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The actual incidence of bone marrow infiltration of human melanoma in clinical practice is underestimated, given it is found in only 7% of in vivo staging procedures, whereas this percentage increases up to 45% of autopsy cases. We performed a systematic review, in order to highlight the main clinico-pathologic features of melanoma bone marrow metastases (BMM), by reviewing 2.526 studies; seventy-three reports were included in the analysis,reporting a total amount of 146 patients. Moreover, as clinical exemples, we also present a collection of three BMM cases, extracted from our Institutional casistic. We found a slight male prevalence, with a median age at the time of BMM of 56.6 years (range: 3-81 years). The skin was the primary site of involvement in most cases (52%), followed by mucosa in 6 cases (8.8%) and uvea in 14 cases (20.5%), while in 13 cases (19%) the primary site of melanoma was not detected. In 36% of cases, BMM were preceded by lymph node involvement, while 64% of cases did not show nodal metastases, but directly to bone marrow (23%), as well as to other anatomical sites (41%). Presenting symptoms of BMM mostly included pain (60.7%), while anemia was the main laboratory alteration (80%), followed by thrombocytopenia, leukoerythroblastosis, pancytopenia, and leukopenia. A disseminated intravascular coagulation (DIC) was detected in 6 (11%) cases. In 12 cases (23.6%) BMM were amelanotic. The prognosis for BMM is poor, with a median time of survival of only 2 months, since currently conventional therapies for this anatomical site of metastasis are still not very successful, therefore, we stress the importance to evaluate bone marrow as a possible metastatic site in melanoma patients.

Background: Agmination and or satellitosis in pigmented blue lesions is a phenomenon rarely mentioned in the literature and not well known. This phenomenon can be expressed by several benign and malignant pigmented blue lesions, such as blue nevi, Spitz nevi, melanocytoma and melanoma. On this spectrum, dermoscopy, reflectance confocal microscopy (RCM) and dynamic Optical coherence tomography (D-OCT) represent non-invasive imaging technologies, which may help clinicians in the diagnosis of melanoma and non-melanoma skin cancers in daily clinical practice. Methods: Currently, in the literature there is a lack of new data about agminated blue lesions and blues lesions with satellitosis, as well as the lack of a recent and updated review of the literature about this topic. Therefore, considering that clinicians must be confident with the diagnosis of these rare skin lesions, we decided to carry out this work. Results: In this paper, four new cases of agminated pigmented cutaneous lesions were described. Moreover, a review of the current literature on this topic was performed. Conclusions: A clinical pathological correlation is often needed to reach a correct diagnosis; currently, dermoscopy and non-invasive diagnostic techniques, such as reflectance confocal microscopy and optical coherence tomography, due to the depth of these skin lesions in the dermis, can only make a partial and limited contribution.

The occurrence of bone marrow metastases (BMM) in melanoma patients is often underestimated, with only 7% detected during in-vivo staging procedures but rising to 45% in autopsy cases. This systematic review aims to shed light on the clinical and laboratory features of BMM in melanoma by analyzing 73 studies selected from 2 482 initially retrieved from PubMed, Embase, and Cochrane CENTRAL databases. Our findings reveal a slight male predominance, with a median age at BMM diagnosis of 56 years. Primary melanoma sites included the skin (52%), mucosa (8.8%), uvea (20.5%) and unidentified (19%). BMM was preceded by lymph node involvement in 36.5% of cases, whereas 63% showed no nodal metastases, with direct BMM occurring in 22.5% and metastases to other sites in 41%. Common BMM symptoms included pain (60.7%), anemia (80%), thrombocytopenia, leukoerythroblastosis, pancytopenia and leukopenia, while disseminated intravascular coagulation was detected in 11% of cases. In 23.6% of cases, BMM was amelanotic. The prognosis for BMM is grim, with a median survival of only 2 months. Conventional therapies for BMM remain largely ineffective, emphasizing the importance of considering bone marrow as a potential metastatic site in melanoma patients.

Potential under- and overtreatment of patients with colorectal cancer liver metastases (CRLM) is considered a clinical problem. Proper patient selection for local and/or systemic treatment strategies may improve outcome in these patients. So, this thesis aimed to tailor personalized treatment plans by making multidisciplinary liver expertise more accessible and to provide new insights in treatment of early recurrent CRLM. Additionally, the performance of radiomics in predicting response to treatment was evaluated. The added value of a dedicated multidisciplinary panel of liver specialists to assess feasibility of local treatment strategies in patients suffering from CRLM is studied in Chapter 2. Diagnostic imaging were reviewed by an expert panel consisting of four hepatobiliary surgeons and two interventional radiologists. In 20.0% of patients initially assigned to systemic treatment of CRLM, upfront local treatment was deemed feasible after re-evaluation by this expert panel. Assessment by such panels may reduce undertreatment of patients with CRLM. The implementation of an online expert panel in clinical practice is reported in Chapter 3. This quality improvement initiative was introduced to provide non-liver centers with online multidisciplinary liver expertise and select patients for referral. Chapter 4 highlights the rules and regulations, which apply for e-consultation services, under current legislation in the Netherlands. There are no legal obstacles or practical objections to the introduction of expert panels in clinical practice, provided that these requirements are met. Chapter 5 describes the perspectives of patients on the use of online expert panels in transmural care. Based on two focus groups, three major themes were identified: ‘data management’, ‘expertise’, and ‘information and coordination’. The potential hazard of privacy violation associated with digital data exchange was accepted, provided that the use of digital data supported a higher purpo

Introduction: The small intestine is the most frequent site of metastatic melanoma. However, its diagnosis continues to be a challenge since it is usually asymptomatic or with non-specific symptoms.Few cases result in complications, peritonitis due to perforation being infrequent. The objective of the work is to report a clinical case of peritonitis due to perforation of a melanoma metastasis in the small intestine. Clinical case: A 66-year-old male patient diagnosed with melanoma of the neck and secondary bone, brain and lung melanoma, underwent emergency surgery for acute peritonitis due to perforation of metastasis in the small intestine, which was resected and anastomosed. The histology confirmed the secondary nature of the cutaneous melanoma. Conclusion: Knowing that the jejunum-ileum is the most frequent site of melanoma metastases, in the presence of non-specific digestive symptoms or anemia, its involvement should be suspected and possible therapeutic alternatives should be evaluated., Introdução: O intestino delgado é o local mais frequente de melanoma metastático.O diagnóstico é um desafio por ser assintomático ou apresentar sintomas inespecíficos.Há poucos casos que apresentam complicações, sendo pouco frequente a peritonite por perfuração.O objetivo deste trabalho é relatar um caso clínico de peritonite por perfuração de metástase de melanoma no intestino delgado. Caso clínico: Paciente do sexo masculino, 66 anos, diagnosticado com melanoma no pescoço com metástase óssea, cefálica e pulmonar. Foi submetido a cirurgia de emergência por peritonite aguda por perfuração de metástases do intestino delgado. O estudo histológico confirmou melanoma cutâneo. Conclusão: Sabendo que o jejuno e o íleo é o local mais frequente de metástase de melanoma, na presença de sintomas digestivos inespecíficos ou anemia deve-se suspeitar de seu acometimento e avaliar possíveis alternativas terapêuticas., Introducción: El intestino delgado es el sitio de asiento más frecuente del melanoma metastásico. Su diagnóstico es un desafío por cursar asintomático o con síntomas inespecíficos. Son pocos los casos que presentan complicaciones, siendo infrecuente la peritonitis por perforación. El objetivo del trabajo es comunicar el caso clínico de una peritonitis por perforación de una metástasis de melanoma en intestino delgado. Caso clínico: Paciente de sexo masculino de 66 años con diagnóstico de melanoma de cuello y secundario óseo, encefálico y pulmonar, fue intervenido de urgencia por peritonitis aguda por perforación de metástasis en intestino delgado. El estudio histológico confirmó secundarismo de melanoma cutáneo. Conclusión: Sabiendo que el yeyuno íleon es el sitio de asiento más frecuente de las metástasis de melanoma, ante la presencia de síntomas digestivos inespecíficos o anemia se debe sospechar su compromiso y evaluar posibles alternativas terapéuticas.

Cancer is one of the main global health problems. Most cancer patients die from metastases rather than from the primary tumor. Therefore, it is of utmost importance to develop novel treatment options to prevent and treat metastases. A promising treatment option for cancer is immunotherapy. Immunotherapy aims to stimulate the patient’s own immune system to destroy the tumors. There are several types of immunotherapy, including antibody therapy. Antibodies have both direct effects and indirect effects. Antibodies bind tumor cells to reduce their growth (direct effect). Simultaneously, antibodies can bind immune cells, including macrophages, natural killer (NK) cells and neutrophils, creating a bridge between these cells and tumor cells. In this way, the immune cells are stimulated to eliminate the tumor cells (indirect effect). In my thesis I investigated multiple strategies to enhance the efficacy of antibody therapy. In Part I of my thesis I focused on the prevention of metastases. In Chapter 2 we discuss the process through which tumor cells detach from the primary tumor in the intestine and grow out as metastasis in the liver. As tumor cells detach from the tumor and enter the blood circulation, they are referred to as circulating tumor cells. It has been described that surgical removal of tumors in the intestine results in an increased number of circulating tumor cells. This increases the chance to develop metastases. Therefore, elimination of circulating tumor cells represents a promising treatment option to prevent development of metastases. In Chapter 3 we investigated if, for this purpose, we could use antibodies against the molecule EGFR that is highly expressed on tumor cells compared to healthy cells. We demonstrated that treatment with anti-EGFR antibodies stimulates macrophages to eat tumor cells. Therefore, we advise to treat patients with anti-EGFR antibodies prior to surgical removal of tumors in the intestine. In this way, macrophages can eat circula

Prostate cancer is the second most common cancer among men. The Gleason score is one of the most important parameters for outcome and based on several growth patterns. Among these patterns, cribriform architecture is associated with worse prognosis.

