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Soft tissue sarcomas (STS) are diverse mesenchymal tumors with few therapeutic options in advanced stages. Trabectedin has global approval for treating STS patients resistant to anthracycline-based regimens. Recent pre-clinical data suggest that trabectedin's antitumor activity extends beyond tumor cells to influencing the tumor microenvironment (TME), especially affecting tumor-associated macrophages and their pro-tumoral functions. We present the phase I/II results evaluating a combination of metronomic trabectedin and low-dose cyclophosphamide on the TME in patients with advanced sarcomas. 50 patients participated: 20 in phase I and 30 in phase II. Changes in the TME were assessed in 28 patients using sequential tumor samples at baseline and day two of the cycle. Treatment notably decreased CD68 + CD163 + macrophages in biopsies from tumor lesions compared to pre-treatment samples in 9 of the 28 patients after 4 weeks. Baseline CD8 + T cell presence increased in 11 of these patients. In summary, up to 57% of patients exhibited a positive immunological response marked by reduced M2 macrophages or increased CD8 + T cells post-treatment. This positive shift in the TME correlated with improved clinical benefit and progression-free survival. This study offers the first prospective evidence of trabectedin's immunological effect in advanced STS patients, highlighting a relationship between TME modulation and patient outcomes.This study was registered with ClinicalTrial.gov, number NCT02406781.
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Antineoplásicos Alquilantes , Sarcoma , Humanos , Trabectedina/uso terapêutico , Estudos Prospectivos , Antineoplásicos Alquilantes/uso terapêutico , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Ciclofosfamida/uso terapêutico , Dioxóis , Microambiente TumoralRESUMO
Most soft-tissue sarcomas (STS) exhibit an immunosuppressive tumor microenvironment (TME), leading to resistance against immune checkpoint inhibitors (ICIs) and limited therapeutic response. Preclinical data suggest that oncolytic viral therapy can remodel the TME, facilitating T cell accumulation and enhancing the immunogenicity of these tumors.We conducted the METROMAJX, a phase II clinical trial, to investigate the combination of JX-594, an oncolytic vaccinia virus engineered for selective tumor cell replication, with metronomic cyclophosphamide and the PD-L1 inhibitor avelumab in patients with advanced, 'cold' STS, characterized by an absence of tertiary lymphoid structures. The trial employed a two-stage Simon design. JX-594 was administered intratumorally at a dose of 1.109 pfu every 2 weeks for up to 4 intra-tumoral administrations. Cyclophosphamide was given orally at 50 mg twice daily in a week-on, week-off schedule, and avelumab was administered at 10 mg/kg biweekly. The primary endpoint was the 6-month non-progression rate.Fifteen patients were enrolled, with the most frequent toxicities being grade 1 fatigue and fever. Fourteen patients were assessable for efficacy analysis. At 6 months, only one patient remained progression-free, indicating that the trial did not meet the first stage endpoint of Simon's design. Analysis of sequential tissue biopsies and plasma samples revealed an increase in CD8 density and upregulation of immune-related protein biomarkers, including CXCL10.Intra-tumoral administration of JX-594 in combination with cyclophosphamide and avelumab is safe and capable of modulating the TME in cold STS. However, the limited efficacy observed warrants further research to define the therapeutic potential of oncolytic viruses, particularly in relation to specific histological subtypes of STS.
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Anticorpos Monoclonais Humanizados , Terapia Viral Oncolítica , Vírus Oncolíticos , Sarcoma , Humanos , Microambiente Tumoral , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos/genética , Vírus Oncolíticos/metabolismo , Sarcoma/terapia , Ciclofosfamida/uso terapêutico , Ciclofosfamida/metabolismoRESUMO
BACKGROUND: Stabilization or spontaneous regressions are demonstrated in more than half of patients affected by primary desmoid-type fibromatosis (DF) in retrospective studies. The objective of this phase II study was to prospectively assess the behavior of primary sporadic DT managed by active surveillance (AS). METHODS: This prospective, multicenter, observational study (NCT01801176) included patients ≥18 years of age with primary sporadic DF located in an extremity or the abdominal/thoracic wall. At inclusion, all patients were initially placed on AS. Follow-up was based on clinical and radiological evaluation by magnetic resonance imaging (MRI) performed at 1, 3, 6, 9, and 12 months, and then every 6 months for 3 years. The primary endpoint was progression-free survival (PFS) at 3 years according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as evaluated by a Central Review Board. RESULTS: Between 2012 and 2015, 100 patients were enrolled. The female/male ratio was 8 and the median age was 34 years (interquartile range [IQR] 30.8-43.9). Median follow-up was 46.6 months (IQR 36.8-61.1) and the 3-year PFS was 53.4% (95% confidence interval 43.5-63.1%). At progression (48 patients), 23 patients received active treatment. Fifty-eight patients (58%) presented with spontaneous tumor regression (decrease > 0% compared with the initial size) during the first 3 months (n = 35, 35%) or after an initial progression (n = 23, 23%), of whom 26 (26%) had partial responses (PRs). The median time to PR was 31.7 months (25.3-not available). CONCLUSIONS: These data support the use of AS as the primary approach to select patients with peripheral DF who require aggressive treatment.
