Effect of vincristine on intraocular pressure and tear fluid oxidative stress biomarkers in canine transmissible venereal tumor.

BACKGROUND: The ocular side effects of cancer chemotherapeutic drugs are relatively uncommon. Nonetheless, the ocular system has a potentially high sensitivity to toxic substances. This study proposed a framework to assess the effect of vincristine chemotherapy on intraocular pressure, tear protein, and oxidative stress in canines with transmissible venereal tumor (TVT). METHODS: The study group comprised 10 dogs with TVT, whose diagnosis was based on cytology, and all dogs were treated with vincristine for 4 weeks. Each animal was given a complete ophthalmic examination, followed by a standard Schirmer tear test. Before and 20 min after administering vincristine, intraocular pressure (IOP) was measured in the eyes with a noncontact tonometer. At any of the times mentioned, tear samples were collected using the Schirmer test procedure and were subjected to protein analysis-oxidative stress index (OSI), total antioxidant capacity (TAC), total oxidant status (TOS), nitric oxide (NO), and malondialdehyde (MDA) were determined, and standard statistical analysis was applied. RESULTS: No significant differences were found in protein in tears, but mean Pre and Postinjection IOP revealed a significant decrease in the eyes each week. Also, results indicated significant differences in oxidative stress markers: increased OSI, NO, and MDA, and reduced TAC. CONCLUSION: The importance of an increase in oxidative stress levels in the tears of vincristine-treated patients should be taken seriously, as it appears to play a role in the pathogenesis of eye disease. Therefore, during the treatment weeks prior to prescribing vincristine, eye diseases should be evaluated and considered.

Transmissible venereal tumor of the uterine stump following successful chemotherapy in a 5-year-old mixed-breed dog.

A 5-year-old spayed female mixed-breed dog was referred to the Atlantic Veterinary College (Charlottetown, Prince Edward Island) because of a 7-month history of intermittent pink, mucoid, vulvar discharge. The dog was imported from the Bahamas at 3.5 y of age and had a history of transmissible venereal tumor (TVT) of the vulva that was successfully treated with a course of vincristine chemotherapy. Complete remission was achieved with a disease-free interval of 6 mo before clinical signs recurred. Abdominal ultrasound and CT scan identified a large caudal abdominal mass thought to arise from the uterine stump. An exploratory laparotomy was performed and the mass grossly excised. Histopathology was consistent with a poorly differentiated round cell tumor, and immunohistochemical analysis confirmed TVT as the most likely diagnosis. No further treatment was carried out. Repeat abdominal ultrasound at 4 mo after surgery showed no evidence of mass recurrence. At 8 mo after surgery, the dog was reported to be doing well clinically. Key clinical message: Transmissible venereal tumor should be considered as a differential diagnosis for masses arising from the deep genital tissues of dogs in cases where there is a history of previous TVT. Transmissible venereal tumor should be considered even in dogs that have had complete resolution of a primary mass after chemotherapy.

Tumeur vénérienne transmissible du moignon utérin à la suite d'une chimiothérapie réussie chez un chien croisé de 5 ans.Une chienne de race mixte de 5 ans, stérilisée, a été référée au Atlantic Veterinary College (Charlottetown, Île-du-Prince-Édouard) en raison d'antécédents de pertes vulvaires roses, mucoïdes et intermittentes depuis 7 mois. Le chien a été importé des Bahamas à l'âge de 3,5 ans et avait des antécédents de tumeur vénérienne transmissible (TVT) de la vulve qui a été traitée avec succès par une chimiothérapie à la vincristine. Une rémission complète a été obtenue avec un intervalle sans maladie de 6 mois avant la réapparition des signes cliniques. L'échographie abdominale et la tomodensitométrie ont identifié une grosse masse abdominale caudale qui proviendrait du moignon utérin. Une laparotomie exploratoire a été réalisée et la masse excisée. L'histopathologie était compatible avec une tumeur à cellules rondes peu différenciée et l'analyse immunohistochimique a confirmé la TVT comme le diagnostic le plus probable. Aucun autre traitement n'a été effectué. Une échographie abdominale répétée 4 mois après la chirurgie n'a montré aucun signe de récidive massive. Huit mois après l'opération, la chienne se portait bien cliniquement.Message clinique clé:Les tumeurs vénériennes transmissibles doivent être considérées comme un diagnostic différentiel pour les masses provenant des tissus génitaux profonds des chiens dans les cas où il existe des antécédents de TVT. Une tumeur vénérienne transmissible doit être envisagée même chez les chiens dont la masse primaire a complètement disparu après chimiothérapie.(Traduit par Dr Serge Messier).

