Intraoperative acridine orange photodynamic therapy and cribriform electron-beam irradiation for canine intranasal tumors: A pilot study

Untreated canine intranasal tumors carry a poor prognosis. We retrospectively evaluated the efficacy of marginal tumor resection in combination with intraoperative acridine orange (AO) photodynamic therapy (PDT) and 1 fraction of 5 Gy megavoltage irradiation for canine intranasal malignant tumors. When cribriform plate invasion or turbinate destruction around the cribriform plate was present, an additional fraction of 20 Gy was delivered with an electron beam during surgery. The study included 6 dogs, 2 of which were classified as stage I, 1 as stage II, and 3 as stage IV. The median local disease-free survival time and overall survival after the treatment were 8.5 and 13 months, respectively. Recurrence was noted in 2 of the 6 dogs after 4 and 7 months. Adverse events were mild (subcutaneous emphysema in 1 case, and rhinitis in 3 cases). Combination AO therapy may increase the tumor control time of dogs with marginally resectable intranasal malignant tumors.     

Pilot study on the treatment with thioproline of 24 small animals with tumors

Thioproline (thiazolidine-4-carboxylic acid) was administered in a 16-week trial by either IM or subcutaneous routes to 23 dogs and 1 cat with solid tumors (12 animals) and incompletely excised malignant tumors (12 animals). Acute partial responses were observed in 3 of the 12 animals with solid tumors. In a mammary gland carcinoma and oral fibrosarcoma, there was tumor enlargement by the 4th day of drug therapy followed by partial regression. Drug activity appeared to be directed against tumor blood supply. Tumor progression occurred in 11 of the 12 other animals (incompletely excised tumors). Although 4 of 5 dogs with intranasal tumors were alive and relatively free of tumorous signs at 9 months or more after surgical operation was done, there was no microscopic evidence of reverse transformation or cytostatic activity in the 2 intranasal tumors that were reoperated upon. There was no hematologic or biochemical toxicosis noted. Apparent pain from injection and abscess formation were the most frequent complications from parenteral administration and would preclude using this method on a long-term basis.     

Preclinical evaluation of 5-aminolevulinic acid-based photodynamic therapy for canine transitional cell carcinoma

As a prelude to photodynamic therapy, 5‐aminolevulinic acid (ALA) was given orally to healthy dogs. ALA‐induced protoporphyrin IX (PpIX) fluorescence significantly increased in the mucosa of the urinary bladder in an ALA dose‐dependent fashion. Vomiting occurred after ALA administration in 70% of the dogs but did not affect PpIX fluorescence. ALA‐based photodynamic therapy (PDT) of the urinary bladder in healthy dogs caused only submucosal oedema within the bladder wall. No haematologic or serum biochemistry abnormalities were observed after ALA administration. Microscopic haematuria was observed in all the dogs after PDT but was mild and self limiting. ALA‐based PDT was administered to six dogs with transitional cell carcinoma (TCC) of the lower urinary tract. ALA‐based PDT resulted in tumour progression‐free intervals from 4 to 34 weeks in five dogs; one dog with pre‐existing hydronephrosis died shortly after PDT. Dogs with TCC represent an outbred, spontaneous, tumour model for developing PDT protocols for humans with bladder cancer.     

Recurrence analysis of intraoperative acridine orange-photodynamic therapy for dogs with intranasal tumors

Intraoperative acridine orange-photodynamic therapy (AO-PDT) and cribriform plate irradiation are used to treat canine intranasal tumors. The purpose of this study was to evaluate the effects of AO-PDT on intranasal tumors and the recurrence rate of tumors after this treatment. Treatments with AO-PDT were performed on 38 dogs through a narrow window of the dorsal nasal cavity. The median progression-free interval was 12 mo and recurrence was detected in 21 dogs. Based on computed tomography, recurrence in 16 dogs was biased to the following areas: lateral (n = 10), medial (n = 2), ventral (n = 0), rostral (n = 0), and caudal (n = 8). Side effects were mild and included subcutaneous emphysema and rhinitis. The median survival time was 24 mo. Although AO-PDT with cribriform irradiation is an effective treatment for intranasal tumors, AO-PDT techniques should be improved to treat the nasal cavity more uniformly and thoroughly.     

