Soft tissue sarcomas (STS), a group of rare malignant tumours with high tissue heterogeneity, still lack effective clinical stratification and prognostic models. Therefore, we conducted this study to establish a reliable prognostic gene signature. Using 189 STS patients’ data from The Cancer Genome Atlas database, a four-gene signature including DHRS3, JRK, TARDBP and TTC3 was established. A risk score based on this gene signature was able to divide STS patients into a low-risk and a high-risk group. The latter had significantly worse overall survival (OS) and relapse free survival (RFS), and Cox regression analyses showed that the risk score is an independent prognostic factor. Nomograms containing the four-gene signature have also been established and have been verified through calibration curves. In addition, the predictive ability of this four-gene signature for STS metastasis free survival was verified in an independent cohort (309 STS patients from the Gene Expression Omnibus database). Finally, Gene Set Enrichment Analysis indicated that the four-gene signature may be related to some pathways associated with tumorigenesis, growth, and metastasis. In conclusion, our study establishes a novel four-gene signature and clinically feasible nomograms to predict the OS and RFS. This can help personalized treatment decisions, long-term patient management, and possible future development of targeted therapy.

Histotripsy is a non-thermal, non-invasive focused ultrasound therapy using controlled acoustic cavitation to mechanically disintegrate tissue into an acellular homogenate. Histotripsy applies microsecond-length, high pressure (> 10 MPa) pulses to initiate the rapid expansion and collapse of nuclei in a millimeter-scale focal region, applying large stresses and strains to targeted tissues. The cavitation "bubble cloud" generated during histotripsy treatment can be visualized in real time on ultrasound imaging, assisting with treatment guidance and monitoring. Past studies have demonstrated histotripsy's potential for a variety of applications, but histotripsy has not yet been investigated for superficial musculoskeletal tumor ablation. Additionally, preliminary investigations using histotripsy to ablate brain tumors are underway, but require advanced histotripsy devices capable of overcoming attenuation of the therapeutic ultrasound signal by the skull and rely on MRI for real-time guidance. As a result, open questions remain regarding ultrasound-guided histotripsy for brain tumors. Early evidence also suggests that histotripsy ablation may induce immunogenic changes in the tumor microenvironment. Continued research is needed to explain and corroborate these findings under conditions more immunologically representative of human cancers, such as in large animal models with spontaneous tumors. This dissertation investigates the safety and feasibility of using ultrasound-guided histotripsy to ablate superficial soft tissue sarcomas (STS), osteosarcomas (OS), and brain tumors and considers the immunological impacts of histotripsy treatment for STS and OS. The research described herein (1) investigates the ability of histotripsy to treat superficial STS tumors in companion animals with spontaneous tumors, (2) investigates the feasibility of treating bone tumors with histotripsy through a series of ex vivo and in vivo studies, and (3) applies histotripsy for the minimally invasive treatment of superficial brain tumors. The completion of this dissertation will provide significant insight into the ability of ultrasound-guided histotripsy to treat novel tumor types (i.e., STS, OS, and brain tumors) and the potential role of histotripsy in veterinary medicine. Future work will build upon the studies detailed in this dissertation to optimize ultrasound-guided histotripsy for the treatment of complete STS, OS, and brain tumors in veterinary and human patients. / Doctor of Philosophy / Histotripsy is a non-invasive focused ultrasound therapy that mechanically breaks down targeted tissues through acoustic cavitation. Histotripsy is currently being developed for a number of clinical applications, including tumor ablation, but its potential for treating many cancer types remains unknown. Histotripsy uses very short, high pressure ultrasound pulses to initiate the nucleation of bubbles in the target region. These bubbles then expand and rapidly collapse to impart large stresses and strains on surrounding tissues, leaving behind only acellular debris. The cavitation "bubble cloud" generated during histotripsy treatment can be visualized on ultrasound imaging, offering real-time treatment guidance and monitoring. Histotripsy has not yet been investigated for superficial musculoskeletal tumor ablation, and preliminary studies using histotripsy to ablate brain tumors are underway, but require advanced histotripsy devices still under development. As a result, open questions remain regarding histotripsy ablation as a treatment for musculoskeletal and brain tumors. Additionally, early evidence suggests that histotripsy ablation may be able to stimulate an immune response, treating not only the targeted tumor but also multifocal or metastatic disease. Continued research is needed to explain and corroborate these findings under conditions more similar to human cancers, such as in large animal models with naturally-occurring tumors. This dissertation investigates the safety and feasibility of using ultrasound-guided histotripsy to ablate superficial soft tissue sarcomas (STS), osteosarcomas (OS), and brain tumors and considers the immunological impacts of histotripsy treatment for STS and OS. This research (1) investigates the ability of histotripsy to treat superficial STS tumors in companion animals with spontaneous tumors, (2) investigates the feasibility of treating bone tumors with histotripsy through a series of ex vivo and in vivo studies, and (3) applies histotripsy for the minimally invasive treatment of superficial brain tumors. The completion of this dissertation will provide significant insight into the ability of ultrasound-guided histotripsy to treat novel tumor types (i.e., STS, OS, and brain tumors) and the potential role of histotripsy in veterinary medicine. Future work will build upon the studies detailed in this dissertation to optimize ultrasound-guided histotripsy for the treatment of complete STS, OS, and brain tumors in veterinary and human patients.

