A single dose of intravenous combretastatin A4-phosphate is reasonably well tolerated and significantly reduces tumour vascularization in canine spontaneous cancers.

Combretastatin A4-phosphate (CA4P) is an anti-tumour vascular targeting agent which selectively blocks tumour blood flow. Research on CA4P in rodent tumour models is extensive; however, knowledge of its effect on spontaneous cancer is scarce. This study was conducted in canine patients with spontaneous solid tumours. The goal was to assess the toxicity and efficacy of CA4P in various spontaneous tumour types. Eight dogs with spontaneous tumours were enrolled and treated with a single dose of 75 mg m-2 intravenous CA4P. The dogs were screened and monitored before and after injection. Pre- and post-treatment tumour blood flow was analysed in vivo by power Doppler ultrasound (PDUS) and contrast-enhanced ultrasound (CEUS). Vessel destruction and tumour necrosis were evaluated by histopathology. Clinically relevant toxicity was limited to one case of temporary tetraparesis; other adverse events were mild. Significant cardiovascular changes were mostly confined to changes in heart rate and cTnI levels. Macroscopic tumour size reduction was evident in 2 dogs. Based on PDUS and CEUS, CA4P induced a significant decrease in vascular index and tumour blood flow. Post-treatment, histopathology revealed a significant increase of necrotic tumoural tissue and a significant reduction in microvessel density in tumoural tissue. Anti-vascular and necrotizing effects of CA4P were documented in a variety of canine spontaneous cancers with only minimal side effects. This is the first study reporting the administration of CA4P to canine cancer patients with in vivo and ex vivo assessment, and a first step toward implementing CA4P in combination therapies in veterinary oncology patients. The use of CA4P in canine patients was approved and registered by the Belgian Federal Agency for Medicines and Health Products (FAMHP) (approval number 0002588, registration number 6518 ID 2F12).

Biodistribution and tolerance of intravenous iodine-131-labelled hypericin in healthy dogs.

Hypericin (Hyp) is a necrosis-avid compound that can be efficiently labelled with radioiodine for both diagnostic and therapeutic purposes. Before 131 I-Hyp can be considered as a clinically useful drug in a combination therapy for canine cancer patients, evaluation of its toxicity is necessary. The aim of this study was to investigate the biodistribution and tolerance of a single dose administration of 131 I-Hyp. Three healthy dogs were included. 131 I-Hyp at a dose of 0.2 mg/kg and an activity of 185 MBq was intravenously injected. The effects on physical, haematological and biochemical parameters were characterized and the biodistribution and elimination pattern, the effective half-life and dose rate were assessed. Drug-related adverse events were limited to mild gastrointestinal signs, resolving within 48 hours. No significant differences were found in blood haematology and serum biochemistry before and after treatment. Following administration, highest percentage of injected dose (%ID ± SD) was found in the liver (5.5 ± 0.33), the lungs (4.17 ± 0.14) and the heart (3.11 ± 0.78). After 24 hours, highest %ID was found in colon (4.25 ± 1.45) and liver (3.45 ± 0.60). Clearance from all organs was effective within 7 days. Effective half-life was established at 80 hours, and the dose rate fell below <20 µSv/h at 1 m within 1 day. The current study reveals that single dose treatment with 131 I-Hyp at the described dose is well tolerated by healthy dogs and supports the use of radioiodinated hypericin in a combination therapy for canine cancer patients.

A dose-escalation study of combretastatin A4-phosphate in healthy dogs.

Combretastatin A4-Phosphate (CA4P) is a vascular disrupting agent revealing promising results in cancer treatments for humans. The aim of this study was to investigate the safety and adverse events of CA4P in healthy dogs as a prerequisite to application of CA4P in dogs with cancer. Ten healthy dogs were included. The effects of escalating doses of CA4P on physical, haematological and biochemical parameters, systolic arterial blood pressure, electrocardiogram, echocardiographic variables and general wellbeing were characterised. Three different doses were tested: 50, 75 and 100 mg m-2 . At all 3 CA4P doses, nausea, abdominal discomfort as well as diarrhoea were observed for several hours following administration. Likewise, a low-grade neutropenia was observed in all dogs. Doses of 75 and 100 mg m-2 additionally induced vomiting and elevation of serum cardiac troponine I levels. At 100 mg m-2 , low-grade hypertension and high-grade neurotoxicity were also observed. In healthy dogs, doses up to 75 mg m-2 seem to be well tolerated. The severity of the neurotoxicity observed at 100 mg m-2 , although transient, does not invite to use this dose in canine oncology patients.

