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HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.
Assuntos
Proteína HMGA1a , Sarcoma , Trabectedina , Trabectedina/farmacologia , Humanos , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Sarcoma/genética , Sarcoma/metabolismo , Proteína HMGA1a/metabolismo , Proteína HMGA1a/genética , Animais , Linhagem Celular Tumoral , Camundongos , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Prognóstico , Feminino , Leiomiossarcoma/tratamento farmacológico , Leiomiossarcoma/patologia , Leiomiossarcoma/genética , Leiomiossarcoma/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The value of neoadjuvant chemotherapy in soft tissue sarcoma (STS) is not completely understood. This study investigated the benefit of neoadjuvant chemotherapy according to prognostic stratification based on the Sarculator nomogram for STS. METHODS: This study analyzed data from ISG-STS 1001, a randomized study that tested 3 cycles of neoadjuvant anthracycline plus ifosfamide (AI) or histology-tailored (HT) chemotherapy in adult patients with STS. The 10-year predicted overall survival (pr-OS) was estimated with the Sarculator and was stratified into higher (10-year pr-OS < 60%) and lower risk subgroups (10-year pr-OS ≥ 60%). RESULTS: The median pr-OS was 0.63 (interquartile range [IQR], 0.51-0.72) for the entire study population, 0.62 (IQR, 0.51-0.70) for the AI arm, and 0.64 (IQR, 0.51-0.73) for the HT arm. Three- and 5-year overall survival (OS) were 0.86 (95% confidence interval [CI], 0.82-0.93) and 0.81 (95% CI, 0.71-0.86) in lower risk patients and 0.69 (95% CI, 0.70-0.85) and 0.59 (95% CI, 0.51-0.72) in the higher risk patients (log-rank test, P = .004). In higher risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.68 and 0.58, respectively, and 0.85 and 0.66, respectively, in the AI arm (P = .04); the corresponding figures in the HT arm were 0.69 and 0.60, respectively, and 0.69 and 0.55, respectively (P > .99). In lower risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.85 and 0.80, respectively, and 0.89 and 0.82, respectively, in the AI arm (P = .507); the corresponding figures in the HT arm were 0.87 and 0.81, respectively, and 0.86 and 0.74, respectively (P = .105). CONCLUSIONS: High-risk patients treated with AI performed better than predicted, and this adds to the evidence for the efficacy of neoadjuvant AI in STS. LAY SUMMARY: People affected by soft tissue sarcomas of the extremities and trunk wall are at some risk of developing metastasis after surgery. Preoperative or postoperative chemotherapy has been tested in clinical trials to reduce the chances of distant metastasis. However, study findings have not been conclusive. This study stratified the risk of metastasis for people affected by sarcomas who were included in a clinical trial testing neoadjuvant chemotherapy. Exploiting the prognostic nomogram Sarculator, it found a benefit for chemotherapy when the predicted risk, based on patient and tumor characteristics, was high.
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Sarcoma , Neoplasias de Tecidos Moles , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Humanos , Ifosfamida , Terapia Neoadjuvante , Medição de Risco , Sarcoma/patologiaRESUMO
Solitary fibrous tumor is a rare subtype of soft-tissue sarcoma with a wide spectrum of histopathological features and clinical behaviors, ranging from mildly to highly aggressive tumors. The defining genetic driver alteration is the gene fusion NAB2-STAT6, resulting from a paracentric inversion within chromosome 12q, and involving several different exons in each gene. STAT6 (signal transducer and activator of transcription 6) nuclear immunostaining and/or the identification of NAB2-STAT6 gene fusion is required for the diagnostic confirmation of solitary fibrous tumor. In the present study, a new gene fusion consisting of Nuclear Factor I X (NFIX), mapping to 19p13.2 and STAT6, mapping to 12q13.3 was identified by targeted RNA-Seq in a 74-year-old female patient diagnosed with a deep-seated solitary fibrous tumor in the pelvis. Histopathologically, the neoplasm did not display nuclear pleomorphism or tumor necrosis and had a low proliferative index. A total of 378 unique reads spanning the NFIXexon8-STAT6exon2 breakpoint with 55 different start sites were detected in the bioinformatic analysis, which represented 59.5% of the reads intersecting the genomic location on either side of the breakpoint. Targeted RNA-Seq results were validated by RT-PCR/ Sanger sequencing. The identification of a new gene fusion partner for STAT6 in solitary fibrous tumor opens intriguing new hypotheses to refine the role of STAT6 in the sarcomatogenesis of this entity.
