varied in the level of CD133 expression and very efficiently formed highly invasive and/or vascular tumors upon intracerebral implantation into immunodeficient mice. As a novel therapeutic strategy for glioblastoma-derived cancer stem-like cells (GBM-SC), we have tested oncolytic herpes simplex virus (oHSV) vectors. We show that although ICP6 (UL39)-deleted mutants kill GBM-SCs as efficiently as wild-type HSV, the deletion of gamma34.5 significantly attenuated the vectors due to poor replication. However, this was significantly reversed by the additional deletion of alpha47. Infection with oHSV G47Delta (ICP6(-), gamma34.5(-), alpha47(-)) not only killed GBM-SCs but also inhibited their self-renewal as evidenced by the inability of viable cells to form secondary tumor spheres. Importantly, despite the highly invasive nature of the intracerebral tumors generated by GBM-SCs, intratumoral injection of G47Delta significantly prolonged survival. These results for the first time show the efficacy of oHSV against human GBM-SCs, and correlate this cytotoxic property with specific oHSV mutations. This is important for designing new oHSV vectors and clinical trials. Moreover, the new glioma models described in this study provide powerful tools for testing experimental therapeutics and studying invasion and angiogenesis.
\n \n\n \n \nHSV-1 was one of the first oncolytic viruses to have been investigated for its therapeutic potential against cancer. Among the dozens of oncolytic HSV-1 vectors that have so far been reported, some carry transgenes, including interleukins, anti-angiogenic peptides, and prodrug-converting enzymes. 'Arming' of HSV-1 with therapeutic transgenes such as these is expected to enhance its efficacy. HSV-1 is a 152-kb double-stranded DNA virus, and the generation of armed HSV usually takes several months to achieve by conventional homologous recombination methods. Recently, bacterial artificial chromosome (BAC)-based systems termed 'HSVQuik' and 'Flip-Flop HSV-BAC' were developed to enable the fast generation of recombinant HSV-1 vectors within weeks by using site-specific recombinases. These systems provide powerful tools for screening potential transgenes that might greatly enhance the efficacy of HSV-1 vectors. This review discusses the current state of research into the development of oncolytic HSV-1 vectors, and highlights the promise that armed oncolytic HSV-1 vectors might hold for the future.
\n \n\n \n \nOncolytic viruses are one of many emerging cancer therapies. The surgical management of peripheral nerve tumors carries an inherent risk of damaging the nerves involved and so the search for novel therapies with reduced risk of morbidity continues. In this review the authors discuss the use of oncolytic herpes simplex virus (HSV) in the treatment of peripheral nerve tumors. Herpes simplex virus has a number of characteristics that make it a useful oncolytic vector, including its large, sequenced genome that can accommodate multiple transgenes, its lack of insertional mutagenesis, its ability to infect a wide array of cell types in various species, and the availability of well-established antiviral therapies to treat it. The efficacy of oncolytic HSV therapy against schwannomas and malignant peripheral nerve sheath tumors has been studied in multiple experimental models both in vitro and in vivo. The virus utilizes cell pathways unique to tumors to enhance its oncolytic efficacy, preferentially and effectively targeting and destroying peripheral nerve tumor cells without harming normal cells. This effect is augmented by transgenes expressing antiangiogenic factors, such as dominant-negative fibroblast growth factor receptor and platelet factor 4, and displays synergy with chemotherapy. Different oncolytic HSV vectors have been tested, including hrR3, G207, and G47D. In addition, new animal models have been developed to test the efficacy of oncolytic HSV therapy in peripheral nerve tumors. The safety of oncolytic HSV is well established and has been tested in nonhuman primates and in human clinical trials.
\n \n\n \n \nBACKGROUND: To our knowledge there are no cases in the literature of traumatic vascular injury of the brachial artery by elbow hyperextension without elbow dislocation based on either clinical or radiological evidence. CASE PRESENTATION: We present the first case of complete brachial artery rupture resulting from a hyperextension injury to an elbow, without dislocation. The history, early assessment and operative treatment with figures are presented. CONCLUSION: We advocate prompt clinical assessment by orthopaedic and vascular teams and early surgical exploration and repair.
