Impact of palliative-intent radiotherapy with or without chemotherapy on lameness in flat coat retrievers with localised periarticular histiocytic sarcoma - a retrospective cohort, single institution study.

Histiocytic sarcoma (HS) is a common tumour in flat coat retrievers (FCRs) often affecting periarticular tissues and joints. Palliative-intent radiotherapy, seeks to achieve local tumour control, pain relief and improve limb function. However, the effect of palliative-intent radiotherapy on analgesic levels of dogs with localised HS has not been studied. We hypothesised that palliative-intent radiotherapy could improve lameness in dogs affected by localised HS. This study aimed to assess the impact of palliative-intent radiotherapy on lameness of FCRs with localised HS. A retrospective cohort single institution study was performed. Medical records of FCR dogs with HS that received external beam radiotherapy between 2003 and 2022 were reviewed and included demographic, staging, severity of baseline lameness, therapeutic management and outcome data. Descriptive statistics, McNemar's chi-squared test, Fisher's exact test and Kaplan-Meier analysis were used for statistical analysis. Thirty-nine dogs were included with a median age of 7.2 years, 25 were male and 14 were female. HS was most commonly located in the forelimb (29 dogs, 74.3%), affecting the shoulder joint (19 dogs, 48.7%). Staging was performed in all 39 dogs with 22 (56.4%) dogs having localised HS, six (15.3%) dogs had localised HS with node metastasis and 11 (28.2%) dogs had localised HS with systemic metastasis. All dogs received palliative-intent hypo-fractionated radiation therapy, 32 (82%) dogs showed improvement in lameness. In conclusion, palliative intent radiation treatment has an analgesic effect reducing lameness or clinical signs associated with affected tumour-bearing joints.

Sarcoma Predisposition in Dogs with a Comparative View to Human Orthologous Disease.

Sarcomas are malignant tumors arising from the embryonic mesodermal cell lineage. This group of cancers covers a heterogenous set of solid tumors arising from soft tissues or bone. Many features such as histology, biological behavior and molecular characteristics are shared between sarcomas in humans and dogs, suggesting that human sarcoma research can be informative for canine disease, and that dogs with sarcomas can serve as relevant translational cancer models, to aid in the understanding of human disease and cancer biology. In the present paper, risk factors for the development of sarcoma in dogs are reviewed, with a particular focus on recent advances in clinical genetics, and on the identification of simple and complex genetic risk factors with a comparison with what has been found in human orthologous disease.

Serum amyloid A and other clinicopathological variables in cats with intermediate- and large-cell lymphoma.

OBJECTIVES: Serum amyloid A (SAA) concentrations are increased in cats with lymphoma vs healthy cats; however, the association between SAA concentrations and prognosis in cats with lymphoma is unclear. The aim of this study was to evaluate if SAA concentrations were different in cats with nasal vs non-nasal lymphoma, if SAA concentrations are prognostic in patients treated with high-dose chemotherapy and if SAA concentrations are correlated with other clinicopathological variables. METHODS: Cats diagnosed with intermediate- or large-cell lymphoma between 2012 and 2022 with SAA concentration data available were included. Associations between tumour site (nasal vs non-nasal), stage, response to treatment and SAA concentration were evaluated using non-parametric statistics. Associations between SAA concentrations and stage with survival time were evaluated using Cox regression analysis. Patients with nasal tumours and those not receiving high-dose chemotherapy were excluded from the survival analyses. RESULTS: Thirty-nine cats were included. Median SAA concentrations were significantly higher in non-nasal compared with nasal lymphoma (42 µg/ml [range <0.3-797] vs <0.3 µg/ml [range <0.3-0.9]; P = 0.026). SAA concentrations did not correlate with tumour stage. Median survival time for patients with non-nasal tumour and undergoing chemotherapy was 49 days (range 2-1726). Responders had a better median survival time than non-responders (273 days [range 43-1728] vs 39 days [range 2-169]; P <0.001), whereas SAA concentrations were not associated with survival time. Lower haematocrit at presentation was associated with a reduced median survival time (P = 0.007). CONCLUSIONS AND RELEVANCE: In the population examined, no correlation between serum concentration of SAA and prognosis in patients with lymphoma was identified, while low haematocrit and lack of response to treatment were both found to be associated with survival time. SAA concentrations were elevated in patients with non-nasal lymphoma vs patients with tumours confined to the nasal cavity.

