RESUMO
BACKGROUND: Peritoneal sarcomatosis (PS) is a difficult entity to treat with limited options and guarded prognosis. We aimed to determine if the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) could offer superior local recurrence-free survival in patients with retroperitoneal sarcoma at high risk of developing PS as opposed to extended resection alone. METHODS: This is a single arm, phase II intervention study where all patients with recurrent localized retroperitoneal sarcoma considered at high risk of developing PS were considered for enrolment (ClinicalTrials.gov identifier: NCT03792867). Upon enrolment, patients underwent vigorous preoperative testing to ensure fitness for the procedure. During surgery, patients underwent extended resection and HIPEC with doxorubicin. Patients were followed-up every 2 weeks (± 10 days) for the first month and subsequently every three months (± 1 month) up to a year post-surgery, and were assessed for potential chemotherapy toxicity and post-treatment complications. After a year from resection and HIPEC, patients were followed-up either during routine clinic review or contacted via telephone every year (± 1 month) for 3 years. RESULTS: Six patients were recruited but one patient dropped out due to adverse and unexpected intraoperative events. The remaining patients completed the procedure uneventfully. Post-HIPEC, all patients recurred with a disease-free interval ranging from six to 24 months. Three patients died due to complications from recurrent disease whereas the remaining three patients are alive as of their last visit. The overall survival at time at reporting ranged between 22 to 56 months. CONCLUSION: The procedure is feasible with no major morbidity to patients. However, we are unable to recommend for it to be implemented as a routine procedure at this current stage due to lack of improved survival outcomes. Further multi-institutional studies may be conducted to yield better results.
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Hipertermia Induzida , Neoplasias Peritoneais , Neoplasias Retroperitoneais , Sarcoma , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Hipertermia Induzida/métodos , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Peritoneais/cirurgia , Projetos Piloto , Neoplasias Retroperitoneais/cirurgia , Sarcoma/tratamento farmacológico , Sarcoma/cirurgiaRESUMO
PURPOSE: To analyze the current practice of regional hyperthermia (RHT) for soft tissue sarcoma (STS) at 12 European centers to provide an overview, find consensuses and identify controversies necessary for future guidelines and clinical trials. METHODS: In this cross-sectional survey study, a 27-item questionnaire assessing clinical subjects and procedural details on RHT for STS was distributed to 12 European cancer centers for RHT. RESULTS: We have identified seven controversies and five consensus points. Of 12 centers, 6 offer both, RHT with chemotherapy (CTX) or with radiotherapy (RT). Two centers only offer RHT with CTX and four centers only offer RHT with RT. All 12 centers apply RHT for localized, high-risk STS of the extremities, trunk wall and retroperitoneum. However, eight centers also use RHT in metastatic STS, five in palliative STS, eight for superficial STS and six for low-grade STS. Pretherapeutic imaging for RHT treatment planning is used by 10 centers, 9 centers set 40-43 °C as the intratumoral target temperature, and all centers use skin detectors or probes in body orifices for thermometry. DISCUSSION: There is disagreement regarding the integration of RHT in contemporary interdisciplinary care of STS patients. Many clinical controversies exist that require a standardized consensus guideline and innovative study ideas. At the same time, our data has shown that existing guidelines and decades of experience with the technique of RHT have mostly standardized procedural aspects. CONCLUSIONS: The provided results may serve as a basis for future guidelines and inform future clinical trials for RHT in STS patients.
