Molecular docking, ADMET and molecular dynamics simulation revealed metralindole as a multitargeted inhibitor for division kinases / Ancoragem molecular, ADMET e simulação de dinâmica molecular revelaram o metralindol como inibidor multialvo para divisão quinases

Lung cancer is the most common type of cancer in the world, and alone, in 2020, almost 2.21 million new cases were diagnosed, with 1.80 million deaths, and are increasing daily. Non-small cell lung (NSCLC) is the primary type of lung cancer, predominantly forms around 80% of cases compared to small cell carcinoma, and about 75% of patients are already in an advanced state when diagnosed. Despite notable advances in early diagnosis and treatment, the five-year survival rate for NSCLC is not encouraging. Therefore, it is crucial to investigate the molecular causes of non-small cell lung cancer to create more efficient therapeutic approaches. Lung cancer showed a more significant and persistent binding affinity and energy landscape with the target CDK2 staurosporine and FGF receptor-1. In this study, we have picked two essential target proteins, human cyclin-dependent kinase-2 and Human Protein Kinase CK2 Holoenzyme and screened the entire prepared DrugBank prepared library of 1,55,888 compounds and identified 2-(2-methyl-5-nitroimidazole-1-yl) ethanol (Metralindole) as a major inhibitor. Metralindole has displayed high docking scores of -5.159 Kcal/mol and -5.99 Kcal/mol with good hydrogen bonding and other bonding topologies such as van der Waals force, and ADMET results shown excellent bioavailability, outstanding solubility, no side effects, and toxicity. The molecular dynamics simulation for 100ns in a water medium confirmed the compound's stability and interaction pattern with the lowest deviation and fluctuations. Our in-silico study suggests Metralindole, an experimental compound, can effectively cure lung cancer. Further, the experimental validation of the compound is a must before any prescription.

O câncer de pulmão é o tipo de câncer mais comum no mundo, e, apenas em 2020, foram diagnosticados quase 2,21 milhões de novos casos, com 1,8 milhão de óbitos, e isso vem aumentando diariamente. O câncer de pulmão de células não pequenas (CPCNP) é o tipo primário de câncer de pulmão, forma que predomina em cerca de 80% dos casos em comparação com o carcinoma de pequenas células, e cerca de 75% dos pacientes já estão em estado avançado quando diagnosticados. Apesar dos avanços notáveis no diagnóstico e tratamento precoces, a taxa de sobrevida em cinco anos para CPCNP não é animadora. Portanto, é crucial investigar as causas moleculares do CPCNP para criar abordagens terapêuticas mais eficientes. O câncer de pulmão mostrou uma afinidade de ligação e perfil energético mais significativos e persistentes com a estaurosporina CDK2 alvo e o receptor-1 de FGF. Neste estudo, escolhemos duas proteínas-alvo essenciais, a quinase dependente de ciclina humana-2 e a holoenzima CK2 da proteína quinase humana, examinamos toda a biblioteca preparada pelo DrugBank de 1,55,888 compostos e identificamos 2-(2-metil-5-nitroimidazol-1-il) etanol (metralindol) como inibidor principal. O metralindol apresentou altas pontuações de ancoragem de -5,159 Kcal/mol e -5,99 Kcal/mol, com boas ligações de hidrogênio e outras topologias de ligação, como a força de Van der Waals, e os resultados do ADMET mostraram excelente biodisponibilidade e solubilidade, sem efeitos colaterais e toxicidade. A simulação de dinâmica molecular para 100ns em meio aquoso confirmou a estabilidade e o padrão de interação do composto com os menores desvios e flutuações. Nosso estudo in silico sugere que o metralindol, um composto experimental, pode efetivamente curar o câncer de pulmão. Além disso, a validação experimental do composto é obrigatória antes de qualquer prescrição.

Primary pulmonary chondrosarcoma in a bitch

Background: Primary lung neoplasms are uncommon in veterinary medicine, and when they develop, they are more frequently observed to be of epithelial origin. Although chondrosarcomas are the second most diagnosed type of neoplasm in dogs at skeletal sites, their development in extraskeletal tissues, including the spleen, aorta, heart, tongue, peritoneum, and lungs, corresponds to approximately only 1% of cases. Therefore, the occurrence of primary pulmonary chondrosarcoma is considered very rare in domestic animals. Considering the rare occurrence and scarcity of data regarding its development, the present report describes the clinical and pathological aspects of a case of primary pulmonary chondrosarcoma in a bitch. Case: A 8-year-old mixed-breed bitch, weighing 14.2 kg, was examined at one private veterinary clinic with the principal complaint of prolonged respiratory distress and resistance to exercise. Clinical evaluation revealed tachypnea with expiratory dyspnea due to intense pleural effusion, tachycardia, and diffusely pale mucous membranes. Thoracocentesis was performed with drainage of 1000 mL of modified transudate, and fluid cytology, blood count, and chest radiography were performed. Cytological analysis of the thoracic fluid did not identify neoplastic cells, the blood count showed intense regenerative anemia, and the radiograph showed an extensive area of consolidation in the left caudal lung lobe, compatible with neoplasia. The results of the tests performed, in addition to the evolution of the clinical picture and the impossibility of performing the indicated surgical intervention, culminated in the patient's unfavorable prognosis, followed by euthanasia, necropsy, and histopathological evaluation of the collected material. Necropsy revealed a white neoplastic formation with reddish areas and firm consistency that diffused into the parenchyma of the left caudal lung lobe with invasion of the rib cage, fracture of the fifth and sixth left ribs, diaphragmatic metastasis, intense hydrothorax, and moderate hydroperitoneum. Microscopically, in the histological sections of the lung and diaphragm, poorly differentiated mesenchymal cells with moderate anisocytosis and anisokaryosis and interspersed with them, moderately differentiated chondrocytes surrounded by chondroid matrix, moderate anisocytosis and anisokaryosis, and a low mitotic index culminated in the diagnosis of primary pulmonary mesenchymal chondrosarcoma. Discussion: Malignant epithelial neoplasms were suspected; however, the histopathological features observed were compatible with primary pulmonary chondrosarcoma. The characteristics of the fluid collected through thoracentesis led to its classification as a modified transudate, which is often associated with neoplastic and hemorrhagic processes; both alterations were present in this case. The diagnosis of primary pulmonary chondrosarcoma was established based on the histopathological findings since the cell type and distribution observed in the present case were compatible with the typical pattern observed in extraskeletal chondrosarcomas. An unfavorable prognosis is common in cases of primary or metastatic lung neoplasm since, in most cases, the condition is identified in the advanced stages of the disease, making therapeutic management challenging. Given the increase in the number of dog deaths due to neoplasms in recent years, this case report may contribute to a better understanding of the biological behavior of pulmonary chondrosarcoma and assist in the choice of treatment to be adopted when required.