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Fusão Gênica , Fatores de Transcrição NFI/genética , Proteínas de Fusão Oncogênica/genética , Fator de Transcrição STAT6/genética , Tumores Fibrosos Solitários/genética , Tumores Fibrosos Solitários/patologia , Idoso , Feminino , Humanos , PrognósticoRESUMO
BACKGROUND: Reference centers (RCs) are a key point for improving the survival of patients with soft-tissue sarcomas (STS). The aim of this study was to evaluate selected items in the management of patients with STS, comparing results between RC and local hospitals (LHs). MATERIALS AND METHODS: Diagnostic and therapeutic data from patients diagnosed between January 2004 and December 2011 were collected. Correlation with outcome was performed. RESULTS: A total of 622 sarcomas were analyzed, with a median follow-up of 40 months. Imaging of primary tumor preoperatively (yes vs. no) correlated with a higher probability of free surgical margins (77.4% versus 53.7%; p = .006). The provenance of the biopsy (RC vs. LH) significantly affected relapse-free survival (RFS; 3-year RFS 66% vs. 46%, respectively; p = .019). Likewise, 3-year RFS was significantly worse in cases with infiltrated (55.6%) or unknown (43.4%) microscopic surgical margins compared with free margins (63.6%; p < .001). Patients managed by RCs had a better 3-year overall survival compared with those managed by LHs (82% vs. 70.4%, respectively; p = .003). Perioperative chemotherapy in high-risk STS, more frequently administered in RCs than in LHs, resulted in significantly better 3-year RFS (66% vs. 44%; p = .011). In addition, patients with stage IV disease treated in RCs survived significantly longer compared with those in LHs (30.4 months vs. 18.5 months; p = .036). CONCLUSION: Our series indicate that selected quality-of-care items were accomplished better by RCs over LHs, all with significant prognostic value in patients with STS. Early referral to an RC should be mandatory if the aim is to improve the survival of patients with STS. IMPLICATIONS FOR PRACTICE: This prospective study in patients diagnosed with soft-tissue sarcoma shows the prognostic impact of reference centers in the management of these patients. The magnitude of this impact encompasses all steps of the process, from the initial management (performing diagnostic biopsy) to the advanced disease setting. This is the first prospective evidence showing improvement in outcomes of patients with metastatic disease when they are managed in centers with expertise. This study provides extra data supporting referral of patients with sarcoma to reference centers.
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Institutos de Câncer/estatística & dados numéricos , Recidiva Local de Neoplasia/epidemiologia , Encaminhamento e Consulta/estatística & dados numéricos , Sarcoma/cirurgia , Biópsia/estatística & dados numéricos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Prognóstico , Estudos Prospectivos , Sistema de Registros/estatística & dados numéricos , Sarcoma/diagnóstico , Sarcoma/mortalidade , Sarcoma/patologia , Espanha/epidemiologia , Fatores de TempoRESUMO
BACKGROUND: Previous trials from our group suggested an overall survival benefit with five cycles of adjuvant full-dose epirubicin plus ifosfamide in localised high-risk soft-tissue sarcoma of the extremities or trunk wall, and no difference in overall survival benefit between three cycles versus five cycles of the same neoadjuvant regimen. We aimed to show the superiority of the neoadjuvant administration of histotype-tailored regimen to standard chemotherapy. METHODS: For this international, open-label, randomised, controlled, phase 3, multicentre trial, patients were enrolled from 32 hospitals in Italy, Spain, France, and Poland. Eligible patients were aged 18 years or older with localised, high-risk (high malignancy grade, 5 cm or longer in diameter, and deeply located according to the investing fascia), soft-tissue sarcoma of the extremities or trunk wall and belonging to one of five histological subtypes: high-grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma. Patients were randomly assigned (1:1) to receive three cycles of full-dose standard chemotherapy (epirubicin 60 mg/m2 per day [short infusion, days 1 and 2] plus ifosfamide 3 g/m2 per day [days 1, 2, and 3], repeated every 21 days) or histotype-tailored chemotherapy: for high-grade myxoid liposarcoma, trabectedin 1·3 mg/m2 via 24-h continuous infusion, repeated every 21 days; for leiomyosarcoma, gemcitabine 1800 mg/m2 on day 1 intravenously over 180 min plus dacarbazine 500 mg/m2 on day 1 intravenously over 20 min, repeated every 14 days; for synovial sarcoma, high-dose