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Identification of hypoxia-induced metabolism-associated genes in canine tumours. 犬肿瘤中缺氧诱导代谢相关基因的鉴定。
IF 2.3 2区 农林科学 Q1 VETERINARY SCIENCES Pub Date : 2024-09-01 Epub Date: 2024-05-07 DOI: 10.1111/vco.12979
Taiki Kato, Masashi Sakurai, Kenji Watanabe, Yoichi Mizukami, Takayuki Nakagawa, Kenji Baba, Takuya Mizuno, Masaya Igase

Canine tumours including urothelial carcinoma, lung adenocarcinoma, mammary gland tumour, squamous cell carcinoma, and melanoma have been identified as causes of death, but effective therapies are limited due to insufficient knowledge of the molecular mechanisms involved. Within the tumour microenvironment, hypoxia activates hypoxia-inducible factor 1α (HIF1α) in tumour cells. High HIF1α expression correlates with enhanced glycolysis and poorer outcomes in human cancers. However, the molecular mechanisms underlying hypoxic tumour cells remain elusive in dogs. In our study, we investigated upregulated genes in a canine malignant melanoma cell line during hypoxia using RNA-sequencing analysis. Glycolysis and HIF1 signalling pathways were upregulated in hypoxic melanoma cells. HIF1α knockout melanoma cells revealed that the glycolysis marker MCT4 is regulated by HIF1α activation. Hypoxia induces high lactate secretion due to enhanced glycolysis in canine melanoma cells. Furthermore, we examined monocarboxylate transporter 4 (MCT4) expression in malignant melanoma and eight other types of canine tumour tissues using immunohistochemistry (IHC). Membrane-localized MCT4 protein was mostly detected in urothelial carcinoma and lung adenocarcinoma rather than malignant melanoma. We conclude that canine MCT4 protein plays a role in lactic acid efflux from glycolytic cells and may serve as a marker for hypoxia and glycolysis in canine tumours. These findings could inform future therapeutic strategies targeting MCT4.

包括尿道癌、肺腺癌、乳腺肿瘤、鳞状细胞癌和黑色素瘤在内的犬肿瘤已被确定为死亡原因,但由于对其中涉及的分子机制了解不足,有效的疗法受到限制。在肿瘤微环境中,缺氧会激活肿瘤细胞中的缺氧诱导因子 1α(HIF1α)。HIF1α 的高表达与糖酵解增强和人类癌症的不良预后有关。然而,狗体内肿瘤细胞缺氧的分子机制仍然难以捉摸。在我们的研究中,我们利用 RNA 序列分析研究了犬恶性黑色素瘤细胞系在缺氧过程中的上调基因。缺氧黑色素瘤细胞中糖酵解和 HIF1 信号通路上调。HIF1α基因敲除黑色素瘤细胞显示,糖酵解标志物MCT4受HIF1α激活的调节。在犬黑色素瘤细胞中,由于糖酵解增强,缺氧会诱导高乳酸分泌。此外,我们还利用免疫组化(IHC)技术检测了单羧酸盐转运体4(MCT4)在恶性黑色素瘤和其他八种犬肿瘤组织中的表达。膜定位的 MCT4 蛋白主要在尿路上皮癌和肺腺癌中检测到,而不是在恶性黑色素瘤中。我们的结论是,犬 MCT4 蛋白在糖酵解细胞的乳酸外流中发挥作用,可作为犬肿瘤缺氧和糖酵解的标记物。这些发现可为未来针对 MCT4 的治疗策略提供依据。
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引用次数: 0
Molecular and Pathobiology of Canine Mammary Tumour: Defining a Translational Model for Human Breast Cancer. 犬乳腺肿瘤的分子和病理生物学:确定人类乳腺癌的转化模型。
IF 2.3 2区 农林科学 Q1 VETERINARY SCIENCES Pub Date : 2024-09-01 Epub Date: 2024-07-16 DOI: 10.1111/vco.12996
Adália F Oliveira-Lopes, Marcelo M Götze, Belarmino E Lopes-Neto, Denise D Guerreiro, Ivan Cunha Bustamante-Filho, Arlindo Alencar Moura

