Inter- and intra-rater reliability and agreement in determining subcutaneous tumour margins in dogs.

The objective of this prospective study was to evaluate agreement and reliability of calliper-based measurements of locally invasive subcutaneous malignant tumours in dogs. Four raters measured the longest diameter of 12 subcutaneous tumours (7 soft tissue sarcomas and 5 mast cell tumours) from 11 client-owned dogs during 3 randomized, blinded measurement trials, both pre- and post-sedation. Inter- and intra-rater reliability was evaluated using intra-class correlation coefficient (ICC) and agreement was evaluated using Bland-Altman plots. Inter- and intra-rater reliability was good (ICC range of 0.8694-0.89520) and excellent (ICC range of 0.9720-0.9966), respectively. For agreement calculations, an a priori clinically relevant limit of agreement of 10 mm was set. Inter- and intra-rater agreement was unacceptable with inter-rater limits of agreement ranging from 15.9 to 55.6 mm and intra-rater limit of agreement ranging from 11.9 to 28.1 mm. Review of the measurement trial photographs revealed that calliper orientation changes were frequent, occurring in 9/12 (75%) and 8/12 (67%) pre- and post-sedation cases. No significant correlation was found between inter-rater measurement standard deviations and calliper orientation changes or dog body condition score. These findings suggest veterinarians may have poor agreement in determining the gross edge of tumours, which is expected to introduce bias and inconsistency in tumour staging, assessing response to therapy, and surgical margin planning. Due to the potential consequences for veterinary cancer patients, future studies are needed to validate the present findings.

Characterizing Microscopical Invasion Patterns in Canine Mast Cell Tumours and Soft Tissue Sarcomas.

Stromal invasion is identified commonly in cutaneous malignancies; however, invasive patterns are defined inconsistently and their clinical relevance is uncertain. This study aimed to define objective, quantifiable histomorphological invasive patterns in low-grade canine mast cell tumours (MCTs) and grade I/II soft tissue sarcomas (STSs), and correlate invasive patterns with overall excisional status. Haematoxylin and eosin-stained glass slides prepared for routine histopathology of surgically-excised tumours from client-owned dogs were evaluated for invasion beyond their subgross edge, asymmetrical invasion, satellite lesions, lymphovascular invasion, perineurovascular growth, growth along fascial planes, intramuscular invasion and multicompartmental involvement. Digital histological tumour-free margins <1 mm in any direction were considered to represent an incomplete excision. Fifty-one dogs with 69 tumours (50 MCTs and 19 STSs) were included in the study. Invasion in both circumferential and deep directions was significantly greater in MCTs compared with STSs (exact 2-tailed P <0.0001 circumferential; P = 0.0095 deep). Within the MCT group, circumferential invasion was greater than deep invasion (P = 0.0076). Multivariate logistic regression analysis found two variables that were significantly associated with incomplete MCT excision: intraoperative grossly normal circumferential surgical margin size (odds ratio of 0.776, 95% confidence interval: 0.651-0.925) and asymmetry invasion index (odds ratio of 1.318, 95% confidence interval: 1.039-1.671). These data may help create evidence-based strategies for planning surgical resections of cutaneous malignancies. Presence of asymmetrical microscopical invasion might prompt pathologists to perform more comprehensive surgical margin evaluation.

Preliminary evaluation of serum total cholesterol concentrations in dogs with osteosarcoma.

OBJECTIVES: To determine if total serum cholesterol concentrations were altered in dogs with osteosarcoma. To evaluate association of total serum cholesterol concentration with clinical outcomes in dogs with appendicular osteosarcoma. MATERIALS AND METHODS: Retrospective, multi-institutional study on 64 dogs with osteosarcoma. Control population consisted of dogs with traumatic bone fractures (n=30) and healthy patients of similar age and weight as those of the osteosarcoma cases (n=31). Survival analysis was done on 35 appendicular osteosarcoma patients that received the current standard of care. Statistical associations were assessed by univariable and multi-variable analysis. Information about age, sex, primary tumour location, total cholesterol concentration, monocytes and lymphocyte counts and alkaline phosphatase were also included. RESULTS: Total cholesterol was elevated above the reference interval (3·89 to 7·12 mmol/L) (150 to 275 mg/dL) in 29 of 64 (45·3%) osteosarcoma-bearing dogs, whereas similar elevations were found in only 3 of 30 (10%) fracture controls (P<0·0001) and 2 of 31 (6·5%) similar age/weight controls (P=0·0002). Elevated total cholesterol was significantly associated with a reduced hazard ratio (0·27, P=0·008) for overall mortality in dogs with osteosarcoma. CLINICAL SIGNIFICANCE: These results suggest that elevated total cholesterol is associated with canine osteosarcoma and may have prognostic significance.