[Resumen]: Aunque inicialmente descritos como “ruido transcripcional”, los noncoding RNA o ncRNAs (RNA no codificantes) han surgido como moléculas vitales en diversos procesos celulares y en el desarrollo de muchas enfermedades. Hay dos tipos principales de ncRNA, ncRNA cortos o ncRNA largos, y son precisamente estos últimos los que se han relacionado con un amplio rango de patologías humanas. Así, los long non-coding RNA o lncRNAs (ncRNAs largos) se describen como transcritos mayores a 200 nucleótidos que carecen de la capacidad para codificar proteínas, aunque si pueden hacerlo para péptidos funcionales. Los lncRNAs pueden clasificarse según su posición relativa respecto a los genes codificadores de proteínas o según la función que desempeñen. Los lncRNAs están implicados en la regulación de la expresión génica tanto a nivel transcripcional pudiendo interaccionar con la cromatina o influir en la transcripción; como a nivel postranscripcional, alterando la estabilidad del RNAm. En el cáncer, los lncRNAs tienden a expresarse de forma aberrante, lo que se relaciona con características de las células cancerígenas como pueden ser la evasión de los supresores del crecimiento, la metástasis o la resistencia a medicamentos. En este contexto, algunos de los lncRNAs más estudiados son MEG3, MALAT1 y H19, respectivamente. MEG3 interacciona con el supresor de tumores p53 en el cáncer de cuello de útero, influyendo en la proliferación celular. MALAT1 por su parte se relaciona con un elevado riesgo de metástasis y con un mal pronóstico en pacientes con cáncer de pulmón. Por último, H19 está implicado en el desarrollo de resistencia a la quimioterapia con paclitaxel en el cáncer de mama. Por todo ello, el estudio de los lncRNAs marca un camino hacia su uso como marcadores de diagnóstico y de pronóstico, pudiendo ser utilizados para desarrollar terapias contra el cáncer., [Resumo]: Aínda que inicialmente os lncRNAs foron descritos como “ruido transcripcional”, os noncoding RNA ou ncRNAs (RNA non codificantes) xurdiron como moléculas vitais en diversos procesos celulares e no desenvolvemento de moitas enfermidades. Hai dous tipos principais de ncRNA, ncRNA curtos e ncRNA longos, e son precisamente estes últimos os que están relacionados cun amplo rango de patoloxías humanas. Así, os long non-coding RNA ou lncRNAs (ncRNAs longos) descríbense como transcritos maiores a 200 nucleótidos que carecen da capacidade para codificar proteínas, ainda que si poden facelo para péptidos funcionáis. Os lncRNAs poden clasificarse segundo a súa posición relativa respeto aos xenes codificadores de proteínas ou segundo a función que desempeñen. Os lncRNAs están implicados na regulación da expresión xénica tanto a nivel transcripcional, puidendo interacionar coa cromatina ou influir na transcripción; como a nivel postranscripcional, alterando a estabilidade do RNAm. No cancro, os lncRNAs tenden a expresarse de forma aberrante, e a súa presencia relaciónase con características das células canceríxenas como poden ser a evasión dos supresores do crecemento, a metástase ou a resistencia a medicamentos. Neste contexto, algúns dos lncRNAs mellor estudiados son MEG3, MALAT1 e H19 respetivamente. MEG3 interaciona con supresor de tumores p53 no cancro de colo de útero, influindo na proliferación celular. MALAT1 pola súa parte relaciónase cun elevado risco de metástase e cun mal pronóstico en pacientes con cancro de pulmón. Por último, H19 está implicado no desenvolvemento de resistencia á quimioterapia con paclitaxel no cancro de peito. Por todo isto, o estudo dos lncRNAs marca un camiño cara o seu uso como marcadores de diagnóstico e de pronóstico, puidendo ser utilizados para desenvolver terapias contra o cancro., [Abstract]: Although at the beginning they were described as “transcriptional noise”, noncoding RNA (ncRNA) have emerged now as essentials molecules in many cellular processes and in the develop of many diseases. There’re two main classes of ncRNA: short ncRNA and long ncRNA, and precisely the latter’s ones are more associated with a wide range of human diseases. Thereby, long noncoding RNA are described as transcripts made by more than 200 nucleotides that lacked of the ability to encode proteins, though they can encode functional peptides. LncRNAs can be classified according to their position respect the protein coding genes or according to the function that they carry out in the genome. LncRNAs are implicated in the gene expression regulation at different levels, for example, lncRNAs can be related with transcription processes (transcriptional variations) or they can have influence in RNAm stability (post-transcriptional variations). In cancer, lncRNA are expressed in a strange way, and their presence are associated with some of the cancer cell characteristics as evading growth suppressors, metastasis, or drug resistance. In that way, some of the most studied lncRNAs are MEG3, MALAT and H19, respectively. MEG3 interacts with tumor suppressor p53 in uterine neck cancer, having an influence in cellular proliferation. MALAT1, for its part, is connected with a metastasis high risk and also with bad prognosis in lung cancer patients. Lastly, H19 is involved in chemotherapy resistance in breast cancer. For this reason, lncRNAs studies pave the way for their use as diagnosis and prognosis indicator and they also can be used for cancer therapies develop.

Patients treated with bladder augmentation have a higher risk of developing bladder cancer than the general population. In these patients, tumours are most frequently primary bladder cancers. Metastasis in an augmentation cystoplasty is extremely rare and here we describe the first case of metastasis from lobular breast carcinoma in an ileal patch. A 52-year-old woman, with a medical history of invasive lobular breast cancer, presented with gross hematuria seven years after an ileal augmentation cystoplasty. A large bladder mass was found exclusively on the enteric patch, with lymphadenopathies from iliac vessels to right kidney hilum. Asurgical resection of the ileal segment with trigonal preservation was performed, associated with a complete cytoreduction. The bladder was reconstructed with a new ileal segment. Pathology confirmed the diagnosis of metastatic lobular breast carcinoma. Patients treated with augmentation cystoplasty need a close and long follow-up to detect the warning signs of tumor development. We herein report our experience of a metastatic lesion on the enteric part of a cystoplasty. Unusual characteristics of the bladder tumor and personal oncologic history of the patient may be suggestive of a secondary lesion., SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

The canine transmissible venereal tumor is a type of round cell cancer that have the particularity of implanting in mucous tissue, when they lose their integrity, at which point the tumour proliferates and may even develop metastases. The tumor typically responds well to vincristine sulfate chemotherapy, although there are cases of resistance to the drug correlated with the tumoral phenotype. We describe herein a genital mixed TVTC case with metastases at spleen and failure at vincristine sulfate chemotherapeutic treatment in a five years old Australian Cattle Dog female. After the cytological, histological and cytogenetic diagnostic, the primary tumor was still characterized in progression phase and showed low major histocompatibility complex expression MHC (4,4 ± 2% class I e 11 ± 4,1% class II. The dog underwent therapeutic splenectomy and ovariohysterectomy and did not present tumor recurrence within 12 months of clinical follow-up., O Tumor Venéreo Transmissível Canino (TVTC) é uma neoplasia de células redondas que tem a particularidade de se implantar em mucosas que tenham perdido a sua integridade. Nesse local o tumor prolifera e ocasionalmente origina metástase. Em geral, o tumor responde ao tratamento com sulfato de vincristina, porém a resistência quimioterápica associada ao fenótipo tumoral tem sido documentada. Objetivou-se relatar um caso de TVTC genital de fenótipo citológico misto com metástase esplênica e o insucesso da quimioterapia com sulfato de vincristina, em uma fêmea canina, da raça Australian Cattle Dog, de cinco anos de idade. Após diagnóstico citológico e histológico, o tumor primário foi ainda caracterizado em fase de progressão e mostrou baixa expressão de moléculas do complexo principal de histocompatibilidade MHC (4,4 ± 2% classe I e 11 ± 4,1% classe II). A cadela foi submetida à ovariohisterectomia e esplenectomia terapêutica e não apresentou recidiva do tumor após 12 meses de acompanhamento clínico., O Tumor Venéreo Transmissível Canino (TVTC) é uma neoplasia de células redondas que tem a particularidade de se implantar em mucosas que tenham perdido a sua integridade. Nesse local o tumor prolifera e ocasionalmente origina metástase. Em geral, o tumor responde ao tratamento com sulfato de vincristina, porém a resistência quimioterápica associada ao fenótipo tumoral tem sido documentada. Objetivou-se relatar um caso de TVTC genital de fenótipo citológico misto com metástase esplênica e o insucesso da quimioterapia com sulfato de vincristina, em uma fêmea canina, da raça Australian Cattle Dog, de cinco anos de idade. Após diagnóstico citológico e histológico, o tumor primário foi ainda caracterizado em fase de progressão e mostrou baixa expressão de moléculas do complexo principal de histocompatibilidade MHC (4,4 ± 2% classe I e 11 ± 4,1% classe II). A cadela foi submetida à ovariohisterectomia e esplenectomia terapêutica e não apresentou recidiva do tumor após 12 meses de acompanhamento clínico.