Tumor venéreo transmissível canino em laringe com metástase pulmonar / Canine transmissible venereal tumor in the larynx with pulmonary metastasis

Background: Canine transmissible venereal tumor (TVT) is one of the most common canine neoplasms in Brazil. Lesions develop mainly in the genital tissue and less frequently in other areas, in the extragenital form. Metastasis is rare, and the disease progression depends on the patient’s immune status. The treatment of choice is chemotherapy with vincristine sulfate, considered an effective and safe modality. The present work describes the first case of extragenital TVT in the larynx with pulmonary metastasis at the time of diagnosis. Case: An approximately 4-month-old mixed-breed bitch was attended manifesting acute clinical respiratory signs. The patient had been rescued from the street 2 months beforehand. Physical examination revealed pale mucous membranes and crackling pulmonary auscultation. Thoracic radiography was performed in 3 projections, showing multiple nodules in the lung parenchyma, followed by cytopathological examination using fine needle puncture guided by thoracic ultrasound, confirming the diagnosis of TVT. Considering the cytological finding and the absence of primary tumor lesions in the genital, oral, cutaneous or nasal regions, endoscopy was performed in order to locate a possible primary focus. The exam revealed a small erythematous tumor with smooth and regular surface, measuring approximately 2.5 cm, located in the larynx, between the arytenoid cartilages. Chemotherapy was performed with vincristine sulfate with radiographic follow-up throughout the treatment. Full remission of the pulmonary and laryngeal nodules was achieved at the end of the protocol. The animal remained in complete remission for a period of 2 years. Discussion: TVT is more frequently observed in animals of active reproductive age, and rarely in animals under 1 year of age, as in the case...

Synergistic effect of oxytetracycline as a combination treatment with Carboplatin on MCF-7 breast cancer cell line / Efeito sinérgico da oxitetraciclina em um tratamento combinado com Carboplatina na linhagem de células cancerígenas pulmonares MCF-7

In breast cancer treatment, chemotherapy resistance is a major problem where many receptive tumors rebound and develop resistance. When provided in combination, cancer drugs are most successful, thus reducing the risk of developing resistant cancer cells. However, the evaluation of combination therapies has increased rapidly in recent years. Consequently, by repurposing old treatments, the discovery of additional medicines that may interact synergistically with chemotherapy is considered a current medical aim through discovering a new cancer medication or therapeutic strategy. The purpose of this research is to increase the anti-cancer activity of carboplatin (CP) by increasing the apoptotic effect of breast cancer cells (MCF-7) during in vitro experiments in combination with oxytetracycline. Our results showed a high synergistic effect between oxytetracycline and carboplatin, MCF-7 representative cell treated with carboplatin with/without different concentrations of oxytetracycline (5% and 10% of IC50). Oxytetracycline, which potentiated the action of carboplatin and/or had notable activity was reported as a single agent. This research demonstrated the synergistic relationship between oxytetracycline and carboplatin in viability assays. Surprisingly, our findings suggest that inhibiting treatment strategies can extend carboplatin's therapeutic window, potentially allowing for cancer therapy.(AU)

No tratamento do câncer de pulmão a resistência à quimioterapia é o maior problema no qual muitos tumores receptivos apresentam um rebote e desenvolvem a resistência. Quando oferecidas em combinações, as drogas anticancerígenas apresentam maior taxa de sucesso, reduzindo assim o risco de desenvolvimento de células cancerígenas resistentes. Contudo, a avaliação das terapias de combinação tem crescido muito rapidamente. Consequentemente, por reaproveitamento de tratamentos antigos, a descoberta de novos medicamentos adicionais que podem interagir sinergicamente com a quimioterapia que é considerada como auxílio médico na corrente busca à descoberta de novas medicações anticancerígenas ou estratégias terapêuticas. O propósito da presente pesquisa é aumentar a atividade anticancerígena da Carboplatina (CP) pelo incremento do efeito apoptótico de células de câncer pulmonar (MCF-7) em experimentos in vitro pela combinação com oxitetraciclina. Os resultados obtidos confirmaram elevado efeito sinérgico entre oxitetraciclina e Carboplatina em células MCF-7 representativas tratadas com Carboplatina, com e sem diferentes concentrações de oxitetraciclina (5% e 10% de IC50). A oxitetracilina que potencializou a ação da Carboplatina e/ou teve uma notável atividade relatada como um agente isolado. A pesquisa demonstrou a relação sinérgica entre oxitetraxiclina e Carboplatina nos ensaios de viabilidade. Surpreendentemente, os resultados obtidos sugeriram que as estratégias de tratamento inibidor podem aplicar um janela terapêutica da Carboplatina com potencial para a terapia do câncer.(AU)

Pulmonary adenocarcinoma in a captive ocelot (Leopardus pardalis): morphologic and immunophenotypic characterization - case report / Adenocarcinoma pulmonar em uma jaguatirica (Leopardus pardalis) de cativeiro: caracterização morfológica e imunofenotípica - relato de caso

Pulmonary adenocarcinoma is a malignant epithelial neoplasia that usually arises from conducting airways or alveolar parenchyma. It has rarely been described in wild felids, with no previous reports in ocelots. In domestic cats it is a very aggressive neoplasm with a high metastatic rate that usually evolves to death. This report aimed to describe a pulmonary adenocarcinoma in a captive and senile ocelot (Leopardus pardalis), with a thorough morphologic and immunophenotypically characterization, evidencing the epithelial-mesenchymal transition (EMT) phenomenon in a high metastatic carcinoma, an important feature rarely described in veterinary medicine, even in domestic cats.(AU)

