Endoscopic Endonasal Surgery for Resection of a Pterygopalatine Fossa Malignant Peripheral Nerve Sheath Tumor: 2-Dimensional Operative Video.

The pterygopalatine fossa (PPF) is an inverted, pyramid-shaped space immediately behind the posterior wall of the maxillary sinus, and lesions arising here include juvenile angiofibromas, schwannomas, and, in exceptionally rare cases, malignant peripheral nerve sheath tumors.1,2 Surgical access to the PPF is challenging and has been historically achieved via an open transmaxillary approach associated with facial scaring/deformity as well as potential injury to facial and infraorbital nerve branches.3 We present the case of a 67-year-old woman with facial numbness secondary to a presumed trigeminal schwannoma in the right PPF on magnetic resonance imaging. This surgical video highlights the key stages in performing an endoscopic endonasal excision of a PPF tumor. We start with a wide medial maxillary antrostomy, mobilization of the inferior turbinate, ethmoidectomy, and sphenoidotomy. The posterior wall of the maxillary sinus is then lifted off the anterior aspect of the tumor. The soft tissue attachment medial to the tumor containing the sphenopalatine artery is then cauterized and divided. This is followed by circumferential blunt dissection of the tumor until it is sufficiently mobile to remove in a piecemeal fashion. The PPF is then examined for any residual tumor and any bleeding from the maxillary artery within the fat pad. Hemostasis and reattachment of the inferior turbinate into the lateral nasal wall is demonstrated. The patient did not have any new deficits postoperatively, but histology indicated a malignant peripheral nerve sheath tumor and she underwent postoperative proton beam therapy. Postoperative surveillance magnetic resonance imaging at 14 months showed no tumor recurrence. The patient consented to the procedure in a standard fashion (Video 1).

Corrigendum to "Joint Consensus Statement of the Indian National Association for Study of the Liver and Indian Radiological and Imaging Association for the Diagnosis and Imaging of Hepatocellular Carcinoma Incorporating Liver Imaging Reporting and Data System" [J Clin Expt Hepatol 9 (2019) 625-651].

[This corrects the article DOI: 10.1016/j.jceh.2019.07.005.].

Joint Consensus Statement of the Indian National Association for Study of the Liver and Indian Radiological and Imaging Association for the Diagnosis and Imaging of Hepatocellular Carcinoma Incorporating Liver Imaging Reporting and Data System.

Hepatocellular carcinoma (HCC) is the 6th most common cancer and the second most common cause of cancer-related mortality worldwide. There are currently no universally accepted practice guidelines for the diagnosis of HCC on imaging owing to the regional differences in epidemiology, target population, diagnostic imaging modalities, and staging and transplant eligibility. Currently available regional and national guidelines include those from the American Association for the Study of Liver Disease (AASLD), the European Association for the Study of the Liver (EASL), the Asian Pacific Association for the Study of the Liver, the Japan Society of Hepatology, the Korean Liver Cancer Study Group, Hong Kong, and the National Comprehensive Cancer Network in the United States. India with its large population and a diverse health infrastructure faces challenges unique to its population in diagnosing HCC. Recently, American Association have introduced a Liver Imaging Reporting and Data System (LIRADS, version 2017, 2018) as an attempt to standardize the acquisition, interpretation, and reporting of liver lesions on imaging and hence improve the coherence between radiologists and clinicians and provide guidance for the management of HCC. The aim of the present consensus was to find a common ground in reporting and interpreting liver lesions pertaining to HCC on imaging keeping LIRADSv2018 in mind.

An extended phase Ib study of epertinib, an orally active reversible dual EGFR/HER2 tyrosine kinase inhibitor, in patients with solid tumours.

BACKGROUND: Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity. PATIENTS AND METHODS: Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8. RESULTS: We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months. CONCLUSION: Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases. EUDRACT NUMBER: 2009-017817-31.

Combination of oncolytic herpes simplex viruses armed with angiostatin and IL-12 enhances antitumor efficacy in human glioblastoma models.

Oncolytic 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 (G47Δ-mAngio) and IL-12 (G47Δ-mIL12) in two orthotopic human GBM models. Intratumoral injection of G47Δ-mAngio and G47Δ-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.

Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model.

Glioblastoma (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). G47Δ-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-γ 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 G47Δ-mIL12 provides a multifaceted approach to targeting GSCs, tumor microenvironment, and the immune system, with resultant therapeutic benefit in a stringent glioblastoma model.

Neuralgia of the glossopharyngeal and vagal nerves: long-term outcome following surgical treatment and literature review.

This 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.

Human glioblastoma-derived cancer stem cells: establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors.

Glioblastoma, 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.

Recent advances in the development of oncolytic HSV-1 vectors: 'arming' of HSV-1 vectors and application of bacterial artificial chromosome technology for their construction.

HSV-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.

Oncolytic herpes simplex virus therapy for peripheral nerve tumors.

Oncolytic 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.

A case of elbow hyperextension leading to complete brachial artery rupture.

BACKGROUND: 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.

Solitary neurofibroma in the male breast.

BACKGROUND: 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.