BACKGROUND: Soft tissue sarcomas (STSs) are a diverse group of cancers that originate from mesenchymal tissue and are estimated to result in 13,130 new cases and 5,350 deaths this year. These neoplasms are hard to detect, which results in physicians struggling to treat late-stage STSs with a limited number of ineffective treatments. Currently, surgical excision is the primary treatment with radiation therapy administered when possible. However, even with optimal margins, the rate of recurrence is high, and the overall survival is low. There is a desperate need for new, more effective treatments. Immune checkpoint blockade (ICB) has recently had widespread success in treating melanoma, and in recent trials, SARC028 and Alliance A091401, have shown demonstrated activity of ICBs in STS in the neoadjuvant setting. Two histological subtypes of STS showed more promise than others: dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS). Another issue plaguing the field of STS is that there is no universal indicator of response. The percentage of hyalinization found within the tumor was recently identified as a better marker of response than radiographic imaging or percent viable tumor. METHODS: This study was an investigator-initiated, single-center, randomized, open-label, phase II study (NCT03307616), in which 23 patients with either DDLPS of the retroperitoneum (RP) or UPS of the extremity/trunk (ET) were separated by disease into Cohort 1 and 2, respectively. Subjects in each cohort were randomized into two neoadjuvant treatment arms per cohort. Arm A (n=7) of Cohort 1 received nivolumab (anti-PD-1) monotherapy, while Arm B (n=7) of Cohort 1 received nivolumab and ipilimumab (anti-CTLA-4) combination therapy. Arm C (n=5) of Cohort 2 received nivolumab monotherapy and radiation therapy, whereas Arm D (n=4) of Cohort 2 received nivolumab/ipilimumab combination therapy and radiation therapy. A tumor biopsy was obtained before treatment, and another sample was taken during the primary treatment of surgical excision. These samples were processed and analyzed by a pathologist who determined the percentage of viable tumor, hyalinization, and necrosis in each sample. Radiographic imaging was also taken throughout to make RECIST 1.1 response determinations. RESULTS: The average treatment response (1 - % viable tumor) for Cohort 1 was 25 ± 23 and there was no difference between Arm A and Arm B, p=0.48. The average treatment response in Cohort 2 was higher at 85 ± 27, but there was also no significant difference between the arms, p = 0.46. The mean percent hyalinization for Cohort 1 was 13 ± 13%, and for Cohort 2 was 69 ± 35%. Again, there was no significant difference between the arms in the Cohort 1 or 2, p = 0.45 and p = 0.54, respectively. Lastly, the mean % necrosis in Cohort 1 was 13 ± 13 %, and in Cohort 2 was 17 ± 24%, and neither had significantly different results in the arms, p = 0.60 and p = 0.92. The RECIST 1.1 results were independent of the arms of the study, and the radiographic response (percent image change) did not correlate to any metric of histologic response. Those who received Ipilimumab had higher rates of adverse events. CONCLUSION: There is significant evidence that ICBs elicited a response in RP DDLPS and ET UPS, and the response of ET UPS was profound. However, there was no apparent benefit from the combination therapy compared to the monotherapy in either cohort. The higher response in ET UPS may be due to the additional radiation therapy or to the nature of UPS itself. Finally, radiographic imaging does not show the response which is apparent at the histological level, so treatment regimens and future experiments should no longer rely on radiographic imaging as a marker for response. / 2021-06-07T00:00:00Z

Ribavirin, a synthetic nucleoside, was found to inhibit the replication of Rous sarcoma viruses (RSV) and subsequent cell transformation in chick embryo fibroblasts (CEF). It also blocked the transformation of normal rat kidney (NRK) cells infected with temperature-sensitive mutants of RSV. The action of Ribavirin was found to be reversible as removal of the drug from the NRK cells reversed the effects on cell transformation. Ribavirin appears to have a static effect on cell growth of both NRK and CEF cells. In addition, guanosine, xanthosine and inosine altered the effect of Ribavirin on cell growth.

