Prognostic significance of serum alkaline phosphatase activity in canine appendicular osteosarcoma

Sixty-one dogs with appendicular osteosarcoma were treated with amputation and chemotherapy of cisplatin and doxorubicin. Serum samples were obtained before and after treatment for determination of total alkaline phosphatase (TALP) activity as well as the activities of the constituent bone (BALP), liver (LALP), and corticosteroid-induced (CALP) isoenzymes. The relationship between alkaline phosphatase activities and survival was examined by Cox proportional hazards regression analysis and Kaplan-Meier log rank analysis. Mean activity of TALP, BALP, and LALP decreased significantly after treatment (P < .001). TALP and LALP activities before treatment were significantly correlated with survival (P = .006 and .001, respectively). The correlation between BALP activity before treatment and survival approached significance (P = .054). CALP activity and TALP, BALP, and LALP activities after treatment were not significantly correlated with survival. Dogs with normal pretreatment TALP and BALP activities survived significantly longer than dogs with increased pretreatment activities (P = .001 and .003, respectively). Median survival times for dogs with normal or increased TALP activities before treatment were 12.5 and 5.5 months, respectively; and median survival times for dogs with normal or increased BALP activities before treatment were 16.6 and 9.5 months, respectively. In the design of future clinical trials involving dogs with osteosarcoma, consideration should be given to stratifying the randomization according to alkaline phosphatase activity. In addition, alkaline phosphatase activity should be a factor considered by clinicians attempting to tailor the aggressiveness of adjuvant chemotherapy to the needs of individual patients or owners.     

Prognostic significance of morphological subtypes in canine malignant lymphomas during chemotherapy

The aim of this study was to determine the response of different morphological subtypes of canine lymphoma to a standardized therapeutic protocol. Diagnosis of lymphoma was based on cytohistological analysis and immunophenotyping with antibodies against CD3 and CD79a of an enlarged lymph node or an extranodal mass. Fifty-seven cases were classified according to the updated Kiel classification adapted to the canine species, into 24 B-cell lymphomas (20 centroblastic polymorphic and four Burkitt-type subtypes), and 33 T-cell lymphomas (10 pleomorphic mixed, 10 lymphoblastic, eight unclassifiable high grade plasmacytoid, and five small clear-cell subtypes). All dogs were clinically staged at diagnosis. The protocol used l-asparaginase, vincristine, cyclophosphamide, doxorubicin, and prednisone. First remission duration and overall survival time were evaluated. Although the T-cell phenotype was associated, on the whole, with a poor prognosis, as previously reported in veterinary and human medicine, the study showed significant prognostic differences between the B- and the T-cell subtypes of canine lymphoma and suggests that clinico-morphological characterization of the disease is justified in dogs, as in humans.     

Principles of treatment for soft-tissue sarcomas in the dog

Soft-tissue sarcomas develop from a variety of mesenchymal tissues, but they are often considered collectively, due to similarity in clinical behavior and histologic features. These tumors are locally invasive, with poorly defined histologic margins and neoplastic cells that often infiltrate through fascial planes. In general, local recurrence is common following conservative excision. Pretreatment biopsy provides information on tumor type and grade, which will allow the clinician to properly plan for an aggressive first surgery. Adopted from human medicine, the canine histopathologic grading system is predictive. Specifically, mitotic rate is predictive for metastasis, and necrosis and mitotic rate are predictive for survival. Diagnostic imaging is useful to determine the extent of disease and for treatment planning. The most effective treatment for soft-tissue sarcomas is surgical excision. Surgery with curative intent requires preoperative biopsy, planning, and a wide first excision. Increasingly, surgery is being replaced by a combined-modality approach. Radiation therapy plays an important role in the management of soft-tissue sarcomas, but it has little role as a single treatment modality. Radiation therapy is appropriate for incompletely excised tumors or for preoperative treatment. Chemotherapy's role is most appropriate in the adjunct setting, and is mainly used to treat incompletely resected tumors, high-grade tumors, and metastatic disease.     

