Everolimus is an agent frequently associated with specific toxicities. Predictive markers of efficacy are needed to help define which patients could benefit from it. The goal of this exploratory ...study was to identify potential predictive biomarkers in the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activation pathway using primary tumor samples collected during the phase II tamoxifen plus everolimus (TAMRAD) trial.
Tumor tissues were collected retrospectively from the TAMRAD trial. Immunohistochemistry was carried out using specific antibodies directed toward proteins that result in mTORC1 activation canonical phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR or alternative pathways. DNA was extracted from the tumor tissue; mutation screening in the PIK3CA gene (exons 9 and 20) and the KRAS gene (exons 2 and 3) was first carried out using Sanger direct sequencing, and then completed by next-generation sequencing for PIK3CA. An exploratory analysis of everolimus efficacy in terms of a time-to-progression (TTP) increase was carried out in each biomarker subgroup (high versus low expression referring to the median percentage of marked cells).
A total of 55 primary tumor samples from the TAMRAD trial—25 from the tamoxifen-alone group and 30 from the tamoxifen/everolimus group—were evaluated for biomarkers. The subgroups most likely to have an improvement in TTP with tamoxifen/everolimus therapy, compared with tamoxifen alone, were patients with high p4EBP1, low 4EBP1, low liver kinase B1, low pAkt, and low PI3K. Among the 45 samples screened for mutation status, nine samples (20%; 95% CI 9.6–34.6) had a PIK3CA mutation. KRAS mutation was observed in one patient.
A positive correlation between late effectors of mTORC1 activation, a positive correlation between Akt-independent mTORC1 activation, and an inverse correlation between canonical PI3K/Akt/mTOR pathway and everolimus efficacy were observed in this exploratory analysis. However, these correlations need to be validated in larger studies before applying the findings to routine clinical practice.
Options in second-line therapy after doxorubicin-based chemotherapy for metastatic/advanced leiomyosarcoma include gemcitabine (G), trabectedin and pazopanib (P) monotherapy. Currently, no ...combination therapy is better than monotherapy. LMS03 is an open-label multicentre single-group phase II study designed to assess the efficacy and tolerance of G + P in the second-line setting.
Patients (pts), ECOG ≤2, with metastatic leiomyosarcomas (LMS) after first-line doxorubicin chemotherapy failure were eligible. Pts were treated with G 1000 mg/m2 on days 1 and 8 of each 21 days (maximum eight cycles), in combination with oral daily P (800 mg), until disease progression/toxicity. 9-month progression-free survival (PFS) rate was the primary endpoint. Inacceptable and promising 9-month PFS rates were defined, in the intent-to-treat population, as 32% and 44%.
106 pts were included with a mean age of 59.8 years and an ECOG 0 in 63.5%; the primary tumour site was uterus in 61%. Pts were treated with P + G for a median of 3.8 mo, and P for a median of 4.2 mo. The 9-month PFS rate was 32.1% (95% CI 23.1–41.1). After a median follow-up of 14.2 months, the PFS was 6.5 months (95% CI 5.6–8.2), and the overall survival was 22.4 months (95% CI 16.9–26.5). The best response was 23.8%. The most frequent reported grade 3–4 adverse events were haematological.
LMS03 failed to show that second-line therapy, with gemcitabine combined with pazopanib, followed by pazopanib alone, was beneficial for advanced LMS patients.
Eudract N°2011-001308-36 and NCT01442662.
•Gemcitabine combined with pazopanib in second-line leiomyosarcoma after doxorubicine failure is feasible without limiting toxicity.•The 12-week disease control rate was 83.6%, and the best response during the treatment was 23.8%.•The LMS03 study failed to meet its primary objective but is nearly positive when considering per-protocol results with a median PFS 7.1 months.
In a comparison of tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin inhibitor (mTORi) in patients with metastatic clear-cell renal cell carcinoma who received a 1st-line TKI for at ...least 6 months, the TKI-TKI sequence was favored over the TKI-mTORi. Long-term 2nd-line responders were more likely to have received a second TKI and to have been long-term responders to a 1st-line TKI.
Although sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1).
Retrospective multicenter study (2004–2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123). End points: Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM).
Sequence effect in the overall cohort was in favor of the TKI–TKI sequence over the TKI–mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI–TKI superiority was attributed in large part to the 11–22 month (TD1) subgroup of patients which displayed significantly better outcomes HR ≈ 0.5; median PFS (months): 9.4 (5.9–12.2) versus 3.9 (3.0–5.5), P = 0.003; TTF(months): 8.0 (5.5–11.0) versus 3.6 (3.0–4.6), P = 0.009. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI.
m-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.
This multinational, double-blind, randomized, placebo-controlled, phase III trial assessed the efficacy and tolerability of the oral platinum analog satraplatin in patients with metastatic ...castrate-refractory prostate cancer (CRPC) experiencing progression after one prior chemotherapy regimen.