Canine mammary tumours (CMT) have histological, clinicopathological and molecular resemblances to human breast cancer (HBC), positioning them as viable models for studying the human disease. CMT initiation and progression occur spontaneously in immune-competent animals, which challenge the suggested limitations of genetically modified mice, also enabling the evaluation of immunotherapies in canine patients. Dogs have shorter life expectancy compared to humans, and cancer advances more rapidly in this species. This makes it possible to perform studies about the clinical efficacy of new therapeutic modalities in a much shorter time than in human patients. The identification of biomarkers for tumour subtypes, progression and treatment response paves the way for the development of novel therapeutic and diagnostic approaches. This review addresses the similarities between CMT and HBC and the molecular signatures identified in CMT samples that have been explored to date. We proposed a detailed molecular exploration of the CMT stroma using state-of-the-art methods in transcriptomics and proteomics. Using CMT as an analog for HBC not only helps to understand the complexities of the disease, but also to advance comparative oncology to the next level to prove the claim of dogs as a valid translational model.

犬乳腺肿瘤(CMT)在组织学、临床病理学和分子学方面与人类乳腺癌(HBC)相似,因此可作为研究人类疾病的可行模型。乳腺肿瘤的发生和发展是在免疫功能正常的动物体内自发进行的,这对转基因小鼠的局限性提出了挑战,同时也有利于对犬病患者的免疫疗法进行评估。与人类相比,狗的预期寿命较短,癌症在这一物种中发展得更快。因此,可以在比人类患者短得多的时间内对新治疗方法的临床疗效进行研究。确定肿瘤亚型、进展和治疗反应的生物标志物为开发新型治疗和诊断方法铺平了道路。本综述探讨了 CMT 和 HBC 之间的相似性,以及迄今为止在 CMT 样本中发现的分子特征。我们建议使用最先进的转录组学和蛋白质组学方法对 CMT 基质进行详细的分子探索。将 CMT 作为 HBC 的类似物不仅有助于了解该疾病的复杂性,还能将比较肿瘤学推向新的高度,证明狗是一种有效的转化模型。
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引用次数: 0
DNA Methylation and Its Effects on TRIM29 Gene Expression in the Equine Sarcoid Tissue. 马肉瘤组织中的 DNA 甲基化及其对 TRIM29 基因表达的影响
IF 2.3 2区 农林科学 Q1 VETERINARY SCIENCES Pub Date : 2024-09-01 Epub Date: 2024-07-10 DOI: 10.1111/vco.12994
Semik-Gurgul Ewelina, Zaborowska Anna, Pędziwiatr Rafał, Witkowski Maciej

Sarcoids are the most frequently diagnosed dermatological tumour in horses. It is a disease that can affect various species of equids, such as donkeys, mules and zebras. This type of tumour can develop in all horse breeds, regardless of age and gender. Treatment options depend on many factors, such as the type of lesion, location, extent, owner preference and financial considerations. In the present study, we investigated the TRIM29 expression, the methylation status of its first exon and its involvement in the formation of equine sarcoids. Bisulfite sequencing PCR (BSP) was used to determine DNA methylation at CpG sites and real-time quantitative polymerase chain reaction (qPCR) was used to detect TRIM29 expression level. Our results showed that TRIM29 is significantly downregulated in lesional samples (FC = -3.72; p < 0.001). Furthermore, TRIM29 expression was significantly correlated (R = -0.73; p < 0.001) with hypermethylation of its specific CpG sites in the first exon of this gene. Our research has demonstrated that the identification of increased methylation of CpG sequences in horse sarcoids, along with the decreased expression of the TRIM29 gene, is an important step towards understanding the molecular mechanisms underlying the disease. These findings can serve in the future as a diagnostic biomarker for horse sarcoids and help in detecting the disease.

肉瘤是马最常见的皮肤肿瘤。驴、骡和斑马等不同种类的马都可能患上这种疾病。无论年龄和性别,所有品种的马都可能患上这种肿瘤。治疗方案取决于多种因素,如病变类型、位置、范围、马主偏好和经济考虑。在本研究中,我们调查了 TRIM29 的表达、其第一个外显子的甲基化状态及其与马肉瘤形成的关系。亚硫酸氢盐测序 PCR(BSP)用于确定 CpG 位点的 DNA 甲基化,实时定量聚合酶链反应(qPCR)用于检测 TRIM29 的表达水平。结果显示,TRIM29在病变样本中明显下调(FC = -3.72; p
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引用次数: 0
Use of Lomustine and Prednisolone as First-Line Treatment in Canine Multicentric Lymphoma. 将洛莫司汀和泼尼松龙作为犬多中心淋巴瘤的一线治疗药物
IF 2.3 2区 农林科学 Q1 VETERINARY SCIENCES Pub Date : 2024-09-01 Epub Date: 2024-06-18 DOI: 10.1111/vco.12990
Chiara Catalucci, Marco Luigi Bianchi, Elisabetta Treggiari, Marta Pieri, Katja Ruess, Paola Valenti

