Extracellular heat shock protein 70 levels in tumour-bearing dogs and cats treated with radiation therapy and hyperthermia.

Hyperthermia is a form of a cancer treatment which is frequently applied in combination with radiotherapy (RT) to improve therapy responses and radiosensitivity. The mode of action of hyperthermia is multifactorial; the one hand by altering the amount of the blood circulation in the treated tissue, on the other hand by modulating molecular pathways involved in cell survival processes and immunogenic interactions. One of the most dominant proteins induced by hyperthermia is the major stress-inducible heat shock protein 70 (Hsp70). Hsp70 can be found in the blood either as a free-protein (free HSP70) derived from necrotic cells, or lipid-bound (liposomal Hsp70) when it is actively released in extracellular vesicles (EVs) by living cells. The aim of the study was to evaluate the levels of free and liposomal Hsp70 before and after treatment with RT alone or hyperthermia combined with radiotherapy (HTRT) in dogs and cats to evaluate therapy responses. Peripheral blood was collected from feline and canine patients before and at 2, 4, 6 and 24 h after treatment with RT or HTRT. Hsp70 enzyme-linked immunosorbent assays (ELISAs) were performed to determine the free and liposomal Hsp70 concentrations in the serum. The levels were analysed after the first fraction of radiation to study immediate effects and after all applied fractions to study cumulative effects. The levels of free and liposomal Hsp70 levels in the circulation were not affected by the first singular treatment and cumulative effects of RT in cats however, after finalizing all treatment cycles with HTRT free and liposomal Hsp70 levels significantly increased. In dogs, HTRT, but not treatment with RT alone, significantly affected liposomal Hsp70 levels during the first fraction. Free Hsp70 levels were significantly increased after RT, but not HTRT, during the first fraction in dogs. In dogs, on the other hand, RT alone resulted in a significant increase in liposomal Hsp70, but HTRT did not significantly affect the liposomal Hsp70 when cumulative effects were analysed. Free Hsp70 was significantly induced in dogs after both, RT and HTRT when cumulative effects were analysed. RT and HTRT treatments differentially affect the levels of free and liposomal Hsp70 in dogs and cats. Both forms of Hsp70 could potentially be further investigated as potential liquid biopsy markers to study responses to RT and HTRT treatment in companion animals.

[Radiation therapy for the treatment of macroscopic canine anal gland tumors - a retrospective study]. / Strahlentherapie zur Behandlung makroskopischer Analbeuteltumoren des Hundes ­ eine retrospektive Studie.

INTRODUCTION: Canine anal gland tumors are locally invasive and early metastasize to the loco-regional pelvic lymph nodes. Radiation therapy is a good method for loco-regional tumor control, especially in inoperable tumors. Since the organs in the pelvic area are sensitive to both acute and late radiation damage (chronic diarrhea, bleeding, strictures or intestinal perforations) and such damage mainly depends on the fraction size, we examined the radiation protocol used in this study with a reduced number of fractions (hypofractionated) regarding effectiveness and side effects. This retrospective study describes 13 dogs with macroscopic anal gland carcinoma that were irradiated with imaging-guided, intensity-modulated radiation therapy with a hypofractionated curative protocol of 12 × 3,8 Gy. Gross pathology was either in the region of the anal gland and/or in the sublumbar lymph nodes. Ten of the 13 dogs had advanced tumor diseases (stage 3a or 3b). The acute radiation reactions were mild to moderate and had been reported for some of the dogs in a previous study. The mean study time was 572 days (range 105-1292 days). Disease progression was observed or suspected in 7/13 dogs during the study period: local or loco-regional progression occurred in 3 dogs (23 %) and distant metastases in 4 dogs (31 %). Median progression-free survival was 480 days (95 %CI, 223-908), median survival was 597 days (95 %CI, 401-908). One year after treatment, 76,9 % (95 %CI, 53,5-100) of the dogs were still alive. The likelihood of tumor progression was lower with increasing age, otherwise none of the examined tumor or patient factors showed a prognostic influence on progression or survival time. No clinically relevant late side effects were observed apart from slight alopecia, pigmentation changes or dry, scaly skin, Medium to long-term tumor control can be expected in dogs with macroscopic anal gland tumors treated with a moderately hypofractionated radiation therapy protocol (12 × 3,8 Gy). During long-term monitoring no serious side effects or side effects requiring treatment were observed.