The canine transmissible venereal tumor is a type of round cell cancer that have the par-ticularity of implanting in mucous tissue, when they lose their integrity, at which point the tumour proliferates and may even develop metastases. The tumor typically responds well to vincristine sulfate chemotherapy, although there are cases of resistance to the drug correlated with the tumoral phenotype. We describe herein a genital mixed TVTC case with metastases at spleen and failure at vincristine sulfate chemotherapeutic treatment in a five years old Australian Cattle Dog female. After the cytological, histological and cytogenetic diagnostic, the primary tumor was still characterized in progression phase and showed low major histocompatibility complex expression MHC (4,4 ± 2% class I e 11 ± 4,1% class II. The dog underwent therapeutic splenectomy and ovariohysterectomy and did not present tumor recurrence within 12 months of clinical follow-up., O Tumor Venéreo Transmissível Canino (TVTC) é uma neoplasia de células redondas que tem a particularidade de se implantar em mucosas que tenham perdido a sua integridade. Nesse local o tumor prolifera e ocasionalmente origina metástase. Em geral, o tumor responde ao tratamento com sulfato de vincristina, porém a resistência quimioterápica associada ao fenótipo tumoral tem sido documentada. Objetivou-se relatar um caso de TVTC genital de fenótipo citológico misto com metástase esplênica e o insucesso da quimioterapia com sulfato de vincristina, em uma fêmea canina, da raça Australian Cattle Dog, de cinco anos de idade. Após diagnóstico citológico e histológico, o tumor primário foi ainda caracterizado em fase de progressão e mostrou baixa expressão de moléculas do complexo principal de histocompatibilidade (MHC) (4,4 ± 2% classe I e 11 ± 4,1% classe II). A cadela foi submetida à ovariohisterectomia e esplenectomia terapêutica e não apresentou recidiva do tumor após 12 meses de acompanhamento clínico.

This article contains a morphological description of a case of early presentation lymphoma in a lamb, characterised by its unusual clinical history and advanced lesions. The primary tumour was located in the skin in the carpal region, and metastases were observed in the brain, right eye, all the pulmonary lobes, the myocardium and endocardium of the heart, left adrenal gland, abdominal portion of the vagal nerve, serosa of the rumen, the body of lumbar vertebra L3, and the submandibular, mediastinal and mesenteric lymph nodes. Histopathological examination revealed that it was a large cell lymphoma. Immunohistochemical analysis was carried out with antibodies for MUM1/IRF4, CD79a, CD3, CD10 and Ki67, used here for the first time as markers to characterise a lymphoma in this species. The result revealed that it was a B-cell lymphoma., Resumo Neste artigo descreve-se morfologicamente um caso de linfoma de apresentação precoce na espécie ovina, caracterizado pela historia clínica incomum e as lesões avançadas. O tumor primário foi encontrado na pele do carpo e metástase foi observada no cérebro, olho direito, todos os lobos pulmonares, miocárdio e endocárdio do coração, a glándula adrenal esquerda, nervo vago na porção abdominal, a serosa do rúmen, o corpo vertebral lombar L3, linfonodos submandibulares, mediastinos e mesentéricos. O exame histopatológico revelou linfoma não-Hodgkin de células grandes. A análise imuno-histoquímica foi realizada com anticorpos para MUM-1/IRF-4, CD79a, CD3, CD10 e Ki-67, os quais usaram-se por primeira vez como marcadores para caracterizar um linfoma nessa espécie. O resultado revelou que se tratou de linfoma de células-B., Resumen En este artículo se describe morfológicamente un caso de linfoma de presentación temprana en la especie ovina, el cual se caracterizó por lo inusual de su historia clínica y lo avanzado de las lesiones. El tumor primario se localizó en la piel del carpo y se observaron metástasis en el cerebro, el ojo derecho, todos los lóbulos pulmonares, el miocardio y endocardio del corazón, la glándula adrenal izquierda, el nervio vago en su porción abdominal, la serosa del rumen, el cuerpo vertebral lumbar L3, los linfonodos submandibulares, mediastínicos y mesentéricos. El examen histopatológico reveló un linfoma no Hodgkin de células grandes. El análisis inmunohistoquímico se realizó con anticuerpos para MUM-1/IRF-4, CD79a, CD3, CD10 y Ki-67, los cuales se usaron por primera vez como marcadores para caracterizar un linfoma en esta especie. El resultado reveló que se trató de un linfoma de células-B.

The canine transmissible venereal tumor is a type of round cell cancer that have the par-ticularity of implanting in mucous tissue, when they lose their integrity, at which point the tumour proliferates and may even develop metastases. The tumor typically responds well to vincristine sulfate chemotherapy, although there are cases of resistance to the drug correlated with the tumoral phenotype. We describe herein a genital mixed TVTC case with metastases at spleen and failure at vincristine sulfate chemotherapeutic treatment in a five years old Australian Cattle Dog female. After the cytological, histological and cytogenetic diagnostic, the primary tumor was still characterized in progression phase and showed low major histocompatibility complex expression MHC (4,4 ± 2% class I e 11 ± 4,1% class II. The dog underwent therapeutic splenectomy and ovariohysterectomy and did not present tumor recurrence within 12 months of clinical follow-up., O Tumor Venéreo Transmissível Canino (TVTC) é uma neoplasia de células redondas que tem a particularidade de se implantar em mucosas que tenham perdido a sua integridade. Nesse local o tumor prolifera e ocasionalmente origina metástase. Em geral, o tumor responde ao tratamento com sulfato de vincristina, porém a resistência quimioterápica associada ao fenótipo tumoral tem sido documentada. Objetivou-se relatar um caso de TVTC genital de fenótipo citológico misto com metástase esplênica e o insucesso da quimioterapia com sulfato de vincristina, em uma fêmea canina, da raça Australian Cattle Dog, de cinco anos de idade. Após diagnóstico citológico e histológico, o tumor primário foi ainda caracterizado em fase de progressão e mostrou baixa expressão de moléculas do complexo principal de histocompatibilidade (MHC) (4,4 ± 2% classe I e 11 ± 4,1% classe II). A cadela foi submetida à ovariohisterectomia e esplenectomia terapêutica e não apresentou recidiva do tumor após 12 meses de acompanhamento clínico.

This article contains a morphological description of a case of early presentation lymphoma in a lamb, characterised by its unusual clinical history and advanced lesions. The primary tumour was located in the skin in the carpal region, and metastases were observed in the brain, right eye, all the pulmonary lobes, the myocardium and endocardium of the heart, left adrenal gland, abdominal portion of the vagal nerve, serosa of the rumen, the body of lumbar vertebra L3, and the submandibular, mediastinal and mesenteric lymph nodes. Histopathological examination revealed that it was a large cell lymphoma. Immunohistochemical analysis was carried out with antibodies for MUM1/IRF4, CD79a, CD3, CD10 and Ki67, used here for the first time as markers to characterise a lymphoma in this species. The result revealed that it was a B-cell lymphoma., Resumo Neste artigo descreve-se morfologicamente um caso de linfoma de apresentação precoce na espécie ovina, caracterizado pela historia clínica incomum e as lesões avançadas. O tumor primário foi encontrado na pele do carpo e metástase foi observada no cérebro, olho direito, todos os lobos pulmonares, miocárdio e endocárdio do coração, a glándula adrenal esquerda, nervo vago na porção abdominal, a serosa do rúmen, o corpo vertebral lombar L3, linfonodos submandibulares, mediastinos e mesentéricos. O exame histopatológico revelou linfoma não-Hodgkin de células grandes. A análise imuno-histoquímica foi realizada com anticorpos para MUM-1/IRF-4, CD79a, CD3, CD10 e Ki-67, os quais usaram-se por primeira vez como marcadores para caracterizar um linfoma nessa espécie. O resultado revelou que se tratou de linfoma de células-B., Resumen En este artículo se describe morfológicamente un caso de linfoma de presentación temprana en la especie ovina, el cual se caracterizó por lo inusual de su historia clínica y lo avanzado de las lesiones. El tumor primario se localizó en la piel del carpo y se observaron metástasis en el cerebro, el ojo derecho, todos los lóbulos pulmonares, el miocardio y endocardio del corazón, la glándula adrenal izquierda, el nervio vago en su porción abdominal, la serosa del rumen, el cuerpo vertebral lumbar L3, los linfonodos submandibulares, mediastínicos y mesentéricos. El examen histopatológico reveló un linfoma no Hodgkin de células grandes. El análisis inmunohistoquímico se realizó con anticuerpos para MUM-1/IRF-4, CD79a, CD3, CD10 y Ki-67, los cuales se usaron por primera vez como marcadores para caracterizar un linfoma en esta especie. El resultado reveló que se trató de un linfoma de células-B.

