Radiomics model for predicting distant metastasis in soft tissue sarcoma of the extremities and trunk treated with surgery.

PURPOSE: The aim of this study was to develop a radiomics model based on magnetic resonance imaging (MRI) for predicting metastasis in soft tissue sarcomas (STSs) treated with surgery. METHODS/PATIENTS: MRI and clinical data of 73 patients with STSs of the extremities and trunk were obtained from TCIA database and Jiangsu Cancer Hospital as the training set, data of other 40 patients were retrospectively collected at our institution as the external validation set. Radiomics features were extracted from both intratumoral and peritumoral regions of fat-suppressed T2-weighted images (FS-T2WIs) of patients, and 3D ResNet10 was used to extract deep learning features. Recursive feature elimination (RFE) and least absolute shrinkage and selection operator (LASSO) algorithms were used for the selection of features. Based on 4 different sets of features, 5 machine learning algorithms were used to construct intratumor, peritumor, combined intratumor and peritumor radiomics models and deep learning radiomics (DLR) model. The area under the ROC curve (AUC) and Decision curve analysis (DCA) were used to evaluate the ability of models to predict metastasis. RESULTS AND CONCLUSIONS: Based on 20 selected features from the deep-learning and radiomics features set, the DLR model was able to predict metastasis in the validation dataset, with an AUC of 0.9770. The DCA and Hosmer-Lemeshow test revealed that the DLR model had good clinical benefit and consistency. By getting richer information from MRI, The DLR model is a noninvasive, low-cost method for predicting the risk of metastasis in STSs, and can help develop appropriate treatment programs.

Impact of anthracycline-based chemotherapy on RB1 gene methylation in peripheral blood leukocytes and biomarkers of oxidative stress and inflammation in sarcoma patients.

PURPOSE: We investigated the impact of anthracycline-based chemotherapy on methylation status of RB1 gene in peripheral blood leukocytes together with parameters of oxidative stress and inflammation in sarcoma patients. PATIENTS/METHODS: Blood samples were collected from 51 consecutive newly diagnosed sarcoma patients admitted to University Hospital Center Zagreb (Zagreb, Croatia) for first-line chemotherapy before the first cycle and post-chemotherapy. Methylation and copy number variation (CNV) of leukocyte RB1 gene were assessed using MS-MLPA probes. In addition, in blood samples, parameters of oxidative stress (ROS, MDA, SOD, and GSH) and inflammation (CRP, WBC, and NBC) were followed. RESULTS: In pre-chemotherapy samples, no CNVs and aberrant methylation of CpG106 promoter region of RB1 gene were detected; however, one patient had hypermethylation (by approximately 10%) of imprinted locus CpG85 in intron 2 of RB1 gene. In addition, a very good correlation of the tumor burden and CRP and tumor burden and GSH was found. The anthracycline-based chemotherapy reverts methylation of RB1 gene-imprinted locus CpG85 to normal level. Moreover, inflammation and oxidative stress parameters such as CRP, WBC, ROS, and MDA were significantly decreased in post-chemotherapy samples. CONCLUSION: This single-centered study on a cohort of consecutive sarcoma patients indicates that sarcoma patients can have aberrant germline DNA methylation and confirms the relationship of tumor burden with inflammation and oxidative stress. The applied chemotherapy protocols reverted RB1 gene methylation to normal level and decreased the level of inflammation and oxidative damage, thus indicating chemotherapy benefit to the patient's health status.

Efficacy of second and third lines of treatment in advanced soft tissue sarcomas: a real-world study.

BACKGROUND: Soft tissue sarcomas (STSs) are an uncommon and heterogeneous group of tumours. Several drugs and combinations have been used in clinical practice as second-line (2L) and third-line (3L) treatment. The growth modulation index (GMI) has previously been used as an exploratory efficacy endpoint of drug activity and represents an intra-patient comparison. METHODS: We performed a real-world retrospective study including all patients with advanced STS who had received at least 2 different lines of treatment for advanced disease between 2010 and 2020 at a single institution. The objective was to study the efficacy of both 2L and 3L treatments, analysing the time to progression (TTP) and the GMI (defined as the ratio of TTP between 2 consecutive lines of therapy). RESULTS: Eighty-one patients were included. The median TTP after 2L and 3L treatment was 3.16 and 3.06 months, and the median GMI was 0.81 and 0.74, respectively. The regimens most frequently used in both treatments were trabectedin, gemcitabine-dacarbazine, gemcitabine-docetaxel, pazopanib and ifosfamide. The median TTP by each of these regimens was 2.80, 2.23, 2.83, 4.10, and 5.00 months, and the median GMI was 0.78, 0.73, 0.67, 1.08, and 0.94, respectively. In terms of histotype, we highlight the activity (GMI > 1.33) of gemcitabine-dacarbazine in undifferentiated pleomorphic sarcoma (UPS) and in leiomyosarcoma, pazopanib in UPS, and ifosfamide in synovial sarcoma. CONCLUSIONS: In our cohort, regimens commonly used after first-line STS treatment showed only slight differences in efficacy, although we found significant activity of specific regimens by histotype.

Pelvic soft tissue sarcomas.

