Controlled infection with a therapeutic virus defines the activation kinetics of human natural killer cells in vivo.

Human natural killer (NK) cells play an important role in anti-viral immunity. However, studying their activation kinetics during infection is highly problematic. A clinical trial of a therapeutic virus provided an opportunity to study human NK cell activation in vivo in a controlled manner. Ten colorectal cancer patients with liver metastases received between one and five doses of oncolytic reovirus prior to surgical resection of their tumour. NK cell surface expression of the interferon-inducible molecules CD69 and tetherin peaked 24-48 h post-infection, coincident with a peak of interferon-induced gene expression. The interferon response and NK cell activation were transient, declining by 96 h post-infection. Furthermore, neither NK cell activation nor the interferon response were sustained in patients undergoing multiple rounds of virus treatment. These results show that reovirus modulates human NK cell activity in vivo and suggest that this may contribute to any therapeutic effect of this oncolytic virus. Detection of a single, transient peak of activation, despite multiple treatment rounds, has implications for the design of reovirus-based therapy. Furthermore, our results suggest the existence of a post-infection refractory period when the interferon response and NK cell activation are blunted. This refractory period has been observed previously in animal models and may underlie the enhanced susceptibility to secondary infections that is seen following viral infection.

Viral warfare! Front-line defence and arming the immune system against cancer using oncolytic vaccinia and other viruses.

BACKGROUND: Despite mankind's many achievements, we are yet to find a cure for cancer. We are now approaching a new era which recognises the promise of harnessing the immune system for anti-cancer therapy. Pathogens have been implicated for decades as potential anti-cancer agents, but implementation into clinical therapy has been plagued with significant drawbacks. Newer 'designer' agents have addressed some of these concerns, in particular, a new breed of oncolytic virus: JX-594, a genetically engineered pox virus, is showing promise. OBJECTIVE: To review the current literature on the use of oncolytic viruses in the treatment of cancer; both by direct oncolysis and stimulation of the immune system. The review will provide a background and historical progression for the surgeon on tumour immunology, and the interplay between oncolytic viruses, immune cells, inflammation on tumourigenesis. METHODS: A literature review was performed using the Medline database. CONCLUSIONS: Viral therapeutics hold promise as a novel treatment modality for the treatment of disseminated malignancy. It provides a multi-pronged attack against tumour burden; direct tumour cell lysis, exposure of tumour-associated antigens (TAA), induction of immune danger signals, and recognition by immune effector cells.

Repeat hepatic resection for colorectal liver metastases.

BACKGROUND: Some 75-80 per cent of patients undergoing liver resection for colorectal liver metastases develop intrahepatic recurrence. A significant number of these can be considered for repeat liver surgery. This study examined the outcomes of repeat liver resection for the treatment of recurrent colorectal metastases confined to the liver. METHODS: Patients who underwent repeat liver resection in a single tertiary referral hepatobiliary centre were identified from a database. Clinicopathological variables were analysed to assess factors predictive of survival. RESULTS: A total of 195 patients underwent repeat resection between 1993 and 2010. Median age was 63 years, and the median interval between first and repeat resection was 13·8 months. Thirty-three patients (16·9 per cent) underwent completion hemihepatectomy or extended hemihepatectomy and the remainder had non-anatomical or segmental resection. The 30-day mortality rate was 1·5 per cent, and the overall 30-day morbidity rate was 20·0 per cent. Overall 1-, 3- and 5-year survival rates were 91·2, 44·3 and 29·4 per cent respectively. Tumour size 5 cm or greater was the only independent predictor of overall survival (relative risk 1·71, 95 per cent confidence interval 1·08 to 2·70; P = 0·021). Neoadjuvant chemotherapy before resection, perioperative blood transfusion, bilobar disease, R1 resection margin and multiple metastases were among factors that did not significantly influence survival. CONCLUSION: Repeat hepatic resection remains the only curative option for patients presenting with recurrent colorectal liver metastases.

Macrocytosis and sudden sensorineural hearing loss: a case report.

BACKGROUND: Although other blood dyscrasias are known to cause sudden sensorineural hearing loss, macrocytosis has not previously been implicated in the absence of another causative agent. CASE REPORT: We present a case of bilateral sequential sudden sensorineural hearing loss in a patient with significant macrocytosis (mean corpuscular volume at presentation 124 fl) secondary to alcohol-induced liver dysfunction. CONCLUSION: A possible pathophysiological mechanism linking macrocytosis and sudden sensorineural hearing loss was identified, suggesting areas for further investigation.

Streptomycin perfusion of the labyrinth in the treatment of Menière's disease: a modified technique.

The ideal surgical procedure for Menière's disease would combine the high rate of vertigo control and the good hearing preservation of vestibular nerve section with the low morbidity of labyrinthectomy. Shea's technique of streptomycin perfusion of the labyrinth has been modified by making an additional opening into the posterior semicircular canal in an effort to limit the amount of streptomycin going into the cochlea. Seventeen patients with definite Menière's with poor hearing have had this procedure. Vertigo was controlled in 94% and the hearing preserved in 55%. Vestibular rehabilitation was not a problem. It is speculated that hearing preservation would be better if the procedure were not restricted to those with poor hearing. This method of destruction of the vestibular system carries the possibility of hearing preservation and maintains the possibility of cochlear implantation should this ever be required.