Michael G. Bourke

The emerging role of viruses in the treatment of solid tumours

There is increasing optimism for the use of non-pathogenic viruses in the treatment of many cancers. Initial interest in oncolytic virotherapy was based on the observation of an occasional clinical resolution of a lymphoma after a systemic viral infection. In many cancers, by comparison with normal tissues, the competency of the cellular anti-viral mechanism is impaired, thus creating an exploitable difference between the tumour and normal cells, as an unimpeded viral proliferation in cancer cells is eventually cytocidal. In addition to their oncolytic capability, these particular viruses may be engineered to facilitate gene delivery to tumour cells to produce therapeutic effects such as cytokine secretion and anti -tumour immune responses prior to the eventual cytolysis. There is now promising clinical experience with these viral strategies, particularly as part of multimodal studies, and already several clinical trials are in progress. The limitations of standard cancer chemotherapies, including their lack of specificity with consequent collateral toxicity and the development of cross-resistance, do not appear to apply to viral-based therapies. Furthermore, virotherapy frequently restores chemoradiosensitivity to resistant tumours and has also demonstrated efficacy against cancers that historically have a dismal prognosis. While there is cause for optimism, through continued improvements in the efficiency and safety of systemic delivery, through the emergence of alternative viral agents and through favourable clinical experiences, clinical trials as part of multimodal protocols will be necessary to define clinical utility. Significant progress has been made and this is now a major research area with an increasing annual bibliography.

Management of the acute scrotum in a district general hospital: 10-year experience.

The acutely painful scrotum is a common urologic emergency. The primary objective of management is to avoid testicular loss. This requires a high index of clinical suspicion and prompt surgical intervention. In our series conducted between January 1996 and December 2005, 119 patients (age range: 4–62 years) underwent emergency operative exploration for acute scrotal pain. The most common finding was torted cyst of Morgagni (63/119, 52.9%), followed by testicular torsion (41/119, 34.4%). The majority of testicular torsions occurred in the pubertal group (22/41, 53.6%). Only one patient in this group had an unsalvageable testis necessitating orchidectomy, a testicular loss rate in torsion of 2.4%. There were no postoperative wound infections or scrotal haematomas. Testicular salvage depends critically on early surgical intervention, so the delay incurred in diagnostic imaging may extend the period of ischaemia. Furthermore, all radiological investigations have a certain false-negative rate. We advocate immediate surgical exploration of the acute scrotum. We report a low orchidectomy rate (2.4%) in testicular torsion.

Electrochemotherapy for the treatment of ocular basal cell carcinoma; a novel adjunct in the disease management

Basal Cell Carcinoma (BCC) affecting the ocular region is potentially problematic due to its ability to infiltrate aesthetic and functional structures. Due to the paucity of local tissue, resection frequently requires reconstruction with skin grafts or local flaps. Surgical treatment may not be suitable for patients with multiple co-morbidities. Electrochemotherapy (ECT) is a technique where cells are temporarily permeabilized after exposure to a brief electrical field and when combined with normally impermeant chemotherapy drugs can resolve cutaneous cancers - even those previously recalcitrant to chemotherapy or radiotherapy. Its particular advantage is its speed of application and the minimal damage to the surrounding healthy tissue structures. We present a series of 3 patients with BCCs in the peri-ocular region and significant co-morbidities deemed unsuitable for surgical resection, who underwent ECT. The lesions were all primary BCC ranging in size from 0.5 cm(2) to 1 cm(2). Two lesions were on the upper eyelid and one on the lower eyelid. ECT was performed using an 8-needle electrode and a CE approved electroporation generator with intra-lesional Bleomycin. All lesions responded to treatment. All BCCs completely resolved, with acceptable scarring. No side effects were reported from the Bleomycin or the electric pulses. ECT for peri-ocular BCC is an adjunct to surgical excision in the management of surgically problematic lesions. This technique could provide a useful initial treatment option for patients who are medically unfit or where resection and would be associated with significant morbidity.

Preclinical evaluation of an endoscopic electroporation system

BACKGROUND AND STUDY AIMS Targeted delivery of specific chemotherapeutic drugs into tumors can be achieved by delivering electrical pulses directly to the tumor tissue. This causes a transient formation of pores in the cell membrane that enables passive diffusion of normally impermeant drugs. A novel device has been developed to enable the endoscopic delivery of this tumor permeabilizing treatment. The aim of the preclinical studies described here was to investigate the efficacy and safety of this nonthermal ablation system in the treatment of gastrointestinal cancer models. METHODS Murine, porcine, and canine gastrointestinal tumors and tissues were used to assess the efficacy and safety of electroporation delivered through the special device in combination with bleomycin. Tumor cell death, volume, and overall survival were recorded. RESULTS Murine tumors treated with electrochemotherapy showed excellent responses, with cell death being induced rapidly, mainly via an apoptotic-type mechanism. Use of the system in canine gastrointestinal cancers demonstrated successful local endoluminal tumor resolution, with no safety or adverse effects noted. CONCLUSIONS Electroporation via the new device in combination with bleomycin offers a nonthermal tumor ablative approach, and presents clinicians with a new option for the management of gastrointestinal cancers.

Non-viral immune electrogene therapy induces potent antitumour responses and has a curative effect in murine colon adenocarcinoma and melanoma cancer models

Antitumour efficacy of electroporated pEEV, coding for granulocyte–macrophage colony-stimulating factor and the B7-1 costimulatory immune molecule (pEEVGmCSF-b7.1) in growing solid tumours, was investigated and compared with a standard plasmid. Application of pEEVGmCSF-b7.1 led to complete tumour regression in 66% of CT26-treated tumours and 100% in the B16F10-treated tumours at day 150 post-treatment. pEEVGmCSF-b7.1 treatment was found to significantly enhance levels of both innate and adaptive immune populations in tumour and systemic sites, which corresponded to significantly increased tissue levels of proinflammatory cytokines including interferon-γ (IFN-γ) and interleukin-12 (IL-12). In contrast, pEEVGmCSF-b7.1 treatment significantly reduced the T-regulatory populations and also the anti-inflammatory cytokine IL-10. Upon further characterisation of functional immune responses, we observed a significant increase in cytotoxic (CD107a+) and IFN-γ-producing natural killer cells and also significantly more in IL-12-producing B cells. Importantly, splenocytes isolated from pEEVGmCSF-b7.1-treated ‘cured’ mice were tumour-specific and afforded significant protection in a tumour rechallenge model (Winn assay). Our data indicate that electroimmunogene therapy with the non-viral pEEVGmCSF-b7.1 is able to induce potent and durable antitumour immune responses that significantly reduce primary and also secondary tumour growth, and thus represents a solid therapeutic platform for pursuing future clinical trials.