O adenocarcinoma pulmonar é uma neoplasia epitelial maligna originada do epitélio respiratório das vias aéreas inferiores e do parênquima alveolar. É uma neoplasia raramente descrita em felinos selvagens, sem nenhum relato em jaguatiricas. Em gatos domésticos, é uma neoplasia muito agressiva, com alta taxa de metástase, e geralmente evolui para o óbito do paciente. O presente relato objetiva descrever um adenocarcinoma pulmonar em uma jaguatirica (Leopardus pardalis) senil de cativeiro, com detalhada caracterização morfológica e imunofenotípica, evidenciando o fenômeno de transição epitelial-mesenquial (TEM) em um carcinoma altamente metastático, uma característica importante, com escassos relatos na medicina veterinária, mesmo em gatos domésticos.(AU)

Mediastinal extraskeletal osteosarcoma in a canine with pulmonary and cerebral metastasis

Background: Extraskeletal osteosarcoma (EOS), a rare variant of osteosarcoma (OS), is a malignant neoplasm that develops insoft tissues without primary bone involvement. This study aims to describe a case of EOS with a mediastinal location in a canine.Case: A 10-year-old male Uruguayan Cimarron dog, was presented to the Laboratório Regional de Diagnóstico, Faculdadede Veterinária, Universidade Federal de Pelotas (LRD/FV/UFPel) for necropsy. The dog had a history of submandibularswelling, progressive hind limb paralysis, muscle atrophy, and breathing difficulties. During necropsy, in the thoracic cavity,approximately 900 mL of serosanguinous exudate and a reddish-brown, bossed mediastinal mass measuring 15.0 cm in thelongest axis were also noted. The lung exhibited multifocal to coalescent, white, firm nodules extending from the pleurato the parenchyma and measuring up to 4.5 cm in diameter. In the parietal and occipital region of the brain, a matte winemass measuring 2.3 cm in the longest axis was observed. Fragments of the neoplastic mass, organs of the abdominal andthoracic cavities, and the brain were harvested and fixed in 10% buffered formalin. After 48 h, the samples were routinelyprocessed, incorporated in paraffin, cut into 3 µm-thick sections, and stained using Hematoxylin and Eosin (HE). Selectedsections of the neoplasm, the lung, and the brain were subjected to Von Kossa staining and immunohistochemical (IHC)analysis. For IHC, primary anti-cytokeratin monoclonal antibodies (clone AE1 / AE3, BioCare Medical) at a 1:100 dilution, vimentin (clone V9, BioCare Medical) at a 1:100 dilution, S100 Protein (clone 15E2E2, BioCare Medical) at a 1:100dilution, and Ki67 (SP6 clone, BioCare Medical) at a 1:50 dilution were used. Immunostaining ...

Mediastinal extraskeletal osteosarcoma in a canine with pulmonary and cerebral metastasis

Background: Extraskeletal osteosarcoma (EOS), a rare variant of osteosarcoma (OS), is a malignant neoplasm that develops insoft tissues without primary bone involvement. This study aims to describe a case of EOS with a mediastinal location in a canine.Case: A 10-year-old male Uruguayan Cimarron dog, was presented to the Laboratório Regional de Diagnóstico, Faculdadede Veterinária, Universidade Federal de Pelotas (LRD/FV/UFPel) for necropsy. The dog had a history of submandibularswelling, progressive hind limb paralysis, muscle atrophy, and breathing difficulties. During necropsy, in the thoracic cavity,approximately 900 mL of serosanguinous exudate and a reddish-brown, bossed mediastinal mass measuring 15.0 cm in thelongest axis were also noted. The lung exhibited multifocal to coalescent, white, firm nodules extending from the pleurato the parenchyma and measuring up to 4.5 cm in diameter. In the parietal and occipital region of the brain, a matte winemass measuring 2.3 cm in the longest axis was observed. Fragments of the neoplastic mass, organs of the abdominal andthoracic cavities, and the brain were harvested and fixed in 10% buffered formalin. After 48 h, the samples were routinelyprocessed, incorporated in paraffin, cut into 3 µm-thick sections, and stained using Hematoxylin and Eosin (HE). Selectedsections of the neoplasm, the lung, and the brain were subjected to Von Kossa staining and immunohistochemical (IHC)analysis. For IHC, primary anti-cytokeratin monoclonal antibodies (clone AE1 / AE3, BioCare Medical) at a 1:100 dilution, vimentin (clone V9, BioCare Medical) at a 1:100 dilution, S100 Protein (clone 15E2E2, BioCare Medical) at a 1:100dilution, and Ki67 (SP6 clone, BioCare Medical) at a 1:50 dilution were used. Immunostaining ...(AU)

Tumor de células granulares pulmonar em um equino / Pulmonar granular cell tumor in a horse