Radiation treatment for incompletely resected soft-tissue sarcomas in dogs

OBJECTIVE: To evaluate efficacy of radiation for treatment of incompletely resected soft-tissue sarcomas in dogs. DESIGN: Prospective serial study. ANIMALS: 48 dogs with soft-tissue sarcomas. PROCEDURE: Tumors were resected to < 3 cm3 prior to radiation. Tumors were treated on alternate days (three 3-Gy fractions/wk) until 21 fractions had been administered. Cobalt 60 radiation was used for all treatments. RESULTS: Five-year survival rate was 76%, and survival rate was not different among tumor types or locations. Four (8%) dogs developed metastases. Eight (17%) dogs had tumor recurrence after radiation. Development of metastases and local recurrence were significantly associated with reduced survival rate. Median survival time in dogs that developed metastases was 250 days. Median disease-free interval for all dogs was 1,082 days. Median time to recurrence was 700 days. Dogs that developed recurrence after a prolonged period responded well to a second surgery. Acute radiation toxicosis was minimal; osteosarcoma developed at the radiation site in 1 dog. CONCLUSIONS AND CLINICAL RELEVANCE: An excellent long-term survival rate may be achieved by treating soft-tissue sarcomas in dogs with resection followed by radiation. Amputation is not necessary for long-term control of soft-tissue sarcomas in limbs. Development of metastases and recurrence of local tumors after radiation treatment are associated with decreased survival rate. Acute and delayed radiation toxicosis was minimal with the protocol used in this study.     

Prognostic significance of a new histologic grading system for canine osteosarcoma

Histologic grade is an important determinant in clinical outcome of human osteosarcoma (OS). In this study, the histologic characteristics of primary and metastatic canine OS were evaluated using a new classification system. Histologic characteristics were classified in 166 primary and 34 metastatic canine OS. Prognostic variables for clinical outcome were determined using multivariate analysis. Most OS were histologically characterized by severe to extreme cellular pleomorphism, a variable number of mitoses, small to moderate amounts of matrix, a high percentage of tumor cells, and minimal to moderate amounts of necrosis. Tumor invasion into vessels was present in 117/152 (71%) tumors, and 12/50 (24%) of the regional lymph nodes had evidence of metastasis. Classification of the 166 tumors resulted in seven (4%) grade 1, 34 (21%) grade II, and 125 (75%) grade III OS. In the multivariate analysis, histologic grade III OS and elevated pretreatment plasma alkaline phosphatase (AP) levels were independent predictors of clinical outcome. Dogs with high-grade tumors and elevated AP should be carefully evaluated for the presence of metastatic disease before starting adjunctive therapy protocols.     

Prognostic significance of morphotypes in canine lymphomas: A systematic review of literature

Correlation between morphotypes and prognosis of canine lymphomas presented discordant results in literature, leading to some dilemma for application in clinical practice. The aim of this study was to present a systematic review of literature on the prognostic significance of morphotypes in canine lymphomas. Standardized Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) criteria were applied. Retrospective and prospective studies were included. Level of evidence was determined for each study. Some acceptable evidence suggested a significant prognostic impact of morphotypes in canine lymphomas. However, the evidence is not sufficiently robust to determine with precision the most appropriate classification scheme. Updated Kiel and World Health Organization (WHO) classifications seem to remain the most appropriate classification systems with regards to the number of available studies and their levels of evidence. Limitations included lack of randomized control trial, and relative lack of prospective studies available. Current recommended classification of canine lymphoma is the systematic determination of morphotype in each new case. The Updated Kiel and the WHO classifications adapted to dog both remain the schemes with the most valuable interest. Prospective studies in larger population, and international consensus to define precisely each morphotype, are warranted, with application of standardized staging method and treatment.     

Correlation of quantified contrast-enhanced power Doppler ultrasonography with immunofluorescent analysis of microvessel density in spontaneous canine tumours

Conventionally, tumour vascularity is assessed invasively by immunofluorescent analysis. Quantified contrast-enhanced power Doppler ultrasound has been used to measure tumour angiogenesis non-invasively in humans and experimental animals. The purpose of this study was to correlate quantified contrast-enhanced power Doppler ultrasound with immunofluorescent results in 45 spontaneous canine tumours. With power Doppler, mean vascularity was high in squamous cell carcinomas, moderate in malignant oral melanomas and low in sarcomas. There was high mean vascularity in squamous cell carcinomas and low mean vascularity in sarcomas and malignant oral melanomas. Although Doppler parameters correlated moderately with microvascular density for all tumours (P=0.004, r=0.4), they did not correlate within histology groups. These analyses show that vascularity differs among canine tumour histology groups. However, dependent on the method used, measurement of tumour vascularity can provide different biological information.     

