James R. Tysome

Lister strain of vaccinia virus armed with endostatin–angiostatin fusion gene as a novel therapeutic agent for human pancreatic cancer

Survival after pancreatic cancer remains poor despite incremental advances in surgical and adjuvant therapy, and new strategies for treatment are needed. Oncolytic virotherapy is an attractive approach for cancer treatment. In this study, we have evaluated the effectiveness of the Lister vaccine strain of vaccinia virus armed with the endostatin–angiostatin fusion gene (VVhEA) as a novel therapeutic approach for pancreatic cancer. The Lister vaccine strain of vaccinia virus was effective against all human pancreatic carcinoma cells tested in vitro, especially those insensitive to oncolytic adenovirus. The virus displayed inherently high selectivity for cancer cells, sparing normal cells both in vitro and in vivo, with effective infection of tumors after both intravenous (i.v.) and intratumoral (i.t.) administrations. The expression of the endostatin–angiostatin fusion protein was confirmed in a pancreatic cancer model both in vitro and in vivo, with evidence of inhibition of angiogenesis. This novel vaccinia virus showed significant antitumor potency in vivo against the Suit-2 model by i.t. administration. This study suggests that the novel Lister strain of vaccinia virus armed with the endostatin–angiostatin fusion gene is a potential therapeutic agent for pancreatic cancer.

A Novel Therapeutic Regimen to Eradicate Established Solid Tumors with an Effective Induction of Tumor-Specific Immunity

Purpose: The efficacy of oncolytic viruses depends on multiple actions including direct tumor lysis, modulation of tumor perfusion, and stimulation of tumor-directed immune responses. In this study, we investigated whether a sequential combination of immunologically distinct viruses might enhance antitumor efficacy through the induction of tumor-specific immunity and circumvention or mitigation of antiviral immune responses. Experimental Design: The Syrian hamster as an immune-competent model that supports replication of both adenovirus and vaccinia virus was evaluated in vitro and in vivo. The antitumor efficacy of either virus alone or sequential combination of the two viruses was examined in pancreatic and kidney cancer models. The functional mechanism of the regimen developed here was investigated by histopathology, immunohistochemistry staining, CTL assay, and T-cell depletion. Results: The Syrian hamster is a suitable model for assessment of oncolytic adenovirus and vaccinia virus. Three low doses of adenovirus followed by three low doses of vaccinia virus resulted in a superior antitumor efficacy to the reverse combination, or six doses of either virus alone, against pancreatic and kidney tumors in Syrian hamsters. A total of 62.5% of animals bearing either tumor type treated with the sequential combination became tumor-free, accompanied by the induction of effective tumor-specific immunity. This enhanced efficacy was ablated by CD3+ T-cell depletion but was not associated with humoral immunity against the viruses. Conclusion: These findings show that sequential treatment of tumors with oncolytic adenovirus and vaccinia virus is a promising approach for cancer therapy and that T-cell responses play a critical role. Clin Cancer Res; 18(24); 6679–89. ©2012 AACR.

CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells

The changes in cancer cell surface molecules and intracellular signaling pathways during tumorigenesis make delivery of adenovirus-based cancer therapies inefficient. Here we have identified carcinoembryonic antigen- related cell adhesion molecule 6 (CEACAM6) as a cellular protein that restricts the ability of adenoviral vectors to infect cancer cells. We have demonstrated that CEACAM6 can antagonize the Src signaling pathway, downregulate cancer cell cytoskeleton proteins, and block adenovirus trafficking to the nucleus of human pancreatic cancer cells. Similar to CEACAM6 overexpression, treatment with a Src-selective inhibitor significantly reduced adenovirus replication in these cancer cells and normal human epithelial cells. In a mouse xenograft tumor model, siRNA-mediated knockdown of CEACAM6 also significantly enhanced the antitumor effect of an oncolytic adenovirus. We propose that CEACAM6-associated signaling pathways could be potential targets for the development of biomarkers to predict the response of patients to adenovirus-based therapies, as well as for the development of more potent adenovirus-based therapeutics.

