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MAPK has been reported as a key oncogenic pathway for canine histiocytic sarcoma, which can be pharmacologically targeted with trametinib, a small inhibitor of MEK1/2. Preliminary data showed promising antitumor activity in in vitro and in vivo models and represented a proof of concept to translate the findings from bench to bedside. In this phase I, dose escalating study using a 3 + 3 cohort design, trametinib was evaluated in 18 dogs with cancer. Adverse events were graded according to VCOG-CTCAE v2. Blood samples and tumour biopsies were collected for pharmacokinetic and pharmacodynamic assessment. Trametinib was well tolerated with a maximum tolerated dose of 0.5 mg/m2/day, PO. Dose-limiting toxicities included systemic hypertension, proteinuria, lethargy and elevated ALP, and were all Grade 3. The drug exposures increased more than linearly with dose since the elimination of trametinib was saturable. At a dose of 500 µg Q24h (0.5 mg/m2/day in a 30 kg dog), approximately 70% of dogs had an average steady-state concentration of 10 ng/mL, achieved after approximately 2 weeks. This threshold was associated with clinical efficacy in humans. Target engagement was not observed in biospecimens collected on Days 0 and 7. In conclusion, trametinib was considered safe in dogs with cancer, and the dose of 0.5 mg/m2/day was the recommended dose for phase II studies.
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Antineoplásicos , Doenças do Cão , Neoplasias , Piridonas , Pirimidinonas , Cães , Animais , Piridonas/farmacocinética , Piridonas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Piridonas/farmacologia , Pirimidinonas/farmacocinética , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Pirimidinonas/uso terapêutico , Pirimidinonas/farmacologia , Doenças do Cão/tratamento farmacológico , Feminino , Masculino , Neoplasias/tratamento farmacológico , Neoplasias/veterinária , Antineoplásicos/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a DrogaRESUMO
Canine malignant melanoma provides a clinically relevant, large animal parallel patient population to study the GD2-reactive hu14.18-IL-2 immunocytokine as it is similar to human melanoma and expresses GD2. The objectives of this study were to evaluate safety, radiation fractionation, and identify informative biomarkers of an in-situ tumor vaccine involving local radiation therapy plus intratumoral-immunocytokine in melanoma tumor-bearing dogs. Twelve dogs (six dogs/arm) with locally advanced or metastatic melanoma were randomized to receive a single 8â Gy fraction (arm A) or three 8â Gy fractions over 1 week (arm B) to the primary site and regional lymph nodes (when clinically involved) with the single or last fraction 5 days before intratumoral-immunocytokine at 12â mg/m 2 on 3 consecutive days. Serial tumor biopsies were obtained. All 12 dogs completed protocol treatment, and none experienced significant or unexpected adverse events. Evidence of antitumor activity includes one dog with a complete response at day 60, one dog with a partial response at day 60, and four dogs with mixed responses. Histology of serial biopsies shows a variably timed increase in intratumoral lymphocytic inflammation in some dogs. Canine NanoString analyses of serial biopsies identified changes in gene signatures of innate and adaptive cell types versus baseline. There were no significant differences in NanoString results between arm A and arm B. We conclude that intratumoral-immunocytokine in combination with local radiation therapy in canine melanoma is well tolerated and has antitumor activity with the potential to inform clinical development in melanoma patients.
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Doenças do Cão , Interleucina-2 , Melanoma , Cães , Animais , Melanoma/radioterapia , Melanoma/imunologia , Melanoma/patologia , Doenças do Cão/radioterapia , Doenças do Cão/imunologia , Neoplasias Cutâneas/radioterapia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Feminino , MasculinoRESUMO
Objective.The objective of this work is to: (1) demonstrate fluorine-19 (19F) MRI on a 3T clinical system with a large field of view (FOV) multi-channel torso coil (2) demonstrate an example parameter selection optimization for a19F agent to maximize the signal-to-noise ratio (SNR)-efficiency for spoiled gradient echo (SPGR), balanced steady-state free precession (bSSFP), and phase-cycled bSSFP (bSSFP-C), and (3) validate detection feasibility inex vivotissues.Approach.Measurements were conducted on a 3.0T Discovery MR750w MRI (GE Healthcare, USA) with an 8-channel1H/19F torso coil (MRI Tools, Germany). Numerical simulations were conducted for perfluoropolyether to determine the theoretical parameters to maximize SNR-efficiency for the sequences. Theoretical parameters were experimentally verified, and the sensitivity of the sequences was compared with a 10 min acquisition time with a 3.125 × 3.125 × 3 mm3in-plane resolution. Feasibility of a bSSFP-C was also demonstrated in phantom andex vivotissues.Main Results. Flip angles (FAs) of 12 and 64° maximized the signal for SPGR and bSSFP, and validation of optimal FA and receiver bandwidth showed close agreement with numerical simulations. Sensitivities of 2.47, 5.81, and 4.44ms-0.5mM-1 and empirical detection limits of 20.3, 1.5, and 6.2 mM were achieved for SPGR, bSSFP, and bSSFP-C, respectively. bSSFP and bSSFP-C achieved 1.8-fold greater sensitivity over SPGR (p< 0.01).Significance.bSSFP-C was able to improve sensitivity relative to simple SPGR and reduce both bSSFP banding effects and imaging time. The sequence was used to demonstrate the feasibility of19F MRI at clinical FOVs and field strengths withinex-vivotissues.