This report from Groote Schuur therefore sets out to review cases of postradiation sarcomas, including malignant mixed mullerian tumors (MMMT), presenting to the Radiation Oncology Departments of Groote Schuur Hospital and the affiliated hospitals (Frere Hospital, East London and Provincial Hospital, Port Elizabeth) or known to have occurred in patients initially treated in these hospitals. It aims [1] to establish the features of the initial malignancy as well as the latent period for the development of postradiation sarcoma, the type of postradiation tumor and the outcome of the disease; [2] to establish as accurately as possible dose levels at which the postradiation tumors have developed; and [3] to briefly describe possible risk factors such as a genetic predisposition to the development of malignancy, repeated courses of radiotherapy, surgery as part of the treatment of the initial tumor, and chemotherapy. Questions regarding the genesis of postradiation sarcomas cannot be answered by a review of 20 cases, even when combined with an analysis of literature. This review aims to add relevant information to the body of data from which the final answers may come. In view of the late diagnosis often made in cases of postradiation sarcoma (25, 94) the review also aims to heighten awareness of the condition so that it may be more often reported at a curable stage.

O sarcoma de aplicação em felinos (SAF) é uma neoplasia rara de origem mesenquimal e com prognóstico desfavorável que se desenvolve em local previamente utilizado para aplicações de medicamentos injetáveis ou submetido a traumas. Poucos estudos foram encontrados na literatura descrevendo os aspectos imaginológicos do SAF. O objetivo dessa pesquisa foi descrever os aspectos das imagens de tomografia computadorizada e ultrassonografia do SAF (modo B e Doppler colorido e amplitude), verificando características comuns, particularidades da formação recidivante e correlações com variáveis clínicas. A pesquisa contemplou uma fase prospectiva e outra retrospectiva, totalizando 32 felinos. Ao exame tomográfico, observou-se com maior frequência formas neoplásicas irregulares (62,5%), com prolongamentos digitiformes (100%), realce periférico e heterogêneo (67,7%), borramento dos planos adiposos (68,8%) e áreas sugerindo necrose intratumoral (68,8%). Ao exame ultrassonográfico observou-se contornos irregulares, presença de halo hiperecogênico, ecotextura heterogênea, tecido hiperecogênico contíguo à formação e espessamento hipoecogênico do subcutâneo adjacente, além de ecogenicidade mista, devido à presença de áreas sugerindo necrose intratumoral (83,3%). Ao estudo Doppler, observou-se distribuição vascular mais evidente na região periférica (83,3%), com calibre homogêneo (83,3%), fluxo regular (50%) e misto (50%). A quantidade de vasos neoplásicos detectados pela TC foi maior do que por US Doppler (p=0,024). O volume e o tempo de evolução da formação apresentaram alta correlação nos casos não recidivantes (p<0,001). A presença de metástase salteada foi mais comum em formações recidivantes (p=0,001). O uso de meio de contraste intravenoso e do recurso MPR permitiu melhor delimitação das margens da formação pela TC e uma mensuração neoplásica mais criteriosa. Os histogramas revelaram uma quantidade representativa de gordura na composição do SAF, e foi observada quantidades superiores de músculos acometidos na presença de um espessamento da gordura adjacente à formação (p=0,003). Os exames de diagnóstico por imagem foram importantes para caracterização do SAF, especialmente no que se refere a delimitação de suas margens e na avaliação dos tecidos adjacentes, além de fornecerem informações relevantes para o estadiamento neoplásico e para terapêutica. / The feline injection-site sarcoma (FIIS) is a rare mesenchymal neoplasm and has poor prognosis. It develops in a site previously used for intravenous applications or undergone trauma. Few studies were found in the literature describing the imaging features of FIIS. The aim of this research was to describe computed tomographic (CT) and ultrasonographic (B mode, color and power Doppler) images of FIIS to find common characteristics, particularities of disease recurrence and correlations with clinical variables. The study had a prospective and a retrospective phases, totaling 32 cats. At the CT scan it was observed more frequently an irregular neoplastic forms (62,5%) with fingerlike projections (100%), peripheral and heterogeneous enhancements (67,7%), blurring of the adjacent fat (68,8%) and areas suggesting intratumoral necrosis (68,8%). At the ultrasound it was observed irregular outlines, with hyperechoic halo, heterogeneous echotexture, hyperechogenic tissue adjacent at the tumor and thickening of the adjacent hypoechogenic subcutaneous tissue. Mixed echogenicity with areas suggesting intratumoral necrosis was generally observed (83,3%). Doppler study showed more evident vascular distribution in the peripheral region (83,3%) with homogeneous diameter (83,3%), smooth (50%) and mixed (50%) flow. The quantity of tumor vessels was higher at CT than Doppler ultrasound (p=0,024). The presence of a vessel tumor coming from vessels of the abdominal cavity on CT may be an important finding for surgical planning. Tumor volume and time of presentation were correlated with non-recurrent cases (p<0,001). Skip metastasis showed high correlation with recurrent cases (p=0,001). The use of postcontrast phase at CT scans and MPR allowed better delineation of tumor margins and a more carreful measurement. Histograms revealed a representative amount of fat in tumor composition. A tendency of higher amounts of muscles being involved was observed with fat thickening near the tumor (p=0,003). Diagnostic imaging was important to characterization of FIIS, especially to delimitate tumor extension, evaluate compromised adjacent tissues providing relevant information for tumor staging and therapeutic planning.

