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Feasibility and safety of whole lung irradiation in the treatment of canine appendicular osteosarcoma.

ABSTRACT: Whole lung irradiation (WLI) has been used successfully in humans as an adjuvant treatment for osteosarcoma. The aim of this study is to describe the feasibility and safety of WLI in dogs with appendicular osteosarcoma. Twelve client-owned dogs with appendicular osteosarcoma that had successfully completed amputation and four doses of carboplatin without evidence of gross metastasis were enrolled in this prospective clinical trial. Ten once-daily fractions of 1.75 Gy were administered to the planning target volume encompassing the lungs. Overall, WLI was well tolerated in these patients. No dogs developed symptoms of pneumonitis or pulmonary fibrosis. Haematopoietic toxicity evaluated during radiation therapy was found to be mild. The median disease free interval for WLI treated dogs was not significantly different than the median DFI for a group of historic control dogs (376 days for WLI treated dogs versus 304.5 days for control dogs; p = 0.5461). Although no significant improvement in outcome was observed with this study, WLI appears to be safe in dogs and warrants further investigation to characterize the efficacy and toxicity.

SUBMITTER: Brehm A

PROVIDER: S-EPMC9290556 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Prognostic factors in canine appendicular osteosarcoma - a meta-analysis.

Project description:BackgroundAppendicular osteosarcoma is the most common malignant primary canine bone tumor. When treated by amputation or tumor removal alone, median survival times (MST) do not exceed 5 months, with the majority of dogs suffering from metastatic disease. This period can be extended with adequate local intervention and adjuvant chemotherapy, which has become common practice. Several prognostic factors have been reported in many different studies, e.g. age, breed, weight, sex, neuter status, location of tumor, serum alkaline phosphatase (SALP), bone alkaline phosphatase (BALP), infection, percentage of bone length affected, histological grade or histological subtype of tumor. Most of these factors are, however, only reported as confounding factors in larger studies. Insight in truly significant prognostic factors at time of diagnosis may contribute to tailoring adjuvant therapy for individual dogs suffering from osteosarcoma. The objective of this study was to systematically review the prognostic factors that are described for canine appendicular osteosarcoma and validate their scientific importance.ResultsA literature review was performed on selected studies and eligible data were extracted. Meta-analyses were done for two of the three selected possible prognostic factors (SALP and location), looking at both survival time (ST) and disease free interval (DFI). The third factor (age) was studied in a qualitative manner. Both elevated SALP level and the (proximal) humerus as location of the primary tumor are significant negative prognostic factors for both ST and DFI in dogs with appendicular osteosarcoma. Increasing age was associated with shorter ST and DFI, however, was not statistically significant because information of this factor was available in only a limited number of papers.ConclusionsElevated SALP and proximal humeral location are significant negative prognosticators for canine osteosarcoma.

| S-EPMC3482154 | biostudies-literature

The Prognostic Role of Preoperative Hematological and Inflammatory Indices in Canine Appendicular Osteosarcoma.

Project description:Hematological indices play a prognostic role in human osteosarcoma (OSA), but data are limited in dogs. The aim of this retrospective multicentric cohort study was to investigate the prognostic significance of pre-operative hematological/inflammatory indices in a cohort of client-owned dogs with appendicular OSA receiving standardized treatment. Cut-offs associated with progression-free survival (PFS) for pre-operative hematological values/ratios were established using the minimal p-value approach. Historical prognostic factors were also assessed. Statistical analyses were performed for the whole population and after the exclusion of sighthounds. Fifty-nine dogs were included (13 were sighthounds). Multivariable analysis revealed that a low neutrophil count (<4.37 × 109/L, HR0.28, CI 95% 0.13-0.61, p = 0.001), a high red blood cell count (≥7.91, HR3.5, CI 95% 1.56-7.9, p = 0.002), and a proximal humerus location (HR3.0, CI 95% 1.48-6.1, p = 0.002) were associated with shorter PFS. In the sighthound-only population, only OSA location was significantly associated with PFS in univariable analysis. When sighthounds were excluded, a low neutrophil count, a low monocyte count, and a proximal humerus location were associated with shorter PFS, in multivariable analysis. Neutrophil count and possibly monocyte and red blood cell counts can be useful prognostic markers in canine OSA treated with amputation and adjuvant carboplatin. However, not all indices are appropriate in sighthounds.

| S-EPMC10459974 | biostudies-literature

Influence of genetic background on tumor karyotypes: evidence for breed-associated cytogenetic aberrations in canine appendicular osteosarcoma.