Nine hundred fifty patients were randomly assigned (2:1) to receive oral satraplatin (n = 635) 80 mg/m(2) on days 1 to 5 of a 35-day cycle and prednisone 5 mg twice daily or placebo (n = 315) and prednisone 5 mg twice daily. Primary end points were progression-free survival and overall survival (OS). The secondary end point was time to pain progression (TPP).
A 33% reduction (hazard ratio HR = 0.67; 95% CI, 0.57 to 0.77; P < .001) was observed in the risk of progression or death with satraplatin versus placebo. This effect was maintained irrespective of prior docetaxel treatment. No difference in OS was seen between the satraplatin and placebo arms (HR = 0.98; 95% CI, 0.84 to 1.15; P = .80). Compared with placebo, satraplatin significantly reduced TPP (HR = 0.64; 95% CI, 0.51 to 0.79; P < .001). Satraplatin was generally well tolerated, although myelosuppression and GI disorders occurred more frequently with satraplatin.
Oral satraplatin delayed progression of disease and pain in patients with metastatic CRPC experiencing progression after initial chemotherapy but did not provide a significant OS benefit. Satraplatin was generally well tolerated. These results suggest activity for satraplatin in patients with CRPC who experience progression after initial chemotherapy.
Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those ...involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure–activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.
In this open-label trial of first-line treatment for HIV-1 in Cameroon, a dolutegravir-based regimen was found to be noninferior to a low-dose efavirenz–based regimen as initial antiretroviral ...therapy. However, more weight gain and a higher incidence of obesity occurred in the dolutegravir group.
Purpose
There has been much debate regarding the use of intra-articular injections of platelet-rich plasma (PRP) as symptomatic treatment for knee osteoarthritis. The objective of this consensus was ...to develop guidelines for PRP injections in knee osteoarthritis according to the French National Authority for Health recommendations.
Methods
Fifteen physicians from different French-speaking countries (10 rheumatologists, 4 specialists in rehabilitation and sports medicine and 1 radiologist) were selected for their expertise in the areas of PRP and osteoarthritis. A comprehensive literature review was conducted on Medline including all published therapeutic trials, open studies, meta-analysis and systematic reviews focusing on the effects of PRP in knee OA, as well as fundamental studies concerning the characteristics of the various types of PRP and their mechanisms, indexed before April 2019. Using the method recommended by the French National Authority for Health inspired by the Delphi consensus process, 25 recommendations were finally retained and evaluated. The recommendations were classified as appropriate or not appropriate, with strong or relative agreement, or uncertain if a consensus was not achieved.
Results
Among the 25 recommendations selected, the main ones are the following: (1) Intra-articular injections of PRP are an effective symptomatic treatment for early to moderate knee osteoarthritis. This recommendation was considered appropriate with a relative agreement (Median = 8; rank = 6–9). Level of evidence 1A. (2) A PRP treatment sequence in knee osteoarthritis may include 1–3 injections. This recommendation was considered appropriate with a strong agreement (Median = 9; rank = 7–9). Level of evidence 1A. (3) Leucocytes-poor PRP should be preferred in knee osteoarthritis. This recommendation was considered appropriate with a relative agreement (Median = 8; rank = 5–9). Level of evidence 5. (4) Intra-articular PRP knee injections should be performed under ultrasound or fluoroscopic guidance. This recommendation was considered uncertain with no consensus (Median = 8; rank = 3–9). Level of evidence 5. (5) PRP should not be mixed with an anesthetic or intra-articular corticosteroid. This recommendation was considered appropriate with a relative agreement (Median = 9; rank = 6–9). Level of evidence 5
Conclusion
Those 25 recommendations should standardize and facilitate the use of IA PRP injections, which are considered by experts as an effective treatment especially in early or moderate knee OA. Although a strong or relative agreement from the experts was obtained for most of the recommendations, many of them had a very low level of evidence (Level 5) and were principally based on the clinical experience of the experts.
Who dies from prostate cancer? Patrikidou, A; Loriot, Y; Eymard, J-C ...
Prostate cancer and prostatic diseases,
12/2014, Letnik:
17, Številka:
4
Journal Article
Recenzirano
Odprti dostop
During the last 30 years, there has been a major shift in initial staging in prostate cancer (CaP) in Western countries, with the incidence of metastases at diagnosis decreasing from over 50% in the ...1970s to currently less than 10%. Yet, CaP is still the second cause of cancer death in men. We used two monthly curated databases of patients with castration-resistant prostate cancer (CRPC) to describe the natural history of patients dying of CaP in the modern era.
The outcome of 190 men with metastatic CRPC treated from 2008 to 2011 was studied. The characteristics of the patients who died from CaP (n = 113 patients, 61%) were analyzed.
All 113 patients who died of CaP were assessable for the presence of metastases at diagnosis. Sixty-three patients (56%) had detectable metastases at diagnosis: 67%, 11% and 43% had bone, visceral and lymph node metastases, respectively. The median time to CRPC was 16 months and median overall survival (OS) was 5.2 years.Among the patients with localized CaP at diagnosis (n = 50, 44%), 46% had T stage ⩾ 3 and 38% had a Gleason score ⩾ 8. Overall, 64% of patients were classified as having a high-risk CaP. Only 26% who died from CaP had a Gleason score ⩽ 6. Median OS was 8.8 years.
