Radiodynamic Therapy with Acridine Orange Is an Effective Treatment for Bone Metastases.

Current multimodal treatment of bone metastases is partially effective and often associated with side effects, and novel therapeutic options are needed. Acridine orange is a photosensitizing molecule that accumulates in acidic compartments. After photo- or radiodynamic activation (AO-PDT or AO-RDT), acridine orange can induce lysosomal-mediated cell death, and we explored AO-RDT as an acid-targeted anticancer therapy for bone metastases. We used osteotropic carcinoma cells and human osteoclasts to assess the extracellular acidification and invasiveness of cancer cells, acridine orange uptake and lysosomal pH/stability, and the AO-RDT cytotoxicity in vitro. We then used a xenograft model of bone metastasis to compare AO-RDT to another antiacid therapeutic strategy (omeprazole). Carcinoma cells showed extracellular acidification activity and tumor-derived acidosis enhanced cancer invasiveness. Furthermore, cancer cells accumulated acridine orange more than osteoclasts and were more sensitive to lysosomal death. In vivo, omeprazole did not reduce osteolysis, whereas AO-RDT promoted cancer cell necrosis and inhibited tumor-induced bone resorption, without affecting osteoclasts. In conclusion, AO-RDT was selectively toxic only for carcinoma cells and effective to impair both tumor expansion in bone and tumor-associated osteolysis. We therefore suggest the use of AO-RDT, in combination with the standard antiresorptive therapies, to reduce disease burden in bone metastasis.

Sorafenib for the Treatment of Unresectable Hepatocellular Carcinoma: Preliminary Toxicity and Activity Data in Dogs.

Unresectable nodular and diffuse hepatocellular carcinoma (HCC) have a poor prognosis with limited treatment options. Systemic traditional chemotherapy has been only rarely reported, with unsatisfactory results. The aim of this prospective, non-randomized, non-blinded, single center clinical trial was to investigate safety profile, objective response rate, time to progression and overall survival of sorafenib in comparison with metronomic chemotherapy (MC) consisting of thalidomide, piroxicam and cyclophosphamide in dogs with advanced, unresectable HCC. Between December 2011 and June 2017, 13 dogs were enrolled: seven received sorafenib, and six were treated with MC. Median time to progression was 363 days (95% CI, 191-535) in dogs treated with sorafenib versus 27 days (95% CI, 0-68) in dogs treated with MC (p = 0.044). Median overall survival was 361 days (95% CI, 0-909) in dogs receiving sorafenib, while 32 days (95% CI, 0-235) in those receiving MC (p = 0.079). Sorafenib seems to be a good candidate for the treatment of dogs with advanced HCC, due to a benefit in disease control and an acceptable safety profile, offering a good basis on which new randomized prospective clinical trials should be undertaken to compare the efficacy and drawback of sorafenib versus MC or traditional chemotherapy.

Radiation therapy for the treatment of canine progressive cutaneous angiomatosis: Description of 2 cases.

Two dogs with histologically confirmed progressive cutaneous angiomatosis were presented because of extensive and progressive cutaneous lesions of 1 hind limb causing pain and lameness. Radiation therapy was offered to treat disease recurrence after amputation in the first case and as first treatment in the second case. Metronomic therapy was added in both dogs. Complete and partial regression of the cutaneous lesions was achieved, respectively, with a period of 31 months of disease-free interval (first case) and 12 months of stable disease (second case). Self-limiting grades I and II acute side effects were observed. Radiation therapy can be an alternative to surgery in the treatment of inoperable cutaneous progressive angiomatosis.

Radiothérapie pour le traitement de l'angiomatose cutanée progressive canine : description de 2 cas. Deux chiens ayant un diagnostic d'angiomatose cutanée progressive confirmé par histologie ont été présentés en raison de lésions cutanées vastes et progressives d'un membre postérieur qui causaient de la douleur et de la boiterie. La radiothérapie a été offerte pour traiter la récidive de la maladie après l'amputation dans le premier cas et comme premier traitement dans le deuxième cas. La thérapie métronomique a été ajoutée chez les deux chiens. Une régression complète et partielle des lésions cutanées a été obtenue, respectivement, avec un intervalle de 31 mois sans maladie (premier cas) et de 12 mois de maladie stable (deuxième cas). Des effets secondaires aigus spontanément résolutifs de grades I et II ont été observés. La radiothérapie peut représenter un traitement de remplacement à la chirurgie pour le traitement de l'angiomatose cutanée progressive inopérable.(Traduit par Isabelle Vallières).