Background: The occurrence of neoplasms in horses is relatively low. Granular cell tumor is a seldom diagnosed neoplasm, usually benign, of mesenchymal origin. Controversies exist regarding its origin, which is possibly from Schwann cells or cells with neuroendocrine differentiation. Despite being one of the main primary neoplasms in the lungs of horses, the number of cases is low in comparison to that of secondary lung tumors. Thus, this study proposes to report the anatomopathological aspects in a horse with granular cell tumor of primary pulmonary origin. Case: An 11-year-old female Quarter Horse breed underwent exploratory right lateral thoracotomy after presenting with chronic respiratory changes. During the operation, tumor masses were found in the right and left caudal pulmonary lobes. Due to the severity of clinical respiratory signs and the extent of the lesions, the animal was subjected to euthanasia and anatomopathological examination. Upon necroscopic examination, a tumor mass was found in the middle third of the left caudal lobe, rounded to flattened, measuring 10.0 × 8.0 cm in height and length, white in color, of firm consistency, smooth and regular surface and rising to the lung surface. When sectioned, the mass showed to be composed of multiple firm and dense circular lobes, separated by a thin layer of connective tissue. The tumor invaded the lumen of nearby segmental and subsegmental bronchi, which were partially or totally obstructed by the mass. In the right lung, multiple similar nodules were observed, accompanied by peritumoral hemorrhage. Histopathological analysis of the new formation revealed a dense cluster of cells that expanded over the lung parenchyma. The neoplastic cells were pleomorphic, moderately cohesive, without defined borders, with abundant cytoplasm, densely eosinophilic and finely granular. Intracytoplasmic granules were well evidenced by periodic acid Schiff staining (PAS). The cell nucleus was rounded to oval, excentric, markedly basophilic and with dense chromatin. There was moderate anisocytosis and mild anisokaryosis, with rare mitotic figures. Immunohistochemical analysis revealed positive staining for anti-vimentin and anti-S100 antibodies, confirming the diagnosis of granular cell tumor. Discussion: Granular cell tumors have no predisposition as to breed, sex or age. However, most of the described cases are reported in female horses aged around 13 years. The advanced age of the diagnosed animals may be related to late definitive diagnosis, since the clinical signs are nonspecific and treated palliatively like other respiratory diseases. Macroscopically, this tumor is more common in the multinodular form and, as observed in this case, it has a greater capacity for infiltration. Histologically, the visualization of large, polygonal cells, with a wide cytoplasm containing eosinophilic granules leads to the diagnosis of granular cell tumor. However, PAS staining and immunohistochemical tests were essential for the diagnostic conclusion in this report, confirming the presence of cytoplasmic granules and the mesenchymal and neuroectodermal origin of this neoplasm, respectively. Thus, considering the low occurrence of pulmonary granular cell tumor, the description of this case contributes to the basis of the knowledge of medical-veterinary professionals about this tumor in its clinical and diagnostic aspects.

Pulmonary adenocarcinoma in dogs: surgical treatment with real-time video-thermometry

Background: Pulmonary neoplasia is an abnormal proliferation of cells at the lung tissue, and may be classified as primary, secondary or metastatic, and multisystemic. However, primary neoplasia is rare in canids. Additionally, neoplasms may be classified according to their biological behavior as either malignant or benign. Malignant tumors are more prevalent. The diagnosis can be difficult due to nonspecific symptoms, taking into account that some affected patients do not have symptoms at all; thus, the real incidence of the disease might remain undiagnosed on certain occasions. Therefore, we aimed to report an unprecedented successful case of lung lobectomy surgery in dogs with the aid of infrared video thermometry, which showed real-time images during the surgical procedure. Case: A 10-year-old male dog, crossbreed with Cocker Spaniel, was attended with a history of lethargy, dullness, progressive weight loss, cough, and difficulty breathing. Due to the chronic severity of the clinical signs and the normal physiological clinical examination, complementary exams were requested, such as radiography of the cervical and thoracic regions, cranial and thoracoabdominal computed tomography (TCT). The results of the exams showed the presence of a nodule mass in the right caudal pulmonary lobe which caused a lateral deviation to the left hemithorax of the cardiac silhouette. The patient underwent a surgical procedure with an approach through the thoracic region, at the height of the seventh intercostal space, and a total lobectomy was performed. Throughout the surgical procedure, video thermometry in real-time through the MART station (Metabolic Activity in Real-Time FLIR SC325®) was used to determine the viability of adjacent tissues through temperature differences measured in degrees Celsius. The surgical fragment containing the direct caudal pulmonary lobe and the mass were sent to the pathology sector for anatomopathological evaluation. An abundant papillary epithelial proliferation was visualized through microscopy, presenting areas of necrosis and inflammatory polymorphonuclear infiltrate. The nodule was diagnosed as lung papillary adenocarcinoma. Discussion: Adenocarcinomas consist of papillary, acinar, solid, or mixed glandular structures. They may originate from the airways, bronchial glands, or bronchoalveolar region, and often show invasive growth presenting a rudimentary and irregular shape. The clinical signs are non-specific, including exercise intolerance, non-productive cough, chronic respiratory signs such as tachypnoea or dyspnea, reduced appetite, weight loss, lethargy, chest palpation pain, hemothorax, pneumothorax, and pleural effusion. The diagnosis is concluded through imaging diagnostic tests, of which chest radiography is the most important, followed by magnetic resonance and computed tomography. Also, histopathological examination is essential to determine a definitive diagnosis. The treatment of choice for adenocarcinoma nodules is a surgical excision of the tumor mass. However, the type of surgical approach is determined by different factors such as size, location, and involvement of adjacent structures. The ablation of pulmonary masses may be performed either via partial or total lobectomies. Nevertheless, partial lobectomy is more often performed on non-neoplastic masses or to obtain material for biopsy, whilst total lobectomy is recommended for a malignant neoplasm removal. The prognosis is always guarded, having a more favorable outcome in masses of the smaller diameter without the involvement of adjacent structures.(AU)

Pulmonary metastasis of transmissible venereal tumour in a dog: a case report / Metastase pulmonar de tumor venéreo transmissível em um cão: relato de caso

The transmissible venereal tumour (TVT) is one of the most frequent neoplasias in dogs. This tumour has specific characteristics, and it is exclusively of canines. Its transmission occurs through viable neoplastic cell transplantation when in contact with mucosa or unhealthy skin and rarely metastasise. This paper aims to report a rare presentation of pulmonary metastasis of widespread transmissible venereal tumours in a Blue Heeler dog. The patient was cachectic, dyspnoeic, and dehydrated and had multiple skin and pharynx nodulations. The cytology of all cutaneous nodulations showed round vacuolated cells with large eccentric nuclei and loose chromatin, which is compatible with TVT’s microscopic characteristics. Owing to the clinical evolution and reserved prognosis, the patient was euthanized. Necroscopy revealed a mass in the right pulmonary caudal lobe. The mass showed the same histopathologic characteristic of the others: not encapsulated infiltrative neoplastic proliferation of round vacuolated cells. The atypical manifestation of cutaneous metastasis and mainly pulmonary metastasis, in this case, denote the importance of TVT inclusion as a differential in cutaneous neoplasia, even if they show distant organ metastasis. Therefore, it emphasised the importance of cytology and histology in the diagnosis of nodular affections.

