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Else-Kröner-Fresenius Stiftung, HOMFOR

As metástases pulmonares de uma malignidade extrapulmonar primária costumam ser uma manifestação de disseminação generalizada, a ressecção agressiva de metástases pulmonares isoladas tornou-se um tratamento amplamente aceito para pacientes adequadamente selecionados. A decisão de prosseguir com a metastasectomia pulmonar requer uma abordagem multidisciplinar que inclui o oncologista médico, oncologista de radiação e cirurgião torácico, o objetivo é oferecer cirurgia apenas aos pacientes que têm maior probabilidade de se beneficiar, seja em termos de prolongamento da sobrevida ou paliação dos sintomas, e otimizar o tempo de intervenção cirúrgica. Existem poucas diretrizes publicadas de grupos de especialistas que tratam da seleção de pacientes para metastasectomia pulmonar. As diretrizes disponíveis incluem as diretrizes baseadas em consenso para ressecabilidade de metástases pulmonares de câncer colorretal da National Comprehensive Cancer Network e um documento de consenso sobre metastasectomia pulmonar da Society of Thoracic Surgeons.

Este artigo relata o caso de uma mulher de 66 anos de idade, com diagnóstico de câncer de esôfago em estágio IV. A paciente recebeu suporte nutricional oral e por sonda nasogástrica durante a hospitalização, no intuito da recuperação de seu estado nutricional.

National audience; Testis tumors are uncommon in oncology, and testicular metastasis from distant solid tumors are even rarer. We present two cases encountered in our department of pathology in CHU de Rennes, France. Moreover, we collected all reported cases in the Medline/PubMed databases of non-hematopoietic secondary testis tumors in adults, excluding autopsy studies, to propose an integrative study on this topic. In total, we report 98 cases of secondary testis lesions to prostate (n=38, 38.77 %), colorectal (n=19, 19.39%), gastric (n=12, 12.24%), kidney (n=7, 7.14%), lung (n=6, 6.12%) and other primary cancers. The median age at diagnosis was 66.5 years. We identified significantly more prostate adenocarcinoma (P

Le cancer de la prostate (CaP) représente la 3ème cause de mortalité par cancer chez l’homme en France. Il est reconnu pour son potentiel pouvoir métastatique au niveau de l’os et préférentiellement au niveau du squelette axial. Nous en décrivons dans ce travail les particularités diagnostiques, thérapeutiques actuels et évolutifs d’une métastase crânienne du CaP.Patient de 69 ans, sans antécédents pathologiques connus, reçu en consultation au service d’Urologie du CHU Yalgado Ouédraogo du Burkina Faso pour des SBAU. L’examen clinique a retrouvé un globe vésical, une prostate d’allure suspecte après la vidange vésicale et une voussure crânienne de l’os pariétal droit. L’élévation de la valeur du PSA total à 110 ng/ml a permis de faire une biopsie prostatique échoguidée qui a révélé à l’histologie un adénocarcinome ISUP 4. La tomodensitométrie thoraco-abdomino-pelvienne a montré un envahissement du plancher vésical, des méats urétéraux et du rectum. La scintigraphie osseuse a montré de multiples lésions métastatiques, dont l’os pariétal droit du crâne. Le diagnostic retenu était un adénocarcinome prostatique classé pT4N1M1c. Le patient a choisi comme traitement, une castration chirurgicale (pulpectomie) après un counseling bien conduit. Les suites opératoires ont été simples. A M3 post opératoire, il y avait une nette régression de la voussure crânienne.Les métastases crâniennes du CaP sont rares. La prise en charge thérapeutique par suppression androgénique donne de bons résultats. Prostate cancer is the third leading cause of cancer death in men in France. It is recognized for its potential metastatic power to bone and preferentially to the axial skeleton. We describe in this work the diagnostic, current and evolving therapeutic particularities of a cranial metastasis of prostate cancer. 69-year-old patient, with no known pathological history, seen in the Urology Department of the Yalgado Ouedraogo Teaching Hospital in Burkina Faso for SBAU. Clinical examination found a distended bladder, a suspicion of prostate cancer after bladder emptying and a cranial arch of the right parietal bone. Raising the total PSA value to 110 ng / ml allowed ultrasound-guided prostate biopsy to be performed, which revealed on histology an ISUP 4 adenocarcinoma. Thoraco-abdominal-pelvic computed tomography showed invasion of the bladder floor, ureteral meatus and rectum. The bone scintigraphy showed multiple metastatic lesions, including the right parietal bone of the cranium. The diagnosis was a prostatic adenocarcinoma classified as pT4N1M1c. The patient chose surgical castration (pulpectomy) as a treatment after well-conducted counseling. The postoperative follow-up was straightforward. At M1 postoperative, there was a clear regression of the cranial arch.Cranial prostate cancer metastases are rare. Therapeutic management by androgen suppression gives good results.

Dissertação de mestrado em Biophysics and Bionanosystems, O câncro da mama é um dos tipos de câncer mais comuns e uma das principais causas de mortalidade por câncer em mulheres1. A metástase é a causa básica da mortalidade relacionada ao câncer e, como o câncer é uma doença dinâmica e heterogênea, é crucial monitorizar a progressão da doença para combater a sua evolução2. Os métodos atualmente utilizados na clínica não são ideais, pois não representam o real estado do tumor. Para promover uma maior precisão na biomedicina a fim de melhorar o diagnóstico clínico e as decisões terapêuticas, é necessário desenvolver novas estratégias de detecção dos biomarcadores3. Por meio da biópsia líquida (LB), que é um método minimamente invasivo, é possível aceder informações sobre o tumor em tempo real, superando as limitações da biópsia solida4, permitindo um diagnóstico mais preciso, precoce e uma terapia personalizada. LB analisa vários biomarcadores de câncer, incluindo ctDNA5. O DNA tumoral circulante (ctDNA) é um DNA fragmentado que se origina no tumor ou em células tumorais circulantes (CTCs) que circulam livremente no sangue do paciente, resultantes do fenômeno da metástase. Ao ser proveniente das células, é liberado após sua morte, por diferentes processos como apoptose, necrose e autofagia, assim o ctDNA apresenta menor uniformidade de tamanho e integridade quando relacionado ao DNA livre de células6. Estudos anteriores sobre o ctDNA mostraram que ele representa um biomarcador valioso para identificar mutações específicas que fornecem informações valiosas para o manejo clínico de pacientes com câncer, pois representa uma fonte em tempo real de informações relacionadas ao tumor, relevantes para a progressão do câncer e personalização do tratamento do paciente para melhorar a sua resposta. No entanto, as técnicas atuais de extração de ctDNA são complicadas e pouco eficientes7–9. Microfluídica é a área da ciência de manipulação e controlo de fluidos e partículas em microcanais10. Apresenta múltiplas vantagens no manuseio de amostras biológicas, como a possibilidade de dispositivos portáteis, descartáveis e de baixo custo, e a oferta de capacidade de integração para que toda a gama de protocolos laboratoriais de bancada, desde o manuseio de amostras até a reação, separação e deteção, possam ser incorporados e automatizados num único chip 11., Breast cancer is one of the most common cancer types and a leading cause of cancer-related mortality in women1 . Metastasis is the underlying cause of cancer-related mortality, and since cancer is a dynamic and heterogeneous disease, it is crucial to monitor disease progression to fight cancer evolution2 . The methods currently used in the clinic, are not ideal as they fail to represent the real state of the tumor. To promote greater precision in biomedicine to improve clinical diagnosis and therapeutic decisions, it is necessary to develop new biomarker detection strategies3 . Through liquid biopsy (LB), which is a minimally invasive method, it is possible to access information about the tumor in real-time, overcoming the limitations of tissue biopsy4 , and allowing a more precise and early diagnosis and personalized therapy. LB analyses several cancer biomarkers, including ctDNA5 . Circulating tumor DNA (ctDNA) is fragmented DNA that originates in the tumor or in circulating tumor cells (CTCs) circulating freely in the patient's blood, resulting from the phenomenon of metastasis. When coming from cells, it is released upon their death, by different processes such as apoptosis, necrosis, and autophagy, thus ctDNA exhibits less uniformity in size and integrity when related to cell-free DNA6 . Previous ctDNA studies have shown that it represents a valuable biomarker to identify specific mutations that provide valuable information for the clinical management of cancer patients as it represents a real-time source of tumor-related information, relevant to cancer progression and personalize patient treatment to improve their response. However, current techniques for ctDNA extraction are complicated and not very efficient7–9 . Microfluidics is the area of science of handling and controlling fluids and particles in microchannels10. It presents multiple advantages to handling biological samples, such as the possibility of portable, disposable, and inexpensive devices, and the offer of integration capability so that the entire range of benchtop laboratory protocols, from sample handling to reaction, separation, and detection, can be incorporated and automated on a single chip11.

Knochenmetastasen sind unter den drei häufigsten Manifestationsorten metastatischer Absiedelungen von fortgeschrittenen Tumorerkrankungen. Dabei sind insbesondere Patientinnen und Patienten mit Prostata- und Mammakarzinom von Knochenmetastasen betroffen. Diese Knochenmetastasen führen häufig zu einer deutlichen Verschlechterung der Lebensqualität und zu einer Begrenzung der Therapieoptionen auf lediglich palliative Ansätze. Die biologisch aktive Form von Vitamin D3, 1,25(OH)2-Vitamin D3, zeigt in präklinischen Studien antiproliferative und differenzierende Effekte auf Tumorzellen (101, 102, 104), die haupsächlich durch die Bindung an den Vitamin D-Rezeptor (VDR) vermittelt werden. Darüberhinaus konnte präklinisch gezeigt werden, dass eine niedrige Expression des VDRs, ligandenunabhängig, die Knochenmetastasierung und das Tumorwachstum begünstigt (118). Eine niedrige VDR-Expression ist in Primärtumoren in klinischen Studien mit aggressiven Tumoreigenschaften assoziiert (111, 113, 115) und kann zudem mit einer erhöhten/früheren ossären Metastasierung einhergehen (167). Zudem gibt es Hinweise auf einen dysregulierten 1,25(OH)2-Vitamin D3-Katabolismus durch eine erhöhte Expression des 1,25(OH)2-Vitamin D3 katabolisierenden Enzyms CYP24A1/24-Hydroxylase in primärem Tumorzellen (70, 121, 122). Durch die Untersuchungen der Primärtumoren ist damit zu hypothetisieren, dass die Expression des VDRs und von CYP24A1 bei der Tumorprogression und Knochenmetastasierung von Bedeutung sein könnte. Entsprechende Untersuchungen des VDRs und der 24-Hydroxylase in Knochenmetastasen fehlen allerdings. Deshalb wurde in dieser Arbeit die Expression des VDRs und von CYP24A1 in Knochenmetastasen unterschiedlicher Primärtumoren von 66 Patientinnen und Patienten untersucht und mögliche Assoziationen mit aggressiven Tumoreigenschaften analysiert. Der VDR konnte sowohl im Zytoplasma als auch im Nukleus nachgewiesen werden, während CYP24A1 nur im Zytoplasma lokalisiert war. Dabei wiesen insgesamt 71 % der Knochenmetastasen eine hohe VDR-Expression im Nukleus und 56 % im Zytoplasma auf. 59 % der Knochenmetastasen wiesen eine hohe Expression des VDRs insgesamt auf. CYP24A1 war ebenso in 59 % der Knochenmetastasen hoch exprimiert. Bei der Auswertung des Zusammenhangs zwischen den TNM-Stadien und des Gradings zeigte sich ein nicht signifikanter Trend von schlecht differenzierten Tumoren hin zu einer niedrigeren nukleären VDR-Expression (p=0.07, siehe Abbildung 33). Bezüglich der T-Stadien zeigten sich keine Unterschiede der Expression des VDRs und von CYP24A1 in den Knochenmetastasen zwischen lokal fortgeschrittenen und kleinen Primärtumoren. Weiterhin hatten Patientinnen und Patienten mit Lymphknotenmetastasen tendenziell eine verminderte VDR- und auch CYP24A1-Expression in den Knochenmetastasen im Vergleich zu Patienten und Patientinnen ohne Lymphknotenmetastasen (pVDR=0.15, pCYP24A1=0.06, siehe Abbildung 35). Außerdem hatten Patientinnen und Patienten mit multiple metastasierten Tumoren eine signifikant niedrigere nukleäre VDR- und auch CYP24A1-Expression im Vergleich zu Patientinnen und Patienten mit ausschließlich ossärer Metastasierung (pVDR=0.03, pCYP24A1=0.01, Abbildung 36). Die Proteinexpression des VDRs- und von CYP24A1 korrelierten signifikant (p=0.001). Somit konnte mit dieser Arbeit die Proteinexpression des VDRs und von CYP24A1 in Knochenmetastasen durch Immunhistologie nachgewiesen werden. Insgesamt wurde der VDR und CYP24A1 von Knochenmetastasen diverser Entität unterschiedlich stark exprimiert. Jedoch könnten insbesondere Patienten mit VDR-exprimierenden Knochenmetastasen von einer Vitamin D3-Supplementierung profitieren, die häufig einen 25-OH-Vitamin D3 Mangel zeigen (165, 166). Ebenso könnte eine Untersuchung auf einen niedrigen VDR-Status in Primärtumoren dabei helfen, Krebspatienten mit einem hohen Metastasierungsrisiko zu identifizieren. Allerdings sind weitere und größere Studien inbesondere mit Evaluation des gesamten Vitamin D-Metabolismus und -Signalwegs notwendig, um diesen Zusammenhang weiter zu untersuchen., Bone metastases are among the three most frequent sites of metastatic manifestation of late-stage cancers, particularly of prostate and breast cancers. Bone metastases often reduce patient’s quality of life due to skeletal-related events. Additionally, bone metastatic tumor treatment is predominantly restricted to palliative measures. In preclinical studies, the biologically active form of vitamin D3, 1,25(OH)2-vitamin D3, has been demonstrated to have antiproliferative and differentiating effects on cancer cells (101, 102, 104), which are mostly mediated by binding to the vitamin D receptor (VDR). Moreover, the VDR expression itself may affect cancer growth and the metastatic potential to bone. For example, preclinically, it has been shown that VDR knockdown promotes bone metastases manifestation and growth (118). Furthermore, low VDR expression is associated to aggressive cancer characteristics in primary cancers (111, 113, 115) and also linked to earlier bone metastasis manifestation in breast cancer (120). In addition, there is evidence that 1,25(OH)2-vitamin D3- catabolism is altered in cancer cells. Thus, inactivation of local 1,25(OH)2-vitamin D3-levels in cancer cells may be increased (70, 121, 122). VDR and CYP24A1 expression could therefore be important concerning cancer progression and bone metastases manifestation and growth. However, there are currently no reports of studies investigating VDR expression and vitamin D-metabolism in bone metastases. The aim of this study was hence to assess VDR and CYP24A1 (vitamin D-catabolizing enzyme) expression in bone metastases of 66 patients secondary to prostate-, breast-, kidney-, lung-, follicular thyroid- and colorectal cancers using immunohistochemistry (132). While the VDR was localised in the nucleus and cytoplasm, CYP24A1 was identified in the cytoplasm only. A high VDR nuclear protein expression was detected in 47/66 (71 %) and cytoplasmatic in 37/66 (56 %). 39/66 (59 %) of bone metastases had a high total VDR expression. CYP24A1 was also strongly expressed in 39/66 (59 %) of bone metastases. Expression levels were correlated to patient data and cancer characteristics. There was a non-significant trend of high-grade cancers towards low nuclear VDR expression (p=0.07, see figure 33). Additionally, patients with lymph node metastases (N-stage) tended to have a reduced bone metastatic VDR and CYP24A1 expression compared to patients without lymph node metastases (pVDR=0.15, pCYP24A1=0.06, see figure 35). There was no difference of VDR and CYP24A1 expression in bone metastases between locally advanced and small primary cancers (T-stage). Interestingly, patients with further metastases other than bone metastases had reduced nuclear VDR and CYP24A1 levels compared to patients without other distant metastases (pVDR=0.03, pCYP24A1=0.01, see figure 36). Nuclear VDR and CYP24A1 expression showed a significant positive correlation (p=0.001). In conclusion, this study demonstrated that the VDR and CYP24A1 are widely expression in bone metastases of various origin. Therefore, patients with VDR-expressing bone metastases could, in particular, benefit from vitamin D3-supplementation, as vitamin D deficiency is frequent in patients with bone metastases (165, 166). Additionally, screening for a low VDR status in primary cancers could help to identify cancer patients at a high risk of metastasis. However, further and larger studies, that evaluate the entire vitamin D metabolism and signalling pathway, are needed to investigate this association.