Multiagent chemotherapy is considered the most effective treatment for canine high-grade lymphoma; however, due to cost and time requirements, single-agent protocols have also been described. The aim of our study was to evaluate the outcome and prognostic factors of dogs affected by multicentric lymphoma treated with lomustine and prednisolone as first-line treatment. Cases of medium-large-cell multicentric lymphoma treated with lomustine and prednisolone were included in the study. Response to therapy, time to progression (TTP), median disease-free interval (MDFI) and median survival time (MST) were retrospectively described. Thirty cases were included. Eleven (36.67%) were T cell, 11 (36.67%) were B cell and 8 (26.66%) had unknown immunophenotype. The overall response rate (RR) was 87%, with 15 patients achieving CR (50%) and 11 patients PR (37%). The median TTP, MDFI and MST were 42, 63 and 90 days, respectively. The only factor significantly associated with MDFI and MST was the stage. Dogs with multicentric lymphoma treated with lomustine and prednisolone have lower RR, TTP, MDFI and MST compared with dogs receiving multiagent protocols. Based on the short-lasting response, this study confirms that this protocol might have minimal utility beyond palliation.

多药化疗被认为是犬高级淋巴瘤最有效的治疗方法;然而,由于成本和时间要求,也有描述单药方案的。我们的研究旨在评估以洛莫司汀和泼尼松龙作为一线疗法的多中心淋巴瘤患犬的疗效和预后因素。研究对象包括接受洛莫司汀和泼尼松龙治疗的中大细胞多中心淋巴瘤病例。对治疗反应、进展时间(TTP)、中位无病间隔时间(MDFI)和中位生存时间(MST)进行了回顾性描述。研究共纳入 30 个病例。11例(36.67%)为T细胞,11例(36.67%)为B细胞,8例(26.66%)免疫表型不明。总反应率(RR)为87%,其中15名患者达到CR(50%),11名患者达到PR(37%)。中位TTP、MDFI和MST分别为42天、63天和90天。与MDFI和MST明显相关的唯一因素是分期。与接受多药方案治疗的犬相比,接受洛莫司汀和泼尼松龙治疗的多中心淋巴瘤犬的RR、TTP、MDFI和MST均较低。由于反应持续时间较短,本研究证实该方案除了缓解病情外,可能作用甚微。
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引用次数: 0
Immunohistochemical and transcriptomic characterization of T and myeloid cell infiltrates in canine malignant melanoma. 犬恶性黑色素瘤中 T 细胞和骨髓细胞浸润的免疫组织化学和转录组学特征。
IF 2.3 2区 农林科学 Q1 VETERINARY SCIENCES Pub Date : 2024-09-01 Epub Date: 2024-05-16 DOI: 10.1111/vco.12981
Kathryn E Cronise, Jonathan Coy, Steven Dow, Marlene L Hauck, Daniel P Regan

Immune checkpoint inhibitor therapy can provide significant clinical benefit in patients with certain cancer types including melanoma; however, objective responses are only observed for a subset of patients. Mucosal melanoma is a rare melanoma subtype associated with a poor prognosis and, compared with cutaneous melanoma, is significantly less responsive to immune checkpoint inhibitors. Spontaneous canine tumours have emerged as valuable models to inform human cancer studies. In contrast to human melanoma, most canine melanomas are mucosal-an incidence that may be leveraged to better understand the subtype in humans. However, a more comprehensive understanding of the immune landscape of the canine disease is required. Here, we quantify tumour infiltrative T and myeloid cells in canine mucosal (n = 13) and cutaneous (n = 5) melanomas using immunohistochemical analysis of CD3 and MAC387 expression, respectively. Gene expression analysis using the Canine IO NanoString panel was also performed to identify genes and pathways associated with immune cell infiltration. T and myeloid cell densities were variable with geometric means of 158.7 cells/mm2 and 166.7 cells/mm2, respectively. Elevated T cell infiltration was associated with increased expression of cytolytic genes as well as genes encoding the coinhibitory checkpoint molecules PD-1, CTLA-4, TIM-3 and TIGIT; whereas increased myeloid cell infiltration was associated with elevated expression of protumourigenic cytokines. These data provide a basic characterization of the tumour microenvironment of canine malignant melanoma and suggest that, like human melanoma, inherent variability in anti-tumour T cell responses exists and that a subset of canine melanomas may respond better to immunomodulation.