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Estudos de Viabilidade , Razão Sinal-Ruído , Tronco , Humanos , Tronco/diagnóstico por imagem , Imagens de Fantasmas , Imagem por Ressonância Magnética de Flúor-19/instrumentação , Imagem por Ressonância Magnética de Flúor-19/métodos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/instrumentaçãoRESUMO
Profiling the T cell receptor (TCR) repertoire using next-generation sequencing has become common in both human and translational research. Companion dogs with spontaneous tumors, including canine melanoma, share several features, e.g., natural occurrence, shared environmental exposures, natural outbred population, and immunocompetence. T cells play an important role in the adaptive immune system by recognizing specific antigens via a surface TCR. As such, understanding the canine T cell response to vaccines, cancer, immunotherapies, and infectious diseases is critically important for both dog and human health. Off-the-shelf commercial reagents, kits and services are readily available for human, non-human primate, and mouse in this context. However, these resources are limited for the canine. In this study, we present a cost-effective protocol for analysis of canine TCR beta chain genes. Workflow can be accomplished in 1-2 days starting with total RNA and resulting in libraries ready for sequencing on Illumina platforms.
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Receptores de Antígenos de Linfócitos T alfa-beta , Linfócitos T , Cães , Animais , Camundongos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Sequenciamento de Nucleotídeos em Larga Escala/veterináriaRESUMO
Preventative anti-cancer vaccination strategies have long been hampered by the challenge of targeting the diverse array of potential tumor antigens, with successes to date limited to cancers with viral etiologies. Identification and vaccination against frameshift neoantigens conserved across multiple species and tumor histologies is a potential cancer preventative strategy currently being investigated. Companion dogs spontaneously develop cancers at a similar incidence to those in people and are a complementary comparative patient population for the development of novel anti-cancer therapeutics. In addition to an intact immune system with tumors that arise in an autochthonous tumor microenvironment, dogs also have a shorter lifespan and temporally compressed tumor natural history as compared to humans, which allows for more rapid evaluation of safety, immunogenicity, and efficacy of cancer vaccination strategies. Here we describe the study protocol for the Vaccination Against Canine Cancer Study (VACCS), the largest interventional cancer clinical trial conducted in companion dogs to date. In addition to safety and immunogenicity, the primary endpoint of VACCS is the cumulative incidence (CI) of dogs developing malignant neoplasia of any type at the end of the study period. Secondary endpoints include changes in incidence of specific tumor types, survival times following neoplasia diagnosis, and all-cause mortality.
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Vacinas Anticâncer , Doenças do Cão , Neoplasias , Animais , Cães , Vacinas Anticâncer/administração & dosagem , Doenças do Cão/prevenção & controle , Neoplasias/prevenção & controle , Neoplasias/veterinária , Microambiente Tumoral , Vacinação/veterináriaRESUMO
Pet dogs with naturally occurring cancers play an important role in studies of cancer biology and drug development. We assessed tolerability, efficacy, and pharmacokinetic/pharmacodynamic relationships with a first-in-class small molecule inhibitor of valosin-containing protein (VCP/p97), CB-5339, administered to 24 tumor-bearing pet dogs. Tumor types assessed included solid malignancies, lymphomas, and multiple myeloma. Through a stepwise dose and schedule escalation schema, we determined the maximum tolerated dose to be 7.5 mg/kg when administered orally on a 4 days on, 3 days off schedule per week for 3 consecutive weeks. Adverse events were minimal and mainly related to the gastrointestinal system. Pharmacokinetic/pharmacodynamic data suggest a relationship between exposure and modulation of targets related to induction of the unfolded protein response, but not to tolerability of the agent. An efficacy signal was detected in 33% (2/6) of dogs with multiple myeloma, consistent with a mechanism of action relating to induction of proteotoxic stress in a tumor type with abundant protein production. Clinical trials of CB-5339 in humans with acute myelogenous leukemia and multiple myeloma are ongoing.