INTRODUCTION: Les tumeurs des glandes anales canines sont localement invasives et métastasent rapidement dans les ganglions lymphatiques loco-régionaux pelviens. La radiothérapie est une bonne méthode de contrôle des tumeurs loco-régionales, en particulier pour les tumeurs inopérables. Étant donné que les organes de la région pelvienne sont sensibles aux dommages aigus et tardifs de la radiation (diarrhée chronique, saignements, sténoses ou perforations intestinales) et que ces dommages dépendent principalement de la taille des fractions, nous avons étudié le protocole de radiations utilisé dans cette étude avec un nombre réduit de fractions (hypofractionné) en terme d'efficacité et d'effets secondaires. Cette étude rétrospective décrit 13 chiens atteints de carcinome macroscopique de la glande anale qui ont été traités par une radiothérapie à modulation d'intensité guidée par imagerie avec un protocole curatif hypofractionné de 12 × 3,8 Gy. La pathologie macroscopique se trouvait soit dans la région de la glande anale et/ou dans les ganglions lymphatiques sublombaires. Dix des 13 chiens présentaient des pathologies tumorales avancées (stade 3a ou 3b). Les réactions aiguës aux radiations étaient légères à modérées et avaient été signalées pour certains des chiens dans une étude précédente. La durée moyenne de l'étude était de 572 jours (fourchette 105­1292 jours). Une progression de la maladie a été observée ou suspectée chez 7/13 chiens au cours de la période d'étude : une progression locale ou loco-régionale est survenue chez 3 chiens (23 %) et des métastases à distance chez 4 chiens (31 %). La survie médiane sans progression était de 480 jours (95 %CI, 223­908), la survie médiane était de 597 jours (95 %CI, 401­908). Un an après le traitement, 76,9 % (95 %CI, 53,5­100) des chiens étaient encore en vie. La probabilité de progression de la tumeur était plus faible avec l'âge, mais aucun des facteurs examinés concernant la tumeur ou le patient n'a montré d'influence pronostique sur la progression ou la durée de survie. Aucun effet secondaire tardif cliniquement pertinent n'a été observé, hormis une légère alopécie, des changements de pigmentation ou une peau sèche et squameuse, On peut s'attendre à un contrôle tumoral à moyen et long terme chez les chiens atteints de tumeurs macroscopiques de la glande anale traités par un protocole de radiothérapie modérément hypofractionnée (12 × 3,8 Gy). Au cours du suivi à long terme, aucun effet secondaire grave ou nécessitant un traitement n'a été observé.

Near-infrared fluorescent image-guided lymph node dissection compared with locoregional lymphadenectomies in dogs with mast cell tumours.

OBJECTIVES: Near-infrared fluorescent imaging has been described for intraoperative mapping of the draining lymph nodes in human cancer and canine oral tumours. The aim of this study was to retrospectively describe the results of lymphadenectomies in dogs with mast cell tumours treated either by standard unguided locoregional lymph node dissection or near-infrared fluorescent image-guided lymph node dissection. METHODS: Medical records between 2012 and 2020 were reviewed for dogs that were presented for surgical resection of mast cell tumours with concurrent lymphadenectomy either with (near-infrared fluorescent image-guided lymph node dissection) or without near-infrared fluorescence image guidance (lymph node dissection). The number and location of lymph nodes planned for surgical dissection and actually dissected nodes, presence of metastases and perioperative complications were recorded. RESULTS: Thirty-five patients underwent near-infrared fluorescent image-guided lymph node dissection, and 43 lymph node dissections. The number of nodes preoperatively planned for resection were 70 and 68, respectively. Fifty-eight of those (83%) were identified during near-infrared fluorescent image-guided lymph node dissection procedures, compared with 50 (74%) during lymph node dissection. near-infrared fluorescent image-guided lymph node dissection resulted in resection of additional fluorescent nodes not corresponding to locoregional nodes in 15 of 35 dogs. Using near-infrared fluorescent image-guided lymph node dissection, we identified at least one metastatic node in 68% of dogs (24 of 35) compared with 33% (14 of 43) when lymph node dissection was used without imaging. No complications related to near-infrared fluorescent imaging were reported. CLINICAL SIGNIFICANCE: The present study suggests that near-infrared imaging is a promising technique for intraoperative detection of the draining lymph nodes in dogs with mast cell tumours. Further validation of the technique is required to assess if near-infrared fluorescent imaging can detect the true sentinel lymph node.