Como otros tumores sólidos, el sarcoma de Ewing (SE) requiere de un aporte vascular adecuado que permita nutrir y oxigenar a las células tumorales. En el SE, la vascularización tumoral se encuentra caracterizada principalmente por los procesos de vasculogenesis, mimetismo vascular y angiogénesis. Considerando la participación de CAV1 en el aporte vascular, nos planteamos demostrar que CAV1 juega un papel importante en el desarrollo vascular de la enfermedad. Estableciendo tres nuevos modelos de baja expresión de CAV1 en células se SE (RDES, SKES1 y TC71), fue posible observar la reducción en el desarrollo tumoral en xenoinjertos, y a su vez esta reducción fue relacionada con la disminución en la densidad micro-vascular. Este trabajo demuestra el efecto directo del silenciamiento de CAV1 sobre el proceso angiogénico en el SE, regulando la respuesta de la célula endotelial ante las señales producidas por la célula tumoral. Nuestros resultados mostraron que las células endoteliales presentan mayor migración ante el estímulo de las señales producidas por la célula tumoral. Mediante el análisis de expresión de diferentes factores utilizando RT-PCR, fue posible determinar que la expresión de bFGF era afectada en los modelos analizados como efecto del silenciamiento de CAV1. Para determinar el mecanismo molecular a través del cual CAV1 regula la angiogénesis en el sarcoma de Ewing, partimos del análisis de expresión de 3 miembros de la familia Eph descritos como pieza clave en el desarrollo vascular. La expresión del receptor EphA2 en los modelos de baja expresión de CAV1 mostró una disminución en los clones, donde el silenciamiento de CAV1 conlleva la redistribución y reducción EphA2. Los análisis mostraron además una interacción entre ambas proteínas. Establecida la relación EphA2/CAV1, analizamos el efecto de la estimulación de EphA2 a partir de EfnA1 y confirmamos que las células con baja expresión de CAV1 presentaban una respuesta menor. La estimulación resultó en el incremento de la fosforilación de AKT, sugiriendo que los efectos podrían depender de la actividad quinasa del receptor. Para respaldar esto, las células RDES y TC71 fueron transfectadas con un dominante negativo de EphA2 que no modificaba la expresión de CAV1 (EphA2-Kd). Los modelos EphA2-Kd reprodujeron los resultados observados en los modelos de baja expresión de CAV1. La estimulación del modelo TC71-EphA2-Kd con la proteína recombinante EfnA1, mostró tanto la activación de AKT como la sobreexpresión de bFGF, reproduciendo en cierta medida lo observado por el silenciamiento de CAV1 y destacando la importancia de la actividad dependiente de quinasa de EphA2 en el proceso angiogénico de la enfermedad. Considerando que CAV1 es necesario para el correcto funcionamiento de las rutas de señalización controladas por EphA2 en el SE, decidimos determinar la implicación de CAV1 y EphA2 en el mimetismo vascular de la enfermedad. Se decidió analizar el papel independiente de quinasa del receptor EphA2 como una posible pieza clave en el proceso de mimetismo vascular en el SE. Nuestros resultados mostraron que el silenciamiento de CAV1 reduce el desarrollo de vasos miméticos in vivo e impide la formación tubular in vitro. Además, el efecto de bloquear la actividad quinasadependiente del receptor EphA2 mostró que la actividad quinasa del receptor no afecta al proceso de mimetismo vascular en esta entidad tumoral. Para confirmar la participación de EphA2 en el proceso de formación de vasos miméticos, se transfectó un mutante que carece de toda la región citoplasmática del receptor EphA2 (ΔCyto), eliminando así sus funciones dependientes e independientes de quinasa. Los resultados mostraron que el bloqueo total del receptor tenía un efecto negativo en la formación de estructuras tubulares. Estos resultados confirman la importancia de la actividad prooncogénica del receptor EphA2 en el sarcoma de Ewing. / We established low CAV1 expressing models by knocking down CAV1 in TC71, RDES and SKES1 Ewing sarcoma (ES) cells by stably transfecting a previously validated shRNA construct. In vivo studies showed a decrease in tumor volume from the CAV1 knocked-down clones when compared with controls. This correlated with