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Antineoplásicos , Linfoma , Mieloma Múltiplo , Proteína com Valosina , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Cães , Inibidores Enzimáticos/uso terapêutico , Linfoma/tratamento farmacológico , Linfoma/patologia , Linfoma/veterinária , Dose Máxima Tolerável , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Mieloma Múltiplo/veterinária , Resposta a Proteínas não Dobradas , Proteína com Valosina/antagonistas & inibidoresRESUMO
Mast cell neoplasms are one of the most frequently diagnosed malignancies in dogs. The clinical picture, course, and prognosis vary substantially among patients, depending on the anatomic site, grade and stage of the disease. The most frequently involved organ is the skin, followed by hematopoietic organs (lymph nodes, spleen, liver, and bone marrow) and mucosal sites of the oral cavity and the gastrointestinal tract. In cutaneous mast cell tumors, several grading and staging systems have been introduced. However, no comprehensive classification and no widely accepted diagnostic criteria have been proposed to date. To address these open issues and points we organized a Working Conference on canine mast cell neoplasms in Vienna in 2019. The outcomes of this meeting are summarized in this article. The proposed classification includes cutaneous mast cell tumors and their sub-variants defined by grading- and staging results, mucosal mast cell tumors, extracutaneous/extramucosal mast cell tumors without skin involvement, and mast cell leukemia (MCL). For each of these entities, diagnostic criteria are proposed. Moreover, we have refined grading and staging criteria for mast cell neoplasms in dogs based on consensus discussion. The criteria and classification proposed in this article should greatly facilitate diagnostic evaluation and prognostication in dogs with mast cell neoplasms and should thereby support management of these patients in daily practice and the conduct of clinical trials.
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RATIONALE: Murine syngeneic tumor models have revealed efficacious systemic antitumor responses following primary tumor in situ vaccination combined with targeted radionuclide therapy to secondary or metastatic tumors. Here we present studies on the safety and feasibility of this approach in a relevant translational companion dog model (n = 17 dogs) with advanced cancer. METHODS: The three component of the combination immuno-radiotherapy approach were employed either separately or in combination in companion dogs with advanced stage cancer. In situ vaccination was achieved through the administration of hypofractionated external beam radiotherapy and intratumoral hu14.18-IL2 fusion immunocytokine injections to the index tumor. In situ vaccination was subsequently combined with targeted radionuclide therapy using a theranostic pairing of IV 86Y-NM600 (for PET imaging and subject-specific dosimetry) and IV 90Y-NM600 (therapeutic radionuclide) prescribed to deliver an immunomodulatory 2 Gy dose to all metastatic sites in companion dogs with metastatic melanoma or osteosarcoma. In a subset of dogs, immunologic parameters preliminarily assessed. RESULTS: The components of the immuno-radiotherapy combination were well tolerated either alone or in combination, resulting in only transient low grade (1 or 2) adverse events with no dose-limiting events observed. In subject-specific dosimetry analyses, we observed 86Y-NM600 tumor:bone marrow absorbed-dose differential uptakes ≥2 in 4 of 5 dogs receiving the combination, which allowed subsequent safe delivery of at least 2 Gy 90Y-NM600 TRT to tumors. NanoString gene expression profiling and immunohistochemistry from pre- and post-treatment biopsy specimens provide evidence of tumor microenvironment immunomodulation by 90Y-NM600 TRT. CONCLUSIONS: The combination of external beam radiotherapy, intratumoral immunocytokine, and targeted radionuclide immuno-radiotherapy known to have activity against syngeneic melanoma in murine models is feasible and well tolerated in companion dogs with advanced stage, spontaneously arising melanoma or osteosarcoma and has immunomodulatory potential. Further studies evaluating the dose-dependent immunomodulatory effects of this immuno-radiotherapy combination are currently ongoing.