[no abstract]

Metastatic disease is by far the most common malignant liver tumors. The liver is a fertile ground for metastases that spread via blood circulation and although some primary histotypes are more frequent, metastases may develop virtually from any organ. In recent decades, the improvement of chemotherapy drugs and new surgical technologies have significantly improved the prognosis of patients with liver metastases. The chapter aims to give an overview about the development and clinical presentation of liver metastases by focusing on the treatment of the latter. Throughout this chapter, we attempt to clarify the mechanism by which liver is a privileged seat of metastases. We also describe some promising current therapies for liver metastases.

Micro-Abstract Breast cancer has a high risk of dissemination during biopsy. Tumor cell displacement rates to the needle tract and sentinel lymph node metastasis rates have previously been reported for different biopsy techniques. We evaluated the effect of preoperative ultrasound-guided core needle biopsy performed with different needle sizes on the rate of sentinel lymph node metastases in patients with breast cancer.

Le neuroblastome est une tumeur maligne fréquente du jeune enfant. De nombreuses voies de recherches thérapeutiques sont en cours d’étude, que ce soit au niveau angiogénique, génétique ou immunologique. Malgré cela, le pronostic des neuroblastomes de haut grade reste très mauvais. L’accès à de nouvelles voies de thérapies, risque de provoquer de nouveaux effets secondaires mais aussi de nouvelles localisations lors des rechutes. Nous rapportons ici le cas d’un jeune garçon qui durant ses traitements a présenté une rechute inhabituelle sous forme de métastase cérébrale. Les thérapeutiques actuelles ont peu d’effet sur le système nerveux central et influencent probablement le mode de rechute actuel des neuroblastomes. Il est donc primordial de développer en sus des protocoles de suivi spécifiques pour ces patients, des nouvelles thérapies tenant compte des potentiels sites de récidive comme le cerveau, Neuroblastoma is a common malignant tumor in young children. Several therapeutic researches are ongoing, whether at the angiogenic, genetic, or immunological level. Nevertheless, the prognosis of high-grade neuroblastoma remains very poor. Using new therapeutic modalities poses the risk of new side-effects, along with new relapse locations. We report the case of a young boy who presented brain metastasis during treatment, an uncommon relapse feature. The current treatments that have little effect on the central nervous system may likely change the well-known pattern of neuroblastoma relapses. It is essential to develop specific follow-up protocols for these patients, along with new therapies targeting this metastasis site.

Hemangiosarcoma (HSA) is a type of cancer that has different clinical presentations and therefore different effects, since, depending on each case, different treatment options will exist. While in the case of cutaneous HSA the first line of treatment is always surgical removal of the tumor, metastatic foci should be sought and then perform chemotherapy, despite them having a low metastatic potential. Moreover, the low survival that exists in this type of cancer is a factor that should be communicated to those responsible for the pets, so that, with all available information, they can make a free and informed choice about the treatment they want for their pet, considering the financial commitment, survival time and quality of life associated with chemotherapy. This article describes the clinical case of a female greyhound dog of eight years of age that was brought to consultation for a skin tumor on the right hind limb in the distal tibia. She was diagnosed with noninvasive cutaneous HSA through histopathology, reason why the owners chose not to do the chemotherapy; however, 10 months later she presented recurrent skin lesions and a popliteal lymph node corresponding to hemangiosarcoma and hemangioma respectively, and three weeks later the patient developed cardiac tamponade due to a cardiac mass with associated spill, which resulted in her euthanasia., O hemangiossarcoma (HSA) é um tipo de câncer que tem diferentes apresentações clínicas e, portanto, diferentes consequências, já que, dependendo de cada caso, existirão diferentes opções terapêuticas. Se bem no caso do HSA cutâneo a primeira linha de tratamento sempre é a extração cirúrgica do tumor, se devem procurar focos metastáticos e depois realizar quimioterapia, apesar de ter potencial metastático baixo. Por outra parte, a baixa sobrevivência que existe neste tipo de neoplasia é um fator que se deve informar aos responsáveis das mascotes, para que assim, com toda a informação disponível, possam tomar uma decisão livre e informada sobre o tratamento que desejam para sua mascote, considerando o compromisso financeiro, o tempo de sobrevivência e a qualidade de vida associada à quimioterapia. Este artigo descreve o caso clínico de uma fêmea canina de raça galgo de 8 anos de idade, que foi levada à consulta por causa um tumor cutâneo no membro posterior direito na tíbia distal. Foi diagnosticada com HSA cutâneo não invasivo mediante histopatológica, razão pela qual os proprietários optaram por não realizar tratamento de quimioterapia; no entanto, 10 meses depois apresentou lesões recorrentes na pele e em um linfonodo poplíteo correspondentes a hemangiossarcoma e hemangioma respectivamente, e três semanas depois a paciente apresentou tamponamento cardíaco por uma massa cardíaca com derrame associado, o que levou à sua eutanásia., El hemangiosarcoma (HSA) es un tipo de cáncer que tiene diferentes presentaciones clínicas y, por ende, diferentes consecuencias, ya que, dependiendo de cada caso, existirán distintas opciones terapéuticas. Si bien en el caso del HSA cutáneo la primera línea de tratamiento siempre es la extracción quirúrgica del tumor, se deben buscar focos metástasicos y luego realizar quimioterapia, a pesar de tener potencial metastásico bajo. Por otra parte, la baja supervivencia que existe en este tipo de neoplasia es un factor que se debe informar a los responsables de las mascotas, para que así, con toda la información disponible, puedan tomar una decisión libre e informada sobre el tratamiento que desean para su mascota, considerando el compromiso financiero, el tiempo de supervivencia y la calidad de vida asociada a la quimioterapia. Este artículo describe el caso clínico de una hembra canina de raza galgo de 8 años de edad, que fue presentada a consulta por un tumor cutáneo en el miembro posterior derecho en la tibia distal. Fue diagnosticada con HSA cutáneo no invasivo mediante histopatología, razón por la cual los propietarios optaron por no hacer quimioterapia; sin embargo, 10 meses después presentó lesiones recurrentes en piel y en un linfonodo poplíteo correspondientes a hemangiosarcoma y hemangioma respectivamente, y tres semanas después la paciente presentó tamponamiento cardiaco por una masa cardiaca con derrame asociado, lo que desencadenó su eutanasia.

With the improvement of techniques in liver surgery, indications to hepatic resections have been extended in the last decades to liver metastases secondary to non-colorectal, non-neuroendocrine tumors. Here we describe the results about the outcome of patients who underwent liver resection for metastases from lung cancer. Metastatic lung cancer has a poor prognosis when associated to diffuse disease. However when liver oligometastases are detected after the resection of primary tumor and no extrahepatic disease is present, the prognosis can improve if the metastases can be completely removed. In such cases a specialized hepatobiliary center, which can assess the resectability of the tumor, should evaluate the patients. The cases reported in the last decade had a more favorable outcome, which can be explained by the combination of better diagnostic imaging, a better understanding of the disease biology, and progresses in hepatobiliary surgery.

Hemangiosarcoma (HSA) is a type of cancer that has different clinical presentations and therefore different effects, since, depending on each case, different treatment options will exist. While in the case of cutaneous HSA the first line of treatment is always surgical removal of the tumor, metastatic foci should be sought and then perform chemotherapy, despite them having a low metastatic potential. Moreover, the low survival that exists in this type of cancer is a factor that should be communicated to those responsible for the pets, so that, with all available information, they can make a free and informed choice about the treatment they want for their pet, considering the financial commitment, survival time and quality of life associated with chemotherapy. This article describes the clinical case of a female greyhound dog of eight years of age that was brought to consultation for a skin tumor on the right hind limb in the distal tibia. She was diagnosed with noninvasive cutaneous HSA through histopathology, reason why the owners chose not to do the chemotherapy; however, 10 months later she presented recurrent skin lesions and a popliteal lymph node corresponding to hemangiosarcoma and hemangioma respectively, and three weeks later the patient developed cardiac tamponade due to a cardiac mass with associated spill, which resulted in her euthanasia., O hemangiossarcoma (HSA) é um tipo de câncer que tem diferentes apresentações clínicas e, portanto, diferentes consequências, já que, dependendo de cada caso, existirão diferentes opções terapêuticas. Se bem no caso do HSA cutâneo a primeira linha de tratamento sempre é a extração cirúrgica do tumor, se devem procurar focos metastáticos e depois realizar quimioterapia, apesar de ter potencial metastático baixo. Por outra parte, a baixa sobrevivência que existe neste tipo de neoplasia é um fator que se deve informar aos responsáveis das mascotes, para que assim, com toda a informação disponível, possam tomar uma decisão livre e informada sobre o tratamento que desejam para sua mascote, considerando o compromisso financeiro, o tempo de sobrevivência e a qualidade de vida associada à quimioterapia. Este artigo descreve o caso clínico de uma fêmea canina de raça galgo de 8 anos de idade, que foi levada à consulta por causa um tumor cutâneo no membro posterior direito na tíbia distal. Foi diagnosticada com HSA cutâneo não invasivo mediante histopatológica, razão pela qual os proprietários optaram por não realizar tratamento de quimioterapia; no entanto, 10 meses depois apresentou lesões recorrentes na pele e em um linfonodo poplíteo correspondentes a hemangiossarcoma e hemangioma respectivamente, e três semanas depois a paciente apresentou tamponamento cardíaco por uma massa cardíaca com derrame associado, o que levou à sua eutanásia., El hemangiosarcoma (HSA) es un tipo de cáncer que tiene diferentes presentaciones clínicas y, por ende, diferentes consecuencias, ya que, dependiendo de cada caso, existirán distintas opciones terapéuticas. Si bien en el caso del HSA cutáneo la primera línea de tratamiento siempre es la extracción quirúrgica del tumor, se deben buscar focos metástasicos y luego realizar quimioterapia, a pesar de tener potencial metastásico bajo. Por otra parte, la baja supervivencia que existe en este tipo de neoplasia es un factor que se debe informar a los responsables de las mascotas, para que así, con toda la información disponible, puedan tomar una decisión libre e informada sobre el tratamiento que desean para su mascota, considerando el compromiso financiero, el tiempo de supervivencia y la calidad de vida asociada a la quimioterapia. Este artículo describe el caso clínico de una hembra canina de raza galgo de 8 años de edad, que fue presentada a consulta por un tumor cutáneo en el miembro posterior derecho en la tibia distal. Fue diagnosticada con HSA cutáneo no invasivo mediante histopatología, razón por la cual los propietarios optaron por no hacer quimioterapia; sin embargo, 10 meses después presentó lesiones recurrentes en piel y en un linfonodo poplíteo correspondientes a hemangiosarcoma y hemangioma respectivamente, y tres semanas después la paciente presentó tamponamiento cardiaco por una masa cardiaca con derrame asociado, lo que desencadenó su eutanasia.