a reduction in microvascular density (MVD) and higher levels of necrosis. Conditioned media from CAV1 knocked-down cells showed reduced capability to promote migration of endothelial cells with no changes in proliferation. Different pro-angiogenic factors were analyzed by RT-PCR in the models and, downregulation of bFGF was observed in all four. Results suggested that CAV1 was indirectly affecting bFGF expression. EphA2 expression was observed in ES cell lines and tumor samples. CAV1 knocked-down cells showed a reduction in EphA2 phosphorylation as well as a displacement from the membrane to the cytoplasm. Furthermore, we showed that the CAV1/EphA2 interaction was necessary for Eph-mediated signaling. To further support these results, RDES and TC71 cells were stably transfected with a dominant negative of EphA2 that did not alter the expression of CAV1 (EphAh2-kd). EphA2-Kd models were able to replicate the effects observed in the CAV1 knocked-down models, where the stimulation of the TC71-EphA2-Kd model with the recombinant protein EfnA1, showed both the activation of AKT and the overexpression of bFGF. These results replicate the effect of silencing CAV1 and highlighted the importance of the kinase-dependent activity of EphA2 in the angiogenic process in ES. We decided to analyze the kinaseindependent role of EphA2 as a possible key in the process of vascular mimicry in ES. Our results showed that the silencing of CAV1 reduces the development of mimetic vessels in vivo and prevents the tubular formation in vitro. In addition, our results showed that the kinase-dependent activity of the receptor does not affect the process of vascular mimicry in ES. Moreover, we stably transfected a mutant that lacks all the cytoplasmic region of EphA2, blocking its kinase-dependent and –independent activities. Results showed a negative effect on the formation of tubular structures. These results confirm the importance of the pro-oncogenic activity of EphA2 in ES.

O sarcoma de aplicação em felinos (SAF) é uma neoplasia rara de origem mesenquimal e com prognóstico desfavorável que se desenvolve em local previamente utilizado para aplicações de medicamentos injetáveis ou submetido a traumas. Poucos estudos foram encontrados na literatura descrevendo os aspectos imaginológicos do SAF. O objetivo dessa pesquisa foi descrever os aspectos das imagens de tomografia computadorizada e ultrassonografia do SAF (modo B e Doppler colorido e amplitude), verificando características comuns, particularidades da formação recidivante e correlações com variáveis clínicas. A pesquisa contemplou uma fase prospectiva e outra retrospectiva, totalizando 32 felinos. Ao exame tomográfico, observou-se com maior frequência formas neoplásicas irregulares (62,5%), com prolongamentos digitiformes (100%), realce periférico e heterogêneo (67,7%), borramento dos planos adiposos (68,8%) e áreas sugerindo necrose intratumoral (68,8%). Ao exame ultrassonográfico observou-se contornos irregulares, presença de halo hiperecogênico, ecotextura heterogênea, tecido hiperecogênico contíguo à formação e espessamento hipoecogênico do subcutâneo adjacente, além de ecogenicidade mista, devido à presença de áreas sugerindo necrose intratumoral (83,3%). Ao estudo Doppler, observou-se distribuição vascular mais evidente na região periférica (83,3%), com calibre homogêneo (83,3%), fluxo regular (50%) e misto (50%). A quantidade de vasos neoplásicos detectados pela TC foi maior do que por US Doppler (p=0,024). O volume e o tempo de evolução da formação apresentaram alta correlação nos casos não recidivantes (p<0,001). A presença de metástase salteada foi mais comum em formações recidivantes (p=0,001). O uso de meio de contraste intravenoso e do recurso MPR permitiu melhor delimitação das margens da formação pela TC e uma mensuração neoplásica mais criteriosa. Os histogramas revelaram uma quantidade representativa de gordura na composição do SAF, e foi observada quantidades superiores de músculos acometidos na presença de um espessamento da gordura adjacente à formação (p=0,003). Os exames de diagnóstico por imagem foram importantes para caracterização do SAF, especialmente no que se refere a delimitação de suas margens e