Canine transmissible venereal tumor - From general to molecular characteristics: A review.

Cancer is a group of complex diseases resulting from the accumulation of genetic and epigenetic changes affecting control and activity of several genes, especially those involved in cell differentiation and growth processes, leading to an abnormal proliferation. When the disease reaches an advanced stage, cancer can lead to metastasis in other organs. Interestingly, recent studies have shown that some types of cancer spread not only through the body, but also can be transmitted among individuals. Therefore, these cancers are known as transmissible tumors. Among the three types of transmissible tumors that occur in nature, the canine transmissible venereal tumor (CTVT) is known as the oldest cancer in the world, since it was originated from a single individual 11 000 years ago. The disease has a worldwide distribution, and its occurrence has been documented since 1810. The CTVT presents three types of cytomorphological classification: lymphocytoid type, mixed type, and plasmacytoid type, the latter being chemoresistant due to overexpression of the ABCB1 gene, and consequently increase of the P-glycoprotein. More knowledge about the epidemiology and evolution of CTVT may help to elucidate the pathway and form of the global spread of the disease.

Immunotherapy for the treatment of canine transmissible venereal tumor based in dendritic cells pulsed with tumoral exosomes.

Context: Exosomes secreted by tumor cells are a good source of cellular components that stimulate the immune response, such as alarmins (mRNA, tetraspanins (CD9, CD63, CD81), heat-shock proteins, major histocompatibility complex class I molecules) and tumor-associated antigens. These properties permit to pulsed dendritic cells in the immunotherapy for many cancers types. The aim of this study was to demonstrate the use of exosomes derived from canine transmissible venereal tumor (CTVT) as an antigen to pulsed dendritic cells and its administration in dogs with CTVT as treatment against this disease. Material and methods: From primary culture of CTVT cells the exosomes were isolated and characterized by scanning electron microscopy assay, dot blot and protein quantification. The monocytes of each patient were differentiated to dendritic cells (DC) and pulsed with CTVT exosomes (CTVTE). Phagocytosis, tumor size, populations of lymphocytes and IFN-c levels were evaluated. Results: The CTVTE showed a size around 90 nm. CD81, CD63, CD9 and Hsp70 were expressed. Monocytes showed an expression of 85.71% for CD14+, 12.3% for CD80+, 0.1% for CD83+ and 0.8% for DLA-II. In DC 5.1% for CD14+, 86.7% for CD80+, 90.1% for CD83+ and 92.6% for DLA-II and a phagocytosis of 63% was obtained by FITC Dextran test. No side effects were observed in the experimental groups with our therapy. Tumor regression was of 100% at the seventh week, as well as an increase in the level of IFN-γ (142 pg/ml), and CD4+ (28%) and CD8+ (34%) cell percentage. Discusion and conclusion: These results have shown that DC pulsed with tumor exosomes induce regression of the TVT in dogs.

Immunology of naturally transmissible tumours.

Naturally transmissible tumours can emerge when a tumour cell gains the ability to pass as an infectious allograft between individuals. The ability of these tumours to colonize a new host and to cross histocompatibility barriers contradicts our understanding of the vertebrate immune response to allografts. Two naturally occurring contagious cancers are currently active in the animal kingdom, canine transmissible venereal tumour (CTVT), which spreads among dogs, and devil facial tumour disease (DFTD), among Tasmanian devils. CTVT are generally not fatal as a tumour-specific host immune response controls or clears the tumours after transmission and a period of growth. In contrast, the growth of DFTD tumours is not controlled by the Tasmanian devil's immune system and the disease causes close to 100% mortality, severely impacting the devil population. To avoid the immune response of the host both DFTD and CTVT use a variety of immune escape strategies that have similarities to many single organism tumours, including MHC loss and the expression of immunosuppressive cytokines. However, both tumours appear to have a complex interaction with the immune system of their respective host, which has evolved over the relatively long life of these tumours. The Tasmanian devil is struggling to survive with the burden of this disease and it is only with an understanding of how DFTD passes between individuals that a vaccine might be developed. Further, an understanding of how these tumours achieve natural transmissibility should provide insights into general mechanisms of immune escape that emerge during tumour evolution.