Comparison of the Clinical Characteristics of Histiocytic Sarcoma in Bernese Mountain Dogs and Flat-Coated Retrievers.

Histiocytic sarcoma (HS) is an aggressive malignant tumor of histiocytes, which can affect almost any organ in the body and is characterized by a broad array of tumor locations and clinical presentations. So far, no complete overview exists of the array of clinical aspects of HS in specific dog breeds in large groups. Therefore, we investigated the clinical characteristics of HS in a population of Bernese Mountain Dogs (BMD; n = 365) and Flat-Coated Retrievers (FCR; n = 289), which are two of the most affected dog breeds. Cases were selected from databases from different pathology services, and clinical information was retrospectively collected for each case. Localized HS was reported significantly more frequently in the FCR (60.6%) than in the BMD (39.2%), and disseminated HS was recorded significantly more frequently in the BMD (60.8%) than in the FCR (39.4%). Lameness was seen more often in FCR than in BMD, and the vast majority (78.1%) of LHS leading to lameness was located in the front legs in the FCR, while in the BMD, there was a more even distribution. BMD had significantly more often leukocytosis and thrombocytopenia, even corrected for the type of HS, than FCR. No significant difference in the frequency of anemia was recorded between BMD and FCR. In those dogs in which blood examination was performed, hypercalcemia was diagnosed in 15 BMD, while none of the FCR had hypercalcemia. The new information provided in this study can aid the diagnostic process and allow for prompt treatment recommendations.

Effect of radiotherapy on freedom from seizures in dogs with brain tumors.

BACKGROUND: Seizures are a common presenting sign in dogs with brain tumors. HYPOTHESIS/OBJECTIVES: To investigate the effect of radiotherapy on freedom from brain tumor-associated seizures and survival time in dogs. ANIMALS: Thirty-two client-owned dogs with brain tumor-associated seizures; 18 received medical treatment and radiotherapy, 14 received medical treatment alone. METHODS: Multicenter retrospective study. Baseline characteristics (seizure semiology, magnetic resonance imaging [MRI] characteristics, and treatment) and duration of seizure freedom were recorded for the 2 treatment groups. Duration of seizure freedom between groups was compared (log-rank test) using Cox's proportional hazard analysis, with baseline characteristics entered as covariates. RESULTS: The duration of seizure freedom and survival time were significantly longer in the radiotherapy group (P < .001), with a mean of 24 months (95% confidence interval [CI], 14.3-33.8) versus 1.7 months in the control group (95% CI, 0.5-2.9) and a mean of 34.6 months (95% CI: 25.2-44.1) versus 6.2 months in the control group (95% CI, 2.6-9.7) respectively. Baseline characteristics were not associated with duration of seizure freedom after the start of treatment. In the radiotherapy group, 5 dogs were euthanized during the study period because of causes other than seizures. In the control group, recurrence of seizures was observed before death in all dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: A longer period of seizure freedom and longer survival time was observed in dogs with brain tumors after radiotherapy compared to medical treatment only. The pathophysiological mechanisms of epileptogenesis and the effect of radiation therapy on seizure control are unclear to date. Further prospective studies are needed.

Cross-species genomic landscape comparison of human mucosal melanoma with canine oral and equine melanoma.

Mucosal melanoma is a rare and poorly characterized subtype of human melanoma. Here we perform a cross-species analysis by sequencing tumor-germline pairs from 46 primary human muscosal, 65 primary canine oral and 28 primary equine melanoma cases from mucosal sites. Analysis of these data reveals recurrently mutated driver genes shared between species such as NRAS, FAT4, PTPRJ, TP53 and PTEN, and pathogenic germline alleles of BRCA1, BRCA2 and TP53. We identify a UV mutation signature in a small number of samples, including human cases from the lip and nasal mucosa. A cross-species comparative analysis of recurrent copy number alterations identifies several candidate drivers including MDM2, B2M, KNSTRN and BUB1B. Comparison of somatic mutations in recurrences and metastases to those in the primary tumor suggests pervasive intra-tumor heterogeneity. Collectively, these studies suggest a convergence of some genetic changes in mucosal melanomas between species but also distinctly different paths to tumorigenesis.