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Hipertermia Induzida , Sarcoma , Humanos , Sarcoma/terapia , Hipertermia Induzida/métodos , Europa (Continente) , Inquéritos e Questionários , Estudos Transversais , ConsensoRESUMO
BACKGROUND: Increased time to diagnosis in sarcoma is associated with poor prognosis and patient outcomes. Research is needed to identify whether opportunities to expedite the diagnosis of sarcoma in general practice exist. AIM: To examine pre-diagnostic GP clinical activity before sarcoma diagnosis. DESIGN AND SETTING: An Australian retrospective cohort study using hospital registry data (Australian Comprehensive Cancer Outcomes and Research Database [ACCORD]) linked to two primary care datasets (Patron and MedicineInsight). METHOD: The frequency of general practice healthcare utilisation events (general practice attendances, prescriptions, blood test, and imaging requests) were compared in 377 patients with soft tissue sarcoma (STS) and 64 patients with bone sarcoma (BS) in the year pre-diagnosis. Poisson regression models were used to calculate monthly incidence rate ratios (IRR) for the 24 months pre-diagnosis and estimate inflection points for when healthcare use started to increase from baseline. RESULTS: In the 6 months pre-diagnosis, patients with sarcoma had a median of 3-4 general practice attendances, around one-third had a GP imaging request (33% [n = 21] BS and 36% [n = 134] STS), and approximately one in five had multiple imaging requests (19% [n = 12] BS and 21% [n = 80] STS). GP imaging requests progressively increased up to eight-fold from 6 months before sarcoma diagnosis (IRR 8.43, 95% confidence interval [CI] = 3.92 to 18.15, P<0.001) and general practice attendances increased from 3 months pre-diagnosis. CONCLUSION: Patients with sarcoma have increased GP clinical activity from 6 months pre-diagnosis, indicating a diagnostic window where potential opportunities exist for earlier diagnosis. Interventions to help identify patients and promote appropriate use of imaging and direct specialist centre referrals could improve earlier diagnosis and patient outcomes.
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Medicina Geral , Sarcoma , Humanos , Sarcoma/diagnóstico , Sarcoma/epidemiologia , Medicina Geral/estatística & dados numéricos , Estudos Retrospectivos , Austrália/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/epidemiologia , Adulto , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/epidemiologia , Encaminhamento e Consulta/estatística & dados numéricos , Idoso , Sistema de Registros , Padrões de Prática Médica/estatística & dados numéricos , Detecção Precoce de Câncer/estatística & dados numéricosRESUMO
Angiosarcoma is a rare soft tissue sarcoma originating from endothelial cells. Given that current treatments for advanced disease have shown limited efficacy, alternative therapies need to be identified. In rare diseases, patient-derived cell models are crucial for screening anti-tumour activity. In this study, cell line models were characterised in 2D and 3D cultures. The cell lines' growth, migration and invasion capabilities were explored, confirming them as useful tools for preclinical angiosarcoma studies. By screening a drug library, we identified potentially effective compounds: 8-amino adenosine impacted cell growth and inhibited migration and invasion at considerably low concentrations as a single agent. No synergistic effect was detected when combining with paclitaxel, gemcitabine or doxorubicin. These results suggest that this compound could be a potentially useful drug in the treatment of AGS.
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Hemangiossarcoma , Sarcoma , Humanos , Hemangiossarcoma/tratamento farmacológico , Células Endoteliais/patologia , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Sarcoma/tratamento farmacológico , Paclitaxel/farmacologia , Paclitaxel/uso terapêuticoRESUMO
BACKGROUND: High-grade soft tissue sarcoma is rare and associated with poor prognosis. This study examines racial and ethnic variation in presentation and outcomes at a Southeastern US cancer center. METHODS: Among an institutional cohort of patients seen between January 2016-December 2021, racial and ethnic differences were evaluated using chi-squared tests, Kaplan Meier curves, and Cox proportional hazards models. RESULTS: There were 295 patients (71 â% Non-Hispanic White, 24 â% Black, 3 â% Hispanic White, 2 â% Other). Black representation was greater than national cohorts (24 â% vs. 12 â%). Histological subtype varied by race/ethnicity (p â= â0.007). Adjusting for histology and stage, survival was worse for Black vs. White patients (HR 1.71, 95 â% CI 1.07-2.76) and those with metastatic disease (5.47, 3.54-8.44). In non-metastatic patients, survival differences for Black vs. White patients were attenuated by receipt of multi-modal treatment (1.53, 0.82-2.88). CONCLUSION: Observed racial disparities in survival of high-grade sarcoma may be addressed by early, multidisciplinary management.