Project description:Recurrent chromosomal aberrations in solid tumors can reveal the genetic pathways involved in the evolution of a malignancy and in some cases predict biological behavior. However, the role of individual genetic backgrounds in shaping karyotypes of sporadic tumors is unknown. The genetic structure of purebred dog breeds, coupled with their susceptibility to spontaneous cancers, provides a robust model with which to address this question. We tested the hypothesis that there is an association between breed and the distribution of genomic copy number imbalances in naturally occurring canine tumors through assessment of a cohort of Golden Retrievers and Rottweilers diagnosed with spontaneous appendicular osteosarcoma. Our findings reveal significant correlations between breed and tumor karyotypes that are independent of gender, age at diagnosis, and histological classification. These data indicate for the first time that individual genetic backgrounds, as defined by breed in dogs, influence tumor karyotypes in a cancer with extensive genomic instability.

| S-EPMC3758998 | biostudies-literature

Unraveling the chaotic genomic landscape of primary and metastatic canine appendicular osteosarcoma with current sequencing technologies and bioinformatic approaches.

Project description:Osteosarcoma is a rare disease in children but is one of the most common cancers in adult large breed dogs. The mutational landscape of both the primary and pulmonary metastatic tumor in two dogs with appendicular osteosarcoma (OSA) was comprehensively evaluated using an automated whole genome sequencing, exome and RNA-seq pipeline that was adapted for this study for use in dogs. Chromosomal lesions were the most common type of mutation. The mutational landscape varied substantially between dogs but the lesions within the same patient were similar. Copy number neutral loss of heterozygosity in mutant TP53 was the most significant driver mutation and involved a large region in the middle of chromosome 5. Canine and human OSA is characterized by loss of cell cycle checkpoint integrity and DNA damage response pathways. Mutational profiling of individual patients with canine OSA would be recommended prior to targeted therapy, given the heterogeneity seen in our study and previous studies.

| S-EPMC7870011 | biostudies-literature

Safety evaluation of the canine osteosarcoma vaccine, live Listeria vector.

Project description:Canine osteosarcoma (OSA) is an aggressive bone tumour in dogs. Standard-of-care treatment typically results in relatively short survival times; thus, alternative treatments are needed to confer a survival advantage. It has been shown that OSA is an immunogenic tumour, suggesting that immune modulation may result in superior outcomes. A cryopreserved, Listeria-based OSA vaccine was recently developed and an initial study in dogs reported prolonged survival for patients receiving the vaccine in conjunction with standard-of-care. The goal of the current observational study was to report on the safety of the lyophilized formulation of this vaccine (the canine OSA vaccine, live Listeria vector [COV-LLV]) in a group of dogs previously diagnosed with OSA. Forty-nine (49) dogs received the COV-LLV and were included for analysis. Adverse events (AEs) noted during and after vaccinations were recorded. The AEs observed were typically mild and self-limiting, with nausea, lethargy and fever being most common. Four dogs (8%) cultured positive for Listeria (three infections including an amputation site abscess, septic stifle joint and bacterial cystitis; and one dog whose lungs cultured Listeria-positive on necropsy within 24 hours of COV-LLV administration). These cases join the previously reported Listeria-positive thoracic abscess that developed in a canine following use of COV-LLV. Although uncommon, it is important to realize this clinically significant AE is possible in patients treated with live therapeutic Listeria vaccines. As Listeria is zoonotic, caution is required not only for the patient receiving the vaccine, but also for the health care workers and family caring for the patient.

| S-EPMC7891610 | biostudies-literature

Canine pimary osteosarcoma tissues vs. matched lung metastases

Project description:Osteosarcomas (OS) have highly chaotic genomes, yet their cancer drivers are poorly defined. Given that cancer genes are conserved among mammals, cross-species genomics of naturally arising cancers opens a powerful approach to identifying oncogenic drivers to broaden the therapeutic opportunities for aggressive cancers. Here, we utilized a dog-to-human cross-species genomics combined with gain- and loss-of-function analysis to uncover novel OS driver genes.

2021-08-03 | GSE118130 | GEO

The autophagy inhibitor spautin-1, either alone or combined with doxorubicin, decreases cell survival and colony formation in canine appendicular osteosarcoma cells.

Project description:Dogs diagnosed with appendicular osteosarcoma typically succumb to metastatic disease within a year of diagnosis. The current standard of care for curative intent, amputation followed by adjuvant chemotherapy, increases survival time but chemoresistance is a major contributor to mortality. Unfortunately, the mechanisms driving the progression of metastatic disease and the development of chemoresistance are unknown. One theory is that autophagy may contribute to chemoresistance by providing neoplastic cells with a mechanism to survive chemotherapy treatment. Our objective was to evaluate the effect of combining an autophagy inhibitor with a standard chemotherapeutic drug on response to chemotherapy in canine appendicular osteosarcoma cells. We hypothesized that combining the autophagy inhibitor spautin-1 with doxorubicin treatment would enhance chemoresponsiveness. Using commercial (D17) and primary cell lines derived from 1° and 2° sites of osteosarcoma, we showed that this combination treatment enhances cell killing and inhibits colony formation. Our findings support the theory that autophagy contributes to chemoresistance in canine appendicular osteosarcoma and indicate that adding an autophagy inhibitor to the standard of care has the potential to improve outcome.

| S-EPMC6205606 | biostudies-literature

Comparison of carboplatin and doxorubicin-based chemotherapy protocols in 470 dogs after amputation for treatment of appendicular osteosarcoma.