免疫检查点抑制剂疗法可为包括黑色素瘤在内的某些癌症类型患者带来显著的临床获益;然而,只有一部分患者能观察到客观反应。粘膜黑色素瘤是一种罕见的黑色素瘤亚型,预后较差,与皮肤黑色素瘤相比,对免疫检查点抑制剂的反应明显较弱。自发性犬肿瘤已成为人类癌症研究的重要参考模型。与人类黑色素瘤不同的是,犬黑色素瘤大多为粘膜瘤--这种发病率可用于更好地了解人类黑色素瘤的亚型。然而,我们需要更全面地了解犬类疾病的免疫状况。在这里,我们分别使用 CD3 和 MAC387 表达的免疫组化分析方法对犬粘膜(13 例)和皮肤(5 例)黑色素瘤中的肿瘤浸润性 T 细胞和髓细胞进行了量化。还使用犬 IO NanoString 面板进行了基因表达分析,以确定与免疫细胞浸润相关的基因和通路。T 细胞和骨髓细胞密度各不相同,几何平均数分别为 158.7 个细胞/mm2 和 166.7 个细胞/mm2。T细胞浸润的增加与细胞溶解基因以及共同抑制检查点分子PD-1、CTLA-4、TIM-3和TIGIT的编码基因的表达增加有关;而髓样细胞浸润的增加与原发肿瘤细胞因子的表达增加有关。这些数据提供了犬恶性黑色素瘤肿瘤微环境的基本特征,并表明与人类黑色素瘤一样,抗肿瘤 T 细胞反应也存在固有的变异性,而且犬黑色素瘤亚群可能对免疫调节反应更好。
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引用次数: 0
Distribution of Inflammatory Infiltrate in Feline Mammary Lesions: Relationship With Clinicopathological Features. 猫科动物乳腺病变中炎性浸润的分布:与临床病理特征的关系
IF 2.3 2区 农林科学 Q1 VETERINARY SCIENCES Pub Date : 2024-09-01 Epub Date: 2024-06-11 DOI: 10.1111/vco.12987
Joana Rodrigues-Jesus, Ana Canadas-Sousa, Pedro Oliveira, Ana Catarina Figueira, Carla Marrinhas, Gonçalo N Petrucci, Hugo Gregório, Flora Tinoco, Andrea Goulart, Helena Felga, Hugo Vilhena, Patrícia Dias-Pereira

Inflammation is a frequent finding in feline mammary neoplasms. Recent research suggests that the presence and location of tumour-associated immune cells might play a significant role in the clinical outcome of feline mammary carcinomas. The present study aimed to characterise the overall inflammatory infiltrates in healthy, hyperplastic/dysplastic, benign and malignant lesions of the feline mammary gland, and to evaluate its association with clinicopathological features. Perilesional and intralesional inflammatory foci were evaluated in 307 lesions from 185 queens, and categorised according to its distribution and intensity. The presence, location and density of tertiary lymphoid structures were also assessed. A control group included 24 queens without mammary changes. The presence of intralesional and perilesional inflammatory infiltrate was observed in a majority of the lesions (80.8% and 90.2%, respectively), but differed according to the type of mammary lesion, being more remarkable in malignant neoplasms. Only scarce individual cells were observed in 28.1% of the normal mammary glands. Data analysis revealed statistically significant associations (p < 0.05) between the presence of a more prominent intralesional and perilesional inflammatory reaction and several clinicopathological features associated with worse prognosis, including clinical stage, tumour size, mitotic count, lymphovascular invasion and lymph node metastasis. Furthermore, tertiary lymphoid structures were significantly more frequent in tumours with an infiltrative growth and lymph node metastasis. According to our results, the inflammatory reaction present in different types of feline mammary lesions is associated with the development of more aggressive tumours.