Antagonism of serotonin receptor 1B decreases viability and promotes apoptosis in the COS canine osteosarcoma cell line.

Serotonin receptor 1B (5HTR1B) traditionally exhibits anti-proliferative activity in osteoblasts. We examined the expression and function of 5HTR1B in the COS canine osteosarcoma cell line and normal canine osteoblasts. Equal levels of 5HTR1B gene and protein expression were found between normal and malignant osteoblasts. Treatment with serotonin enhanced viability of osteosarcoma cells but not normal osteoblasts. Challenge with the 5HTR1B agonist anpirtoline caused no change in cell viability. Rather incubation with the specific receptor antagonist SB224289 caused reduction in osteoblast viability, with this effect more substantial in osteosarcoma cells. Investigation of this inhibitory activity showed 5HTR1B antagonism induces apoptosis in malignant cells. Evaluation of phosphorylated levels of CREB and ERK, transcriptional regulators associated with serotonin receptor signalling in osteoblasts, revealed aberrant 5HTR1B signalling in COS. Our results confirm the presence of 5HTR1B in a canine osteosarcoma cell line and highlight this receptor as a possible novel therapeutic target.

Evaluation of toxicities from combined metronomic and maximal-tolerated dose chemotherapy in dogs with osteosarcoma.

OBJECTIVE: To evaluate the tolerability of a piroxicam and cyclophosphamide metronomic treatment protocol combined with carboplatin alone or carboplatin and doxorubicin at maximal-tolerated doses. METHODS: Retrospective study of 30 dogs diagnosed with osteosarcoma. All dogs underwent amputation and chemotherapy treatment with one of the two maximal-tolerated dose protocols. Metronomic chemotherapy was administered in conjunction with these protocols, and continued subsequently. The protocols included 0 · 3 mg/kg piroxicam and 10 to 12 mg/M(2) cyclophosphamide with 300 mg/M(2) carboplatin alone, or 300 mg/M(2) carboplatin alternating with 30 mg/M(2) doxorubicin. RESULTS: Fourteen dogs were treated with the carboplatin and metronomic protocol and 16 were treated with the carboplatin alternating with doxorubicin and metronomic protocol. Grades 3 and 4 toxicities overall were significantly (P = 0 · 018) more common in the former group. The disease-free interval of the carboplatin and metronomic group was 192 days, which was not significantly different (P = 0 · 916) to the 182 days for the carboplatin alternating with doxorubicin and metronomic group. The median survival times of the two groups were 217 and 189 days, respectively. CLINICAL SIGNIFICANCE: Piroxicam and cyclophosphamide metronomic protocols can be safely administered in combination with maximal-tolerated dose chemotherapy protocols. A significantly higher frequency of toxicities was observed in dogs treated with the carboplatin and metronomic protocol.

Neurobiological basis of relapse prediction in stimulant-induced psychosis and schizophrenia: the role of sensitization.

A number of consistent clinical observations provide direction for the hypothesis that pathological sensitization of neuronal systems may be an important factor for relapse or the onset of stimulant-induced psychosis (eg, methamphetamine or amphetamine psychosis, cocaine psychosis and phencyclidine psychosis) and schizophrenia. First, psychotic symptoms can be produced in normal subjects by stimulants. Secondly, a large portion of schizophrenic patients exhibit exacerbation of psychotic symptoms in response to stimulants at doses which would not be psychotogenic in normal subjects. Lastly, the ability of stress to precipitate the onset and relapse of schizophrenia is well documented. In this regard, acute responses to stimulants provide useful information for relapse prediction of schizophrenia and substance abuse. This paper addresses the nature and role of pathological sensitization in relapse of stimulant- and phencyclidine-induced psychosis and schizophrenia, and its relation to pathophysiology of schizophrenia.

Olfactory memory in unmedicated schizophrenics.

Previous studies have indicated that schizophrenic patients have olfactory deficits. The question as to whether olfactory deficits are due to chronic effects of medication has not been addressed. This is the first paper to report that never-medicated schizophrenic patients also have olfactory deficits. Twenty four normal subjects and twenty unmedicated schizophrenic patients were examined with two tests of olfactory function: the University of Pennsylvania Smell Identification Test (UPSIT) and a match-to-sample olfactory memory test. Results indicated that schizophrenics did poorly on both the UPSIT and the olfactory match-to-sample memory test relative to sex and age-matched controls. ANCOVA showed that the deficit in performance on the olfactory match-to-sample test was still present even when the variance due to the UPSIT was taken out of the analysis. Deficits in olfactory identification and olfactory memory are consistent with the concept that schizophrenics have dysfunctional limbic systems.