O tumor venéreo transmissível (TVT) é uma das neoplasias mais frequentes em cães. Com características específi-cas, esse tumor é exclusivo da espécie canina. Sua transmição acontece através da transplantação de células neoplásicas viáveis quando em contato com mucosas ou pele não íntegra, raramente ocorrendo metástases. Este trabalho visa relatar a apresen-tação rara de metástase pulmonar de tumor venéreo transmissível generalizado em um cão Blue Heeler. O paciente apresen-tava-se caquético, dispneico, desidratado e com diversas nodulações cutâneas e em faringe. A citologia de todas as nodulações cutâneas evidenciaram células redondas vacuolizadas, com núcleo excêntrico grande e cromatina frouxa, compatível com as características microscópicas de TVT. Em decorrência da evolução clínica e prognóstico reservado, o paciente foi eutanasiado. No exame macroscópico foi evidenciado massa em lobo caudal do pulmão direito com as mesmas características histopatoló-gicas dos demais nódulos, proliferação neoplásica de células redondas vacuolizadas infiltrativas não encapsuladas. A manifes-tação atípica de metástases cutâneas e principalmente pulmonar neste caso denota a importância da inclusão do TVT como diferencial de neoplasias cutâneas mesmo com metástase em órgãos. Com isso ressalta-sea importância de exames de citopa-tologia e histopatologia no diagnóstico de afecções nodulares.

Pulmonary metastasis of transmissible venereal tumour in a dog: a case report / Metastase pulmonar de tumor venéreo transmissível em um cão: relato de caso

The transmissible venereal tumour (TVT) is one of the most frequent neoplasias in dogs. This tumour has specific characteristics, and it is exclusively of canines. Its transmission occurs through viable neoplastic cell transplantation when in contact with mucosa or unhealthy skin and rarely metastasise. This paper aims to report a rare presentation of pulmonary metastasis of widespread transmissible venereal tumours in a Blue Heeler dog. The patient was cachectic, dyspnoeic, and dehydrated and had multiple skin and pharynx nodulations. The cytology of all cutaneous nodulations showed round vacuolated cells with large eccentric nuclei and loose chromatin, which is compatible with TVTs microscopic characteristics. Owing to the clinical evolution and reserved prognosis, the patient was euthanized. Necroscopy revealed a mass in the right pulmonary caudal lobe. The mass showed the same histopathologic characteristic of the others: not encapsulated infiltrative neoplastic proliferation of round vacuolated cells. The atypical manifestation of cutaneous metastasis and mainly pulmonary metastasis, in this case, denote the importance of TVT inclusion as a differential in cutaneous neoplasia, even if they show distant organ metastasis. Therefore, it emphasised the importance of cytology and histology in the diagnosis of nodular affections.(AU)

O tumor venéreo transmissível (TVT) é uma das neoplasias mais frequentes em cães. Com características específi-cas, esse tumor é exclusivo da espécie canina. Sua transmição acontece através da transplantação de células neoplásicas viáveis quando em contato com mucosas ou pele não íntegra, raramente ocorrendo metástases. Este trabalho visa relatar a apresen-tação rara de metástase pulmonar de tumor venéreo transmissível generalizado em um cão Blue Heeler. O paciente apresen-tava-se caquético, dispneico, desidratado e com diversas nodulações cutâneas e em faringe. A citologia de todas as nodulações cutâneas evidenciaram células redondas vacuolizadas, com núcleo excêntrico grande e cromatina frouxa, compatível com as características microscópicas de TVT. Em decorrência da evolução clínica e prognóstico reservado, o paciente foi eutanasiado. No exame macroscópico foi evidenciado massa em lobo caudal do pulmão direito com as mesmas características histopatoló-gicas dos demais nódulos, proliferação neoplásica de células redondas vacuolizadas infiltrativas não encapsuladas. A manifes-tação atípica de metástases cutâneas e principalmente pulmonar neste caso denota a importância da inclusão do TVT como diferencial de neoplasias cutâneas mesmo com metástase em órgãos. Com isso ressalta-sea importância de exames de citopa-tologia e histopatologia no diagnóstico de afecções nodulares.(AU)

Lung-digit syndrome related to an adenosquamous feline lung carcinoma

Background: The lung-digit syndrome is a rare syndrome characterized by the presence of a primary pulmonar neoplasiamanifesting metastasis to the digit, occurring exclusively in felines. The diagnosis is based on the clinical signs, associatedwith radiographic and histopathological exams. There are no therapeutic protocols well-established, and surgical excisionis considered controversial due to high recurrence and metastasis rates. The prognosis is considered poor, with low survivalrates. The aim of this paper is to report a case of lung-digit syndrome attended in Rio de Janeiro.Case: A 12-year-old female cat, no defined race, was attend with the complaint of weight loss and injury in the right thoraciclimb, already having histopathological diagnosis of squamous differentiation adenocarcinoma through biopsy. Physicalexamination showed no other clinical signs at first, including no signs of respiratory disease. Laboratory and imaging examswere performed, and the radiographic examination showed alterations in the pulmonary parenchyma showing a nodulararea of increased radiographic density. Followed up by the manifestation of breathing noise at rest, as the first respiratorysigns. The association of the clinical evaluation, medical history, and histopathological report from the limb lesion, leadto the suspicion diagnostic of lung-digit syndrome. The owners decide for the palliative treatment with chemotherapy, using carboplatin and prednisolone. Only the first session was performed, with the animal being euthanized due to clinicalworsening 48 days after the initial manifestation of clinical signs. The diagnosis was confirmed...