Endoscopic photodynamic therapy using talaporfin sodium for recurrent intranasal carcinomas after radiotherapy in three dogs

Radiation is the treatment of choice for canine nasal tumours but, in almost all cases, there is local recurrence associated with poor prognosis. This report describes the effect of endoscopic photodynamic therapy using talaporfin sodium for canine intranasal carcinoma recurring after radiation therapy. Rhinoscopic photodynamic therapy was administered after radiation therapy in three dogs with recurrent intranasal carcinoma. Two to 24 illuminations of a 665‐nm diode laser were performed two hours after intravenous bolus injection of 5·0 mg/kg of talaporfin sodium. Photodynamic therapy induced almost complete remission and prolonged survival time in all cases suggesting that it might be a useful treatment for intranasal carcinomas that recur after radiation.     

Phase I clinical trial of the use of zinc phthalocyanine tetrasulfonate as a photosensitizer for photodynamic therapy in dogs

OBJECTIVE: To determine the threshold for acute toxicosis of parenterally administered zinc phthalocyanine tetrasulfonate (ZnPcS(4)), a candidate second-generation photosensitizer, in mice and evaluate the compound's safety in a phase I clinical trial of ZnPcS(4)-based photodynamic therapy (PDT) in pet dogs with naturally occurring tumors. ANIMALS: Male Swiss-Webster mice and client-owned dogs with naturally occurring neoplasms. PROCEDURES: For the study of acute toxicosis, mice were given graded doses of ZnPcS(4). To determine safety, a rapid-titration phase I clinical trial of ZnPcS(4)-based PDT in tumor-bearing dogs was conducted. RESULTS: In mice, administration of >or= 100 mg of ZnPcS(4)/kg resulted in renal tubular necrosis 24 hours after IP injection. In tumor-bearing dogs, ZnPcS(4) doses 相似文献   

SURVIVAL TIMES FOR CANINE INTRANASAL SARCOMAS TREATED WITH RADIATION THERAPY: 86 CASES (1996–2011)

Sarcomas comprise approximately one‐third of canine intranasal tumors, however few veterinary studies have described survival times of dogs with histologic subtypes of sarcomas separately from other intranasal tumors. One objective of this study was to describe median survival times for dogs treated with radiation therapy for intranasal sarcomas. A second objective was to compare survival times for dogs treated with three radiation therapy protocols: daily‐fractionated radiation therapy; Monday, Wednesday, and Friday fractionated radiation therapy; and palliative radiation therapy. Medical records were retrospectively reviewed for dogs that had been treated with radiation therapy for confirmed intranasal sarcoma. A total of 86 dogs met inclusion criteria. Overall median survival time for included dogs was 444 days. Median survival time for dogs with chondrosarcoma (n = 42) was 463 days, fibrosarcoma (n = 12) 379 days, osteosarcoma (n = 6) 624 days, and undifferentiated sarcoma (n = 22) 344 days. Dogs treated with daily‐fractionated radiation therapy protocols; Monday, Wednesday and Friday fractionated radiation therapy protocols; and palliative radiation therapy protocols had median survival times of 641, 347, and 305 days, respectively. A significant difference in survival time was found for dogs receiving curative intent radiation therapy vs. palliative radiation therapy (P = 0.032). A significant difference in survival time was also found for dogs receiving daily‐fractionated radiation therapy vs. Monday, Wednesday and Friday fractionated radiation therapy (P = 0.0134). Findings from this study support the use of curative intent radiation therapy for dogs with intranasal sarcoma. Future prospective, randomized trials are needed for confirmation of treatment benefits.     