Pelvic soft tissue sarcomas (PSTS) are a rare, heterogeneous group of tumors. They have been usually analyzed with retroperitoneal sarcomas (RPS), but actually have key differences. Due to their unique anatomic location, symptomatic presentation of PSTS may be more common than RPS. Adequate imaging approach is paramount for guiding differential diagnosis, while preoperative biopsy is mandatory, especially when preoperative treatment may be considered as initial approach. The most frequent histologic subtype is leiomyosarcoma, which is different as expected in the retroperitoneum where liposarcoma is the commonest histology. Also solitary fibrous tumor is commonly diagnosed in the pelvis. Surgical approach for PSTS differs from that for RPS mainly due to anatomic relations. Similarly, in the lack of definite evidence from specific trials about neoadjuvant and adjuvant treatments, the anatomic constraints to obtain wide margins in the pelvis as well as the expected functional outcome in case of organ resections should be factored into decision for individualized treatment offer. Vascular and genitourinary involvement are frequent, as well as herniation through pelvic foramina. For these reasons a multidisciplinary surgical team should always be considered. Early referral of these patients to high-volume centers is critical and may impact on survival, given that optimal initial resection is a major predictor of curative treatment. International consensus on PSTS treatment is advocated, similarly to the recent efforts realized for RPS.

Síndrome de Li-Fraumeni Presentación metacrónica de sarcoma de tejidos blandos, sarcoma cardiaco y cáncer gástrico / Li-Fraumeni Syndrome Metachronous presentation of soft-tissue sarcoma, heart sarcoma and gastric cancer

Resumen El síndrome de Li-Fraumeni (SLF) es un trastorno autosómico dominante hereditario con predisposición al cáncer, está asociado con anomalías en el gen de la proteína tumoral p53 (TP53), que se manifiesta por una amplia gama de neoplasias malignas que aparecen a una edad temprana. Se expone al caso de un adulto joven en quien hicimos este diagnóstico, y se describen las perspectivas terapéuticas en investigación. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2198).

Abstract Li-Fraumeni syndrome (LFS) is a hereditary autosomal dominant disorder with a predisposition to cancer. It is associated with abnormalities of the tumor protein p53 (TP53) gene, manifesting with a broad range of malignant neoplasms which appear at an early age. We discuss the case of a young adult in whom we did this diagnosis, and we describe the therapeutic perspectives being researched. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2198).

Análise de marcadores sanguíneos em pacientes com osteossarcoma, sarcomas de partes moles e tumor desmóide / Analysis of blood markers in patients with soft tissue sarcoma and desmoid tumor

Introdução: O tumor desmoide (TD) é uma neoplasia rara com altas taxas de recorrência local, composto por células fibroblásticas que se caracterizam pela expressão de moléculas-chave, incluindo o filamento intermediário vimentina, ciclooxigenase-2 (COX-2) e ß-catenina nuclear. Células tumorais circulantes (CTCs) isoladas do sangue periférico de pacientes com sarcomas e outras neoplasias podem ser utilizadas como biomarcadores precoces de invasão e disseminação tumoral. A família dos Receptores do Fator de Crescimento Epidérmico (Epidermal Growth Factor Receptor, EGFR) também podem influenciar no processo de invasão das CTCs, na formação de metástases e na recolonização de seus tumores de origem por meio de um processo de "auto-semeadura do tumor". Objetivo: Nosso objetivo foi identificar CTCs no sangue periférico de pacientes com TD ou sarcomas e avaliar a expressão das proteínas ß-catenina, TGF-ßRI (do Inglês, Transforming Growth Factor-ß Receptor I), COX-2 (Cyclooxygenase2), vimentina, GLUT-1 (Glucose Transporter 1), LGR5 (G-Protein Coupled Receptor 5) e EGFR, e sua correlação com sobrevidas global (SG) e livre de progressão (SLP). Materiais e Métodos: Foi realizado um estudo prospectivo de pacientes com diagnóstico inicial ou TD recidivado com doença mensurável. Para sarcomas, utilizamos amostras coletadas de forma prospectiva e retrospectiva. As amostras de sangue de cada paciente foram processadas e filtradas pelo ISET® (Rarecells, França) para isolamento e quantificação de CTCs. A expressão das proteínas foi analisada por imunocitoquímica (ICC). Para análise molecular das CTCs provenientes de pacientes com TD foi padronizado o método de PCR digital. Resultados: Foram incluídos 18 pacientes com TD, todos com CTCs detectáveis, com níveis que variaram entre 0,5­13 CTCs/mL. Encontramos uma concordância da expressão de ß-catenina em CTCs e tumores primários de 42,8% (6/14) dos casos usando ICC e imunohistoquímica, respectivamente. Nos nossos testes prévios de PCR digital, encontramos cópias mutadas de S45Pro em 4 pacientes (40%) e de S45Phe em apenas um paciente (10%). Em contraste, não foram encontradas mutações Th41Ala. Nas amostras de sarcomas, analisamos 30 amostras e encontramos CTCs em 93% dos pacientes e os níveis variaram de 0-11,25 CTCs/mL. Observamos também que a SG dos pacientes positivos para EGFR (p=0,027) eram inferiores às sobrevidas dos pacientes negativos para as mesmas proteínas. Conclusões: Nosso estudo identificou alta prevalência de CTCs em pacientes com TD e sarcomas. A concordânciada expressão de ß-catenina entre tumor primário e CTCs traz novas perspectivas para avaliar a dinâmica das CTCs no compartimento sanguíneo, abrindo novos caminhos para o estudo da biologia e comportamento do TD. Este é o primeiro estudo a demonstrar a expressão da proteína LGR5 em CTCs de pacientes com diferentes tipos de sarcomas, o que pode abrir novas oportunidades para futuras investigações. O próximo passo é caracterizar CTCs em uma coorte maior de pacientes para entender melhor o papel do LGR5 e das demais proteínas no processo de metástases tumorais em sarcomas. Além disso, esses resultados abrem a possibilidade de usar CTCs para prever a dinâmica do TD no momento da progressão da doença e tratamento. Mais estudos com tamanhos de amostra maiores são necessários para validar nossos achados tanto em TD como em sarcomas