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Fibromatose Agressiva , Humanos , Masculino , Feminino , Adulto , Fibromatose Agressiva/patologia , Conduta Expectante , Estudos Retrospectivos , Estudos Prospectivos , Critérios de Avaliação de Resposta em Tumores SólidosRESUMO
OBJECTIVES: Radiomics of soft tissue sarcomas (STS) is assumed to correlate with histologic and molecular tumor features, but radiogenomics analyses are lacking. Our aim was to identify if distinct patterns of natural evolution of STS obtained from consecutive pre-treatment MRIs are associated with differential gene expression (DGE) profiling in a pathway analysis. METHODS: All patients with newly diagnosed STS treated in a curative intent in our sarcoma reference center between 2008 and 2019 and with two available pre-treatment contrast-enhanced MRIs were included in this retrospective study. Radiomics features (RFs) were extracted from fat-sat contrast-enhanced T1-weighted imaging. Log ratio and relative change in RFs were calculated and used to determine grouping of samples based on a consensus hierarchical clustering. DGE and oncogenesis pathway analysis were performed in the delta-radiomics groups identified in order to detect associations between delta-radiomics patterns and transcriptomics features of STS. Secondarily, the prognostic value of the delta-radiomics groups was investigated. RESULTS: Sixty-three patients were included (median age: 63 years, interquartile range: 52.5-70). The consensus clustering identified 3 reliable delta-radiomics patient groups (A, B, and C). On imaging, group B patients were characterized by increase in tumor heterogeneity, necrotic signal, infiltrative margins, peritumoral edema, and peritumoral enhancement before the treatment start (p value range: 0.0019-0.0244), and, molecularly, by downregulation of natural killer cell-mediated cytotoxicity genes and upregulation of Hedgehog and Hippo signaling pathways. Group A patients were characterized by morphological stability of pre-treatment MRI traits and no local relapse (log-rank p = 0.0277). CONCLUSIONS: This study highlights radiomics and transcriptomics convergence in STS. Proliferation and immune response inhibition were hyper-activated in the STS that were the most evolving on consecutive imaging. KEY POINTS: ⢠Three consensual and stable delta-radiomics clusters were identified and captured the natural patterns of morphological evolution of STS on pre-treatment MRIs. ⢠These 3 patterns were explainable and correlated with different well-known semantic radiological features with an ascending gradient of pejorative characteristics from the A group to C group to B group. ⢠Gene expression profiling stressed distinct patterns of up/downregulated oncogenetic pathways in STS from B group in keeping with its most aggressive radiological evolution.
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Sarcoma , Neoplasias de Tecidos Moles , Humanos , Pessoa de Meia-Idade , Transcriptoma , Estudos Retrospectivos , Recidiva Local de Neoplasia , Imageamento por Ressonância Magnética/métodos , Sarcoma/diagnóstico por imagem , Sarcoma/genética , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologiaRESUMO
OBJECTIVES: Synovial sarcomas (SS) of the extremities are rare soft tissue sarcomas that are more common in young adults. We deciphered the imaging phenotype of SS with the aim to determine if imaging could provide an incremental value to currently known prognostic factors (PF)-age and histological grade-to predict long-term overall survival (OS). METHODS: This retrospective multicenter study included consecutive pediatric and adult patients with synovial sarcomas of the extremities from December 2002 to August 2020. Inclusion criteria were (i) a follow-up greater than 5 years and (ii) available pre-therapeutic MRI. A subset analysis included MRI and CT-scan. Clinical, pathological, and imaging variables were collected in all patients. The primary endpoint was to evaluate the association of these variables with OS using univariate and multivariate Cox regressions. RESULTS: Out of 428 patients screened for eligibility, 98 patients (mean age: 37.1 ± 15.2 years) were included (MRI: n = 98/98, CT scan: n = 34/98; 35%). The median OS was 75.25 months (IQR = 55.50-109.12) and thirty-six patients (n = 36/98;37%) died during follow-up. The recurrence rate was 12.2% (n =12/98). SS lesions were mostly grade 2 (57/98; 58%). On MRI, SS had a mean long-axis diameter of 67.5 ± 38.3 mm. On CT scan, 44% (15/34) were calcified. Grade (hazard ratio [HR] = 2.71; 95%CI = 1.30-5.66; p = 0.008), size of the lesions evaluated on MRI (HR = 1.02; 95% CI = 1.01-1.03; p < 0.001), and calcifications on CT scan (HR = 0.10; 95% CI = 0.02-0.50; p = 0.005) were independent PF of OS. CONCLUSIONS: This study demonstrated that imaging biomarkers can be used to predict long-term outcome in patients with SS. Strikingly, the presence of calcifications on CT scan is associated with favorable outcome and provides an incremental value over existing PF such as age, grade, and size. KEY POINTS: ⢠Beyond its diagnostic value, MRI is a pre-operative prognostic tool in synovial sarcomas of the extremities since the size of the lesion is an important prognostic factor. ⢠Calcifications on CT scans are independently and significantly associated with prolonged overall survival.