Canine intranasal tumours treated with alternating carboplatin and doxorubin in conjunction with oral piroxicam: 29 cases

Few veterinary studies have evaluated the response to chemotherapy treatment of canine intranasal tumours, while many have focused on the efficacy of radiation therapy. Given the higher costs and limited access to radiation therapy, alternative treatment options are needed. The study describes a cohort of dogs with histologically confirmed intranasal tumours treated with chemotherapy as a sole therapy. This retrospective study was conducted using data from the Melbourne Veterinary Specialist Centre (MVSC) database between 2004 and 2017. Dogs with a histologically confirmed intranasal tumour who received chemotherapy treatment were included. Signalment, presenting signs, tumour type, chemotherapy details, adverse events (AEs) and survival times were reviewed. Twenty‐nine dogs met the inclusion criteria. Overall median survival time for dogs in the study was 234 days (range 12‐1698 days). Median survival for dogs with adenocarcinoma or carcinoma (n = 12) was 280 days, transitional cell carcinoma (n = 6) 163 days, squamous cell carcinoma, anaplastic carcinoma or undifferentiated carcinoma (n = 7) 59 days and all sarcomas (n = 4) 448 days. Adverse events were reported following 28% of treatments and 69% of dogs experienced at least one AE. Twenty four per cent of all dogs experienced grade 3 or 4 toxicities. The chemotherapy protocol was generally well tolerated. The study suggests potential benefit in the use of chemotherapy for dogs with adenocarcinoma, carcinoma and sarcoma.     

Prognostic factors and survival after radiotherapy for intranasal neoplasms in dogs: 70 cases (1974-1985)

Survival time and 31 prognostic factors were analyzed for 70 dogs undergoing radiotherapy for intranasal tumors at the Veterinary Hospital of the University of Pennsylvania between 1974 and 1985. At the time of analysis (January 1987), 14.3% (10 of 70) of the dogs were alive. Of the remaining dogs, 34 died because of tumor recurrence, 14 died because of intercurrent disease, and 12 were lost to follow-up evaluation. Pretreatment prognostic factors that were significantly correlated with disease-free interval or long-term survival could not be identified. Notably, presence of a facial mass was not prognostically significant, suggesting that extensive disease should not preclude treatment. Median survival time of dogs with all tumor types was 16.5 months, with a 1-, 2-, and 3-year survival of 54%, 43%, and 35%, respectively. Median survival time of dogs with carcinoma was 13.5 months, with 1-year survival of 51%, 2-year survival of 37%, and 3-year survival of 31%. Orthovoltage radiation was efficacious in the treatment of canine intranasal tumors.     

A Candidate Second‐Generation Photosensitizer for Photodynamic Therapy in Veterinary Medicine

Introduction:  Photodynamic therapy (PDT) involves the light activation of a drug within a tumor causing selective tumor cell death. Unfortunately, some photosensitizing drugs have been associated with adverse reactions in veterinary patients. Zinc phthalocyanine tetrasulfonate (ZnPcS4) is a promising second‐generation photosensitizer for use in veterinary medicine, however, it cannot be applied clinically until safety and efficacy data are available.
Methods:  Increasing intraperitoneal doses of ZnPcS4 were given to Swiss Webster mice to assess acute toxicity. Based on mouse toxicity data, a phase I clinical trial of ZnPcS4‐based PDT in tumor‐bearing dogs was designed, using an accelerated titration scheme starting at 0.5% of the minimum toxic dose in mice. 24‐hours after ZnPcS4 administration tumors were irradiated with 675 nm light and dogs were evaluated by routine hematology and serum biochemistry at regular intervals after PDT.
Results:  Doses >125 mg/kg were associated with acute toxicity and mortality in Swiss Webster mice, suggesting the minimum toxic dose is 120–125 mg/kg. One dog, a Golden retriever with a massive malignant fibrous histiocytoma, has been entered into the phase I clinical trial. No deleterious effects were noted after ZnPcS4 administration. Within 48 hours of PDT, the tumor was dark and necrotic, with no grossly visible changes to the surrounding normal tissues. Histological examination of the PDT‐treated tumor confirmed widespread necrosis and thrombosis consistent with PDT‐mediated damage. The owner reported no adverse effects after treatment.
Conclusions:  Although preliminary data are encouraging, additional evaluation of ZnPcS4‐based PDT is required to determine its role in veterinary medicine.     