Lung-digit syndrome related to an adenosquamous feline lung carcinoma

Background: The lung-digit syndrome is a rare syndrome characterized by the presence of a primary pulmonar neoplasiamanifesting metastasis to the digit, occurring exclusively in felines. The diagnosis is based on the clinical signs, associatedwith radiographic and histopathological exams. There are no therapeutic protocols well-established, and surgical excisionis considered controversial due to high recurrence and metastasis rates. The prognosis is considered poor, with low survivalrates. The aim of this paper is to report a case of lung-digit syndrome attended in Rio de Janeiro.Case: A 12-year-old female cat, no defined race, was attend with the complaint of weight loss and injury in the right thoraciclimb, already having histopathological diagnosis of squamous differentiation adenocarcinoma through biopsy. Physicalexamination showed no other clinical signs at first, including no signs of respiratory disease. Laboratory and imaging examswere performed, and the radiographic examination showed alterations in the pulmonary parenchyma showing a nodulararea of increased radiographic density. Followed up by the manifestation of breathing noise at rest, as the first respiratorysigns. The association of the clinical evaluation, medical history, and histopathological report from the limb lesion, leadto the suspicion diagnostic of lung-digit syndrome. The owners decide for the palliative treatment with chemotherapy, using carboplatin and prednisolone. Only the first session was performed, with the animal being euthanized due to clinicalworsening 48 days after the initial manifestation of clinical signs. The diagnosis was confirmed...(AU)

Adenocarcinoma pulmonar associado à infecção por Mycobacterium sp. em vaca - relato de caso / [Pulmonary adenocarcinoma associated with infection by Mycobacterium sp. in a cow - case report]

Descrevem-se os aspectos clínicos, anatomopatológicos, imuno-histoquímicos, microbiológicos e moleculares de um caso de adenocarcinoma pulmonar associado à infecção por Mycobacterium sp. em uma vaca. O animal apresentou hiporexia, emagrecimento, vocalizações, postura ortopneica, ingurgitamento da jugular, estase venosa positiva, gemido expiratório e morte. Na necropsia, os pulmões estavam aumentados e apresentavam, na superfície pleural, nódulos branco-amarelados, firmes, multifocais a coalescentes, interpostos por áreas avermelhadas. Ao corte, os nódulos aprofundavam-se ao parênquima e possuíam múltiplos focos de aspecto caseoso e friável e áreas de mineralização. O saco pericárdico e os linfonodos traqueobrônquicos, ilíacos, lombares aórticos e mamários apresentavam lesões semelhantes. Histologicamente, observou-se neoformação carcinomatosa associada a áreas multifocais de necrose e mineralização. As células neoplásicas foram fortemente imunomarcadas pelo anticorpo antipancitoqueratina AE1/AE3. Na cultura microbiológica de fragmentos dos pulmões, houve crescimento de colônias bacterianas compatíveis com micobactérias atípicas. O sequenciamento molecular submetido ao BLASTn identificou o Mycobacterium sp. WCM 7299 (ID: gb|KJ873243.1|).(AU)

The clinical, anatomopathological, immunohistochemical, microbiological and molecular aspects of a case of pulmonary adenocarcinoma associated with infection by Mycobacterium sp. in a cow are described. The animal presented hyporexia, weight loss, vocalizations, orthopneic posture, jugular engorgement, positive venous stasis, expiratory groaning and death. At necropsy, the lungs were enlarged and presented firm, multifocal to coalescent yellowish nodules, interposed by reddish areas on the pleural surface. At cut, the nodules deepened to the parenchyma and had multiple foci of caseous and friable appearance and areas of mineralization. The pericardial sac and tracheobronchial, iliac, aortic lumbar and mammary lymph nodes showed similar lesions. Histologically, a carcinomatous neoformation, associated with multifocal areas of necrosis and mineralization, was observed. Neoplastic cells were strongly immunolabelled by anti-PanCytokeratin antibody AE1/AE3. Microbiological culture of lung fragments showed growth of bacterial colonies compatible with atypical mycobacteria. Molecular sequencing submitted to BLASTn identified the Mycobacterium sp. WCM 7299 (ID: gb|KJ873243.1|).(AU)

Melanoma oral amelanótico metastático com acometimento neurológico e gonadal em um cão fêmea - relato de caso / [Metastatic oral amelanotic melanoma with neurologic and gonadal involvement in a female dog - case report]

Relata-se um caso de melanoma oral disseminado em uma cadela de dois anos, com protrusão de bulbo ocular unilateral e quadro convulsivo progressivo. Os exames de imagem revelaram aumento de volume nas regiões submandibular, maxilar e cerebral, padrão nodular pulmonar e aumento das dimensões ovarianas. A citologia da massa submandibular indicou proliferação epitelial maligna, enquanto a biópsia excisional foi sugestiva de melanoma amelanótico. Na necropsia, havia uma massa gengival localmente infiltrativa e nodulações brancas nos linfonodos, nos rins, no pulmão, no cérebro e nos ovários, indicativas de metástase. O diagnóstico histopatológico consistiu de neoplasia maligna metastática indiferenciada, indicativo de melanoma amelanótico. Células caracterizadas por núcleo com cromatina espessa, múltiplos nucléolos bem evidentes, mitoses atípicas e multinucleações consistiram nos principais critérios de malignidade. No espaço peritrabecular ósseo facial, havia rara diferenciação pigmentar melanocítica, confirmada histoquimicamente pela técnica de Fontana-Massom e Giemsa. Algumas células foram positivas pela imuno-histoquímica para PNL-2 e Melan-A, e o diagnóstico de melanoma amelanótico disseminado foi firmado. A indiferenciação neoplásica marcante, com disseminação metastática multissistêmica e acometimento mútuo de sítios anatômicos pouco comuns, conjuntamente com a ampla variação dos padrões celulares, foi responsável pelo desafio diagnóstico do presente caso, ressaltando o papel decisivo da imuno-histoquímica para confirmação diagnóstica. A importância clínica deste trabalho consiste ainda em alertar a comunidade clínica e científica acerca da dificuldade diagnóstica, devendo-se considerar o melanoma amelanótico como diferencial mesmo em casos de lesões orais menos perceptíveis e/ou desprovidas de pigmentação.(AU)