[Massive unresectable hepatocellular carcinoma in a dog treated with -intensity-modulated radiation therapy]. / Massives inoperables hepatozelluläres Karzinom bei einem Hund behandelt mittels intensitätsmodulierter Strahlentherapie.

INTRODUCTION: This case report describes a 12-year-old female spayed mixed-breed dog referred for treatment of a large, inoperable hepatocellular carcinoma. A computed tomography (CT) scan confirmed the previous ultrasonographic and laparoscopic findings of a large, lobulated, poorly defined mass on the left and central aspect of the liver. Multiple biopsies confirmed the diagnosis of hepatocellular carcinoma. Due to the large extent of the tumor, the vascular association to the Vena cava caudalis and the associated high risk of intraoperative bleeding, a resection of the mass was refrained from and a radiotherapeutic treatment was chosen. The dog underwent radiation therapy (RT) with a 6MV linear accelerator with 5×6 Gy, total dose 30 Gy. In the follow up examinations three months and one year after therapy, the dog presented in normal condition and had normal Alanine-amino-transferase (ALT) and alkaline phosphatase (AP). The tumor size measured in the CT-examinations decreased by 61% and 90%, respectively. Two years after radiation therapy the dog has a normal general condition and liver enzymes are within the normal limits.

INTRODUCTION: Ce rapport décrit le cas d'une chienne de race mixte, stérilisée, âgée de 12 ans et référée pour traitement d'un important carcinome hépatocellulaire inopérable. Une tomodensitométrie (TDM) a confirmé les résultats échographiques et laparoscopiques antérieurs, à savoir une grande masse mal définie sur la partie gauche et centrale du foie. De multiples biopsies ont confirmé le diagnostic de carcinome hépatocellulaire. En raison de l'étendue de la tumeur, de l'association à la veine cave caudale et du risque élevé associé d'hémorragies peropératoires, on a renoncé à une résection de la masse et un traitement radiothérapeutique a été choisi. Le chien a subi une radiothérapie (RT) avec un accélérateur linéaire de 6 MV avec 5 × 6 Gy, dose totale 30 Gy. Lors des examens de suivi, trois mois et un an après le traitement, le chien présentait un état normal et avait une alanine-amino­-transférase (ALT) et une phosphatase alcaline (PA) normales. La taille de la tumeur mesurée lors des examens tomodensitométriques avait diminué de 61% respectivement de 90%. Deux ans après la radiothérapie, le chien présente un état général normal et les enzymes hépatiques sont dans la norme.

[Acromegaly due to a pituitary tumor in a dog - diagnosis, therapy and long-term follow-up]. / Akromegalie aufgrund eines Hypophysentumors bei einem Hund ­ Diagnose, Therapie und Verlauf.

INTRODUCTION: Acromegaly due to a pituitary tumor has so far only been described in 3 dogs. The present case report describes a 7-year-old male-castrated Labrador Retriever which was referred because of difficult-to-control diabetes. Physical examination revealed markedly enlarged head, tongue and paws, widened interdental spaces and thickening of the skin in the head and neck area. IGF-1 and GH were increased and the latter continued to be abnormal after somatostatin application. Computed tomography demonstrated a space-occupying lesion in the pituitary gland and the diagnosis of acromegaly due to a GH-producing tumor of the pituitary was made. The dog underwent radiation therapy with a 6MV linear accelerator (3×8Gy) and improved substantially. Two and a half years after radiation therapy the dog developed lethargy and anorexia and was euthanized. Necropsy was not permitted. This case report represents the description of a dog suffering from pituitary-dependent acromegaly which was successfully treated and had a long-term survival.