Der Hedgehog-Signalweg reguliert in Säugern während der frühen Embryogenese die Form- und Musterbildung, Polarität und Morphogenese von vielen Organen und Geweben. In den meisten adulten Geweben ist der Signalweg anschließend gedämpft, kann aber durch Verletzungen reaktiviert werden und fördert die Heilung und Regeneration. Eine abberante Aktivität des Hedgehog-Signalwegs in zahlreichen humanen Tumoren verdeutlicht seine wichtige Rolle in der Karzinogenese. In Drosophila melanogaster ist dfu an der Fortleitung des Hedgehog-Signals unterhalb des Rezeptors smoothened beteiligt und notwendiger Bestandteil für die Aktivierung des Transkriptionsfaktors ci. Im humanen Hedgehog-Signalweg scheint die Funktion nicht vollständig konserviert zu sein. Hier sollte nun die Rolle der STK36 im humanen Hedgehog-Signalweg aufgeklärt werden und die Kinase als ein mögliches therapeutisches Ziel in vitro und in vivo validiert werden. Im Rahmen dieser Arbeit konnte gezeigt werden, dass STK36 am humanen Hedgehog-Signalweg beteiligt ist. Eine Überexpression von STK36 korreliert positiv mit der Überexpression des Transkriptionsaktivators GLI1 und folglich mit der abberanten Aktivität des Signalwegs in Patientenproben des Pankreaskarzinoms und Ovarialkarzinoms. In Zelllinien des Pankreaskarzinoms und des malignen Melanoms konnte STK36 sowohl auf Protein- als auch auf mRNA-Ebene nachgewiesen werden. Die Herunterregulierung von STK36 in diesen Zelllinien verringert die Expression der Transkriptionsfaktoren des Signalwegs GLI2 und GLI3 und beeinflusst die Expression von Hedgehog-Zielgenen. So kann die Proliferation von Tumorzellen des Pankreaskarzinoms und des malignen Melanoms durch Herunterregulierung von STK36 verringert werden. Die Hemmung des klassischen Hedgehog-Signalwegs durch SMO-Inhibitoren führt ebenso zu einer Proliferationsverringerung. Die Migration von Tumorzellen wird nicht über den klassischen, sondern über den alternativen Hedgehog-Signalweg gesteuert. Eine Behandlung der Tumo, In mammals Hedgehog Signaling regulates tissue patterning, polarity and morphogenesis of many organs and tissues in early embryogenesis. In most adult tissues Hedgehog Signaling is downregulated but may be activated by lesions and promotes regeneration. Abberant pathway activation in numerous human tumors illustrates its central role in carcinogenesis. In Drosophila melanogaster dfu is involved in the transmission of Hedgehog signaling downstream of the receptor smoothened and essential for the activation of the transcriptional activator ci. In humans function of Hedgehog Signaling seems to have not been completely conserved. This thesis should clarify the role of STK36 in human Hedgehog Signaling and validate STK36 as a potential therapeutic target both in vitro and in vivo. In the scope of this work it was found that STK36 is a part of the human Hedgehog signaling pathway. Overexpression of STK36 correlates positively with the overexpression of the transcription factor GLI1 and therefor with the abberant activity of this pathway in samples from patients with pancreatic and ovarian carcinoma. In cell lines of pancreatic cancer and malignant melanoma STK36 has been detected on RNA and protein level. In these cell lines downregulation of STK36 decreases the expression of the transcription factors GLI2 and GLI3 and affects the expression of Hedgehog target genes. In this way the proliferation of pancreatic and melanoma cancer cells can be reduced by downregulation of STK36. Inhibition of canonical Hedgehog Signaling by SMO-Inhibitors also reduces proliferation, but the migration of cancer cells is regulated by non-canonical Hedgehog Signaling. The treatment of tumor cells with ligand binding antibody a-SHH 5E1 and the downregulation of STK36 leads to deceleration of migration rate whereby inhibition of the canonical pathway does not show any impact. Downregulation of STK36 reduced tumor growth in vivo and increased necrosis in the center of the tumor. In addition diff

Metastatic spread is the leading cause of death of solid tumours. Especially patients with metastasis show dramatically reduced LysoPC plasma levels. In previous studies the pre-treatment of murine melanoma cells (B16.F10) with saturated Lysophosphatidylcholine (LysoPC) resulted in strongly reduced settlement in an in vivo lung metastasis model in mice, by influencing tumour cell adhesion and tumour cell motility. For a better understanding of the mechanisms responsible for these anti-metastatic effects, the interactions of several different tumour cell lines with defined LysoPC-species (saturated and mono-unsaturated) were explored. All investigated epithelial solid tumour cells show an extremely fast degradation of LysoPC to free fatty acids (FFA) and glycerophosphocholine. Since LysoPC diffuses much faster into tissues than FFA, LysoPC might serve as a carrier for fatty acids (FA) towards tumour tissues, where it is rapidly hydrolysed outside the tumour cells thus establishing a high extracellular FFA concentration in the tumour cell environment. Subsequently, FFA are incorporated into the tumour cells due to the established concentration gradient. An increase of the via LysoPC delivered FA is observed followed by an enormous increase of cellular triglycerides (TG). The increase of TG also causes the formation of lipid droplets (LD), which play a pivotal role in cell signalling, carrying enzymes involved in the inflammatory eicosanoid synthesis. The increase of non-n-6-FA in the LD is assumed to reduce the biosynthesis of inflammatory eicosanoids. Furthermore, due to treating cells with saturated as well as mono-unsaturated (n-9) LysoPC, the cell membrane rigidity is increased by reducing the ratio of higher unsaturated FA in the cell membranes with consequences on cellular function. The investigation of the metastatic potential of B16.F10 tumour cells pre-treated with saturated and mono-unsaturated LysoPC-species, respectively, in a mouse model shows that both L, Metastasierung ist der Hauptgrund für die hohe Sterblichkeit bei Patienten mit soliden Tumoren. Insbesondere Patienten mit Metastasen haben deutlich reduzierte Lysophosphatidylcholin (LysoPC) Spiegel im Plasma. In vorangegangenen Untersuchungen konnte die Vorbehandlung von murinen Melanomzellen (B16.F10) mit gesättigtem LysoPC die Ansiedlung dieser Tumorzellen in einem Lungenmetastasen-Modell in Mäusen durch die Beeinflussung der Zelladhäsion und motilität deutlich reduzieren. Um die Mechanismen, die diesen anti-metastatischen Effekt hervorrufen, besser zu verstehen, wurden die Interaktionen von verschiedenen Tumorzelllinien mit bestimmten LysoPC-Spezies (gesättigt und ungesättigt) genauer untersucht. Alle analysierten epithelialen, soliden Tumorzellen bauen LysoPC extrem schnell zu freier Fettsäure (FFS) und Glycerophosphocholin ab. Da LysoPC sehr viel schneller ins Gewebe diffundieren kann als FFS, dient LysoPC dem Tumorgewebe wahrscheinlich als Fettsäure (FS)-Lieferant, wo es außerhalb der Tumorzellen rasch hydrolysiert wird und somit eine hohe Konzentration an FFS in der Umgebung der Tumorzellen entsteht. Daran anschließend werden die FFS dem Konzentrationsgefälle folgend in die Tumorzellen aufgenommen. Der Anteil der durch LysoPC zugeführten Fettsäure steigt stark an und es wird ein deutlicher Anstieg an zellulären Triglyceriden (TG) beobachtet. Die Zunahme an TG hat die Bildung von Lipid droplets (LD) zur Folge, welche wiederum eine zentrale Rolle bei zellulären Signalprozessen einnehmen. Sie sind mit Enzymen assoziiert, die an der Entstehung von entzündungsfördernden Eicosanoiden aus n -6-Fettsäuren beteiligt sind, deren Anteil nach der Behandlung mit LysoPC reduziert ist. Darüber hinaus hat durch die Behandlung der Zellen mit gesättigten und einfach-ungesättigten (n-9) LysoPC-Spezies die Zellmembran-Rigidität zugenommen, da der Anteil an mehrfach ungesättigten FS in den Zellmembranen reduziert wird, was auch Konsequenzen für zelluläre Funktionen hat. Untersu