Metastasis is the leading cause of cancer-related death in pancreatic ductal adenocarcinomas (PDAC). All hallmark mutations in PDAC (KRAS, p16, TP53 and SMAD4) are known to modulate the metastatic process. The complex metastatic cascade can be divided into three major phases, (i) physical translocation of cancer cells from its primary tumor location to the microenvironment of a secondary site, (ii) colonization and (iii) ultimately growth into a metastatic lesion. In this regard, circulating tumor cells (CTCs) represent an intermediate stage of metastasis, a subset of which require stem-like properties for tumor-initiation and growth at the secondary site. It is therefore essential to delineate the pathways that maintain these CTCs and miCSCs. MEK is downstream of the oncogenic driver mutation KRAS and has been reported to show outstanding relevance in PDAC biology. Thus, our first aim was to establish the role of RAS/MEK/ERK signaling to promote EMT and support stem-like phenotypes in disseminating cells. Using primary murine cancer cell lines with a Slug – YFP reporter system and MEK inhibitors, we established the contribution of MEK signaling on survival, migration and self-renewal capacity in PDAC. In brief, TGFβ-induced EMT can be abrogated by MEK inhibition, evidenced by strong decrease of Slug-expressing cells, which translates into a significant reduction in CTCs in mice. Furthermore, RAS/MEK signaling does not act in an isolated manner, as secreted factors from within the tumor microenvironment, independently as well as in combination with other secreted factors, promote metastasis. CXCL12 is one such chemokine and exerts its effects primarily via CXCR4. Besides, a subset of cancer stem cells (CSCs) called migrating cancer stem cells (miCSCs) with CXCR4 and CD133 receptors can be detected in abundance within the invasive front of PDAC and are exclusively responsible for metastasis. Therefore, our next aim was to describe the relevance of CXCL12/CXCR4 signaling for the maintenance of CSCs and miCSCs in context of the microenvironment. Using co-cultures of PDAC cells and pancreatic stellate cells (PSCs), we demonstrate the importance of tumor – stroma crosstalk on CSC and miCSC maintenance. PSCs in co-culture with PDAC cells secrete elevated levels of CXCL12, enabling tumor cells to self-renew and to migrate, and ultimately to metastasize. Mechanistically, CXCL12 acts through CXCR4 to activate multiple pathways that include sonic hedgehog, AKT and NF-κΒ, which further promotes NANOG and BMI1 expression. In addition, BMI1 plays the molecular link between inducing stemness and activating different EMT programs. We established CXCR4 as a prominent target for therapeutic interventions to reduce CSCs and abrogate miCSCs. It is imperative to develop and investigate novel approaches to combat metastasis. Having successfully established the crucial role of CXCR4, our final aim was to exploit human endogenous peptides to eliminate miCSCs. We showed JM#21, an EPI-X4 peptide derivative, to be a highly potent inhibitor of CXCR4, even in the presence of CXCL12. JM#21 strongly reduced sphere formation capacity and sensitized PDAC cells towards chemotherapy. Aiming at a potential therapy, we further modified JM#21 by conjugation with fatty acids to improve stability, or encapsulated JM#21 in silica nanoparticles for improved delivery. These modified compounds drastically reduced chemoresistance and stemness features in PDAC cells co-cultured with PSCs. In addition, they also decreased key factors responsible for EMT and eliminated the miCSC population. In conclusion, the data in the present study (i) demonstrate the importance of RAS/MEK/ERK signaling on CTC initiation, (ii) provide novel molecular insights on CSC and miCSC maintenance and (iii) explore human endogenous peptides as innovative therapy for targeting miCSCs and migration / metastasis. In addition, tumor-educated PSCs were shown to secrete elevated levels of CXCL12, which promotes EMT, stemness and chemoresistance via CXCR4. CXCL12 was also revealed to activate BMI1, which we describe as a downstream molecular link between EMT and stemness.

Macrófagos se mostram como os leucócitos mais abundantes em biópsias tumorais, destacando seu papel na tumorigênese e sua participação no processo de metástase, principalmente aqueles de perfil M2. Dessa forma, o objetivo no presente trabalho foi esclarecer os mecanismos pelos quais esses imunócitos influenciam nesse processo. Para isso, foi realizada uma revisão de literatura utilizando os termos “neoplasias, macrófagos e metástase” nas plataformas PubMed e Scielo. Foram selecionados 81 artigos publicados entre os anos de 1989 e 2019. Por fim, constatou-se a participação dos macrófagos M2 tanto na formação de tumores diante de um microambiente inflamatório como no estabelecimento e manutenção de nichos metastáticos.

In breast, the adenomyoepithelioma is a lesion which terminology suggests to be a benign tumor. Making a review in a literature, it shows with potential to develop metastasis in axillary nodes. In this paper the authors show a case occurred after breast feeding. The lesion was treated under local surgery and the patient is maintained in follow-up. O adenomioepitelioma é uma lesão cuja terminologia sugere ser um tumor benigno, mas observado na literatura médica com potencialidade para o aparecimento de metástases, principalmente em gânglios axilares. Os autores apresentam um caso ocorrido após a lactação. A lesão foi tratada com cirurgia local e a paciente continua em segmento contínuo.

A matriz extracelular (MEC) trata-se de um componente não celular presente em todos os tecidos e órgãos e atua não apenas como uma estrutura física importante para os constituintes celulares, mas também como ponto de partida para eventos bioquímicos e biomecânicos essenciais para a morfogênese, diferenciação e homeostase do tecido. A MEC é composta de um conjunto complexo de proteínas fibrosas, proteoglicanos e outras moléculas, tais como citocinas, fatores de crescimento e hormônios, cuja composição varia de tecido para tecido e é alterada frente a diferentes condições fisiológicas (renovação e reparo tecidual) e associadas às doenças, incluindo câncer, razão pela qual componentes da MEC são denominados como Hallmarks do câncer. Neste contexto, a remodelação da MEC é uma das estratégias que os tumores utilizam para criar um microambiente que promove a tumorigênese e metástase através de diferentes mecanismos. Nesta revisão as características funcionais da MEC serão abordadas e também destacado o entendimento atual dos mecanismos físicos, celulares e moleculares pelos quais a MEC do tumor afeta a eficiência da quimioterapia, radioterapia e imunoterapia.

Objetivo: relatar e discutir um caso de síndrome colestática por compressão linfonodal decorrente de câncer de próstata metastático.Relato do caso: JPS, masc., 74 anos, portador de hipertensão arterial sistêmica e dislipidemia, foi encaminhado para avaliação de hepatomegalia e encontrava-se em tratamento de adenocarcinoma de próstata.Discussão: O câncer de próstata metastático (CPM) pode se apresentar com uma variedade de sintomas inespecíficos ou relacionados ao sítio de instalação metastática.Conclusão: colestase devido à linfodomegalia por metástase é incomum, mas deve ser considerada no diagnóstico diferencial.

Despite being a benign tumor of the maxillofacial region, some cases of ameloblastoma can be categorized as malignant ameloblastoma (or metastasizing) when metastases occur. The aim of this study is to report a rare case of lung metastasis from mandibular ameloblastoma, in order to review its risk and analyze the main anatomic sites that can occur with this disease. The case of a 48-year-old woman is described. She presented a metastatic pulmonary ameloblastoma 7 years after the removal of a mandibular ameloblastoma. During routine exams, a tumor in the left lung was observed. It was asymptomatic, near to the mediastinum, measured 7x5.5 cm. Transthoracic needle biopsy revealed ameloblastoma with the same histological characteristics of the primary tumor. After radiotherapy, the patient presented regression of the tumor. The patient has been under follow-up for 5 years and there is no presence of tumor. Ameloblastoma is an aggressive tumor not only in the region of origin, but also in distant regions, mainly in cases of recurrence. Metastases can cause high rates of morbidity, a fact that requires early treatment. RESUMO Apesar de ser um tumor benigno da região maxilofacial, alguns casos de ameloblastoma podem ser categorizados como ameloblastoma maligno (ou metastizante) quando ocorrem metástases. O objetivo deste trabalho é relatar um caso raro de metástase pulmonar de ameloblastoma mandibular, a fim de revisar seu risco e analisar os principais sítios anatômicos que podem ocorrer com esta doença. Descreve-se o caso de uma mulher de 48 anos. Ela apresentou um ameloblastoma pulmonar metastático 7 anos após a remoção de um ameloblastoma mandibular. Durante os exames de rotina foi observado tumor no pulmão esquerdo. Assintomático, próximo ao mediastino, medindo 7x5,5 cm. A biópsia transtorácica com agulha revelou ameloblastoma com as mesmas características histológicas do tumor primário. Após radioterapia, o paciente apresentou regressão do tumor. O paciente está em acompanhamento há 5 anos e não há presença de tumor. O ameloblastoma é um tumor agressivo não só na região de origem, mas também em regiões distantes, principalmente nos casos de recorrência. As metástases podem causar altas taxas de morbidade, fato que requer tratamento precoce.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Breast cancer is the major disease that affects women, especially the triple negative phenotype, which has the worst prognosis and metastatic potential. Included, metastasis is still the main cause of death in cancer patients and its development involves several stages and characters that play important roles, such as the tumor microenvironment and the extracellular matrix (ECM). Integrins also contribute to metastasis, especially the αvβ3 integrin whose overexpression is associated with every step in tumor progression. Among the molecules that interact with integrins, there are disintegrins, which are small proteins derived from snake venom metalloproteases. DisBa-01 (Disintegrin of Bothrops alternatus-01) is a recombinant protein derived from the Bothrops alternatus venom (urutu-cruzeiro) snake, which has a high affinity for this integrin. Thus, this work aimed to study the effects of silencing the β3 subunit in tumor cells of the triple negative breast adenocarcinoma cell line (MDA-MB-231). Therefore, the methods adopted involved the cell culture of human kidney embryonic (293FT) and wild and modified triple negative breast adenocarcinoma (MDA-MB-231) cell lines; production of ITGB3 shRNA lentivirus as well as target cell transduction and the validation of silencing by RTqPCR and immunofluorescence. We also verified possible alterations in the expression of other integrin subunits; functional assays (inhibition of adhesion, migration by wound healing and transwell), and the identification of metalloproteases (MMP) (MMP-2 and MMP-9). We compared the cellular responses of the silenced lineage with the action of DisBa-01 (1000 nM). The silencing took to a 69% reduction in ITGB3 mRNA and a 49% reduction in FN rich microenvironment, with an increase in β1, α1 and α5 subunits; increased adherence to FN (58%) and COL I (83%) proteins; decreased transwell migration (69% inhibition) and MMP-9, responses different from those obtained with DisBa-01. The generation of this new cell line opens perspectives for its use as a tool in future studies of the basic biology of breast cancer. O câncer de mama é a principal doença a acometer mulheres, especialmente o fenótipo triplo negativo, o qual apresenta o pior prognóstico por seu elevado potencial metastático. A metástase ainda consiste na principal causa de mortes de pacientes com câncer e seu desenvolvimento envolve várias etapas e personagens que desempenham papéis importantes, como o microambiente tumoral e a matriz extracelular (MEC). As integrinas, receptores de superfície celular que conectam as células à MEC, também contribuem para as metástases, destacando-se a integrina αvβ3 cuja superexpressão está associada a diversas etapas da progressão tumoral. Dentre as moléculas que interagem com integrinas, tem-se as desintegrinas que são pequenas proteínas derivadas de metaloproteases de peçonhas de serpentes. A DisBa-01 (Disintegrin of Bothrops alternatus-01) é uma proteína recombinante derivada da peçonha da serpente Bothrops alternatus (urutu-cruzeiro), que possui uma alta afinidade a integrina αvβ3. Assim, este trabalho teve como objetivo estudar os efeitos do silenciamento da subunidade β3 em células tumorais da linhagem celular de adenocarcinoma triplo negativo de mama (MDA-MB-231). Portanto, os métodos adotados envolveram o cultivo de linhagens de células embrionárias de rim humano (293FT) e de adenocarcinoma triplo negativo de mama (MDA-MB-231) selvagem e modificadas; produção de lentivírus shRNA ITGB3 bem como a transdução da célula alvo e a validação do silenciamento por RTqPCR e imunofluorescência. Também verificamos possíveis alterações na expressão de outras subunidades de integrinas; ensaios funcionais (inibição da adesão, migração por wound healing e transwell), e a identificação de metaloproteases de matriz (MMP) (MMP-2 e MMP-9). Confrontamos as respostas celulares da linhagem silenciada com a ação de DisBa-01 (1000 nM). O silenciamento levou a redução de 69% do mRNA ITGB3 e 49% da proteína em FN, com aumento das subunidades β1, α1 e α5; aumento da adesão a FN (58%) e COL I (83%); diminuição da migração transwell (69% de inibição) e da MMP-9, respostas essas, diferentes daquelas obtidas com a DisBa-01. A geração dessa nova linhagem celular abre perspectivas de seu uso como ferramenta em estudos futuros da biologia básica do câncer de mama. 88887.485864/2020-00

CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior A doxorrubicina (DOX) apresenta uma potente ação antineoplásica e vem sendo utilizada no tratamento de diversos tumores. Entretanto, graves efeitos tóxicos têm limitado seu uso, principalmente a cardiotoxicidade. Recentemente, nanocarreadores híbridos obtidos pela fusão das membranas lipídicas de exossomas e lipossomas vêm sendo estudados, a fim de aumentar a eficácia antitumoral, minimizar os efeitos adversos e contornar os problemas relacionados a resistência de quimioterápicos. A proposta desse estudo consistiu na fusão de exossomas derivados de células de mama tumorais com lipossomas pH-sensíveis de circulação prolongada contendo DOX para tratamento de câncer de mama (ExoSpHL-DOX). O diâmetro médio das vesículas foi de 100,8 ± 7,8 nm, o índice de polidispersão igual a 0,122 ± 0,004 e o teor de DOX encapsulado foi de 83,5 ± 2,5%. A fusão de exossomas com lipossomas pH-sensíveis de circulação prolongada foi confirmada por espectroscopia de infravermelho com transformada de Fourier, espectroscopia Raman e nanocitometria de fluxo. A avaliação da estabilidade de armazenamento dos ExoSpHL-DOX a 4°C comprovou a manutenção das características físico-químicas da formulação por 60 dias. O estudo de liberação de DOX a partir de ExoSpHL-DOX em meios de diluição apresentando diferentes valores de pH, comprovou a característica de pH-sensibilidade do nanossistema. A formulação mostrou-se citotóxica para células tumorais 4T1 de mama murina. A toxicidade aguda foi determinada pela avaliação da mortalidade e morbidade dos animais, análises hematológicas, bioquímicas e histopatológicas, após uma única administração intravenosa de ExoSpHL-DOX. O intervalo de dose letal mediana (LD50) encontrado após o tratamento com ExoSpHL-DOX (17,5 - 20 mg/kg) é maior do que o encontrado com DOX livre (12,5 - 15 mg/kg). Além disso, ExoSpHL-DOX não apresentou sinais de nefrotoxicidade mesmo na dose mais elevada de DOX, indicando que o nanocarreador híbrido pode alterar a distribuição de DOX e reduzir o dano renal. Em relação à atividade antitumoral, ExoSpHL-DOX inibiu em aproximadamente 50% o crescimento do tumor comparado ao grupo controle. Além disso, o nanocarreador híbrido de exossomas-lipossomas reduziu o número de focos metastáticos nos pulmões. Esses resultados indicam que ExoSpHL-DOX pode ser um nanocarreador promissor para o tratamento do câncer de mama, reduzindo a toxicidade e inibindo a metástase, principalmente nos pulmões. Doxorubicin (DOX) has a potent antineoplastic action and has been used in the treatment of several tumors. However, serious toxic effects have limited its use, especially cardiotoxicity. Recently, hybrid nanocarriers obtained by fusion of lipid membranes of exosomes and liposomes have been studied in order to increase antitumor efficacy, minimize adverse effects and overcome problems related to chemotherapy resistance. Thus, the purpose of this study was the fusion of exosomes derived from breast tumor cells with long-circulating and pH-sensitive liposomes containing DOX (ExoSpHL-DOX) for the treatment of breast cancer. The mean diameter of ExoSpHL-DOX was 100.8 ± 7.8 nm, the polydispersity index was 0.122 ± 0.004, and the encapsulated DOX content was equal to 83.5 ± 2.5%. The fusion of exosomes with long-circulating and pH-sensitive liposomes was confirmed by Fourier transform infrared spectroscopy, Raman spectroscopy, and nano-flow cytometry. The physicochemical characteristics of ExoSpHL-DOX were maintained for 60 days, at 4°C. The study of the release of DOX from ExoSpHL-DOX in dilution media with different pH values showed the pH-sensitivity of the nanosystem. The cytotoxic study against the 4T1 breast cancer cell line demonstrated that ExoSpHL-DOX treatment significantly reduced the cancer cell viability. Acute toxicity was determined by evaluating the mortality and morbidity of the animals, hematological, biochemical, and histopathological analyses, after a single intravenous administration of ExoSpHL-DOX. The results of the study indicated that the median lethal dose range (LD50) of the ExoSpHL-DOX treatment (17.5 - 20 mg/kg) is higher than that found for treatment with free DOX (12.5 - 15 mg/kg). In addition, ExoSpHL-DOX treatment showed no signs of nephrotoxicity even at the highest dose of DOX, indicating that the presence of hybrid nanocarrier may alter the distribution of DOX and reduce kidney damage. Regarding to the antitumor activity, ExoSpHL-DOX treatment inhibited close to 50% the tumor growth compared to control group. Furthermore, the hybrid nanocarrier of tumor-derived exosomes fused with long-circulating and pH-sensitive liposomes reduced the number of metastatic foci in the lungs. These results indicate that ExoSpHL-DOX may be a promising nanocarrier for the treatment of breast cancer, reducing toxicity and inhibiting metastasis, mainly in the lungs.