INTRODUCTION: L'acromégalie due à une tumeur hypophysaire n'a jusqu'à présent été décrite que chez 3 chiens. Le présent rapport de cas décrit un Labrador Retriever de 7 ans mâle castré, qui a été référé en raison d'un diabète difficile à contrôler. L'examen physique a révélé une tête, une langue et des pattes de taille nettement augmentée, des espaces interdentaires élargis et un épaississement de la peau dans la région de la tête et du cou. L'IGF-1 et la GH étaient augmentées et la seconde restait anormale après l'application de somatostatine. La tomodensitométrie a mis en évidence une masse dans la région de l'hypophyse et le diagnostic d'acromégalie due à une tumeur de l'hypophyse productrice de GH a été posé. Le chien a subi une radiothérapie avec un accélérateur linéaire de 6MV (3×8Gy) et son état s'est considérablement amélioré. Deux ans et demi après la radiothérapie, le chien développa une léthargie et une anorexie et fut euthanasié. L'autopsie n'a pas été autorisée. Ce rapport de cas représente la description d'un chien souffrant d'acromégalie dépendant de l'hypophyse, traité avec succès et ayant une survie à long terme.

A prospective pilot study on early toxicity from a simultaneously integrated boost technique for canine sinonasal tumours using image-guided intensity-modulated radiation therapy.

In order to overcome the common local treatment failure of canine sinonasal tumours, integrated boost techniques were tried in the cobalt/orthovoltage era, but dismissed because of unacceptable early (acute) toxicity. Intriguingly, a recent calculation study of a simultaneously integrated boost (SIB) technique for sinonasal irradiation using intensity-modulated radiation therapy (IMRT) predicted theoretical feasibility. In this prospective pilot study we applied a commonly used protocol of 10 × 4.2 Gy to the planning target volume (PTV) with a 20%-SIB dose to the gross tumour volume (GTV). Our hypothesis expected this dose escalation to be clinically tolerable if applied with image-guided IMRT. We included 9 dogs diagnosed with sinonasal tumours without local/distant metastases. For treatment planning, organs at risk were contoured according to strict anatomical guidelines. Planning volume extensions (GTV/CTV/PTV) were standardized to minimize interplanner variability. Treatments were applied with rigid patient positioning and verified daily with image guidance. After radiation therapy, we set focus on early ophthalmologic complications as well as mucosal and cutaneous toxicity. Early toxicity was evaluated at week 1, 2, 3, 8 and 12 after radiotherapy. Only mild ophthalmologic complications were found. Three patients (33%) had self-limiting moderate to severe early toxicity (grade 3 mucositis) which was managed medically. No patient developed ulcerations/haemorrhage/necrosis of skin/mucosa. The SIB protocol applied with image-guided IMRT to treat canine sinonasal tumours led to clinically acceptable side effects. The suspected increased tumour control probability and the risk of late toxicity with the used dose escalation of 20% has to be further investigated.

Survival analysis of dogs with advanced primary lung carcinoma treated by metronomic cyclophosphamide, piroxicam and thalidomide.

Unresectable or metastatic (advanced) primary pulmonary carcinoma (PPC) represents a therapeutic challenge where surgery may be contraindicated and the therapeutic role of maximum-tolerated dose (MTD) chemotherapy remains uncertain. This study was undertaken to explore the impact of metronomic chemotherapy (MC) in dogs with advanced PPC. Previously untreated dogs with advanced (T3 or N1 or M1) PPC, with complete staging work-up and follow-up data, receiving MC (comprising low-dose cyclophosphamide, piroxicam and thalidomide), surgery, MTD chemotherapy or no oncologic treatment were eligible for inclusion. For all patients, time to progression (TTP) and survival time (ST) were evaluated. Quality-of-life (QoL) was only evaluated in patients receiving MC. To assess QoL, owners of dogs receiving MC were asked to complete a questionnaire before and during treatment. Ninety-one dogs were included: 25 received MC, 36 were treated with surgery, 11 with MTD chemotherapy and 19 received no treatment. QoL was improved in dogs receiving MC. Median TTP was significantly longer in patients receiving MC (172 days) than patients undergoing surgery (87 days), receiving MTD chemotherapy (22 days), or no oncologic treatment (20 days). Median ST was similarly longer in patients receiving MC (139 days) than those undergoing surgery (92 days), MTD chemotherapy (61 days) and no oncologic treatment (60 days). In dogs with advanced PPC, MC achieved a measurable clinical benefit without significant risk or toxicity. This makes MC a potential alternative to other recognized management approaches.

Dosimetric benefit of adaptive radiotherapy in the neoadjuvant management of canine and feline thymoma-An exploratory case series.

