Transient Inhibition of PI3Kδ Enhances the Therapeutic Effect of Intravenous Delivery of Oncolytic Vaccinia Virus.

Tumor-targeting oncolytic viruses such as vaccinia virus (VV) are attractive cancer therapeutic agents that act through multiple mechanisms to provoke both tumor lysis and anti-tumor immune responses. However, delivery of these agents remains restricted to intra-tumoral administration, which prevents effective targeting of inaccessible and disseminated tumor cells. In the present study we have identified transient pharmacological inhibition of the leukocyte-enriched phosphoinositide 3-kinase δ (PI3Kδ) as a novel mechanism to potentiate intravenous delivery of oncolytic VV to tumors. Pre-treatment of immunocompetent mice with the PI3Kδ-selective inhibitor IC87114 or the clinically approved idelalisib (CAL-101), prior to intravenous delivery of a tumor-tropic VV, dramatically improved viral delivery to tumors. This occurred via an inhibition of viral attachment to, but not internalization by, systemic macrophages through perturbation of signaling pathways involving RhoA/ROCK, AKT, and Rac. Pre-treatment using PI3Kδ-selective inhibitors prior to intravenous delivery of VV resulted in enhanced anti-tumor efficacy and significantly prolonged survival compared to delivery without PI3Kδ inhibition. These results indicate that effective intravenous delivery of oncolytic VV may be clinically achievable and could be useful in improving anti-tumor efficacy of oncolytic virotherapy.

Endoscopic Endonasal Repair and Reconstruction of Traumatic Anterior Skull Base Defects.

Eighty percent of cerebrospinal fluid leaks (CSF) occur following trauma and complicate 12 to 13% percent of all basilar skull fractures (Prosser, Vender, and Solares, 2011). An endoscopic endonasal approach (EEA) is often the preferred method of repair with greater than 90% success rates (Prosser, Vender, and Solares, 2011). We report a case of a 37-year-old man who presented to our regional level 1 trauma centre with multiple facial injuries. Initial cross-sectional imaging revealed multiple, continuous anterior skull base fractures with associated pneumocephalus. Though initially managed conservatively, the patient represented five days later with unilateral left-sided rhinorrhoea. An endoscopic endonasal repair with a multilayer fat, tensor fascia lata, free mucosal graft, and vascularised local flap reconstruction was undertaken. This case highlights the importance of maintaining a high level of suspicion for delayed CSF leak in traumatic base of skull injury. The EEA enables meticulous dissection and thorough inspection of the skull base, facilitating multilayered repair and reconstruction of defects.

Basal cell carcinoma of the nipple-areola complex.

BACKGROUND: Basal cell carcinoma (BCC) of the nipple-areola complex is uncommon. It has been suggested that BCCs in this region behave more aggressively, with a higher potential for distant spread, than in other anatomical sites. OBJECTIVE: To address questions about etiology, behavior, optimal treatment, and prognosis of this entity. METHODS AND MATERIALS: A literature search identifying all cases of BCC of the nipple and nipple-areola complex in the English literature from 1893 to 2008. RESULTS: Thirty-four cases of BCC of the nipple, areola, or both were identified, mostly affecting middle-aged men. The majority of patients were treated with tissue-sparing surgery. There was a metastatic rate of 9.1%, and one patient died from the disease (3.0%). CONCLUSIONS: The optimal treatment of this condition should be local excision, but patients with this condition should be followed up for primary site recurrence and axillary metastasis, because there is greater incidence than with BCC at other anatomical sites. Furthermore, proven axillary metastasis should be surgically treated.

Narrative review of contemporary treatment options in the care of patients with obstructive sleep apnoea.

Snoring and obstructive sleep apnoea (OSA) are increasingly common conditions, and confer a significant health and socioeconomic burden. Furthermore, untreated OSA represents a significant mortality risk. Patients require careful assessment, including detailed clinical history and examination, sleep study and drug-induced sleep endoscopy (DISE). Although nasal continuous positive airway pressure (nCPAP) is the gold standard treatment for moderate and severe OSA, multidisciplinary team assessment is often required to develop the best treatment plan for an individual, especially when nasal CPAP is poorly tolerated. There is a wide range of medical and surgical treatment options, and following appropriate patient selection and assessment, a focused site-specific, often multilevel, intervention is indicated. There is an increasing body of evidence in the literature supporting these multilevel interventions and with agreement on standardized outcome measures more trials are likely to improve the robustness of these data further.