MACC1 wurde als prognostischer Biomarker für die Tumorprogression und das Metastasen-freie Überleben im KRK sowie in anderen soliden Tumoren beschrieben. Das Gen induziert Zellmotilität und Proliferation in Zellkultur sowie die Metastasierung im Mausmodell. Damit stellt MACC1 ein vielversprechendes Ziel für die Intervention bei Tumorprogression und –metastasierung und damit für die Behandlung von KRK-Patienten dar. Unser Ziel war es, die Transkription von MACC1 zu inhibieren. Hierfür identifizierten wir zunächst die Promoter-Region von MACC1 und untersuchten MACC1s transkriptionelles Regulationsnetzwerk. Durch ortsgerichtete Mutagenese, Chromatin Immunopräzipitation und Electrophoretic Mobility Shift Assay ermittelten wir, dass Transkriptionsfaktoren wie Ap-1, Sp1, C/EBPs und GIPC1 an den MACC1-Promoter binden und die Transkription des MACC1-Gens kontrollieren. Darüberhinaus konnten wir durch Hochdurchsatz-Screening die bisher ersten Inhibitoren gegen MACC1 identifizieren: Rottlerin und Lovastatin. Wir zeigten, dass diese spezifisch auf den endogenen MACC1-Promoter wirken, was eine zeit- und konzentrationsabhängige Reduktion der MACC1-Expression zur Folge hatte. Beide Inhibitoren begrenzten das Expressionsniveau von Sp1 und interferierten mit der Bindung von c-Jun mit dem MACC1-Promoter, was in einer Inhibition der MACC1-Transkription resultierte. Ferner führte die tägliche Behandlung von Xenograft-Mausmodellen mit Rottlerin zu einer Inhibition der MACC1-Expression im Primärtumor und einer damit einhergehenden Begrenzung des Tumorwachstums. Zusammenfassend lässt sich festhalten, dass in der vorliegenden Arbeit zum ersten Mal der MACC1-Promoter und seine transkriptionelle Regulation beleuchtet wurden. Die neuen Erkenntnisse wurden zur Identifizierung der ersten Inhibitoren gegen MACC1 genutzt. Zur Behandlung von KRK-Patienten mit einem hohen Risiko für MACC1-induzierte Metastasierung könnten diese Inhibitoren Potential für die klinische Anwendung beherbergen., MACC1 has been reported as a prognostic biomarker for tumor progression and metastasis-free survival in CRC along with other solid tumors. It induces cell motility and proliferation in cell culture and metastasis in mouse models. Consequently, targeting MACC1 to intervene in tumor progression and metastasis formation holds a promising approach to treat CRC patients. We designed a strategy to inhibit MACC1 via targeting its transcription. We first identified MACC1 gene promoter by creating various promoter-luciferase constructs. We then established that transcription factors such as Ap-1, Sp1, C/EBPs and GIPC1 bind to the MACC1 promoter and govern MACC1 transcription, expression and thus motility in vitro and in CRC patients. Using a high throughput screening targeting the MACC1 promoter, we identified small molecule MACC1 inhibitors, Rottlerin and Lovastatin. These inhibitors specifically restricted endogenous MACC1 promoter leading to reduced MACC1 expression in a time- and concentration-dependent manner. In vitro functional assays demonstrated the impact of the small molecule inhibitors on retarding cell proliferation and motility. Both inhibitors restricted Sp1 levels and interfered with the binding of c-Jun to the MACC1 promoter, thereby inhibiting MACC1 transcription. The study further described the effect of Rottlerin on a CRC-xenografted mouse model. Daily treatment of xenografted mice with Rottlerin resulted in the inhibition of MACC1 expression in the primary tumor accompanied with the restricted tumor growth. To summarize, this is the first study unraveling the MACC1 promoter, its transcriptional regulation and identification of newly identified MACC1 inhibitors. In clinical settings, inhibition of MACC1 expression using these inhibitors might provide immense potential for the treatment of CRC patients who are at high risk for MACC1-induced metastasis linked to shorter survival.

MACC1 wurde als prognostischer Biomarker für die Tumorprogression und das Metastasen-freie Überleben im KRK sowie in anderen soliden Tumoren beschrieben. Das Gen induziert Zellmotilität und Proliferation in Zellkultur sowie die Metastasierung im Mausmodell. Damit stellt MACC1 ein vielversprechendes Ziel für die Intervention bei Tumorprogression und –metastasierung und damit für die Behandlung von KRK-Patienten dar. Unser Ziel war es, die Transkription von MACC1 zu inhibieren. Hierfür identifizierten wir zunächst die Promoter-Region von MACC1 und untersuchten MACC1s transkriptionelles Regulationsnetzwerk. Durch ortsgerichtete Mutagenese, Chromatin Immunopräzipitation und Electrophoretic Mobility Shift Assay ermittelten wir, dass Transkriptionsfaktoren wie Ap-1, Sp1, C/EBPs und GIPC1 an den MACC1-Promoter binden und die Transkription des MACC1-Gens kontrollieren. Darüberhinaus konnten wir durch Hochdurchsatz-Screening die bisher ersten Inhibitoren gegen MACC1 identifizieren: Rottlerin und Lovastatin. Wir zeigten, dass diese spezifisch auf den endogenen MACC1-Promoter wirken, was eine zeit- und konzentrationsabhängige Reduktion der MACC1-Expression zur Folge hatte. Beide Inhibitoren begrenzten das Expressionsniveau von Sp1 und interferierten mit der Bindung von c-Jun mit dem MACC1-Promoter, was in einer Inhibition der MACC1-Transkription resultierte. Ferner führte die tägliche Behandlung von Xenograft-Mausmodellen mit Rottlerin zu einer Inhibition der MACC1-Expression im Primärtumor und einer damit einhergehenden Begrenzung des Tumorwachstums. Zusammenfassend lässt sich festhalten, dass in der vorliegenden Arbeit zum ersten Mal der MACC1-Promoter und seine transkriptionelle Regulation beleuchtet wurden. Die neuen Erkenntnisse wurden zur Identifizierung der ersten Inhibitoren gegen MACC1 genutzt. Zur Behandlung von KRK-Patienten mit einem hohen Risiko für MACC1-induzierte Metastasierung könnten diese Inhibitoren Potential für die klinische Anwendung beherbergen., MACC1 has been reported as a prognostic biomarker for tumor progression and metastasis-free survival in CRC along with other solid tumors. It induces cell motility and proliferation in cell culture and metastasis in mouse models. Consequently, targeting MACC1 to intervene in tumor progression and metastasis formation holds a promising approach to treat CRC patients. We designed a strategy to inhibit MACC1 via targeting its transcription. We first identified MACC1 gene promoter by creating various promoter-luciferase constructs. We then established that transcription factors such as Ap-1, Sp1, C/EBPs and GIPC1 bind to the MACC1 promoter and govern MACC1 transcription, expression and thus motility in vitro and in CRC patients. Using a high throughput screening targeting the MACC1 promoter, we identified small molecule MACC1 inhibitors, Rottlerin and Lovastatin. These inhibitors specifically restricted endogenous MACC1 promoter leading to reduced MACC1 expression in a time- and concentration-dependent manner. In vitro functional assays demonstrated the impact of the small molecule inhibitors on retarding cell proliferation and motility. Both inhibitors restricted Sp1 levels and interfered with the binding of c-Jun to the MACC1 promoter, thereby inhibiting MACC1 transcription. The study further described the effect of Rottlerin on a CRC-xenografted mouse model. Daily treatment of xenografted mice with Rottlerin resulted in the inhibition of MACC1 expression in the primary tumor accompanied with the restricted tumor growth. To summarize, this is the first study unraveling the MACC1 promoter, its transcriptional regulation and identification of newly identified MACC1 inhibitors. In clinical settings, inhibition of MACC1 expression using these inhibitors might provide immense potential for the treatment of CRC patients who are at high risk for MACC1-induced metastasis linked to shorter survival.

