Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade.

Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation would up-regulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous administration will not deliver virus to this site. We show, in a window-of-opportunity clinical study, that intravenous infusion of oncolytic human Orthoreovirus (referred to herein as reovirus) leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus up-regulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.

David Price--Pioneer of digital ICP monitoring, neurosurgeon and teacher.

In early 1970s first personal desk-top computers started to be available in hospitals. Mr Price was one of the pioneers introducing his own software to identify Marmarou's model of CSF space during infusion studies to diagnose patients suffering from hydrocephalus. His closed-loop control system for infusion of mannitol to manage patients at risk of intracranial hypertension was designed in 1977. The system worked successfully for 10 years in Pinderfields Hospital in Wakefield, UK. In the middle 1980's he initiated international cooperation with Children's Health Centre in Poland in long-term computer-assisted monitoring and analysis of ICP. Software designed in a course of this cooperation paved the way for contemporary package of ICM+ (Intensive Care Monitor, University of Cambridge, UK). Our scientific portfolio from these years (1985-1995) contains hundreds of head injured patients with waveform ICP analysis, introduction of compensatory reserve index RAP, few highly cited papers. Now, we understand ICP much better thanks to David's personal passion and extremely friendly support.

Cerebellopontine angle metastasis of a parotid mucoepidermoid carcinoma arising from perineural invasion along the facial nerve.

A 72-year-old male was referred with left sided hearing loss, tinnitus and disequilibrium with radiological appearances suggestive of an intracanalicular left vestibular schwannoma. The patient then developed left sided trigeminal nerve sensory loss over the next 9 months with an enlarging parotid swelling. The eventual diagnosis was a destructive lesion in the left cerebellopontine angle (CPA) arising from metastatic perineural invasion along the facial nerve by a parotid mucoepidermoid carcinoma. Surgical resection and targeted beam radiotherapy achieved a survival period of 9 months.

Malignant transformation of a neurenteric cyst in the posterior fossa following complete excision.

We present a case of a 46-year-old man who developed malignant transformation of a neurenteric cyst felt to be completely removed 14 years previously. He re-presented with non-specific symptoms and hydrocephalus, and subsequent evidence of a complex lesion surrounding the lower brain stem and upper cervical cord. Histologically the original lesion was a benign neurenteric cyst, whereas the recurrent lesion showed a well differentiated adenocarcinoma. This is only the second case reported in the literature.

Angioleiomyoma of the internal auditory meatus: a rare occurrence in the internal auditory canal.

We describe a case of angioleiomyoma of the internal auditory meatus. A finding of this tumor at this site is very unusual. In fact, our review of the literature revealed that only 1 case has been previously reported. In our patient, the tumor was clinically and radiologically difficult to distinguish from an acoustic neuroma. It would be important to recognize this rare small tumor preoperatively because it may be appropriate to manage it conservatively.