Photodynamic therapy of superficial nasal planum squamous cell carcinomas in cats: 55 cases

Background: Squamous cell carcinomas (SCCs) are common skin tumors in cats. We investigated photodynamic therapy (PDT) using the photosensitizing agent 5‐aminolaevulinic acid (5‐ALA) topically and a high‐intensity red light source. Hypothesis: PDT is a safe and effective treatment for feline SCCs. Animals: Fifty‐five client‐owned cats with superficial nasal planum SCCs. Methods: Prospective, uncontrolled clinical trial. PDT was performed using topical 5‐ALA and light of peak wavelength 635 nm. Adverse effects, response, and tumor control were evaluated. Results: 53/55 (96%) cats responded to therapy, and there was a complete response in 47/55 (85%). Six cats (11%) had a partial response. Of the 47 cats with complete response to a single treatment, 24 recurred (51%), with a median time to recurrence of 157 days (95% confidence interval, 109–205 days). Repeat PDT was performed in 22 cats, and at a median follow‐up of 1,146 days, 23 (45%) cats were alive and disease free, 17 (33%) had to be euthanized due to tumor recurrence, and 11 (22%) were euthanized for other reasons. Only transient mild local adverse effects were observed after treatment. Conclusions and Clinical Importance: PDT using 5‐ALA and a red light source was safe, well tolerated, and effective in the treatment of superficial nasal planum SCCs of cats and offers an alternative to conventional therapy. Although initial response rates were high, this treatment did not lead to a durable remission or cure in all cases.     

Clinical, Serologic, and Parasitologic Follow-Up after Long-Term Allopurinol Therapy of Dogs Naturally Infected with Leishmania infantum

Canine leishmaniasis usually is treated with antimony compounds, but frequent relapses, adverse effects, high costs, and development of resistance to long-term antimonial therapy emphasize the importance of searching for alternative antileishmanial drugs. Allopurinol was used at a dosage of 10 mg/kg/day PO to treat 10 dogs naturally infected with Leishmania infantum for a period of 2-24 months. Nine dogs recovered within 2-6 months of chemotherapy, and no relapses were observed during the treatment of up to 20 months. However, 3 of 4 dogs relapsed after treatment was discontinued. These dogs again recovered clinically when therapy was resumed. Parasite-specific immunoglobulin concentrations (IgG2) were high in all dogs before therapy and remained high even in clinically cured dogs during or after therapy. On the other hand, specific IgG1 reactions, which have been shown to be detectable in symptomatic animals, persisted in 7 dogs for long periods after clinical recovery. Three of these dogs relapsed within 2-4 weeks after interrupting therapy. However, 1 dog with no detectable specific IgG1 reaction at the end of therapy did not relapse in the following 4 months. Parasites could be detected in 8 of 9 dogs after clinical improvement by in vitro cultivation or polymerase chain reaction (PCR) testing of lymph node aspirates. In 4 of these dogs, parasites also were detected in blood samples by PCR. Hence, these clinically cured dogs must be regarded as reservoirs of Leishmania and allopurinol cannot be recommended in endemic areas.     

Biodistribution of three photosensitizers in dogs with spontaneous tumors

Photodynamic therapy (PDT) has been considered a potential method for tumor eradication. The present study was designed to assess the efficacy of PDT as an alternative treatment approach. Photosensitizers, such as porfimer sodium, tin ethyl etiopurpurin, and aluminum chlorophthalocyanine, were administered i.v. to dogs, and tissue samples were harvested 24 to 300 hours later. The uptake of the photosensitizers in tumor (fibrosarcoma) and adjacent normal tissue biopsies was quantified by tissue solubilization technique and fluorimetry. In addition, the pharmacokinetics and selectivity of the photosensitizers were addressed by two-phase exponential function and specific uptake ratio, respectively. Porfimer sodium exhibited a longer elimination half-life (175.3 hr), slower clearance (0.0028 L/kg/hr), and a larger area under the curve (1075 microg/g/hr) in tumors than did tin ethyl etiopurpurin or aluminum chlorophthalocyanine. As a result, porfimer sodium showed a good selectivity in tumors located in muscle and skin. The study provided clinical information for determination of the efficacy of different PDT alternatives.     