ifosfamide 14 g/m2, given over 14 days via an external infusion pump, every 28 days; for malignant peripheral nerve sheath tumour, intravenous etoposide 150 mg/m2 per day (days 1, 2, and 3) plus intravenous ifosfamide 3 g/m2 per day (days 1, 2, and 3), repeated every 21 days; and for undifferentiated pleomorphic sarcoma, gemcitabine 900 mg/m2 on days 1 and 8 intravenously over 90 min plus docetaxel 75 mg/m2 on day 8 intravenously over 1 h, repeated every 21 days. Randomisation was stratified by administration of preoperative radiotherapy and by country of enrolment. Computer-generated random lists were prepared by use of permuted balanced blocks of size 4 and 6 in random sequence. An internet-based randomisation system ensured concealment of the treatment assignment until the patient had been registered into the system. No masking of treatment assignments was done. The primary endpoint was disease-free survival. The primary and safety analyses were planned in the intention-to-treat population. We did yearly futility analyses on an intention-to-treat basis. The study was registered with ClinicalTrials.gov, number NCT01710176, and with the European Union Drug Regulating Authorities Clinical Trials, number EUDRACT 2010-023484-17, and is closed to patient entry. FINDINGS: Between May 19, 2011, and May 13, 2016, 287 patients were randomly assigned to a group (145 to standard chemotherapy and 142 to histotype-tailored chemotherapy), all of whom, except one patient assigned to standard chemotherapy, were included in the efficacy analysis (97 [34%] with undifferentiated pleomorphic sarcoma; 64 [22%] with high-grade myxoid liposarcoma; 70 [24%] with synovial sarcoma; 27 [9%] with malignant peripheral nerve sheath tumour; and 28 [10%] with leiomyosarcoma). At the third futility analysis, with a median follow-up of 12·3 months (IQR 2·75-28·20), the projected disease-free survival at 46 months was 62% (95% CI 48-77) in the standard chemotherapy group and 38% (22-55) in the histotype-tailored chemotherapy group (stratified log-rank p=0·004; hazard ratio 2·00, 95% CI 1·22-3·26; p=0·006). The most common grade 3 or higher adverse events in the standard chemotherapy group (n=125) were neutropenia (107 [86%]), anaemia (24 [19%]), and thrombocytopenia (21 [17%]); the most common grade 3 or higher adverse event in the histotype-tailored chemotherapy group (n=114) was neutropenia (30 [26%]). No treatment-related deaths were reported in both groups. In agreement with the Independent Data Monitoring Committee, the study was closed to patient entry after the third futility analysis. INTERPRETATION: In a population of patients with high-risk soft-tissue sarcoma, we did not show any benefit of a neoadjuvant histotype-tailored chemotherapy regimen over the standard chemotherapy regimen. The benefit seen with the standard chemotherapy regimen suggests that this benefit might be the added value of neoadjuvant chemotherapy itself in patients with high-risk soft-tissue sarcoma. FUNDING: European Union grant (Eurosarc FP7 278472).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neurilemoma/terapia , Sarcoma/patologia , Sarcoma/terapia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapia , Parede Abdominal , Adolescente , Adulto , Idoso , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dorso , Quimioterapia Adjuvante/métodos , Criança , Dacarbazina/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Dioxóis/administração & dosagem , Intervalo Livre de Doença , Docetaxel , Epirubicina/administração & dosagem , Etoposídeo/administração & dosagem , Extremidades , Humanos , Ifosfamida/administração & dosagem , Leiomiossarcoma/terapia , Lipossarcoma Mixoide/terapia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Neutropenia/induzido quimicamente , Fatores de Risco , Sarcoma Sinovial/terapia , Taxoides/administração & dosagem , Tetra-Hidroisoquinolinas/administração & dosagem , Parede Torácica , Trombocitopenia/induzido quimicamente , Trabectedina , Adulto Jovem , GencitabinaRESUMO
Connective tissue nevi are benign hamartomatous lesions in which one or several of the components of the dermis (collagen, elastin, glicosaminoglycans) show predominance or depletion. Recently, de Feraudy et al broadened the spectrum of connective tissue nevus, describing fibroblastic connective tissue nevus (FCTN), which is characterized by proliferation of CD34(+) cells of fibroblastic and myofibroblastic lineage. Only solitary papules and nodules have been described. We present the first case of FCTN with multiple agminated lesions on the leg of an infant and the difficulties encountered in the differential diagnosis with dermatofibrosarcoma protuberans.