Submitted by Maria Aparecida (cidazen@gmail.com) on 2022-09-01T11:50:47Z No. of bitstreams: 1 Hiran Reis Sousa Tese.pdf: 26481051 bytes, checksum: b2350c389a662d62ab8a926aff5f1bf2 (MD5) Made available in DSpace on 2022-09-01T11:50:47Z (GMT). No. of bitstreams: 1 Hiran Reis Sousa Tese.pdf: 26481051 bytes, checksum: b2350c389a662d62ab8a926aff5f1bf2 (MD5) Previous issue date: 2022-07-28 Cancer is a pleiotropic disease caused by uncontrolled cell proliferation and is the second leading cause of death, after cardiovascular disease, worldwide. Recent surveys point to an acceleration in the number of cases that already cause death in one in eight men and in eleven women worldwide, of which lung and breast cancer are predominant. Cancer is a multifactorial disorder, presenting several conventional therapies for its treatment, which have enormous side effects due to their lack of specificity, being able to attack healthy cells. In the last two decades, phytochemicals have been studied as an alternative form of treatment and an adjunct to conventional anticancer therapy. Of the various polyphenol molecules that exhibited potent anticancer properties, myricetin was one of the substances that most stood out in recent years, as it has several pharmacological properties that also include antioxidant, anti-inflammatory, anticancer and epigenetic modulation activities. Therefore, our group set out to investigate the antitumor effect of myricetin through the mechanism of PDI inhibition by inducing oxidative stress in a tumor microenvironment model, using in vitro cytotoxicity assessment techniques and 3D cell culture techniques that mimic closer to in vivo, quantification of H2O2 and NO and co- culture with platelets. Our results show that myricetin promoted a cytotoxic effect in normal breast tissue cells, in a discrete way, and in breast cancer cells in a more accentuated and dose-dependent way, mainly in the lineage with greater invasive and metastatic power. It was also evident in our results that myricetin reduces the formation of spheroids and their stabilization, this effect being more expressive in MDA-MB-231 triple negative breast cancer cells, which are metastatic. There was an increase in the production of H2O2 and NO, in a dose-dependent manner and more evident in cells with more metastatic power and their levels consistent with levels of cell death signaling. There was a dose- dependent and more significant reduction in the interaction of tumor cells with platelets in the MDA-MB-231 lineage. Although there are many studies showings its cytotoxic effect on tumor cells, studies are unanimous in stating that there is much to be researched on the antineoplastic effect of myricetin, as its effect is proven to be broad on several molecular targets that involve the progression of different types of cancer, confirmed by different studies. Therefore, our next investigative steps will be to evaluate the oxidative stress of the tested cells and how myricetin interferes in cell interactions crucial for the formation and stabilization of spheroids, as well as in the formation of the physical shield of platelets with circulating tumor cells. O câncer é uma doença pleiotrópica causada pela proliferação descontrolada de células e é a segunda causa de morte, depois das doenças cardiovasculares, em todo o mundo. Levantamentos recentes apontam aceleração nos números de casos que já chegam a causar morte em um a cada oito homens e a cada onze mulheres em todo o mundo, dos quais, o câncer de pulmão e de mama são predominantes, respectivamente. O câncer é um distúrbio multifatorial, apresentando várias terapias convencionais para o seu tratamento, que têm enormes efeitos colaterais devido à sua falta de especificidade, podendo atacar células saudáveis. Nas últimas duas décadas, os fitoquímicos têm sido estudados como forma alternativa de tratamento e adjuvante na terapia anticâncer convencional. Das várias moléculas de polifenois que exibiram propriedades anticancerígenas potentes, a miricetina foi uma das substâncias que mais se destacou nos últimos anos, por apresentar diversas propriedades farmacológicas que também incluem atividade antioxidante, anti-inflamatórias, anticâncer e modulação epigenética. Diante disso, nosso grupo se propôs investigar o efeito antitumoral da miricetina através do mecanismo de inibição da PDI induzindo o estresse oxidativo em modelo de microambiente tumoral, utilizando técnicas de avaliação da citotoxicidade in vitro e técnicas de cultura celular em 3D que mimetizam tecidos tumorais mais próximo do in vivo, quantificação de H2O2 e NO e co-cultura com plaquetas. Nossos resultados mostram que a miricetina promoveu efeito citotóxico em células de tecido mamário normal, de forma discreta, e nas células de câncer de mama de forma mais acentuada e dose- dependente, principalmente na linhagem de maior poder invasivo e metastático (MDA- MB-231). Também ficou evidente, em nossos resultados, que a miricetina reduz a formação de esferoides e sua estabilização, sendo esse efeito mais expressivo nas células de câncer de mama triplo negativas MDA-MB-231, que são metastáticas. Houve um aumento na produção de H2O2 e NO, de forma dose-dependente e mais evidente nas células mais poder metastático e seus níveis condizentes com níveis de sinalização de morte celular. Houve redução na interação de células tumorais com plaquetas, de forma dose-dependente e mais significativo na linhagem MDA-MB-231. Os estudos são unânimes em afirmar que muito se tem a pesquisar sobre o efeito antineoplásico da miricetina, pois seu efeito é comprovadamente amplo sobre vários alvos moleculares que envolvem a progressão de diversos tipos de câncer, confirmada por diferentes estudos. Diante disso nossos próximos passos investigativos serão de avaliar o estresse oxidativo das células testadas e como a miricetina interfere nas interações celulares crucias para a formação e estabilização dos esferoides, bem como na formação do escudo físico de plaquetas com células tumorais circulantes.

Objective: The objective of the presented study was to describe a clinical case of a male patient, 45 years old, diagnosed with colorectal adenocarcinoma, however, in stage IV, with the presence of liver and lung metastases. Methodology: This case was carried out in a retrospective, descriptive and observational manner, by direct collection of patient data through access to medical records, patient interview and results of complementary exams. Case description: Patient, A.A.S.F, 45 years old, complaining about abdominal cramps, rectal tenesmus and ribbon stools who was diagnosed with Metastatic Colorectal Adenocarcinoma in 2011, therefore, with a follow-up of approximately ten years. In this case, several therapies were used and several chemotherapy sessions were performed with the aim of remission of the disease. In addition, imaging tests, for example, PET CT, were of paramount importance for the management of the case, in addition to the measurement of serum levels of the tumor marker CEA. Conclusion: Severe cases like this require different approaches, and early diagnosis is important for more favorable prognoses. The patient, having been diagnosed late, evolves with liver and lung metastases, making treatment difficult, which required a very aggressive therapeutic approach. Objetivo: El objetivo del presente estudio fue describir un caso clínico de un paciente masculino, de 45 años, diagnosticado de adenocarcinoma colorrectal, sin embargo, en estadio IV, con presencia de metástasis hepáticas y pulmonares. Metodología: Este estudio de caso se realizó de manera retrospectiva, descriptiva y observacional, mediante la recolección directa de datos de los pacientes a través del acceso a la historia clínica, entrevista al paciente y resultados de exámenes complementarios. Descripción del caso: Paciente, A.A.S.F, de 45 años de edad, quejoso abdominal, tenesmo rectal y heces de heridas con cinta adhesiva que fue diagnosticado con adenocarcinoma colorrectal metastásico en 2011, por lo tanto, con un seguimiento de aproximadamente diez años. En este caso se utilizaron varias terapias y se realizaron varias sesiones de quimioterapia con el objetivo de lograr la remisión de la enfermedad. Además, las pruebas de imagen, por ejemplo, PET/TC, fueron de suma importancia para el manejo del caso, además de la medición de los niveles séricos del marcador tumoral CEA. Conclusión: casos graves como este requieren diferentes abordajes, y el diagnóstico precoz es importante para un pronóstico más favorable. El paciente, al haber sido diagnosticado tardíamente, evoluciona con metástasis hepáticas y pulmonares, lo que dificulta el tratamiento, que requirió un abordaje terapéutico muy agresivo. Objetivo: O objetivo do presente estudo foi descrever um caso clínico de um paciente do sexo masculino, 45 anos de idade, com diagnóstico adenocarcinoma colorretal estágio IV com presença de metástases hepáticas e pulmonares. Metodologia: Este estudo de caso foi realizado de forma retrospectiva, descritiva e observacional, por coleta direta de dados da paciente por meio do acesso aos prontuários e resultados de exames complementares. Descrição do caso: Paciente, A.A.S.F, 45 anos, sexo masculino, com queixa de cólica abdominal, tenesmo retal e fezes em fita, com diagnóstico de Adenocarcinoma Colorretal metastático em 2011, em acompanhamento há aproximadamente dez anos. Durante o tratamento, foram utilizados diversos esquemas terapêuticos, dentre esses, várias sessões de quimioterapia, com finalidade de remissão da doença. Ademais, exames de imagem, por exemplo, o PET CT foi de suma importância para a condução do caso, além da dosagem dos níveis séricos do marcador tumoral CEA. Conclusão: Casos complexos como esse necessitam de diagnóstico precoce, para prognósticos mais favoráveis. O paciente, por ter sido diagnosticado tardiamente, evoluiu com metástases hepáticas e pulmonares, dificultando o tratamento, o qual necessitou de uma abordagem terapêutica muito agressiva.

Background: Papillary thyroid cancers (PTCs) are common, usually indolent malignancies. Still, a small but significant percentage of patients have aggressive tumors and develop distant metastases leading to death. Currently, it is not possible to discriminate aggressive lesions due to lack of prognostic markers. Long noncoding RNAs (lncRNAs), which are selectively expressed in a context-dependent manner, are expected to represent a new landscape to search for molecular discriminants. Transforming growth factor β (TGFβ) is a multifunctional cytokine that fosters epithelial-to-mesenchymal transition and metastatic spreading. In PTCs, it triggers the expression of the metastatic marker Cadherin 6 (CDH6). Here, we investigated the TGFβ-dependent lncRNAs that may cooperate to potentiate PTC aggressiveness. Methods: We used a genome-wide approach to map enhancer (ENH)-associated lncRNAs under TGFβ control. Linc00941 was selected and validated using functional in vitro assays. A combined approach using bioinformatic analyses of the thyroid cancer (THCA) - the cancer genome atlas (TCGA) dataset and RNA-seq analysis was used to identify the processes in which linc00941 was involved in and the genes under its regulation. Correlation with clinical data was performed to evaluate the potential of this lncRNA and its targets as prognostic markers in THCA. Results: Linc00941 was identified as transcribed starting from one of the TGFβ-induced ENHs. Linc00941 expression was significantly higher in aggressive cancer both in the TCGA dataset and in a separate validation cohort from our institution. Loss of function assays for linc00941 showed that it promotes response to stimuli and invasiveness while restraining proliferation in PTC cells, a typical phenotype of metastatic cells. From the integration of TCGA data and linc00941 knockdown RNA-seq profiling, we identified 77 genes under the regulation of this lncRNA. Among these, we found the prometastatic gene CDH6. Linc00941 knockdown partially recapitulates the effects observed upon CDH6 silencing, promoting cell cytoskeleton and membrane adhesions rearrangements and autophagy. The combined expression of CDH6 and linc00941 is a distinctive feature of highly aggressive PTC lesions. Conclusions: Our data provide new insights into the biology driving metastasis in PTCs and highlight how lncRNAs cooperate with coding transcripts to sustain these processes.

Globalmente, o câncer de mama é o câncer mais comum e a segunda principal causa de mortalidade e morbidade em mulheres. No Brasil, dados INCA mostram que esse câncer é o mais incidente no público feminino, além de ser a principal causa de morte por câncer neste gênero. Diversos fatores são responsáveis pela alta taxa de mortalidade do câncer de mama, onde a metástase para órgãos vitais é identificada como o principal dentre eles. Um crescente número de evidências tem associado o splicing alternativo disfuncional de genes e as atividades e/ou expressões alteradas de moléculas chaves deste processo a fenótipos metastáticos e carcinogênicos. Nesse sentido, as serine/arginine protein kinases (SRPKs), que atuam fosforilando fatores de splicing da família SR, têm sido encontradas superexpressas em diferentes tipos de câncer, incluindo o câncer de mama metastático. Neste estudo foi investigada a atividade biológica de um conjunto de novas moléculas derivadas de um inibidor de SRPKs (SRPIN340) sobre células de câncer de mama e de outros tumores cuja expressão de SRPKs já foi demonstrada. A substância MR48 foi identificada por apresentar atividade citotóxica nos ensaios de viabilidade e por apresentar efeitos antimetastáticos em linhagem de célula de câncer de mama metastático 4T1, este composto também prejudicou a atividade de SRPK1 intracelularmente. Adicionalmente, foi também realizado estudo piloto visando estabelecer um modelo murino de câncer de mama metastático baseado na inoculação da linhagem 4T1 em camundongos. Para tal, animais BALB/c fêmeas foram inoculadas com suspensões das células 4T1 em diferentes densidades na 4 ª glândula mamária. O curso da doença foi monitorado, no entanto, os animais não foram capazes de gerar tumores de forma satisfatória. Novos ensaios devem ser realizados visando otimizar o estabelecimento deste modelo de câncer de mama. Em suma, este trabalho identificou uma molécula promissora que deve ser melhor avaliada em futuros estudos in vitro e in vivo. Palavras-chave: Serine Arginine Protein kinases. Células murinas. Câncer de mama metastático. Globally, breast cancer is the most common cancer and the second leading cause of mortality and morbidity in women. In Brazil, INCA data show that this cancer is the most common among women, besides being the main cause of death by cancer in this gender. Several factors are responsible for the high mortality rate of breast cancer, where metastasis to vital organs is identified as the main one among them. A growing body of evidence has associated dysfunctional alternative gene splicing and altered activities and/or expressions of key molecules in this process with metastatic and carcinogenic phenotypes. In this regard, serine/arginine protein kinases (SRPKs), which act by phosphorylating SR family splicing factors, have been found to be overexpressed in different types of cancer, including metastatic breast cancer. In this study, the biological activity of a set of novel molecules derived from an inhibitor of SRPKs (SRPIN340) on breast cancer cells and other tumors whose expression of SRPKs has already been demonstrated was investigated. The substance MR48 was identified as showing cytotoxic activity in viability assays and antimetastatic effects in 4T1 metastatic breast cancer cell line, this compound also impaired SRPK1 activity intracellularly. In addition, a pilot study was also conducted to establish a murine model of metastatic breast cancer based on the inoculation of the 4T1 cell line in mice. For this purpose, female BALB/c animals were inoculated with suspensions of the 4T1 cells at different densities in the 4th mammary gland. The course of the disease was monitored, however, the animals were not able to generate tumors satisfactorily. New assays should be performed in order to optimize the establishment of this breast cancer model. In summary, this work identified a promising molecule that should be further evaluated in future in vitro and in vivo studies. Keywords: Serine Arginine Protein kinases. Murine cells. Breast câncer metastatic.

