[Adjuvant treatment of canine splenic hemangiosarcoma with autologous dendritic cell therapy - a prospective, randomized double-blind study]. / Adjuvante Behandlung des caninen Hämangiosarkoms der Milz mit der autologen dendritischen Zelltherapie ­ eine prospektive, placebokontrollierte, randomisierte Doppelblindstudie.

OBJECTIVE: Canine splenic hemangiosarcomas (HSA) are malignant mesenchymal tumors with a high tendency for metastasis. Median survival times after splenectomy followed by adjuvant chemotherapy usually range between 5 and 8 months. The aim of this prospective randomized double-blinded study was to examine the efficacy of a commercially available dendritic cell therapy (PetBioCell) following splenectomy. In addition, possible side effects of this therapy were evaluated. MATERIAL AND METHODS: Twenty-one dogs with histologically confirmed splenic HSA without metastasis (stages I or II) were included in the study. Ten dogs received the dendritic cell therapy, and 11 dogs received a placebo. Injections were administered according to the manufacturer's instructions monthly for the first 3 months and then every 3 months until death. Survival times and toxicoses of both groups were compared. RESULTS: Follow-up data were available for all 21 patients; the observation period ranging until euthanasia or metastasis-related death. One patient that had received the dendritic cell therapy was euthanized due to prostatitis and experienced the longest survival time (668 days). One dog in the placebo-group lived for 448 days after splenectomy. The median survival times in the dendritic cell therapy and the placebo group amounted to 74 and 126 days, respectively. There was no significant difference in tumor-free interval (t(18) = 1.4, p = 0.911) and survival times (t(19) = -0.094, p = 0.463) between the 2 groups. Toxicoses reported in both groups were mild and self-limiting. CONCLUSION: Immunotherapy using autologous, immature and unprimed dendritic cells according to the PetBioCell method failed to show efficacy on tumor-free interval and survival time in the presented dog population with splenic hemangiosarcoma.

Frontal sinus carcinoma in forty-one dogs (2001-2022).

Reports on canine frontal sinus carcinomas (FSCs) are scarce. This retrospective review of 41 dogs with FSC (2001-2022) describes demographic and clinical characteristics of canine FSC and reports the clinical experience and overall survival following treatment with toceranib phosphate (TOC) and meloxicam in 10 cases. Median age at diagnosis was 10.6 years (range: 6.5-15.4 years). There was a male-to-female-ratio of 2.4:1. The most common breeds were Jack Russell Terriers (JRT) (n = 7; 17.1%) and Rottweilers (n = 3, 7.3%). Mesocephalic breeds (70.6%) were most commonly affected, brachycephalics accounted for 8.8%. The most frequent clinical signs included skull deformation dorsomedial to the eye (87.5%), pain/head-shyness (40.0%), ocular (22.5%)/nasal (17.5%) discharge, and exophthalmos (17.5%). Duration of symptoms prior to diagnosis varied from a few days to 9 months. There were no neurological signs at initial presentation despite imaging evidence of osteolysis of the lamina interna of the frontal bone in most dogs (69.4%). In 11.5%, pulmonary changes suggestive of metastasis or concurrent primary pulmonary neoplasia were present. Tumour types included squamous cell carcinoma (58.5%), unspecified carcinoma (29.3%), and adenocarcinoma (9.8%). Ten dogs were treated with TOC (median 2.8 mg/kg EOD or three times per week) and meloxicam (0.1 mg/kg, EOD) (TOC-M), resulting in subjective regression of skull deformity in 8/10 (80.0%) patients. Overall median survival time with TOC-M was 183.5 days (range: 120-434 days). FSCs typically present with skull deformation, but no overt neurological signs. Male dogs and JRT may be overrepresented. The use of TOC-M in FSC appears promising and warrants further prospective evaluation.

Ovariectomy reduces the risk of tumour development and influences the histologic continuum in canine mammary tumours.

Influence of neutering on canine mammary tumorigenesis has been a source of vivid discussion over the last decades. The purpose of this retrospective study was to describe the association between neuter status, tumour size and degree of malignancy in a large population of 625 female dogs with altogether 1459 removed mammary tumours (MTs). MT-bearing dogs were predominantly intact (80.3%) and intact dogs were overrepresented in the tumour population compared to the control group of >19 000 females (p < .0001). Multiple MT occurred in 340 patients (54.4%) and were significantly more common in intact dogs (57.8% vs. 40.7% spayed). Neutered dogs were not only significantly more likely to have a malignant MT (p < .0001) but were significantly more often affected by more aggressive tumour subtypes (p < .0001). Positive correlation between increasing tumour size and increasingly malignant phenotype was slightly stronger in spayed (rs  = .217; p = .021) compared to intact (rs  = .179; p = .0003) patients. After ovariectomy, progression from benign to malignant occurs in smaller size tumours, as MT ≥2 cm in diameter were malignant in 86.9% of the spayed patients, compared to 62.0% in intact patients (p = .0002). Intact bitches have a higher risk for MTs and tumour multiplicity. MTs in neutered females are more often malignant and belong to more aggressive subtypes compared to MTs in intact dogs. In neutered bitches, histologic progression from benign to malignant and further along the cancer progression continuum occurs at smaller tumour sizes.

BRAF mutation status and its prognostic significance in 79 canine urothelial carcinomas: A retrospective study (2006-2019).