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Anticorpos Monoclonais/uso terapêutico , Interleucina-2/uso terapêutico , Melanoma/terapia , Osteossarcoma/terapia , Compostos Radiofarmacêuticos/uso terapêutico , Animais , Anticorpos Monoclonais/efeitos adversos , Medula Óssea/química , Medula Óssea/metabolismo , Medula Óssea/patologia , Terapia Combinada , Cães , Estudos de Viabilidade , Feminino , Expressão Gênica , Interleucina-2/efeitos adversos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Melanoma/imunologia , Melanoma/patologia , Melanoma/veterinária , Osteossarcoma/imunologia , Osteossarcoma/veterinária , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/química , Vacinação , Radioisótopos de Ítrio/químicaRESUMO
PURPOSE: The mTOR pathway has been identified as a key nutrient signaling hub that participates in metastatic progression of high-grade osteosarcoma. Inhibition of mTOR signaling is biologically achievable with sirolimus, and might slow the outgrowth of distant metastases. In this study, pet dogs with appendicular osteosarcoma were leveraged as high-value biologic models for pediatric osteosarcoma, to assess mTOR inhibition as a therapeutic strategy for attenuating metastatic disease progression. PATIENTS AND METHODS: A total of 324 pet dogs diagnosed with treatment-naïve appendicular osteosarcoma were randomized into a two-arm, multicenter, parallel superiority trial whereby dogs received amputation of the affected limb, followed by adjuvant carboplatin chemotherapy ± oral sirolimus therapy. The primary outcome measure was disease-free interval (DFI), as assessed by serial physical and radiologic detection of emergent macroscopic metastases; secondary outcomes included overall 1- and 2-year survival rates, and sirolimus pharmacokinetic variables and their correlative relationship to adverse events and clinical outcomes. RESULTS: There was no significant difference in the median DFI or overall survival between the two arms of this trial; the median DFI and survival for standard-of-care (SOC; defined as amputation and carboplatin therapy) dogs was 180 days [95% confidence interval (CI), 144-237] and 282 days (95% CI, 224-383) and for SOC + sirolimus dogs, it was 204 days (95% CI, 157-217) and 280 days (95% CI, 252-332), respectively. CONCLUSIONS: In a population of pet dogs nongenomically segmented for predicted mTOR inhibition response, sequentially administered adjuvant sirolimus, although well tolerated when added to a backbone of therapy, did not extend DFI or survival in dogs with appendicular osteosarcoma.
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Neoplasias Ósseas/terapia , Neoplasias Ósseas/veterinária , Doenças do Cão/terapia , Osteossarcoma/terapia , Osteossarcoma/veterinária , Animais de Estimação , Sirolimo/administração & dosagem , Amputação Cirúrgica , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Carboplatina/administração & dosagem , Quimioterapia Adjuvante , Terapia Combinada/veterinária , Doenças do Cão/mortalidade , Cães , Osteossarcoma/genética , Osteossarcoma/mortalidade , Estudos Prospectivos , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Taxa de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Most dogs with sinonasal tumors (SNT) treated with radiation therapy (RT) died because of local disease progression. HYPOTHESIS/OBJECTIVES: Our hypothesis is that the majority of local failure and residual disease would occur within the radiation field. ANIMALS: Twenty-two dogs with SNT treated with RT. METHODS: Retrospective cohort study. INCLUSION CRITERIA: dogs with SNT receiving 10 daily fractions of 4.2 Gy with intensity modulated radiation therapy (IMRT)/image guided radiation therapy (IGRT) and follow-up cone beam computed tomography (CBCT). Each CBCT was registered with the original radiation planning CT and the gross tumor volume (GTV) contoured. The GTV was classified as residual (GTVr) or a failure (GTVf). The dose statistic for each GTV was calculated with the original IMRT plan. For GTVf, failures were classified as "in-field," "marginal," or "out-field" if at least 95, 20-95, or less than 20% of the volume of failure was within 95% (D95) of the total prescription dose, respectively. RESULTS: There were 52 follow-up CBCT/CTs. Overall there was a GTVr for 20 dogs and GTVf for 16 dogs. The majority of GTVr volume was within the original GTV. GTVf analysis showed that 75% (12/16) were "in-field," 19% (3/16) were "marginal" and 6% (1/16) were "out-field." CONCLUSION AND CLINICAL IMPORTANCE: In-field failures are the main pattern for local recurrence, and there is evidence of radioresistant subvolumes within the GTV.