Le mélanome est caractérisé par un remodelage métabolique important, participant à la métastase et à la résistance aux traitements. Les coactivateurs 1 du récepteur activé par le proliférateur du peroxisome (PPARγ), ou PGC-1s, constituent une famille de coactivateurs qui potentialisent la transcription de gènes du métabolisme et de la biogenèse mitochondriale, participant ainsi à la reprogrammation métabolique des cellules cancéreuses. Les différents cancers de la peau expriment des niveaux variables de PGC-1s et les tumeurs qui expriment fortement les PGC-1s présentent un profil pro-inflammatoire et immunosuppresseur favorisant l’évasion immunitaire. Ceci suggère un rôle des PGC-1s dans la réponse à l’immunothérapie. Nous montrons d’abord que la déplétion en PGC-1β diminue la prolifération de lignées cellulaires de mélanome en plus d’induire l’expression de cytokines pro-inflammatoires et de transcrits immunosuppresseurs. À ce jour, les mécanismes permettant de réguler l’expression et l’activité des PGC-1s demeurent inconnus. Nous montrons que différents stress cellulaires affectant des procédés métaboliques, épigénétiques ou la traduction diminuent l’expression des PGC-1s et la viabilité de lignées cellulaires de mélanome. Nous montrons également un mécanisme de régulation de PGC-1β par une protéine de liaison à l’ARN soutenant le rôle de PGC-1β dans la réponse à différents stress et la survie des cellules de mélanome. Cette régulation serait importante pour l’immunosuppression du mélanome et dicterait la réponse à l’immunothérapie. En conclusion, ces travaux illustrent bien le rôle de PGC-1β dans la reprogrammation métabolique et la réponse au stress du mélanome, ces processus pouvant influencer l’inflammation et l’immunosuppression du microenvironnement afin d’assurer la progression tumorale., Melanoma is characterized by a significant metabolic remodeling, which contributes to metastasis and treatment resistance. Peroxisome proliferator-activated receptor gamma (PPARγ) coactivators 1, or PGC-1s, are a family of coactivators that potentiate the transcription of genes involved metabolism and mitochondrial biogenesis, thus participating in the metabolic reprogramming of cancer cells. Different skin cancers express varying levels of PGC-1s and tumors that strongly express PGC-1s exhibit a proinflammatory and immunosuppressive profile that favors immune evasion. This suggests that PGC-1s play a role in melanoma response to immunotherapy. We first show that PGC-1β knockdown decreases the proliferation of melanoma cell lines. Moreover, it induces the expression of proinflammatory cytokines and immunosuppressive transcripts. To date, the mechanisms that regulate the expression and activity of PGC-1s remain unknown. We show that different cellular stresses affecting metabolic and epigenetic processes or translation decrease PGC-1s expression and the viability of melanoma cell lines. We also show a mechanism of regulation of PGC-1β by an RNA-binding protein enhencing the role of PGC-1β in the response to different stresses and the survival of melanoma cells. This regulation could contribute to melanoma immunosuppression and determine the tumor’s response to immunotherapy. In conclusion, this work illustrates well the role of PGC-1β in melanoma metabolic reprogramming and stress response, processes that regulate inflammation and create an immunosuppressive tumor microenvironment in order to ensure tumor progression.

Introduction: Nasopharyngeal carcinoma has the highest metastatic potential of all head and neck cancers. The survival time of patients with nasopharyngeal carcinoma has improved significantly in the last decades due to the use of combination of chemotherapy and radiotherapy, as well as advances in radiotherapy techniques. However, appropriately 30% of patients with nasopharyngeal carcinoma suffer a poor prognosis, mainly due to distant metastasis. Objective: The study aimed to identify the survival and prognostic factors in metastatic nasopharyngeal carcinoma. Methods: A retrospective analysis was conducted in patients treated for synchronous metastatic nasopharyngeal carcinoma or metachronous metastatic nasopharyngeal carcinoma for 14years (2003–2016). Overall survival was analyzed using the Kaplan-Meier method and compared using the log-rank test for the whole population and both groups of patients. Multivariate analysis was performed using the Cox model; p-values < 0.05 were considered to indicate statistical significance. Results: One hundred and twelve patients with metastatic nasopharyngeal carcinoma were included (51 patients with metastatic nasopharyngeal carcinoma, and 61 patients with metachronous metastatic nasopharyngeal carcinoma). In the whole population, the median overall survival was 10 months (1–156 months). In the multivariate analysis, female gender, poor performance status (WHO > 1) and metachronous metastasis were independent prognostic factors. In the metastatic nasopharyngeal carcinoma patients, the median overall survival was 13 months (1–156 months). In multivariate analysis, independent prognostic factors were non-oligometastatic disease, severe (G3–G4) chemotherapy toxicity and the lack of nasopharyngeal and metastatic site irradiation. In the metachronous metastatic nasopharyngeal carcinoma patients, the median overall survival was 7 months (1–41 months). In multivariate analysis, the poor performance status (WHO > 1) was an independent metastatic nasopharyngeal carcinoma prognostic factor. Conclusion: Oligometastatic patients with synchronous metastatic nasopharyngeal carcinoma had better survival. The locoregional treatment of primitive nasopharyngeal carcinoma improved survival in patients with metastatic nasopharyngeal carcinoma who responded to induction chemotherapy. Local irradiation of metastatic sites improved survival of metastatic nasopharyngeal carcinoma patients. Grade 3 or 4 chemotherapy toxicity altered survival among patients with synchronous metastatic nasopharyngeal carcinoma. Resumo Introdução: O carcinoma nasofaríngeo tem o maior potencial metastático de todos os tipos de câncer de cabeça e pescoço. O tempo de sobrevida dos pacientes com carcinoma nasofaríngeo melhorou significativamente nas últimas décadas devido ao uso combinado de quimioterapia e radioterapia e os avanços nas técnicas de radioterapia. No entanto, aproximadamente 30% dos pacientes com carcinoma nasofaríngeo têm um prognóstico ruim, principalmente devido a metástases a distância. Objetivo: Identificar a sobrevida e os fatores prognósticos no carcinoma nasofaríngeo metastático. Método: Foi feita uma análise retrospectiva de pacientes tratados por carcinoma nasofaríngeo metastático sincrônico ou carcinoma nasofaríngeo metastático metacrônico por 14 anos (2003-2016). A sobrevida global foi analisada pelo método de Kaplan-Meier e comparada pelo teste de log-rank para toda a população e ambos os grupos de pacientes. A análise multivariada foi feita com o modelo de Cox; valores de p < 0,05 foram considerados como significância estatística. Resultados: Foram incluídos 112 pacientes com carcinoma nasofaríngeo metastático (51 com carcinoma nasofaríngeo metastático sincrônico e 61 com carcinoma nasofaríngeo metastático metacrônico). Em toda a população, a mediana da sobrevida global foi de 10 meses (1–156 meses). Na análise multivariada, sexo feminino, baixo status de desempenho (OMS > 1) e metástase metacrônica foram fatores prognósticos independentes. Nos pacientes com carcinoma nasofaríngeo metastático sincrônico, a mediana da sobrevida global foi de 13 meses (1–156 meses). Na análise multivariada, os fatores prognósticos independentes foram doença não oli-gometastática, toxicidade grave à quimioterapia (G3 – G4) e falta de irradiação nasofaríngea e do sítio metastático. Nos pacientes com carcinoma nasofaríngeo metastático metacrônico, a mediana da sobrevida global foi de 7 meses (1–41 meses). Na análise multivariada, o baixo status de desempenho (OMS > 1) foi um fator prognóstico independente. Conclusão: Pacientes oligometastáticos com carcinoma nasofaríngeo metastático sincrônico tiveram melhor sobrevida. O tratamento locorregional do carcinoma nasofaríngeo primário melhorou a sobrevida em pacientes com carcinoma nasofaríngeo metastático sincrônico que responderam à quimioterapia de indução. A irradiação local dos locais metastáticos melhorou a sobrevida dos pacientes com carcinoma nasofaríngeo metastático. A toxicidade de quimioterapia de grau 3 ou 4 alterou a sobrevida entre pacientes com carcinoma nasofaríngeo metastático sincrônico.

RESUMO 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. ABSTRACT 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.

International audience; We report a case of malignant melanoma revealed by a metastasis to the pituitary gland. The tumor was misdiagnosed as a pituitary adenoma and aggressive transsphenoidal surgery was complicated by a cerebrospinal fluid fistula. Nine weeks later, the patient presented multiple leptomeningeal and brain metastases spreading from the sellar region. Regarding these observations, we conducted a systematic review of the literature in order to investigate clinicoradiological features that should lead clinicians to suspect pituitary metastasis and how it should impact the surgical management.

Context Although health-related quality of life (HRQoL) is a fundamental outcome in oncological clinical trials, its evaluation in the neuroendocrine neoplasm (NEN) research field is still limited. Objectives This study assessed the role of clinical severity (ie, presence or absence of metastasis and lines of therapies) and heterogeneity (ie, primary site, types of therapy, biology, and surgery) of NEN in relation to HRQoL, as well as resilience as a moderator between clinical severity and HRQoL. Design Cross-sectional multicentric study. Setting Italian university hospitals. Patients A total of 99 Italian patients (53 men and 46 women) with NEN and ranged in age from 22–79 years old. Main Outcome Measure Severity and heterogeneity of NENs, HRQoL, and resilience. Results The presence of metastasis and a greater number of therapies affected the global health and some physical symptoms. Resilience was associated with global health, functional status, and some physical symptoms, and it moderated the impact of metastases on constipation and of the multiple therapies on diarrhea and financial problems. Patients with NEN in districts other than the gastroenteropancreatic system and those in follow-up perceived fewer physical symptoms than their counterparts. Patients with a sporadic NEN perceived their functional status, global health, and disease-related worries as better than those with a hereditary NEN. Patients who underwent surgery were lower in constipation than their counterparts. Conclusion These findings highlight the need to assess the relationships between the clinical severity and heterogeneity of NEN with HRQoL and the role of resilience in improving patients’ HRQoL.

BACKGROUND The therapeutic approach of metastatic renal cell carcinoma (RCC) represents a real challenge for clinicians, because of the variable clinical course; the recent availability of numerous targeted therapies that have significantly improved overall oncological results, but still with a low percentage of complete responses; and the increasing role of metastasectomy (MSX) as an effective strategy to achieve a durable cure, or at least defer initiation of systemic therapies, in selected patients and in the context of multimodality treatment strategies. CASE SUMMARY We report here the case of a 40-year-old man who was referred to our unit in November 2004 with lung and mediastinal lymph nodes metastases identified during periodic surveillance 6 years after a radical nephrectomy for RCC; he underwent MSX of multiple lung nodules and mediastinal lymphadenectomy, with subsequent systemic therapy with Fluorouracil, Interferon-alpha and Interleukin 2. The subsequent clinical course was characterized by multiple sequential abdominal and thoracic recurrences, successfully treated with multiple systemic treatments, repeated local treatments, including two pancreatic resections, conservative resection and ablation of multiple bilobar liver metastases, resection and stereotactic body radiotherapy of multiple lung metastases. He is alive without evidence of recurrence 20 years after initial nephrectomy and sequential treatment of recurrences in multiple sites, including resection of more than 38 metastases, and 5 years after his last MSX. CONCLUSION This case highlights that effective multimodality therapeutic strategies, including multiple systemic treatments and iterative aggressive surgical resection, can be safely performed with long-term survival in selected patients with multiple metachronous sequential metastases from RCC.

Introduction: Nasopharyngeal carcinoma, an epithelial-derived malignant tumor which because of its anatomical location and atypical early symptoms, when diagnosed invasion and metastasis often have occurred. This requires a better understanding of the development mechanism, identifying diagnostic markers, and developing new treatment strategies. Objective: To study the relationship of LMP1 and Cripto-1 in nasopharyngeal carcinoma. Methods: The expression of LMP1 and Cripto-1 in specimens obtained from nasopharyngeal carcinoma patients (n = 42) and nasopharyngitis patients (n = 22) were examined. The expression of LMP1 and Cripto-1 in LMP1-negative and LMP1-positive (CNE1-LMP1) cells were also examined. Results: The expression of LMP1 and Cripto-1 was significantly higher in nasopharyngeal carcinoma than in nasopharyngitis (p

Abstract Background Triple-negative breast cancer (TNBC) is a uniquely aggressive cancer with high rates of relapse due to resistance to chemotherapy. TNBC expresses higher levels of programmed cell death-ligand 1 (PD-L1) compared to other breast cancers, providing the rationale for the recently approved immunotherapy with anti-PD-L1 monoclonal antibodies (mAbs). A huge effort is dedicated to identify actionable biomarkers allowing for combination therapies with immune-checkpoint blockade. Platelet-derived growth factor receptor β (PDGFRβ) is highly expressed in invasive TNBC, both on tumor cells and tumor microenvironment. We recently proved that tumor growth and lung metastases are impaired in mouse models of human TNBC by a high efficacious PDGFRβ aptamer. Hence, we aimed at investigating the effectiveness of a novel combination treatment with the PDGFRβ aptamer and anti-PD-L1 mAbs in TNBC. Methods The targeting ability of the anti-human PDGFRβ aptamer toward the murine receptor was verified by streptavidin-biotin assays and confocal microscopy, and its inhibitory function by transwell migration assays. The anti-proliferative effects of the PDGFRβ aptamer/anti-PD-L1 mAbs combination was assessed in human MDA-MB-231 and murine 4 T1 TNBC cells, both grown as monolayer or co-cultured with lymphocytes. Tumor cell lysis and cytokines secretion by lymphocytes were analyzed by LDH quantification and ELISA, respectively. Orthotopic 4 T1 xenografts in syngeneic mice were used for dissecting the effect of aptamer/mAb combination on tumor growth, metastasis and lymphocytes infiltration. Ex vivo analyses through immunohistochemistry, RT-qPCR and immunoblotting were performed. Results We show that the PDGFRβ aptamer potentiates the anti-proliferative activity of anti-PD-L1 mAbs on both human and murine TNBC cells, according to its human/mouse cross-reactivity. Further, by binding to activated human and mouse lymphocytes, the aptamer enhances the anti-PD-L1 mAb-induced cytotoxicity of lymphocytes against tumor cells. Importantly, the aptamer heightens the antibody efficacy in inhibiting tumor growth and lung metastases in mice. It acts on both tumor cells, inhibiting Akt and ERK1/2 signaling pathways, and immune populations, increasing intratumoral CD8 + T cells and reducing FOXP3 + Treg cells. Conclusion Co-treatment of PDGFRβ aptamer with anti-PD-L1 mAbs is a viable strategy, thus providing for the first time an evidence of the efficacy of PDGFRβ/PD-L1 co-targeting combination therapy in TNBC.

RESUMO 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. ABSTRACT 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.