Canine transmissible venereal tumor and seminoma: a cytohistopathology and chemotherapy study of tumors in the growth phase and during regression after chemotherapy.

In this study, 12 dogs affected by canine transmissible venereal tumor (CTVT) and testicular seminoma tumor were studied retrospectively. The cytological sample was smeared onto a glass slide and either air-dried for May-Grünwald-stain, and masses were surgically removed. The tumors were grossly examined, and sections of 4-µm thick were obtained from each sample and stained with H&E. For chemotherapy, vincristine sulfate was administered weekly as an infusion over 3 min via the cephalic vein at a dose of 0.025 mg/kg after diluting with physiological saline to a total amount of 10 ml. If no remission was observed after 8 weeks, chemotherapy was continued with weekly doxorubicin infusion at a dose of 1 mg/kg. All the tumor samples were divided into four cytohistopathologic groups, namely: multilobular (six cases), papillary (two cases), pedunculated (two cases), and tubular (two cases of seminoma). The most frequently represented tumor type was multilobular (6/10, 60 %) followed by pedunculated (2/10, 20 %), papillary (2/10, 20 %), and tubular (two cases of seminoma, 100 %). Cytological smears from eight tumors in regression after chemotherapy were poorly cellular, and many cells were fragmented. In two progressive tumors, there was an average of 1,406 ± 972 CTVT 200 cells/µl or 96.71 % of total cells counted. Thus, tumor cells represented 96.71 % of total cells within the biopsy specimens and the leukocytes 4.29 % (leukocyte, tumor cell ratio=0.062 ± 0.031). In eight regressive tumors, there was an average of 1,245 ± 1,032 CTVT 200 cells/µl or 97.31 % of total cells counted. Thus, tumor cells represented 97.31 % of total cells and leukocytes 2.69 % (leukocyte, tumor cell ratio=0.071 ± 0.174). Our data suggested that combination treatment with vincristine and doxorubicin in the future could be an excellent therapeutic alternative for the treatment of TVT for probably reducing the resistance to vincristine, and also, treatment success could easily be followed by the cytological changes.

A case of ocular canine transmissible venereal tumor.

A 1-year-old, intact female mixed-breed dog was presented to St. George's University Small Animal Clinic in Grenada for a third eyelid mass. The dog was diagnosed with a rare ocular transmissible venereal tumor (TVT) and concurrent anaplasmosis, ehrlichiosis and dirofilariasis. Treatment with vincristine sulfate resulted in complete resolution of the TVT.

Cas de tumeur vénérienne canine oculaire transmissible. Une chienne de race croisée intacte âgée de 1 an a été présentée à la clinique pour petits animaux de l'Université St. George de la Grenade pour une masse de la troisième paupière. La chienne a été diagnostiquée avec une rare tumeur vénérienne oculaire transmissible (TVT) et l'anaplasmose, l'ehrlichiose et la dirofilariose concomitantes. Le traitement au sulfate de vincristine a produit une résolution complète de la TVT.(Traduit par Isabelle Vallières).

Canine transmissible venereal tumor in Morocco: Clinical and pathological findings in 64 dogs-insights from a descriptive epidemiological study (2020-2023).