Lister Vaccine Strain of Vaccinia Virus Armed with the Endostatin–Angiostatin Fusion Gene: An Oncolytic Virus Superior to dl1520 (ONYX-015) for Human Head and Neck Cancer

Oncolytic viral therapy represents a promising strategy for the treatment of head and neck squamous cell carcinoma (HNSCC), with dl1520 (ONYX-015) the most widely used oncolytic adenovirus in clinical trials. This study aimed to determine the effectiveness of the Lister vaccine strain of vaccinia virus as well as a vaccinia virus armed with the endostatin-angiostatin fusion gene (VVhEA) as a novel therapy for HNSCC and to compare them with dl1520. The potency and replication of the Lister strain and VVhEA and the expression and function of the fusion protein were determined in human HNSCC cells in vitro and in vivo. Finally, the efficacy of VVhEA was compared with dl1520 in vivo in a human HNSCC model. The Lister vaccine strain of vaccinia virus was more effective than the adenovirus against all HNSCC cell lines tested in vitro. Although the potency of VVhEA was attenuated in vitro, the expression and function of the endostatin-angiostatin fusion protein was confirmed in HNSCC models both in vitro and in vivo. This novel vaccinia virus (VVhEA) demonstrated superior antitumor potency in vivo compared with both dl1520 and the control vaccinia virus. This study suggests that the Lister strain vaccinia virus armed with an endostatin-angiostatin fusion gene may be a potential therapeutic agent for HNSCC.

Systematic review of middle ear implants: do they improve hearing as much as conventional hearing aids?

Objective: A systematic review to determine whether middle ear implants (MEIs) improve hearing as much as hearing aids. Data Sources: Databases included MEDLINE, EMBASE, DARE, and Cochrane searched with no language restrictions from 1950 or the start date of each database. Study Selection: Initial search found 644 articles, of which 17 met the inclusion criteria of MEI in adults with a sensorineural hearing loss, where hearing outcomes and patient-reported outcome measures (PROMs) compared MEI with conventional hearing aids (CHAs). Data Extraction: Study quality assessment included whether ethical approval was gained, the study was prospective, eligibility criteria specified, a power calculation made and appropriate controls, outcome measures, and analysis performed. Middle ear implant outcome analysis included residual hearing, complications, and comparison to CHA in terms of functional gain, speech perception in quiet and in noise, and validated PROM questionnaires. Data Synthesis: Because of heterogeneity of outcome measures, comparisons were made by structured review. Conclusion: The quality of studies was moderate to poor with short follow-up. The evidence supports the use of MEI because, overall, they do not decrease residual hearing, result in a functional gain in hearing comparable to CHA, and may improve perception of speech in noise and sound quality. We recommend the publication of long-term results comparing MEI with CHA, reporting a minimum of functional gain, speech perception in quiet and in noise, complications, and a validated PROM to guide the engineering of the new generation of MEI in the future.

Tests of Eustachian tube function: a review.

Eustachian tube (ET) dysfunction is a common but poorly understood cause of patient symptoms, and an important aetiological factor in the development of middle ear pathology. Despite this, there are no specific tests of ET function in widespread clinical use and no identified ‘gold standard’ with which to diagnose the disease.

