The role of both hormonal contraception and pregnancy on the outcomes of desmoid-type fibromatosis (DF) is debatable.
In the present study, we selected female patients of childbearing age from the ...prospective ALTITUDES cohort. The primary study endpoint was event-free survival (EFS), with an event defined as relapse or progression. We estimated the risk of events according to the use of hormonal contraception estrogen–progestin (EP) and progestin and pregnancy status using multivariate time-dependent models, controlling for major confounders.
A total of 242 patients (median age, 34.7 years) were included in the present study. The abdominal wall was the most common tumor site (51%). Patients were managed by active surveillance (80%) or surgery (20%). Pregnancy occurred within 24 months before, at the time of, and after DF diagnosis in 33%, 5%, and 10% of the cases, respectively. Exposure to hormonal contraception was documented within 24 months before, at the time of, and after diagnosis in 44%, 34%, and 39% of the cases, respectively. The 2-year EFS was 75%. After adjusting for DF location, tumor size, front-line treatment strategy, and hormonal contraception, we observed an increased risk of events occurring at 24 months after pregnancy hazard ratio (HR) = 2.09, P = 0.018. We observed no statistically significant association between the risk of events and current EP exposure (HR = 1.28, P = 0.65), recent EP exposure (within 1-24 months, HR = 1.38, P = 0.39), current progestin exposure (HR = 0.81, P = 0.66), or recent progestin exposure (HR = 1.05, P = 0.91).
In our study, a recent history of pregnancy was associated with an increased risk of progression/relapse in patients with newly diagnosed DF, whereas hormonal contraception did not demonstrate an association with progression/relapse.
•The role of hormonal contraception or pregnancy on DF outcomes is debatable.•We estimated the risk of progression or relapse according to the use of hormonal contraception and pregnancy status.•We found that recent exposure to hormonal contraception was not associated with DF outcomes.•A recent pregnancy was associated with a statistically significant increase in progression/relapse.•Abdominal wall DF outcomes showed similar findings as other DF outcomes.
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11506
Background: U-LMS and ST-LMS are rare tumors with poor prognosis when locally advanced or metastatic, and with moderate chemosensitivity. Overall response rates (ORR) given in the ...1
st
-line setting do not exceed 50% for U-LMS and 35% for ST-LMS with a mean response duration of 3- 6 months without impact on overall survival (OS). In 2015 we reported very encouraging results of the LMS-02 study (NCT02131480) with ORR of 59.6% in U-LMS, and 39.3% in ST-LMS with manageable toxicity (Pautier; Lancet oncol 2015). Herein, we report the updated results of progression-free survival (PFS) and final results of overall survival (OS). Methods: Patients (pts) received 60 mg/m² intravenous Doxo followed by trabectedin 1.1 mg/m
2
as a 3-hour infusion on Day 1 and pegfilgrastim on Day 2, repeated every 3 weeks for up to 6 cycles. Surgery for residual disease was permitted. Patients were stratified into U-LMS and ST-LMS groups. Results: Overall, 108 patients with LMS with a median age of 59 years and mostly metastatic disease (85%) were enrolled. Of those, 77 patients (71.3%) have received all 6 cycles of treatment, and 20 patients (18.5%) had metastasis resection. With a median follow-up of 7.2 years (95% CI: 6.9 - 8.2), the overall median PFS was 10.1 months (95% CI: 8.5 - 12.6), being 8.3 months (95 CI: 7.4 - 10.3) and 12.9 months (95% CI: 9.2 - 14.1) in U and ST group, respectively. Median OS was 34.4 months (95% CI: 26.9 - 42.7), being 27.5 months (95% CI: 17.9 - 38.2) in U-LMS and 38.7 months (95% CI: 31.0 - 52.9) in ST-LMS group. The median OS among the 20 pts with surgery was not reached vs 31.6 months in the population without surgery (95% IC: 23.9 - 35.4). Conclusions: The Doxo +Trab combination is an effective 1st-line therapy for pts with LMS, with promising PFS and OS results and an acceptable safety profile. Merely for comparison, the most recent results of Doxo alone in metastatic LMS, given in 1st-line setting in a phase III ANNOUNCE trial conducted during the same period, reported median PFS of 6.9 months, and median OS of 21.9 months (ASCO 2019 LBA3). Results of the LMS04 trial (NCT02997358), a randomized phase III study comparing this combination vs Doxo alone in 1st-line therapy in metastatic LMS are pending. Clinical trial information: NCT02131480 .
Abstract
Background
API Generation Program evaluated the effectiveness of the BACE1 inhibitor umibecestat and the active immunotherapy CAD106 in delaying the onset of AD symptoms in APOE4 carriers. ...Data from imaging (vMRI and PET scans), and fluid biomarkers (blood and CSF) were collected during the 12‐week Screening phase. In this presentation, we will summarize results across the two studies and investigate the relationships between the various biomarkers and key baseline characteristics.