Urothelial carcinoma (UC) is the most common tumour of the canine urinary bladder. Recently, BRAF mutation testing emerged as a diagnostic option, but its prognostic significance is unknown. This study investigates the relationship between BRAF (variant V595E) mutation status and overall survival in UC-bearing dogs. Seventy-nine patients histologically diagnosed with UC of the bladder and/or urethra between 2006 and 2019 were included in this retrospective single-centre-study. Treatment consisted of meloxicam (n = 39, group 1 'Melox'), mitoxantrone and meloxicam (+/- followed by metronomic chlorambucil; n = 23, group 2 'Chemo') or partial cystectomy followed by meloxicam +/- mitoxantrone (n = 17, group 3 'Sx'). Survival was significantly influenced by treatment (p = .0002) and tumour location (p < .001) in both uni- and multivariable analyses. BRAF mutation was identified in 51 tumours (=64.6%) and had no statistically significant influence on overall survival: MST for BRAF-negative patients 359 versus 214 days for BRAF-positive dogs (p = .055). However, in BRAF-positive dogs, survival depended significantly on type of treatment in univariable analysis: MSTs for groups 1-3 were 151, 244 and 853 days, respectively (p = .006); In BRAF-positive group 2 ('Chemo')-patients, adjuvant metronomic chlorambucil after mitoxantrone more than doubled MST compared to patients receiving mitoxantrone alone (588 vs. 216 days; p = .030). In contrast, MSTs were not significantly different in BRAF-negative patients among the three treatment groups (p = .069). Multivariate analysis of these data was not possible due to group size limitations. This study identified tumour location and treatment type, but not BRAF mutation status, as independent prognostic factors for overall survival.

Canine mammary tumours: Size matters-a progression from low to highly malignant subtypes.

The purpose of this study was to evaluate a possible association between mammary tumour size and increasing degree of malignancy. Data of 625 dogs with a total of 1459 mammary tumours were analysed retrospectively. 80.3% dogs were intact, mean age at diagnosis was 9.7 ± 2.5 years, 75.8% were pure breed dogs. Median body weight was 20.0 kg. Malignant tumours (n = 580) were significantly larger than their benign counterparts (1.94 cm vs 0.90 cm in mean, respectively; P ≤ .0001), resulting in a positive correlation between increasing tumour size and a change from benign to malignant (P ≤ .0001; rs  = 0.214). When malignant tumours were grouped into four degrees of increasing malignancy (complex/simple/solid/anaplastic carcinomas) a significant positive correlation between increasing tumour size and more malignant tumour degree (P ≤ .0001; rs  = 0.195) could be demonstrated. In a number of cases, highly malignant tumours were found to arise within less malignant lesions, supporting the concept of a further progression within the malignant tumour subtypes. In patients with multiple tumours, mean tumour sizes for malignant tumours were significantly smaller compared to patients with only one tumour (1.67 vs 2.71 cm in mean, respectively; P < .0001). These findings suggest that mammary tumours progress not only from benign to malignant but also from low to highly malignant. An increase in diameter of only a few millimetres may therefore have a big impact on the patient's outcome.

Regulation of Alzheimer's disease-associated proteins during epileptogenesis.

Clinical evidence and pathological studies suggest a bidirectional link between temporal lobe epilepsy and Alzheimer's disease (AD). Data analysis from omic studies offers an excellent opportunity to identify the overlap in molecular alterations between the two pathologies. We have subjected proteomic data sets from a rat model of epileptogenesis to a bioinformatics analysis focused on proteins functionally linked with AD. The data sets have been obtained for hippocampus (HC) and parahippocampal cortex samples collected during the course of epileptogenesis. Our study confirmed a relevant dysregulation of proteins linked with Alzheimer pathogenesis. When comparing the two brain areas, a more prominent regulation was evident in parahippocampal cortex samples as compared to the HC. Dysregulated protein groups comprised those affecting mitochondrial function and calcium homeostasis. Differentially expressed mitochondrial proteins included proteins of the mitochondrial complexes I, III, IV, and V as well as of the accessory subunit of complex I. The analysis also revealed a regulation of the microtubule associated protein Tau in parahippocampal cortex tissue during the latency phase. This was further confirmed by immunohistochemistry. Moreover, we demonstrated a complex epileptogenesis-associated dysregulation of proteins involved in amyloid ß processing and its regulation. Among others, the amyloid precursor protein and the α-secretase alpha disintegrin metalloproteinase 17 were included. Our analysis revealed a relevant regulation of key proteins known to be associated with AD pathogenesis. The analysis provides a comprehensive overview of shared molecular alterations characterizing epilepsy development and manifestation as well as AD development and progression.

Outcome comparison between radiation therapy and surgery as primary treatment for dogs with periarticular histiocytic sarcoma: An Italian Society of Veterinary Oncology study.

Localized histiocytic sarcoma may occur as a primary lesion in periarticular tissues of large appendicular joints. Treatment options for the primary lesion include radical surgical excision, radiation therapy (RT), or both, in combination with chemotherapy for potential systemic metastases. In an effort to better characterize the time to progression (TTP) following surgical vs non-surgical approaches for periarticular histiocytic sarcoma (PAHS), a contemporary European population of affected dogs was retrospectively surveyed. Medical records were queried for newly-diagnosed PAHS cases undergoing surgery (predominantly limb amputation) or RT followed by systemic chemotherapy. Of 49 dogs, 34 underwent RT and 15 underwent surgery. All dogs received adjuvant chemotherapy. There was no statistically significant difference in TTP or overall survival between groups. The median TTP was 336 days for the operated dogs and 217 days for the irradiated dogs (P = .117). The median overall survival time was 398 days for the operated dogs and 240 days for the irradiated dogs (P = .142). On multi-variable analysis, the variables significantly associated with an increased risk of both tumour progression and tumour-related death were regional lymph node and distant metastasis at admission. Survival and local control rates following RT may be comparable to radical resection. These data may better inform shared decision-making processes between multi-disciplinary care providers and owners.