Urinary tract infections due to Mycoplasma canis in dogs

Urine samples were obtained from 100 dogs with symptoms of lower urinary tract disease by cystocentesis and were examined for mycoplasmas. Urinalysis, haematological and biochemical analyses were also performed. Bacteria were isolated from urine in 41 of 100 dogs; Mycoplasma canis was isolated from four of 100 (4%) urine samples and three were pure culture. Selective mycoplasma media were used for isolation. In growth inhibition test, propagation of the four M. canis isolates was inhibited by their specific hyperimmune sera and there was no cross reactivity between isolates and hyperimmune sera of other mycoplasmas. Dogs in which M. canis was isolated were azotemic. All dogs were treated with enrofloxacin, furosemide, and supportive therapy (fluid therapy, ascorbic acid). In all animals, clinical improvements were observed after treatment.     

Clinicopathological changes and effect of imidocarb therapy in dogs experimentally infected with Babesia canis

In this study one spleen-intact dog (A) and two splenectomised dogs (BSE, CSE) were infected with Babesia canis. All animals developed an acute disease characterised by fever, haemoglobinuria and anaemia, the latter being more severe in the splenectomised dogs. Fever and parasitised red blood cells were detected for three days after imidocarb treatment in the splenectomised animals. Haematological abnormalities included regenerative anaemia, thrombocytopenia and leukopenia (due to neutropenia and lymphopenia) in the acute phase, soon followed by leukocytosis, neutrophilia and left shift a few days later. Acute hepatopathy was detected in all dogs with elevated ALT activity, which was more seriously altered in the splenectomised dogs. Diffuse changes in liver structure and hepatomegaly were seen by ultrasonography. Liver biopsy and histology revealed acute, non-purulent hepatitis in the splenectomised dogs. Both splenectomised dogs were successfully cured after collection of 400 ml highly parasitised blood, proving that large-amount antigen production is possible with rescuing the experimental animals. Whole blood transfusion, imidocarb and supportive care with infusions, antipyretics, glucocorticoids and diuretics were applied. The spleen-intact dog clinically recovered after receiving supportive treatment, with no imidocarb therapy. Microbial infections developed in both splenectomised animals (BSE: haemobartonellosis, CSE: osteomyelitis caused by Escherichia coli), probably as a consequence of immunosuppression after splenectomy and glucocorticoid therapy.     

Retrospective study of orthovoltage radiation therapy for nasal tumors in 42 dogs

Megavoltage radiation therapy currently is the standard of care for dogs with nasal tumors. Some studies report that surgery and adjunctive orthovoltage radiation therapy result in longer control of these tumors than does megavoltage radiation therapy alone. This study reports less effective control of nasal tumors in dogs treated with surgery and orthovoltage radiation than previously observed, supporting the superiority of megavoltage radiation therapy for these tumors. In addition, this study suggests 2 new prognostic indicators for dogs with nasal tumors and describes toxicity associated with surgery and orthovoltage therapy. Forty-two dogs with nasal tumors were treated with surgical cytoreduction and 48 Gy orthovoltage radiation therapy administered in twelve 4-Gy fractions. Median survival was 7.4 months. One- and 2-year survival rates were 37% and 17%, respectively. Dogs with facial deformity had shorter survival than those without deformity (P = .005). Dogs with resolution of clinical signs after treatment had longer survival than those with chronic nasal signs (P = .0001). Acute radiation toxicity was moderate to severe for skin and eye and negligible for oral mucosa. Toxicity healed within 1 month after radiation therapy. Late toxicity was mild, but 70% of evaluable dogs experienced persistent ocular signs. Only 39% of dogs achieved a disease-free period.     

192iridium brachytherapy, using an intracavitary afterload device, for treatment of intranasal neoplasms in dogs.