Quantitative morphology in canine cutaneous soft tissue sarcomas

Stained cytological specimens from 24 dogs with spontaneous soft tissue sarcomas [fibrosarcoma (n = 8), liposarcoma (n = 8) and haemangiopericytoma (n = 8)], and 24 dogs with reactive connective tissue lesions [granulation tissue (n = 12) and dermal fibrosis (n = 12)] were analysed by computer‐assisted nuclear morphometry. The studied morphometric parameters were: mean nuclear area (MNA; µm²), mean nuclear perimeter (MNP; µm), mean nuclear diameter (MND mean; µm), minimum nuclear diameter (D_min; µm) and maximum nuclear diameter (D_max; µm). The study aimed to evaluate (1) possibility for quantitative differentiation of soft tissue sarcomas from reactive connective tissue lesions and (2) by using cytomorphometry, to differentiate the various histopathological soft tissue sarcomas subtypes in dogs. The mean values of all nuclear cytomorphometric parameters (except for D_max) were statistically significantly higher in reactive connective tissue processes than in soft tissue sarcomas. At the same time, however, there were no considerable differences among the different sarcoma subtypes. The results demonstrated that the quantitative differentiation of reactive connective tissue processes from soft tissue sarcomas in dogs is possible, but the same was not true for the different canine soft tissue sarcoma subtypes. Further investigations on this topic are necessary for thorough explication of the role of quantitative morphology in the diagnostics of mesenchymal neoplasms and tumour‐like fibrous lesions in dogs     

Prognostic significance of specific magnetic resonance imaging features in canine nasal tumours treated by radiotherapy

Objectives : To investigate the prognostic significance of the magnetic resonance (MR) findings of meningeal hyperintensity of the olfactory bulbs and tumour extension into the caudal nasal recess (CNR) in dogs with nasal tumours treated by radiotherapy. Methods : MR images of 41 dogs with nasal tumours treated with radiotherapy were reviewed. The occurrence of neurological signs and survival of patients with and without meningeal hyperintensity of the olfactory bulbs and tumour extension into the CNR were analysed together with possible confounding factors including intracranial extension and patient age. Results : There was no significant association between the presence of meningeal hyperintensity or CNR involvement and the occurrence of neurological signs. Although there was a tendency towards shorter survival in dogs with tumour extension into the CNR, multivariable analysis showed no significant difference in survival between dogs with/without CNR involvement, meningeal hyperintensity or intracranial tumour extension (P=0·12, 0·50 and 0·57, respectively). Clinical Significance : In dogs with nasal tumours treated with radiotherapy, tumour extension into the cranium is not necessarily associated with shorter survival in patients without neurological signs at time of diagnosis. Although a definite influence of CNR involvement on case outcome could not be demonstrated, studies with a larger population are warranted.     

Prognostic variables in canine multicentric lymphosarcoma

This paper presents the results of a prospective study to investigate the prognostic value of clinical staging, histological grading, immunophenotype, mitotic count and average numbers of argyrophilic nucleolar organiser region counts in dogs with multicentric lymphosarcoma treated with a standard chemotherapy protocol comprising vincristine, cyclophosphamide and prednisolone. Forty-nine dogs were treated according to the study protocol. Univariate and multivariate analysis with regression modelling was used to evaluate the prognostic importance of patient and tumour variables upon tumour response and relapse-free survival. Thirty-seven dogs (76 per cent) achieved a complete remission, seven (14 per cent) a partial remission and five (10 per cent) failed to respond to treatment. None of the variables examined had a statistically significant effect upon tumour response. Tumour immunophenotype was the only parameter found to have a significant influence on patient survival, the hazard ratio for T-cell versus B-cell immunophenotype was 3.99 with 95 per cent confidence interval from 1.399 to 11.372, P = 0.035.     