The objective of this study was to describe the case of a three-year-old dog of the Shih-tzu breed, whole and not cryptorchid, treated at the Veterinary Hospital of the Centro Universitário INTA-UNINTA in the city of Sobral - CE, with a complaint of increased volume in the scrotal region. Upon physical examination, it was verified that both testes were present in the scrotum, with bilateral increase in volume, noting a firm and adherent mass in the incision region for a vasectomy procedure performed six months ago in another veterinary establishment. The animal was referred for surgical treatment with orchiectomy, scrotal ablation and subsequent exploratory laparotomy, in view of the findings at the time of orchiectomy and abdominal ultrasound indications. The macroscopic and microscopic analyzes of the testes and the entire extension of the affected omentum, observed during the operation, led to the diagnosis of seminoma with metastasis to the omentum. In view of the above, the importance of the description of this case brings veterinary clinical relevance that can facilitate research and new reports with the same content addressed, associated with the scarcity of works that can relate the performance of vasectomy with the boost in the development and dissemination of testicular neoplasms, as well as adds epidemiological data to seminomas in dogs, taking into account that early assessment of the male reproductive system can influence the achievement of better prognostic results for patients, providing more information to the study of testicular neoplasms. El objetivo de este estudio fue describir el caso de un perro de raza Shih-tzu de tres años, entero y no criptorquídeo, atendido en el Hospital Veterinario del Centro Universitário INTA-UNINTA en el municipio de Sobral - CE, con una queja de aumento de volumen en la región del escroto En el médico veterinario se verificó la presencia de dos testículos ecrotales, con aumento de tejido en masa y región de incisión firme para examen físico hace seis meses en otro establecimiento. El animal fue remitido para tratamiento quirúrgico con orquiectomía, ablación escrotal y posterior en vista de los hallazgos al momento de la orquiectomía y las indicaciones ecográficas. Como exámenes macroscópicos y microscópicos de los testículos y toda la extensión de la afectación, observados en el período intraoperatorio, condujeron al diagnóstico de seminoma con metástasis al epiplón. En vista de lo anterior, la importancia de la descripción de este caso trae relevancia clínica veterinaria que puede facilitar investigaciones y nuevos informes con el mismo contenido abordado, asociado a la escasez de trabajos que puedan relacionar la realización de la vasectomía con el impulso en el desarrollo y diseminación de las neoplasias testiculares, así como agrega datos epidemiológicos a los seminomas en perros, teniendo en cuenta que la evaluación temprana del aparato reproductor masculino puede influir en la consecución de mejores resultados pronósticos para los pacientes, aportando mayor información al estudio de las neoplasias testiculares. O objetivo deste trabalho foi descrever o caso de um cão da raça Shih-tzu, três anos, inteiro e não criptorquida, atendido no Hospital Veterinário do Centro Universitário INTA-UNINTA no município de Sobral - CE, com queixa de aumento de volume em região escrotal. Ao exame físico, observou-se a presença dos dois testículos na bolsa escrotal, com aumento de volume bilateral, notando-se massa aderida e firme em região de incisão para a realização de um procedimento de vasectomia executado anteriormente. O animal foi encaminhado para tratamento cirúrgico com realização de orquiectomia, ablação escrotal e posterior laparotomia exploratória, tendo em vista os achados no momento da orquiectomia e indicativos ultrassonográficos abdominais. As análises macroscópicas e microscópicas dos testículos e toda extensão do omento comprometido, observado no transoperatório, levaram ao diagnóstico de seminoma com metástase para omento. Perante o exposto, a importância da descrição deste caso traz relevância clínica veterinária que pode facilitar pesquisas e novos relatos com o mesmo conteúdo abordado, associada a escassez de trabalhos que possam relacionar a realização de vasectomia com o impulsionamento no desenvolvimento e disseminação das neoplasias testiculares, bem como acrescenta dados epidemiológicos aos seminomas em cães, levando-se em conta que avaliação precoce do sistema reprodutor masculino pode influenciar na obtenção de melhores resultados prognósticos aos pacientes, fornecendo mais informações ao estudo de neoplasias testiculares.

Submitted by Isabela Fernanda Spinelli Perossi (isabela.perossi@unesp.br) on 2022-04-03T15:48:15Z No. of bitstreams: 1 Dissertação Isabela Fernanda Spinelli Perossi.pdf: 1723514 bytes, checksum: 7872279c3a389cf1d66c1ecd044ca121 (MD5) Approved for entry into archive by Vivian Letícia Duarte Parisi (vivian.parisi@unesp.br) on 2022-04-04T14:06:49Z (GMT) No. of bitstreams: 1 perossi_ifs_me_sjrp.pdf: 1723514 bytes, checksum: 7872279c3a389cf1d66c1ecd044ca121 (MD5) Made available in DSpace on 2022-04-04T14:06:49Z (GMT). No. of bitstreams: 1 perossi_ifs_me_sjrp.pdf: 1723514 bytes, checksum: 7872279c3a389cf1d66c1ecd044ca121 (MD5) Previous issue date: 2022-03-07 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) O câncer de mama (CM) é um relevante problema de saúde pública, pois representa a segunda principal causa de morte relacionada ao câncer em mulheres em todo o mundo. Os cães são utilizados como modelo para estudos desses tumores, pois além da grande ocorrência, possuem semelhanças biológicas e fisiopatológicas. A via PIK3CA/AKT/mTOR está fortemente desregulada no câncer de mama e desempenha papel central na homeostase celular. A literatura recente retrata que todas as mutações somáticas identificadas a partir do gene PIK3CA alteraram as sequências de aminoácidos, dentre eles a variante c.3140A> G. Esse gene participa da regulação de uma ampla gama de atividades celulares relevantes englobando várias proteínas importantes. Na medicina veterinária o estudo desta via é incipiente. O objetivo deste trabalho foi analisar a variante c.3140A>G do gene PI3KCA e a expressão das proteínas alvo PIK3CA, PTEN, HIF, VHL, ZEB1, ZEB 2, Caspase-3 e PARP1 como marcadores prognósticos em um estudo prospectivo, verificando a expressão gênica dessa variante e, em um estudo retrospectivo, avaliando a expressão proteica e gênica de alvos moleculares à jusante da via correlacionando com o prognóstico nas cadelas. No estudo retrospectivo, o DNA de 24 fragmentos de tumores mamários caninos e 20 fragmentos normais de mama de cadelas foi extraído e a mutação verificada usando TaqMan® Mutation Detection Assay. A imunohistoquímica foi realizada com o kit Reveal HRP Conjugate e sua análise pelo método Histoscore. Duas pacientes (8,3%) apresentaram a mutação c.3140A> G, sendo que uma paciente apresentou metástase pulmonar e morreu em 30 dias após o diagnóstico e a outra paciente permanece viva. Os dados de imunohistoquímica revelaram que a expressão das proteínas PIK3CA, HIF, ZEB2 e PARP1 foi maior na paciente que veio a óbito em comparação com a que permanece viva (p G. This gene participates in the regulation of a wide range of relevant cellular activities encompassing several important proteins. In veterinary medicine, the study of this pathway is incipient. The objective of this work was to analyze the c.3140A>G variant of the PI3KCA gene and the expression of the target proteins PIK3CA, PTEN, HIF, VHL, ZEB1, ZEB 2, Caspase-3 and PARP1 as prognostic markers in a prospective study, verifying the gene expression of this variant and, in a retrospective study, evaluating the protein and gene expression of molecular targets downstream of the pathway correlating with the prognosis in bitches. In the retrospective study, DNA from 24 canine mammary tumor fragments and 20 canine normal mammary fragments was extracted and mutation verified using the TaqMan® Mutation Detection Assay. Immunohistochemistry was performed with the Reveal HRP Conjugate kit (Spring®) and its analysis was performed using the Histoscore method. Two patients (8.3%) had the c.3140A>G mutation, one patient had lung metastasis and died within 30 days of diagnosis and the other patient remains. Immunohistochemistry data revealed that the expression of PIK3CA, HIF, ZEB2 and PARP1 proteins was higher in the patient who died compared to the one who remained alive (p

Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq This doctoral thesis was divided into three parts, resulting in three scientific articles. The first article aimed to investigate the presence of lesions indicative of solar or viral etiology in cutaneous squamous cell carcinomas (SCCs) of dogs and cats and to relate them to the expression of p53 and p16 proteins, and to evaluate the degree of intraepidermal pigmentation. A total of 152 cases of SCCs were evaluated, 89 in dogs and 63 in cats. Lesions indicative of solar etiology (55/152) predominated in SCCs in region exposed to solar radiation. There was a statistically significant association between histological lesions indicative of solar etiology with a low degree of intraepidermal pigmentation in SCCs of dogs and cats. A statistically significant association between histological lesions indicative of solar etiology and p53 expression was observed only in dogs. On the other hand, lesions suggestive of a viral etiology (19/152) were frequent in SCCs in regions protected from solar radiation. There was a statistically significant association between lesions suggestive of viral etiology and p16 expression only in SCCs in cats. Immunostaining for papillomavirus was rarely present (in p16 positive cases and with lesions suggestive of viral origin). The second study aimed to evaluate the prevalence and anatomopathological characterization of metastatic SCCs in dogs and cats. In 36 years, 478 cases of SCCs were received for diagnosis, among which metastases were present in 21 cases (4.39%), twelve in dogs (57%) and nine in cats (43%). Regional metastases predominated. Lymph nodes (19/21) and lung (7/21) were the most affected organs. Moderately differentiated SCCs metastasized more frequently (9/21). The mitotic count and the AgNOR index varied greatly between species and between histological grades. The collective migration and invasion pattern predominated in the well-differentiated SCCs and the individual cell pattern in the poorly-differentiated SCCs. All metastatic SCCs were associated with a marked desmoplastic reaction. The presence of myofibroblasts was detected by immunohistochemistry (IHC) in the desmoplastic reaction, mainly in the “tumor invasion front”. The third article aimed to report two unusual cases of SCCs with mucinous metaplasia in dogs. On histology, both dogs showed a proliferation of neoplastic keratinocytes with intratumoral mucin production. From the histological findings associated with an IHC panel, it was possible to rule out other differential diagnoses. Thus, this report described the mucin-producing subtype in two cutaneous SCCs in dogs. Esta tese de doutorado foi dividida em três partes, resultando em três artigos científicos. O primeiro artigo constituiu em investigar a presença de lesões indicativas de etiologia solar ou viral em carcinomas de células escamosas (CCEs) cutâneos de cães e gatos, relacioná-las com a expressão das proteínas p53 e p16 e avaliar o grau de pigmentação intraepidérmico. Foram avaliados 152 casos de CCEs, sendo 89 em cães e 63 em gatos. As lesões indicativas de etiologia solar (55/152) predominaram nos CCEs em locais expostos à radiação solar. Houve uma associação estatística significativa entre as lesões histológicas indicativas de etiologia solar com um baixo grau de pigmentação intraepidérmico em CCEs de cães e gatos. Uma associação estatística significativa entre as lesões histológicas indicativas de etiologia solar com a expressão da p53 foi observada somente em cães. Já as lesões sugestivas de etiologia viral (19/152) eram frequentes nos CCEs em regiões protegidos da radiação solar. Houve uma associação estatística significativa entre as lesões sugestivas de etiologia viral e a expressão da p16 somente nos CCEs em gatos. A imunomarcação para papilomavírus estava raramente presente (em casos p16 positivos e com lesões sugestivas de origem viral). O segundo estudo teve como objetivo avaliar a prevalência e caracterização anatomopatológica de CCEs metastáticos em cães e gatos. Em 36 anos foram recebidos para diagnóstico 478 casos de CCEs, dentre os quais as metástases estavam presentes em 21 casos (4,39%), doze em cães (57%) e nove em gatos (43%). As metástases regionais predominaram. Os linfonodos (19/21) e o pulmão (7/21) foram os órgãos mais acometidos. Os CCEs moderadamente diferenciados metastatizaram com mais frequência (9/21). A contagem mitótica e o índice AgNOR variaram muito em relação às espécies e entre os graus histológicos. O padrão de migração e invasão coletivo predominou nos CCEs bem diferenciados e o padrão de células individuais nos CCEs pouco diferenciados. Todos os CCEs metastáticos estavam associados a uma reação desmoplásica acentuada. A presença de miofibroblastos foi detectada por imuno-histoquímica (IHQ) na reação desmoplásica, principalmente na “frente de invasão tumoral”. O terceiro artigo teve como objetivo relatar dois casos incomuns de CCEs com metaplasia mucinosa em cães. Na histologia, ambos os cães apresentaram uma proliferação de ceratinócitos neoplásicos com produção de mucina intratumoral. A partir dos achados histológicos associados à um painel de IHQ foi possível descartar outros diagnósticos diferenciais. Dessa forma, esse relatado descreveu o subtipo produtor de mucina em dois CCEs cutâneos em cães.

A incidência de melanoma cutâneo tem aumentado nas últimas décadas, enquanto os pacientes com melanoma em estágio inicial, I ou II, têm um prognóstico favorável com a cirurgia como o principal e único tratamento necessário, e aqueles com melanoma em estágio III ou IV têm prognóstico pior. A cirurgia continua a ter um papel fundamental no tratamento em face dessas terapias sistêmicas mais eficazes para melanoma avançado e pode estar associada a uma melhor sobrevida em longo prazo. Os pacientes com suspeita de doença metastática à distância devem ser submetidos a uma avaliação abrangente para avaliar os locais e a carga da doença antes de considerar a cirurgia. O fígado e o SNC são locais comuns e frequentemente a causa de morte por melanoma metastático. Outros locais incluem pele, pulmão, nódulos linfáticos, trato gastrointestinal, glândula adrenal, pâncreas, baço e osso.

Hintergrund: Stichkanalmetastasierung ist in der lokalen Behandlung des hepatozellulären Karzinoms (HCC) für die kathetergestützte Hochdosis-Brachytherapie (HDR-BT), eine neuartige lokale Ablationsmethode, noch nicht untersucht worden. Material und Methoden: Es handelt sich um eine retrospektive Analyse von 100 Patienten, die An 233 HCC-Läsionen mit HDR-BT behandelt wurden (mit insgesamt 588 Kathetern). Eine Bestrahlung des Stichkanals fand nicht statt. Der Follow-Up-Zeitraum betrug mindestens 6 Monate. Bei Verdacht auf eine Stichkanalmetastasierung (intra- und/oder extrahepatisch) im Follow-Up-Zeitraum wurde die Bildfusion der Nachbeobachtungs-CT/MRT mit dem 3D- Bestrahlungsplan verwendet, um die Lage einer neuen Tumorabsiedelung innerhalb des Pfades eines Brachytherapiekatheters zum Zeitpunkt der Behandlung zu überprüfen. Ergebnisse: Es wurden 9 Stichkanalmetastasen identifiziert, was einem Katheter-basierten Risiko von 1,5 % für jeden Ort des Auftretens entspricht. Insgesamt 7 Metastasen befanden Sich innerhalb der Leber (katheterbasiertes Risiko, 1,2 %), und 2 Metastasen befanden sich extrahepatisch (katheterbasiertes Risiko, 0,3 %). 8 von 9 Stickkanalmetastasen wurden erfolgreich durch eine weitere HDR-BT behandelt. Schlussfolgerungen: Das Risiko einer Stichkanalmetastasierung nach interstitieller HDR-BT Des HCC ist vergleichbar mit früheren Berichten über perkutane Biopsien und Radiofrequenzablation (RFA), insbesondere im Fall von extrahepatischen Stichkanalmetastasen. Um das Risiko einer Aussaat zu kompensieren, sollte in der klinischen Routine eine Bestrahlungstechnik eingesetzt werden, die der Spurablation bei der RFA ähnelt. Durch diese Maßnahme könnte die interstitielle Brachytherapie zunehmend einen Stellenwert Bei der Therapie des HCC auch in Hinblick auf besonders stichkanalmetastasensensible Indikationen wie der Überbrückung („Bridging“) zur Lebertransplantation erreichen.