A neoplasia da glândula mamária é o segundo tumor mais frequente em cães, embora, nas cadelas seja o mais comumente encontrado. Estima-se que a incidência de malignidade de neoplasias mamárias no Brasil seja de 68,4% a 73,4%. Nesse sentido, todo o aumento de volume do tecido mamário deve ser avaliado para possível diagnóstico de neoplasias, observando-se a coloração da pele, a presença de lesões, secreções e o tamanho das mamas. A citologia por aspiração com agulha fina (CAAF) pode indicar se a formação é ou não neoplásica, porém nem sempre é fácil a interpretação. Contudo, salienta-se sua importância na distinção entre processos inflamatórios, hiperplásicos e neoplásicos, o estabelecimento do prognóstico do tumor e a identificação de locais de metástase, com vista à rápida ação no tratamento e monitorização de possíveis recidivas locais. Na literatura veterinária, quando se avaliam as duas técnicas, os resultados demonstram que a histopatologia permite um diagnóstico mais definitivo por proporcionar uma visão de conjunto, onde a arquitetura tecidual está completa.

Chacur M.G.M., Agostinho B.F., Pessoa V.M. & Yamasaki L.P. [Clinical and laboratory evaluation of squamous cell carcinoma of the prepuce with the invasion of the spinal cord in a horse. A case report.] Avalia- ção clínica e laboratorial do carcinoma das células escamosas no prepúcio com invasão da coluna vertebral em equino. Relato de Caso. Revista Brasileira de Medicina Veterinária, 36(1):24-28, 2014. Departamento de Clínicas e Reprodução Animal, Universidade do Oeste Paulista, Rod. Raposo Tavares, Km 572, Campus II, Presidente Prudente, SP 19067-175, Brasil. E-mail: chacur@unoeste.br The squamous cell carcinoma is a malignant tumor that originates in the epidermal layer skin from the differentiation of keratinocytes. It has high incidence in dogs, cats, horses and cattle. Horses often occur in mucocutaneous junctions, areas like penis and foreskin are the most affected. The incidence is higher in castrated equines with more than 16 years old. This case describes a castrated crossbred horse, actually with 7 years old. The animal presented a mass in foreskin region with evolution of three months. Diagnosed as squamous cell carcinoma by aspirative cytology and biopsy. Surgical tumor mass excision was chosen as treatment. Two months after surgery there was local recurrence of tumor. Euthanasia was performed and a necropsy later in which was found the tumor invaded the adjacent musculature extending from the spine in sacral region between vertebres S1 and S2. Therefore is important to perform tests such as aspirative cytology and biopsy to diagnosis of squamous cell carcinoma. To prognosis the presence of metastasis must be investigate., O carcinoma de células escamosas é uma neoplasia maligna que se origina na camada epidérmica da pele a partir da diferenciação de queratinócitos. Apresenta alta incidência em cães, gatos, equinos e bovinos. Nos equinos ocorre com frequência em junções muco cutâneas, sendo a região do pênis e prepúcio a mais acometida. A incidência é maior em equinos machos, não castrados, com idade superior a 16 anos. Descreve-se o caso de um equino mestiço castrado, com idade atual de sete anos. O animal apresentava aumento de volume na região do prepúcio com evolução de três meses, diagnosticado como carcinoma de células escamosas por meio de exame citológico e histopatológico. A excisão cirúrgica da massa tumoral foi preconizada como tratamento. Dois meses após o procedimento cirúrgico, houve recidiva local da neoplasia. Foi realizada a eutanásia do animal e posterior exame necroscópico, no qual foi constatado que a neoplasia invadia a musculatura abdominal estendendo-se até a coluna vertebral na região sacral entre as vértebras S1 e S2. Conclui-se que a realização de exames complementares como a citologia aspirativa por agulha fina (CAAF) e a biópsia são importantes para o diagnóstico do carcinoma das células escamosas. Para o prognóstico a presença de metástases deve ser investigada.

Osteosarcoma is considered the most common bone tumor in dogs, usually affecting the appendicular skeleton of animals adults or seniors with an average age of seven years. The etiology of canine appendicular osteosarcoma remains unknown. Some factors predispose the animals to the emergence of neoplasia, including: size, race and family. The tumor can be classified by macroscopic and radiological features in simple, compound, or pleomorphic. This article is a case report of osteosarcoma of the composite type with metastases in the pericardium, lung, pleura, intercostal muscles, liver and kidney in a dog breed Labrador Retriver. This presents the history of the animal, which together with the necropsy findings and histopathological examination confirmed the cause of death. We conclude that histopathological examination is an important tool for classify tumor depending on the cellular pattern and identifying the presence metastases in the different organs collected., O osteossarcoma é considerado o tumor ósseo mais comum em cães, acometendo principalmente o esqueleto apendicular de animais adultos ou idosos, com idade média de sete anos. A etiologia do osteossarcoma apendicular canino permanece desconhecida. Alguns fatores predispõem os animais ao surgimento da neoplasia, incluindo: tamanho, raça e família. A neoplasia pode ser classificada pelas características macroscópicas e radiológicas em simples, composta ou pleomórfica. O presente artigo é um relato de caso de osteossarcoma do tipo composto com metástases em pericárdio, pulmão, pleura, músculos intercostais, fígado e rim em uma cadela de raça Labrador Retriver. Neste, apresenta o histórico do animal, que em conjunto com os achados necroscópicos e o exame histopatológico confirmaram a causa da morte. Conclui-se que o exame histopatológico é importante para classificar o tumor dependendo do padrão celular e para identificar a presença de metástase nos diferentes órgãos coletados., El osteossarcoma es considerado el tumor óseo más común en perros, afecta principalmente el esqueleto apendicular de animales adultos o seniles, con edad media de siete años. La etiología del osteossarcoma apendicular canino aún permanece desconocida. Algunos factores predisponen al surgimiento de esta neoplasia, tales como: tamaño, raza y familia. La neoplasia puede ser clasificada por las características macroscópicas y radiológicas en simple, compuesta o pleomórfica. El presente artículo es un relato de caso de osteossarcoma de tipo compuesto con metástasis en pericardio, pulmón, pleura, músculos intercostales, hígado y riñones en una perra de raza Labrador Retriver. En este, se describe la historia clínica del animal, que junto con las alteraciones observadas en la necropsia y el examen histopatológico confirmaron la causa de la muerte. Se concluye que el examen histopatológico es importante para clasificar el tumor por su patrón celular e identificar la presencia de metástasis en los diferentes órganos colectados.

Osteosarcoma is considered the most common bone tumor in dogs, usually affecting the appendicular skeleton of animals adults or seniors with an average age of seven years. The etiology of canine appendicular osteosarcoma remains unknown. Some factors predispose the animals to the emergence of neoplasia, including: size, race and family. The tumor can be classified by macroscopic and radiological features in simple, compound, or pleomorphic. This article is a case report of osteosarcoma of the composite type with metastases in the pericardium, lung, pleura, intercostal muscles, liver and kidney in a dog breed Labrador Retriver. This presents the history of the animal, which together with the necropsy findings and histopathological examination confirmed the cause of death. We conclude that histopathological examination is an important tool for classify tumor depending on the cellular pattern and identifying the presence metastases in the different organs collected., O osteossarcoma é considerado o tumor ósseo mais comum em cães, acometendo principalmente o esqueleto apendicular de animais adultos ou idosos, com idade média de sete anos. A etiologia do osteossarcoma apendicular canino permanece desconhecida. Alguns fatores predispõem os animais ao surgimento da neoplasia, incluindo: tamanho, raça e família. A neoplasia pode ser classificada pelas características macroscópicas e radiológicas em simples, composta ou pleomórfica. O presente artigo é um relato de caso de osteossarcoma do tipo composto com metástases em pericárdio, pulmão, pleura, músculos intercostais, fígado e rim em uma cadela de raça Labrador Retriver. Neste, apresenta o histórico do animal, que em conjunto com os achados necroscópicos e o exame histopatológico confirmaram a causa da morte. Conclui-se que o exame histopatológico é importante para classificar o tumor dependendo do padrão celular e para identificar a presença de metástase nos diferentes órgãos coletados., El osteossarcoma es considerado el tumor óseo más común en perros, afecta principalmente el esqueleto apendicular de animales adultos o seniles, con edad media de siete años. La etiología del osteossarcoma apendicular canino aún permanece desconocida. Algunos factores predisponen al surgimiento de esta neoplasia, tales como: tamaño, raza y familia. La neoplasia puede ser clasificada por las características macroscópicas y radiológicas en simple, compuesta o pleomórfica. El presente artículo es un relato de caso de osteossarcoma de tipo compuesto con metástasis en pericardio, pulmón, pleura, músculos intercostales, hígado y riñones en una perra de raza Labrador Retriver. En este, se describe la historia clínica del animal, que junto con las alteraciones observadas en la necropsia y el examen histopatológico confirmaron la causa de la muerte. Se concluye que el examen histopatológico es importante para clasificar el tumor por su patrón celular e identificar la presencia de metástasis en los diferentes órganos colectados.