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Dermatofibrossarcoma/diagnóstico , Nevo/patologia , Neoplasias Cutâneas/patologia , Diagnóstico Diferencial , Humanos , Lactente , Masculino , Nevo/diagnóstico , Nevo Pigmentado/patologiaRESUMO
BACKGROUND: We report a case of stroke due to stenosis caused by a myxoma in the common carotid artery with no evidence of a cardiac origin. Only 1 such case has been reported previously in the literature. METHODS: A previously healthy 37-year-old woman presented with repeated episodes of acute focal deficits together with motor, sensory, and language symptoms typical of left internal carotid territory involvement. Brain magnetic resonance imaging showed acute and subacute ischemic lesions in the territory of the left middle cerebral artery and border zone infarcts (middle cerebral artery with anterior and posterior cerebral arteries). Magnetic resonance angiography showed a filling defect in the distal portion of the left common carotid artery causing stenosis over 70%. Transesophageal echocardiography showed no embolic sources. Blood tests ruled out a prothrombotic state. RESULTS: The image was initially interpreted as a possible subacute thrombus and anticoagulation was started. No changes were observed in the follow-up carotid ultrasound examination after 12 days of treatment. A gelatinous mass was removed during carotid surgery. No subjacent lesion was observed in the vessel wall. Pathology examination showed a spindle cell fibromyxoid tissue with fibrinoid material typical of myxoma. CONCLUSIONS: We hypothesize that the myxoma originated in the vessel, or alternatively, that a cardiac myxoma embolized without leaving a residual cardiac tumor. Although exceptional, myxoma should be added to the list of unusual causes of carotid artery stenosis causing stroke.
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Artérias Carótidas/patologia , Constrição Patológica/complicações , Mixoma/complicações , Acidente Vascular Cerebral/etiologia , Adulto , Constrição Patológica/etiologia , Feminino , Humanos , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Acidente Vascular Cerebral/diagnósticoRESUMO
AIM: Today, free margin surgery is the gold-standard management for soft-tissue sarcoma patients and one of the most important predictors of recurrence and survival. To obtain optimal results, a multidisciplinary approach is necessary. The aim of this study was to evaluate the evolution of patients with RPS treated by «en bloc«surgical resection versus those treated with enucleation in the first surgery. METHODS: Fifty-six adult patients were divided into 2 groups. Patients in Group A underwent enucleation surgery, and patients in Group B underwent en bloc surgery. The endpoints of the study were survival time and time to recurrence, according to histological type and first surgical strategy. RESULTS: Disease-free survival was longer for en bloc surgery (P<0,05), but there was no difference in overall survival. When comparing the histology of patients who underwent enucleation surgery and en bloc resection surgery, the disease-free survival and overall survival rates were longer for liposarcoma. In the multivariate analysis, only free margins and histology of liposarcoma were significantly associated with a better survival. CONCLUSIONS: The surgical management of patients with retroperitoneal sarcoma must be very aggressive, often requiring multivisceral resection. Considering the disease-free survival and overall survival rates obtained, it is clear that it is critical to manage patients as early as possible by a radical en bloc surgery.
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Neoplasias Retroperitoneais/cirurgia , Sarcoma/cirurgia , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Retroperitoneais/mortalidade , Sarcoma/mortalidade , Procedimentos Cirúrgicos Operatórios/métodosRESUMO
Poor long-term survival in localized high-risk soft tissue sarcomas (STSs) of the extremities and trunk highlights the need to identify new prognostic factors. CXCR4 is a chemokine receptor involved in tumor progression, angiogenesis, and metastasis. The aim of this study was to evaluate the association between CXCR4 expression in tumor tissue and survival in STSs patients treated with neoadjuvant therapy. CXCR4 expression was retrospectively determined by immunohistochemical analysis in serial specimens including initial biopsies, tumors post-neoadjuvant treatment, and tumors after relapse. We found that a positive cytoplasmatic expression of CXCR4 in tumors after neoadjuvant treatment was a predictor of poor recurrence-free survival (RFS) (p = 0.003) and overall survival (p = 0.019) in synovial sarcomas. We also found that positive nuclear CXCR4 expression in the initial biopsies was associated with poor RFS (p = 0.022) in undifferentiated pleomorphic sarcomas. In conclusion, our study adds to the evidence that CXCR4 expression in tumor tissue is a promising prognostic factor for STSs.