A case of disseminated oral melanoma in a two year old female dog with unilateral protuberance of the eye bulb and progressive seizure is described. Imaging exams revealed increase of the submandibular, maxillary and cerebral regions, nodular pattern in lungs and increased ovarian dimensions. The cytology of the submandibular mass indicated a malignant epithelial proliferation, whereas the excisional biopsy indicated an amelanotic melanoma. At necropsy, a locally infiltrating gingival mass and white nodules in the lymph nodes, kidneys, lung, brain and ovaries were observed, indicative of metastases. Histopathological diagnosis consisted of an undifferentiated malignant metastatic neoplasm. Nucleus with coarse chromatin, prominent nucleoli, bizarre mitotic figures and multinucleated cells were the major malignant features. There was a poor melanocytic pigment differentiation in the peritrabecular space of facial bones, confirmed by Fontana-Masson and Giemsa histochemical techniques. Only a few cells were immunohistochemically positive for PNL-2 and Melan-A and the diagnosis of a disseminated amelanotic melanoma was performed. The diagnostic challenge was based on marked neoplastic undifferentiation, with multisystemic metastasis and mutual involvement of uncommon anatomic sites, associated with a large variability of cellular patterns, highlighting the decisive role of immunohistochemistry for diagnostic confirmation. Therefore, the clinical importance of this study is to warn the clinical and scientific community about the diagnostic challenge, considering the amelanotic melanoma as a differential even in cases of poorly apparent and/or nonpigmented oral lesions.(AU)

Cutaneous metastatic melanoma in a Siberian tiger (Panthera tigris altaica) - case report / Melanoma cutâneo metastático em um tigre-siberiano (Panthera tigris altaica) - relato de caso

A male 15-year-old captive Siberian tiger (Panthera tigris altaica) developed pelvic limb hypermetry over the past 10 years. Recently, an ulcerated black nodule located caudally to the right ear was observed. The animal was submitted to surgery for removing the tumor, but died during anesthetic recovery. At necropsy, another infiltrative nodule was observed caudally to the right ear. Histologically, both nodules corresponded to melanocytic neoplasia, varying from heavily pigmented to amelanotic, with metastasis to mediastinal lymph nodes, spleen and lung. Lipofuscinosis and corpora amylacea were histologically observed in the central nervous system. Macroscopic and histologic findings confirmed the diagnosis of skin metastatic melanoma in a captive adult Siberian tiger.(AU)

Um tigre-siberiano (Panthera tigris altaica) de cativeiro, macho, de 15 anos de idade, apresentou hipermetria dos membros pélvicos nos últimos 10 anos, e recentemente, foi observado um nódulo preto e ulcerado caudalmente à orelha direita. O animal foi submetido à cirurgia para remoção do nódulo e morreu durante a recuperação anestésica. À necropsia, outro nódulo infiltrativo, foi detectado caudalmente a orelha direita. Histologicamente, ambos os nódulos correspondiam à neoplasia melanocítica, com células variando de fortemente pigmentadas a amelanóticas, com metástase para linfonodos mediastinais, baço e pulmão. Havia lipofucsinose e corpora amilácea no sistema nervoso central. Os achados macroscópicos e histológicos confirmam o diagnóstico de melanoma cutâneo metastático em um tigre-siberiano adulto de cativeiro.(AU)

Cutaneous metastatic melanoma in a Siberian tiger (Panthera tigris altaica) - case report / Melanoma cutâneo metastático em um tigre-siberiano (Panthera tigris altaica) - relato de caso

A male 15-year-old captive Siberian tiger (Panthera tigris altaica) developed pelvic limb hypermetry over the past 10 years. Recently, an ulcerated black nodule located caudally to the right ear was observed. The animal was submitted to surgery for removing the tumor, but died during anesthetic recovery. At necropsy, another infiltrative nodule was observed caudally to the right ear. Histologically, both nodules corresponded to melanocytic neoplasia, varying from heavily pigmented to amelanotic, with metastasis to mediastinal lymph nodes, spleen and lung. Lipofuscinosis and corpora amylacea were histologically observed in the central nervous system. Macroscopic and histologic findings confirmed the diagnosis of skin metastatic melanoma in a captive adult Siberian tiger.(AU)

Um tigre-siberiano (Panthera tigris altaica) de cativeiro, macho, de 15 anos de idade, apresentou hipermetria dos membros pélvicos nos últimos 10 anos, e recentemente, foi observado um nódulo preto e ulcerado caudalmente à orelha direita. O animal foi submetido à cirurgia para remoção do nódulo e morreu durante a recuperação anestésica. À necropsia, outro nódulo infiltrativo, foi detectado caudalmente a orelha direita. Histologicamente, ambos os nódulos correspondiam à neoplasia melanocítica, com células variando de fortemente pigmentadas a amelanóticas, com metástase para linfonodos mediastinais, baço e pulmão. Havia lipofucsinose e corpora amilácea no sistema nervoso central. Os achados macroscópicos e histológicos confirmam o diagnóstico de melanoma cutâneo metastático em um tigre-siberiano adulto de cativeiro.(AU)

Meningioma microcístico com metástase pulmonar em canino: relato de caso / Microcystic meningioma with pulmonary metastasis in canine: case report

Meningiomas são os principais tumores primários do sistema nervoso central (SNC) que afetam cães e gatos. Na maioria dos casos, são neoplasias benignas, geralmente expansivas, causando compressão do SNC, e raramente fazem metástase para outros órgãos. O presente trabalho tem como objetivo relatar a ocorrência de um meningioma microcístico com metástase pulmonar em um canino de 11 anos de idade, com sinais clínicos de andar cambaleante, compressão da cabeça contra objetos, agitação, salivação e agressividade. Na necropsia, foram observadas, no encéfalo, massas bem delimitadas pardo-avermelhadas, firmes, de aspecto granular, localizadas no córtex parietal e nos núcleos da base. Inúmeras micronodulações de aspecto semelhante foram observadas no pulmão. Histologicamente observaram-se nódulos formados por células neoplásicas fusiformes, com núcleos grandes e alongados e nucléolos evidentes, dispostas de forma frouxa, formando vacúolos e microcistos. À imuno-histoquímica, o meningioma apresentou marcação fortemente positiva para citoqueratina e negativa para vimentina. Por meio da histopatologia e da imuno-histoquímica, foi possível estabelecer a classificação histológica de meningioma microcístico, bem como diferenciá-lo de outras doenças que cursam com sinais nervosos.(AU)