Megavoltage Radiotherapy for the Treatment of Degenerative Joint Disease in Dogs: Results of a Preliminary Experience in an Italian Radiotherapy Centre.

The aim of the study was to evaluate the efficacy and toxicity of a low-dose radiotherapy treatment in dogs with osteoarthritis (OA). Inclusion criteria were dogs affected by OA of one or multiple joints, with lameness, previously treated with medical therapy and referred for radiotherapy because of chronic unresponsive pain. After suspension of medical therapy, dogs underwent external beam radiotherapy treatments delivered in three fractions of 2 Gy each. Four of these dogs had one (three dogs) to four (one dog) additional courses of radiation. Medical records were reviewed and follow-up information was collected by clinical recheck and owners interview. Twenty-five dogs matched the inclusion criteria; among them, 21 had one course of RT and 4 underwent multiple treatments, respectively 218, 266, 39, and 1,384 days after the first treatment. Clinical improvement was observed in 92% of patients with median benefit duration of 356 days after the first treatment, and 418 days after the second treatment. No side effects were recorded. In this group of patients, radiotherapy was effective, well tolerated, and repeatable, leading to an improvement of quality of life in dogs with degenerative joint disease unresponsive to medical treatments.

Randomized, placebo-controlled, double-blinded chemoimmunotherapy clinical trial in a pet dog model of diffuse large B-cell lymphoma.

PURPOSE: Active immunotherapy is a promising antitumoral strategy; however its use in combination with chemotherapy in dogs with large B-cell lymphoma (DLBCL) remains largely untested. Heat shock proteins (HSP) bind the small peptides they chaperone (HSPPC), allowing for immunization of the host against a large repertoire of tumor-associated antigens. Hydroxylapatite vehicles HSPPCs and acts as an immunologic adjuvant. The aim of this study was to show that an autologous vaccine with hydroxylapatite and tumor-derived HSPPCs is safe and therapeutically effective in dogs with DLBCL. EXPERIMENTAL DESIGN: Nineteen dogs with naturally occurring DLBCL were entered into a prospective randomized placebo-controlled double-blinded trial of HSPPCs-hydroxylapatite plus chemotherapy versus chemotherapy alone. Endpoints included time to progression (TTP), lymphoma-specific survival (LSS), and incidence of toxicoses. RESULTS: Median first TTP after randomization to the vaccine arm was 304 days versus 41 days for the control arm (P = 0.0004). There was also a statistically significant difference in duration of second remission between the two groups (P = 0.02). Median LSS was 505 days for the vaccinated dogs versus 159 days for the unvaccinated dogs (P = 0.0018). Six vaccinated dogs achieved molecular remission, as shown by clonal immunoglobulin H (IgH) rearrangement. Toxicoses were comparable between the two treatment arms. CONCLUSIONS: The results of this trial demonstrate that the autologous vaccine tested here is safe and efficacious in prolonging TTP and LSS in dogs with DLBCL when used in combination with dose-intense chemotherapy. On the basis of these results, additional evaluation of this novel therapeutic strategy is warranted in human DLBCL.

Use of contrast-enhanced ultrasound for characterization of focal splenic lesions.

Contrast-enhanced ultrasound was used to study focal and multifocal lesions of the spleen in 26 dogs and two cats affected by 11 benign and 18 malignant splenic diseases. A second-generation microbubble contrast medium (Sonovue) was injected into the cephalic vein and enhancement patterns were subjectively described and time intensity curves calculated. Final diagnosis was obtained by histopathologic examination after splenectomy (n=19) or by needle aspiration and sonographic follow-up after 4 and 8 weeks (n=9). Contrast-enhanced ultrasound parameters, improving the characterization between benign and malignant lesions, were established. The most useful criterion was the hypoechogenicity of the lesion in the wash-out phase combined with the presence of tortuous feeding vessels, which was observed in association with malignancy. All malignant lesions were hypoechoic to the surrounding spleen 30s after starting the contrast medium injection. Lymphosarcoma and hemangiosarcoma had characteristic perfusion patterns. Lymphosarcoma had rapid time to peak and early wash-out phase with a honeycomb pattern during the wash-out. Hemangiosarcomas were large nonperfused masses in all phases surrounded by hypervascular splenic parenchyma. Benign lesions except one hematoma and a benign histiocytoma had the same perfusion pattern as the surrounding spleen. Ultrasonographic and contrast-enhanced ultrasound findings of an accessory spleen are reported. Contrast-enhanced ultrasound can improve the characterization of focal or multifocal lesions of the spleen.