The purpose was to describe first and subsequent relapses in patients from the OS2006/Sarcome-09 trial, to help future trial design. We prospectively collected and analysed relapse data of all French ...patients included in the OS2006/Sarcome-09 trial, who had achieved a first complete remission. 157 patients experienced a first relapse. The median interval from diagnosis to relapse was 1.7 year (range 0.5-7.6). The first relapse was metastatic in 83% of patients, and disease was not measurable according to RECIST 1.1 criteria in 23%. Treatment consisted in systemic therapy (74%) and surgical resection (68%). A quarter of the patients were accrued in a phase-II clinical trial. A second complete remission was obtained for 79 patients. Most of them had undergone surgery (76/79). The 3-year progression-free and overall survival rates were 21% and 37%, respectively. In patients who achieved CR2, the 3y-PFS and OS rates were 39% and 62% respectively. Individual correlation between subsequent PFS durations was poor. For osteosarcoma relapses, we recommend randomised phase-II trials, open to patients from all age categories (children, adolescents, adults), not limited to patients with measurable disease (but stratified according to disease status), with PFS as primary endpoint, response rate and surgical CR as secondary endpoints.
Asf1 is a conserved histone chaperone implicated in nucleosome assembly, transcriptional silencing, and the cellular response to DNA damage. We solved the NMR solution structure of the N-terminal ...functional domain of the human Asf1a isoform, and we identified by NMR chemical shift mapping a surface of Asf1a that binds the C-terminal helix of histone H3. This binding surface forms a highly conserved hydrophobic groove surrounded by charged residues. Mutations within this binding site decreased the affinity of Asf1a for the histone H3/H4 complex in vitro, and the same mutations in the homologous yeast protein led to transcriptional silencing defects, DNA damage sensitivity, and thermosensitive growth. We have thus obtained direct experimental evidence of the mode of binding between a histone and one of its chaperones and genetic data suggesting that this interaction is important in both the DNA damage response and transcriptional silencing.
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11507
Background: PD1 inhibition has shown limited activity in all comers clinical trials including patients with advanced soft-tissue sarcomas (STS). In the PEMBROSARC study, objective ...response rate, progression-free (PFS) and overall survival (OS) were respectively 2.1%, 1.4 and 7.1 months respectively (Toulmonde et al. Jama Oncol 2017). We have recently shown that the presence of tertiary lymphoid structures (TLS) may represent a biomarker to select patients who are more likely to benefit from immunotherapy (PetitPrez et al., Nature 2020). We report here the first clinical trial investigating the efficacy of PD1 inhibition in TLS-positive STS. Methods: PEMBROSARC is an open-label multicenter phase II study of pembrolizumab in combination with low-dose cyclophosphamide in pts with STS selected based on the presence of TLS. TLS status has been assessed centrally has previously described (PetitPrez et al., Nature 2020). Eligible patients received pembrolizumab 200mg IV q21 days and cyclophosphamide 50 mg BID 1week on, 1 week off. All patients had confirmed progressive disease at inclusion based on central review of two imaging performed at less than 6 months interval. The primary efficacy endpoint was 6-month non-progression (as per RECIST evaluation criteria v1.1). Based on the following hypotheses: 15% 6-month non-progression rate (H0), 40% acceptable 6-month non-progression rate (H1), 5% type I error rate, 90% power, a total of 29 assessable patients were necessary and 8 patients or more had to be progression-free at 6 months to reach the first endpoint. Results: 240 patients were screened for TLS status between September 2018 and January 2020 in 7 centers of the French Sarcoma Group. Among them, 48 were found to be TLS+ as per central review and 35 were included in the study. The three most frequent histological subtypes were: well-differentiated/dedifferentiated liposarcoma (n = 13); UPS (n = 6), and leiomyosarcoma (n = 4). 30 patients were eligible for efficacy. Of those, as per central imaging review, 13 patients (43.3%) had tumor shrinkage resulting in partial response in 8 patients (26.7%) and stable disease in 5 cases (16.7%). 10 patients had progressive disease. Twelve patients were progression-free at 6 months (40.0% 95%CI = 22.7 – 59.4).Median PFS and OS were 4.1 months (95%CI, 1.4-9.6) and 14.5 months (95%CI, 8.5- 18.3 months), respectively. Conclusions: With an objective response and a 6-month non-progression rates of 26.7% and 40% respectively versus 2.1% and 4.2% in all comers, the PEMBROSARC study confirms that selection based on TLS status is an efficient approach to tailor immunotherapy in STS patients. Clinical trial information: NCT02406781.