While surgery is the treatment of choice for thymomas, complete excision is not possible in a significant proportion of cases. For these patients, radiotherapy can be used as neoadjunctive, post-operative adjunctive or sole therapy. During radiotherapy, rapid biological clearance of tumour cells is often observed, requiring adaptation of the treatment plan. Adaptive radiation therapy (RT) is a dynamic process, whereby the treatment plan is altered throughout the treatment course due to changes in morphologic, functional or positioning changes. With the hypothesis, that individually adapted replanning will massively reduce the dose to organs at risk (OAR) in a fast-changing environment such as a rapidly responding thymoma, the dosimetric impact of adaptive treatment planning in 5 patients with large thymoma was measured. In all patients rapid tumour-shrinkage of the gross tumour volume was observed after 1 week of therapy, with a mean shrinkage of 31.0% ± 15.2%, or a tumour regression of 5.2% per day. In consequence, there was a considerable change in position of organs such as heart and lung, both of them moving cranially into the high dose area upon tumour regression. After mid-therapy replanning, the dose to OAR was significantly reduced, with -18.2% in the mean heart dose and -27.9% in the V20 lung dose. Adaptive planning led to a significantly reduced radiation dose and hence protection of OAR for these patients. It can be concluded that adaptive replanning should be considered for canine and feline thymoma patients receiving fractionated RT.

Principles for ethical treatment decision-making in veterinary oncology.

Many owners of companion animals with cancer are overwhelmed by having to choose the "right course of action." With the aim of reducing the burden on owners who are forced to act as surrogates for their animals, this work discusses principles that apply to ethical treatment decision-making for animal patients with cancer. Four principles frequently used for ethical decision-making in human medicine will be considered for their potential applicability in veterinary medicine. As a result of these considerations, preliminary guidelines are presented, along which a decision-making discussion can be held. The deliberate integration of the non-maleficence and beneficence principles into the purely empirical facts of what is medically possible helps to maintain a moral perspective in specialized veterinary medicine. At the same time, such guidelines may contribute to individual decision-making in a way that animal patients neither have to endure unnecessarily severe side effects, nor that they are euthanized prematurely.

Novel hyperthermia applicator system allows adaptive treatment planning: Preliminary clinical results in tumour-bearing animals.

Hyperthermia (HT) as an adjuvant to radiation therapy (RT) is a multimodality treatment method to enhance therapeutic efficacy in different tumours. High demands are placed on the hardware and treatment planning software to guarantee adequately planned and applied HT treatments. The aim of this prospective study was to determine the effectiveness and safety of the novel HT system in tumour-bearing dogs and cats in terms of local response and toxicity as well as to compare planned with actual achieved data during heating. A novel applicator with a flexible number of elements and integrated closed-loop temperature feedback control system, and a tool for patient-specific treatment planning were used in a combined thermoradiotherapy protocol. Good agreement between predictions from planning and clinical outcome was found in 7 of 8 cases. Effective HT treatments were planned and verified with the novel system and provided improved quality of life in all but 1 patient. This individualized treatment planning and controlled heat exposure allows adaptive, flexible and safe HT treatments in palliatively treated animal patients.

The role of sentinel lymph node mapping in small animal veterinary medicine: A comparison with current approaches in human medicine.

The relevance of regional lymph node (LN) assessment to quantify the metastatic spread of cancer is well recognized in veterinary oncology. Evaluation of LNs is critical for tumour staging. However, sampling the correct LN may not be possible without sentinel lymph node (SLN) mapping. Methods for diagnostic imaging and intraoperative detection of SLNs are well established in human medicine, in particular, the combination of lymphoscintigraphy and intraoperative application of blue dyes. Nevertheless, alternative imaging techniques are available and have gained increasing interest. Successful implementation of these techniques in dogs have been reported in both clinical and experimental studies. This review aims to provide an overview of SLN mapping techniques in human and veterinary medicine.

Outcome in dogs with advanced (stage 3b) anal sac gland carcinoma treated with surgery or hypofractionated radiation therapy.