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Doenças do Cão , Neoplasias , Radioterapia Guiada por Imagem , Radioterapia de Intensidade Modulada , Animais , Progressão da Doença , Doenças do Cão/diagnóstico por imagem , Doenças do Cão/radioterapia , Cães , Neoplasias/veterinária , Radioterapia Guiada por Imagem/veterinária , Radioterapia de Intensidade Modulada/veterinária , Estudos RetrospectivosRESUMO
The objective of this retrospective study was to evaluate the effects of surgery on outcome for dogs with naturally occurring urinary bladder transitional cell carcinoma. Forty-seven dogs met the inclusion criteria. Thirty-one dogs (Group A) were treated with partial cystectomy and adjunctive medical therapy and 16 dogs (Group B) were treated with medical therapy alone. Overall survival was greater in dogs treated with partial cystectomy and adjunctive medical therapy (498 days for Group A versus 335 days for Group B, hazard ratio 2.5; 95% confidence interval: 1.1 to 5.7; P = 0.026). Progression-free survival was not different between groups (85 days for Group A versus 83 days for Group B; P = 0.663). No prognostic factors were identified for progression-free survival. Due to the many cases in Group A that were lost to follow-up, time-to-event survival analysis was performed. No significant difference in overall survival was noted, and no prognostic factors were identified in the time-to-event analysis. Prospective, randomized studies are needed to determine the role of partial cystectomy in the treatment of transitional cell carcinoma.
Résultats cliniques des chiens atteints d'un carcinome à cellules transitionnelles recevant un traitement médical, avec et sans cystectomie partielle. L'objectif de cette étude rétrospective était d'évaluer les effets de la chirurgie sur les résultats chez des chiens atteints d'un carcinome à cellules transitionnelles de la vessie d'origine naturelle. Quarante-sept chiens répondaient aux critères d'inclusion. Trente et un chiens (Groupe A) ont été traités par cystectomie partielle et traitement médical d'appoint et 16 chiens (Groupe B) ont été traités par thérapie médicale seule. La survie globale était plus élevée chez les chiens traités par cystectomie partielle et traitement médical d'appoint (498 jours pour le Groupe A contre 335 jours pour le Groupe B, rapport de risque de 2,5; intervalle de confiance à 95 % : 1,1 à 5,7; P = 0,026). La survie sans progression n'était pas différente entre les groupes (85 jours pour le Groupe A contre 83 jours pour le Groupe B; P = 0,663). Aucun facteur pronostique n'a été identifié pour la survie sans progression. En raison des nombreux cas dans le Groupe A qui ont été perdus de vue lors du suivi, une analyse du temps de survie a été realisée. Aucune différence significative dans la survie globale n'a été notée et aucun facteur pronostique n'a été identifié dans l'analyse du temps de survive. Des études prospectives randomisées sont nécessaires pour déterminer le rôle de la cystectomie partielle dans le traitement du carcinome à cellules transitionnelles.(Traduit par Dr Serge Messier).
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Carcinoma de Células de Transição , Doenças do Cão , Neoplasias da Bexiga Urinária , Animais , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/cirurgia , Carcinoma de Células de Transição/veterinária , Cistectomia/veterinária , Doenças do Cão/tratamento farmacológico , Doenças do Cão/cirurgia , Cães , Estudos Prospectivos , Estudos Retrospectivos , Resultado do Tratamento , Bexiga Urinária , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/veterináriaRESUMO
The updated VCOG-CTCAE v2 guidelines contain several important updates and additions since the last update (v1.1) was released in 2011 and published within Veterinary and Comparative Oncology in 2016. As the Veterinary Cooperative Oncology Group (VCOG) is no longer an active entity, the original authors and contributors to the VCOG-CTCAE v1.0 and v1.1 were consulted for input, and additional co-authors sought for expansion and refinement of the adverse event (AE) categories. VCOG-CTCAE v2 includes expanded neurology, cardiac and immunologic AE sections, and the addition of procedural-specific AEs. It is our intent that, through inclusion of additional authors from ACVIM subspecialties and the American College of Veterinary Surgery, that we can more comprehensively capture AEs that are observed during clinical studies conducted across a variety of disease states, clinical scenarios, and body systems. It is also our intent that these updated veterinary CTCAE guidelines will offer improved application and ease of use within veterinary practice in general, as well as within clinical trials that assess new therapeutic strategies for animals with a variety of diseases. Throughout the revision process, we strived to ensure the grading structure for each AE category was reflective of the decision-making process applied to determination of dose-limiting events. As phase I trial decisions are based on these criteria and ultimately determine the maximally tolerated dose, there is impact on standard dosing recommendations for any new drug registration or application. This document should be updated regularly to reflect ongoing application to clinical studies carried out in veterinary patients.