Made available in DSpace on 2016-08-10T10:38:36Z (GMT). No. of bitstreams: 1 DIEGO FRANCIEL MARQUES MUHLBEIER.pdf: 2283104 bytes, checksum: 4b3910db11a5426da6161c55a1de78bc (MD5) Previous issue date: 2012-03-12 / Sarcomas are a heterogeneous group of tumors that arise from mesenchymal tissues which represent about 1% of all diagnosed solid malignant tumors in adults. Changes that affect the tumor growth such as the deregulation of apoptosis, through overexpression of the Bcl-2 family proteins, have been associated with the prognosis of patients in various types of cancers, including soft tissue sarcomas (SPM). The Bcl-2 family proteins include anti-apoptotic and proapoptotic proteins such as proteins Bcl-2 and Bax, respectively. Despite the evidence, the prognostic value of these proteins, as well as the association with clinicopathological factors, remain controversial. The objective of this study was to investigate the clinical significance of the expression of apoptosis-related markers Bcl-2 and Bax in 86 patients with STS of extremities by immunohistochemical analysis on a tissue microarray construction. Cytoplasmic expression of Bax and Bcl-2 was detected in 25.9% and 66.7% of the cases, respectively. Overexpression of both Bcl-2 and Bax was directly associated with synovial sarcoma, histological grade and clinical stage. A significant association between Bax and Bcl-2 expression was also observed. The 5-year overall survival (OS) for the group was 57%, being lower for cases with Bcl-2 overexpression (47.6% vs 58.3%) and Bax overexpression (50% vs 66.7%), although such difference was not significant. After multivariate analysis, the histological grade remained as an independent prognostic factor (p=0.043, HR=8.0, 95% CI, 1.1-60.1). Bcl-2 family proteins have been tested as therapeutic targets in some clinical studies in several cancers. In our study, overexpression of both Bcl-2 and Bax was associated with histological grade and clinical stage of the tumors, which are classical factors of poor prognosis. Thus, we suggest the use of these proteins as potential prognostic markers in STS of extremities, providing a more appropriate therapeutic planning for each patient. / Os sarcomas constituem um grupo heterogêneo de tumores que surgem a partir de tecidos mesenquimais e que representam cerca de 1% de todos os tumores sólidos malignos diagnosticados em adultos. Alterações que afetam o crescimento tumoral, como a desregulação da apoptose, por meio da hiperexpressão de proteínas da família Bcl-2, têm sido associadas ao prognóstico dos pacientes em diversos tipos de cânceres, incluindo os sarcomas de partes moles (SPM). A família Bcl-2 inclui proteínas pró-apoptóticas e anti-apoptóticas, tais como as proteínas Bax e Bcl-2, respectivamente. Apesar das evidências, o valor prognóstico dessas proteínas, assim como a associação com fatores clínicopatológicos, ainda permanecem controversos. O objetivo desse estudo foi investigar o significado clínico da via da apoptose, por meio da avaliação da expressão imuno-histoquímica de Bcl-2 e Bax, em um grupo de 86 casos de SPM de extremidades, utilizando microarranjos de tecidos (tissue microarray). A expressão citoplasmática de Bcl-2 e Bax foi detectada em 25,9% e 66,7% dos casos, respectivamente. A hiperexpressão de ambos, Bcl-2 e Bax, foi associada aos sarcomas sinoviais, ao grau histológico e ao estadiamento clínico. Uma associação significativa entre a expressão das proteínas Bcl-2 e Bax também foi observada. A sobrevida global em cinco anos foi de 57%, sendo menor para os casos com hiperexpressão de Bcl-2 (47,6% x 58,3%) e Bax (50% x 66,7%), porém, esta diferença não foi estatisticamente significativa. Após análise multivariada, o grau histológico apresentou-se como fator prognóstico independente (p = 0.043, HR = 8.0, IC 95%, 1.1-60.1). Proteínas da família Bcl-2 vêm sendo testadas como alvos terapêuticos em diversos estudos clínicos em vários tipos de cânceres. Em nosso estudo, a expressão de Bcl-2 e Bax foi associada com o grau histológico e o estadiamento clínico, que são fatores clássicos de mau prognóstico. Assim, sugerimos o uso da expressão imunohistoquímica de Bcl-2 e Bax como potencial marcador prognóstico em SPM de extremidades, possibilitando um planejamento terapêutico mais adequado para cada caso.