Stage 3b anal sac gland carcinoma (ASGC) can be life-threatening. A surgical approach is not always possible or may be declined. Dogs with stage 3b ASGC treated with surgery or conformal radiation therapy (RT) with 8 × 3.8 Gy (total dose 30.4 Gy, over 2.5 weeks) were retrospectively evaluated. Patient characteristics, median progression-free interval (PFI) and median survival time (MST) were compared. Twenty-eight dogs were included; 15 underwent surgery, 13 underwent RT. At the time of presentation, 21% showed life-threatening obstipation and 25% showed hypercalcaemia. PFI and MST for surgery cases were 159 days (95% CI: 135-184 days) and 182 days (95% CI: 146-218 days), both significantly lower than for RT cases with 347 days (95% CI: 240-454 days) and 447 days (95% CI: 222-672 days), (P = 0.01, P = 0.019). Surgery as well as RT led to a fast relief of symptoms. PFI and survival of surgical patients were significantly inferior to that of a comparable patient group treated with conformal hypofractionated RT.

Safety, tolerability and pharmacokinetic properties of the novel triazene TriN 2755 in tumour bearing dogs - a phase I study†.

TriN 2755 is an alkylating antineoplastic agent for intravenous (IV) use, carrying the triazene group as the cytotoxic principal. Using a standard 3 + 3 design, a phase I study was performed in tumour bearing dogs to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), and pharmacokinetic (PK) profile of TriN 2755. Thirty dogs were included in the study. TriN 2755 was administered over 20 min on two consecutive weeks per month for a total of three cycles. The starting dose was 25 mg kg-1 and the MTD was 74.6 mg kg-1 . Three dogs experienced DLT, which was characterized by gastrointestinal adverse events. The PKs of TriN 2755 and its main metabolites in plasma and sputum are described in a two-compartment model. The response rate for 19 of 30 dogs was 47.3% (six partial remission, three stable disease) and the median progression-free interval (PFI) for the responders was 47 days (range: 21-450 days).

A complication probability planning study to predict the safety of a new protocol for intracranial tumour radiotherapy in dogs.

Technical advances make it possible to deliver radiation therapy for canine intracranial tumours in fewer fractions, under the assumption of equivalent tumour control. With the aim of estimating the late toxicity risk profile for various tumour sizes and locations, the present paper evaluates the normal tissue complication probability (NTCP) values for the intracranial organs at risk. By making isoeffect calculations, a new 10-fraction radiation protocol was developed with the same tumour control probability (TCP) as a currently used 20-fraction standard protocol, and complication risk profiles for brain, brainstem and optic chiasm were modelled using a representative population of 64 dogs with brain tumours. For >59% of cases, the new 10-fraction protocol yielded an acceptable, low risk estimate of late toxicity (<10%). Our calculations suggest that it may be safe to treat small to intermediate-sized tumours that are neither located near the optic chiasm nor at the brainstem with 10 daily fractions of 4.35 Gy.

Efficacy and side effects of radiation therapy in comparison with radiation therapy and temozolomide in the treatment of measurable canine malignant melanoma.

Prognosis for unresectable canine malignant melanoma (MM) is typically poor, and therapeutic approaches remain largely palliative. A bi-institutional trial was conducted to compare efficacy and safety of radiation therapy (RT) and RT with post-radiation temozolomide in dogs with chemotherapy-naïve, measurable MM. RT consisted of 5 × 6 Gy fractions over 2.5 weeks. Dogs whose owners wished to pursue chemotherapy received adjuvant oral temozolomide (60 mg m-2 for 5 days every 28 days). Fifteen dogs were treated with RT only (Group 1) and 12 dogs subsequently received temozolomide (Group 2). Overall response rate was similar between Group 1 (86.7%) and Group 2 (81.1%). Median time to progression (TTP) was significantly longer in Group 2 (205 days) compared to Group 1 (110 days; p = 0.046). Survival time was not significantly different between groups. Both treatments were well tolerated. Post-radiation temozolomide has a good safety profile, and may improve TTP in MM when compared to coarse fractionated RT.

An open-label phase 1 dose-escalation clinical trial of a single intravenous administration of gemcitabine in dogs with advanced solid tumors.