Project description:BackgroundMany chemotherapy protocols have been reported for treatment of canine appendicular osteosarcoma (OSA), but outcome comparisons in a single population are lacking.ObjectiveTo evaluate the effects of protocol and dose intensity (DI) on treatment outcomes for carboplatin and doxorubicin-based chemotherapy protocols.AnimalsFour hundred and seventy dogs with appendicular OSA.MethodsA retrospective cohort study was performed comprising consecutive dogs treated (1997-2012) with amputation followed by 1 of 5 chemotherapy protocols: carboplatin 300 mg/m(2) IV q21d for 4 or 6 cycles (CARBO6), doxorubicin 30 mg/m(2) IV q14d or q21d for 5 cycles, and alternating carboplatin 300 mg/m(2) IV and doxorubicin 30 mg/m(2) IV q21d for 3 cycles. Adverse events (AE) and DI were evaluated. Kaplan-Meier survival curves and Cox proportional hazards regression were used to compare disease-free interval (DFI) and survival time (ST) among protocols.ResultsThe overall median DFI and ST were 291 days and 284 days, respectively. A lower proportion of dogs prescribed CARBO6 experienced AEs compared to other protocols (48.4% versus 60.8-75.8%; P = .001). DI was not associated with development of metastases or death. After adjustment for baseline characteristics and prognostic factors, none of the protocols provided a significant reduction in risk of development of metastases or death.Conclusions and clinical importanceAlthough choice of protocol did not result in significant differences in DFI or ST, the CARBO6 protocol resulted in a lower proportion of dogs experiencing AEs, which could be advantageous in maintaining high quality of life during treatment. DI was not a prognostic indicator in this study.

| S-EPMC4857984 | biostudies-literature

Feasibility and safety of fiber optic micro-imaging in canine peripheral airways.

Project description:PurposeTo assess the feasibility and safety of imaging canine peripheral airways (<1 mm) with an experimental micro-imaging fiber optic bronchoscope.MethodsTwenty healthy dogs were scoped with a micro-imaging fiber optic bronchoscope (0.8 mm outer diameter). Images at various levels of the bronchioles, mucosal color, and tracheal secretions were recorded. The apparatus was stopped once it was difficult to insert. CT imaging was performed simultaneously to monitor progression. The safety of the device was evaluated by monitoring heart rate (HR), respiratory rate (RR), mean artery pressure (MAP), peripheral oxygen saturation (SpO2) and arterial blood gases (partial pressure of arterial carbon-dioxide, PaCO2, partial pressure of arterial oxygen, PaO2, and blood pH).Results(1) According to the CT scan, the micro-imaging fiber was able to access the peripheral airways (<1 mm) in canines. (2) There was no significant change in the values of HR, MAP, pH and PaCO2 during the procedure (P>0.05). Comparing pre-manipulation and post-manipulation values, SpO2 (F = 13.06, P<0.05) and PaO2 (F = 3.01, P = 0.01) were decreased, whereas RR (F = 3.85, P<0.05) was elevated during the manipulation. (3) Self-limited bleeding was observed in one dog; severe bleeding or other complications did not occur.ConclusionAlthough the new apparatus had little effect on SpO2, PaO2 and RR, it can probe into small peripheral airways (<1 mm), which may provide a new platform for the early diagnosis of bronchiolar diseases.

| S-EPMC3886988 | biostudies-literature

Modeling radiation-induced lung injury: lessons learned from whole thorax irradiation.

Project description:Models of thoracic irradiation have been developed as clinicians and scientists have attempted to decipher the events that led up to the pulmonary toxicity seen in human subjects following radiation treatment. The most common model is that of whole thorax irradiation (WTI), applied in a single dose. Mice, particularly the C57BL/6J strain, has been frequently used in these investigations, and has greatly informed our current understanding of the initiation and progression of radiation-induced lung injury (RILI). In this review, we highlight the sequential progression and dynamic nature of RILI, focusing primarily on the vast array of information that has been gleaned from the murine model. Ample evidence indicates a wide array of biological responses that can be seen following irradiation, including DNA damage, oxidative stress, cellular senescence and inflammation, all triggered by the initial exposure to ionizing radiation (IR) and heterogeneously maintained throughout the temporal progression of injury, which manifests as acute pneumonitis and later fibrosis. It appears that the early responses of specific cell types may promote further injury, disrupting the microenvironment and preventing a return to homeostasis, although the exact mechanisms driving these responses remains somewhat unclear. Attempts to either prevent or treat RILI in preclinical models have shown some success by targeting these disparate radiobiological processes. As our understanding of the dynamic cellular responses to radiation improves through the use of such models, so does the likelihood of preventing or treating RILI.

| S-EPMC6483900 | biostudies-literature

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