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Doenças do Gato , Doenças do Cão , Animais , Doenças do Gato/tratamento farmacológico , Gatos , Doenças do Cão/tratamento farmacológico , Cães , Oncologia , Terapias em Estudo/veterinária , Estados UnidosRESUMO
The potential for companion (pet) species with spontaneously arising tumors to act as surrogates for preclinical development of advanced cancer imaging technologies has become more apparent in the last decade. The utility of the companion model specifically centers around issues related to body size (including spatial target/normal anatomic characteristics), physical size and spatial distribution of metastasis, tumor heterogeneity, the presence of an intact syngeneic immune system and a syngeneic tumor microenvironment shaped by the natural evolution of the cancer. Companion species size allows the use of similar equipment, hardware setup, software, and scan protocols which provide the opportunity for standardization and harmonization of imaging operating procedures and quality assurance across imaging protocols, imaging hardware, and the imaged species. Murine models generally do not replicate the size and spatial distribution of human metastatic cancer and these factors strongly influence image resolution and dosimetry. The following review will discuss several aspects of comparative cancer imaging in more detail while providing several illustrative examples of investigational approaches performed or currently under exploration at our institutions. Topics addressed include a discussion on interested consortia; image quality assurance and harmonization; image-based biomarker development and validation; contrast agent and radionuclide tracer development; advanced imaging to assess and predict response to cytotoxic and immunomodulatory anticancer agents; imaging of the tumor microenvironment; development of novel theranostic approaches; cell trafficking assessment via non-invasive imaging; and intraoperative imaging to inform surgical oncology decision making. Taken in totality, these comparative opportunities predict that safety, diagnostic and efficacy data generated in companion species with naturally developing and progressing cancers would better recapitulate the human cancer condition than that of artificial models in small rodent systems and ultimately accelerate the integration of novel imaging technologies into clinical practice. It is our hope that the examples presented should serve to provide those involved in cancer investigations who are unfamiliar with available comparative methodologies an understanding of the potential utility of this approach.
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BACKGROUND: Rabacfosadine (RAB), a novel antineoplastic agent conditionally licensed for the treatment of lymphoma in dogs, is efficacious in both naïve and previously treated dogs. Its use in combination with L-asparaginase (L-ASP) has not been studied. HYPOTHESIS/OBJECTIVES: To evaluate the safety and efficacy of L-ASP given concurrently with RAB in dogs with relapsed multicentric lymphoma. ANIMALS: Fifty-two dogs with relapse of lymphoma after treatment with at least 1 doxorubicin-based chemotherapy protocol. METHODS: Open-label, multicenter, prospective single-arm clinical trial. Dogs were treated with RAB at 1.0 mg/kg IV every 21 days for up to a total of 5 doses. L-asparaginase was administered at 400 IU/kg SQ concurrently with the first 2 treatments of RAB. RESULTS: The overall response rate (ORR) for all dogs was 67%, with 19 dogs (41%) achieving a complete response (CR). The median progression-free survival time (MPFS) was 63 days (range 5-428 days). Dogs experiencing a CR as their best response had an MPFS of 144 days (range 44-428 days). Adverse events were similar to previous studies evaluating single agent RAB. Failure to achieve a CR and having previously received L-ASP were negative prognostic factors on multivariate analysis. CONCLUSIONS AND CLINICAL IMPORTANCE: Concurrent RAB/L-ASP appears to be both efficacious and safe for treating relapsed multicentric lymphoma in dogs. Adverse events were most often mild and no unexpected toxicoses were observed.
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Alanina/análogos & derivados , Antineoplásicos/uso terapêutico , Asparaginase/uso terapêutico , Doenças do Cão/tratamento farmacológico , Linfoma/veterinária , Recidiva Local de Neoplasia/veterinária , Purinas/uso terapêutico , Alanina/administração & dosagem , Alanina/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Asparaginase/administração & dosagem , Colorado , Intervalo Livre de Doença , Cães , Feminino , Linfoma/tratamento farmacológico , Linfoma/mortalidade , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Prospectivos , Purinas/administração & dosagem , Indução de Remissão , Washington , WisconsinRESUMO
MLN4924 (pevonedistat) is a potent and selective NEDD8-activating enzyme (NAE) inhibitor. The NEDD8-regulated neddylation system is responsible for the regulated degradation of intracellular proteins with important cellular functions in cancer cell growth, apoptosis, angiogenesis and metastasis. In human melanoma, inhibition of NAE results in induction of DNA re-replication, S phase cell cycle arrest, DNA damage and apoptosis. The study aimed to assess the anti-cancer effect of MLN4924 on canine malignant melanoma cell lines and patient samples and to elucidate the underlying mechanisms. Canine melanoma cell lines and primary patient samples were evaluated for cell viability after incubation with varying concentrations of MLN4924 or dimethyl sulfoxide. Apoptosis, cell proliferation and senescence assays were performed to address underlying mechanisms of MLN4924-mediated anti-tumour effects. Gene expression of seven previously identified deregulated genes in human melanoma was compared in sensitive vs resistant samples. MLN4924 treatment significantly reduced the viability of canine melanoma cell lines and primary samples in a dose- and time-dependent manners. MLN4924 promoted cell apoptosis and inhibited cell growth through induction of DNA re-replication and cell senescence. While the majority of canine melanoma samples demonstrated sensitivity at nanomolar ranges, some samples were resistant to the treatment. Modulation of P21 levels correlated with canine melanoma cell sensitivity. These results provided justification for further exploration of MLN4924 as a treatment of canine melanoma.