BACKGROUND: A broad range of gemcitabine dosages have been used in dogs. HYPOTHESIS/OBJECTIVES: To determine maximally tolerated dose (MTD), dose-limiting toxicity (DLT), and preliminary antitumor activity of intravenous administration of gemcitabine in dogs with advanced solid tumors. ANIMALS: Twenty-two client-owned dogs. METHODS: Dogs with advanced cancer were prospectively enrolled in an open-label Phase 1 study of gemcitabine. Gemcitabine was administered as a 30-minute intravenous bolus starting at 800 mg/m(2), using escalation of 50 mg/m(2) increments with 3 dogs per dose level. MTD was established based on the number of dogs experiencing DLT assessed after 1 cycle. Treatment continued until disease progression or unacceptable toxicosis. Additional dogs were enrolled at MTD to better characterize tolerability, and to assess the extent and duration of gemcitabine excretion. RESULTS: Twenty-two dogs were treated at 4 dose levels, ranging from 800 to 950 mg/m(2). Neutropenia was identified as DLT. MTD was 900 mg/m(2). DLT consisting of grade 4 febrile neutropenia was observed at 950 mg/m(2) in 2 dogs. There were no nonhematologic DLTs. Twenty dogs received multiple doses, and none had evidence of severe toxicosis from any of their subsequent treatments. At 900 mg/m(2), 2 complete and 5 partial responses were observed in dogs with measurable tumors. The amount of gemcitabine excreted in urine decreased over time, and was undetectable after the first 24 hours. CONCLUSIONS AND CLINICAL IMPORTANCE: The recommended dose of gemcitabine for future Phase 2 studies is weekly 900 mg/m(2). In chemotherapy-naïve dogs with advanced solid tumor this dose level merits further evaluation.

Prolactin--to be reconsidered in canine mammary tumourigenesis?

Mammary tumours represent the most common neoplastic disease of the female dog, and the incidence in female dogs is much higher than in women. Whereas the influence of sexual steroids on breast cancer (BC) development in dogs has been studied, very little is known about the role of prolactin (PRL). New studies show that until recently, the importance of PRL in human BC development and progression has been highly underestimated. PRL plays a role in promoting benign as well as malignant neoplastic cell growth in BC in vitro and in vivo. Sporadic publications proposed a tumour promotor role in the dog. The goal of this review is to summarize our knowledge about PRL and human BC as well as canine mammary tumourigenesis, and propose future research in this area.

Use of epothilone B (patupilone) in refractory lymphoma and advanced solid tumors in dogs.

BACKGROUND: The epothilones are microtubule-stabilizing agents with promising antitumor effect in refractory and metastatic tumors in humans. The toxicity profile is considered more favorable than in taxanes. The safety of epothilone B (patupilone) has not been evaluated in tumor-bearing dogs. OBJECTIVES: To evaluate the inhibition of proliferation in canine tumor cells after patupilone treatment. To assess toxicity profile and maximally tolerated dose of patupilone in dogs with refractory tumors. ANIMALS: Twenty client-owned dogs with various malignancies. METHODS: Prospective clinical study. The inhibition of proliferation was assessed with a proliferation assay in vitro in canine hemangiosarcoma and lymphoma cell lines. Dogs received patupilone IV once a week for 2 treatments (= 1 treatment cycle). Dose was escalated with 3 dogs per cohort and 20% increments. Adverse effects were graded according to the VCOG-CTCAE v1.0. RESULTS: Both canine cell lines were sensitive to patupilone with approximately 50% decrease in proliferative activity at 0.2-1 nM. In vivo, dose-limiting adverse effects occurred at 3.3 mg/m(2); main adverse effects were diarrhea, anorexia, vomiting, and nausea. Neither neutropenia nor peripheral neuropathy was observed. Maximally tolerated dose for 2 patupilone administrations once weekly IV is 2.76 mg/m(2). Three per 11 dogs receiving more than 1 treatment cycle showed partial remission in the short period of observation. CONCLUSIONS AND CLINICAL IMPORTANCE: Canine tumor cells show inhibition of proliferation to patupilone in vitro. Clinically, a dose of 2.76 mg/m(2) IV is well tolerated in dogs with spontaneously occurring tumors.

Massive haematoma formation associated with proximal popliteal artery haemangioendothelioma in a dog.

A mixed breed dog presented with diffuse unilateral hind limb swelling, which ultrasound and cytology confirmed to be caused by severe haematoma formation. Multi-detector computed tomography (MDCT) angiography allowed distinct visualisation of an anomalous segment of the proximal popliteal artery, the presumed origin of the self-sustaining haematoma. Histopathology classified the malformed vessel as a haemangioendothelioma, a neoplasia of intermediate malignancy. Considering this as differential diagnosis to a neoplastic vascular alteration of high malignancy (such as haemangiosarcoma) might alter choice of treatment in future cases with similar clinical and imaging findings.