\n \n\n \n \nBACKGROUND: Neurofibroma of the male breast outside of neurofibromatosis is extremely rare with only one previous case having been reported. CASE PRESENTATION: A 48 year old male patient with a neurofibroma in the breast presenting with gynaecomastia is reported. Clinical and mammogram findings with fine needle aspiration cytology and full histology are presented. CONCLUSION: To our knowledge this is only the second case of a neurofibroma in a male breast in the English literature and the first report to include the mammographic findings.
\n \n\n \n \nThe presence of hormonal receptors in meningiomas has been known for decades. More recently, evidence has shown increased prevalence of meningiomas in patients taking certain types of hormonal treatments, such as oral contraceptives, progestins or hormone replacement therapy. Epidemiological evidence suggests that patients undergoing hormonal therapy harbor higher mutational rates of the oncogene PIK3CA. Due to the relative paucity of literature describing the intersection of hormone therapy and mutated PIK3CA pathways in meningioma, we have conducted a narrative review on this topic. Similarly, the clinical trial landscape for hormonal therapies for meningioma currently focuses on somatostatin receptor-targeted therapies and peptide receptor radionucleotide therapy, and the PIK3CA-hormonal signaling axis has not been explicitly targeted. Given the role of PIK3CA mutations in promoting cancer progression in other hormone-sensitive tumors, such as breast and prostate cancer, exploring this axis could inform drug repurposing including hormonal therapy specifically for these tumors.
\n \n\n \n \nReinforcement learning is a fundamental process for how humans and other animals attain rewards for themselves. However, to act prosocially, we must also learn how our choices reward others. The ventromedial prefrontal cortex has been independently linked to reinforcement learning and prosocial behaviour, yet its causal impact on prosocial reinforcement learning and the roles of its multiple subregions remain unknown. Here, a large group of adults with rare focal ventromedial prefrontal cortex damage (n=28), and two carefully age- and gender-matched control groups (lesions elsewhere, n=21; healthy controls, n=124) completed a reinforcement learning task where they learnt to win rewards for another person (prosocial), for themselves (self), or in a control condition where participants saw points but they were not translated into rewards for either individual (no one, control condition) on separate trials. A novel computational model which incorporated separate learning rates for positive and negative prediction errors best explained behaviour in all groups. Importantly, compared to both control groups, patients with ventromedial prefrontal cortex damage were less accurate and had lower learning rates from positive prediction errors when rewarding another person relative to when no one benefitted, and higher learning rates for negative prediction errors when learning for others relative to self. Unlike controls, ventromedial prefrontal cortex lesion patients also showed a reduced self-benefitting advantage. They were equally accurate and learnt at a similar rate from positive prediction errors for self and neither individual. Strikingly, voxel-based lesion-symptom mapping revealed that damage to subgenual anterior cingulate cortex and anterior cingulate cortex gyrus specifically disrupted prosocial reinforcement learning. These findings highlight the importance of ventromedial prefrontal cortex integrity for multiple aspects of reinforcement learning, with damage to subgenual anterior cingulate cortex and anterior cingulate cortex gyrus critical for learning to reward others.
\n \n\n \n \nBackground/Objectives: Cerebrospinal fluid (CSF) rhinorrhoea carries a significant risk of life-threatening intracranial complications. This review provides a contemporary overview of current management strategies for CSF rhinorrhoea. Methods: We conducted a literature review, examining studies from Medline, Embase, and Google Scholar published within the last 20 years. This narrative synthesis summarises the current and future trends in the management of CSF rhinorrhoea. Results: The management of CSF leaks requires a multidisciplinary approach, encompassing a thorough clinical assessment, targeted diagnostic testing, and a spectrum of surgical and non-surgical interventions. Endoscopic techniques, particularly the use of vascularised flaps such as the nasoseptal flap, has become central to anterior skull base reconstruction. Numerous graft and flap choices provide tailored solutions based on defect size and CSF flow characteristics, with reported success rates exceeding 90%. Conclusions: Endoscopic repair of CSF rhinorrhoea continues to evolve, with modern techniques significantly enhancing success rates and reducing morbidity. Further understanding of underlying aetiologies, advances in technology, and refinement in surgical technique are areas for future innovation in CSF rhinorrhoea management.
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