Meningiomas are the main tumors of the central nervous system (CNS) affecting dogs and cats. In most of the cases they are benign neoplasms, usually expansive, causing compression of the CNS and rarely metastasize to other organs. We describe the occurrence of a microcystic meningioma with pulmonary metastasis in an 11 - year - old canine with clinical signs of staggering gait, head compression against objects, agitation, salivation and aggressiveness. At necropsy, well-defined, firm, granular-looking masses located in the parietal cortex and nuclei of the base were observed in the encephalon. Numerous micronodulations of similar appearance were observed in the lung. Histologically, nodules formed by spindle neoplastic cells with large, elongated nuclei and evident nuclei were loosely arranged, forming vacuoles and microcysts. Immunohistochemistry were strongly positive for cytokeratin and negative for vimentin. Through the histopathology and immunohistochemistry, it was possible to establish the histological classification of microcystic meningioma, as well as to differentiate from other diseases that present with nervous signals.(AU)

Meningioma microcístico com metástase pulmonar em canino: relato de caso / Microcystic meningioma with pulmonary metastasis in canine: case report

Meningiomas são os principais tumores primários do sistema nervoso central (SNC) que afetam cães e gatos. Na maioria dos casos, são neoplasias benignas, geralmente expansivas, causando compressão do SNC, e raramente fazem metástase para outros órgãos. O presente trabalho tem como objetivo relatar a ocorrência de um meningioma microcístico com metástase pulmonar em um canino de 11 anos de idade, com sinais clínicos de andar cambaleante, compressão da cabeça contra objetos, agitação, salivação e agressividade. Na necropsia, foram observadas, no encéfalo, massas bem delimitadas pardo-avermelhadas, firmes, de aspecto granular, localizadas no córtex parietal e nos núcleos da base. Inúmeras micronodulações de aspecto semelhante foram observadas no pulmão. Histologicamente observaram-se nódulos formados por células neoplásicas fusiformes, com núcleos grandes e alongados e nucléolos evidentes, dispostas de forma frouxa, formando vacúolos e microcistos. À imuno-histoquímica, o meningioma apresentou marcação fortemente positiva para citoqueratina e negativa para vimentina. Por meio da histopatologia e da imuno-histoquímica, foi possível estabelecer a classificação histológica de meningioma microcístico, bem como diferenciá-lo de outras doenças que cursam com sinais nervosos.(AU)

Meningiomas are the main tumors of the central nervous system (CNS) affecting dogs and cats. In most of the cases they are benign neoplasms, usually expansive, causing compression of the CNS and rarely metastasize to other organs. We describe the occurrence of a microcystic meningioma with pulmonary metastasis in an 11 - year - old canine with clinical signs of staggering gait, head compression against objects, agitation, salivation and aggressiveness. At necropsy, well-defined, firm, granular-looking masses located in the parietal cortex and nuclei of the base were observed in the encephalon. Numerous micronodulations of similar appearance were observed in the lung. Histologically, nodules formed by spindle neoplastic cells with large, elongated nuclei and evident nuclei were loosely arranged, forming vacuoles and microcysts. Immunohistochemistry were strongly positive for cytokeratin and negative for vimentin. Through the histopathology and immunohistochemistry, it was possible to establish the histological classification of microcystic meningioma, as well as to differentiate from other diseases that present with nervous signals.(AU)

Do alterations in gene expressions influence tumorigenesis in the transmissible venereal tumor in dogs? / Alterações nas expressões gênicas influenciam na tumorigênese no tumor venéreo transmissível em cães?

Canine transmissible venereal tumor (CTVT) is a transmissible neoplasm, which spreads naturally between dogs through the halogenic transfer of tumor cells, mainly during coitus. It is the oldest known tumoral lineage in nature and reports on gene mutations have been extended. Also, this tumor shares several genetic mutations with some cancers in humans, among them lung carcinomas, melanoma, prostate, breast, among other cancers. Thus, expression of tumor suppressor genes such as TP53, P21, and apoptosis-related genes such as BAX, BCL-2, and BCL-xL, both in vivo and in vitro (primary cell culture) were quantified. In the present study, the comparison of gene expression, the TP53 gene, in most cases, was shown to be high in the majority of tissues (65%) and primary cell culture (100%), while BCL-2, BCL-xL, and BAX presented variation among the animals analyzed. Moreover, in these situations, the results suggested that the apoptotic regulation of these genes did not occur for TP53. The P21 gene was shown to be mostly normal (70%); although, absence (6%) and underexpressions (24%) were also observed. Statistical analysis of the BCL-xL gene demonstrated significant differences between the tissues of the animals when compared to the cell cultures; however, to the other genes, no statistical difference was observed between the groups. Preliminarily, the results suggested the presence of alterations in the gene expressions of the TP53, P21, BAX, BCL-2 and BCL-xL leading to loss of function in these genes, which affect the tumorigenesis of CTVT.(AU)

O tumor venéreo transmissível canino (TVTC) se trata de uma neoplasia transmissível, que se propaga naturalmente entre os cães pela transferência halogênica de células tumorais, principalmente, durante o coito. É a mais antiga linhagem tumoral conhecida na natureza e relatos sobre mutações gênicas vêm sendo ampliadas. Além disso, este tumor compartilha uma série de mutações genéticas com alguns cânceres em seres humanos, dentre eles, carcinomas de pulmão, melanoma, próstata, mama, entre outros tipos de câncer. Assim, quantificou-se a expressão de genes supressores de tumores, como TP53, P21 e genes relacionados à apoptose, como BAX, BCL-2 e BCL-xL, tanto in vivo quanto in vitro (cultura celular primária). No presente estudo, na comparação das expressões gênicas, o gene TP53 se mostrou elevado na maioria dos casos em tecidos (65%) e em cultura celular primária (100%), enquanto BCL-2, BCL-xL e BAX apresentaram-se variáveis entre os animais analisados. Ademais, nessas situações os resultados sugerem que não ocorreu regulação apoptótica desses genes pelo TP53. O gene P21 mostrou-se, em sua maioria, normal (70%), embora a ausência (6%) e subexpressões (24%) também tenham sido observadas. A análise estatística do gene BCL-xL demonstrou diferenças significativas entre os tecidos dos animais, quando comparadas às culturas celulares, entretanto, para os demais genes, não foi observada diferença estatística entre os grupos. Preliminarmente, os resultados sugerem a presença de alterações nas expressões gênicas dos genes TP53, P21, BAX, BCL-2 e BCL-xL, levando a perda de função desses genes, os quais afetam a tumorigênese do CTVT.(AU)