Background: Canine transmissible venereal tumor (CTVT) is a widely spread, contagious neoplasm commonly found in dogs. Mostly affects the external genitalia, however, it may also exhibit unusual clinical presentations. Aim: To describe the epidemiology, clinical appearance, cytologic and histopathologic features of dogs with TVT in Morocco. Methods: Within the realm of a nation-wide study on canine and feline tumors in Morocco between September 2020 and March 2023, dogs with histologically diagnosed TVT were identified and data on epidemiologic, clinical as well as cytologic, and histologic features were compiled and analyzed. Results: A total of 64 cases of canine TVT were diagnosed. 52 dogs were cross-breed (81.2%) while 4 Siberian Huskies (6.2%) and 3 German shepherds (4.7%) were the most affected pure-breed dogs. The median age of dogs at diagnosis was 3 years (range, 1-10years) and male gender was more common (male:female ratio; 1.3:1). Tumor was located exclusively in the genital area in 58 cases (90.6%), whereas 6 dogs (9.4%) had an atypical occurrence of TVT with locations including skin and nasal cavity. Cytology allowed for an early diagnosis in 2 cases. Histology revealed no differences between the genital and extragenital forms. Immunohistochemistry was necessary in 4 cases and revealed positive staining for vimentin and Alpha-1-antitrypsin, negative marking for CD3, CD20, and AE1/AE3, and low cytoplasmic labeling for lysozyme. Conclusion: CTVT is a widely distributed neoplasm in Morocco, mostly showing presence in young, cross-breed, and oftentimes stray dogs. An adequate understanding of this tumor's epidemiological features is necessary for its management and eradication.

Immunohistochemical expression of vimentin, E-cadherin, and CD45 in natural cases of canine cutaneous round tumors.

Round cell tumors are common cutaneous lesions in dogs, with increased occurrence percentages among different skin tumors. This study aimed to investigate the frequency as well as gross and pathological characteristics of round cell tumors in natural cases of tumorous dogs in relation to breed, sex, and age. Moreover, it aimed to evaluate the immunohistochemical expression of a panel of immunohistochemical stains, including vimentin, E-cadherin, and cluster of differentiation (CD45) as an adjunct technique for the differential diagnosis of cutaneous round cell neoplasm. Data were collected from 64 dogs of both sexes (36 females and 28 males), various breeds, and different ages (8 months to 7 years). The histopathological nature of neoplastic growth was reported, and neoplasm prevalence was classified using age, sex, breed, and site on the body. We observed 48 cases of transmissible venereal tumors, 12 cutaneous histiocytomas, and 4 histiocytic sarcoma. Immunohistochemical characterization revealed an intense positive immunoreactivity for vimentin in transmissible venereal tumor cells and moderate positive immunoreactivity for E-cadherin and CD45 in cutaneous histiocytoma and histiocytic sarcoma cells. In conclusion, the canine transmissible venereal tumor was the most frequent form of round cell tumor; thus, a definitive cutaneous neoplasm diagnosis should be based on histopathological morphology and immunohistochemical findings.

Transmission of canine transmissible venereal tumour between two dogs in the UK.

Canine transmissible venereal tumour (CTVT) is a contagious cancer spread by transfer of living cancer cells. Occasional cases are observed in the UK in dogs imported from endemic regions. Here, we report a case of imported canine transmissible venereal tumour that was transmitted to a second dog within the UK. Transmission of genital canine transmissible venereal tumour occurred despite neutered status of the second dog. The aggressive course of disease in both cases, which included metastasis, resistance to therapeutic interventions and ultimate euthanasia of both dogs, is described. The diagnosis of canine transmissible venereal tumour was made using a combination of cytology, histology, immunohistochemistry and PCR to detect the LINE-MYC rearrangement. Practitioners unfamiliar with canine transmissible venereal tumour are reminded of this disease of concern, particularly when imported dogs are placed in multi-dog households, irrespective of neuter status.

Concise review: transmissible animal tumors as models of the cancer stem-cell process.

Tasmanian devil facial tumor disease (DFTD) and canine transmissible venereal tumor (CTVT) are highly unusual cancers capable of being transmitted between animals as an allograft. The concept that these tumors represent a cancer stem-cell process has never been formally evaluated. For each, evidence of self-renewal is found in the natural history of these tumors in the wild, tumor initiation in recipient animals, and serial transplantation studies. Additional data for stem-cell-specific genes and markers in DFTD also exist. Although both tumor types manifest as undifferentiated cancers, immunocytohistochemistry supports a histiocytic phenotype for CTVT and a neural crest origin, possibly a Schwann-cell phenotype, for DFTD. In these data, differential expression of lineage markers is seen which may suggest some capacity for differentiation toward a heterogeneous variety of cell types. It is proposed that DFTD and CTVT may represent and may serve as models of the cancer stem-cell process, but formal investigation is required to clarify this. Appreciation of any such role may act as a stimulus to ongoing research in the pathology of DFTD and CTVT, including further characterization of their origin and phenotype and possible therapeutic approaches. Additionally, they may provide valuable models for future studies of their analogous human cancers, including any putative CSC component.