Method
Amyloid levels were assessed via CSF and/or Amyloid PET scan in both studies for the APOE4 carriers. Generation Study 2 enrolled heterozygotes based on the following elevated amyloid inclusion criteria: Roche Elecsys® CSF p‐Tau/Abeta42 ratio > 0.024 and/or PET scans with any of the 3 amyloid F
18
tracers (florbetapir, flutemetamol or florbetaben). If the centralized visual read of PET scan was negative, the SUVr was calculated (cortical composite in reference to whole cerebellum) for the three tracers in order to assess borderline cases. Thresholds for amyloid positivity equivalent to SUVR of 1.1 with florbetapir were used for the final decision on inclusion.
Result
Across both studies, over 500 lumbar punctures, 2700 amyloid PET scans and about 150 tau PET scans (conducted using flortaucipir) were performed. In Generation Study 1, over 200 FDG PET scans were also performed. Participants underwent amyloid testing during screening, blood sampling (plasma and serum) and underwent MRI scans for safety and to measure brain volumes. All baseline biomarker data will be presented, including available concentrations from CSF Tau/p‐Tau/Aβ42/Aβ40 along with the eligibility ratio for pTau/ab42. In about 150 participants, concordance between elevated/non elevated amyloid status by CSF and PET (using centiloids) will be shown. Baseline brain volume (whole brain and hippocampus) will be summarized for the different co‐variates (age, sex, cognition, genotype and amyloid status). Correlations among the various fluid biomarkers and imaging will be discussed.
Conclusion
These data describe the biomarker signature of the world’s largest cohort of cognitively unimpaired APOE4 carriers with and without elevated amyloid. The anonymized study data, biomarker samples as well as images collected will be shared with the scientific community after study completion and reporting. ELECSYS is a registered trademark of Roche.
Background
API Generation Program evaluated the effectiveness of the BACE1 inhibitor umibecestat and the active immunotherapy CAD106 in delaying the onset of AD symptoms in APOE4 carriers. Data from ...imaging (vMRI and PET scans), and fluid biomarkers (blood and CSF) were collected during the 12‐week Screening phase. In this presentation, we will summarize results across the two studies and investigate the relationships between the various biomarkers and key baseline characteristics.
Method
Amyloid levels were assessed via CSF and/or Amyloid PET scan in both studies for the APOE4 carriers. Generation Study 2 enrolled heterozygotes based on the following elevated amyloid inclusion criteria: Roche Elecsys® CSF p‐Tau/Abeta42 ratio > 0.024 and/or PET scans with any of the 3 amyloid F18 tracers (florbetapir, flutemetamol or florbetaben). If the centralized visual read of PET scan was negative, the SUVr was calculated (cortical composite in reference to whole cerebellum) for the three tracers in order to assess borderline cases. Thresholds for amyloid positivity equivalent to SUVR of 1.1 with florbetapir were used for the final decision on inclusion.
Result
Across both studies, over 500 lumbar punctures, 2700 amyloid PET scans and about 150 tau PET scans (conducted using flortaucipir) were performed. In Generation Study 1, over 200 FDG PET scans were also performed. Participants underwent amyloid testing during screening, blood sampling (plasma and serum) and underwent MRI scans for safety and to measure brain volumes. All baseline biomarker data will be presented, including available concentrations from CSF Tau/p‐Tau/Aβ42/Aβ40 along with the eligibility ratio for pTau/ab42. In about 150 participants, concordance between elevated/non elevated amyloid status by CSF and PET (using centiloids) will be shown. Baseline brain volume (whole brain and hippocampus) will be summarized for the different co‐variates (age, sex, cognition, genotype and amyloid status). Correlations among the various fluid biomarkers and imaging will be discussed.
Conclusion
These data describe the biomarker signature of the world’s largest cohort of cognitively unimpaired APOE4 carriers with and without elevated amyloid. The anonymized study data, biomarker samples as well as images collected will be shared with the scientific community after study completion and reporting. ELECSYS is a registered trademark of Roche.
The placebo-controlled phase-2 REGOSARC trial demonstrated the efficacy of regorafenib in patients with leiomyosarcoma, synovial sarcoma and other non-adipocytic sarcoma but not in liposarcoma. ...Patients initially allocated to placebo were allowed to receive regorafenib after progression. We report here an updated analysis of the trial including evaluation of regorafenib activity after cross-over.
From June 2013 to December 2014, 139 patients were enrolled in the non-adipocytic sarcoma cohorts. Median follow-up is now 32.4 months. Benefit of regorafenib versus placebo in terms of progression-free survival (PFS) and overall survival (OS) from randomisation was estimated by hazard ratio (HR) in Cox models. In the placebo arm, intra-patient benefit of regorafenib after cross-over was evaluated by the growth modulation index (GMI) (GMI was here, for each patient, PFS after cross-over regorafenib divided by PFS with placebo). Furthermore, the activity of delayed (after cross-over) versus early (at study entry) regorafenib was evaluated by comparing PFS after cross-over to regorafenib to PFS after randomisation in the regorafenib arm.