Introduction: Desmoid tumor (DT) is a rare neoplasm with high rates of local recurrence, composed of fibroblast cells that are characterized by the expression of key molecules, including the intermediate filament vimentin, cyclooxygenase-2 (COX-2) and ß-catenin. Circulating tumor cells (CTCs) isolated from the peripheral blood of patients with sarcomas and other neoplasms can be used as early biomarkers of tumor invasion and dissemination. The Epidermal Growth Factor Receptor (EGFR) family can also influence the process of CTC invasion, metastasis formation and recolonization of their tumors of origin through a process of "tumor selfseeding". Objective: Our objective was to identify CTCs in the peripheral blood of patients with TD or sarcomas and to evaluate the expression of ßcatenin proteins, transforming growth factor receptor beta I (TGF-ßRI), COX-2 (cyclooxygenase-2), vimentin, GLUT-1 (Glucose transporter 1), LGR5 (Gprotein coupled receptor 5) and EGFR and their relation with progression free (PFS) and overall suvival (OS). Methods: We performed a prospective study of patients with initial diagnosis or relapsed TD with measurable disease. For sarcomas, we used samples collected prospectively and retrospectively. Blood samples from each patient were processed and filtered by ISET® (Rarecells, France) for isolation and quantification of CTCs. Protein expression was analyzed by immunocytochemistry (ICC). For the molecular analysis of CTCs from patients with TD, the digital PCR method was standardized. Results: Eighteen TD patients were included, all with detectable CTCs, with levels ranging from 0.5­13 CTCs/mL. We found a concordance ofß-catenin expression in CTCs and primary tumors of 42.8% (6/14) of cases using ICC and immunohistochemistry, respectively. In our previous digital PCR tests, we found mutated copies of S45Pro in 4 patients (40%) and of S45Phe in only one patient (10%). In contrast, no Th41Ala mutations were found. In the sarcoma samples, we analyzed 30 samples and found CTCs in 93% of the patients and the levels ranged from 0-11.25 CTCs/mL. We also observed that the OS of EGFR positive patients (p=0.027) were lower than the survival of negative patients for the same proteins. Conclusions: Our study identified a high prevalence of CTCs in patients with TD and sarcomas. The agreement of ß-catenin expression between primary tumor and CTCs brings new perspectives to evaluate the dynamics of CTCs in the blood compartment, opening newavenues for the study of the biology and behavior of TD. This is the first study to demonstrate the expression of LGR5 protein in CTCs from patients with different types of sarcomas, which may open new opportunities for future investigations. The next step is to characterize CTCs in a larger cohort of patients to better understand the role of LGR5 and other proteins in the process of tumor metastases in sarcomas. Furthermore, these results open up the possibility of using CTCs to predict the dynamics of TD at the time of disease progression and treatment. More studies with larger sample sizes areneeded to validate our findings in both TD and sarcomas

Epidemiological profile of soft tissue sarcomas of the extremities: Incidence, histological subtypes, and primary sites.

BACKGROUND: Soft tissue sarcomas (STS) are a heterogeneous group of rare tumours that represent less than 1% of all malignant, solid tumours in adults. There is limited epidemiological information regarding STS in Latin America. Therefore, the objective of this study is to present an epidemiological profile of these tumours observed at a single reference centre. METHODS: A retrospective study was carried out based on hospital records obtained from a registry of 879 patients with STS of the extremities who were treated at the National Cancer Institute of Mexico from January 1, 1994 to December 31, 2017. Epidemiological variables and relevant clinical data were collected. Five-year survival rates were analysed using Kaplan-Meier estimates, and a multivariate Cox proportional-hazards model measured associations. RESULTS: A total of 879 records were collected. The median age was 45 years (15-95 years), and the ratio of men to women was 1:1, with 433 men (49.3%), and 446 women (50.7%). The median tumour size was 11.4 cm (2-49 cm). The most prevalent histological variants were liposarcomas and synovial sarcomas. The lower limb was the most frequently affected extremity, with the thigh being the most common site followed by the leg. A majority of the patients were diagnosed at clinical stages IIIA-IV. CONCLUSIONS: The data collected from the present cohort provides an overview of the epidemiological profile of STS at a single reference centre in Latin America, and allow comparison with global data.

Progesterone and estrogen receptor expression by canine cutaneous soft tissue sarcomas / Expressão de receptores para progesterona e estrógeno em sarcomas de tecidos moles cutâneos em cães

Canine soft tissue sarcomas (STS) comprise a heterogeneous group of malignancies that share similar histopathological features, a low to moderate recurrence rate and low metastatic potential. In human medicine, the expression of estrogen receptors (ER) and progesterone receptors (PR) in sarcomas has been studied to search for prognostic factors and new treatment targets. Similar studies have yet to be conducted in veterinary medicine. The objective of this study was therefore to investigate by immunohistochemistry (IHC) the ER and PR expression in a series of 80 cutaneous and subcutaneous sarcomas in dogs with histopathological features of peripheral nerve sheath tumor (PNST) and perivascular wall tumor (PWT). All cases were positive for PR and negative for ER. Tumors of high malignancy grade (grade III) exhibited higher PR expression than low-grade tumors (grade I). Tumors with mitotic activity greater than 9 mitotic figures/10 high power fields also exhibited higher PR expression. In addition, there was a positive correlation between cell proliferation (Ki67) and PR expression. Therefore, it is possible that progesterone plays a greater role than estrogen in the pathogenesis of these tumors. Future studies should explore the potential for selective progesterone receptor modulators as therapeutic agents in canine STS, as well as evaluating PR expression as a predictor of prognosis.(AU)