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BACKGROUND: Anthracycline-based neoadjuvant chemotherapy (NAC) may modify tumour immune infiltrate. This study characterized immune infiltrate spatial distribution after NAC in primary high-risk soft tissue sarcomas (STS) and investigate association with prognosis. METHODS: The ISG-STS 1001 trial randomized STS patients to anthracycline plus ifosfamide (AI) or a histology-tailored (HT) NAC. Four areas of tumour specimens were sampled: the area showing the highest lymphocyte infiltrate (HI) at H&E; the area with lack of post-treatment changes (highest grade, HG); the area with post-treatment changes (lowest grade, LG); and the tumour edge (TE). CD3, CD8, PD-1, CD20, FOXP3, and CD163 were analyzed at immunohistochemistry and digital pathology. A machine learning method was used to generate sarcoma immune index scores (SIS) that predict patient disease-free and overall survival (DFS and OS). FINDINGS: Tumour infiltrating lymphocytes and PD-1+ cells together with CD163+ cells were more represented in STS histologies with complex compared to simple karyotype, while CD20+ B-cells were detected in both these histology groups. PD-1+ cells exerted a negative prognostic value irrespectively of their spatial distribution. Enrichment in CD20+ B-cells at HI and TE areas was associated with better patient outcomes. We generated a prognostic SIS for each tumour area, having the HI-SIS the best performance. Such prognostic value was driven by treatment with AI. INTERPRETATION: The different spatial distribution of immune populations and their different association with prognosis support NAC as a modifier of tumour immune infiltrate in STS. FUNDING: Pharmamar; Italian Ministry of Health [RF-2019-12370923; GR-2016-02362609]; 5 × 1000 Funds-2016, Italian Ministry of Health; AIRC Grant [ID#28546].
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Linfócitos do Interstício Tumoral , Terapia Neoadjuvante , Sarcoma , Humanos , Sarcoma/tratamento farmacológico , Sarcoma/mortalidade , Sarcoma/imunologia , Sarcoma/patologia , Feminino , Masculino , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Prognóstico , Pessoa de Meia-Idade , Adulto , Idoso , Resultado do Tratamento , Microambiente Tumoral/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Imuno-HistoquímicaRESUMO
PURPOSE: A randomized trial was conducted to compare neoadjuvant standard (S) anthracycline + ifosfamide (AI) regimen with histology-tailored (HT) regimen in selected localized high-risk soft tissue sarcoma (STS). The results of the trial demonstrated the superiority of S in all STS histologies except for high-grade myxoid liposarcoma (HG-MLPS) where S and HT appeared to be equivalent. To further evaluate the noninferiority of HT compared with S, the HG-MLPS cohort was expanded. PATIENTS AND METHODS: Patients had localized high-grade (cellular component >5%; size ≥5 cm; deeply seated) MLPS of extremities or trunk wall. The primary end point was disease-free survival (DFS). The secondary end point was overall survival (OS). The trial used a noninferiority Bayesian design, wherein HT would be considered not inferior to S if the posterior probability of the true hazard ratio (HR) being >1.25 was <5%. RESULTS: From May 2011 to June 2020, 101 patients with HG-MLPS were randomly assigned, 45 to the HT arm and 56 to the S arm. The median follow-up was 66 months (IQR, 37-89). Median size was 107 mm (IQR, 84-143), 106 mm (IQR, 75-135) in the HT arm and 108 mm (IQR, 86-150) in the S arm. At 60 months, the DFS and OS probabilities were 0.86 and 0.73 (HR, 0.60 [95% CI, 0.24 to 1.46]; log-rank P = .26 for DFS) and 0.88 and 0.90 (HR, 1.20 [95% CI, 0.37 to 3.93]; log-rank P = .77 for OS) in the HT and S arms, respectively. The posterior probability of HR being >1.25 for DFS met the Bayesian monitoring cutoff of <5% (4.93%). This result confirmed the noninferiority of trabectedin to AI suggested in the original study cohort. CONCLUSION: Trabectedin may be an alternative to standard AI in HG-MLPS of the extremities or trunk when neoadjuvant treatment is a consideration.