Outcomes following surgical excision or surgical excision combined with adjunctive, hypofractionated radiotherapy in dogs with oral squamous cell carcinoma or fibrosarcoma.

OBJECTIVE To compare outcomes of dogs treated surgically for oral, nontonsillar, squamous cell carcinomas (SCCs) and fibrosarcomas (FSAs) with outcomes of dogs treated with a combination of surgery and postoperative radiotherapy; to explore whether postoperative, hypofractionated radiotherapy improved outcomes of dogs with incomplete excisions; and to identify prognostic factors associated with outcome. DESIGN Retrospective cohort study. ANIMALS 87 client-owned dogs that had undergone maxillectomy or mandibulectomy for treatment of oral SCC or FSA between 2000 and 2009. PROCEDURES Medical records were retrospectively reviewed. Survival analysis was performed with Kaplan-Meier and Cox regression analyses to evaluate potential prognostic factors associated with patient outcome. RESULTS Median survival time (MST) for all 87 dogs was 2,049 days, but was not reached for dogs with SCC, and was only 557 days for dogs with FSA; tumor type was a significant predictor of survival time. Dogs undergoing postoperative radiotherapy after incomplete excision of oral SCCs had a significantly longer MST (2,051 days) than did dogs with incompletely excised tumors and no radiotherapy (MST, 181 days). Postoperative radiotherapy of dogs with incompletely excised FSAs did not appear to offer protective value (MST, 299 days with radiotherapy and 694 days without radiotherapy). CONCLUSIONS AND CLINICAL RELEVANCE Wide-margin surgical excision should be considered the gold-standard treatment for dogs with oral SCC or FSA. For dogs with oral SCCs without clean surgical margins, survival times may be improved by providing postoperative, hypofractionated radiotherapy.

Morphological Distinction of Histiocytic Sarcoma from Other Tumor Types in Bernese Mountain Dogs and Flatcoated Retrievers.

BACKGROUND/AIM: Histiocytic sarcoma (HS) represents a group of malignant canine tumors to which Bernese Mountain Dogs (BMD) and Flatcoated Retrievers (FCR) are predisposed. The differential diagnosis for HS is broad, encompassing round cell tumors, sarcomas and other histiocytic diseases. The aim of this study was to establish morphological and immunohistochemical criteria for routine use on formalin-fixed, paraffin-embedded samples and cytological smears for the recognition and differentiation of canine HS and its subtypes. MATERIALS AND METHODS: Retrospectively, tumor sections were reviewed from 449 BMD and 380 FCR with confirmed or suspected HS, other histiocytic conditions, or a disease of the differential diagnosis of HS. RESULTS: In a large proportion of cases, 47.5% for histology and for 46.3% cytology, the initial diagnosis was changed after the revision process. A large variation in morphological features of HS was observed in this study, making the existence of several subtypes in dogs also very likely. Furthermore, the different percentage of morphological features between BMD and FCR indicates the different mixture of cell type origins resulting possibly from genetic or environmental differences at the onset of HS in those breeds. CONCLUSION: This study stresses the value of a strictly applied and standardized scoring system for microscopic evaluation of tumor sections and smears, and the implementation of review and revision of pathological diagnoses.

Feline mediastinal lymphoma: a retrospective study of signalment, retroviral status, response to chemotherapy and prognostic indicators.