Summary
Factor XI (FXI)‐deficient patients may develop excessive bleeding after trauma or surgery. Replacement therapy should be considered in high‐risk situations, especially when FXI levels are ...below 20 IU dL−1. HEMOLEVEN is a human plasma‐derived factor XI concentrate available in France since 1992, but there are few data regarding its use by physicians. This prospective study assessed the use, efficacy and safety of HEMOLEVEN in common clinical practice. HEMOLEVEN was evaluated in FXI‐deficient patients in 13 French centres in a 3‐year postmarketing study. Forty‐four patients (30 females, 14 males) received 67 treatments. The median age was 37 years (8 months–91 years). Basal FXI levels were <1 to 51 IU dL−1 (median: 5.5); 29 patients were severely FXI‐deficient (<20 IU dL−1). FXI was administered prophylactically before 43 surgical procedures, 10 invasive procedures, 8 vaginal deliveries, or as curative treatment for six bleeds. The efficacy was assessed as excellent/good in 63, moderate in two and undetermined in two treatments. Seven patients experienced seven adverse effects, including two rated as serious: one sudden massive pulmonary embolism with fatal outcome and one case of inhibitor to FXI. HEMOLEVEN is effective for bleeding prevention in FXI deficiency. However, considering the benefit/risk ratio observed in relation to dosage in this study; firstly, it should be used sparingly due to its potential prothrombotic effect; secondly, new prescription procedures should be defined to adapt the dosage, especially in patients with intrinsic and/or acquired risk factors for thrombosis.
Five‐year overall survival (OS) of localized RMS exceeds 70% in children (<18) but is very poor in adult patients. We analyzed the outcome and prognostic factors (PF) of a national series of adult ...patients with RMS in a large study. The study population consisted of two different cohorts: a retrospective cohort (157 adult patients treated in 13 reference centers between 05/1981 and 02/2010) and the prospective cohort (292 patients with RMS diagnosed and treated between 01/2010 and 12/2014 in France) included in the NetSarc database. A descriptive analysis of patients’ characteristics and prognostic factors was conducted on both series which were compared. In the retrospective series, histological subtypes were embryonal (E‐RMS) for 21% of patients, alveolar (A‐RMS) for 35% of patients, and “adult‐type” P‐RMS (pleomorphic, spindle cell RMS, not otherwise specified) (P) for 44% patients. This distribution significantly differed in the prospective cohort: A‐RMS: 18%; E‐RMS: 17%; and P‐RMS 65%. With a median follow‐up of 8.5 years, 5‐year OS for localized RMS and advanced RMS (with nodes and/or metastases) was 43% and 5%, respectively, (P < 0.0001), and median OS was 51, 33, and 16 months for E‐RMS, A‐RMS, and P‐RMS, respectively, in the retrospective cohort. The median OS was less than 40 months for the prospective nationwide cohort for the entire population. In a multivariate analysis of the retrospective study, independent prognostic factors for OS were A‐RMS, R0 resection, and adjuvant radiotherapy (RT). For localized RMS, age and use of pediatric chemotherapy (CT) regimen are independent prognostic factors. Adult patients with RMS have a poorer overall survival than pediatric patients, and survival varies considerably across histological subtypes.
This is the largest study analyzing all factors in univariate analysis and multivariate analysis for localized and metastatic isease and for each histological subtype. Specific management for A‐RMS and E‐RMS using a pediatric protocol chemotherapy and carcinologic surgery is the cornerstone to improving survival. The FSG experience emphasizes the urgent need to build a worldwide clinical trial using these rare entities that exhibit a dismal prognosis.