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Sarcoma Sinovial , Sarcoma , Humanos , Prognóstico , Sarcoma Sinovial/diagnóstico por imagem , Sarcoma/patologia , Extremidades/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Estudos RetrospectivosRESUMO
BACKGROUND: Because of long diagnostic intervals, soft-tissue sarcoma (STS) patients can undergo several MRIs before treatments. However, only the latest pre-treatment MRI is used in clinical practice and the natural changes in MRI presentations of STS occurring before any medical procedure remain unknown. PURPOSE: To qualitatively and quantitatively depict the natural history of MRI presentations of STS prior to medical intervention, to investigate their prognostic value, and to compare methods to calculate the changes in radiomics features (named delta-radiomics features). STUDY TYPE: Retrospective. SUBJECTS: Sixty-eight patients with locally advanced histologically proven STS and two pre-treatment contrast-enhanced (CE) MRIs (median age: 64 years, median delay between MRIs: 77 days). FIELD STRENGTH/SEQUENCE: Two-dimensional (2D) turbo spin echo (TSE) T1-weighted-imaging (WI) and T2-WI; 2D TSE or 3D gradient echo CE-T1-WI at 1.5 T. Radiomics analysis was performed on 2D TSE CE-T1-WI. ASSESSMENT: Three radiologists independently reported morphological features, evaluating changes in STS dimensions, intra-tumoral necrotic and hemorrhagic signals and heterogeneity, and changes in the tumor peritumoral enhancement, edema, and tail sign. After homogenizing the MRIs to account for differences in acquisition parameters, STS were 3D-segmented on both CE-T1-WI MRIs and radiomic features (RFs) were extracted. Changes in RFs between the two MRIs were calculated according to five methods: absolute, absolute/time between MRIs, relative, relative/time between MRIs, and log ratio. Histopathological samples were reviewed to count mitosis and Ki67 immunostaining. Survival data regarding local relapse, metastatic relapse, and disease-related deaths were collected. STATISTICAL TESTS: Reproducibility analysis (using intra-class correlation coefficient and [weighted] kappa), hierarchical clusterings based on changes in RFs, survival analyses (using Cox regressions), and association with histopathology (using Student's t-test, Wilcoxon, or Chi-squared test). A P-value of <0.05 was considered to be statistically significant. RESULTS: There were 15 and 26 local and metastatic progressions, respectively. Average tumor size increase between scans was +39.8%. Metastatic relapse-free survival (MFS) was associated with: increases in size, tumor heterogeneity on T1-WI, T2-WI, and CE-T1-WI, necrotic signal, peritumoral enhancement, and tail sign. Local relapse-free survival (LFS) was associated with: increase in tumor heterogeneity on T1-WI, necrotic signal, hemorrhagic signal and peritumoral edema, and clusters based on the logarithmic changes in RFs (Log-RF). Increase in heterogeneity on CE-T1-WI and Log-RF clusters were independent predictors for MFS and LFS, respectively, in stepwise multivariate Cox regression (hazard ratio [HR] = 2.78 and HR = +∞ respectively). Associations were found between changes in necrotic signal, heterogeneity on CE-T1-WI and peritumoral enhancement, and histological markers of proliferation. DATA CONCLUSION: Changes in MRI presentation of STS before any treatment are frequent, associated with histopathology, and could help in patients' prognostication, in addition to baseline MRI feature. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.
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Sarcoma , Neoplasias de Tecidos Moles , Edema , Humanos , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sarcoma/diagnóstico por imagem , Sarcoma/patologia , Neoplasias de Tecidos Moles/diagnóstico por imagem , Neoplasias de Tecidos Moles/patologiaRESUMO
BACKGROUND: Magnetic resonance imaging (MRI)-based radiomics features (RFs) quantify tumors radiological phenotypes but are sensitive to postprocessing parameters, including the intensity harmonization technique (IHT), while mappings enable objective quantitative assessment. PURPOSE: To investigate whether T2 mapping could improve repeatability, reproducibility, and performances of radiomics compared to conventional T2-weighted imaging (T2WI). STUDY TYPE: Prospective. SUBJECTS: Twenty-six healthy adults. FIELD STRENGTH/SEQUENCE: Respiratory-trigged radial turbo spin echo (TSE) multiecho T2 mapping (prototype) and conventional TSE T2WI of the abdomen were acquired twice at 1.5 T. ASSESSMENT: T2 maps were reconstructed using a two-parameter exponential fitting model. Volumes-of-interest (VOIs) were manually drawn in six tissues: liver, kidney, pancreas, muscle, bone, and spleen. After co-registration, conventional T2WIs were processed with two IHTs (standardization [std] and histogram-matching [HM]) resulting in four paired input image types: initial T2WI, T2WIstd , T2WIHM , and T2-map. VOIs were propagated to extract 45 RFs from MRI-1 and MRI-2 of each image type (LIFEx, v5.10). STATISTICAL TESTS: Influence of the input data type on RF values was evaluated with analysis of variance. RFs test-retest repeatability and reproducibility over multiple segmentations were evaluated with intra-class correlation coefficient (ICC). Correlations between k-means clusters and the six tissues depending on the RFs dataset were investigated with adjusted-Rand-index (ARI). RESULTS: About 41 of 45 (91.1%) RFs were significantly influenced by the input image type (P values < 0.05), which was the most influential factor on repeatability of RFs (P-value < 0.05). Repeatability ICCs from T2-map displayed intermediate values between the initial T2WI (range: 0.407-0.736) and the T2WIHM (range: 0.724-0.817). The number of RFs with interobserver and intraobserver reproducibility ICCs ≥ 0.90 was 37/45 (82.2%) for T2WIHM , 33/45 (73.3%) for T2WIstd , 31/45 (68.9%) for T2 map, and 25/45 (55.6%) for the initial T2WI. T2 map provided the best tissue discrimination (ARI = 0.414 vs. 0.157 with T2WIHM ). DATA CONCLUSION: T2 mapping provided RFs with moderate to substantial repeatability and reproducibility ICCs, along with the most preserved discriminative information. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: 1.