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Disparidades nos Níveis de Saúde , Sarcoma , Humanos , Etnicidade , Modelos de Riscos Proporcionais , Sarcoma/etnologia , Sarcoma/terapia , Sudeste dos Estados Unidos/epidemiologia , Estados Unidos/epidemiologia , Grupos RaciaisRESUMO
To explore the anti-tumor effects of Radix Astragali on osteosarcoma and its mechanism. We analyzed the PPI network of Radix Astragali's potential targets for treating osteosarcoma and got the hub targets. We used KM curves to screen hub targets that could prolong sarcoma patients' survival time. We performed GO and KEGG enrichment analysis of Radix Astragali's potential targets and predicted Radix Astragali's molecular mechanism and function in treating osteosarcoma. The binding process between the hub targets, which could prolong sarcoma patients' survival time, and Radix Astragali was simulated through molecular docking. PPI network analysis of potential therapeutic targets discriminated 25 hub targets. The KM curves of the hub targets showed there were 13 hub targets that were effective in improving the 5-year survival rate of sarcoma patients. GO and KEGG enrichment demonstrated that Radix Astragali regulates multiple signaling pathways of osteosarcoma. Molecular docking results indicated that Radix Astragali could bind freely to the hub target, which could prolong the sarcoma patient's survival time. Radix Astragali act on osteosarcoma by regulating a signaling network formed by hub targets connecting multiple signaling pathways. Radix Astragali has the potential to become a drug for treating osteosarcoma and prolonging the sarcoma patient's survival time.
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Neoplasias Ósseas , Medicamentos de Ervas Chinesas , Osteossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Osteossarcoma/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Ósseas/tratamento farmacológicoRESUMO
To explore the anti-tumor effects of Scutellaria baicalensis on osteosarcoma and its mechanism. Network pharmacology and molecular docking techniques were applied to investigate the effect and mechanism of Scutellaria baicalensis on osteosarcoma (OS). We analyzed the protein-protein interaction (PPI) network for potential targets of Scutellaria baicalensis for treating osteosarcoma and identified hub targets. We used KM curves to screen for hub targets that could effectively prolong the survival time of OS patients. We systematically performed gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis of the Scutellaria baicalensis potential targets and predicted the Scutellaria baicalensis molecular mechanism and function in treating osteosarcoma. Through molecular docking, the binding process between the hub targets, which could prolong the survival time of sarcoma patients, and Scutellaria baicalensis was simulated. PPI network analysis of potential therapeutic targets discriminated 12 hub targets. The KM curves of the hub targets showed that upregulation of RXRA, RELA, ESR1, TNF, IL6, IL1B, and RB1 expression, and downregulation of MAPK1, VEGFA, MAPK14, CDK1, and PPARG expression were effective in improving the 5-year survival rate of OS patients. GO and KEGG enrichment demonstrated that Scutellaria baicalensis regulated multiple signaling pathways of OS. Molecular docking results indicated that Scutellaria baicalensis could bind freely to the above hub target, which could prolong the survival time of sarcoma patients. Scutellaria baicalensis acted on osteosarcoma by regulating a signaling network formed by hub targets connecting multiple signaling pathways. Scutellaria baicalensis appears to have the potential to serve as a therapeutic drug for osteosarcoma and to prolong the survival of OS patients.
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Neoplasias Ósseas , Medicamentos de Ervas Chinesas , Osteossarcoma , Sarcoma , Humanos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Scutellaria baicalensis , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genéticaRESUMO
Endometrial cancer and uterine sarcoma represent the two major types of uterine cancer. In advanced stages, both cancer entities are challenging to treat and correlate with a meagre survival and prognosis. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is a form of localized chemotherapy that is heated to improve the chemotherapeutic effect on peritoneal metastases. The aim of the current review is to study the role of HIPEC in the treatment of uterine cancer. A literature review was conducted using the MEDLINE and LIVIVO databases with a view to identifying relevant studies. By employing the search terms "hyperthermic intraperitoneal chemotherapy", "uterine cancer", "endometrial cancer", and/or "uterine sarcoma", we managed to identify 26 studies published between 2004 and 2023. The present work embodies the most up-to-date, comprehensive review of the literature centering on the particular role of HIPEC as treatment modality for peritoneally metastasized uterine cancer. Patients treated with cytoreductive surgery, alongside HIPEC, seem to profit from not only higher survival but also lower recurrence rates. Factors such as the completeness of cytoreductive surgery, the peritoneal cancer index, the histologic subtype, or the applied chemotherapeutic agent, all influence HIPEC therapy effectiveness. In summary, HIPEC seems to represent a promising treatment alternative for aggressive uterine cancer.