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Lipossarcoma Mixoide , Sarcoma , Neoplasias de Tecidos Moles , Adulto , Humanos , Terapia Neoadjuvante , Lipossarcoma Mixoide/tratamento farmacológico , Trabectedina/uso terapêutico , Polônia , Teorema de Bayes , Ifosfamida/uso terapêutico , Sarcoma/terapia , Neoplasias de Tecidos Moles/terapia , Antibióticos Antineoplásicos/uso terapêutico , Antraciclinas/uso terapêutico , ItáliaRESUMO
PURPOSE: Prognostic biomarkers remain necessary in sporadic desmoid tumor (DT) because the clinical course is unpredictable. DT location along with gene expression between thoracic and abdominal wall locations was analyzed. METHOD: Sporadic DT patients (GEIS Registry) diagnosed between 1982 and 2018 who underwent upfront surgery were enrolled retrospectively in this study. The primary endpoint was relapse-free survival (RFS). Additionally, the gene expression profile was analyzed in DT localized in the thoracic or abdominal wall, harboring the most frequent CTNNB1 T41A mutation. RESULTS: From a total of 454 DT patients, 197 patients with sporadic DT were selected. The median age was 38.2 years (1.8-89.1) with a male/female distribution of 33.5/66.5. Most of them harbored the CTNNB1 T41A mutation (71.6 %), followed by S45F (17.8 %) and S45P (4.1 %). A significant worse median RFS was associated with males (p = 0.019), tumor size ≥ 6 cm (p = 0.001), extra-abdominal DT location (p < 0.001) and the presence of CTNNB1 S45F mutation (p = 0.013). In the multivariate analysis, extra-abdominal DT location, CTNNB1 S45F mutation and tumor size were independent prognostic biomarkers for worse RFS. DTs harboring the CTNNB1 T41A mutation showed overexpression of DUSP1, SOCS1, EGR1, FOS, LIF, MYC, SGK1, SLC2A3, and IER3, and underexpression of BMP4, PMS2, HOXA9, and WISP1 in thoracic versus abdominal wall locations. CONCLUSION: Sporadic DT location exhibits a different prognosis in terms of RFS favoring the abdominal wall compared to extra-abdominal sites. A differential gene expression profile under the same CTNNB1 T41A mutation is observed in the abdominal wall versus the thoracic wall, mainly affecting the Wnt/ß-catenin, TGFß, IFN, and TNF pathways.
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AIMS: Benign (BPNST) and malignant (MPNST) peripheral nerve sheath tumours occur either sporadically or are related to neurofibromatosis (NF). The mechanisms involved are well known in NF-related tumours, but still remain unclear in sporadic cases. Somatic BRAF and KRAS mutations represent the most frequent genetic events in melanocytic neoplastic lesions. Because melanocytes and Schwann cells both derive from neural crest cells, we hypothesized that BRAF and KRAS mutations might influence BPNST and MPNST development. METHODS AND RESULTS: BRAF exon 15 and KRAS exons 2 and 3 polymerase chain reaction (PCR) sequencing was performed in formalin-fixed/paraffin-embedded samples of 99 BPNST and MPNST, related and non-related to NF types 1 and 2. Oncogenic BRAF V600E mutations were found in four of 40 schwannomas (including one acoustic neuroma) and one of 13 MPNST, not associated with NF. A KRAS G12S mutation was also evident in one sporadic schwannoma. CONCLUSION: Our findings suggest that RAS pathway activation due to BRAF V600E and KRAS mutations is an important event in a subset of peripheral nerve sheath tumours not related to NF.