PFS benefit of regorafenib as compared to placebo was confirmed with longer follow-up (HR = 0.50; 95% CI: 0.35–0.71; p < .0001). OS was not statistically significant different (HR = 0.78; 0.54–1.12; p = .18). This finding may partially be explained by the fact that 55/68 patients who progressed on placebo (81%) received cross-over Regorafenib after progression: 59% of them had a GMI ≥ 1.3 (95% CI, 45–71%). Delayed start of regorafenib was associated with a statistically non-significant shorter PFS as compared to early treatment (HR = 1.21; 0.84–1.73; p = .30) without impact on OS.
Observed PFS confirms that regorafenib warrants further clinical investigation in refractory non-adipocytic sarcomas.
•Regorafenib improves progression-free survival in pretreated non-adipocytic sarcoma as compared to placebo.•Regorafenib slows down tumour growth in 59% of cross-over patients.•After exposure placebo and cross-over, regorafenib is an active drug in non-adipocytic sarcomas.
Abstract
Background
In addition to early mild non‐progressive cognitive worsening, BACE inhibitors have been associated with early non‐progressive reductions in hippocampal and whole brain volume in ...trial participants with elevated amyloid (A+, Egan et al, 2019). We have begun to evaluate the effects of umibecestat treatment and discontinuation on cognitively unimpaired amyloid‐positive (A+) and A‐ APOE4 homozygotes and A+ heterozygotes, testing the hypotheses that BACE inhibitor‐related hippocampal and whole brain shrinkage is apparent soon after treatment initiation, non‐progressive, limited to A+ participants, and reversible following discontinuation.
Method
The API Generation Program had begun to evaluate umibecestat in 1,623 cognitively unimpaired 60‐75 year‐old participants including 921 A+ APOE4 heterozygotes and 702 homozygotes (A+ or A‐).Following randomization, volumetric brain MRIs were scheduled at month 6, month 12 and then annually. After discontinuation of study medication, participants continued to be assessed under double‐blind conditions, and MRIs were acquired within 3 months after the last dose. We investigated 6‐month hippocampal and whole brain volume changes and their relationship to RBANS immediate, delayed and total memory score changes; and we plan to investigate the persistence or reversibility of these changes within 3 months of discontinuation after study completion in Q2 2020.
Result
Umibecestat was associated with significant 6‐month hippocampal and whole brain shrinkage in the aggregate APOE4 homozygote and A+ heterozygote group, but not in the A‐ homozygotes. While an early non‐progressive worsening in RBANS immediate, delayed, and total memory scores (Graf et al, AAIC 2020 submitted) was seen in the overall population as well as in A‐ HMs, we failed to demonstrate any significant association between brain shrinkage and cognitive worsening in the overall group (R2 coefficient <0.1) in the active treatment group for any of the visits (on‐ and off‐ treatment).
Conclusion
BACE inhibitor‐related brain shrinkage appears to be early, non‐progressive, related to pre‐existing amyloid plaque burden, and unrelated to its cognitive worsening. Pending findings will help to clarify the extent to which it is also reversible. Together, our cognitive and MRI findings could help to assess potential benefits versus risks of BACE inhibitors in future prevention trials.
Background
In addition to early mild non‐progressive cognitive worsening, BACE inhibitors have been associated with early non‐progressive reductions in hippocampal and whole brain volume in trial ...participants with elevated amyloid (A+, Egan et al, 2019). We have begun to evaluate the effects of umibecestat treatment and discontinuation on cognitively unimpaired amyloid‐positive (A+) and A‐ APOE4 homozygotes and A+ heterozygotes, testing the hypotheses that BACE inhibitor‐related hippocampal and whole brain shrinkage is apparent soon after treatment initiation, non‐progressive, limited to A+ participants, and reversible following discontinuation.
Method
The API Generation Program had begun to evaluate umibecestat in 1,623 cognitively unimpaired 60‐75 year‐old participants including 921 A+ APOE4 heterozygotes and 702 homozygotes (A+ or A‐).Following randomization, volumetric brain MRIs were scheduled at month 6, month 12 and then annually. After discontinuation of study medication, participants continued to be assessed under double‐blind conditions, and MRIs were acquired within 3 months after the last dose. We investigated 6‐month hippocampal and whole brain volume changes and their relationship to RBANS immediate, delayed and total memory score changes; and we plan to investigate the persistence or reversibility of these changes within 3 months of discontinuation after study completion in Q2 2020.
Result
Umibecestat was associated with significant 6‐month hippocampal and whole brain shrinkage in the aggregate APOE4 homozygote and A+ heterozygote group, but not in the A‐ homozygotes. While an early non‐progressive worsening in RBANS immediate, delayed, and total memory scores (Graf et al, AAIC 2020 submitted) was seen in the overall population as well as in A‐ HMs, we failed to demonstrate any significant association between brain shrinkage and cognitive worsening in the overall group (R2 coefficient <0.1) in the active treatment group for any of the visits (on‐ and off‐ treatment).
Conclusion
BACE inhibitor‐related brain shrinkage appears to be early, non‐progressive, related to pre‐existing amyloid plaque burden, and unrelated to its cognitive worsening. Pending findings will help to clarify the extent to which it is also reversible. Together, our cognitive and MRI findings could help to assess potential benefits versus risks of BACE inhibitors in future prevention trials.
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