炎症是猫科动物乳腺肿瘤的常见症状。最近的研究表明,肿瘤相关免疫细胞的存在和位置可能对猫乳腺癌的临床结果起着重要作用。本研究旨在描述猫乳腺健康、增生/发育不良、良性和恶性病变中整体炎症浸润的特征,并评估其与临床病理特征的关联。对来自 185 只猫科动物的 307 个病灶的周围和内部炎症病灶进行了评估,并根据其分布和强度进行了分类。此外,还评估了三级淋巴结构的存在、位置和密度。对照组包括 24 只没有乳腺病变的皇后。在大多数病变(分别为 80.8% 和 90.2%)中都观察到了乳腺内部和周围的炎症浸润,但根据乳腺病变的类型而有所不同,恶性肿瘤中的炎症浸润更为明显。在 28.1%的正常乳腺中仅观察到稀少的单个细胞。数据分析显示,在统计意义上(p
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引用次数: 0
Pilot study to evaluate isolation by size of circulating tumour cells in canine oral melanoma. 评估犬口腔黑色素瘤循环肿瘤细胞大小分离的试点研究。
IF 2.3 2区 农林科学 Q1 VETERINARY SCIENCES Pub Date : 2024-09-01 Epub Date: 2024-06-04 DOI: 10.1111/vco.12982
Victor Nowosh, Alexcia Camila Braun, Anna Paula Carreta Ruano, Ludmilla Thomé Domingos Chinén, Cristina de Oliveira Massoco

Liquid biopsy for circulating tumour cell (CTC) detection is generally unexplored in veterinary medicine. Dogs with highly aggressive and heterogeneous tumours, such as oral malignant melanoma (OMM), could benefit from studies involving size-based isolation methods for CTCs, as they do not depend on specific antibodies. This pilot study aimed to detect CTCs from canine OMM using Isolation by Size of Epithelial Tumor Cells (ISET), a microfiltration methodology, followed by immunocytochemistry (ICC) with Melan-A, PNL2, and S100 antibodies. Ten canine patients diagnosed by histopathology and confirmed as OMM by immunohistochemistry were enrolled, their prognostic data was assessed, and blood samples were collected for CTC analysis. Results have shown the detection of intact cells in 9/10 patients. ICC has shown 3/9 Melan-A-positive, 3/9 PNL2-positive, and 8/9 S100-positive patients, confirming the importance of opting for a multimarker assay. A significant number of negative-stained CTCs were found, suggesting their high heterogeneity in circulation. Microemboli stained with either PNL2 or S100 were found in a patient with a high isolated cell count and advanced clinical stage. Preliminary statistical analysis shows a significant difference in CTC count between patients with and without lymph node metastasis (p < .05), which may correlate with tumour metastatic potential. However, we recommend further studies with more extensive sampling to confirm this result. This pilot study is the first report of intact CTC detection in canine OMM and the first application of ISET in veterinary medicine, opening new possibilities for liquid biopsy studies in canine OMM and other tumours.

在兽医领域,用于循环肿瘤细胞(CTC)检测的液体活检技术通常还未得到开发。口腔恶性黑色素瘤(OMM)等具有高度侵袭性和异质性肿瘤的狗可以从基于大小的 CTC 分离方法研究中获益,因为这种方法不依赖于特异性抗体。这项试验性研究的目的是利用微滤方法 "上皮肿瘤细胞大小分离"(ISET)检测犬口腔恶性黑色素瘤的 CTC,然后用 Melan-A、PNL2 和 S100 抗体进行免疫细胞化学分析(ICC)。十名经组织病理学诊断并通过免疫组化确诊为 OMM 的犬类患者被纳入研究,他们的预后数据得到了评估,并被采集血液样本用于 CTC 分析。结果显示,9/10 的患者检测到了完整的细胞。ICC显示3/9的患者Melan-A阳性,3/9的患者PNL2阳性,8/9的患者S100阳性,这证实了选择多标记检测的重要性。发现了大量阴性染色的 CTC,这表明它们在血液循环中具有高度异质性。在一名孤立细胞数量较多且处于临床晚期的患者身上,发现了被 PNL2 或 S100 染色的微栓子。初步统计分析表明,有淋巴结转移和没有淋巴结转移的患者之间的 CTC 数量存在显著差异(p
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引用次数: 0
One Health: Therapies Targeting Genetic Variants in Human and Canine Histiocytic and Dendritic Cell Sarcomas. 一个健康:针对人类和犬组织细胞肉瘤和树突状细胞肉瘤基因变异的疗法。
IF 2.3 2区 农林科学 Q1 VETERINARY SCIENCES Pub Date : 2024-09-01 Epub Date: 2024-06-12 DOI: 10.1111/vco.12988
Suzanne Agnes Erich, Erik Teske