Analysis of complex cytogenetic alterations in three canine mammary sarcomas.

Cells of mammary sarcomas in three dogs were analysed cytogenetically. In an osteoidsarcoma, hyperdiploidy with a range of 92 to 98 chromosomes, and several structural aberrations (for example, a derivative chromosome 1, isochromosome 13 and several bi-armed markers) were observed. Isochromosome 13 was also present in a case of an osteoidchondrosarcoma. In a case of chondro-osteosarcoma both hypodiploidy with a chromosome range of 60 to 66 and hyperdiploidy with a range of 115 to 128 and several centric fusions were observed.     

Treatment of vascular and soft-tissue sarcomas in dogs using an alternating protocol of ifosfamide and doxorubicin

A retrospective analysis was done to assess the toxicity and efficacy associated with an alternating chemotherapy protocol of ifosfamide (375 mg m^?2) and doxorubicin (30 mg m^?2) for adjuvant treatment of 39 dogs with sarcomas. Twelve dogs had various soft‐tissue sarcomas and 27 dogs had hemangiosarcoma (HSA). Complete blood counts were evaluated 7 days after the first dose of ifosfamide and doxorubicin. One dog had grade 4 neutropenia (<500 µL^?1) after treatment with ifosfamide and one dog had grade 3 neutropenia (500–1000 µL^?1) after treatment with doxorubicin. One dog treated with doxorubicin was hospitalized for 24 h due to vomiting. The median survival time (ST) for the 27 dogs with HSA treated by surgery and with doxorubicin/ifosfamide was 149 days (mean 366 days). Although the protocol of alternating ifosfamide and doxorubicin was well tolerated, it failed to result in a statistically significant improvement in the ST when compared to a historical population of dogs with stage 2 splenic HSA treated by surgery alone.     

Prognostic factors for cutaneous and subcutaneous soft tissue sarcomas in dogs

Soft tissue sarcomas (STSs) develop from mesenchymal cells of soft tissues, and they commonly occur in the skin and subcutis of the dog. Although phenotypically diverse with frequently controversial histogenesis, STSs are considered as a group because they have similar features microscopically and clinically. Following resection, local recurrence rates are low in general but vary according to histologic grade and completeness of surgical margins. Complete margins predict nonrecurrence. Even most grade I STSs with "close" margins will not recur, but propensity for recurrence increases with grade. The frequency of metastasis has not been accurately estimated, but it is believed to be rare for grade I STSs and most likely to occur with grade III STSs. However, metastasis does not necessarily equate with poor survival. High mitotic index is prognostic for reduced survival time. Further research is needed to determine more precise estimates for recurrence rates and survival as related to completeness of surgical margins and to delineate potential differences in metastatic rate and median survival time between grades. Other potential indicators of prognosis that presently require further investigation include histologic type, tumor dimension, location, invasiveness, stage, markers of cellular proliferation, and cytogenetic profiles. Common issues limiting prognostic factor evaluation include biases from retrospective studies, small sample sizes, poor verification of metastasis, inconsistent STS classification and use of nomenclature, difficulties in differentiating STS phenotype, and diversity of the study population (stage of disease and treatment status).     

Intra-operative cisplatin for the treatment of canine extremity soft tissue sarcomas

Nineteen dogs with histologically confirmed soft tissue sarcomas of the extremities were treated with a combination of marginal surgery and intra-operative chemotherapy in the form of cisplatin in a biodegradable implant delivery system (Atrigel^®; Atrix Laboratories, Fort Collins, Co, USA). None of the dogs had evidence of metastasis at time of treatment. The median dose of cisplatin was 52.1 mg/m² (mean 55.4 mg/m², range 18.5–108.6 mg/m²). Wound complications were noted in 16 dogs (84.2%). Median follow-up time was 874 days (mean 777 days, range 125–1463 days). Nine dogs (47.3%) were alive at the time of analysis. Local recurrence occurred in three dogs (16.6%). The time to recurrence was 214, 264 and 874 days.     

Blood vessel density in canine osteosarcoma.