Historically, feline mediastinal lymphoma has been associated with young age, positive feline leukaemia virus (FeLV) status, Siamese breed and short survival times. Recent studies following widespread FeLV vaccination in the UK are lacking. The aim of this retrospective multi-institutional study was to re-evaluate the signalment, retroviral status, response to chemotherapy, survival and prognostic indicators in feline mediastinal lymphoma cases in the post-vaccination era. Records of cats with clinical signs associated with a mediastinal mass and cytologically/histologically confirmed lymphoma were reviewed from five UK referral centres (1998-2010). Treatment response, survival and prognostic indicators were assessed in treated cats with follow-up data. Fifty-five cases were reviewed. The median age was 3 years (range, 0.5-12 years); 12 cats (21.8%) were Siamese; and the male to female ratio was 3.2:1.0. Five cats were FeLV-positive and two were feline immunodeficiency-positive. Chemotherapy response and survival was evaluated in 38 cats. Overall response was 94.7%; complete (CR) and partial response (PR) rates did not differ significantly between protocols: COP (cyclophosphamide, vincristine, prednisone) (n = 26, CR 61.5%, PR 34.0%); Madison-Wisconsin (MW) (n = 12, CR 66.7%, PR 25.0%). Overall median survival was 373 days (range, 20-2015 days) (COP 484 days [range, 20-980 days]; MW 211 days [range, 24-2015 days] [P = 0.892]). Cats achieving CR survived longer (980 days vs 42 days for PR; P = 0.032). Age, breed, sex, location (mediastinal vs mediastinal plus other sites), retroviral status and glucocorticoid pretreatment did not affect response or survival. Feline mediastinal lymphoma cases frequently responded to chemotherapy with durable survival times, particularly in cats achieving CR. The prevalence of FeLV-antigenaemic cats was low; males and young Siamese cats appeared to be over-represented.

Breed-predispositions to cancer in pedigree dogs.

Cancer is a common problem in dogs and although all breeds of dog and crossbred dogs may be affected, it is notable that some breeds of pedigree dogs appear to be at increased risk of certain types of cancer suggesting underlying genetic predisposition to cancer susceptibility. Although the aetiology of most cancers is likely to be multifactorial, the limited genetic diversity seen in purebred dogs facilitates genetic linkage or association studies on relatively small populations as compared to humans, and by using newly developed resources, genome-wide association studies in dog breeds are proving to be a powerful tool for unravelling complex disorders. This paper will review the literature on canine breed susceptibility to histiocytic sarcoma, osteosarcoma, haemangiosarcoma, mast cell tumours, lymphoma, melanoma, and mammary tumours including the recent advances in knowledge through molecular genetic, cytogenetic, and genome wide association studies.

Evaluation of variants of melanoma-associated antigen genes and mRNA transcripts in melanomas of dogs.

OBJECTIVE-To characterize variability in melanoma-associated antigen (MAA) genes and gene expression in melanomas of dogs. ANIMALS-18 dogs with malignant melanomas and 8 healthy control dogs. PROCEDURES-cDNA was prepared from malignant melanoma biopsy specimens and from pigmented oral mucocutaneous tissues of healthy control dogs. Genomic DNA was extracted from poorly pigmented melanomas. A PCR assay was performed by use of Melan-A, SILV, or tyrosinase-specific primers. RESULTS-Splice variants of Melan-A and SILV were identified in malignant melanomas and also in healthy pigmented tissues, whereas a tyrosinase splice variant was detected in melanoma tissues only. A short interspersed nuclear element (SINE) insertion mutation was identified in the SILV gene in 1 of 10 poorly pigmented melanomas. Six novel exonic single nucleotide polymorphisms (SNPs; 3 synonymous and 3 nonsynonymous) were detected in the tyrosinase gene, and 1 nonsynonymous exonic SNP was detected in the SILV gene. CONCLUSIONS AND CLINICAL RELEVANCE-Variants of MAA mRNA were detected in malignant melanoma tissues of dogs. The importance of MAA alternative transcripts expressed in melanomas and normal pigmented tissues was unclear, but they may have represented a means of regulating melanin synthesis. The tyrosinase splice variant was detected only in melanomas and could potentially be a tumor-specific target for immunotherapy. A SILV SINE insertion mutation was identified in a melanoma from a Great Dane, a breed known to carry this mutation (associated with merle coat color). The nonsynonymous SNPs detected in tyrosinase and SILV transcripts did not appear to affect tumor pigmentation.