CD137 und CD137L stellen ein Rezeptor-Liganden-Paar dar, welches auf vielen Immunzellen exprimiert wird und eine wichtige Rolle im Rahmen der Immunstimulation spielt. CD137L fungiert jedoch nicht nur als Ligand sondern auch als Rezeptor und vermittelt als ein solcher Signale in die ihn exprimierende Zelle. Neben seinem Vorkommen auf Immunzellen wird CD137L auch von einigen Tumorzellen exprimiert, unter anderem auch auf denen des Kolonkarzinoms. In dieser Tumorentität korreliert eine hohe CD137L-Expression mit dem Auftreten von Fernmetastasen und einer insgesamt schlechteren Prognose. Die genaue Rolle von CD137L im Kolonkarzinom ist bislang kaum erforscht. Im Rahmen dieser Arbeit wurden daher die Auswirkungen einer CD137L-Aktivierung auf die Proliferation sowie die Proteinexpression und -sekretion von Kolonkarzinomzellen untersucht. Die Ergebnisse deuten erstmals darauf hin, dass die CD137L-Stimulation in vitro die Proliferation der entarteten Zellen reduziert und die Expression bzw. Sekretion der Proteine Vimentin, TLR7, VEGF und PDGF steigert. Hieraus wird geschlossen, dass eine Stimulation des von den Kolonkarzinomzellen exprimierten CD137L dazu führt, dass sich der Phänotyp der Tumorzellen von einem epithelialen in Richtung eines mesenchymalen Zelltyps verändert. Darüber hinaus werden vermehrt Proteine exprimiert und sezerniert, welche über unterschiedliche Signalwege an der Invasion und Migration der entarteten Zellen beteiligt sind. Folglich lässt sich annehmen, dass CD137L eine entscheidende Rolle im Metastasierungsprozess von humanen Kolonkarzinomzellen spielt. Sollte sich dies in weiterführenden Untersuchungen bestätigen, könnte eine pharmazeutische Beeinflussung der beteiligten Signalwege möglicherweise die Prognose von an Kolonkarzinomen erkrankten Patient:innen deutlich verbessern., CD137 and CD137L represent a receptor/ligand-pair expressed on a variety of immune cells which exerts an important immunostimulatory effect. Besides its function as a ligand to CD137, CD137L also acts as a receptor itself, thereby transmitting signals into the cell via reverse signaling. Apart from being expressed on immune cells CD137L is also found on many tumor cells, including colon carcinoma cells. In this tumor entity the expression is positively correlated with distant metastases and poor prognosis, nevertheless little is known about the function of CD137L in the progression of colon cancer. The aim of this study was to investigate the effects of CD137L-mediated reverse signaling on protein expression and secretion in human colon cancer cells in vitro. The results indicate for the first time that a stimulation of the cells via CD137L induces a decreased proliferation and an increased expression or secretion of the proteins vimentin, TLR7, VEGF and PDGF. Reverse signaling via CD137L proposedly leads to a transition of the cancer cells from an epithelial to a mesenchymal phenotype. In addition, the increasingly expressed and secreted proteins presumably activate signaling pathways which are involved in the invasion and migration of the tumor cells. Hence it is suggested, that CD137L plays a crucial role in the process of metastasis of human colon cancer cells. Should this be confirmed by further studies, impairing this pathway could represent a promising new therapeutic approach which could improve the prognosis of patients suffering from colon cancer.

Die Kenntnis möglicher Risikofaktoren für Speicheldrüsentumoren, sowie deren Differenzierung, insbesondere in maligne und benigne, sind Voraussetzung für eine optimale Therapieplanung. Es erfolgte die retrospektive Analyse von 625 Patienten, die im JWK Minden an der Gl. parotis operiert wurden. Neben dem histologischen Ergebnis wurden Patientenmerkmale und deren Konsumverhalten analysiert. Zudem wurden Daten zur prä- und postoperativen Funktion des N. facialis und der präoperativen Bildgebung gesammelt. Prä- und postoperative Facialisparesen zeigten sich vermehrt bei Speicheldrüsenkarzinomen und Tumormetastasen. Für Warthin-Tumoren und Nikotinkonsum konnte eine positive Korrelation nachgewiesen werden. Warthin-Tumoren traten deutlich häufiger auf als pleomorphe Adenome. Verglichen mit älteren Quellen zeigen aktuelle Studien eine verhältnismäßige Zunahme der Warthin-Tumoren zu den pleomorphen Adenomen. Hierfür konnte bisher keine eindeutige Ursache nachgewiesen werden.

Ependymomas are commonly classified as low-grade tumors, although they may harbor a malignant behavior characterized by distant neural dissemination and spinal drop metastasis. Extra-CNS ependymoma metastases are extremely rare and only few cases have been reported in the lung, lymph nodes, pleura, mediastinum, liver, bone, and diaphragmatic, abdominal, and pelvic muscles. A review of the literature yielded 14 other case reports metastasizing outside the central nervous system, but to our knowledge, no studies describe metastasis in the paravertebral muscles. Herein, we report the case of a 39-year-old patient with a paraspinal muscles metastasis from a myxopapillary ependymoma. The neoplasm was surgically excised and histologically and molecularly analyzed. Both the analyses were consistent with the diagnosis of muscle metastases of myxopapillary ependymoma. The here-presented case report is first case in the literature of a paraspinal muscles metastasis of myxopapillary ependymoma.

Gastric cancer (GC) is the third cause of cancer-related mortality worldwide. Nevertheless, because GC screening programs are not cost-effective, most patients receive diagnosis in the advanced stages, when surgical options are limited. Peritoneal dissemination occurs in approximately one-third of patients with GC at the diagnosis and is a strong predictor of poor outcome. Despite the clinical relevance, biological and molecular mechanisms underlying the development of peritoneal metastasis in GC remain poorly defined. Here, we report results of a high-throughput sequencing of transcriptome expression in paired samples of non-neoplastic and neoplastic gastric samples from 31 patients with GC with or without peritoneal carcinomatosis. The RNA-seq analysis led to the discovery of a group of highly upregulated or downregulated genes, including the leukemia inhibitory factor receptor (LIFR) and one cut domain family member 2 (ONECUT2) that were differentially modulated in patients with peritoneal disease in comparison with patients without peritoneal involvement. Both LIFR and ONECUT2 predicted survival at univariate statistical analysis. LIFR and its major ligand LIF belong to the interleukin-6 (IL-6) cytokine family and have a central role in immune system regulation, carcinogenesis, and dissemination in several human cancers. To confirm the mechanistic role of the LIF/LIFR pathway in promoting GC progression, GC cell lines were challenged in vitro with LIF and a LIFR inhibitor. Among several GC cell lines, MKN45 cells displayed the higher expression of the receptor, and their exposure to LIF promotes a concentration-dependent proliferation and epithelial–mesenchymal transition (EMT), as shown by modulation of relative expression of E-cadherin/vimentin along with JAK and STAT3 phosphorylation and acquisition of a migratory phenotype. Furthermore, exposure to LIF promoted the adhesion of MKN45 cells to the peritoneum in an ex vivo assay. These effects were reversed by the pharmacological blockade of LIFR signaling. Together, these data suggest that LIFR might have a major role in promoting disease progression and peritoneal dissemination in patients with GC and that development of LIF/LIFR inhibitors might have a role in the treatment of GC.

Trotz der Fortschritte in den therapeutischen Konzepten der Behandlung solider Tumoren wie dem Plattenepithelkarzinom des Kopf-Hals-Bereiches (HNSCC– head neck squamous cell carcinoma), die sich hauptsächlich auf chirurgische, strahlen- und/oder chemotherapeutische Interventionen stützen hat sich die 5-Jahres-Überlebensrate in den letzten 20 Jahren kaum verändert. Die Onkogene Bruton’sche Tyrosinkinase (BTK) und der Adenosinrezeptor 2B (ADORA2B) könnten in Zukunft im Rahmen einer zielgerichteten Chemotherapie anvisiert werden. Der BTK-Inhibitor „Ibrutinib“ ist bereits zur Behandlung von Erkrankungen des hämatopoetischen Systems zugelassen. Der ADORA2B-Antagonist PSB-603 zeigte bereits in einigen Studien zu Prostatakarzinomen und HNSCCs vielversprechende Ergebnisse. Das Ziel dieser Arbeit war, weiteren Aufschluss über die Verwendung von BTK-Inhibitoren und ADORA2B-Antagonisten in HNSCC hinsichtlich des Einflusses auf die Metastasierung und Invasion zu bekommen. Solide Tumoren nutzen den Prozess der epithelial-mesenchymalen Transition (EMT) zur Migration von Krebszellen. Die vorliegende Arbeit zeigt das sowohl der ADORA2B- Antagonist PSB-603, sowie der BTK- Inhibitor AVL-292 Einfluss auf morphologische Veränderungen der HNSSC-Zelllinie UD-SCC 1 hat. Zusätzlich werden EMT-Marker auf mRNA- und Proteinebene signifikant beeinflusst. Dies wurde mittels quantitativer Echtzeit- Polymerase-Kettenreaktion (qRT-PCR), sowie Western-Blot-Analysen untersucht. Die Ergebnisse zeigten viele Diskrepanzen, welche schlussendlich suggerierten, dass die Behandlungen mit AVL-292 bzw. PSB-603 zu einer Ausbildung eines intermediären EMT-Phänotypen führten. In vorherigen Studien kam hervor, dass im Zusammenhang mit HNSCC womöglich andere als die in dieser Arbeit untersuchten EMT Marker bzw. Signalwege eine Rolle spielen. Diese würden mehr Aufschluss über das Metastasierungs- und Invasionspotenzial geben. Der zweite Teil der vorliegenden Arbeit beschäftigte sich mit Methylierung, welche eine epigenetische Modifikation ist. Die Literatur der jüngsten Vergangenheit zeigt, dass in soliden Tumoren (z.B. Mammakarzinom oder Kolonkarzinom) andere Isoformen der BTK exprimiert werden als im hämatopoetischen System. Western-Blot-Analysen dieser Arbeit zeigten ebenfalls eine Expression der tumorspezifischen Isoform BTKp80 in Kopf-Hals-Tumor-Zelllinien. Aus diesem Grund stellte sich die Frage nach der Regulation der Isoform BTKp80, welche mittels Pyrosequenzierung untersucht wurde. Die Regulation der BTKp80-Isoform findet über einen alternativen Promotor statt. Die Untersuchungen zweier Sequenzen innerhalb der BTK-Promotorregion zeigten signifikante Unterschiede der Methylierung zwischen Tumorzelllinien und B-Zellen gesunder Spender, welche BTKp80 nicht exprimieren. Die Ergebnisse der vorliegenden Arbeit bezüglich der Methylierung der alternativen Promotorregion von BTK zeigten vielversprechende Ergebnisse, welche jedoch durch Untersuchungen an Ursprungsgeweben ergänzt werden sollten. Weiterhin muss die Interpretation der Ergebnisse unter der Fehlerquote der Methode kritisch betrachtet werden.

Purpose Scientific knowledge on health-related quality of life (HRQoL) in patients with neuroendocrine neoplasm (NEN) is still limited and longitudinal assessment of HRQoL over the time in NEN patients are scarce. The current study aimed to assess the role of clinical severity and heterogeneity of NEN, as well as resilience, in the HRQoL of NEN patients over the course of a year. Methods 39 consecutive NEN patients (25 men and 14 women) aged from 29 to 73 years participated in a longitudinal Italian multicentric study. The main outcome measure concerned the severity and heterogeneity of NEN, HRQoL, and resilience. Results Over the course of a year, higher levels of the global health (GH) were associated to the absence of distant metastases, while the presence of metastases with higher levels of fatigue, diarrhea, and financial difficulties. Higher levels of resilience are still associated with better GH and lower levels of fatigue, diarrhea, and financial difficulties, but no longer with constipation. Furthermore, patients with gastroenteropancreatic NEN still have higher scores on constipation, but not on GH, fatigue, diarrhea, and financial difficulties. Patients with hereditary NEN continue to have greater GH than those with a sporadic NEN and lower fatigue, diarrhea, and financial difficulties. Conclusion These findings showed that the effects of severity and clinical heterogeneity of the NEN on HRQoL may change over time. This evidence should lead clinicians to monitor the HRQoL of NEN patients throughout the course of the disease and psychologists to implement evidence-based resilience interventions.

Die Ziele dieser Arbeit waren, das aktuelle Informationsbedürfnis von metastasierten Brustkrebspatientinnen und -patienten, deren Einschätzung der Arzt-Patient-Kommunikation sowie erwiesene Prädiktoren der QoL zu erheben und auf einen Zusammenhang mit der aktuellen patientenseitigen QoL zu untersuchen. Zu dieser oder ähnlichen Fragestellungen existieren lediglich Publikationen mit Brustkrebspatientinnen ohne Metastasierung. Studien mit ausschließlich metastasierten Brustkrebs-patientinnen sind generell sehr selten. Die Daten von 30 Patientinnen und einem Patienten mit metastasiertem Brustkrebs, rekrutiert in vier Kliniken in Bayern und Baden-Württemberg im Rahmen der Pilotphase des BRE-4-MED-Projektes, konnten ausgewertet werden. Die Studienteilnehmer waren zum Zeitpunkt der Rekrutierung zwischen 30 und 85 Jahre alt, das Durchschnittsalter betrug 57 Jahre (SD = 13,4). Für die Datenerhebung wurden nebst einzelner ordinalskalierter Fragen standardisierte, teils modifizierte Fragebögen wie die CARE-Skala, PROMIS PF4a, PHQ-4 oder ein Item des EORTC QLQ-C30 verwendet. In der QoL-Messung durch ein Item des EORTC QLQ-C30 Fragebogens erzielten die Probandinnen und Probanden geringfügig schlechtere Werte als eine gesunde deutsche Vergleichspopulation. Angesichts bisheriger Forschungsergebnisse wurde mit unbefriedigten Informations- und Kommunikationsbedürfnissen gerechnet. Außerdem wurden Zusammenhänge zwischen der QoL und unbefriedigten Informationsbedürfnissen, einer schlechten Arzt-Patient-Kommunikation sowie Prädiktoren der QoL erwartet. Diese Hypothesen wurden durch die vorliegende Arbeit zum Teil bestätigt, nämlich das Vorliegen von unerfüllten Informationsbedürfnissen sowie einer Korrelation der QoL mit Depression, körperlicher Funktionalität und mit Schmerz. Ein Zusammenhang mit dem Alter der Befragten bestand, jedoch genau entgegengesetzt der Erwartung. Letzteres Ergebnis sowie die nicht signifikanten Ergebnisse der Studie sind am ehesten durch eine zu geringe Probandenzahl bedingt. In puncto Informationsbedürfnisse der Patienten sowie Prädiktoren der QoL konnte die vorliegende Arbeit die bisherige Forschung größtenteils bestätigen, woraus die ärztlichen Handlungsempfehlungen abgeleitet werden können, auf diese Themen im Umgang mit metastasierten Mammakarzinompatienten besonders einzugehen. Die Aussagekraft der vorliegenden Ergebnisse ist allerdings angesichts der bisherigen Stichprobengröße als gering einzustufen, die Wiederholung der durchgeführten Analysen in der Hauptphase des BRE-4-MED-Projektes wären wünschenswert. Das BRE-4-MED-Register ist zusammenfassend als vielversprechendes Projekt zur Ergänzung der Versorgungsforschung und langfristig zur Verbesserung der Versorgung metastasierter Brustkrebspatienten einzustufen., The objectives of this work were to survey the current information needs of metastatic breast cancer patients, their assessment of physician-patient communication and proven predictors of QoL, and to examine for a correlation with current patient QoL. Only publications with breast cancer patients without metastasis exist on this or similar questions. Studies with exclusively metastasized breast cancer patients are generally rare. The data of 30 female patients and one male patient with metastatic breast cancer, recruited in four hospitals in Bavaria and Baden-Württemberg within the pilot phase of the BRE-4-MED project, could be analyzed. The study participants were between 30 and 85 years old at the time of recruitment, with a mean age of 57 years (SD = 13.4). For data collection, standardized, partly modified questionnaires such as the CARE scale, PROMIS PF4a, PHQ-4 or an item of the EORTC QLQ-C30 were used in addition to single ordinal scaled questions. In the QoL measurement, the patients scored slightly worse than a healthy German comparison population. Given previous research findings, unmet information and communication needs were expected. In addition, correlations between QoL and unmet information needs, poor physician-patient communication and predictors of QoL were expected. These hypotheses were partially confirmed by the present work, namely the presence of unmet information needs and a correlation of QoL with depression, physical functionality and with pain. A correlation with the age of the respondents existed, but opposite to the expectation. The latter result as well as the non-significant results of the study are most likely due to an insufficient number of subjects. With regard to the information needs of the patients as well as predictors of QoL, the present study was able to confirm previous research to a large extent, from which the physicians' recommendations for action can be derived to pay special attention to these topics in dealing with metastasized breast cancer patients. However, given the sample size to date, the significance of the present results must be considered low, and repetition of the analyses performed in the main phase of the BRE-4-MED project would be desirable. In summary, the BRE-4-MED registry can be classified as a promising project to complement health services research and, in the long term, to improve the care of metastatic breast cancer patients.

