Oncolytic vaccinia virus as a vector for therapeutic sodium iodide symporter gene therapy in prostate cancer.

Oncolytic strains of vaccinia virus are currently in clinical development with clear evidence of safety and promising signs of efficacy. Addition of therapeutic genes to the viral genome may increase the therapeutic efficacy of vaccinia. We evaluated the therapeutic potential of vaccinia virus expressing the sodium iodide symporter (NIS) in prostate cancer models, combining oncolysis, external beam radiotherapy and NIS-mediated radioiodide therapy. The NIS-expressing vaccinia virus (VV-NIS), GLV-1h153, was tested in in vitro analyzes of viral cell killing, combination with radiotherapy, NIS expression, cellular radioiodide uptake and apoptotic cell death in PC3, DU145, LNCaP and WPMY-1 human prostate cell lines. In vivo experiments were carried out in PC3 xenografts in CD1 nude mice to assess NIS expression and tumor radioiodide uptake. In addition, the therapeutic benefit of radioiodide treatment in combination with viral oncolysis and external beam radiotherapy was measured. In vitro viral cell killing of prostate cancers was dose- and time-dependent and was through apoptotic mechanisms. Importantly, combined virus therapy and iodizing radiation did not adversely affect oncolysis. NIS gene expression in infected cells was functional and mediated uptake of radioiodide both in vitro and in vivo. Therapy experiments with both xenograft and immunocompetent Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse models showed that the addition of radioiodide to VV-NIS-infected tumors was more effective than each single-agent therapy, restricting tumor growth and increasing survival. In conclusion, VV-NIS is effective in prostate cancer models. This treatment modality would be an attractive complement to existing clinical radiotherapy practice.

Predicting Survival with Brain Metastases in the Stereotactic Radiosurgery Era: are Existing Prognostic Scores Still Relevant? Or Can we do Better?

Predicting survival is essential to tailoring treatment for patients diagnosed with brain metastases. We have evaluated the performance of widely used, validated prognostic scoring systems (Graded Prognostic Assessment and diagnosis-specific Graded Prognostic Assessment) in over 1000 'real-world' patients treated with stereotactic radiosurgery to the brain, selected according to National Health Service commissioning criteria. Survival outcomes from our dataset were consistent with those predicted by the prognostic systems, but with certain cancer subtypes showing a significantly better survival than predicted. Although performance status remains the simplest tool for prediction, total brain tumour volume emerges as an independent prognostic factor, and a new, improved, prognostic scoring system incorporating this has been developed.

Breast cancer brain metastases - A 12 year review of treatment outcomes.

BACKGROUND: Breast cancer (BC) is the 2nd commonest cause of brain metastases (BM). This retrospective review investigates the applicability of prognostic scores and highlights different outcomes for patients with HER2 positive compared to triple negative (TN) subtypes. METHODS: Two hundred and seventy four patients received whole brain radiotherapy for BC BM (01/2000-12/2011). The primary objective was to determine factors influencing overall survival (OS). All information relevant to primary BC, disease recurrence, treatment, outcome and cause of death (either neurological (NP) or systemic progression (SP)) were collected. Univariate (UV) and multivariate (MV) Cox regression analysis were used. RESULTS: One hundred and forty four patients (53%) were ER positive, 104 (38%) HER2 positive and 57 (21%) TN. Median age at BM was 53 (27-81) years and median OS from BM diagnosis 7.3 (5.7-8.9) months. On MV analysis, Her2 status, RPA score, surgery, stereotactic radiotherapy, and absence of TN disease were independent prognostic factor for OS. NP was the cause of death in 69.2% of HER2 positive patients and 17.3% had SP. Of the TN patients, 29.8% had NP and 54.4% SP (p < 0.001). CONCLUSION: A consistent OS advantage is noted for HER2 positive BM cases and inclusion of BC subtype in the breast GPA score should improve the prognostic factors' sensitivity. The unique presentations, response to treatment and causes of death for HER2 positive patients means more aggressive focal therapy should be considered and studied in the context of clinical trials. For TN BM patients with poor performance status, best supportive care may be appropriate.

Achieving the relocation accuracy of stereotactic frame-based cranial radiotherapy in a three-point thermoplastic shell.