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TPS11078
Background: We have recently identified a gene expression signature so called “CINSARC” which is related with chromosomal instability and highly predictive of metastasis-free ...and overall survival in soft-tissue sarcoma (STS) patients. The prognostic relevance of this signature has been validated recently in an independent set of sarcomas from the Cancer Genome Atlas (TCGA) consortium. Despite optimal locoregional treatment, patients with high-risk CINSARC have a very poor outcome.However, the main issues with peri-operative chemotherapy in STS patients are the identification of patients who are more likely to benefit from this approach and the characterization of the best chemotherapy regimen. Indeed, in all clinical trials investigating peri-operative chemotherapy in STS, patients were included on the basis of classical histological criteria (grade, tumor size, deep location). The CINSARC is more discriminant than grade to evaluate the prognosis of STS patients (35% of grade 3 are low-risk CINSARC and 40% of grade are high-risk CINSARC). We hypothesize than: (1) 6 cycles of anthracyclines-ifosfamide is associated with improved outcome in comparison to 3 cycles of chemotherapy (ISG-STS 10-01) in patients with high-risk CINSARC STS; (2) Chemotherapy-free strategy is not associated with detrimental outcome in low-risk CINSARC STS. Methods: This is a multicenter phase III trial (sponsor: Institut Bergonié) which aims to evaluate the efficacy (intent-to-treat analysis) of 6 cycles of neoadjuvant doxorubicin + ifosfamide based chemotherapy+ surgery +/-radiotherapy (Arm B) in comparison with 3 cycles of neoadjuvant doxorubicin + ifosfamide based chemotherapy + surgery +/- radiotherapy (Arm A) in terms of 3-year progression-free survival (PFS) in high-risk CINSARC patients with resectable STS. Patients with low-risk CINSARC signature will be treated at investigator discretion. 334 patients will have to be recruited over 36 months in 10 centers of the French Sarcoma Group. This is the first study assessing the impact of peri-operative chemotherapy in STS based on a prognostic molecular signature. The study is open for accrual at time of submission. Clinical trial information: NCT03805022.
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e23537
Background: R0 surgery in reference centers is the cornerstone for sarcomas treatment with better local control and survival and is mandatory for ESMO-EURACAN and NCCN ...guidelines. The medical community is out on this issue for cutaneous sarcomas, if they have to follow suit. This retrospective descriptive study focused on margin status and local relapse-free survival (LRFS) and overall survival (OS) of patients (pts) with cutaneous sarcomas. Methods: Between 01/01/10 and 30/12/17, surgery was performed on 2044 pts with cutaneous sarcomas from 20 centers. Data were collected from the NETSARC national network database ( http://netsarc.sarcomabcb.org ). Diagnosis of cutaneous sarcoma was reviewed and histologically confirmed by a local expert pathologist of RRePS (“Network for expert pathology diagnosis in sarcoma”). Dermatofibrosarcoma, Kaposi sarcoma and rare subtypes (< 20 cases in the database) were excluded. Univariate analyses were conducted using log rank test or Cox test. Multivariate analyses were conducted using Cox test. Age and tumor size were analyzed as continuous values. Two-sided significant p level was set at < 0.05. Results: Mean age was 66 years. Primary tumor was localized in lower limb, trunk wall, head and neck and upper limb for 30%, 26%, 26% and 18% pts respectively. Main subtypes were leiomyosarcoma, undifferentiated sarcoma, and myxofibrosarcoma for 29%, 29%, and 14% pts respectively. Angiosarcoma was the subtype of 9% of the patients (n = 193). Mean size was 45 mm. FNCLCC grade was 1, 2, and 3 for 14%, 29.5%, and 24% tumors respectively. Before surgery, imaging and biopsy were performed for 21% and 51% pts respectively. Surgery was carried out in a NETSARC center for 26% of the pts. Margin status after initial surgery was R0, R1, and R2 for 35% (n = 724), 34% (n = 696), and 12% pts (n = 246) respectively. Re-excision was performed for 34% (703/2044 pts), leading to a subsequent R0 margin for 74% of them (523/703 pts, equivalent to 26% of the overall population). Local relapse occurred for 21% of pts after a median time of 10 months. Metastatic relapse occurred for 13% of pts after a median time of 11 months. One hundred and ninety-three pts (9%) died. Median follow-up was 12 months. In multivariate analyses, statistically significant favorable prognostic factors for LRFS were: young age, small tumor size and non-angiosarcoma subtype. Significant prognostic factors associated with longer OS were: young age, small tumor size, non-angiosarcoma subtype, FNCLCC grade (1 vs 2 and 1 vs 3) and initial R0 surgery. Conclusions: Cutaneous sarcomas share same favorable clinical prognostic factors than non-cutaneous sarcomas. Quality of surgery remains the mainstay for OS.