Les sarcomes de haut grade présentent une progression métastatique dans approximativement 50 % des cas. Les bénéfices des traitements de chimiothérapie palliatifs pour les métastases à distance restent modestes. L’objectif primaire de cette étude est d’évaluer la progression de la maladie et la survie des patients diagnostiqués avec un sarcome des tissus mous métastatique traité par chimiothérapie palliative. Une revue de dossiers rétrospective des 68 patients ayant reçu de la chimiothérapie palliative pour leurs sarcomes métastatiques entre 2003 et 2013 à l’Hôpital Maisonneuve- Rosemont a été réalisée. Une mise en banque des données d’un groupe n’ayant pas eu de chimiothérapie de 36 patients ayant eu un diagnostic de sarcomes métastatiques des tissus mous sans traitement de chimiothérapie a été effectuée rétrospectivement. La survie globale médiane obtenue avec traitements de chimiothérapie était plus du double de celle sans traitement, soit de 20 mois et 7 mois, respectivement (p =0.0001). La survie globale de tous les groupes histologiques ayant eu des traitements de chimiothérapie était améliorée, particulièrement pour les léiomyosarcomes et sarcomes synoviaux, bien que la différence entre les groupes traités et non traités n’était pas statistiquement significative. Lorsque la chimiothérapie était administrée en thérapie combinée lors de la première ligne de traitement, la survie sans évènement était significativement augmentée (p=0.0184) et les taux de réponse favorables étaient deux fois plus élevés. En conclusion, les résultats ont montré une survie significativement améliorée pour tous les groupes histologiques ayant eu des traitements de chimiothérapie. Néanmoins, les patients avec une réponse favorable demeurent avec une faible espérance de vie. D’autres options de traitements sont nécessaires. / High-grade sarcomas present a metastatic progression in approximately 50% of cases. The effectiveness of palliative chemotherapy as a treatment of systemic metastases is still modest. The main objective of this study is to assess disease progression and survival of patients diagnosed with metastatic soft tissue sarcomas treated with palliative chemotherapy. A retrospective chart review of 68 patients treated with palliative chemotherapy for metastatic soft tissue sarcomas between 2003 and 2013 at Maisonneuve-Rosemont Hospital was achieved. Data for control group of 36 patients with metastatic soft tissue sarcomas not treated with chemotherapy was collected retrospectively. Median overall survival with chemotherapy treatments was more than two times overall survival without treatments, which were 20 months and 7 months, respectively (p=0.0001). Overall survival was improved for all histologic subtypes with chemotherapy treatments, especially for leiomyosarcomas and synovial sarcomas, even though the difference in survival was not statistically significant between treated and untreated groups. When chemotherapy was given in combined therapy during first line of treatment, event-free survival was statistically longer (p=0.0184) and favorable responses rates were doubled. In conclusion, results have shown a significantly improved overall survival in all histological groups with chemotherapy treatments. Nevertheless, patients with favorable response to chemotherapy have poor outcomes. Additional treatment options are needed.