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Neoplasias do Endométrio , Hipertermia Induzida , Neoplasias Peritoneais , Sarcoma , Neoplasias Uterinas , Feminino , Humanos , Terapia Combinada , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/secundário , Neoplasias Uterinas/tratamento farmacológico , Neoplasias do Endométrio/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sarcoma/tratamento farmacológico , Taxa de Sobrevida , Estudos RetrospectivosRESUMO
INTRODUCTION: Neoadjuvant chemotherapy and radiotherapy for the management of soft tissue sarcomas (STS) are still preferably delivered sequentially, with or without concurrent hyperthermia. Concurrent delivery of chemo-, radio- and thermotherapy may produce synergistic effects and reduce chemotherapy-free intervals. The few available studies suggest that concurrent chemoradiation (CRT) has a greater local effect. Data on the efficacy and toxicity of adding hyperthermia to CRT (CRTH) are sparse. MATERIALS AND METHODS: A cohort of 101 patients with STS of the extremities and trunk who received CRT (n = 33) or CRTH (n = 68) before resection of macroscopic tumor (CRT: n = 19, CRTH: n = 49) or re-resection following a non-oncological resection, so called 'whoops procedure', (CRT: n = 14, CRTH: n = 19) were included in this retrospective study. CRT consisted of two cycles of doxorubicine (50 mg/m2 on d2) plus ifosfamide (1500 mg/m2 on d1-5, q28) plus radiation doses of up to 60 Gy. Hyperthermia was delivered in two sessions per week. RESULTS: All patients received the minimum dose of 50 Gy. Median doses of ifosfamide and doxorubicin were comparable between CRT (75%/95%) and CRTH (78%/97%). The median number of hyperthermia sessions was seven. There were no differences in acute toxicities. Major wound complications occurred in 15% (CRT) vs. 25% (CRTH) (p = 0.19). In patients with macroscopic disease, the addition of hyperthermia resulted in a tendency toward improved remission: regression ≥90% occurred in 21/48 (CRTH) vs. 4/18 (CRT) patients (p = 0.197). With a median postoperative follow-up of 72 months, 6-year local control and overall survival rates for CRTH vs. CRT alone were 85 vs. 78% (p = 0.938) and 79 vs. 71% (p = 0.215). CONCLUSIONS: Both CRT and CRTH are well tolerated with an expected rate of wound complications. The results suggest that adding hyperthermia may improve tumor response.
Assuntos
Hipertermia Induzida , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Terapia Neoadjuvante , Ifosfamida , Estudos Retrospectivos , Sarcoma/terapia , Neoplasias de Tecidos Moles/terapia , Hipertermia , Quimiorradioterapia , Doxorrubicina/uso terapêuticoRESUMO
BACKGROUND: The therapy of high-risk soft tissue sarcomas (STS) remains an interdisciplinary challenge. Regional hyperthermia (RHT) sparked interest as it has been shown to improve overall survival when added to perioperative chemotherapy (CTX). However, questions arise on how RHT should be optimally integrated into current multi-modal therapies. MATERIALS AND METHODS: We performed a systematic literature review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies written in English and focused mainly on radiative RHT and superficial hyperthermia were evaluated and included. Studies including patients below the age of 18, with metastatic disease or review articles, were excluded. RESULTS: We identified 15 clinical reports from 1990 until July 2022. Three articles combined RHT + CTX, and twelve focused on combined RHT + radiotherapy (RT) or neoadjuvant chemoradiotherapy (CRT). Most treatments were based on invasive thermometry, and less on magnetic resonance imaging (MRI)-based, noninvasive thermometry for STS of the extremities. Perioperative chemotherapy was used for the combination of RHT and CTX, mostly Ifosfamide-based. The effectiveness of RT appeared to be increased by RHT, especially with two RHT sessions/week. The trimodal simultaneous approach of neoadjuvant RHT and CRT was also feasible. No significant toxicity of RHT was reported. CONCLUSIONS: The gathered data strengthen the beneficial role of RHT in the multimodal setting. Further expert consensus and clinical trials are required to determine the optimal integration of RHT in treating STS.