Systemic delivery of oncolytic viruses: hopes and hurdles.

Despite recent advances in both surgery and chemoradiotherapy, mortality rates for advanced cancer remain high. There is a pressing need for novel therapeutic strategies; one option is systemic oncolytic viral therapy. Intravenous administration affords the opportunity to treat both the primary tumour and any metastatic deposits simultaneously. Data from clinical trials have shown that oncolytic viruses can be systemically delivered safely with limited toxicity but the results are equivocal in terms of efficacy, particularly when delivered with adjuvant chemotherapy. A key reason for this is the rapid clearance of the viruses from the circulation before they reach their targets. This phenomenon is mainly mediated through neutralising antibodies, complement activation, antiviral cytokines, and tissue-resident macrophages, as well as nonspecific uptake by other tissues such as the lung, liver and spleen, and suboptimal viral escape from the vascular compartment. A range of methods have been reported in the literature, which are designed to overcome these hurdles in preclinical models. In this paper, the potential advantages of, and obstacles to, successful systemic delivery of oncolytic viruses are discussed. The next stage of development will be the commencement of clinical trials combining these novel approaches for overcoming the barriers with systemically delivered oncolytic viruses.

Meta-analysis of minimally invasive video-assisted thyroidectomy.

OBJECTIVES: The aim of this study is to compare minimally invasive video-assisted thyroidectomy (MIVAT) to conventional thyroidectomy. STUDY DESIGN: A systematic review of the literature and meta-analysis. METHODS: All published prospective controlled trials that compared MIVAT to conventional thyroidectomy were identified. The trials data were extracted and statistical analyzed using Statsdirect 2.5.7. RESULTS: Five trials were identified. The total number of patients was 318. The primary outcome measures were pain, postoperative hypocalcaemia, and postoperative recurrent laryngeal nerve palsy. There was no difference in rates of postoperative hypocalcaemia or postoperative recurrent laryngeal nerve palsy between the techniques. Reported pain scores at 24 hours were significantly lower in MIVAT compared to conventional surgery. Pooled effect size was -4.496 (95% confidence interval [CI] = -7.146 to -2.045, P = .0004). The secondary outcome measures were operative time, blood loss, and cosmesis. There was significant improvement in patient reported scores for cosmesis with MIVAT. The pooled effect size was 3.669 (95% CI 0.636-60.702, P = .0178). MIVAT was associated with a significant increase in operative time. Pooled effect size was 1.681 (95% CI 0.600-2.762, P = .0023). There was no difference in blood loss between the groups. CONCLUSIONS: This study demonstrates that MIVAT is as safe as the existing gold standard operation. Furthermore, it has better cosmetic and pain outcomes for patients when compared to conventional surgery. MIVAT is a promising new technique, with obvious benefits over the established surgery, for small-volume thyroid disease that mainly affects a young female patient population.

Analysis of complications following surgical treatment of benign parotid disease.

BACKGROUND: The objective of the study was to study the incidence of, and risk factors for developing complications following parotidectomy for benign disease, to improve preoperative patient counselling and better inform future surgical management. METHODS: An 11-year retrospective review of 162 parotidectomies for benign disease, collecting and analysing data about presentation, investigations, surgical treatment, postoperative facial nerve function, Frey's syndrome and other surgical complications. RESULTS: The mean age at presentation was 58 years. The commonest pathology was benign pleomorphic adenoma (43%), followed by Warthin's tumour (30%) and chronic sialadenitis (22%). Sialadenitis was a significant risk factor for facial nerve palsy and increased the incidence of salivary fistulas. Parotid duct ligation increased the risk of nerve palsy in the distribution of zygomatic and buccal branches. Operations for Warthin's tumour were associated with an increased risk of dysfunction of the cervical branch of the nerve. Half the patients had intraoperative facial nerve stimulation and this did not influence the likelihood of facial paresis. The recovery of facial nerve function showed a biphasic distribution, with 90% of patients having normal function within 12 months, followed by a slower recovery rate for up to 2 years. CONCLUSION: The incidence of postoperative complications was influenced by the pathology, with inflammatory lesions significantly increasing the risk of facial nerve dysfunction and other complications, but also by variations in surgical practice, such as parotid duct ligation. Overall, the incidence of permanent facial paralysis was less than 2%, but temporary nerve palsy was common at 40%, with most patients regaining normal function within 1 year of the operation.