The precise cause of HS/DCS is still unknown. The relatively low incidence in humans urges for an animal model with a high incidence to accelerate knowledge about genetics and optimal treatment of HS/DCS. Namely, until now, the therapies targeting genetic variants are still more experimental and sparsely used, while consensus is missing. In addition, the literature about variants and possible mutation-targeted therapies in humans and dogs consists mainly of case reports scattered throughout the literature. Therefore, an overview is provided of all currently known genetic variants in humans and dogs with HS/DCS and its subtypes, their possible mutation-targeted therapies, their efficacy, and a contemplation about the future. Several genetic variants have already been discovered in HS/DCS, of which many are shared between canine and human HS/DCS, but unique variants exist as well. Unfortunately, none of these already found variants seem to be specifically causal for HS/DCS, and the puzzle of its landscape of genetic variation is far from complete. The use of mutation-targeted therapies, including MAPK-/MEK-inhibitors and the future use of PTPN11-, CDK4/6- and PD-1-inhibitors, seems to be promising for these specific variants, but clearly, clinical trials are needed to determine optimal inhibitors and standardised protocols for all variants. It can be concluded that molecular analysis for variants and subsequent mutation-targeted therapy are an essential addition to cancer diagnostics and therapy. A joint effort of humans and dogs in research is urgently needed and will undoubtedly increase knowledge and survival of this devastating disease in dogs and humans.

HS/DCS 的确切病因尚不清楚。由于人类的发病率相对较低,因此需要一种发病率较高的动物模型来加速对 HS/DCS 遗传学和最佳治疗方法的了解。也就是说,到目前为止,针对基因变异的治疗方法仍然更多是实验性的,而且很少使用,还没有达成共识。此外,有关人类和狗的变异和可能的基因突变靶向疗法的文献主要是散见于文献中的病例报告。因此,本文概述了目前已知的人类和犬 HS/DCS 基因变异及其亚型、可能的基因突变靶向疗法、其疗效以及对未来的展望。在 HS/DCS 中已经发现了几种基因变异,其中许多变异在犬和人类 HS/DCS 中是共有的,但也存在独特的变异。遗憾的是,这些已发现的变异似乎都不是 HS/DCS 的特定致病因素,而且其基因变异情况的谜团还远未解开。使用突变靶向疗法,包括 MAPK/MEK 抑制剂和未来使用的 PTPN11、CDK4/6 和 PD-1 抑制剂,似乎对这些特定变异很有希望,但显然还需要进行临床试验,以确定针对所有变异的最佳抑制剂和标准化方案。可以得出的结论是,变异的分子分析和随后的突变靶向治疗是癌症诊断和治疗的重要补充。目前迫切需要人类和犬类共同努力开展研究,这无疑将增加人们对这种毁灭性疾病的了解,提高犬类和人类的存活率。
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引用次数: 0
Population Pharmacokinetics, Pharmacodynamics and Safety Properties of Trametinib in Dogs With Cancer: A Phase I Dose Escalating Clinical Trial. 癌症犬服用曲美替尼的群体药代动力学、药效学和安全性特性:I 期剂量递增临床试验。
IF 2.3 2区 农林科学 Q1 VETERINARY SCIENCES Pub Date : 2024-09-01 Epub Date: 2024-06-18 DOI: 10.1111/vco.12989
Marilia Takada, Keita Kitagawa, Yongzhen Zhang, Jürgen B Bulitta, Steven Moirano, Abigail Jones, Jennifer Borgen, Ashley Onsager, Tuddow Thaiwong, David M Vail

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.