After surgical removal of a primary intranasal neoplasm, an implant device, designed to deliver 192iridium (192Ir) brachytherapy, was positioned in the nasal cavity of 8 dogs. Ribbons containing 192Ir seeds were placed in the device, using an afterloading technique. Dosimetry, to a dose of 7,000 to 10,000 centiGray (cGy), was calculated to encompass the site previously occupied by the tumor and a 1-cm margin of surrounding normal tissue. The quantity of 192Ir implanted varied between 16.69 and 100.80 mg of radium equivalent. The duration of implantation ranged from 90 to 168 hours. All dogs tolerated the implant well, but had a mucoid nasal discharge after radiotherapy. The implant device allowed rapid application and removal of the radioactive ribbons. Mean (+/- SD) radiation exposure to each radiotherapist during seed loading and unloading was 14.4 (+/- 5.3) and 4.5 (+/- 0.9) mrem, respectively. A uniform dose distribution around the intranasal implant device was achieved; however, dogs that received doses in excess of 9,400 cGy at the dorsolateral surface of the nose and/or hard palate had bone and soft tissue necrosis between 70 and 120 days after treatment. One dog was euthanatized 50 days after treatment because of metastatic disease, and 2 dogs were euthanatized because of local tumor recurrence at 125 and 212 days. Death, considered unrelated to treatment, occurred in 1 dog that was euthanatized 27 days after treatment and in 3 dogs that died 30, 93, and 456 days after treatment. Necropsy was performed on 3 of these dogs and evidence of intranasal neoplasia was not observed. One dog remained disease-free at 587 days after treatment.     

Sodium iodide I 131 treatment of dogs with nonresectable thyroid tumors: 39 cases (1990-2003)

OBJECTIVE: To determine outcome for dogs with nonresectable thyroid carcinomas treated with sodium iodide I 131 and identify factors associated with outcome. DESIGN: Retrospective case series. Animals-39 dogs. PROCEDURES: A definitive or presumptive diagnosis of thyroid tumor was made on the basis of cytologic or histologic examination, abnormal accumulation of sodium pertechnetate Tc 99m during scintigraphy, or both, and dogs were treated with sodium iodide I 131. Dogs with cervical thyroid tumors were evaluated 3 to 6 weeks after 131I therapy, and residual tumor was resected when feasible. RESULTS: Prior to 131I therapy, 32 dogs had a solitary mass and 7 had metastases; 21 were hyperthyroid, 16 were euthyroid, and 2 were hypothyroid. Median survival time for dogs with local or regional tumors (ie, stage II or III) was significantly longer (839 days) than median survival time for dogs with metastasis (366 days). Tumor site (cervical vs ectopic), dose of sodium iodide I 131, age, body weight, treatment (131I therapy alone vs 131I therapy followed by surgery), and serum T4 concentration prior to 131I therapy were not significantly associated with survival time. Three dogs died of radioiodine-associated myelosuppression within 3 months after treatment, but no specific factor associated with development of toxicosis was identified. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that 131I therapy may result in prolonged survival times in dogs with nonresectable thyroid tumors, regardless of serum thyroxine concentration prior to treatment. Dogs undergoing 131I therapy should be monitored for signs of bone marrow suppression.     

Fluorescence In Situ Hybridization Confirms Clearance of Visible Helicobacter spp. Associated with Gastritis in Dogs and Cats

Background: The results of studies examining the role of Helicobacter spp. in the pathogenesis of canine and feline gastritis are inconclusive. Furthermore, data evaluating the effectiveness of medical therapy for eradication of Helicobacter infection are limited.
Aim: To detect Helicobacter spp. in mucosal biopsies of dogs and cats diagnosed with gastritis, with fluorescence in situ hybridization (FISH).
Animals: Three dogs and 2 cats with signs of chronic gastrointestinal disease.
Methods: Dogs and cats infected with Helicobacter spp. were treated with triple antimicrobial therapy and fed an elimination diet for 21 days. Helicobacter spp. status in endoscopic (3 dogs, 1 cat) or surgical biopsies (1 cat) of gastric mucosa was compared pre- and posttreatment in each animal by histology, FISH analysis, and polymerase chain reaction (PCR).
Results: Gastritis of varying severity with intraglandular spiral bacteria was observed in all animals. Pretreatment diagnostic tests confirmed the presence of mucosal Helicobacter spp. in all animals by FISH and histopathology and in 4/5 animals by PCR. Rapid resolution of vomiting episodes was observed in all animals. Gastric biopsies performed after triple therapy revealed clearance of visible Helicobacter spp. by histopathology and negative FISH analysis, as well as PCR in all animals.
Conclusions and Clinical Importance: Application of FISH to routine biopsy specimens enabled rapid and specific identification of Helicobacter spp. within the gastric mucosa of dogs and cats. Although medical therapy was useful in resolution of clinical signs and clearance of visible Helicobacter spp. in gastric biopsies, gastric inflammation persisted.