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TPS11576
Background: Pts with OS and non-OS of bone are treated with a multimodal sequence therapy of neoadjuvant chemotherapy (CT), surgery and adjuvant CT, followed by a close ...surveillance until recurrence. At recurrence, the prognosis remains poor with objective response rates of 3-29%, and a median Progression-Free Survival (PFS) of less than 4 months in OS. There is a clinical need to reduce the risk of recurrence after the initial treatment sequence. The REGOBONE study reported a significant clinical benefit of regorafenib compared to placebo in patients with relapsed OS (median PFS: 16.4 versus 4.1 weeks). Methods: This multicenter trial is ongoing to study the efficacy and safety of maintenance REGO in pts > = 16 years, with complete remission after initial treatment sequence of their bone sarcoma. 168 pts will be randomly allocated in a 1:1 ratio to receive either oral REGO or its matching placebo (control arm) at a daily dose of 120mg, continuously and for a maximum of 12 months. Randomization will be stratified according to the following risk factors: metastases (mets) at diagnosis and/or poor response to neoadjuvant CT versus no mets at diagnosis and good response to neoadjuvant CT. The primary objective is to compare the efficacy (Relapse-Free Survival) between the 2 arms. The expected 3-year RFS rates are 55% in the control arm and 74.6% in the REGO arm (HR = 0.5). 66 events will provide 80% power to show significant improvement in RFS, using a 2-sided log-rank test at a 5% level. Secondary endpoints include Time to Treatment Failure, Overall Survival, Quality of Life, safety profile, and compliance to treatment. Radiological endpoints will be evaluated using the RECIST 1.1. Translational objectives will be to identify predictive biomarkers for efficacy of REGO as maintenance therapy using liquid biopsies. As of Feb 1st, 2021, 3 patients have been randomized. 15 sites of the French Sarcoma Group will participate. Clinical trial information: NCT04055220.
Desmoid type fibromatosis (DTF) are rare intermediate malignancies with unpredictable outcome. Series containing children and young adults (YA) are lacking.
The aim of this retrospective study was to ...describe the French population of patients<40 years with DTF diagnosed between 2006 and 2017.
Eighty-three children and 881 YA (18–39 years) were included (sex ratio M/F 1.3 and 0.25, respectively). Locations were abdominal wall (40.8%), trunk (23.5 %), extremities (19 %), mesentery (13.5 %) and head and neck (HN) (3.2 %).
Tumors were larger in children (7 vs 5.5 cm for YA, p < 0.001), and more frequently located in the abdomen and mesentery in YA (p < 0.001). Patients with Familial Adenomatous Polyposis condition (5.3 % of the cases) were three times more frequent in the multifocal DTF group, and in mesenteric primary (p < 0.001).
First-line strategy for 548 patients was: surgery (289 patients), active surveillance (AS, 189 patients), medical treatment (57 patients), other local treatment (radio/cryotherapy, 7 patients), or the combination of several active treatments (6 patients).
The 2-year progression free survival (PFS) rate for the whole cohort was 68.3 %, better for YA (69.2 %) than for children (59.5 %, p = 0.0106). Among 548 informative patients, AS was associated with a better PFS (HR = 0.558) and the only variables associated with worse PFS in multivariate analysis were tumor size ≥ 5 cm (HR = 1.785) and location in the extremities (HR = 1.934) or trunk (HR=1.598).
Clinical DTF presentation is more aggressive in children than YA. AS seems to be a valid first-line option preventing overtreatment, and local progression is linked to size and location, regardless of age.
•Clinical DTF presentation is more aggressive in children than young adults.•DTF were larger in children.•DTF were more frequently located in the abdomen and mesentery in young adults.•Active Surveillance seems to be a valid first-line option preventing overtreatment.•Progression is linked to size and location (extremities and trunk), regardless of age.