Obstacles to effective immunotherapeutic anti-cancer approaches include poor immunogenicity of the tumour cells and the presence of tolerogenic mechanisms in the tumour microenvironment. We report an effective immune-based treatment of weakly immunogenic, growing solid tumours using a locally delivered immunogene therapy to promote development of immune effector responses in the tumour microenvironment and a systemic based T regulatory cell (Treg) inactivation strategy to potentiate these responses by elimination of tolerogenic or immune suppressor influences. As the JBS fibrosarcoma is weakly immunogenic and accumulates Treg in its microenvironment with progressive growth, we used this tumour model to test our combined immunotherapies. Plasmids encoding GM-CSF and B7-1 were electrically delivered into 100 mm(3) tumours; Treg inactivation was accomplished by systemic administration of anti-CD25 antibody (Ab). Using this approach, we found that complete elimination of tumours was achieved at a level of 60% by immunogene therapy, 25% for Treg inactivation and 90% for combined therapies. Moreover, we found that these responses were immune transferable, systemic, tumour specific and durable. Combined gene-based immune effector therapy and Treg inactivation represents an effective treatment for weakly antigenic solid growing tumours and that could be considered for clinical development.

INTRODUCTION: We report the case of a 53-year-old farmer with a 5-day history of severe headache, photophobia and neck stiffness. Full blood count (platelets 173), coagulation screen were normal throughout. Liver function tests remained normal apart from an elevated gamma-GT (156). CT Brain was normal. CSF analysis showed a WCC of 454/mm(3) (60% lymphocytes), elevated CSF protein (1.42 g/l) and a normal CSF glucose. He was commenced on IV antibiotics and IV acyclivor and improved. On day 3 of admission, he complained of a sudden severe headache, became unresponsive (GCS 3/15). INVESTIGATIONS: CT Brain showed a massive left intraventricular haemorrhage. He died 4 days later. Subsequent serum serology for leptospirosis was positive. A repeat sample taken 4 days post-admission, showed a rising IgM indicating active leptospirosis. Detailed pathological examination confirmed intracerebral haemorrhage with normal cerebral vasculature. CONCLUSION: Leptospirosis is a rare cause of intracerebral haemorrhage even in the absence of coagulopathy.

OBJECTIVE: We aim to determine if urine cytology was still necessary as a routine part of the evaluation for the presence of urological malignancy and to evaluate its cost effectiveness. METHODS: Urine cytology reports over a 6-year period (2000-2005) were retrieved from our institution's pathology department database. Patients with urine cytology positive for malignant cells were identified. We retrospectively reviewed the charts of these patients for age, sex, flexible cystoscopy and radiological imaging results. The cost of urine cytology was retrieved from the pathology department. RESULTS: There were a total of 2,568 urine cytological examinations. Of these, 25 were positive for malignant cells. There were 19 male (76%) and 6 female (24%) patients with a mean age of 72 years (range: 49-97). In 21 patients with positive cytology, a bladder tumor was identified at flexible cystoscopy and/or imaging studies. For a positive cytology yield of 1%, EUR 210,000 was spent. CONCLUSIONS: Routine urine cytology was not cost effective and did not add to the diagnostic yield beyond cystoscopy and diagnostic imaging. It may be omitted in the initial evaluation of urological malignancy.

Challenges for oncology practitioners and researchers include specific treatment and detection of tumours. The ideal anti-cancer therapy would selectively eradicate tumour cells, whilst minimising side effects to normal tissue. Bacteria have emerged as biological gene vectors with natural tumour specificity, capable of homing to tumours and replicating locally to high levels when systemically administered. This property enables targeting of both the primary tumour and secondary metastases. In the case of invasive pathogenic species, this targeting strategy can be used to deliver genes intracellularly for tumour cell expression, while non-invasive species transformed with plasmids suitable for bacterial expression of heterologous genes can secrete therapeutic proteins locally within the tumour environment (cell therapy approach). Many bacterial genera have been demonstrated to localise to and replicate to high levels within tumour tissue when intravenously (IV) administered in rodent models and reporter gene tagging of bacteria has permitted real-time visualisation of this phenomenon. Live imaging of tumour colonising bacteria also presents diagnostic potential for this approach. The nature of tumour selective bacterial colonisation appears to be tumour origin- and bacterial species- independent. While originally a correlation was drawn between anaerobic bacterial colonisation and the hypoxic nature of solid tumours, it is recently becoming apparent that other elements of the unique microenvironment within solid tumours, including aberrant neovasculature and local immune suppression, may be responsible. Here, we consider the pre-clinical data supporting the use of bacteria as a tumour-targeting tool, recent advances in the area, and future work required to develop it into a beneficial clinical tool.