Disseminated transmissible venereal tumour associated with Leishmaniasis in a dog.

This report addresses an atypical transmissible venereal tumour in an 8-year-old bitch that was pluriparous and seropositive for leishmaniasis. There were ascites and a serosanguineous discharge from the vulva, but no lesions on the external genital mucosa. An aspirate of the peritoneal fluid showed mononuclear round cells characteristic of transmissible venereal tumour (TVT). Exploratory laparotomy revealed light red, granulomatous structures in the peritoneum, omentum, spleen, liver and uterine horns. Cytological and histopathological tests confirmed the diagnosis of intra-abdominal TVT. Dissemination of the TVT to several organs inside the abdominal cavity probably resulted from immunosuppression caused by leishmaniasis, which favoured the presence and aggressiveness of TVT.

Successful management of metastatic transmissible venereal tumour to skin of mammary region.

A Dalmatian female presented with a history of vaginal bleeding and was diagnosed as having transmissible venereal tumour (TVT) after cytological examination of the vaginal growth revealed typical TVT cells. A cytology of the aspirate from multiple nodules in the skin near the abdominal and inguinal pair of mammary glands revealed similar cells suggestive of metastasis to skin of mammary region. Chemotherapy was initiated with weekly injections of vincristine sulphate (0.025 mg/kg BW, IV, SID) and haematological examination was performed pre- and post-treatment to assess the prognosis of the patient and side effects of the drug. The major side effects observed during the course of the treatment were high body temperature, mild neutropaenia and significant decrease in packed cell volume, haemoglobin, total leucocyte and erythrocyte count. Four weekly injections of vincristine were administered, and 4 weeks from initiation of treatment, the tumour and nodules were gone, suggesting complete recovery.

Cell-mediated immunity and expression of MHC class I and class II molecules in dogs naturally infected by canine transmissible venereal tumor: Is there complete spontaneous regression outside the experimental CTVT?

The canine transmissible venereal tumor (CTVT) is a transplantable cancer with the ability evade the immune system, despite strict immune surveillance of the host; in this context, the relationship between inflammatory infiltrate and CTVT prognosis is not entirely understood. Natural canine transmissible venereal tumors of 22 dogs were evaluated for tumor/host interaction through clinical and epidemiological data, cyto-histopathological and cytogenetic findings and, mainly, cell-mediated immune response. We performed analysis on dogs with naturally acquired disease to provide information from the study of CTVT biology in its natural course, as the clinical evolution of the natural tumor in the host is not yet as well known as in the laboratory. Populations for T cell labeling (CD3+ CD4+ CD8+), B cells, NK cells, and macrophages were analyzed by flow cytometry in blood and tumor samples and expressions of MHC class I and class II molecules were quantified by immunohistochemistry and compared mainly between the phases of progression and regression in the natural CTVT. Dogs were also treated with vincristine sulfate and evaluated for chemotherapeutic response. Chemotherapy was effective in 88% of cases and there was no recurrence of the disease 12 months after the cure. Tumor cells displayed a numerical chromosomal variation between 54 and 72, not correlating with the host genotype. Although a greater expression of MHC molecules [18.6 ± 5.8% class I (P < 0.004) and 38.5 ± 6.5% class II (P < 0.003)] was observed in the regression phase, no significant effect was observed between the clinical phase of the tumor and cellular immune response in the analysis by flow cytometry (P > 0.05). We also found no correlation between cytological subtype of the tumor (plasmacytoid, lymphocytoid and mixed) and cellular immune response, suggesting that there is no difference in tumor immunogenicity. Here, we found no immunological evidence to support the theory of the immune-induced complete spontaneous regression in CTVT.

Contagious cancer.