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Abdome , Imageamento por Ressonância Magnética , Estudos Prospectivos , Radiografia , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Patients with Ewing sarcoma or osteosarcoma have a median overall survival of less than 12 months after diagnosis, and a standard treatment strategy has not yet been established. Pharmacological inhibition of MET signalling and aberrant angiogenesis has shown promising results in several preclinical models of Ewing sarcoma and osteosarcoma. We aimed to investigate the activity of cabozantinib, an inhibitor of MET and VEGFR2, in patients with advanced Ewing sarcoma and osteosarcoma. METHODS: We did a multicentre, single-arm, two-stage, phase 2 trial in patients with advanced Ewing sarcoma or osteosarcoma recruited from ten centres in the French Sarcoma Group. Key eligibility criteria were aged 12 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and documented disease progression (according to Response Evaluation Criteria in Solid Tumors version 1.1) before study entry. The number of previous lines of treatment was not limited. Patients received cabozantinib (adults 60 mg, children [<16 years] 40 mg/m2) orally once daily in 28-day cycles until disease progression, unacceptable toxicity, the investigator's decision to discontinue, or participant withdrawal. The primary endpoint for Ewing sarcoma was best objective response within 6 months of treatment onset; for osteosarcoma, a dual primary endpoint of 6-month objective response and 6-month non-progression was assessed. All enrolled patients who received at least one dose of cabozantinib were included in the safety analysis, and all participants who received at least one complete or two incomplete treatment cycles were included in the efficacy population. This study was registered with ClinicalTrials.gov, number NCT02243605. FINDINGS: Between April 16, 2015, and July 12, 2018, 90 patients (45 with Ewing sarcoma 45 with osteosarcoma) were recruited to the study. Median follow-up was 31·3 months (95% CI 12·4-35·4) for patients with Ewing sarcoma and 31·1 months (24·4-31·7) for patients with osteosarcoma. 39 (87%) patients with Ewing sarcoma and 42 (93%) patients with osteosarcoma were assessable for efficacy after histological and radiological review. In patients with Ewing sarcoma, ten (26%; 95% CI 13-42) of 39 patients had an objective response (all partial responses) by 6 months; in patients with osteosarcoma, five (12%; 4-26) of 42 patients had an objective response (all partial responses) and 14 (33%; 20-50) had 6-month non-progression. The most common grade 3 or 4 adverse events were hypophosphataemia (five [11%] for Ewing sarcoma, three [7%] for osteosarcoma), aspartate aminotransferase increase (two [4%] for Ewing sarcoma, three [7%] for osteosarcoma), palmar-plantar syndrome (three [7%] for Ewing sarcoma, two [4%] for osteosarcoma), pneumothorax (one [2%] for Ewing sarcoma, four [9%] for osteosarcoma), and neutropenia (two [4%] for Ewing sarcoma, four [9%] for osteosarcoma). At least one serious adverse event was reported in 61 (68%) of 90 patients. No patients died from drug-related toxic effects. INTERPRETATION: Cabozantinib has antitumor activity in patients with advanced Ewing sarcoma and osteosarcoma and was generally well tolerated. Cabozantinib could represent a new therapeutic option in this setting, and deserves further investigation. FUNDING: Institut Bergonié; French National Cancer Institute; Association pour la Recherche contre le Cancer.
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Anilidas/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Sarcoma de Ewing/tratamento farmacológico , Adulto , Neoplasias Ósseas/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Osteossarcoma/patologia , Prognóstico , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Sarcoma de Ewing/patologia , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Heterogeneity on pretreatment dynamic contrast-enhanced (DCE)-MRI of sarcomas may be prognostic, but the best technique to capture this characteristic remains unknown. PURPOSE: To investigate the best method to extract prognostic data from baseline DCE-MRI. STUDY TYPE: Retrospective, single-center. POPULATION: Fifty consecutive uniformly-treated adults with nonmetastatic high-grade sarcomas. FIELD STRENGTH/SEQUENCE: 1.5T; T2 -weighted-imaging, fat-suppressed fast spoiled gradient echo DCE-MRI. ASSESSMENT: Ninety-two radiomics features (RFs) were extracted at each DCE-MRI phase (11, from t = 0-88 sec). Relative changes in RFs (rRFs) since the acquisition baseline were calculated (11 × 92 rRFs). Curves of rRF as function of time postinjection were integrated (92 integrated-rRFs [irRFs]). Ktrans and area under the time-intensity curve at 88-sec parametric maps were computed and 2 × 92 parametric-RFs (pRFs) were extracted. Five DCE-MRI-based radiomics models were built on: an RFs subset (32 sec, 64 sec, 88 sec); all rRFs; all irRFs; and all pRFs. Two models were elaborated as reference, on: conventional radiological features; and T2 -WI RFs. STATISTICAL TESTS: A common machine-learning approach was applied to radiomics models. Features with P < 0.05 at univariate analysis were entered in a LASSO-penalized Cox regression including bootstrapped 10-fold cross-validation. The resulting radiomics scores (RScores) were dichotomized per their median and entered in multivariate Cox models for predicting metastatic relapse-free survival. Models were compared with integrative area under the curve (AUC) and concordance index. RESULTS: Only dichotomized RScores from models based on rRFs subset, all rRFS and irRFS correlated with prognostic (P = 0.0107-0.0377). The models including all rRFs and irRFs had the highest c-index (0.83), followed by the radiological model. The radiological model had the highest integrative AUC (0.87), followed by models including all rRFs and irRFs. The radiological and full rRFs models were significantly better than the T2 -based radiomics model (P = 0.02). DATA CONCLUSION: The initial DCE-MRI of STS contains prognostic information. It seems more relevant to make predictions on rRFs instead of pRFs. Evidence Level: 3 Technical Efficacy: 3 J. Magn. Reson. Imaging 2020;52:282-297.