Disruption of chromosome 11 in canine fibrosarcomas highlights an unusual variability of CDKN2B in dogs.

BACKGROUND: In dogs in the western world neoplasia constitutes the most frequently diagnosed cause of death. Although there appear to be similarities between canine and human cancers, rather little is known about the cytogenetic and molecular alterations in canine tumours. Different dog breeds are susceptible to different types of cancer, but the genetic basis of the great majority of these predispositions has yet to be discovered. In some retriever breeds there is a high incidence of soft tissue sarcomas and we have previously reported alterations of chromosomes 11 and 30 in two poorly differentiated fibrosarcomas. Here we extend our observations and present a case report on detail rearrangements on chromosome 11 as well as genetic variations in a tumour suppressor gene in normal dogs. RESULTS: BAC hybridisations on metaphases of two fibrosarcomas showed complex rearrangements on chromosome 11, and loss of parts of this chromosome. Microsatellite markers on a paired tumour and blood DNA pointed to loss of heterozygosity on chromosome 11 in the CDKN2B-CDKN2A tumour suppressor gene cluster region. PCR and sequencing revealed the homozygous loss of coding sequences for these genes, except for exon 1beta of CDKN2A, which codes for the N-terminus of p14ARF. For CDKN2B exon 1, two alleles were observed in DNA from blood; one of them identical to the sequence in the dog reference genome and containing 4 copies of a 12 bp repeat found only in the canine gene amongst all species so far sequenced; the other allele was shorter due to a missing copy of the repeat. Sequencing of this exon in 141 dogs from 18 different breeds revealed a polymorphic region involving a GGC triplet repeat and a GGGGACGGCGGC repeat. Seven alleles were recorded and sixteen of the eighteen breeds showed heterozygosity. CONCLUSION: Complex chromosome rearrangements were observed on chromosome 11 in two Labrador retriever fibrosarcomas. The chromosome alterations were reflected in the loss of sequences corresponding to two tumour suppressor genes involved in cell-cycle progression. Sequencing of CDKN2B across many different breeds revealed a widespread polymorphism within the first exon of the gene, immediately before the ankyrin coding sequences.

Development of a multiple-marker polymerase chain reaction assay for detection of metastatic melanoma in lymph node aspirates of dogs.

OBJECTIVE: To develop a reverse transcriptase-polymerase chain reaction (RT-PCR) assay to detect canine melanoma-associated antigens (MAAs) and to use this technique to screen aspirates of lymph nodes (LNs) for evidence of metastatic spread of oral malignant melanoma. ANIMALS: 7 dogs with oral malignant melanoma and 4 dogs with multicentric lymphosarcoma. PROCEDURES: We prepared cDNA from melanoma tumor biopsies and fine-needle aspirates obtained from submandibular LNs of dogs with oral malignant melanoma or multicentric lymphosarcoma. The RT-PCR assay was performed by use of tyrosinase, Melan-A, gp100, tyrosinase-related protein 2 (TRP-2), or melanoma antigen-encoding gene B (MAGE-B)-specific primers. RESULTS: We detected MAGE-B mRNA in canine testicular tissue but not in melanoma biopsy specimens. Tyrosinase, Melan-A, gp100, and TRP-2 mRNAs were detected in tumor biopsy specimens and in 2 of 5 LN aspirates from dogs with melanoma, suggesting metastatic spread in those 2 dogs. We did not detect MAAs in LN aspirates obtained from dogs with multicentric lymphosarcoma. Sequencing of canine Melan-A and gp100 PCR products confirmed the specificity of the assay for these genes. CONCLUSIONS AND CLINICAL RELEVANCE: Clinical staging of dogs with oral malignant melanoma is useful to assist in designing appropriate treatments. However, results of histologic examination of LN biopsy specimens can be inconclusive and, in humans, can underestimate the number of patients with metastatic disease. Molecular staging of melanomas in dogs can be achieved by screening LN aspirates for MAA mRNA, and this can be performed in combination with cytologic examination to aid in detection of metastatic disease.