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Mutação , Neoplasias de Bainha Neural/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Bainha Neural/patologia , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas p21(ras)RESUMO
BACKGROUND: The altered cellular metabolism is one of the hallmarks of the cancer cells, favoring the process of aerobic glycolysis, known as the Warburg effect. The pyruvate dehydrogenase (PDH) complex is one of the elements involved in this metabolic process. The present study aims to evaluate the relationship between the transcriptional expression of PDHB and the risk of local recurrence in patients with oral cavity carcinomas. METHODS: We determined the transcriptional expression of PDHB in biopsies from 41 patients with oral cavity carcinomas treated with surgery. The PDHB expression was categorized according to the local control of the disease with a recursive partitioning analysis. RESULTS: During the follow-up period 13 patients (31.7%) had a local recurrence of the tumor. Considering local disease control as the dependent variable, the recursive partitioning analysis classified the patients in two categories according to high (n=16, 39.0%) or low (n=25, 61.0%) PDHB expression. Five-year local recurrence-free survival for patients with high PDHB expression was 84.8% (95% CI: 65.2-100%), and for patients with low expression it was 54.3% (95% CI: 34.3-74.2 %) (P=0.034). The results of multivariate analysis showed that patients with a low PDHB expression had a 4.90 times higher risk of local recurrence of the tumor (95% CI: 1.02-22.68, P=0.042). CONCLUSION: There is a relationship between the metabolic characteristics of the tumor and its aggressiveness. According to our results, patients with oral cavity carcinomas with low transcriptional expression levels of PDHB have a significantly higher risk of local tumor recurrence.
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Carcinoma , Piruvato Desidrogenase (Lipoamida) , Humanos , Piruvato Desidrogenase (Lipoamida)/genética , Piruvato Desidrogenase (Lipoamida)/metabolismo , Boca/metabolismo , PiruvatosRESUMO
Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.
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BACKGROUND: The Complexity INdex in SARComas (CINSARC) is a transcriptional signature derived from the expression of 67 genes involved in mitosis control and chromosome integrity. This study aims to assess CINSARC value of in an independent series of high-risk patients with localized soft tissue sarcoma (STS) treated with preoperative chemotherapy within a prospective, randomized, phase III study (ISG-STS 1001). PATIENTS AND METHODS: Patients with available pre-treatment samples, treated with 3 cycles of either standard (ST) preoperative or histotype-tailored (HT) chemotherapy, were scored according to CINSARC (low-risk, C1; high-risk, C2). The 10-year overall survival probability (pr-OS) according to SARCULATOR was calculated, and patients were classified accordingly (low-risk, Sarc-LR, 10-year pr-OS>60%; high-risk, Sarc-HR, 10-year pr-OS<60%). Survival functions were estimated using the Kaplan-Meier method and compared using log-rank test. RESULTS: Eighty-six patients were included, 30 C1 and 56 C2, 49 Sarc-LR and 37 Sarc-HR. A low level of agreement between CINSARC and SARCULATOR was observed (Cohen's Kappa = 0.174). The 5-year relapse-free survival in C1 and C2 were 0.57 and 0.55 (p = 0.481); 5-year metastases-free survival 0.63 and 0.64 (p = 0.740); 5-year OS 0.80 and 0.72 (p = 0.460). The 5-year OS in C1 treated with ST and HT chemotherapy was 0.84 and 0.76 (p = 0.251) respectively; in C2 treated it was 0.72 and 0.70 (p = 0.349). The 5-year OS in Sarc-LR treated with S and HT chemotherapy was 0.80 and 0.82 (p = 0.502) respectively; in Sarc-HR it was 0.70 and 0.61 (p = 0.233). CONCLUSIONS: Our results, although constrained by the small size of the series, suggest that CINSARC has weak prognostic power in high-risk, localized STS treated with neoadjuvant chemotherapy.