Made available in DSpace on 2016-08-10T10:39:18Z (GMT). No. of bitstreams: 1 PRISCILLA SILVA ROSA DE ALMEIDA.pdf: 3720637 bytes, checksum: b39a9c071d90058d47a3a8c7aec2c7f3 (MD5) Previous issue date: 2008-07-21 / Soft tissue sarcomas (STS) are tumors with mesodermical origin, comprising about 1% of all adult neoplasms. Because of its effect on the p53 protein coding sequence, and its association with an increased risk for some cancer types, TP53 codon 72 polymorphism has been investigated in several studies. TP53 codon 72 codes for either Arginine (p53Arg), or Proline (p53Pro) at the p53 protein primary sequence. It was demonstrated that such amino acid change affects p53 biochemical and biological properties, and several studies have been developed in order to associate TP53 codon 72 polymorphisms as a risk, and as a prognostic factor for different cancer types. Any published study on the TP53 codon 72 polymorphism in adult soft tissue sarcomas was found in the literature. The present study aimed to investigate TP53Arg/Pro polymorphism as a potential prognostic factor in 100 adult subjects with STS. Patients were assisted at the Hospital Araújo Jorge of the Associação de Combate ao Câncer em Goiás in Goiânia, Brazil. DNA from patients was obtained from formaldehyde-fixed and paraffin-embedded tissue samples stored at the Pathology Department of the institution. Control group included 85 healthy donors randomly selected from Goiânia s population and, for this group, DNA extraction was performed from peripheral blood. Polymorphism genotyping was achieved by using polymerase chain reaction (PCR) with specific primer sets for each polymorphic variant. Statistical analysis was performed by using GenePop Ò web version 3.4 software. In this study, TP53 allelic and genotypic frequencies were investigated for subjects and controls, however, any statistical difference between the two groups was found. Our study supports the evidence that p53Arg is the most frequent allele in Latin American population, but worldwide genic and genetic frequency data are conflicting because of ethnical differences among the studied populations. According to the results, no significant association was demonstrated between TP53 codon 72 polymorphism and clinocopathological characteristics such as gender, age, tumor localization, histology, tumor size, stage, grade, node status, and distant metastasis. The five-year overall survival for the study group was 48.1%. Tumors with p53Pro/Pro genotype demonstrated a reduced survival rate (30%) when compared to p53Arg/Arg (45%), and p53Arg/Pro group (54.9%), but this association was not statistically significant (p = 0.444). In the present study, the p53Arg variant was not statistically associated with a more favorable prognosis in adult STS patients. / Os sarcomas de partes moles (SPM) são tumores de origem mesodérmica, representando cerca de 1% do total das neoplasias em adultos. O polimorfismo do códon 72 do gene TP53 é extensivamente estudado por causar impacto na seqüência codificadora do gene, além de estar associado ao maior risco para o desenvolvimento de alguns tipos de câncer. Este polimorfismo resulta na expressão de arginina (p53Arg) e/ou prolina (p53Pro) na posição 72 da proteína p53. As formas polimórficas de TP53, em relação ao polimorfismo do códon 72, apresentam propriedades bioquímicas e biológicas diferentes, e por esta razão, vários estudos foram conduzidos na tentativa de associar tais formas polimórficas como fator de risco e prognóstico para inúmeras neoplasias. Entretanto, a literatura não relata nenhum estudo que associe este polimorfismo aos sarcomas de partes moles do adulto. Neste contexto, o objetivo do presente estudo foi avaliar o polimorfismo p53Arg/Pro como potencial fator de risco e/ou prognóstico em 100 casos de SPMs em adultos atendidos no Hospital Araújo Jorge da Associação de Combate ao Câncer em Goiás. O grupo controle incluiu 85 indivíduos saudáveis selecionados aleatoriamente da população da cidade de Goiânia. As amostras dos casos constituíram de tecidos fixados em formol e incluídos em parafina e, para a extração de DNA, os tecidos foram previamente desparafinizados. A extração de DNA do grupo controle foi realizada a partir de sangue periférico. Para a genotipagem do polimorfismo, a reação em cadeia da polimerase (PCR) foi realizada utilizando conjuntos de primers específicos para cada variante polimórfica. Após a análise dos dados obtidos, verificou-se que as freqüências alélicas e genotípicas não apresentaram diferenças estatisticamente significativas entre os casos e os controles. Nosso estudo corrobora com as evidências de que o alelo p53Arg é o mais comum em populações latinoamericanas. Entretanto, os dados sobre as freqüências gênicas e genotípicas da literatura mundial são conflitantes, fato que pode ser atribuído às diferenças étnicas descritas entre as populações estudadas. Nenhuma relação estatisticamente significativa foi encontrada entre o polimorfismo do códon 72 de TP53 e as características clínico-patológicas estudadas, como sexo, idade agrupada, localização, histologia, tamanho e grau histológico tumoral, estadiamento e presença de mestástases. A sobrevida global em cinco anos para o grupo estudado foi de 48,1%. As análises de sobrevida em relação ao polimorfismo de TP53 revelaram que os pacientes cujos tumores apresentaram o genótipo p53Pro/Pro tiveram sobrevida inferior (30%), quando comparados ao grupo de pacientes com os genótipos p53Arg/Arg (45%) e p53Arg/Pro (54,9%). Entretanto, essa diferença não foi estatisticamente significativa (p = 0,444). Sabese que a isoforma p53Arg apresenta função apoptótica mais marcante. Esta característica pode conferir ao paciente um melhor prognóstico da doença. No presente trabalho, contudo, não pudemos verificar que esta variante esteve associada a um prognóstico mais favorável em pacientes adultos com SPMs.