Sarcomas de tecidos moles (STM) caninos compreendem um grupo heterogêneo de neoplasias malignas, que apresentam alterações histopatológicas similares, baixa a moderada taxa de recorrência e baixo potencial metastático. Em medicina humana, a expressão de receptor para estrógeno (RE) e receptor para progesterona (RP) nos sarcomas tem sido estudada, visando a busca por fatores prognósticos e novos alvos para tratamentos. Na medicina veterinária, ainda não foram realizados estudos similares. O objetivo deste trabalho foi investigar por imuno-histoquímica a expressão de RE e RP em uma série de 80 sarcomas cutâneos e subcutâneos de cães, com características histopatológicas de tumor de bainha de nervo periférico e tumor de parede perivascular. Todos os casos foram positivos para RP e negativos para RE. Tumores de alto grau de malignidade (grau III) exibiram maior expressão deste receptor que os tumores de baixo grau (grau I). Tumores com atividade mitótica maior que 9 figuras mitóticas/10 campos de grande aumento também exibiram maior expressão do RP. Em adição, houve correlação positiva entre o índice de proliferação celular (Ki67) e a expressão de RP. Assim, é possível que a progesterona desempenhe maior papel que o estrógeno na patogênese desses tumores. Futuros trabalhos poderão explorar o potencial dos moduladores seletivos de RP como agente terapêutico em STM caninos, bem como avaliar a expressão de RP como preditiva de prognóstico.(AU)

Sarcomas de partes blandas en pacientes menores de 2 años. Serie de casos / Soft tissue sarcomas in infants. Case series

Los sarcomas de partes blandas en menores de 2 años son infrecuentes. Durante 2007-2017, 445 pacientes con sarcomas de partes blandas fueron tratados en nuestra Institución; 6 (el 0,5 %) eran menores de 2 años. Se analizaron los resultados clínicos y oncológicos en este grupo. La edad media de diagnóstico fue 15 meses. Cuatro eran varones y 2, mujeres. El seguimiento promedio fue 29 meses. El fibrosarcoma (n = 4) fue la variedad más frecuente. Cinco fueron tratados con cirugía de conservación del miembro; al restante se le realizó amputación. Todos realizaron tratamiento adyuvante con quimioterapia. La supervivencia a 24 meses fue del 100 %. Dos pacientes presentaron recidiva local; ambos casos, antes de los 24 meses.El tratamiento quirúrgico asociado a la quimioterapia impresiona ser la mejor opción terapéutica. La proporción de recurrencia local es alta para este grupo de pacientes luego de la cirugía de conservación del miembro.

Soft tissue sarcomas in children under 2 years of age are infrequent. During 2007-2017, a total of 445 patients diagnosed with soft tissue sarcomas were treated at our institution, 6 (0.5 %) were under 2 years. We analysed clinical and oncologic outcomes in this select group. The mean age of diagnosis was 15 months. Four patients were male and 2 female. The mean follow-up time was 29 months. Fibrosarcoma (n = 4) was the most frequent diagnosis. Five patients were treated with limb salvage surgery, and the remaining one had to undergo amputation. All patients received adjuvant treatment with chemotherapy. The 24-month survival rate was 100 %. Two patients presented a local recurrence before 24-months follow-up. Surgical treatment associated with chemotherapy seems to be the best therapeutic option. Local recurrence rate after limb salvage surgery is high for this group of patients

Progesterone and estrogen receptor expression by canine cutaneous soft tissue sarcomas / Expressão de receptores para progesterona e estrógeno em sarcomas de tecidos moles cutâneos em cães

Canine soft tissue sarcomas (STS) comprise a heterogeneous group of malignancies that share similar histopathological features, a low to moderate recurrence rate and low metastatic potential. In human medicine, the expression of estrogen receptors (ER) and progesterone receptors (PR) in sarcomas has been studied to search for prognostic factors and new treatment targets. Similar studies have yet to be conducted in veterinary medicine. The objective of this study was therefore to investigate by immunohistochemistry (IHC) the ER and PR expression in a series of 80 cutaneous and subcutaneous sarcomas in dogs with histopathological features of peripheral nerve sheath tumor (PNST) and perivascular wall tumor (PWT). All cases were positive for PR and negative for ER. Tumors of high malignancy grade (grade III) exhibited higher PR expression than low-grade tumors (grade I). Tumors with mitotic activity greater than 9 mitotic figures/10 high power fields also exhibited higher PR expression. In addition, there was a positive correlation between cell proliferation (Ki67) and PR expression. Therefore, it is possible that progesterone plays a greater role than estrogen in the pathogenesis of these tumors. Future studies should explore the potential for selective progesterone receptor modulators as therapeutic agents in canine STS, as well as evaluating PR expression as a predictor of prognosis.(AU)