AIMS: To compare the accuracy of fractionated cranial radiotherapy in a standard three-point thermoplastic shell using daily online correction with accuracy in a Gill-Thomas-Cosman relocatable stereotactic frame. MATERIALS AND METHODS: All patients undergoing fractionated radiotherapy for benign intracranial tumours between March 2009 and August 2010 were included. Patients were immobilised in the frame with those unable to tolerate it immobilised in the shell. The ExacTrac imaging system was used for verification/correction. Daily online imaging before and after correction was carried out for shell patients and systematic and random population set-up errors calculated. These were compared with frame patients who underwent standard departmental imaging/correction with fractions 1-3 and weekly thereafter. Set-up margins were calculated from population errors. RESULTS: Systematic and random errors were 0.3-0.7 mm/° before correction and 0.1-0.2 mm/° after correction in all axes in the frame, and 0.6-1.5 mm/° before correction and 0.1-0.4 mm/° after correction in the shell. Isotropic margins required for patient set-up could be reduced from 2 mm to <1 mm in the frame and from 5 mm to <1 mm in the shell. CONCLUSION: Similar set-up accuracy can be achieved in the standard thermoplastic shell as in a relocatable frame despite less precise immobilisation. The use of daily online correction precludes the need for larger set-up margins.

Equivalence of cisplatin and carboplatin-based chemoradiation for locally advanced squamous cell carcinoma of the head and neck: a matched-pair analysis.

BACKGROUND: Carboplatin can be substituted for cisplatin in concomitant chemoradiation (CRT) for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) when the latter is contraindicated. This matched-pair study aimed to compare the efficacy and acute toxicity of carboplatin and cisplatin. METHODS: Patients treated with 2 cycles of concomitant carboplatin-based CRT were matched to patients treated with 2 cycles of cisplatin. Matching criteria included age, tumour site, stage, smoking status and use of induction chemotherapy. Radiation was delivered using conformal techniques. Data on weekly acute toxicity throughout CRT was compared using the chi-squared test for proportions. Kaplan Meier statistics described time to local relapse, distant relapse and overall survival, the log-rank test was used to compare 3-year survival outcomes. RESULTS: Sixty-five patients who received carboplatin were matched to 65 who received cisplatin. Significant differences in toxicity included increased emesis with cisplatin and more anaemia and thrombocytopenia with carboplatin. There was no significant difference in 3-year locoregional control (87% vs. 79%, p=0.54), freedom from distant metastases (88% vs. 85%, p=0.79) and overall survival (59% vs. 68%, p=0.24) between the carboplatin and cisplatin cohorts, respectively. CONCLUSIONS: When cisplatin is contraindicated, carboplatin-based CRT yields equivalent treatment outcomes in patients with LASCCHN.

The release of leptin and its effect on hormone release from human pituitary adenomas.

BACKGROUND: Leptin is the protein product of the obese gene, known to play an important role in body energy balance. The leptin receptor exists in numerous isoforms, the long isoform being the major form involved in signal transduction. Leptin expression has recently been demonstrated in the human pituitary, both in normal tissue and in pituitary adenomas. The long isoform of the leptin receptor has also been shown to be present in pituitary adenomas; however, contrasting results have been obtained regarding its expression in the normal human pituitary. AIM: The aim of this study was (i) to investigate the presence and pattern of distribution of leptin mRNA and the long isoform of its receptor mRNA in the normal pituitary and in different types of pituitary adenomas with RT-PCR; (ii) to study leptin secretion from human pituitary tumours in culture and (iii) to assess in vitro pituitary hormone release following stimulation with human leptin. RESULTS: Leptin receptor long isoform expression was detected in 2/4 GH-secreting adenomas, 12/17 non-functioning adenomas, 5/9 ACTH-secreting adenomas, 1/2 prolactinomas, 2/2 FSH-secreting adenomas and 5/5 normal pituitaries. The receptor long isoform did not segregate with any particular tumour type, and varying levels of expression were detected between the tissues studied. Leptin mRNA was detected at a low level of expression in 2/7 GH-secreting adenomas, 9/14 non-functioning adenomas, 2/3 ACTH-secreting adenomas, 1/3 prolactinomas and 1/3 FSH-secreting adenomas. We were unable to detect leptin mRNA in any of the five normal pituitaries removed at autopsy; however, immunostaining of a non-tumorous pituitary adjacent to an adenoma removed at transsphenoidal surgery showed scattered leptin positive cells. Culture of pituitary adenomas showed that 16/47 released leptin into the incubation media. Leptin release did not correlate with tumour type or with any of the other pituitary hormones released. In vitro leptin stimulation of pituitary tumours caused stimulation of FSH and alpha-subunit secretion from a non-functioning adenoma and TSH secretion from a somatotroph adenoma. CONCLUSION: We conclude that not only is leptin stored within the pituitary, but it may also be released from pituitary cells and modulate other pituitary hormone secretion. Pituitary leptin may therefore be a novel paracrine regulator of pituitary function.