No description available.

Made available in DSpace on 2014-08-20T14:37:57Z (GMT). No. of bitstreams: 1 dissertacao_matheus_folgearin_silveira.pdf: 274999 bytes, checksum: 17765fa39ad1a46f221283537ac0adae (MD5) Previous issue date: 2009-05-20 / Soft tissue sarcomas are mesenchymal origin neoplasms collectively classified according to histological characteristics and biological behaviour similiarities. Various neoplasms are included in this major group, as fibrosarcoma, hemangiosarcoma, peripheral nerve sheath tumor, myxosarcoma, liposarcoma, leiomyosarcoma, rhabdomiosarcoma, malignant fibrous histiocytoma, synovial cell sarcoma and undifferentiated sarcoma. The microvessel density measure has been applied to investigate tumor angiogenesis in many neoplasms. The objectives of this study were to evaluate de microvessel density in canine and feline soft tissue sarcomas and compare the general vessel measurement area and intense vascular areas hot spot. Those data were compared to usually applied prognostic factors like mitotic index, necroses presence and amount and cellular differentiation. Soft tissue sarcomas were collected in Laboratório Regional de Diagnóstico da Universidade Federal de Pelotas from 1978 to 2008 among canine and feline necropsies and biopsies. In a total of 1668 neoplasms cases during this period, 100 were soft tissue sarcomas, 87 canine and 13 feline. Sex prevalence was not observed in the analyzed species. The major prevalence in canine were hemangiosarcomas (n=34) and fibrosarcomas (n=20), being the mongrel dogs (n=35) most. The large breeds presented major frequence (n=22), followed by medium size (n=16) and small sized breeds (n=9). . In feline population, there were not accentuated prevalence, exciding hemangiosarcomas (n=4) and fibrosarcomas (n=4). In those 100 cases, 39 paraffin blocks were obtained, being 36 canine and 3 feline, mostly mongrel specimens, with 9,21(±2,99) medium age. The general vascular and hot spot areas were significantly correlated (r2=0,98; p<0,01). The mitotic index between areas were in those areas (r2=0,95, p<0,01). Hemangiosarcomas presented major vascular media in the techniques, followed by muscular sarcomas and fibrosarcomas (p<0,05). The microvessel density in soft tissue sarcomas do not present correlation to other prognostic factor usually applied. Hot spot areas can be utilized to determine the vascular degree and mitotic index in soft tissue sarcomas. / Os sarcomas de tecidos moles são neoplasmas de origem mesenquimal classificados coletivamente devido a características histológicas e comportamento biológico similares. Vários neoplasmas estão incluídos neste grande grupo, como fibrossarcoma, hemangiossarcoma, tumor de bainha de nervo periférico, mixossarcoma, lipossarcoma, leiomiossarcoma, rabdomiossarcoma, histiocitoma fibroso maligno, sarcoma sinovial e sarcoma indiferenciado. A mensuração da densidade vascular tem sido utilizada para investigar a angiogênese tumoral em diferentes neoplasmas. Este estudo teve como objetivo a determinação da microdensidade vascular de sarcomas de tecidos moles caninos e felinos através da comparação entre a mensuração geral vascular e áreas de intensa proliferação hot spot. Estes dados foram comparados a fatores prognósticos usualmente empregados, como índice mitótico, presença e quantidade de necrose e diferenciação celular. Os