na avaliação dos tecidos adjacentes, além de fornecerem informações relevantes para o estadiamento neoplásico e para terapêutica. / The feline injection-site sarcoma (FIIS) is a rare mesenchymal neoplasm and has poor prognosis. It develops in a site previously used for intravenous applications or undergone trauma. Few studies were found in the literature describing the imaging features of FIIS. The aim of this research was to describe computed tomographic (CT) and ultrasonographic (B mode, color and power Doppler) images of FIIS to find common characteristics, particularities of disease recurrence and correlations with clinical variables. The study had a prospective and a retrospective phases, totaling 32 cats. At the CT scan it was observed more frequently an irregular neoplastic forms (62,5%) with fingerlike projections (100%), peripheral and heterogeneous enhancements (67,7%), blurring of the adjacent fat (68,8%) and areas suggesting intratumoral necrosis (68,8%). At the ultrasound it was observed irregular outlines, with hyperechoic halo, heterogeneous echotexture, hyperechogenic tissue adjacent at the tumor and thickening of the adjacent hypoechogenic subcutaneous tissue. Mixed echogenicity with areas suggesting intratumoral necrosis was generally observed (83,3%). Doppler study showed more evident vascular distribution in the peripheral region (83,3%) with homogeneous diameter (83,3%), smooth (50%) and mixed (50%) flow. The quantity of tumor vessels was higher at CT than Doppler ultrasound (p=0,024). The presence of a vessel tumor coming from vessels of the abdominal cavity on CT may be an important finding for surgical planning. Tumor volume and time of presentation were correlated with non-recurrent cases (p<0,001). Skip metastasis showed high correlation with recurrent cases (p=0,001). The use of postcontrast phase at CT scans and MPR allowed better delineation of tumor margins and a more carreful measurement. Histograms revealed a representative amount of fat in tumor composition. A tendency of higher amounts of muscles being involved was observed with fat thickening near the tumor (p=0,003). Diagnostic imaging was important to characterization of FIIS, especially to delimitate tumor extension, evaluate compromised adjacent tissues providing relevant information for tumor staging and therapeutic planning.

BACKGROUND:Serum protein acidic and rich in cysteine (SPARC) is a matricellular secreted glycoprotein that performs several cellular functions and has been implicated in tumorigenesis in a variety of tumor types. The chemotherapeutic agent nanoparticle albumin-encapsulated (NAB)-paclitaxel has been postulated to exploit SPARC expression to target neoplastic cells. SPARC's role, and potentially the role of NAB-paclitaxel, in the highly heterogeneous class of soft-tissue sarcomas (STS) has not been investigated. Our objective was to explore the pattern of SPARC expression and its prognostic significance in STS.METHODS:27 tissue specimens representing various STS histologies were stained for SPARC expression by immunohistochemistry (IHC). Staining intensity was scored blindly. Survival was determined from patients' medical records and analyzed using Kaplan-Meier and log-rank with respect to SPARC expression level.RESULTS:Elevated SPARC expression was observed in 15/27 (56%) specimens. Overall patient survival segregated strongly based on levels of SPARC expression. Patients who expressed low-to-moderate levels of SPARC exhibited median survival of 22.1months, while the median survival of patients with moderate-to-high expression levels was 4.4months (log rank / p=0.0016).CONCLUSIONS:SPARC expression is elevated in a significant proportion of STS specimens analyzed in this study, but it does not appear to correlate with specific STS histologies. Given our limited sample size, we cannot draw definitive conclusions regarding association of SPARC with STS subtype. Overall survival segregates strongly by degree of SPARC expression, with elevated expression being adverse. If validated in a larger study, our results suggest that trials in STS with agents potentially targeting SPARC, such as NAB-paclitaxel, should be stratified by SPARC expression level.