Sarcomas de tecidos moles (STM) caninos compreendem um grupo heterogêneo de neoplasias malignas, que apresentam alterações histopatológicas similares, baixa a moderada taxa de recorrência e baixo potencial metastático. Em medicina humana, a expressão de receptor para estrógeno (RE) e receptor para progesterona (RP) nos sarcomas tem sido estudada, visando a busca por fatores prognósticos e novos alvos para tratamentos. Na medicina veterinária, ainda não foram realizados estudos similares. O objetivo deste trabalho foi investigar por imuno-histoquímica a expressão de RE e RP em uma série de 80 sarcomas cutâneos e subcutâneos de cães, com características histopatológicas de tumor de bainha de nervo periférico e tumor de parede perivascular. Todos os casos foram positivos para RP e negativos para RE. Tumores de alto grau de malignidade (grau III) exibiram maior expressão deste receptor que os tumores de baixo grau (grau I). Tumores com atividade mitótica maior que 9 figuras mitóticas/10 campos de grande aumento também exibiram maior expressão do RP. Em adição, houve correlação positiva entre o índice de proliferação celular (Ki67) e a expressão de RP. Assim, é possível que a progesterona desempenhe maior papel que o estrógeno na patogênese desses tumores. Futuros trabalhos poderão explorar o potencial dos moduladores seletivos de RP como agente terapêutico em STM caninos, bem como avaliar a expressão de RP como preditiva de prognóstico.(AU)

Prognostic value of neutrophil-to-lymphocyte ratio and other inflammatory markers in patients with high-risk soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) have a high risk of relapse in spite of the use of (neo)adjuvant chemotherapy. In this context, looking for new prognostic biomarkers is an interesting field of research. Our aim is to analyze the prognostic impact of neutrophil-to-lymphocyte ratio (NLR) and other serum markers in patients with STS who received chemotherapy with curative intent. MATERIALS AND METHODS: This is a retrospective observational study. We included all patients with STS (primary tumor, local recurrence or resected metastatic disease) treated with high-dose ifosfamide and epirubicin with curative intent from January 2007 to December 2018. The pretreatment NLR and other serum markers were calculated, selecting the median as the cut-off value for the survival and multivariate analysis. RESULTS: Seventy-nine patients were included. Median NLR, platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) were 2.83, 174.05 and 3.25, respectively. Median progression-free survival (PFS) was significantly longer in patients with low NLR [not reached (NR) vs 21, 92 months, P < 0.01]. No significant differences were found for PFS regarding PLR or LMR. For overall survival (OS), a significant survival advantage was also found for patients with low NLR (NR vs 65.45 months, P = 0.01), without differences for PLR or LMR. In multivariate analysis, NLR remains an independent prognostic factor for PFS. CONCLUSION: In our cohort, low NLR was significantly associated with a longer PFS and OS, and is consolidated as an independent prognostic factor.

Soft tissue sarcomas in infants. Case series. / Sarcomas de partes blandas en pacientes menores de 2 años. Serie de casos.

Soft tissue sarcomas in children under 2 years of age are infrequent. During 2007-2017, a total of 445 patients diagnosed with soft tissue sarcomas were treated at our institution, 6(0.5%) were under 2 years. We analysed clinical and oncologic outcomes in this select group. The mean age of diagnosis was 15 months. Four patients were male and 2 female. The mean follow-up time was 29 months. Fibrosarcoma (n = 4) was the most frequent diagnosis. Five patients were treated with limb salvage surgery, and the remaining one had to undergo amputation. All patients received adjuvant treatment with chemotherapy. The 24-month survival rate was 100 %. Two patients presented a local recurrence before 24-months followup. Surgical treatment associated with chemotherapy seems to be the best therapeutic option. Local recurrence rate after limb salvage surgery is high for this group of patients.

Los sarcomas de partes blandas en menores de 2 años son infrecuentes. Durante 2007-2017, 445 pacientes con sarcomas de partes blandas fueron tratados en nuestra Institución; 6 (el 0,5 %) eran menores de 2 años. Se analizaron los resultados clínicos y oncológicos en este grupo. La edad media de diagnóstico fue 15 meses. Cuatro eran varones y 2, mujeres. El seguimiento promedio fue 29 meses. El fibrosarcoma (n = 4) fue la variedad más frecuente. Cinco fueron tratados con cirugía de conservación del miembro; al restante se le realizó amputación. Todos realizaron tratamiento adyuvante con quimioterapia. La supervivencia a 24 meses fue del 100 %. Dos pacientes presentaron recidiva local; ambos casos, antes de los 24 meses. El tratamiento quirúrgico asociado a la quimioterapia impresiona ser la mejor opción terapéutica. La proporción de recurrencia local es alta para este grupo de pacientes luego de la cirugía de conservación del miembro.

Brazilian consensus on the diagnosis and treatment of extremities soft tissue sarcomas.

INTRODUCTION: Soft tissue sarcomas (STSs) are rare tumors and constitute only 1% of all tumors in adults. Indeed, due to their rarity, most cases in Brazil are not treated according to primary international guidelines. METHODS: This consensus addresses the treatment of STSs in the extremities. It was made by workgroups from Brazilian Societies of Surgical Oncology, Orthopaedics, Clinical Oncology, Pathology, Radiology and Diagnostic Imaging, and Radiation Oncology. The workgroups based their arguments on the best level of evidence in the literature and recommendations were made according to diagnosis, staging, and treatment of STSs. A meeting was held with all the invited experts and the topics were presented individually with the definition of the degree of recommendation, based on the levels of evidence in the literature. RESULTS: Risk factors and epidemiology were described as well as the pathological aspects and imaging. All recommendations are described with the degree of recommendation and levels of evidence. CONCLUSION: Recommendations based on the best literature regional aspects were made to guide professionals who treat STS. Separate consensus on specific treatments for retroperitoneal, visceral, trunk, head and neck sarcomas, and gastrointestinal stromal tumor, are not contemplated into this consensus.