Assuntos
Hipertermia Induzida , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Terapia Combinada , Hipertermia Induzida/métodos , Ifosfamida/uso terapêutico , Sarcoma/terapia , Neoplasias de Tecidos Moles/tratamento farmacológicoRESUMO
Soft tissue sarcomas (STS) form a heterogeneous group of tumors sharing a mesenchymal origin. Despite good local control of the disease, the occurrence of distant metastases often limits survival of STS patients with localized, high-risk tumors of the extremities. Accumulating evidence suggests a central role for the tumor immune microenvironment in determining the clinical outcome and response to therapy. Thus, it has been reported that STS patients with a high immune signature and especially presence of B cells and tertiary lymphoid structures display improved overall survival and response to checkpoint inhibitor treatment. Here, we explored the effect of curative multimodal therapy on the T cell landscape of STS using multiplex immunohistochemistry. We analyzed the phenotype, frequency, and spatial distribution of STS-infiltrating CD8+ T cells by staining for CD8, 4-1BB, Granzyme B, Ki67, PD-1, and LAG-3 as well as CD3+ T helper cells using a panel consisting of CD3, T-bet, GATA3, RORγT, FoxP3, and Ki67. All patients received neoadjuvant radiotherapy plus locoregional hyperthermia with or without chemotherapy. While the treatment-naïve biopsy sample allows an analysis of baseline T cell infiltration levels, both intra- and peritumoral areas of the matched resected tissue were analyzed to assess composition and spatial distribution of the T cell compartment and its therapeutic modulation. Generally, post-treatment tissues displayed lower frequencies of CD3+ and CD8+ T cells. Association with clinical data revealed that higher post-treatment frequencies of peritumoral and intratumoral CD3+ T cells and intratumoral PD-1+ CD8+ T cells were significantly associated with improved disease-free survival (DFS), while these densities had no prognostic significance in the biopsy. Upon spatial analysis, a high ratio of intratumoral to peritumoral CD8+ T cells emerged as an independent prognostic marker for longer DFS. These results indicate that the STS T cell landscape is altered by multimodal therapy and may influence the clinical outcome of patients. An enhanced understanding of the STS immune architecture and its modulation by neoadjuvant therapy may pave the way towards novel treatment modalities and improve the long-term clinical outcome of STS patients.
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Hipertermia Induzida , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Terapia Neoadjuvante , Linfócitos T CD8-Positivos , Receptor de Morte Celular Programada 1 , Antígeno Ki-67 , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Microambiente TumoralRESUMO
The sarcoma virus oncogene (Src) tyrosine kinase, a nonreceptor protein-tyrosine kinase, plays a crucial role in cell survival, migration, differentiation and proliferation. The study of Src has developed considerably since it was first discovered as a proto-oncogene. Src has also been associated with inflammation and bone-related diseases. Src inhibitors (bosutinib, ponatinib, dasatinib, and vandetanib) have been put into clinical use. However, their side effects and cardiovascular toxicity may be a concern. There is an urgent need to explore new Src inhibitors. Traditional Chinese medicine (TCM), which has a vast history, can provide a broad resource base. Many natural compounds and TCM extracts have the potential for anti-Src treatment. This article describes the natural compounds and extracts from TCM.
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Medicina Tradicional Chinesa , Sarcoma , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Quinases da Família src , Sarcoma/tratamento farmacológico , OncogenesRESUMO
OPINION STATEMENT: Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated vascular sarcoma. EHE can have different clinical presentations from indolent to rapidly evolving cases, behaving as a high-grade sarcoma. Serosal effusion and systemic symptoms such as fever and severe pain are known as adverse prognostic factors; however, outcome prediction at disease onset remains a major challenge. In spite of its rarity, an international collaborative effort is in place with the support of patient advocates to increase the knowledge of EHE biology, develop new treatment options, and improve patient access to new active medications. Currently, systemic therapies are indicated only for patients suffering from progressive and/or symptomatic disease and in patients with a high risk of organ dysfunction. Standard systemic agents available so far for treatment of sarcomas, and in particular anthracycline-based chemotherapy, have marginal activity in EHE. On this background, EHE patients should be always considered for clinical study when available. The MEK inhibitor trametinib has been recently investigated prospectively in advanced EHE showing some activity, but the publication of the full dataset is still awaited to better interpret the results. Besides, there are data on response to antiangiogenics such as sorafenib and bevacizumab and, from retrospective studies, interferon, thalidomide, and sirolimus. Unfortunately, none of these agents is formally approved for EHE patients and access to treatments varies greatly between countries causing a huge disparity in patient care from one country to another.