Ewing sarcoma, an aggressive primary bone and soft tissue tumour is characterised by the expression of the chimeric transcription factor EWS-FLI1 in 90% of patients. This alters expression of many genes including activation of the Insulin Growth Factor (IGF) pathway via IGFBP3 supression. Phase I/II trials with an IGF-1 inhibitor have demonstrated tumour regression in a modest number of Ewing sarcoma patients. The aim of this thesis was to identify mechanisms contributing to the heterogeneity of resistance in Ewing sarcoma following inhibition with OSI-906, a dual kinase inhibitor of IGF-1 (IGF-1R) and Insulin (IR) receptors. The hypothesis was that mechanisms of resistance relate to heterogeneity of responses to signalling pathway activation and inhibition. Through selection, disruption of the pathway would identify subpopulations of cells both sensitive and resistant in their response allowing for interrogation of resistance mechanisms. A genome wide approach was taken to model the resistance profile of cell lines. Through developing a method of unbiased quantification, a panel of validated Ewing sarcoma cell lines (EuroBoNet) were imaged and segmented to assess the responses of biomarkers on signalling pathway activation. Heterogeneity was confirmed between cell lines. The application to diagnostic biopsies led to the identification of prognostic classifiers and cellular subpopulations with clinical prognostic significance. The distribution of Ki67 was found to be predictive of survival and cells with lower levels of CD99 in the cytoplasm were most discriminative. Parallel sequencing strategies (RNA-seq, whole exome sequencing, and aCGH/ SNP array) for genome-wide screening was carried out for point mutations, copy number changes and rearrangements. Systematic detection was used to characterise genomic rearrangements and functional validation performed. Resistant clones, formed via ENU mutagenesis of cell lines, were sequenced in order to demonstrate the resistance profile of OSI-906. In summary heterogeneity of Ewing sarcoma at the genomic and proteomic level can influence the signalling dependency of tumours and response to inhibitors. Genomic and proteomic profiling of tumour cells may be relevant to future developments of novel therapies.

Orientador: Maria Aparecida Custódio Domingues / Banca: Flavio de Oliveira Lima / Banca: Gilson Luchese Delgado / Resumo: O Sarcoma Histiocítico (SH) é uma neoplasia maligna caracterizada pela proliferação de células grandes que possuem aspecto morfológico e imunofenotípico semelhantes ao histiócito maduro tecidual. É uma neoplasia rara, perfazendo menos que 1% dos Linfomas Não-Hodgkin. Tal raridade pode ser explicada pela dificuldade de sua caracterização diagnóstica e morfológica, confundindo-se com outras neoplasias malignas pleomórficas. Os objetivos do presente estudo são: avaliar alterações no padrão de ganhos e perdas genômicas pela técnica de Hibridação Genômica Comparativa (CGH-array), avaliação do perfil de MicroRNA (miRNA), apontar os principais critérios morfológicos e marcadores imunoistoquímicos (IMH) que venham a definir esta entidade e identificar quais entidades que erroneamente podem levar a subdiagnostico.Para tanto, foram revisados 7.600 laudos anatomopatológicos e, destes, foram selecionados 47 casos possíveis de SH, com apresentação nodal. Somando-se a estes, quatro casos sabidamente com diagnóstico de SH foram incluídos na análise. Foram avaliados 12 critérios morfológicos e 05 marcadores IMH. Dos 47 casos, foram localizados 07 SH, cujo diagnóstico inicial foi de neoplasia indiferenciada metastática (carcinoma indiferenciado) ou melanoma metastático. Os marcadores IMH que se mostraram mais eficientes para complementação diagnóstica foram CD163 e CD68. A avaliação do perfil de 377 miRNAs demonstrou clusterização de 51 miRNA, quando comparado ao controle, sendo 44 hipoexpresssos e 07 hiperexpressos, sendo os mais relevantes: miR-10b-5p, miR-455-5p e miR-19 (hiperexpressos); miR-486-5p, miR-92a, miR-15b-5p (hiporegulados). Tais miRNA estão envolvidos nas vias da apoptose, crescimento e proliferação celular. Os principais genes envolvidos na patogenia e candidatos a validação com futuros estudos são: ERBB2, TGFB1,TNF(ativados) e TP53 e PD98059 (inibidos).Tais genes podem corresponder a futuros... / Abstract: Histiocytic sarcoma (HS) is a malignant neoplasm characterized by the proliferation of large cells that have morphological and immunophenotypic features