Resultados del tratamiento quirúrgico de sarcomas de partes blandas en adultos / Outcomes of surgical treatment of soft-tissue sarcomas in adults

Antecedentes: los sarcomas de partes blandas son raros tumores mesenquimáticos con varios tipos histológicos y diferentes comportamientos clínicos. Objetivo: describir las características clínicas y patológicas, así como los resultados del tratamiento quirúrgico de una serie de pacientes operados por sarcomas de partes blandas. Material y métodos: se realizó una revisión retrospectiva de las historias clínicas de 2403 pacientes operados entre octubre de 2014 y abril de 2018. Veintidós de ellos (0,91%) presentaron sarcomas de partes blandas. Resultados: el promedio de edad fue 52 años (rango 19-92), 13 (59%) eran mujeres. La localización de los tumores fue: miembro inferior en 12 casos, cabeza y cuello en 5, tronco en 3 y miembro superior en 2. Catorce casos (63,6%) fueron tumores de alto grado. Los tipos patológicos fueron: sarcoma pleomórfico 7 (32%), sarcoma sinovial 4 (18%), liposarcoma 3 (14%), otros 4 (36 %). Todos fueron extirpados en forma completa y en 5 casos (35,7%) requirieron amputación: 4 de miembro inferior y uno superior. Según el tamaño y la ubicación del tumor se emplearon diferentes procedimientos reconstructivos, incluyendo 3 colgajos libres. Aquellos pacientes con lesiones de alto grado o con márgenes histológicamente positivos recibieron radioterapia posoperatoria. Durante el seguimiento (promedio 16 meses), seis pacientes presentaron recidivas locales, cuatro con metástasis pulmonares sincrónicas, todos ellos con tumores de alto grado. La sobrevida global fue del 86,4%. Conclusión: los sarcomas de partes blandas son neoplasias infrecuentes e invasivas, ampliamente distribuidas, que requieren procedimientos quirúrgicos agresivos. Es necesario tratamiento adyuvante en casos seleccionados y seguimiento periódico debido a la alta tasa de recidiva y metástasis a distancia.

Background: Soft-tissue sarcomas (STS) are rare mesenchymal tumors with several histologic subtypes and different clinical patterns. Objective: The aim of this study was to describe the clinical and pathological characteristics and surgical outcomes of a series of patients with STS. Material and methods: The clinical records of 2403 undergoing surgery between October 2014 and April 2018 were retrospectively reviewed. Twenty-two patients (0.91%) presented STS. Results: Mean age was 52 years (range: 19-92) and 13 (59%) were women. The tumors were located in the lower extremities in 12 cases, head and neck in five, trunk in three and upper extremities in two. Fourteen cases (63.6%) were high-grade tumors. Pleomorphic sarcoma was the most common histologic type (32%) followed by synovial sarcoma (18%), liposarcoma (14%), and other types (36%). All the tumors were completely resected and five patients (35.7%) required amputation, four in the lower extremity and on in the upper extremity. Different reconstructive procedures were performed according to tumor size and location, including three free flaps. Those patients with high-grade sarcomas or with positive margins received postoperative radiotherapy. After a mean follow-up of 16 months, six patients presented local recurrences and four patients had synchronous metastatic disease in the lungs; all these patients had high-grade tumors. Overall survival was 86.4%. Conclusion: STS are rare and invasive neoplasms, widely distributed, requiring aggressive and occasionally complex surgical procedures. It is necessary to consider adjuvant treatments in selected cases and to maintain regular follow-up due to the high rate of recurrences and distant metastases.

LONG-TERM RESULTS OF EXTREMITY SOFT TISSUE SARCOMAS LIMB-SPARING SURGERY AND RADIOTHERAPY.

OBJECTIVE: To assess the prognostic factors and results of limb sparing surgery and postoperative radiotherapy (PORT) in patients with non-metastatic soft tissue sarcomas (STS) of the extremities. METHODS: Between 1980-2007, 114 extremity-located STS treated with PORT were analyzed retrospectively. Tumors were mostly localized in the lower extremities (71,9%). The median radiotherapy (RT) dose was 60.9 Gy. Chemotherapy was administered to 37.7% of the patients. Tumor sizes were between 3-26 cm (median 7 cm). The three most frequent histological types included undifferentiated pleomorphic sarcoma (26.3%), liposarcoma (25.4%), and synovial sarcoma (13.2%). The median follow-up for all patients was 60 months, and 81 months for survivors. RESULTS: The 5- and 10-year local control (LC) rates were 77% and 70.4%, respectively; actuarial survival rates for 5 and 10 years were 71.8% and 69.1%, respectively. Increasing the dose above 60 Gy for all patients and the patients with positive margins demonstrated a clear benefit on 5-year LC (p=0.03 and p=0.04, respectively). Based on multivariate analysis, the addition of chemotherapy and RT dose were independent prognostic factors for LC. A recurrent presentation significantly affects the disease-free survival. CONCLUSIONS: PORT for STS of the extremities provides good long-term disease control with acceptable toxicity in a multidisciplinary approach. Level of evidence III, Retrospective study .