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Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia , Sarcoma , Adulto , Humanos , Prognóstico , Estudos Retrospectivos , Sarcoma/diagnóstico por imagemRESUMO
OBJECTIVE: The strongest adverse prognostic factor in myxoid/round cell liposarcomas (MRC-LPS) is the presence of a round cell component above 5% within the tumor bulk. Its identification is underestimated on biopsies and in the neoadjuvant setting. The aim was to improve the prediction of patients' prognosis through a radiomics approach. METHODS: Thirty-five out of 89 patients with MRC-LPS managed at our sarcoma reference center from 2008 to 2017 were included in this IRB-approved retrospective study as they presented with a pre-treatment contrast-enhanced MRI (median age, 49 years old). Two radiologists reported usual conventional/semantic radiological variables. After signal intensity (SI) normalization, voxel size standardization of T2-WI, and whole tumor volume segmentation, 44 3D-radiomics features were extracted. Using least absolute shrinkage and selection operator penalized Cox regression on prefiltered features, a radiomics score based on 3 weighted radiomics features was generated. Four prognostic multivariate models for MRFS were compared using concordance index: (1) clinical model, (2) semantic radiological model, (3) radiomics model, and (4) radiomics + semantic radiological model. RESULTS: Twelve patients showed a metastatic relapse. The radiomics score included FOS_Skewness, GLRLM_LRHGE, and SHAPE_Volume and correlated with MRFS (hazard ratio = 19.37, p = 0.0009) and visual heterogeneity on T2-WI (p < 0.0001). A high score indicated a poorer prognosis. After adjustment, the best predictive performances were obtained with model (4) (concordance index = 0.937) and the lowest with model (1) (concordance index = 0.637). CONCLUSION: Adding selected radiomics features that quantify tumor heterogeneity and shape at baseline to a conventional radiological analysis improves prediction of MRC-LPS patients' prognosis. KEY POINTS: ⢠Fourteen radiomics features quantifying shape and heterogeneity of myxoid/round cell liposarcomas on T2-WI were associated with metastatic relapse in univariate analysis. ⢠A radiomics score based on 3 selected and weighted radiomics features was a strong and independent prognostic factor for metastatic relapse-free survival. ⢠The best prediction of metastatic relapse-free survival for myxoid/round cell liposarcomas was achieved by combining the radiomics score to relevant radiological features.
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Lipossarcoma Mixoide/diagnóstico , Imageamento por Ressonância Magnética/métodos , Recidiva Local de Neoplasia/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Humanos , Lipossarcoma Mixoide/secundário , Lipossarcoma Mixoide/terapia , Extremidade Inferior , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Metástase Neoplásica , Prognóstico , Recidiva , Estudos Retrospectivos , Neoplasias de Tecidos Moles , Carga TumoralRESUMO
OBJECTIVE. The response of desmoid tumors (DTs) to chemotherapy is evaluated with Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in daily practice and clinical trials. MRI shows early change in heterogeneity in responding tumors due to a decrease in cellular area and an increase in fibronecrotic content before dimensional response. Heterogeneity can be quantified with radiomics. Our aim was to develop radiomics-based response criteria and to compare their performances with clinical and radiologic response criteria. MATERIALS AND METHODS. Forty-two patients (median age, 38.2 years) were included in this retrospective multicenter study because they presented with progressive DT and had an MRI examination at baseline, which we refer to as "MRI-0," and an early MRI evaluation performed after the first chemotherapy cycle (mean time after first chemotherapy cycle, 3 months [SD, 28 days]), which we refer to as "MRI-1." After signal intensity normalization, voxel size standardization, discretization, and segmentation of DT volume on fat-suppressed contrast-enhanced T1-weighted imaging, 90 baseline and delta 3D radiomics features were extracted. Using cross-validation and least absolute shrinkage and selection operator-penalized Cox regression, a radiomics score was generated. The performances of models based on the radiomics score, modified Response Evaluation Criteria in Solid Tumors, European Association for the Study of the Liver criteria, Cheson criteria, Choi criteria, and revised Choi criteria from MRI-0 to MRI-1 to predict progression-free survival (PFS, as defined by RECIST 1.1) were assessed with the concordance index. The results were adjusted for performance status, tumor volume, prior chemotherapy, current chemotherapy, and ß-catenin mutation. RESULTS. There were 10 cases of progression. The radiomics score included four variables. A high score indicated a poor prognosis. The radiomics score independently correlated with PFS (adjusted hazard ratio = 5.60, p = 0.003), and none of the usual response criteria independently correlated with PFS. The prognostic model based on the radiomics score had the highest concordance index (0.84; 95% CI, 0.71-0.96). CONCLUSION. Quantifying early changes in heterogeneity through a dedicated radiomics score could improve response evaluation for patients with DT undergoing chemotherapy.
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Fibromatose Agressiva/diagnóstico por imagem , Fibromatose Agressiva/tratamento farmacológico , Imageamento por Ressonância Magnética , Adulto , Progressão da Doença , Feminino , França , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Valor Preditivo dos Testes , Prognóstico , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Aprendizado de Máquina SupervisionadoRESUMO
BACKGROUND: Desmoid tumours are locally aggressive tumours associated with substantial morbidity. No systemic treatments are approved for this disease, with methotrexate-vinblastine the only chemotherapy regimen assessed in a clinical trial setting to date. VEGF overexpression is a common feature in aggressive desmoid tumours. Pazopanib is an oral antiangiogenic agent targeting VEGF receptors 1, 2, and 3, platelet-derived growth factor receptor-like protein (PDGFR) α and ß, and c-KIT tyrosine kinases. We aimed to assess antitumour activity and safety of targeted therapy or combination chemotherapy in progressive desmoid tumours. METHODS: DESMOPAZ was a non-comparative, randomised, open-label, phase 2 trial conducted at 12 centres from the French Sarcoma Group. We enrolled adults (≥18 years) with progressive desmoid tumours, normal organ function and centrally documented progressive disease according to Response Evaluation Criteria in Solid Tumors version 1.1 based on two imaging assessments obtained within less than a 6-month interval. Participants were randomly assigned (2:1) to oral pazopanib 800 mg per day for up to 1 year or to an intravenous regimen combining vinblastine (5 mg/m2 per dose) and methotrexate (30 mg/m2 per dose), administered weekly for 6 months and then every other week for 6 months. Randomisation was stratified according to inclusion centre and tumour location. The primary endpoint was the proportion of patients who had not progressed at 6 months in the first 43 patients who had received one complete or two incomplete cycles of pazopanib. This endpoint was also assessed as a prespecified exploratory endpoint in all patients who had received one complete or two incomplete cycles of methotrexate-vinblastane. Safety analyses were done for all patients who received at least one dose of allocated treatment. This trial was registered with ClinicalTrials.gov, number NCT01876082. FINDINGS: From Dec 4, 2012, to Aug 18, 2017, 72 patients were enrolled and randomly assigned (n=48 in the pazopanib group; n=24 in the methotrexate-vinblastine group). Median follow-up was 23·4 months (IQR 17·1-25·5). 46 patients in the pazopanib group and 20 patients in the methotrexate-vinblastine group were assessable for activity. In the first 43 patients assessable for the primary endpoint in the pazopanib group, the proportion of patients who had not progressed at 6 months was 83·7% (95% CI 69·3-93·2). The proportion of patients treated with methotrexate-vinblastine who had not progressed at 6 months was 45·0% (95% CI 23·1-68·5). The most common grade 3 or 4 adverse events in the pazopanib group were hypertension (n=10, 21%) and diarrhoea (n=7, 15%) and in the methotrexate-vinblastine group were neutropenia (n=10, 45%) and liver transaminitis (n=4, 18%). 11 patients (23%) had at least one serious adverse event related to study treatment in the pazopanib group, as did and six patients (27%) in the methotrexate-vinblastine group. INTERPRETATION: Pazopanib has clinical activity in patients with progressive desmoid tumours and could be a valid treatment option in this rare and disabling disease. FUNDING: GlaxoSmithKline and Novartis.