In the modern era, approximately half of the patients who die from CaP have metastases at diagnosis. The paradigm of progression from localized disease to metastasis and eventually death is only represented in the other half, although possible initial screening and staging errors ought to be taken into consideration. More efforts are needed to conduct trials in patients with newly diagnosed metastatic CaP.
Patient’s preference was well balanced between enzalutamide and darolutamide. Fatigue and cognitive impairments were major concerns under new-generation hormonotherapy (NHT). For the first time, ...cognitive function deterioration under NHT was investigated prospectively. Darolutamide was associated with a significant benefit in verbal learning compared with enzalutamide.
Darolutamide and enzalutamide are second-generation androgen receptor inhibitors with activity in men with castrate-resistant prostate cancer (CRPC) and different toxicity profiles.
ODENZA is a prospective, randomized, multicenter, cross-over, phase 2 trial designed to assess preference between darolutamide and enzalutamide in men with asymptomatic or mildly symptomatic metastatic CRPC (mCRPC).
Patients were randomized 1:1 to receive either darolutamide 1200 mg/d for 12 wk followed by enzalutamide 160 mg/d for 12 wk or enzalutamide followed by darolutamide. In both arms, the second treatment was given in absence of cancer progression.
The primary endpoint was patient preference between the two drugs, as assessed by a preference questionnaire (p value calculated with the Prescott test). After week 24, patients entered an extension period during which they received their preferred treatment until progression or toxicity. The main secondary objectives included reasons for patient preference, response at week 12, tolerance of each drug, and measurement compared with baseline of cognitive outcomes assessed using tablet questionnaires.
Overall, 249 patients, with a median age of 72 yr, were randomized. Among the 200 patients who fulfilled the preplanned criteria for the evaluation of the primary endpoint of preference, 97 (49% 41; 56), 80 (40% 33; 47), and 23 (12% 7; 16) chose darolutamide, chose enzalutamide, and had no preference, respectively (p = 0.92). Reduced fatigue, easier administration, and better quality of life were the main criteria that influenced patient choice. A moderate benefit in episodic memory from darolutamide was observed for the acquisition of new information (least square LS means difference = 2.2, effect size = 0.5) and for the recall of that information after a brief delay (LS means difference = 0.7, effect size = 0.3). Using the Brief Fatigue Inventory questionnaire, patients reported greater fatigue with enzalutamide (3.3 3.0; 3.6) than with darolutamide (2.7 2.4; 3.0). There was no difference in terms of depression, seizures, and falls.
The study did not show a difference in preference between the two treatments. In men with mCRPC, darolutamide was associated with a clinically meaningful benefit in episodic memory and less fatigue compared with enzalutamide.
Preference between darolutamide and enzalutamide was well balanced in men with castrate-resistant prostate cancer. Darolutamide was associated with a significant benefit in verbal learning and less fatigue compared with enzalutamide.
In acute ischemic stroke, the negative susceptibility vessel sign on T2*-weighted images traditionally highlights fibrin-rich clots, which are particularly challenging to remove. In vitro, fast stent ...retrieval improves fibrin-rich clot extraction. We aimed to evaluate whether the speed of stent retrieval influences the recanalization and clinical outcome of patients presenting with the negative susceptibility vessel sign.
Patients were identified from a registry of patients with ischemic stroke receiving mechanical thrombectomy between January 2016 and January 2020. Inclusion criteria were the following: 1) acute ischemic stroke caused by an isolated occlusion of the anterior circulation involving the MCA (Internal Carotid Artery-L, M1, M2) within 8 hours of symptom onset; 2) a negative susceptibility vessel sign on prethrombectomy T2*-weighted images; and 3) treatment with a combined technique (stent retriever + contact aspiration). Patients were dichotomized according to retrieval speed (fast versus slow). The primary outcome was the first-pass recanalization rate.
Of 68 patients who met inclusion criteria, 31 (45.6%) were treated with fast retrieval. Patients receiving a fast retrieval had greater odds of first-pass complete (relative risk and 95% confidence interval RR 95% CI, 4.30 1.80-10.24), near-complete (RR 95% CI, 3.24 1.57-6.68), and successful (RR 95% CI, 2.60 1.53-4.43) recanalization as well as greater odds of final complete (RR 95% CI, 4.18 1.93-9.04), near-complete (RR 95% CI, 2.75 1.55-4.85), and successful (RR 95% CI, 1.52 1.14-2.03) recanalization. No significant statistical differences in procedure-related serious adverse events, distal embolization, or symptomatic intracranial hemorrhage were reported. No differences were noted in terms of functional independence (RR 95% CI, 1.01 0.53-1.93) and all-cause mortality (RR 95% CI, 0.90 0.35-2.30) at 90 days.
A fast stent retrieval during mechanical thrombectomy is safe and improves the retrieval of clots with the negative susceptibility vessel sign.
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