Although cancer can on occasion be caused by infectious agents such as specific bacteria, parasites, and viruses, it is not generally considered a transmissible disease. In rare circumstances, however, direct communication from one host to another has been documented. The Tasmanian devil is now threatened with extinction in the wild because of a fatal transmissible cancer, devil facial tumor disease (DFTD). Another example is canine transmissible venereal tumor (CTVT or Sticker's sarcoma) in dogs. There is a vast difference in prognosis between these two conditions. DFTD is often fatal within 6 months, whereas most cases of CTVT are eventually rejected by the host dog, who then is conferred lifelong immunity. In man, only scattered case reports exist about such communicable cancers, most often in the setting of organ or hematopoietic stem cell transplants and cancers arising during pregnancy that are transmitted to the fetus. In about one third of cases, transplant recipients develop cancers from donor organs from individuals who were found to harbor malignancies after the transplantation. The fact that two thirds of the time cancer does not develop, along with the fact that cancer very rarely is transmitted from person to person, supports the notion that natural immunity prevents such cancers from taking hold in man. These observations might hold invaluable clues to the immunobiology and possible immunotherapy of cancer.

As cancer grows old.

Mutations trace the evolution of an ancient tumor lineage.

Vincristine and ivermectin combination chemotherapy in dogs with natural transmissible venereal tumor of different cyto-morphological patterns: A prospective outcome evaluation.

Vincristine is the first-line drug for the chemotherapy of canine transmissible venereal tumor (CTVT). Drug resistance is related to tumor cyto-morphological patterns of CTVT. There are anti-cancer properties of ivermectin, thus, a combination of ivermectin and vincristine could be an effective chemo-therapeutic treatment regimen for CTVT. Study aims, therefore, were to (1) assess the frequency of CTVT cyto-morphologies, and (2) evaluate treatment efficacy and possible adverse reactions to vincristine compared with a combination vincristine and ivermectin. Dogs (n = 41) with CTVT were characterized by tumor cyto-morphology and disease severity and of those, 20 were randomly allocated into two groups. There was a control group (G-Vin; n = 10) in which there was treatment with vincristine; and an experimental group (G-Iv/Vin; n = 10) in which there was treatment with the ivermectin/vincristine combination. Although dogs in the G-Iv/Vin group had more severe disease at the beginning of the study (P = 0.0031), the number of weeks and chemotherapy sessions until tumor remission were similar among dogs of the two groups, indicating both treatments were effective. There was a decrease in the leukocyte counts (P = 0.0020), related to neutropenia (P = 0.0371) in the G-Vin but not the G-Iv/Vin treatment group. There was no tumor resistance that developed during the study regardless of the treatment regimen used or tumor cytomorphology. In summary, the use of the vincristine/ivermectin combination was well tolerated and efficacious for CTVT treatment.

Combination therapy using intratumoral bacillus Calmette-Guerin (BCG) and vincristine in dogs with transmissible venereal tumours: therapeutic efficacy and histological changes.

Therapeutic efficacy and histological changes after bacillus Calmette-Guerin (BCG), vincristine and BCG/vincristine combination therapy of canine transmissible venereal tumours (CTVT) were studied. Twenty dogs with naturally occurring CTVT in the progression stage were divided into 4 groups and treated with intratumoral BCG, vincristine, BCG/vincristine combination therapy or intratumoral buffered saline (control group). Tumour sizes were determined weekly and tumour response to therapy was assessed. Tumour biopsies were taken weekly to evaluate histological changes. Complete tumour regression was observed in all the dogs treated with BCG, vincristine and BCG/vincristine combination therapy. BCG/vincristine combination therapy had a statistically significantly shorter regression time than BCG or vincristine therapy. No tumour regression was observed in the control group. Intratumoral BCG treatment resulted in the appearance of macrophages and increased numbers of tumour infiltrating lymphocytes (TILs) followed by tumour cell apoptosis and necrosis. Treatment with vincristine resulted in increased tumour cell apoptosis, reduction in the mitotic index and a decrease in the number of TILs. Tumours from dogs on BCG/vincristine combination were characterised by reduction in the mitotic index, and appearance of numerous TILs and macrophages followed by marked tumour cell apoptosis and necrosis. This study indicates that combined BCG and vincristine therapy is more effective than vincristine in treating CTVT, suggesting that the clinical course of this disease may be altered by immunochemotherapy.