OBJETIVO: Avaliar os fatores prognósticos e os resultados da cirurgia poupadora de membro e radioterapia pós-operatória em pacientes com sarcomas de partes moles das extremidades. MÉTODOS: Entre 1980 e 2007, 114 sarcomas de partes moles localizados em extremidades tratados com cirurgia poupadora de membro e radioterapia pós-operatória foram analisados restrospectivamente. Os tumores localizavam-se principalmente na região mais baixa (71,9%). A dose média da radioterapia foi de 60,9 Gy. A quimioterapia foi usada em 37,7% dos pacientes. Os tamanhos do tumores estiveram entre 3 e 26 cm (mediana de 7 cm). Os três tipos histológicos mais frequentes foram, respectivamente, sarcoma pleomórfico indiferenciado (26,3%), lipossarcoma (25,4%) e sarcoma sinovial (13,2%). O tempo médio de acompanhamento para todos os pacientes foi de 60 meses e 81 meses para sobrevivente. RESULTADOS: As taxas de controle local para 5 e 10 anos foram de 77% e 70,4%, respectivamente, e as taxas de sobrevida foram de 71,8% e 69,1%. Aumentar a dose acima de 60 Gy para todos os pacientes e para aqueles com margens positivas demonstrou claro benefício no controle local de 5 anos (p = 0,03 e p = 0,04, respectivamente). Considerando a análise multivariada, a adição de quimioterapia e a dose de radioterapia foram fatores prognósticos independentes para controle local. Apresentação recorrente afetou significativamente a sobrevida livre da doença. CONCLUSÕES: A cirurgia poupadora de membro e radioterapia pós-operatória para sarcomas de partes moles das extremidades fornece bom controle da doença a longo prazo, com toxicidade aceitável na abordagem multidisciplinar. Nível de evidência III, Estudo retrospectivo.

Long-term results of extremity soft tissue sarcomas limb-sparing surgery and radiotherapy / Resultados de longo prazo de sarcomas de extremidade: cirurgia e radioterapia com espuma

ABSTRACT Objective: To assess the prognostic factors and results of limb sparing surgery and postoperative radiotherapy (PORT) in patients with non-metastatic soft tissue sarcomas (STS) of the extremities. Methods: Between 1980-2007, 114 extremity-located STS treated with PORT were analyzed retrospectively. Tumors were mostly localized in the lower extremities (71,9%). The median radiotherapy (RT) dose was 60.9 Gy. Chemotherapy was administered to 37.7% of the patients. Tumor sizes were between 3-26 cm (median 7 cm). The three most frequent histological types included undifferentiated pleomorphic sarcoma (26.3%), liposarcoma (25.4%), and synovial sarcoma (13.2%). The median follow-up for all patients was 60 months, and 81 months for survivors. Results: The 5- and 10-year local control (LC) rates were 77% and 70.4%, respectively; actuarial survival rates for 5 and 10 years were 71.8% and 69.1%, respectively. Increasing the dose above 60 Gy for all patients and the patients with positive margins demonstrated a clear benefit on 5-year LC (p=0.03 and p=0.04, respectively). Based on multivariate analysis, the addition of chemotherapy and RT dose were independent prognostic factors for LC. A recurrent presentation significantly affects the disease-free survival. Conclusions: PORT for STS of the extremities provides good long-term disease control with acceptable toxicity in a multidisciplinary approach. Level of evidence III, Retrospective study.

RESUMO Objetivo: Avaliar os fatores prognósticos e os resultados da cirurgia poupadora de membro e radioterapia pós-operatória em pacientes com sarcomas de partes moles das extremidades. Métodos: Entre 1980 e 2007, 114 sarcomas de partes moles localizados em extremidades tratados com cirurgia poupadora de membro e radioterapia pós-operatória foram analisados restrospectivamente. Os tumores localizavam-se principalmente na região mais baixa (71,9%). A dose média da radioterapia foi de 60,9 Gy. A quimioterapia foi usada em 37,7% dos pacientes. Os tamanhos do tumores estiveram entre 3 e 26 cm (mediana de 7 cm). Os três tipos histológicos mais frequentes foram, respectivamente, sarcoma pleomórfico indiferenciado (26,3%), lipossarcoma (25,4%) e sarcoma sinovial (13,2%). O tempo médio de acompanhamento para todos os pacientes foi de 60 meses e 81 meses para sobrevivente. Resultados: As taxas de controle local para 5 e 10 anos foram de 77% e 70,4%, respectivamente, e as taxas de sobrevida foram de 71,8% e 69,1%. Aumentar a dose acima de 60 Gy para todos os pacientes e para aqueles com margens positivas demonstrou claro benefício no controle local de 5 anos (p = 0,03 e p = 0,04, respectivamente). Considerando a análise multivariada, a adição de quimioterapia e a dose de radioterapia foram fatores prognósticos independentes para controle local. Apresentação recorrente afetou significativamente a sobrevida livre da doença. Conclusões: A cirurgia poupadora de membro e radioterapia pós-operatória para sarcomas de partes moles das extremidades fornece bom controle da doença a longo prazo, com toxicidade aceitável na abordagem multidisciplinar. Nível de evidência III, Estudo retrospectivo.

Evidence mapping based on systematic reviews of therapeutic interventions for soft tissue sarcomas.