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Hemangioendotelioma Epitelioide , Sarcoma , Humanos , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/tratamento farmacológico , Hemangioendotelioma Epitelioide/etiologia , Estudos Retrospectivos , Sorafenibe/uso terapêutico , PrognósticoRESUMO
Canine Soft Tissue Sarcoma (STS) cell line A-72 has been largely employed for antiviral and antiproliferative studies. However, there are few information on their characteristics. Our aim was to evaluate A-72 expression level of genes and proteins involved in the innate immune response and cell cycle, their ability to respond to infective stressors and their possible use as a cellular model for anti-cancer studies in human and animal medicine. For this purpose, we evaluated the basal expression of immune-related, cell cycle and DNA repair genes on this cell line and tumoral tissues. A-72 ability to respond to a wild-type strain of Salmonella typhimurium was assessed. S. typhimurium showed ability to penetrate A-72 causing pro-inflammatory response accompanied by a decrease of cell viability. IL10 and IL18 genes were not expressed in A-72 while CXCL8, NOS2, CXCR4 and PTEN were highly expressed in all samples and TP53 was slightly expressed, as shown in human STS. Our results outline the ability of A-72 to respond to a bacterial agent by modifying the expression of important genes involved in innate immune response and provide a useful model for in vitro evaluation of new therapeutic approaches that could be translated into the human oncology.
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Doenças do Cão , Sarcoma , Animais , Cães , Humanos , Sarcoma/genética , Sarcoma/veterinária , Sarcoma/microbiologia , Linhagem Celular , Salmonella typhimurium/genética , Modelos Animais , Imunidade Inata/genéticaRESUMO
5-aminolevulinic acid (ALA) is used for tumor-targeting phototherapy because it is converted to protoporphyrin IX (PPIX) upon excitation and induces phototoxicity. However, the effect of ALA on malignant cells under unexcited conditions is unclear. This information is essential when administering ALA systemically. We used sarcoma cell lines that usually arise deep in the body and are rarely exposed to light to examine the effects of ALA treatment under light (daylight lamp irradiation) and dark (dark room) conditions. ALA-treated human SW872 liposarcoma cells and human MG63 osteosarcoma cells cultured under light exhibited growth suppression and increased oxidative stress, while cells cultured in the dark showed no change. However, sphere-forming ability increased in the dark, and the expression of stem-cell-related genes was induced in dark, but not light, conditions. ALA administration increased heme oxygenase 1 (HO-1) expression in both cell types; when carbon monoxide (CO), a metabolite of HO-1, was administered to sarcoma cells via carbon-monoxide-releasing molecule 2 (CORM2), it enhanced sphere-forming ability. We also compared the concentration of biliverdin (BVD) (a co-product of HO-1 activity alongside CO) with sphere-forming ability when HO-1 activity was inhibited using ZnPPIX in the dark. Both cell types showed a peak in sphere-forming ability at 60-80 µM BVD. Furthermore, a cell death inhibitor assay revealed that the HO-1-induced suppression of sphere formation was rescued by apoptosis or ferroptosis inhibitors. These findings suggest that in the absence of excitation, ALA promotes HO-1 expression and enhances the stemness of sarcoma cells, although excessive HO-1 upregulation induces apoptosis and ferroptosis. Our data indicate that systemic ALA administration induces both enhanced stemness and cell death in malignant cells located in dark environments deep in the body and highlight the need to pay attention to drug delivery and ALA concentrations during phototherapy.
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Ácido Aminolevulínico , Sarcoma , Humanos , Linhagem Celular , Ácido Aminolevulínico/farmacologia , Ácido Aminolevulínico/uso terapêutico , Apoptose , Morte Celular , Sarcoma/tratamento farmacológico , Heme Oxigenase-1/metabolismo , Protoporfirinas/farmacologiaRESUMO
Responses to therapy often cannot be exclusively predicted by molecular markers, thus evidencing a critical need to develop tools for better patient selection based on relations between tumor phenotype and genotype. Patient-derived cell models could help to better refine patient stratification procedures and lead to improved clinical management. So far, such ex vivo cell models have been used for addressing basic research questions and in preclinical studies. As they now enter the era of functional precision oncology, it is of utmost importance that they meet quality standards to fully represent the molecular and phenotypical architecture of patients' tumors. Well-characterized ex vivo models are imperative for rare cancer types with high patient heterogeneity and unknown driver mutations. Soft tissue sarcomas account for a very rare, heterogeneous group of malignancies that are challenging from a diagnostic standpoint and difficult to treat in a metastatic setting because of chemotherapy resistance and a lack of targeted treatment options. Functional drug screening in patient-derived cancer cell models is a more recent approach for discovering novel therapeutic candidate drugs. However, because of the rarity and heterogeneity of soft tissue sarcomas, the number of well-established and characterized sarcoma cell models is extremely limited. Within our hospital-based platform we establish high-fidelity patient-derived ex vivo cancer models from solid tumors for enabling functional precision oncology and addressing research questions to overcome this problem. We here present 5 novel, well-characterized, complex-karyotype ex vivo soft tissue sarcosphere models, which are effective tools to study molecular pathogenesis and identify the novel drug sensitivities of these genetically complex diseases. We addressed the quality standards that should be generally considered for the characterization of such ex vivo models. More broadly, we suggest a scalable platform to provide high-fidelity ex vivo models to the scientific community and enable functional precision oncology.