similar to mature tissue histiocytes. It is a rare neoplasm, accounting for less than 1% of non-Hodgkin lymphomas. This rarity is partly explained by the difficulties in its diagnostic and morphological characterization, since it is confused with other pleomorphic malignant neoplasms. The objectives of this study were to evaluate changes in genomic gains and losses using the comparative genomic hybridization technique (CGH-array), microRNA profile (miRNA) evaluation, determine the principal morphological criteria and immunohistochemical markers (IMH) that could define this entity, and identify entities that can mistakenly lead to underdiagnosis. To achieve this, 7,600 pathology reports were reviewed and, of these, 47 possible cases of HS with nodal presentation were selected. Four cases with an established diagnosis of HS were also included in the analysis. Twelve morphological criteria and 5 IMH markers were evaluated. Among the 47 cases, 7 cases of HS were identified that had initially been diagnosed as undifferentiated metastatic neoplasm (undifferentiated carcinoma) or metastatic melanoma. The IMH markers that were most efficient for complementary diagnosis were CD163 and CD68. Evaluation of the profiles of 377 miRNAs showed clustering of 51 miRNA compared with the control; 44 were hypoexpressed and 7 were hyperexpressed and the most relevant were: miR-486-5p, miR-92a, miR-15b-5p (hyporegulated); and miR-10b-5p, miR-455-5p and miR-19 (hyperexpressed). These miRNA are involved in apoptosis, cell growth and proliferation pathways. The main genes involved in pathogenesis and candidates for validation in future studies are: ERBB2, TGFB1, TNF (activated); and TP53 and PD98059 (inhibited). These genes may represent future therapeutic targets. The CGH-array proved to be unfeasible in ... / Mestre

Student Number : 9201769X - M Med research report - School of Clinical Medicine - Faculty of Health Sciences / A PROSPECTIVE RANDOMIZED TRIAL OF TWO FRACTIONATION REGIMENS OF RADIATION THERAPY IN THE MANAGEMENT OF AIDSASSOCIATED KAPOSI SARCOMA OBJECTIVE: To compare a standard fractionation scheme with a hypofractionated scheme in the treatment of AIDS-associated Kaposi sarcoma with the aim of showing noninferiority of the shorter schedule. PATIENTS AND METHODS: HIV positive patients with histologically proven Kaposi sarcoma presenting consecutively to Radiation Oncology at Johannesburg Hospital were randomized between January 2003 and May 2004 to receive a standard regimen of 24 Gy in 12 fractions (ARM A) or the study regimen of 20 Gy in 5 fractions (ARM B). The radiation technique used was individualized for each site in accordance with departmental practice. Follow-up assessment was done at monthly intervals. Treatment response and toxicity were recorded at each follow-up visit. RESULTS: A total of 60 patients were recruited, of which 41 were male and 19 were female. The median age was 36 years (range: 23 – 55 years). Thirteen patients died prior to receiving treatment. The remaining 47 patients were treated to 65 sites, of which 35 sites received 24 Gy in 12 fractions (ARM A) and 30 sites received 20 Gy in 5 fractions (ARM B). The main indications for treatment were pain (n=71), oedema (n=44), functional impairment (n=35), cosmesis (n=14) and bleeding (n=4). At the time of reporting 28 patients were alive and 32 patients have died. The overall survival of the whole group was 37% at 1 year. A complete response was recorded at 28 sites, a partial response at 19 sites and stable disease at 3 sites. The mean time to maximum objective response was 3 months (range: 1 – 14 months). The response rates were equal in the 2 treatment arms (p=0.73). Local control was equal in the 2 treatment arms with a median local recurrence free survival of 150 days for ARM A and 455 days for ARM B (p=0.11, log rank test). Acute skin toxicity occurred at 27 sites. Moist desquamation developed at 7 sites while necrosis developed at 2 sites. Acute skin toxicity was equal in the 2 treatment arms (p=0.77). Acute mucosal toxicity occurred at 2 sites. Late skin reactions developed at 21 sites, of which necrosis or ulceration occurred at 5 sites. Chronic skin reactions were equivalent in the 2 treatment arms (p=0.24). Post radiation oedema developed at 5 sites. CONCLUSION: In our experience, 20 Gy in 5 fractions gave similar results to 24 Gy in 12 fractions in terms of treatment response, local recurrence free survival and toxicity in this small group of patients.