PURPOSE: Soft tissue sarcomas are a heterogeneous group of rare tumours of mesenchymal origin. Evidence mapping is one of the most didactic and friendly approaches to organise and summarise the range of research activity in broad topic fields. The objective of this evidence mapping is to identify, describe and organise the current available evidence about therapeutic interventions on soft tissues sarcomas. METHODS: We followed the methodology of global evidence mapping. We performed a search of the PubMed, EMBASE, The Cochrane Library and Epistemonikos to identify systematic reviews (SRs) with or without meta-analyses published between 1990 and March 2016. Two independent literature reviewers assessed eligibility and extracted data. Methodological quality of the included systematic reviews was assessed using AMSTAR. We organised the results according to identified PICO questions and used tables and a bubble plot to display the results. RESULTS: The map is based on 24 SRs that met eligibility criteria and included 66 individual studies. Three-quarters were either observational or uncontrolled clinical trials. The quality of the included SRs was in general moderate or high. We identified 64 PICO questions from them. The corresponding results mostly favoured the intervention arm. CONCLUSIONS: This evidence mapping was built on the basis of SRs, which mostly included non-experimental studies and were qualified by the AMSTAR tool as of moderate quality. The evidence mapping created from PICO questions is a useful approach to describe complex and huge clinical topics through graphical media and orientate further research to fulfil the existing gaps. However, it is important to delimitate the steps of the evidence mapping in a pre-established protocol.

MDR1 not CYP3A4 gene expression is the predominant mechanism of innate drug resistance in pediatric soft tissue sarcoma patients.

BACKGROUND: Intratumoral up-regulation of genes coding for drug transporters and metabolizing enzymes, such as MDR1 and CYP3A4, after chemotherapy are linked to cancer drug resistance. However their expression in primary soft tissue sarcomas (STS) prior to drug treatment and their role in innate resistance remain unclear. OBJECTIVE: The aim of this study was characterize MDR1 and CYP3A4 expression pattern before to chemotherapy and its clinical implication in pediatric STS. METHODS: In this prospective study we analyzed MDR1 and CYP3A4 mRNA expression in both normal and tumor tissues from 28 newly diagnosed STS pediatric and then compared with patients' clinical-pathological data, including chemotherapy response. RESULTS: Our data showed that the expression of the MDR1 gene was significantly higher in malignant tissue than in the normal tissues of patients with STS. In addition, high MDR1 expression was significantly associated with local advances, as well as poor response to treatment. In contrast, CYP3A4 expression level was negligible in both tumoral and non-tumoral tissues. CONCLUSIONS: These results suggest that a significant mRNA level of MDR1 gene was intrinsically present in STS before exposure to chemotherapeutic drugs, suggesting that MDR1 may be important contributors of innate chemoresistance of this tumor type.

EGFR expression in circulating tumor cells from high-grade metastatic soft tissue sarcomas.

INTRODUCTION: Soft tissue Sarcomas (STS) are rare malignances, with high mortality rates. Half of patients develop metastasis. The presence of isolated Circulating Tumor Cells (CTCs) and Circulating Tumor Microemboli (CTM) in the blood may be early markers of tumor invasion. Epidermal Growth Factor (EGF) family receptors can also influence this process. OBJECTIVES: to quantify CTCs and identify CTM as well as the EGF Receptor (EGFR) protein expression in these cells and correlate with clinical outcome in metastatic STS. MATERIALS AND METHODS: Approximately 8mL of blood was prospectively collected from patients with different types of high-grade STS, before the beginning of chemotherapy. The samples were processed and filtered by ISET (Rarecells, France) for the isolation and quantification of CTCs and CTMs. EGFR expression was analyzed by immunocytochemistry (ICC) on CTCs/ CTMs. RESULTS: We analyzed 18 patients with median age of 49 years (18-77 y). The positivity for EGFR protein expression in CTCs was observed in 93.75% of the patients. This result shows that targeting EGFR positive CTCs from STS origen can be translated in clinical benefit for some patients. In addition, if target therapy is chosen, the EGFR expression in CTCs can be used in follow-up to measure treatment effectiveness. CONCLUSIONS: This is the first study to demonstrate the expression of EGFR protein in CTCs from sarcoma patients. It may open an area for future investigations. The next step is to characterize CTCs in a larger cohort of patients to better understand the role of EGFR in sustaining tumor metastasis in sarcomas.

Sarcomas de partes blandas en pacientes pediátricos: análisis de una serie de casos del subtipo no rabdomiosarcoma / Pediatric soft tissue sarcomas: analysis of non rhabdomyosarcoma group

Se evaluó una serie de 29 pacientes con diagnóstico de sarcomas de partes blandas variante no rabdomiosarcomas tratados quirúrgicamente entre2000 y 2010, y se analizó la supervivencia global y los factores que influyen en el pronóstico. La edad media fue de 11,6 años (rango de 3 meses-17 años); 16 pacientes eran de sexo masculino y el tiempo promedio de seguimiento fue de 56 meses (de 8 a 132 meses). Se documentaron 8 variedades histológicas diferentes de tumores malignos, y el sarcoma sinovial resultó ser el más frecuente (14 pacientes). La cirugía de conservación de miembro fue posible en 28 pacientes y se asoció tratamiento adyuvante en 26. La supervivencia global de la serie estudiada fue de 72% a los 5 años y, en 9 pacientes, se diagnosticó una recurrencia local. La presencia de metástasis (p < 0,0001) y la recurrencia local (p < 0,007) resultaron ser factores de pronóstico negativo para la supervivencia global.

We evaluated 29 patients with non rhabdomyosarcoma soft tissue sarcomas treated with surgery between 2000 and 2010; we analyzed overall survival and which factors affect the prognosis. The mean age was 11.6 years (range 3 months-17 years); 16 patients were males and the median follow-up was 56 months (8 to 132 months). Eight different histological malignant tumors were identified, being synovial sarcoma the most prevalent one (14 patients). Twenty-eight patients were treated with limb salvage surgery and in 26 cases, adjuvant therapy was used. Five years overall survival was 72%. Nine of the 29 patients presented a local recurrence. The presence of metastases (p <0.0001) and local recurrence (p <0.007) were negative prognostic factors for overall survival.