据报道,MAPK是犬组织细胞肉瘤的一个关键致癌途径,而MEK1/2的一种小型抑制剂曲美替尼可作为药物靶点。初步数据显示,MEK1/2 在体外和体内模型中具有良好的抗肿瘤活性,是将研究成果从实验室转化为临床应用的概念验证。在这项采用 3+3 队列设计的 I 期剂量递增研究中,对 18 只患癌症的狗进行了曲美替尼评估。研究人员根据 VCOG-CTCAE v2 对不良反应进行了分级,并采集了血液样本和肿瘤活检样本用于药代动力学和药效学评估。曲美替尼耐受性良好,最大耐受剂量为0.5毫克/平方米/天,口服。剂量限制性毒性包括全身性高血压、蛋白尿、嗜睡和ALP升高,均为3级。由于曲美替尼的消除是饱和的,因此药物暴露量随剂量的增加而增加,超过了线性关系。在 500 μg Q24h 的剂量下(30 千克犬 0.5 毫克/平方米/天),约 70% 的犬在约 2 周后达到 10 纳克/毫升的平均稳态浓度。这一阈值与人类的临床疗效相关。在第0天和第7天采集的生物样本中未观察到目标参与。总之,在癌症犬中使用曲美替尼是安全的,0.5毫克/平方米/天的剂量是II期研究的推荐剂量。
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引用次数: 0
Comparison of Three Chemotherapy Protocols With Electrochemotherapy for the Treatment of Feline Cutaneous Squamous Cell Carcinoma. 比较三种化疗方案与电化学疗法治疗猫皮肤鳞状细胞癌的效果
IF 2.3 2区 农林科学 Q1 VETERINARY SCIENCES Pub Date : 2024-09-01 Epub Date: 2024-07-15 DOI: 10.1111/vco.12995
Nicolas Diop, David Sayag, Grégoire Bernardo Marques, Gabriel Chamel, Thomas Chavalle, Jean-Bapiste Eon, Franck Floch, Mathilde Lajoinie, Frédérique Ponce, Laura E Barrett

Electrochemotherapy (ECT) with intravenous (IV) and/or intratumoral (IT) bleomycin has shown considerable efficacy in the treatment of non-resectable feline cutaneous squamous cell carcinoma (cSCC), boasting response rates of up to 95%, but other chemotherapy protocols have not yet been investigated. The objective of this prospective multicentre study was to compare the overall response rate (ORR) and progression-free interval (PFI) between cats with cSCC treated with ECT using IT and IV carboplatin (IV + IT), IV carboplatin (IV) or IV bleomycin (IV). A total of 44 cats with unresectable cSCC across three centres were enrolled and treated with ECT using carboplatin IV + IT (n = 10), carboplatin IV (n = 11) or bleomycin IV (n = 23). Treatment response according to RECIST criteria was recorded at 2 and 4 weeks post-treatment, and patients were followed until disease progression and/or death. All three groups were comparable regarding age, sex, weight, and lesion size. Adverse events were generally mild, localised and similar between groups. ORRs were 90.0% (carboplatin IV + IT), 90.9% (carboplatin IV) and 95.6% (bleomycin IV) and were not significantly different (p = 0.79). Median PFI was not reached for carboplatin IV + IT or carboplatin IV and was 566 days for bleomycin IV, with no significant difference between the three groups (p = 0.81). This study suggests that ECT using IV or IV + IT carboplatin is a reasonable alternative therapeutic option for managing cSCC, and further studies are warranted to compare outcomes between treatment protocols.

使用静脉注射博莱霉素和/或瘤内注射博莱霉素的电化学疗法(ECT)在治疗不可切除的猫皮肤鳞状细胞癌(cSCC)方面疗效显著,反应率高达95%,但尚未对其他化疗方案进行研究。这项前瞻性多中心研究的目的是比较使用IT和静脉注射卡铂(静脉注射+IT)、静脉注射卡铂(静脉注射)或静脉注射博莱霉素(静脉注射)进行ECT治疗的猫皮肤鳞状细胞癌患者的总反应率(ORR)和无进展间隔时间(PFI)。三个中心共招募了44只无法切除的cSCC猫,并使用卡铂静脉注射+IT(10只)、卡铂静脉注射(11只)或博来霉素静脉注射(23只)进行ECT治疗。根据RECIST标准,在治疗后2周和4周记录治疗反应,并随访患者直至疾病进展和/或死亡。三组患者的年龄、性别、体重和病灶大小相当。三组患者的不良反应一般都比较轻微、局部,且组间情况相似。ORR分别为90.0%(卡铂静脉注射+IT)、90.9%(卡铂静脉注射)和95.6%(博莱霉素静脉注射),无显著差异(p = 0.79)。卡铂静脉注射 + IT 或卡铂静脉注射未达到中位 PFI,博莱霉素静脉注射的中位 PFI 为 566 天,三组之间无显著差异(p = 0.81)。这项研究表明,使用静脉注射或静脉注射+IT卡铂的ECT是治疗cSCC的一种合理的替代疗法,有必要进一步研究比较不同治疗方案的疗效。
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Veterinary and comparative oncology
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