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Fibromatose Agressiva/tratamento farmacológico , Metotrexato/administração & dosagem , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Vimblastina/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Fibromatose Agressiva/patologia , Humanos , Indazóis , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Vimblastina/efeitos adversos , Adulto JovemRESUMO
Background Managing soft-tissue sarcoma (STS) relies on histologic grade, which is the strongest prognostic factor and a routine assessment at biopsy. However, underestimation of histologic grade may occur because of tumor heterogeneity. Purpose To identify MRI features that are associated with high-grade STS (grade III) and to determine the relationship between MRI features and patient survival. Materials and Methods In this retrospective single-center study, patients (age ≥16 years) were included if they presented with STS diagnosed between 2008 and 2015, had a baseline contrast material-enhanced MRI study, had a pathologic grade assessed on the whole surgical specimen, and had no history of neoadjuvant treatment. Visceral sarcomas, well-differentiated liposarcomas, and angiosarcomas were excluded. Images were evaluated for size, heterogeneity, architecture, margins, and surrounding tissue at T2-weighted, T1-weighted precontrast, and T1-weighted postcontrast MRI. χ2 tests, Fisher tests, and multivariable binary logistic regression were performed to identify features associated with a final grade of III. The associations between combinations of these features and overall survival and metastasis-free survival were investigated with Kaplan-Meier curves and multivariable Cox models. Results A total of 130 patients were included (53 women [mean age ± standard deviation, 60.7 years ± 19.2]); 72 of the 130 (55.4%) STSs were grade III. At multivariable analysis, three MRI features were associated with grade III STS: peritumoral enhancement (odds ratio [OR], 3.4; P = .003), presence of an area compatible with necrosis (OR, 2.4; P = .03), and heterogeneous signal intensities greater than or equal to 50% at T2-weighted imaging (OR, 2.3; P = .04). The presence of at least two of these three features was an independent predictor of metastasis-free survival (hazard ratio, 4.5; P = .01) and overall survival (hazard ratio, 4.2; P = .04). Conclusion MRI features including necrosis, heterogeneity, and peritumoral enhancement of soft-tissue sarcomas were associated with grade III tumors, metastasis-free survival, and overall survival. © RSNA, 2019 Online supplemental material is available for this article.
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Interpretação de Imagem Assistida por Computador/métodos , Gradação de Tumores/métodos , Sarcoma/diagnóstico por imagem , Neoplasias de Tecidos Moles/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sarcoma/mortalidade , Sarcoma/patologia , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/patologiaRESUMO
BACKGROUND: Evaluating heterogeneity in tumor vascularization through texture analysis could improve predictions of patients' outcome and response evaluation. PURPOSE: To investigate the influence of temporal parameters on texture features extracted from dynamic contrast-enhanced (DCE)-MRI parametric maps. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: Twenty-five adults with soft-tissue sarcoma (STS), median age: 68 years. FIELD STRENGTH/SEQUENCE: DCE-MRI acquisition using a CAIPIRINHA-Dixon-TWIST-VIBE sequence at 1.5T (temporal resolutions: 2 sec, duration: 5 min). ASSESSMENT: The area under time-intensity curve (AUC) and Ktrans maps were generated for several temporal resolution (dt = 2 sec, 4 sec, 6 sec, 8 sec, 10 sec, 12 sec, 20 sec) and scan durations (T = 3 min, 4 min, 5 min for a 6-sec sampling) by downsampling and truncating the initial DCE-MRI sequence. Tumor volume was manually segmented and propagated on all parametric maps. Thirty-two first- and second order-texture features were extracted per map to quantify the intratumoral heterogeneity. STATISTICAL TESTS: The influence of temporal parameters on texture features was studied with repeated-measures analysis of variance (or nonparametric equivalent). The dispersion of each texture feature depending on temporal parameters was estimated with coefficients of variation (CVs). The performances of multivariate models to predict the response to chemotherapy (ie, binary logistic regression based on the baseline texture features) were compared. RESULTS: The temporal resolution had a significant influence on 12/32 (37.5%) and 14/32 (43.8%) texture features evaluated on AUC and Ktrans maps, respectively (range of P < 0.0001-0.0395). Scan duration had a significant influence on 23/32 (71.9%) texture features from Ktrans map (range of P < 0.0001-0.0321). Dispersion was high (mean CV >0.5) with sampling for 2/32 (6.3%) and 10/32 (31.3%) features from AUC and Ktrans maps, respectively; and with truncating for 6/32 (18.8%) features from Ktrans map. The area under the receiver operating characteristics curve of predictive models ranged from 0.77 (95% confidence interval [CI] = [0.54-1.00], with dt = 6 sec T = 4 min) to 0.90 (95% CI = [0.74-1.00], with dt = 6 sec T = 5 min). DATA CONCLUSION: The values of texture features extracted from DCE-MRI parametric maps can be influenced by temporal parameters, which can lead to variations in performance of predictive models. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1773-1788.