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Ciclopentanos/farmacologia , Doenças do Cão/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Melanoma/veterinária , Neoplasias Bucais/veterinária , Pirimidinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Cães , Melanoma/tratamento farmacológico , Melanoma/patologia , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/patologiaRESUMO
This study is a concurrent comparison of two versions of CHOP protocols, a 19-week CHOP and a comparatively overall dose-intense 12-week CHOP. The 12-week protocol was designed to be 58% more dose intense than the 19-week protocol for both doxorubicin and cyclophosphamide; however, it was 21% less dose intense for vincristine (VCR). Forty-seven dogs were included for evaluation, and the characteristics of each population were similar. For dogs receiving the 19-week CHOP protocol, 89.5% experienced a complete response, with a median progression-free survival (PFS) of 245 days and median overall survival (OS) of 347 days. For dogs receiving the 12-week CHOP protocol, 89.3% experienced a complete response, with a median PFS of 141 days and median OS of 229 days. When evaluated by Log-rank analysis, the difference of PFS (P = 0.047) and OS (P = 0.013) between the groups were statistically significant. In summary, these data suggest that despite overall increased dose-intensity, dogs receiving treatment with a 12-week CHOP protocol experience less durable remission than our standard 19-week protocol in this population. Additional prospective investigation will be required to explore the implication that VCR dose intensity and/or shorter overall temporal drug exposure in this protocol may result in diminished efficacy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doenças do Cão/tratamento farmacológico , Linfoma/veterinária , Animais , Ciclofosfamida/administração & dosagem , Cães , Doxorrubicina/administração & dosagem , Esquema de Medicação , Linfoma/tratamento farmacológico , Prednisona/administração & dosagem , Estudos Retrospectivos , Vincristina/administração & dosagemRESUMO
Radiotherapy is the treatment of choice for non-resectable canine thyroid carcinoma. High tumor response rates and median survival times of 2 years or longer have been previously reported with conventionally fractionated and hypofractionated protocols, even in dogs with distant metastasis. The objective of this retrospective, descriptive, case series study was to evaluate the clinical outcomes of dogs with thyroid carcinoma irradiated with palliative intent using hypofractionated radiotherapy at our institution. Medical records of 20 dogs treated between 1999 and 2014 were reviewed. All dogs had macroscopic primary tumors and presented with tumor-related clinical signs. Median longest tumor diameter was 10 cm. Nineteen dogs (95%) had metastasis (7/19 lymph node; 16/19 distant metastasis). Most dogs were treated with four weekly fractions of 6.5-8 Gy. Radiotherapy was well tolerated in 17 dogs; three died of respiratory compromise before completing radiotherapy. Eleven dogs received adjuvant chemotherapy. Five dogs experienced a local tumor response including two complete and three partial responses. Overall median survival time was 170 days (range, 1-824 days; 95% CI: 58-392 days). Of potential variables examined (radiation delivery system and protocol, tumor size and location, vascular/lymphatic invasion, metastatic disease, chemotherapy, tumor response), only achievement of complete or partial response was predictive of overall survival. In contrast to previously reported cohorts, dogs with clinical signs and stage IV disease predominated in this study. Previous studies may over-estimate survival following hypofractionated radiotherapy in dogs with advanced thyroid carcinoma.