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Sarcoma , Neoplasias de Tecidos Moles , Humanos , Medicina de Precisão/métodos , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/diagnóstico , Avaliação Pré-Clínica de Medicamentos , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown modest antitumor activity in unselected advanced sarcomas. Histology driven approach to patient selection is the current standard for off-label anti-programmed cell death 1 (PD1) immunotherapy use. METHODS: We retrospectively reviewed the clinical characteristics and outcomes of patients with advanced sarcoma who were treated with off label anti-PD1 immunotherapy at our center. RESULTS: A total of 84 patients with 25 histological subtypes were included. Nineteen patients (23%) had a cutaneous primary tumor site. Eighteen patients (21%) were classified as having clinical benefit, including 1 patient with complete response, 14 with partial response, and 3 with stable disease lasting over 6 months with previously progressive disease. Cutaneous primary site location was associated with higher clinical benefit rate (58% vs. 11%, p < 0.001), longer median PFS (8.6 vs. 2.5 months, p = 0.003) and OS (19.0 vs. 9.2 months, p = 0.011), compared to non-cutaneous primary. Patients with histological subtypes that pembrolizumab is indicated per current National Comprehensive Cancer Network guidelines had modestly higher rate of clinical benefit versus other histologies, however, the difference was statistically insignificant (29% vs. 15%, p = 0.182) and no statistically significant difference in PFS or OS was observed between these groups. Immune-related adverse events were more frequently seen among patients with clinical benefit (72% vs. 35%, p = 0.007). CONCLUSIONS: Anti-PD1-based immunotherapy is highly efficacious in advanced sarcomas of cutaneous primary site. Cutaneous primary site location is a stronger predictor of ICI response than histologic subtype and should be accounted for in treatment guidelines and clinical trial design.
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Antineoplásicos Imunológicos , Neoplasias Pulmonares , Sarcoma , Humanos , Estudos Retrospectivos , Antineoplásicos Imunológicos/farmacologia , Sarcoma/tratamento farmacológico , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Introduction BCOR::CCNB3-positive undifferentiated sarcomas are rare. Herein, we present clinicopathological features including immunohistochemical and molecular data, along with the radiological profile of 12 such tumors. Methods Tumors were tested for BCOR::CCNB3 fusion by reverse transcription polymerase chain reaction (RT-PCR) technique. Eight tumors were tested for EWSR1 and three for SS18 gene rearrangements by fluorescence in situ hybridization, and two for SS18::SSX fusion by fragment analysis. Results Ten of 12 patients were male with ages ranging between 4 and 17 years (median = 13, average = 14.4). Nine tumors occurred in bones and three in soft tissues (median size = 8â cm). Four of five tumors within the appendicular bones were metadiaphyseal and appeared as permeative lesions, invariably associated with cortical thickening. Three tumors displayed mineralization. Histopathologically, the tumors comprised round to epithelioid cells with round to oval to spindle-shaped nuclei, mostly diffusely arranged in a myxoid stroma with intervening thin-walled vessels. Immunohistochemically, tumor cells were positive for BCOR (10/11), SATB2 (8/9), TLE1 (5/6), cyclinD1 (4/4), and EMA (3/8). All tumors revealed BCOR::CCNB3 fusion transcript. Nine patients underwent neoadjuvant chemotherapy, including five who underwent surgical resection, with two patients, who received adjuvant radiation therapy. A single patient, each, underwent palliative chemotherapy and palliative radiotherapy, respectively. Four patients developed pulmonary metastasis and three developed local recurrences. Four patients were alive-with-disease and two were free-of-disease. Conclusions It is crucial to identify BCOR::CCNB3 fusion-positive sarcomas, given significant treatment-associated implications. Certain clinicoradiological, histopathological features, absent EWSR1 rearrangement and BCOR, SATB2, and TLE1 immunoexpression are useful for triaging these tumors for molecular testing. A review of the literature on these ultra-rare tumors, including their diagnostic mimics is presented.
Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Humanos , Masculino , Feminino , Hibridização in Situ Fluorescente , Proteínas Repressoras/genética , Proteínas Repressoras/análise , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/análise , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/patologia , Fatores de Transcrição/genética , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Proteínas de Fusão Oncogênica/genética , Ciclina B/genéticaRESUMO
Background: Wound healing is particularly important for sarcoma patients who undergo neoadjuvant radiation therapy. Previous studies have demonstrated wound complications in this population approaching 35%. With this high rate of wound healing issues, identifying treatment modalities to minimize these complications is of paramount importance. Methods: All patients with high grade bone and soft tissue sarcoma received 15 days of twice daily amino acid supplementation starting in the immediate post-operative period. We documented the healing status of the surgical wound, the primary outcome, at all follow up appointments until six months after surgery. Non-healing wounds were defined as any wound requiring 1) a return visit to the OR for debridement, 2) IV antibiotics (ABX), and 3) unhealed wounds at 6 months post-operatively.1 For each patient, we collected biometrics with lean body mass analysis at preoperative appointment, and two and six weeks postoperatively. The proportion with non-healing wounds was compared with a historical patient cohort using the chi-square test. In a subgroup of participants with body composition measurements, we also compared changes in mean fat mass, lean mass, and psoas index from pre-operative baseline to 6 months post-operative using generalized linear models. Results: A total of 33 consecutive patients were supplemented with a branched chain amino acid (BCAA) formulation. The historical cohort included 146 participants from the previous 7 years (2010-2017). 26% of patients in the historical cohort experienced wound complications compared to 30% in the supplemented group. (p=0.72) When focusing specifically on lower extremity sarcomas treated with neoadjuvant radiation therapy, 46% of patients in the supplemented group experienced wound healing complications compared to 39% in the non-supplemented group (p=0.68). BCAA supplementation was found to be protective with regards to decreasing muscle wasting with no difference in psoas index measurements throughout the study period compared to a 20% muscle loss in the historical cohort (p=0.02). Conclusion: In our limited sample size, there was no difference in wound healing complications between sarcoma patients who received postoperative BCAA supplementation compared to a historical cohort who were not supplemented. Patients who did not receive supplementation had a significant decline in post-operative psoas index following operative sarcoma removal. Level of Evidence: III.
Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Humanos , Projetos Piloto , Fatores de Risco , Radioterapia Adjuvante/efeitos adversos , Sarcoma/tratamento farmacológico , Sarcoma/cirurgia , Sarcoma/radioterapia , Neoplasias de Tecidos Moles/cirurgia , Suplementos Nutricionais , Estudos RetrospectivosRESUMO
Background: Myxoid soft tissue tumors are rare and diagnostically challenging group of tumors with varied biological behavior ranging from benign, locally aggressive to distantly metastasizing malignant tumors. Aims: The objectives of the study are to identify the relative frequency and distribution of myxoid soft tissue tumors among patients in a tertiary care hospital and to study the clinicopathological features of these tumors. This was a retrospective cross-sectional study conducted in the department of pathology of a tertiary care hospital from January 2008 to December 2013. Materials and Methods: Clinical and pathological details of all the 80 myxoid soft tissue tumors reported during the study period were retrieved from the records of department of pathology. Corresponding Hematoxylin & Eosin (H & E) slides were reviewed, and Immunohistochemistry (IHC) was carried out for confirmation. The relationship among various prognostic variables was analyzed in case of myxoid sarcomas. Results: Myxoid soft tissue tumors accounted for 3.7% among the soft tissue tumors with a predominance of malignant myxoid sarcomas (71.25%) in contrast to the overall picture of sarcomas. Myxoid neurofibroma (34.78%) was the most common benign tumor, while myxofibrosarcoma (33.33%) was the frequent myxoid sarcoma. A statistically significant correlation was seen between tumor size and depth (P-value: 0.038) and also between presence of vascular invasion and histological grade (P-value: 0.012) of sarcomas. Conclusion: Light microscopic morphology, supplemented by ancillary techniques like IHC, remains the cornerstone for diagnosis of myxoid soft tissue tumors.