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Meios de Contraste , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Neovascularização Patológica/diagnóstico por imagem , Sarcoma/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sarcoma/irrigação sanguínea , Sarcoma/patologia , Tempo , Carga TumoralRESUMO
BACKGROUND: Standard of care for patients with high-grade soft-tissue sarcoma (STS) are being redefined since neoadjuvant chemotherapy (NAC) has demonstrated a positive effect on patients' outcome. Yet response evaluation in clinical trials still relies on RECIST criteria. PURPOSE: To investigate the added value of a Delta-radiomics approach for early response prediction in patients with STS undergoing NAC. STUDY TYPE: Retrospective. POPULATION: Sixty-five adult patients with newly-diagnosed, locally-advanced, histologically proven high-grade STS of trunk and extremities. All were treated by anthracycline-based NAC followed by surgery and had available MRI at baseline and after two chemotherapy cycles. FIELD STRENGTH/SEQUENCE: Pre- and postcontrast enhanced T1 -weighted imaging (T1 -WI), turbo spin echo T2 -WI at 1.5 T. ASSESSMENT: A threshold of <10% viable cells on surgical specimens defined good response (Good-HR). Two senior radiologists performed a semantic analysis of the MRI. After 3D manual segmentation of tumors at baseline and early evaluation, and standardization of voxel-sizes and intensities, absolute changes in 33 texture and shape features were calculated. STATISTICAL TESTS: Classification models based on logistic regression, support vector machine, k-nearest neighbors, and random forests were elaborated using crossvalidation (training and validation) on 50 patients ("training cohort") and was validated on 15 other patients ("test cohort"). RESULTS: Sixteen patients were good-HR. Neither RECIST status (P = 0.112) nor semantic radiological variables were associated with response (range of P-values: 0.134-0.490) except an edema decrease (P = 0.003), although 14 shape and texture features were (range of P-values: 0.002-0.037). On the training cohort, the highest diagnostic performances were obtained with random forests built on three features: Δ_Histogram_Entropy, Δ_Elongation, Δ_Surrounding_Edema, which provided: area under the curve the receiver operating characteristic = 0.86, accuracy = 88.1%, sensitivity = 94.1%, and specificity = 66.3%. On the test cohort, this model provided an accuracy of 74.6% but 3/5 good-HR were systematically ill-classified. DATA CONCLUSION: A T2 -based Delta-radiomics approach might improve early response assessment in STS patients with a limited number of features. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:497-510.
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Quimioterapia Adjuvante , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Terapia Neoadjuvante , Sarcoma/diagnóstico por imagem , Sarcoma/tratamento farmacológico , Adulto , Idoso , Algoritmos , Antraciclinas/uso terapêutico , Área Sob a Curva , Reações Falso-Positivas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVES: SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS) is a recently identified aggressive subtype of sarcoma. The aim of this study was to characterize the CT imaging features of SMARCA4-DTS. METHODS: From June 2011 to May 2017, 21 adult patients with histologically proven SMARCA4-DTS were identified in the radiological database of 2 French sarcoma reference centers with at least one chest CT scan available. The locations, sizes, heterogeneity, margin definitions, and local extensions of the tumors were reported together with their impact on surrounding organs and regional and distant metastases. Pathological findings, molecular analyses, and patients' outcomes were retrieved. RESULTS: Of the 21 included patients (median age 48, range 30-74), 18 (85.7%) were male and 18 (85.7%) had a smoking history. Four main radiological patterns were identified depending on the location of the main tumor burden: mediastinal (n = 13), pleural (n = 6), cervical (n = 1), and retroperitoneal (n = 1). Median size was 120 mm (range 46-266). Characteristic CT imaging features of primary tumors included ill-defined margins (n = 21), heterogeneous enhancement after injection (n = 20), multi-compartment extension from mediastinum to lung apex, pleura, or neck (n = 20), compressive effect responsible for atelectasis (n = 11), vascular encasement (n = 16-5 superior vena cava syndrome), and esophagus invasion (n = 5). Primary tumors showed strong 18F-FDG avidity in eight patients with PET-CT. Necrotic lymphadenopathies were found in 19 patients, with a surrounding infiltrate in 13 patients. Metastatic locations at baseline mainly involved adrenal (n = 10), lung (n = 6), and bone (n = 5). Median overall survival was 5 months (range 1-13). CONCLUSION: Most SMARCA4-DTS present with compressive and infiltrative chest masses with ill-defined necrotic lymphadenopathies. The diagnosis of SMARCA4-DTS should enter in the differentials of the radiologist, especially in the case of a rapidly evolving thoracic mass in young smoking males. KEY POINTS: ⢠SMARCA4-DTS is a very aggressive poorly differentiated sarcoma with a predilection for young and middle-aged adult male smokers. ⢠SMARCA4-DTS, which is mostly located in the chest cavity, can compress and infiltrate all adjacent organs leading to superior vena syndrome, lung atelectasis, epiduritis, spinal cord compression, and esophagus invasion. ⢠SMARCA4-DTS typically demonstrates several ill-defined necrotic lymphadenopathies spreading in axillar, subclavian, cervical, mediastinum, and retroperitoneum.