Fundamentos: há uma escassez de dados na literatura quanto à taxa de recorrência e de metástase em pacientes com melanomas in situ (MIS) e melanomas finos (MF) (índice de Breslow ≤ 1,0 mm), bem como dos fatores de risco associados a estes tumores iniciais. Objetivos: avaliar a prevalência e as características dos pacientes com MIS e MF que apresentaram recorrência local (RL), metástase ou óbito. Métodos: foi realizado um estudo observacional, retrospectivo de pacientes com MIS e MF diagnosticados em um período de 23 anos (1997 a 2020), no Departamento de Dermatologia da Oregon Health and Science University, Estados Unidos da América, Serviço de Dermatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade Federal de Minas Gerais e consultório privado localizado em Belo Horizonte, Minas Gerais. Foram analisadas características como sexo, idade, história familiar de melanoma, tempo de seguimento, localização do tumor (cabeça e pescoço, tronco anterior, tronco posterior, membros superiores, membros inferiores e acral), número de melanomas, ocorrência de outras neoplasias não-melanocíticas (carcinoma basocelular e carcinoma espinocelular) e índice de Breslow, e sua associação com a RL, metástase ou óbito. O Teste Exato de Fisher foi utilizado para identificação de fatores prognósticos independentes. As curvas de sobrevida usando o estimador de Kaplan-Meier e comparadas com o teste log-rank para as variáveis foram realizadas. Resultados: foram incluídos 1122 pacientes, com uma taxa de metástases calculada de 1,3% (n = 14), sendo que o tumor inicial era MIS em apenas dois pacientes e os outros 12 (85,7%) eram MF. A taxa de RL encontrada foi de 1,9% (n = 21); destes, 66,7% eram MIS e 33,3% MF. Oito óbitos (0,7%) decorrentes da neoplasia foram encontrados. O índice de Breslow apresentou associação com pior prognóstico (p = 0,01) e a sobrevida global foi pior nos pacientes com MIS localizados na cabeça e pescoço (p = 0,03). Nos MF essa relação foi pior em tumores de tronco posterior e de cabeça e pescoço (p = 0,008). O tempo médio de seguimento do grupo que apresentou RL foi de 121,7 meses 121,7 meses (60,3 ± 5,8 meses 95% IC [5,8 - 246,1]), enquanto nos pacientes com metástases foi de 102,2 meses (102,2 ± 77,7 meses 95% IC [16,1 - 236,1]). Durante o seguimento clínico, 31,9% dos pacientes apresentaram ao menos um carcinoma basocelular e 22,9% ao menos um carcinoma espinocelular. Conclusão: estes achados demonstram que apesar do bom prognóstico em pacientes com MF e MIS, em alguns casos eles podem ser agressivos e possuir a capacidade de metastatização. O achado de outras neoplasias durante o seguimento aliado aos dados de recorrência sugerem a necessidade de vigilância médica a longo prazo de pacientes com melanoma. Background: there is a lack of data regarding the possibility and rate of local recurrence (LR) and metastasis in patients with melanomas in situ (MIS) and thin melanomas (TM) (Breslow thickness ≤ 1.0 mm), as well as risk factors associated with these initial tumors. Objectives: to assess the prevalence and features of patients with MIS and TM who had LR, metastasis or death by melanoma. Methods: this is an observational, retrospective study with MIS and TM, diagnosed in a 23-years-period (1997 to 2020) at the Department of Dermatology from Oregon Health and Science University, United States of America; Dermatology Service of Hospital das Clínicas from Faculdade de Medicina da Universidade Federal de Minas Gerais, Brazil and a private office at Brazil. Features such as sex, age, familial history of melanoma, follow-up duration, tumor site (head and neck, anterior trunk, posterior trunk, upper extremities, lower extremities and acral), number of melanomas, death due to melanoma, occurrence of non melanocytic neoplasms (basal cell carcinoma and squamous cell carcinoma), Breslow thickness, and their relation with LR, metastasis or death, were analyzed. Fisher's Exact test was used to identify independent prognostic factors. Survival curves were calculated using the Kaplan-Meier estimator and compared with the log-rank test. Results: 1122 patients were analyzed, metastasis rate was 1.3% (n = 14), and the initial tumor was MIS in only two patients; the other 12 (85.7%) were TM. LR rate was 1.9% (n = 21), and in this group, 66.7% were MIS and 33.3% TM. Breslow thickness was associated with worse prognosis (p = 0.01) and overall survival rate was worse in patients with MIS located in the head and neck (p = 0.03). In TM, this relationship was worse in tumors located at the posterior trunk and head and neck (p = 0.008). Average follow-up time in the LR group was 121,7 months 121,7 months (60,3 ± 5,8 months 95% CI [5,8 - 246,1]) and 102,2 months (102,2 ± 77,7 months 95% CI [16,1 - 236,1]) in patients that had metastasis. During clinical follow-up, 31.9% of patients had at least one basal cell carcinoma and 22.9% of patients had at least one squamous cell carcinoma. Conclusion: the results demonstrate that despite the good prognosis in patients with TM and MIS, in some cases they can be aggressive and have the ability to metastasize. Findings of other neoplasms during follow-up combined with recurrence data suggest the need for long-term medical surveillance in patients with melanoma.

Submitted by Daniel Coiro da Silva (dcoirosilva@gmail.com) on 2022-02-17T15:41:42Z No. of bitstreams: 1 dissertaçãofinal.pdf: 2497222 bytes, checksum: fad324e14c77093c4e2d7bbfedfacb95 (MD5) Approved for entry into archive by Delba Rosa (delba@ufba.br) on 2022-02-21T19:39:22Z (GMT) No. of bitstreams: 1 dissertaçãofinal.pdf: 2497222 bytes, checksum: fad324e14c77093c4e2d7bbfedfacb95 (MD5) Made available in DSpace on 2022-02-21T19:39:22Z (GMT). No. of bitstreams: 1 dissertaçãofinal.pdf: 2497222 bytes, checksum: fad324e14c77093c4e2d7bbfedfacb95 (MD5) Previous issue date: 2021-12-22 Introdução: A doença metastática óssea dolorosa é responsável por mais de 99% dos tumores malignos que acometem o tecido ósseo. O tratamento passa por uso de medicamentos e protocolos diversos e uma possibilidade seria a utilização de radiofármacos e/ou radioisótopos, atualmente ainda com pouca difusão. Método: Realizou-se uma busca bibliográfica no período de 2010 a 2020, com os descritores câncer, metástase óssea, radioisótopos, radioisótopos e radiofármacos no tratamento das dores ósseas, tanto em português, como nos vocábulos correspondentes na língua inglesa e suas associações. Resultado: Observou-se que vários radiofármacos e/ou radioisótopos já estão disponíveis em outros países. No Brasil, há apenas dois compostos: o Sm153, com produção nacional, e o Ra223, importado. O uso dos radiofármacos e/ou radioisótopos pode trazer um aumento na qualidade de vida dos indivíduos acometidos por essa enfermidade e esse tratamento pode favorecer, além do desenvolvimento da ciência multidisciplinar, a prática de medicina individualizada. Discussão: Percebem-se vários estudos estrangeiros, demonstrando a eficácia no uso de variados radiofármacos e/ou radioisótopos, com atenção às propriedades físicas básicas, em busca de uma melhor efetividade no tratamento. Salienta-se ainda que as doses de radiação administradas em cada caso devem ser controladas para que os benefícios sejam efetivos. Conclusão: O uso de novos radiofármacos e/ou radioisótopos para tratamento de doença óssea metastática dolorosa poderá ser uma opção positiva. Este tratamento poderá estar disponível desde que ajustadas as questões de produção e da legislação existente atual. Introduction: Painful metastatic bone disease is responsible for more than 99% of malignant tumors that affect bone tissue. The treatment involves the use of medication, and one possibility would be the use of radiopharmaceuticals and/or radioisotopes, but with little diffusion. Method: A bibliographic search was carried out from 2010 to 2020, with cancer, bone metastasis, radioisotopes, radioisotopes and radiopharmaceuticals descriptors in the treatment of bone pain both in our language and with correspondence in English and their associations. Results: It was observed that several radiopharmaceuticals and/or radioisotopes that are already available in other countries are not yet available in our country. The use of radiopharmaceuticals and/or radioisotopes could increase the quality of life of individuals affected by this disease, in addition to the development of science in this area since it is multidisciplinary and a matter of individualized medicine. Discussion: It is perceived several studies outside the national territory, demonstrating the efficacy in the use of various radiopharmaceuticals and/or radioisotopes. Closely watched out to the basic physical properties so that you can have a better treatment effectiveness. Also emphasizing that the administered radiation doses in each case must be controlled so that the benefits are effective. Conclusion: The use of new radiopharmaceuticals and/or radioisotopes for the treatment of painful metastatic bone disease may be an available option provided that production issues and current existing legislation are adjusted.

Lysine methylation is a post-translational modification participating to finely regulate cell signaling pathways. While initially restricted as a histone modification and associated to epigenetic phenomena, lysine methylation has been recently recognized as a modification broadly affecting the proteome. In the last years, there were a growing amount of evidence highlighting the essential role of this modification in many fundamental processes. Thus, the deregulation of actors regulating lysine methylation is a frequent event in human pathologies, as neurodegenerative diseases, and cancers.Actors of lysine methylation signaling include lysine methyltransferases, the writers, that can transfer the methyl moiety on lysine residues, and lysine demethylases, the erasers, that have the capacity to remove the methyl. The biological meaning of lysine methylation generally relies on the ability of some proteins, called readers, to specifically dock to the methylated lysine and to transduce a proper response.During my thesis, I focused my interest in the lysine methyltransferase SMYD2. Structural studies told us that SMYD2 is a promiscuous enzyme able to potentially accommodate a wide range of substrates. Moreover, several reports have suggested that SMYD2 expression is deregulated during tumorigenesis and particularly during breast cancer. Therefore the outline of my work was to decipher the role of SMYD2 during breast cancer progression.First, I observed that SMYD2 did not affect primary tumor growth in a mouse model of breast cancer. Rather, SMYD2 was essential to efficiently drive breast cancer metastatic dissemination. I explored the lysine methylome of SMYD2 using SILAC-proteomics and I found the protein BCAR3 as a genuine substrate of SMYD2 and a decisive mediator of this pro-metastatic function. Mechanistically, I showed that BCAR3 methylation acts as a docking site of a family of actin remodellers, the formins FMNLs. Structural studies highlighted the presence of a potential new lysine methyl binding (reader) domain of lysine methylation, located on regulatory domains of FMNLs. Indeed, the anchoring to methylated BCAR3 regulated FMNLs’ ability to accumulate in lamellipodia, a cellular structure essential for mesenchymal cell migration. Then, I found that this signalization promoted cell migration and invasiveness of breast cancer cells, ultimately accelerating metastatic dissemination. Finally, I demonstrated the therapeutic interest to inhibit SMYD2 with as small molecule as SMYD2 inhibition in different in vivo models, including patient-derived xenograft, efficiently prevented metastatic dissemination.Overall, I characterized a new lysine methylation signaling – SMYD2 / BCAR3 / FMNLs axis – involved in breast cancer metastasis. The novel lysine methyl binding domain will be analyzed more thoroughly with additional structural studies in order to design small molecules that could block it, like peptidomimetics. Moreover, we will challenge the idea that BCAR3 methylation might be used as a prognostic or predictive biomarker of cancer aggressiveness. Finally, the therapeutic potential of SMYD2 inhibition to fight metastasis will be followed-up in preclinical and translational studies., La méthylation des lysines est une modification post-traductionnelle participant à une régulation dynamique et précise des voies de signalisation cellulaire. Initialement caractérisée au sein des histones et associée à différents mécanismes épigénétiques, la méthylation des lysines est aujourd’hui connue pour affecter l’ensemble du protéome. Au cours des vingt dernières années, les exemples démontrant le rôle essentiel de cette signalisation au cours de processus biologiques fondamentaux se sont multipliés. Par conséquent, la dérégulation des différents acteurs de cette signalisation a été causalement impliquée dans de nombreuses pathologies humaines, telles que les maladies neurodégénératives et les cancers.Au sein de cette signalisation, nous retrouvons les acteurs pouvant influer sur l’abondance de cette marque, c’est-à-dire les lysine-méthyltransférases, apposant le groupe méthyl sur la lysine, et les lysine-déméthylases, assurant son éviction. Le signal porté par le groupe méthyl est généralement transduit en réponse biologique par différentes classes de protéines, pouvant spécifiquement interagir avec cette modification, que l’on appelle les lecteurs.Au cours de ma thèse, je me suis intéressé à la lysine méthyltransférase SMYD2. Cette enzyme, du fait de sa nature promiscuiste, c’est-à-dire pouvant accommoder un grand nombre de substrats, représentait un défi particulièrement intéressant. Par ailleurs, les différents rapports faisant état de sa dérégulation au cours de la tumorigénèse, en particulier mammaire, laissaient transparaître son fort potentiel thérapeutique. Le leitmotiv qui a rythmé les différentes étapes de ma thèse s’est donc orchestré autour de l’étude du rôle de SMYD2 au cours de la progression du cancer du sein.J’ai pu observer in vivo que SMYD2 n'influençait pas la croissance tumorale primaire, mais était en revanche un facteur essentiel durant la dissémination métastatique du cancer du sein. L’exploration des différents substrats de SMYD2 par protéomique a permis de mettre en évidence la protéine BCAR3, comme acteur principal dans cette fonction pro-métastatique. Mécanistiquement, j’ai montré que la méthylation de BCAR3 servait de point d’ancrage à une famille de remodeleurs du cytosquelette d’actine, les FMNLs. Via des analyses structurales, l’existence d’un nouveau domaine de lecture des lysines méthylées, situé sur le domaine régulateur des FMNLs, a été mis en évidence. Et en effet, cet ancrage à BCAR3 méthylé participait à réguler la localisation des FMNLs, en les concentrant au niveau du lamellipode, une structure essentielle à la migration mésenchymateuse. J’ai pu montrer par la suite que cette signalisation contribuait à promouvoir les capacités invasives des cellules tumorales mammaires et accélérer leur dissémination métastatique in vivo. Enfin, le potentiel thérapeutique de l’inhibition pharmacologique de SMYD2 a été démontré dans le cadre de la prévention des métastases. L’inhibition de SMYD2 dans différents modèles, notamment de xénogreffes dérivées de patientes, permettait en effet de prévenir la colonisation métastatique des cellules tumorales.Au cours de ma thèse, j’ai donc caractérisé une signalisation par méthylation des lysines complète, un axe impliquant les protéines SMYD2-BCAR3-FMNLs, et son rôle central dans la dissémination métastatique mammaire. Le nouveau domaine de lecture de la méthylation sur les formines FMNLs fera l’objet d’analyses structurales plus poussées afin de mettre au point des molécules pouvant bloquer cette fonction, telles que des peptidomimétiques. L’utilisation de la méthylation de BCAR3 comme biomarqueur dans les cancers agressifs sera également à l’étude. Enfin, le potentiel thérapeutique et préventif de l’inhibition de SMYD2 dans la lutte contre les métastases sera poursuivi dans des analyses précliniques et translationnelles.

CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico Vários estudos têm demonstrado que extratos, proteínas e o próprio Trypanossoma cruzi tem ação na redução de tumores em modelos animais e em cultura de células. A proteína recombinante P21 de T. cruzi desempenha diferentes atividades biológicas como atividade quimiotática para células do sistema imunológico, inibe a angiogênese e modula negativamente a replicação do parasito. Além disso foi observado que esta proteína se liga ao receptor de quimiocina CXCR4. Assim esse estudo teve como objetivo avaliar o impacto da rP21 e da infecção por T. cruzi em células de câncer de mama triplo-negativo e células epiteliais não tumorais. Inicialmente realizamos o ensaio de viabilidade e foi visto que o tratamento com rP21 e a infecção por T. cruzi até o tempo de 72 horas, não apresentou uma viabilidade menor que 50%. Após o ensaio de viabilidade verificamos a taxa de invasão, multiplicação e eclosão de parasita no sobrenadante. A linhagem celular de mama normal, MCF-10A é suscetível à infecção por T. cruzi, sendo capaz de fornecer um ambiente propício para a replicação e diferenciação do parasita e a liberação de formas infectantes viáveis. A célula de mama triplo-negativo MDA-MB-231 também apresenta uma suscetibilidade a infecção pelo parasita. Após o tratamento com rP21 e a infecção por T. cruzi, notou-se a diminuição na migração de ambos os grupos tratados. Além disso observamos que a proteína rP21 após a marcação no tempo de 3 horas encontra-se localizada no núcleo da célula o que pode estar relacionada com o receptor CXCR4. Nossos resultados mostram que a expressão de CXCR4 na célula MDA-MB-231 diminui ao longo do tempo, porém apresenta uma curva de crescimento e queda na fluorescência nos tempos observados sugerindo uma translocação do receptor CXCR4 ao longo do tempo. Nas células MCF-10A a fluorescência ao longo dos tempos não apresentou diferença significativa. Quando observamos a interação da infecção do T. cruzi com o receptor CXCR4 vimos que ocorre uma interação entre eles nas células MDA-MB-231 e MCF-10A sugerindo uma relação entre a migração/invasão e proliferação dessas células. Em conclusão rP21 e outras moléculas do T. cruzi podem ser alvos potenciais para a descoberta para drogas contra o tumor. Several studies have shown that extracts, proteins and Trypanosoma cruzi itself have an action in reducing tumors in animal models and in cell cultures. The recombinant protein P21 from T. cruzi performs different biological activities such as chemotactic activity for immune system cells, inhibits angiogenesis and negatively modulates the replication of the parasite. Furthermore, it was observed that this protein binds to the CXCR4 chemokine receptor. Thus, this study aimed to evaluate the impact of rP21 and T. cruzi infection on triple-negative breast cancer cells and non-tumor epithelial cells. Initially, we performed the viability test and it was seen that the treatment with rP21 and the infection by T. cruzi up to 72 hours, did not present a viability lower than 50%. After the viability test, we verified the rate of invasion, multiplication and hatching of the parasite in the supernatant. The normal breast cell line, MCF-10A, is susceptible to infection by T. cruzi, being able to provide a favorable environment for the replication and differentiation of the parasite and the release of viable infective forms. The triple-negative MDA-MB-231 breast cell is also susceptible to parasite infection. After treatment with rP21 and T. cruzi infection, a decrease in migration of both treated groups was noted. After treatment with rP21 and infection by T. cruzi, a decrease in migration of both treated groups was noted. Furthermore, we observed that the rP21 protein after 3 hours labeling is located in the cell nucleus, which may be related to the CXCR4 receptor. Our results show that the expression of CXCR4 in the MDA-MB-231 cell decreases over time, but it presents a growth curve and a decrease in fluorescence at the observed times, suggesting a translocation of the CXCR4 receptor over time. In MCF-10A cells, fluorescence over time did not show any significant difference. When we observed the interaction of T. cruzi infection with the CXCR4 receptor, we saw that there is an interaction between them in MDA-MB-231 and MCF-10A cells, suggesting a relationship between migration/invasion and proliferation of these cells. In conclusion, rP21 and other T. cruzi molecules may be potential targets for the discovery anti-tumor drugs. Dissertação (Mestrado)

Fragestellung: Ein wichtiger Bestandteil der Therapie von lokalisierten Sarkomen ist die chirurgische Resektion. Hinsichtlich des erforderlichen Ausmaßes der Resektion existiert wenig Evidenz. Im Zuge der multimodalen Behandlung wich die Radikalität zunehmend der Erhaltung von Funktionalität. [zum vollständigen Text gelangen Sie über die oben angegebene URL]

Fragestellung: Die Resektion und Rekonstruktion mittels modularer Tumorendoprothese ist eine mögliche Therapieoption bei Patienten mit Knochenmetastasen, insbesondere bei Patienten mit solitärer oder oligometastatischer Krankheitsmanifestation, bei pathologischer Fraktur oder bei fehlgeschlagener [zum vollständigen Text gelangen Sie über die oben angegebene URL]

Introduction: Gastric cancer is the 5th most incident cancer, except for non-melanoma skin tumors and the 3rd leading cause of cancer death in the world. The most common sites of gastric cancer metastases are: liver (48%), peritoneum (32%), lung (15%) and bone (12%). Objective: to present the course of cutaneous metastasis due to gastric adenocarcinoma. Methodology: Descriptive study of the case report type, whose data were obtained from the patient's medical record. Case presentation: We report the case of a 44-year-old female patient who underwent surgical and chemotherapy treatment due to gastric adenocarcinoma. One year and four months after the initial intervention, hyperchromic, painful, diffuse and non-pruritic skin lesions appeared, located mainly on the chest, back and upper limbs. Skin biopsy confirmed the hypothesis of cutaneous metastasis from gastric adenocarcinoma. Conclusion: In the context of gastric cancer treatment, it is important to monitor new signs and symptoms, such as insidious skin lesions, suggesting the possibility of metastatic skin tumor. Introducción: El cáncer gástrico es el quinto cáncer más comun, a excepción de los tumores de piel no melanoma y la tercera causa principal de muerte por cáncer en el mundo. Los sitios más comunes de metástasis de cáncer gástrico son: hígado (48%), peritoneo (32%), pulmón (15%) y hueso (12%). Objetivo: presentar el curso de la metástasis cutánea por adenocarcinoma gástrico. Metodología: Estudio descriptivo del tipo de reporte de caso, cuyos datos se obtuvieron de la historia clínica del paciente. Presentación del caso: Presentamos el caso de una paciente de 44 años que se sometió a tratamiento quirúrgico y quimioterápico por un adenocarcinoma gástrico. Un año y cuatro meses después de la intervención inicial aparecieron lesiones cutáneas hipercrómicas, dolorosas, difusas y no pruriginosas, localizadas principalmente en tórax, espalda y miembros superiores. La biopsia de piel confirmó la hipótesis de metástasis cutánea de adenocarcinoma gástrico. Conclusión: En el contexto del tratamiento del cáncer gástrico, es importante monitorear nuevos signos y síntomas, como lesiones cutáneas insidiosas, que sugieren la posibilidad de un tumor cutáneo metastásico. Introdução: O câncer gástrico é o 5º câncer mais incidente, excetuando-se tumores de pele não melanoma e a 3ª causa de morte decorrente de câncer no mundo. Os locais mais comuns de metástases do câncer gástrico são: fígado (48%), peritônio (32%), pulmão (15%) e osso (12%). Objetivo: apresentar o curso de metástase cutânea em decorrência de um adenocarcinoma gástrico. Metodologia: Estudo descritivo do tipo relato de caso, cujos dados foram obtidos no prontuário físico da paciente. Apresentação do caso: Reportamos o caso de uma paciente do sexo feminino, 44 anos, submetida a tratamento cirúrgico e quimioterápico devido a um adenocarcinoma gástrico. Um ano e quatro meses após a intervenção inicial, observou-se o aparecimento de lesões cutâneas hipercrômicas, dolorosas, difusas e não pruriginosas, localizadas principalmente em tórax, dorso e membros superiores. A biópsia cutânea confirmou a hipótese de metástase cutânea de adenocarcinoma gástrico. Conclusão: No contexto do tratamento do câncer gástrico, faz-se importante a vigilância de novos sinais e sintomas, como lesões cutâneas insidiosas, aventando a possibilidade de tumor cutâneo metastático.

Metastasis is a consequence of a complex biological cascade, which begins with the detachment of tumor cells from the primary site and, via blood or lymph, spread to other sites, where they form a new neoplastic colony. They represent about 1% of all malignant tumors in this region, the oral cavity being the site most affected by neoplasms. Oral and maxillofacial cancer has high morbidity and mortality rates. Thus, it is necessary that the physician and/or dental surgeon take into account metastases to this region, as, despite being a rare case, they are signs of disseminated neoplasms. Given the above, this study aimed to conduct a systematic review of the literature on the sites of the primary tumor that have metastases to the maxillofacial region, as well as the site of metastasis, the most affected gender and the most common histological type. For the construction of this article, a bibliographic survey was carried out in the SciVerse Scopus, Scientific Electronic Library Online (Scielo), U.S. National Library of Medicine (PUBMED) and ScienceDirect databases, with the help of Mendeley. The articles were collected from April to August 2021 and covered between 2010 and 2021. From a systematic review of the literature, 282 cases of metastasis to the maxillofacial region were observed. The primary sites that metastasize the most are lung, kidney, breast and liver. The most affected gender is the male and the mandible is the most affected location, followed by the gums and tongue. The most common histological type is carcinoma. La metástasis es consecuencia de una cascada biológica compleja, que comienza con el desprendimiento de las células tumorales del sitio primario y, a través de la sangre o la linfa, se disemina a otros sitios, donde forman una nueva colonia neoplásica. Representan alrededor del 1% de todos los tumores malignos de esta región, siendo la cavidad bucal el sitio más afectado por las neoplasias. El cáncer oral y maxilofacial tiene altas tasas de morbilidad y mortalidad. Por tanto, es necesario que el médico y / o dentista tenga en cuenta las metástasis a esta región, ya que, a pesar de ser un caso raro, son signos de neoplasias diseminadas. Dado lo anterior, este estudio tuvo como objetivo realizar una revisión sistemática de la literatura sobre los sitios del tumor primario que presentan metástasis a la región maxilofacial, así como el sitio de metástasis, el género más afectado y el tipo histológico más común. Para la construcción de este artículo se realizó un relevamiento bibliográfico en las bases de datos SciVerse Scopus, Scientific Electronic Library Online (Scielo), U.S. National Library of Medicine (PUBMED) y ScienceDirect, con la ayuda de Mendeley. Los artículos fueron recolectados de abril a agosto de 2021 y cubiertos entre 2010 y 2021. A partir de una revisión sistemática de la literatura, se observaron 282 casos de metástasis a la región maxilofacial. Los sitios primarios que más metastatizan son pulmón, riñón, mama e hígado. El género más afectado es el masculino y la mandíbula es la ubicación más afectada, seguida de las encías y la lengua. El tipo histológico más común es el carcinoma. A metástase é consequência de uma cascata biológica complexa, que se inicia com o desprendimento de células tumorais de um sítio primário e, por via hematogênica ou linfática, se disseminam para outras regiões, onde passam a residir e se multiplicar, formando os chamados “implantes secundários” nesses novos locais. As lesões metastáticas na região bucomaxilofacial representam cerca de 1% de todos os tumores malignos desta região, sendo a cavidade oral o principal sítio primário dessas neoplasias. O câncer da região bucomaxilofacial apresenta altas taxas de morbimortalidade. Assim, é necessário que o médico e/ou cirurgião dentista leve em consideração as metástases para essa região, pois, apesar de ser um caso raro, indicam que a neoplasia já se encontra em estágio avançado. Diante do exposto, este estudo teve como objetivo realizar uma revisão sistemática da literatura sobre os locais do tumor primário que possuem metástase para a região bucomaxilofacial, bem como o local da metástase, gênero mais acometido e o tipo histológico mais comum. Para a construção deste artigo foi feito um levantamento bibliográfico nas bases de dados SciVerse Scopus, Scientific Eletronic Library Online (Scielo), U.S. National Library of Medicine (PUBMED) e ScienceDirect, com auxílio do Mendeley. Os artigos foram coletados no período de abril a agosto de 2021 e contemplados entre os anos de 2010 a 2021. A partir de uma revisão sistemática da literatura, observou-se 282 casos de metástase para a região bucomaxilofacial. Os sítios primários que mais metastatizaram foram pulmão, rim, mama e fígado. O gênero mais acometido foi o masculino e a mandíbula foi o local mais acometido, seguido por gengiva e língua. O tipo histológico mais comum foi o carcinoma.

Exosomes or other extracellular vesicles released from cells play an important role in cell-to-cell communication by transferring bio-information (DNA, coding/non-coding RNA, and proteins), which indicates parental cell status to recipient cells in the extracellular environment. Increasingly, evidence shows that tumor-derived exosomes mediate tumor pre-metastatic niche (PMN) remodeling to establish a supportive and receptive niche to promote tumor cell colonization and metastasis. Uptake of genetic information by target cells in the extracellular environment triggers epigenetic changes that contribute to PMN formation. Here, we provide a comprehensive overview of the current understanding of exosomes-mediated reprogramming of cells in PMN formation.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior As neoplasias mamárias são comumente encontradas em cães e a metástase pulmonar é considerada a principal causa de morte. A remodelação da matriz extracelular pode influenciar na progressão, invasão e metástases. Objetivou-se caracterizar o carcinoma mamário canino com e sem metástases pulmonares. Foram selecionadas 26 amostras em blocos de parafina de cães com carcinoma mamário nos arquivos do Laboratório de Patologia Veterinária da UFV. Foram realizadas fotomicrografias e avaliações dos cortes histológicos em hematoxilina e eosina e Picrossirius red com luz polarizada. Nas análises histopatológicas foram realizadas a contagem mitótica, intensidade da necrose e do infiltrado inflamatório e análises morfométricas do núcleo, proporção das células carcinomatosas, necrose, células inflamatórias e vasos sanguíneos e quantificação do colágeno tipo I e III. A contagem mitótica e a intensidade da necrose foram maiores em carcinomas mamários de grau III. Na análise dos colágenos, a concentração dos colágenos tipo I e tipo III não foram influenciadas pelo grau e ocorrência de metástase. Nos carcinomas em tumor misto houve maior quantidade de colágeno tipo I nas neoplasias de grau I. A mensuração dos núcleos e as proporções de células carcinomatosas, necrose, células inflamatórias e vasos sanguíneos não foram significativas em relação aos graus e os grupos. Nos carcinomas em tumor misto houve uma relação significativa entre os núcleos com diâmetros maiores e a ausência de metástases. Os resultados demonstram que há maior relação entre o grau dos carcinomas mamários com as variáveis avaliadas, independente da presença ou ausência de metástase pulmonar. Estudos futuros com maior quantidade de amostras são recomendados para a avaliação das características do carcinoma mamário canino e sua relação com o microambiente tumoral e a metástase pulmonar. Palavras-chave: Câncer de mama. Metástases. Matriz extracelular. Pulmões. Morfometria. Picrossirius red. Prognóstico. Mammary neoplasms are commonly found in dogs and lung metastasis is considered the main cause of death. Extracellular matrix remodeling can influence progression, invasion and metastases. The objective was to characterize canine mammary carcinoma with and without lung metastases. Twenty-six samples were selected in paraffin blocks from dogs with mammary carcinoma from the archives of the Laboratory of Veterinary Pathology at UFV. Photomicrographs and evaluations of the histological sections were performed in hematoxylin and eosin and Picrossirius red with polarized light. In the histopathological analysis, mitotic count, intensity of necrosis and inflammatory infiltrate and morphometric analysis of the nucleus, proportion of carcinoma cells, necrosis, inflammatory cells and blood vessels and quantification of collagen type I and III were performed. Mitotic count and necrosis intensity were higher in grade III breast carcinomas. In the collagen analysis, the concentration of type I and type III collagens were not influenced by the degree and occurrence of metastasis. In mixed tumor carcinomas, there was a greater amount of type I collagen in grade I neoplasms. The measurement of nuclei and the proportions of carcinoma cells, necrosis, inflammatory cells and blood vessels were not significant in relation to grades and groups. In mixed tumor carcinomas, there was a significant relationship between nuclei with larger diameters and the absence of metastases. The results demonstrate that there is a greater relationship between the grade of breast carcinomas and the variables evaluated, regardless of the presence or absence of lung metastasis. Future studies with more samples are recommended to evaluate the characteristics of canine mammary carcinoma and its relationship with the tumor microenvironment and lung metastasis. Keywords: Breast cancer. Metastases. Lungs. Extracellular matrix. Morphometry. Picrosirius red. Prognosis.