Bone mineral density and fractures after surgical menopause: systematic review and meta-analysis.

BACKGROUND: Oophorectomy is recommended for women at increased risk for ovarian cancer. When performed at premenopausal age oophorectomy induces acute surgical menopause, with unwanted consequences. OBJECTIVE: To investigate bone mineral density (BMD) and fracture prevalence after surgical menopause. SEARCH STRATEGY: A literature search of PubMed, EMBASE and Cochrane library was performed with no date restriction. Date of last search was March 1st, 2016. SELECTION CRITERIA: Primary studies reporting on BMD, T-scores or fracture prevalence in women with surgical menopause and age-matched control groups. DATA COLLECTION AND ANALYSIS: Data were extracted on BMD (g/cm2 ), T-scores and fracture prevalence in women with surgical menopause and control groups. Quality was assessed by an adaptation of the Downs and Black checklist. Random effects models were used to meta-analyse results of studies reporting on BMD or fracture rates. MAIN RESULTS: Seventeen studies were included, comprising 43 386 women with surgical menopause. Ten studies provided sufficient data for meta-analysis. BMD after surgical menopause was significantly lower than in premenopausal age-matched women [mean difference lumbar spine, -0.15 g/cm2 (95% CI, -0.19 to -0.11 g/cm2 ); femoral neck, -0.17 g/cm2 (95% CI, -0.23 to -0.11 g/cm2 )] but not lower than in women with natural menopause [lumbar spine, -0.02 g/cm2 (95% CI, -0.04 to 0.00 g/cm2 ); femoral neck, 0.04 g/cm2 (95% CI, -0.09 to 0.16 g/cm2 )]. Hip fracture rate was not higher after surgical menopause compared with natural menopause [hazard ratio: 0.85 (95% CI, 0.70 to 1.04)]. AUTHOR'S CONCLUSIONS: No evident effect of surgical menopause was observed on BMD and fracture prevalence compared with natural menopause. However, available studies are prone to bias and need to be interpreted with caution. TWEETABLE ABSTRACT: Bone health after menopause: no evidence for additional effect of surgical menopause on BMD and fractures.

Combretastatin A4-phosphate and its potential in veterinary oncology: a review.

For many years, research on anticancer therapy has focussed almost exclusively on targeting cancer cells directly, to selectively kill them or restrict their growth. But limited advances in this strategy have led researchers to shift their attention to other potential targets. Active research is now on-going on targeting tumour stroma. Vascular disrupting agents (VDAs) appear a promising class of anticancer drugs that are currently under investigation as a sole or combined therapy in human cancer patients. This article will briefly touch on the history and biology of combretastatin A4-phosphate (CA4P) as a typical example of VDAs and will concentrate on the side effects that can be expected when used in veterinary patients. Particularly, the pathogenesis of these side effects and how they may be prevented and/or treated will be discussed. The purpose of this article is to illustrate the potentials of CA4P as anticancer therapy in veterinary oncology patients.

Malignant aldosterone-producing adrenal tumour: reoccurrence with glucocorticoid excess without hyperaldosteronism.

We describe a case of hypokalaemic hypertension due to hyperaldosteronism caused by a unilateral adrenocortical tumour with unfavourable histopathology suggestive of malignancy. After removal, the aldosterone excess disappeared. The patient's clinical course was uneventful, until she presented with extensive metastases of adrenal carcinoma four years later. Biochemical abnormalities were now consistent with glucocorticoid excess without hyperaldosteronism. She died four months later. Although malignant aldosterone-producing adrenal tumours are very rare, the present case underscores that clinicians should be aware that primary hyperaldosteronism can occur in the context of adrenocortical carcinoma.