Role of thyroidectomy in advanced laryngeal and pharyngolaryngeal carcinoma

Objective: Total thyroidectomy (TThy) or hemithyroidectomy (HThy) in conjunction with a total laryngectomy (TL) or pharyngolaryngectomy (PL) for laryngeal carcinoma often results in hypothyroidism requiring life-long thyroid hormone replacement. The aims were to determine the incidence of thyroid gland (TG) invasion in patients undergoing TL or TPL with TThy or HThy for laryngeal or hypopharyngeal carcinoma and to assess predicative factors. Study Design: Case series with chart review. Setting: Guys Hospital, London, UK. Subjects and Methods: Thirty-five patients from 2004 to 2008 were reviewed. Specimens were examined to determine the incidence of TG invasion and predicative factors. Preoperative imaging was reviewed to assess the radiological evidence of TG invasion. Results: TL and TThy were performed in 19 patients, TL and HThy in three patients, and PL and TThy in 13 patients. Surgery was performed for primary and recurrent carcinoma in 28 and eight patients, respectively. Histological evidence of invasion of the TG was found in three patients (8.5%). No significant relationship was found between TG invasion and patients sex, subsite of primary carcinoma, stage of primary disease at surgery, degree of differentiation, or the presence of subglottic extension. In addition, no significant relationship was found between the presence of TG invasion and recurrent disease. Definite evidence of radiological invasion of the TG was seen in only one patient. Conclusions: Invasion of the TG in patients undergoing TL or TPL is a rare event and limits the need for TThy in most cases.

English consensus protocol evaluating candidacy for auditory brainstem and cochlear implantation in neurofibromatosis type 2

Objective Hearing loss resulting from bilateral vestibular schwannomas (VSs) has a significant effect on the quality of life of patients with neurofibromatosis Type 2 (NF2). A national consensus protocol was produced in England as a guide for cochlear implantation (CI) and auditory brainstem implantation (ABI) in these patients. Study Design Consensus statement. Setting English NF2 Service. Participants Clinicians from all 4 lead NF2 units in England. Main Outcome Measures A protocol for the assessment, insertion and rehabilitation of CI and ABI in NF2 patients. Results Patients should undergo more detailed hearing assessment once their maximum aided speech discrimination score falls below 50% in the better hearing ear. Bamford-Kowal-Bench sentence testing scores below 50% should trigger assessment for auditory implantation, as recommended by the National Institute for Clinical Excellence guidelines on CI. Where this occurs in patients with bilateral stable VS or a unilateral stable VS where the contralateral cochlear nerve was lost at previous surgery, CI should be considered. Where VS surgery is planned, CI should be considered where cochlear nerve preservation is thought possible, otherwise an ABI should be considered. Intraoperative testing using electrically evoked auditory brainstem responses or cochlear nerve action potentials may be used to determine whether a CI or ABI is inserted. Conclusion The NF2 centers in England agreed on this protocol. Multisite, prospective assessments of standardized protocols for auditory implantation in NF2 provide an essential model for evaluating candidacy and outcomes in this challenging patient population.

Squamous Cell Carcinoma of the Temporal Bone: Clinical Outcomes From Radical Surgery and Postoperative Radiotherapy

Objective To review the treatment of squamous carcinoma of the temporal bone at a regional skull base unit for the period 1982–2012. Study Design Retrospective case review. Setting Tertiary referral center. Patients Sixty patients with primary squamous carcinoma of the temporal bone. Interventions Multidisciplinary team approach including surgical resection, reconstruction, and postoperative radiotherapy. Main Outcome Measures Disease-specific survival, overall survival. Results The 5-year disease-specific survival for the whole cohort was 44% (CI, 37%–51%). Multivariable analysis revealed nodal status, poorly differentiated squamous cell histology, and carotid involvement to be poor prognostic indicators. Conclusion Although the survival figures in this series are comparable with the best outcomes from other units, our experience would suggest improvements can still be achieved by reconsidering the selection of patients for neck dissection and temperomandibular joint excision in early stage disease. We also conclude that postoperative radiotherapy should be delivered to all patients, including surgical salvage cases who may have received previous irradiation. Finally, the minority of patients with poor prognostic features should be offered a more palliative therapeutic approach.

Improving prediction of malignancy of cytologically indeterminate thyroid nodules

Fine‐needle aspiration (FNA) is essential in the investigation of thyroid nodules. The British Thyroid Association guidelines recommend clarification of whether follicular nodules are probable follicular neoplasms that require surgical excision. This study assessed the value of the subclassification of cytologically indeterminate thyroid nodules into either follicular neoplasms or other pathology.