Osteosarcoma is considered the most common bone tumor in dogs, usually affecting the appendicular skeleton of animals adults or seniors with an average age of seven years. The etiology of canine appendicular osteosarcoma remains unknown. Some factors predispose the animals to the emergence of neoplasia, including: size, race and family. The tumor can be classified by macroscopic and radiological features in simple, compound, or pleomorphic. This article is a case report of osteosarcoma of the composite type with metastases in the pericardium, lung, pleura, intercostal muscles, liver and kidney in a dog breed Labrador Retriver. This presents the history of the animal, which together with the necropsy findings and histopathological examination confirmed the cause of death. We conclude that histopathological examination is an important tool for classify tumor depending on the cellular pattern and identifying the presence metastases in the different organs collected., O osteossarcoma é considerado o tumor ósseo mais comum em cães, acometendo principalmente o esqueleto apendicular de animais adultos ou idosos, com idade média de sete anos. A etiologia do osteossarcoma apendicular canino permanece desconhecida. Alguns fatores predispõem os animais ao surgimento da neoplasia, incluindo: tamanho, raça e família. A neoplasia pode ser classificada pelas características macroscópicas e radiológicas em simples, composta ou pleomórfica. O presente artigo é um relato de caso de osteossarcoma do tipo composto com metástases em pericárdio, pulmão, pleura, músculos intercostais, fígado e rim em uma cadela de raça Labrador Retriver. Neste, apresenta o histórico do animal, que em conjunto com os achados necroscópicos e o exame histopatológico confirmaram a causa da morte. Conclui-se que o exame histopatológico é importante para classificar o tumor dependendo do padrão celular e para identificar a presença de metástase nos diferentes órgãos coletados., El osteossarcoma es considerado el tumor óseo más común en perros, afecta principalmente el esqueleto apendicular de animales adultos o seniles, con edad media de siete años. La etiología del osteossarcoma apendicular canino aún permanece desconocida. Algunos factores predisponen al surgimiento de esta neoplasia, tales como: tamaño, raza y familia. La neoplasia puede ser clasificada por las características macroscópicas y radiológicas en simple, compuesta o pleomórfica. El presente artículo es un relato de caso de osteossarcoma de tipo compuesto con metástasis en pericardio, pulmón, pleura, músculos intercostales, hígado y riñones en una perra de raza Labrador Retriver. En este, se describe la historia clínica del animal, que junto con las alteraciones observadas en la necropsia y el examen histopatológico confirmaron la causa de la muerte. Se concluye que el examen histopatológico es importante para clasificar el tumor por su patrón celular e identificar la presencia de metástasis en los diferentes órganos colectados.

da Silva F.B., Oriá A.P., Moreira E.L.T., Vieira Filho C.H. da C., Barrouin Melo, S.M. & Larangeira, D.F. [Bronchioloalveolar carcinoma in a cat - Case report]. Carcinoma bronquíolo-alveolar em um felino - Relato de caso. Revista Brasileira de Medicina Veterinária, 35(2):193-196, 2013. Departamento de Anatomia, Patologia e Clínicas Veterinárias, Escola de Medicina Veterinária e Zootecnia, Av. Ademar de Barros. 500, Salvador, BA 40170-110, Brasil. E-mail: arianneoria@ufba.br A 12 year old undefined breed feline was presented with signs of dyspnea. The clinical examination findings, laboratory and radiographic evaluations indicated lung cancer. Necropsy and histopathology of the tumor diagnosed bronchioloalveolar carcinoma with tracheobronchial lymph node, intercostal muscles and diaphragm and pericardium metastasis., Um felino, racialmente indefinido, 12 anos de idade, foi atendido com sinais de dispnéia. Os achados do exame clínico, resultados laboratoriais e avaliação radiográfica levaram a suspeita de neoplasia pulmonar. A necropsia e o histopatológico de tumorações observadas diagnosticaram carcinoma bronquíolo-alveolar, com metástase em linfonodo traqueobrônquico, músculos intercostais, diafragma e pericárdio.

Nous présentons un cas de prolactinome malin chez une femme de 81 ans, porteuse d'un macroprolactinome découvert à l'âge de 59 ans, devenu secondairement résistant aux agonistes dopaminergiques. Trois métastases asymptomatiques intracrâniennes ont été diagnostiquées par imagerie cérébrale en 2010. Elle se présente en salle d'urgence six mois plus tard avec des douleurs neuropathiques périnéales gauches et hémifaciales droites. L'imagerie révèle deux nouvelles lésions tumorales, l'une au contact de l'émergence du nerf trijumeau droit, l'autre comprimant la racine S2 gauche. L'origine métastatique de ces deux lésions est évoquée par les antécédents, l'histoire clinique, une majoration de la prolactinémie malgré de fortes doses de cabergoline, et des concentrations très élevées de prolactine dans le liquide céphalo-rachidien. Même en l'absence d'un examen anatomo-pathologique, vu la cohérence clinico-radiologique et les résultats des examens complémentaires, le diagnostic de métastases d'un prolactinome est posé et un essai de traitement par temozolomide est initié. Ce traitement permet déjà d'obtenir une réponse partielle après trois mois avec une diminution de la prolactinémie de 50% et une réduction de la taille des métastases de 20%.

O melanoma é um tumor de elevada malignidade e representa 3% de todos os tipos de cânceres. O melanoma maligno é a causa mais comum de doença metastática envolvendo o trato gastrointestinal, e o intestino delgado é o sítio mais frequentemente envolvido. As manifestações clínicas são inespecíficas, e o quadro de abdome agudo obstrutivo pode ser a primeira manifestação. O artigo refere um caso de um paciente de 36 anos com antecedentes cirúrgicos de melanoma cutâneo ressecado no dorso em 2009. O paciente desenvolveu obstrução intestinal aguda, que à laparotomia, evidenciou intussuscepção intestinal causada por melanoma metastático a 50 cm do ângulo de Treitz. A peça cirúrgica foi enviada para anátomopatológico, que confirmou a presença de melanoma metastático no intestino delgado. O tratamento do melanoma metastático envolve o tratamento sistêmico associado ao tratamento das complicações. Metástases intestinais devem ser consideradas em qualquer paciente que apresente sintomas gastrointestinais e uma história prévia de melanoma e o tratamento cirúrgico deve ser sempre considerado, pois pode, ocasionalmente, resultar em sobrevida longa.

O câncer de pele não-melanoma é a neoplasia maligna mais comum no Brasil. Seu subtipo menos frequente, o carcinoma espinocelular (CEC), pode ser agressivo, mas, na maioria das vezes, é completamente curado por medidas terapêuticas locais. Relatamos o caso de uma mulher de 75 anos que apresentava lesão de 2,5 cm em dorso da mão esquerda diagnosticada como CEC bem diferenciado. Foi submetida à ressecção da lesão com margem cirúrgica de 1,5 cm. Após 75 dias da cirurgia, paciente retornou com linfadenomegalia axilar esquerda. Foi realizada biópsia, que conclui tratar-se de CEC bem diferenciado metastático. O tratamento proposto foi linfadenectomia axilar com radioterapia adjuvante. Paciente evoluiu com recidiva axilar ulcerada e dor intensa, sendo realizada ressecção ampliada da lesão. Foi proposto à paciente desarticulação interescapulotorácica e a paciente concordou com a realização do procedimento. Atualmente, encontra-se em controle ambulatorial, sem sinais de recidiva ou metástases à distância. O caso clínico mostra uma evolução atípica de um CEC bem diferenciado, com lesão primária em dorso da mão esquerda e metástase linfonodal axilar precoce, com comprometimento da qualidade de vida. Optamos pela desarticulação interescapulotorácica devido à presença de um tumor localmente avançado, a não funcionalidade do membro, a possibilidade de melhor higienização local e a ausência de metástases em outros sítios.

In this paper a 14-years-old Colombian native horse is reported, which was submitted by the presence of a mass in the foreskin region (20 x 20 cm) which blocked the passage of urine. Histopathological analysis of the biopsy of the mass revealed a squamous cell carcinoma. Tumor progression, and its size increased area increasingly committed which complicated surgical resection. Subsequently, the animal showed progressive decay, and the caregiver decided compassionate euthanasia. Histopathological analysis of samples taken at necropsy revealed pulmonary metastases of the foreskin neoplasia with peribronchial distribution., No presente trabalho é reportado o caso de um eqüino de raça local Colombiana de 14 anos, que foi remitido por presença de uma massa na região prepucial (20 x 20 cm) a qual impedia o passo da urina. A análise histopatológica da biopsia da massa evidenciou um carcinoma de células escamoso. A evolução do tumor, e seu incremento do tamanho comprometeu cada vez mais a área o qual complicou a ressecção cirúrgica. Posteriormente, o animal apresentou decaimento progressivo, e o cuidador decidiu a eutanásia compassiva. A análise histopatológica das amostras tomadas à necropsia evidenciou metástase pulmonar da neoplasia prepucial, com distribuição Peri bronquial., En el presente trabajo se reporta el caso de un equino de raza criollo Colombiano de 14 años, que se remitió por la presencia de una masa en la región prepucial (20 x 20 cm) la cual obstruía el paso de la orina. El análisis histopatológico de la biopsia de la masa evidenció un carcinoma de células escamosa. La evolución del tumor, y su incremento del tamaño comprometió cada vez más área lo cual complico la resección quirúrgica. Posteriormente, el animal presentó decaimiento progresivo, y el cuidador decidió la eutanasia compasiva. El análisis histopatológico de las muestras tomadas a la necropsia evidenció metástasis pulmonar de la neoplasia prepucial, con distribución peribronquial.