BACKGROUND: A requirement of an effective acute stroke service is the early arrival of patients to the hospital emergency department (ED). This will allow the possible use of thrombolytic therapy or other acute interventions within a limited time window. AIMS: We investigated the predictors of early arrival in a single hospital serving a mixed urban and rural catchment area. METHODS: A retrospective review of all case notes for 1 year was performed. RESULTS: Of 105 acute strokes, 91 were cerebral infarcts and a total of 71 cases presenting initially to the ED had timing available for analysis. 39.4% presented within 3 h, and 12.7% were potentially suitable for thrombolysis. Those living closer to the hospital were not more likely to arrive within 3 h (Z = -0.411, p = 0.68). Presenting directly to the hospital by emergency services (or private transport) was significantly associated with early arrival in a univariate comparison (p < 0.001), and in a multivariate model. CONCLUSION: The only independent predictor of early arrival to the ED is direct presentation. Improved public education of the importance of recognition of stroke symptoms and rapid contact with the emergency services will improve the early attendance following acute stroke, allowing increased use of acute stroke treatments.

Necrotizing fasciitis (NF) is an uncommon soft-tissue infection in children that carries a high mortality rate. We present a 15-year-old girl with chronic pancytopenia secondary to Fanconi anaemia who developed extensive NF of the lower limb, which unfortunately resulted in a fatal outcome. Immunodeficiency is a known risk factor for the development of this condition. The findings in this case demonstrate that patients with Fanconi anaemia may be susceptible to NF and that the clinical course may be more aggressive due to underlying immunosuppression. Prompt diagnosis of NF is vital in order to initiate appropriate treatment and to optimize patient outcome. Radiological investigation demonstrated extensive soft-tissue gas and destruction affecting the entire lower limb, abdominal wall and retroperitoneum, which led to timely definitive diagnosis and management.

AIM: The aim was to investigate whether the intrathyroid conversion of T4 to T3 in autonomously functioning thyroid adenoma (AFTA) tissue could influence serum T3 levels and suppression of TSH, especially in patients with borderline thyroid function. PATIENTS AND METHODS: In ten patients with AFTA, thyroidal conversion of T4 to T3 was investigated in nodular and paranodular, TSH-suppressed tissue. All patients had normal serum T4 and suppressed TSH. Serum T3 was normal in six, and borderline or slightly increased in four. AFTA and paranodular tissues were surgically removed and frozen at -70 degrees C, then homogenized in a glass homogenizer, centrifuged at 100,000xg, and particulate fraction collected as a pellet. Analysis mixture consisted of thyroid enzyme suspension in 50 mumol/L TRIS buffer with 5 mumol DTT and 200 muL 1.3 mumol T4. Incubation was performed at 37 degrees C and the generation of T3 measured after 5, 10, 20 and 40 minutes respectively. RESULTS: T3 production (pmol/mg protein) was significantly higher in AFTA than in paranodular tissues (8.8 1.2/Mean +/- SE/vs. 1.8 +/- 0.2; p<0.01), and excessively high (9.8, 14.1, 14.2 and 15.0) in four patients with borderline or slightly supranormal serum T3. A significant correlation was found between serum T3 concentrations and T3 generation (T4 conversion) in AFTA tissues. CONCLUSION: Results suggest that increased thyroidal T4 to T3 conversion in AFTA tissue could be involved in an increased delivery of T3, increased serum T3 and suppressed serum TSH, particularly in patients with the disease evolving from euthyroid to an early hyperthyroid phase.

AIM: To evaluate predictors of asymptomatic atrial fibrillation in patients older than 70 years with complete atrioventricular (AV) block, normal left ventricular systolic function, and implanted dual chamber (DDD) pacemaker. METHODS: Hundred and eighty six patients with complete AV block were admitted over one year to the Sisters of Mercy University Hospital. The study recruited patients older than 70 years, with no history of atrial fibrillation, heart failure, or reduced left ventricular systolic function. All the patients were implanted with the same pacemaker. Out of 103 patients who were eligible for the study, 81 (78%) were evaluated. Among those 81 (78%) were evaluated. Eighty one (78%) patients were evaluated. Follow-up time ranged from 12 to 33 months (average +/-standard deviation 23 +/- 5 months). Primary end-point was asymptomatic atrial fibrillation occurrence recorded by the pacemaker. Atrial fibrillation occurrence was defined as atrial high rate episodes (AHRE) lasting >5 minutes. Binary logistic regression was used to identify the predictors of development of asymptomatic atrial fibrillation. Results. The 81 patients were stratified into two groups depending on the presence of AHRE lasting >5 minutes (group 1 had AHRE>5 minutes and group 2 AHRE<5 minutes). AHRE lasting >5 minutes were detected in 49 (60%) patients after 3 months and in 53 (65%) patients after 18 moths. After 3 months, only hypertension (odds ratio [OR], 17.63; P = 0.020) was identified as a predictor of asymptomatic atrial fibrillation. After 18 months, hypertension (OR, 14.0; P = 0.036), P wave duration >100 ms in 12 lead ECG (OR, 16.5; P = 0.001), and intracardial atrial electrogram signal amplitude >4 mV (OR, 4.27; P = 0.045) were identified as predictors of atrial fibrillation. CONCLUSION: In our study population, hypertension was the most robust and constant predictor of asymptomatic atrial fibrillation after 3 months, while P wave duration >100 ms in 12-lead ECG and intracardial atrial signal amplitude were predictors after 18 months.