sarcomas de tecidos moles foram resgatados dos arquivos do Laboratório Regional de Diagnóstico da Universidade Federal de Pelotas entre 1978 a 2008 dentre necropsias e biópsias caninas e felinas. Num total de 1668 neoplasmas deste período, 100 eram sarcomas de tecidos moles, sendo 87 caninos e 13 felinos. Não se observou prevalência de sexo nas espécies analisadas. Em caninos, a maior prevalência foi de hemangiossarcomas (n=34) e fibrossarcomas (n=20), sendo os sem raça definida (n=35) os mais acometidos. Os animais de porte grande apresentaram maior freqüência (n=22), seguidos pelos de porte médio (n=16) e de porte pequeno (n=9). Em felinos não houve uma prevalência acentuada, destacando-se os hemangiossarcomas (n=4) e fibrossarcomas (n=4). Destes 100, obtiveram-se blocos de 39 casos, sendo 36 caninos e 3 felinos, em sua maioria sem raça definida nas duas espécies, com idade média observada foi de 9,21(±2,99 anos). A mensuração vascular geral e de áreas hot spot apresentaram correlação significativa (r2=0,98; p<0,01). O índice mitótico nas duas áreas observadas foram significativas (r2=0,95, p<0,01). Os hemangiossarcomas apresentaram maior média vascular nas duas técnicas, seguidos pelos sarcomas musculares e fibrossarcomas (p<0,05). Houve diferença entre os hemangiossarcomas e os fibrossarcomas, e os sarcomas musculares não diferiram desses (p<0,05). A microdensidade vascular em sarcomas de tecidos moles não apresentou correlação com outros fatores empregados usualmente. A visualização de campos hot spot pode ser utilizada para determinar o grau vascular e índice mitótico.

Hintergrund Es existieren keine Studien zur Inanspruchnahme psychoonkologischer Angebote durch Weichteilsarkompatienten in Deutschland. Ziel war es deshalb, die Häufigkeit der Inanspruchnahme psychoonkologischer Angebote im Krankenhaus in dieser Gruppe zu ermitteln und damit assoziierte Faktoren zu untersuchen. Methode Die Kohortenstudie PROSa (Krankheitslast und Versorgungssituation bei Sarkomen) wurde zwischen 2017 und 2020 in 39 deutschen Studienzentren durchgeführt. Für die vorliegende Analyse wurden Querschnittsdaten von erwachsenen Weichteilsarkompatienten ausgewertet. Faktoren auf Patienten- wie auf Einrichtungsebene wurden als mögliche Prädiktoren der Inanspruchnahme psychoonkologischer Beratung mittels logistischer Regression in einem verallgemeinerten linearen gemischten Modell exploriert. Resultate Bei 910 teilnehmenden Patienten lagen von 576 (63,3 %) Angaben zur Inanspruchnahme vor. 212 Patienten (unter Einbeziehung der fehlenden Angaben 23,3 %, ohne diese 36,7 %) nahmen psychoonkologische Angebote in Anspruch. Negativ mit der Inanspruchnahme assoziiert waren männliches (vs. weibliches) Geschlecht (Odds Ratio [OR] 0,62) und höheres Alter (18–< 40 Jahre vs. 65–< 75 Jahre: OR 0,32; 18–< 40 Jahre vs. ≥ 75 Jahre: OR 0,19). Positiv assoziiert waren Bildungsgrad (Abitur vs. Haupt‑/Volksschulabschluss [OR 2,01]) und Grading (High-grade-Tumoren vs. „low-grade“ [OR 4,41]). Wenn Psychoonkologen am Tumorboard beteiligt waren, war die Inanspruchnahme deutlich höher (OR 6,69). Konklusion Frauen, jüngere Personen, Patienten mit höherer Bildung und fortgeschrittenem Krankheitsstadium nehmen häufiger psychoonkologische Versorgung in Anspruch. Ein struktureller Faktor für eine erhöhte Inanspruchnahme ist die Beteiligung der Psychoonkologie am Tumorboard.