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Sarcoma , Neoplasias de Tecidos Moles , Humanos , Terapia Neoadjuvante , Estudos Prospectivos , Recidiva Local de Neoplasia , Sarcoma/tratamento farmacológico , Sarcoma/genética , PrognósticoRESUMO
BACKGROUND: To analyze the relationship between the transcriptional expression of lactate dehydrogenase A (LDHA) and the disease control in patients with a head and squamous cell carcinoma (HNSCC). METHODS: We determined the transcriptional expression of LDHA in 110 HNSCC patients treated with surgery. RESULTS: Five-year disease-free survival for patients with a high transcriptional expression of LDHA (n = 51) was 39.2% (95% confidence interval [CI]: 25.3%-53.1%), and for patients with a low expression (n = 59), it was 63.6% (95% CI: 51.1%-76.1%) (p = 0.004). According to the results of a multivariate analysis, patients with a high transcriptional expression of LDHA had a 3.4-fold increased risk of tumor recurrence. Patients with a high transcriptional expression of LDHA tended to show a higher intensity of immunohistochemical expression of LDHA at the tumor cells (p = 0.086). CONCLUSION: In HNSCC patients treated with surgery, a high transcriptional expression of LDHA was associated with a significant decrease in disease-free survival.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/cirurgia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , L-Lactato Desidrogenase/metabolismo , Lactato Desidrogenase 5 , Recidiva Local de Neoplasia/genética , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genéticaRESUMO
INTRODUCTION: The effectiveness of trabectedin for the treatment of leiomyosarcoma and liposarcoma (commonly referred to as L-sarcomas) has been widely evidenced in clinical trials and real-world studies. Nevertheless, available literature on non-L-sarcomas is less abundant. The objective of the present study is to evaluate the effectiveness and safety of trabectedin in a cohort of patients with non-L-sarcomas in the real-world setting. METHODS: This retrospective, observational study included 34 patients who received trabectedin in the Hospital de la Santa Creu i Sant Pau (Barcelona, Spain) between October 2013 and July 2020. RESULTS: The most frequent histologic subtypes were undifferentiated spindle cell/pleomorphic sarcoma (n = 11, 32.4%), synovial sarcoma (n = 6, 17.7%), myxofibrosarcoma (n = 5, 14.7%), and malignant peripheral nerve sheath tumor (n = 4, 11.8%). The mean number of cycles with trabectedin was 5.5 (range 2-28). Three patients achieved partial response (8.8%) and eight patients showed stable disease (23.5%). The objective response rate and disease control rate were 8.8% (95% confidence interval (CI), 95% CI 1.9-23.7) and 32.4% (95% CI 17.4-50.5), respectively. Overall, progression-free survival was 2.9 months (95% CI 2.1-3.4). The overall survival was 7.3 months (95% CI 4.7-12.8). The most common trabectedin-related grade 3 adverse events were observed in 10 patients (26.5%), mostly being neutropenia (14.7%) and elevated transaminases (5.9%), whereas one patient (2.9%) reported grade 4 febrile neutropenia that required hospitalization. CONCLUSIONS: The findings of this real-life study consistently support that trabectedin is an effective and safe option for the treatment of patients with non-L-sarcoma after failure of anthracyclines and ifosfamide, or in patients who are unsuited to receive these agents.
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Sarcoma , Neoplasias de Tecidos Moles , Tetra-Hidroisoquinolinas , Adulto , Antineoplásicos Alquilantes/efeitos adversos , Dioxóis/efeitos adversos , Humanos , Estudos Retrospectivos , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/patologia , Tetra-Hidroisoquinolinas/uso terapêutico , Trabectedina/uso terapêuticoRESUMO
Neoadjuvant chemotherapy based on anthracyclines and ifosfamide for high-risk soft tissue sarcomas (STS) of the extremities and trunk is a controversial treatment option. There are substantial interindividual differences in clinical outcomes in patients treated with neoadjuvant chemotherapy. The aim of this study was to evaluate, as biomarkers, polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, or drug targets and their association with toxicity and survival in STS patients treated with neoadjuvant chemotherapy. We analysed variants in genes involved in anthracycline metabolism (ABCB1, ABCC2, NQO1, CBR3, and SLC22A16) and in ifosfamide catabolism (ALDH1A1) in 79 treated patients. Two genes showed significant association after adjusted multivariate analysis: ABCC2 and ALDH1A1. In patients treated with anthracyclines, ABCC2 rs3740066 was associated with risk of febrile neutropenia (p = 0.031), and with decreased overall survival (OS) (p = 0.024). ABCC2 rs2273697 was associated with recurrence-free survival (RFS) (p = 0.024). In patients treated with ifosfamide, ALDH1A1 rs3764435 was associated with RFS (p = 0.046). Our pharmacogenetic study shows for the first time that variants in genes regulating the metabolism of neoadjuvant chemotherapy may be helpful to predict toxicity and survival benefit in high-risk STS treated with neoadjuvant chemotherapy. Further validation studies are needed to establish their clinical utility.
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Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.