Canine osteosarcoma is a prevalent bone neoplasm which has similarities to the human disease. We used a retrospective study to investigate the possibility that tumor vascularity may provide useful prognostic information, indicative of the role of this parameter in progression of this cancer. We quantified microvessel density in 52 histological specimens of primary tumor, immunostained for von Willebrand's Factor to identify vascular endothelium. For the 20 cases not euthanized at presentation or lost to follow-up, we found significantly higher tumor microvascular densities in animals presenting with detectable pulmonary metastases (5 of 20), and significantly lower densities in animals without metastatic disease at presentation, but later surviving to develop pulmonary metastases (7 of 20; P < 0.05). Animals with no evidence of pulmonary metastases at time of death (8 of 20) had intermediate vascular densities in their tumors. The results of this preliminary study suggest that vascularity of the primary tumor may be an indication of tumor progression. Future studies with a larger number of cases should establish whether vascular density can be a useful prognostic parameter for canine osteosarcoma.     

Prognostic usefulness of blood leukocyte changes in canine parvoviral enteritis

BACKGROUND: Despite treatment, many dogs still die of complications related to canine parvoviral (CPV) enteritis. Effective prognostication would be beneficial in managing this disease. HYPOTHESIS: We hypothesize that the occurrence of leukocytopenias at admission and at 24 and 48 hours after admission, and changes in absolute leukocyte counts over time, could be used to predict outcome. ANIMALS: Sixty-two puppies with confirmed CPV. METHODS: A prospective study was performed. CBC was performed daily until discharge or death (in which case a postmortem examination was performed). RESULTS: Of the nonsurvivors (10/62; 16%), 9 died because of complications of the disease and 1 was euthanized because of a poor prognosis. There was a statistical significant difference in the occurrence of leukocytopenias between groups at 24 and 48 hours postadmission. The survivors showed a significant increase over time in certain leukocyte types (specifically lymphocytes) compared with values at admission. The positive predictive value for survivors was high. Nonsurvivors had marked thymic and lymphoid atrophy and marked bone marrow hypocellularity. CONCLUSION: An accurate prognosis could be obtained at 24 hours after admission by evaluating the change in total leukocyte, band neutrophil, lymphocyte, monocyte, and eosinophil counts.     

Intentional marginal excision of canine limb soft tissue sarcomas followed by radiotherapy

Objectives: To evaluate the outcome in a group of dogs treated with postoperative radiotherapy following intentional marginal excision of soft tissue sarcomas from their limbs and to assess parameters for prognostic significance. Method: Patients that had had intentional marginal excision of limb soft tissue sarcomas followed by radiotherapy were selected. A coarse fractionated protocol of four once weekly 8 to 9 Gy by 4 MV x-rays was used. The time to local recurrence was determined. Tumour grade, size, site, number of surgeries, surgeon and time from last surgery to radiotherapy were evaluated as potential prognostic indicators. Results: Fifty-six cases were included. Minor surgical complications occurred in four patients (7%). Tumour recurred locally in 10 dogs (18%). Fourteen dogs died from tumour-related causes (25%). From Cox proportional hazard analysis time from surgery to radiotherapy was the only predictor of tumour recurrence (P=0·039); hazard ratio 8·63. Delaying radiotherapy beyond 4 weeks was associated with improved outcomes. Three dogs developed serious but non-life-threatening local complications; wound dehiscence, self-trauma and osteonecrosis of underlying bone. Clinical Significance: Intentional marginal excision followed by hypofractionated radiotherapy is a viable option for canine limb soft tissue sarcomas, providing good long-term clinical outcomes and low morbidity.     

Ex vivo viability of canine and feline sarcomas: a pilot study

Assay-based chemotherapeutic protocols are common in human gynecologic oncology, most notably for patients with ovarian or breast cancer. The current study examines ex vivo incubation conditions necessary for the assessment of sarcomatous tumor response to potential chemotherapeutic drugs. Slices of sarcomatous tumors were incubated in one of two culture media. Viability indices were measured and compared across time and between media. Neither medium was sufficient to support the growth of sarcomatous tumor tissue slices based on the indices studied. It is likely that sarcomatous tumors require a different approach for ex vivo assessment than their epithelial counterparts. Our long-term goal is to incubate tumor slices with chemotherapeutic agents to predict the in vivo tumor response based on the maintenance or loss of slice viability within this system.