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DNA Helicases/genética , Mutação , Proteínas Nucleares/genética , Sarcoma/diagnóstico por imagem , Sarcoma/genética , Neoplasias Torácicas/diagnóstico por imagem , Neoplasias Torácicas/genética , Fatores de Transcrição/genética , Adulto , Idoso , Feminino , Fluordesoxiglucose F18 , Humanos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Atelectasia Pulmonar/etiologia , Compostos Radiofarmacêuticos , Sarcoma/patologia , Síndrome da Veia Cava Superior/etiologia , Neoplasias Torácicas/complicações , Neoplasias Torácicas/patologia , Tomografia Computadorizada por Raios X , Carga Tumoral , Adulto JovemRESUMO
OBJECTIVES: To investigate the imaging features of alveolar soft-part sarcomas (ASPS) on pre-treatment MRI in order to identify relevant criteria to distinguish ASPS from other soft-tissue tumors. METHODS: A series of 25 patients (mean age, 18.5 years old) with histologically proven ASPS from five French comprehensive cancer centers was compared to a control cohort of 292 patients with various histologically proven benign and malignant soft-tissue tumors representative of the 10-year long activity of one center. All had a baseline MRI with contrast-agent administration. Two radiologists independently reviewed the MRIs. Features assessing location, size, signal, architecture, periphery, and vascularization were reported. Their association with the histological diagnosis of ASPS was evaluated with chi-square or Fisher's test. Their prevalence, sensitivity, specificity, odds ratio, and reproducibility were calculated. RESULTS: Eight MRI features were significantly associated with ASPS: deep location (p < 0.001), high signal intensities on T1-weighted imaging (p < 0.001), central area of necrosis (p = 0.001), absence of fibrotic component (p = 0.003), infiltrative growth pattern (p = 0.003), absence of tail sign (p = 0.001), presence of intra- and peritumoral flow-voids (p < 0.001), and number of flow-voids ≥ 5 (p < 0.001). Twenty out of the 25 (80%) ASPS showed at least 7 of these 8 features compared to only four out of 292 (1.4%) tumors of the control cohort (1 benign vascular tumor, 1 solitary fibrous tumor, 2 high-grade soft-tissue sarcomas). The five ASPS with less than 7 out of 8 features measured less than 40 mm. CONCLUSION: The striking histological uniformity of ASPS translates into imaging. However, ASPS may be misdiagnosed as benign tumors or pseudo-tumors, notably intramuscular benign vascular tumors or vascular malformations. KEY POINTS: ⢠ASPS are rare aggressive mesenchymal tumors displaying recurrent MRI features highly reminiscent of the diagnosis. ⢠Deep-seated tumors presenting with mainly high signal intensity on T1-weighted imaging, an absence of fibrotic component, ill-defined margins without aponeurotic extension, and more than five central and peripheral flow-voids are very likely to be ASPS. ⢠ASPS may be misdiagnosed as intramuscular benign vascular tumor or vascular malformation, which occur in the same age group.
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Imageamento por Ressonância Magnética/métodos , Sarcoma Alveolar de Partes Moles/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , França/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sarcoma Alveolar de Partes Moles/epidemiologia , Neoplasias de Tecidos Moles/epidemiologia , Adulto JovemRESUMO
OBJECTIVES: To determine the acquisition delay after gadolinium-chelate injection that optimizes the prediction of the histological response during anthracycline-based neoadjuvant chemotherapy (NAC) for locally advanced high-grade soft-tissue sarcomas (STS). METHODS: Thirty patients (mean age 62 years) were included in this IRB-approved study. All patients received 5-6 cycles of NAC followed by surgery. A good response was defined as ≤ 10% viable cells on histological analysis of the surgical specimen. DCE-MRI was performed before treatment (MRI0) and after two cycles (MRI1). Images were obtained every 8 s. Change in contrast enhancement (CE) between MRI0 and MRI1 was calculated for each acquisition delay 't' on the whole tumor volume. Area under the receiver-operating characteristics curves (AUROC) for change in CE was calculated at each acquisition delay, as well as the accuracy of the Choi criteria. RESULTS: There were 22 (73.3%) poor responders. Acquisition delay had a significant effect on change in CE and on the response status according to Choi (p = 0.0014 and 0.0270, respectively). The highest AUROC was obtained at t = 58 s (0.792) with an optimal threshold of a -30.5% decrease in CE. At t = 58 s, accuracy to predict a poor response was 82.8% above this threshold, while it was 72.4% and 70% with no objective response according to the Choi criteria and RECIST1.1, respectively. CONCLUSION: Optimization of acquisition delay after injection to estimate change in CE improves the prediction of histological response. For STS undergoing NAC, a 60-s delay can be recommended with MRI. KEY POINTS: ⢠Accuracy of response criteria based on contrast enhancement, like the Choi criteria, is dependent on the acquisition delay after gadolinium-chelate injection. ⢠DCE-MRI helps determine the optimal acquisition delay after gadolinium-chelate injection for improving evaluation of tumor response. ⢠In soft tissue sarcoma, an acquisition delay at 60 s optimizes the evaluation of the response and accuracy of the Choi criteria.
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Sarcoma/diagnóstico por imagem , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/diagnóstico por imagem , Neoplasias de Tecidos Moles/tratamento farmacológico , Adulto , Idoso , Antraciclinas/uso terapêutico , Área Sob a Curva , Quimioterapia Adjuvante/métodos , Meios de Contraste , Feminino , Gadolínio , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Curva ROC , Estudos Retrospectivos , Sarcoma/patologia , Fatores de Tempo , Resultado do TratamentoRESUMO
We report the first case of sarcoidosis-like reaction in a patient treated by anti-PD-L1 for a breast cancer. A 69-year-old woman presented with a histologically confirmed lung metastasis of a triple negative breast cancer. She was treated by nab-paclitaxel plus anti-PD-L1 in first line. After 2 months, a dramatic lung response was noticed but an involvement of mediastinal lymph nodes appeared. Endoscopic ultrasound-guided fine-needle aspiration of these lymph nodes revealed multiple epitheloid granulomas without caseating necrosis in favour of a sarcoidosis-like reaction. The patient remained free of symptom and in complete lung response on anti-PD-L1 treatment as a maintenance therapy.