Assuntos
Doenças do Cão/radioterapia , Radioterapia/veterinária , Neoplasias da Glândula Tireoide/veterinária , Animais , Cães , Feminino , Masculino , Radioterapia/métodos , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/radioterapia , Resultado do TratamentoRESUMO
In humans, advanced mast cell (MC) neoplasms are rare malignancies with a poor prognosis. Only a few preclinical models are available, and current treatment options are limited. In dogs, MC neoplasms are the most frequent malignant skin tumours. Unlike low-grade MC neoplasms, high-grade MC disorders usually have a poor prognosis with short survival. In both species, neoplastic MCs display activating KIT mutations, which are considered to contribute to disease evolution. Therefore, tyrosine kinase inhibitors against KIT have been developed. Unfortunately, clinical responses are unpredictable and often transient, which remains a clinical challenge in both species. Therefore, current efforts focus on the development of new improved treatment strategies. The field of comparative oncology may assist in these efforts and accelerate human and canine research regarding diagnosis, prognostication, and novel therapies. In this article, we review the current status of comparative oncology approaches and perspectives in the field of MC neoplasms.
Assuntos
Mastocitoma/veterinária , Animais , Antineoplásicos/uso terapêutico , Doenças do Cão/tratamento farmacológico , Cães , Humanos , Mastocitoma/classificação , Mastocitoma/tratamento farmacológico , Especificidade da EspécieRESUMO
Primary pulmonary histiocytic sarcoma (PHS) has been reported, but is not well characterized. The aim of this retrospective study was to describe clinical characteristics, characterize prognostic factors and report the outcome of a larger group of dogs with primary PHS. Medical records of dogs diagnosed with primary PHS at 11 institutions were retrospectively reviewed. Thirty-seven dogs were included; 13 received CCNU-based chemotherapy alone, 18 received surgery and adjuvant CCNU-based chemotherapy, 3 received medical management alone and 3 dogs received surgery alone. The overall median progression free survival (PFS) and the median survival (overall survival [OS]) were 197 and 237 days, respectively. Measurable responses were noted in dogs receiving only chemotherapy; however, responses were not durable with PFS (91 days) and OS times (131 days) shorter than overall medians. Dogs that received surgery and chemotherapy had significantly prolonged PFS (276 days, P = 0.001) and OS (374 days, P = 0.001), compared with dogs not receiving surgery. As only three dogs undergoing surgery did not receive chemotherapy, it is not possible to determine the contribution of chemotherapy as an adjuvant to surgery. Dogs without evidence of intra-thoracic metastatic disease were much more likely to undergo surgery (odds ratio = 7.04; P = 0.018). While the presence of metastasis or clinical signs at diagnosis negatively impacted PFS, only the former negatively impacted OS. These data imply that dogs presenting with PHS amenable to surgery (ie, no clinical evidence of metastasis) benefit from surgical intervention; however, the lack of a comparable surgery alone group precludes assessment of the efficacy of post-surgical adjuvant chemotherapy.
Assuntos
Doenças do Cão/patologia , Sarcoma Histiocítico/veterinária , Neoplasias Pulmonares/veterinária , Animais , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Doenças do Cão/diagnóstico , Doenças do Cão/tratamento farmacológico , Doenças do Cão/cirurgia , Cães , Feminino , Sarcoma Histiocítico/diagnóstico , Sarcoma Histiocítico/patologia , Sarcoma Histiocítico/terapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Estudos Retrospectivos , Análise de SobrevidaRESUMO
BACKGROUND: Chemotherapeutic options for the treatment of canine lymphoma have not changed in several decades necessitating the identification of new therapeutics to improve patient outcome. KPT-335 (verdinexor) is a novel orally bioavailable selective inhibitor of nuclear export (SINE) that exhibited anti-tumor activity against non-Hodgkin lymphoma in a prior phase I study. The objective of this phase II study was to expand upon the initial findings and assess the activity and safety in a larger population of dogs with lymphoma. RESULTS: Fifty-eight dogs with naïve or progressive B-cell and T-cell lymphoma were enrolled in this clinical trial. KPT-335 was administered orally in one of three dosing groups, based on the previously established biologically active dose of 1.5 mg/kg three times weekly. Treatment with single-agent, orally administered KPT-335 resulted in an objective response rate (ORR) of 37%, of which dogs with T-cell lymphoma had an ORR of 71%. KPT-335 was well tolerated in all dose groups with grade 1-2 anorexia being the most common adverse event. Anorexia was responsive to symptomatic and supportive medications, including prednisone. CONCLUSIONS: These data demonstrate that KPT-335 has biologic activity in canine lymphoma, and support continued evaluation of SINE compounds such as KPT-335 in combination with standard chemotherapeutics in canine lymphoma.