Niraparib, an inhibitor of poly(adenosine diphosphate ADP-ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients with recurrent ovarian ...cancer after platinum-based chemotherapy, regardless of the presence or absence of
mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown.
In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival.
Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval CI, 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred.
Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.).
Niraparib is an oral poly(adenosine diphosphate ADP-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of ...niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer.
In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival.
Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval CI, 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P<0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications.
Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274 .).
Summary Background Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits ...angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival. Methods For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m2 ) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov , NCT01204749 , and is no longer accruing patients. Findings 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months 5·8–7·4 vs 5·4 months 95% CI 4·3–5·5, respectively, hazard ratio 0·66, 95% CI 0·57–0·77, p<0·0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 54% of 452 patients in the placebo group vs 258 56% of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 17% patients vs 27 6%, respectively) and higher incidences of oedema (294 64% patients had any-grade oedema in the trebananib group vs 127 28% patients in the placebo group). Grade 3 or higher adverse events included ascites (34 8% in the placebo group vs 52 11% in the trebananib group), neutropenia (40 9% vs 26 6%), and abdominal pain (21 5% vs 22 5%). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound-healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 17% vs 46 10%). Interpretation Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent. Funding Amgen.
Low-grade and early-stage endometrioid endometrial carcinomas (EECs) have an overall good prognosis but biomarkers identifying patients at risk of relapse are still lacking. Recently,
CTNNB1
exon 3 ...mutation has been identified as a potential risk factor of recurrence in these patients. We evaluate the prognostic value of
CTNNB1
mutation in a single-centre cohort of 218 low-grade, early-stage EECs, and the correlation with beta-catenin and LEF1 immunohistochemistry as candidate surrogate markers.
CTNNB1
exon 3 hotspot mutations were evaluated by Sanger sequencing. Immunohistochemical staining of mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), p53, beta-catenin, and LEF1 was performed in representative tissue microarrays. Tumours were also reviewed for mucinous and squamous differentiation, and MELF pattern. Nineteen (8.7%) tumours harboured a mutation in
CTNNB1
exon 3. Nuclear beta-catenin and LEF1 were significantly associated with
CTNNB1
mutation, showing nuclear beta-catenin a better specificity and positive predictive value for
CTNNB1
mutation. Tumours with
CTNNB1
exon 3 mutation were associated with reduced disease-free survival (
p
= 0.010), but no impact on overall survival was found (
p
= 0.807). The risk of relapse in tumours with
CTNNB1
exon 3 mutation was independent of FIGO stage, tumour grade, mismatch repair protein expression, or the presence of lymphovascular space invasion.
CTNNB1
exon 3 mutation has a negative impact on disease-free survival in low-grade, early-stage EECs. Nuclear beta-catenin shows a higher positive predictive value than LEF1 for
CTNNB1
exon 3 mutation in these tumours.
Graphical abstract
In this work, we performed systematic studies on the oxidation of zinc nitride metastable layers using a climate chamber with controlled temperature and relative humidity. The electrical properties ...of the samples were in situ analyzed using a programmable microprocessor with a voltage divider, while the structural and optical properties were ex situ measured by scanning electron microscopy, elastic recoil detection analysis, and spectroscopic ellipsometry. Our results show that zinc nitride transformation proceeds in a top-down way, with a progressive substitution of N by O, which leads to the formation of pores and a remarkable swelling effect. The overall behavior is well explained by a universal logistic growth model. Considering this model, we successfully fabricated and tested a zinc nitride-based dehydration sensor for biomedical applications.
No review to date has evaluated the association between physical fitness and health-related quality of life (HRQoL) in healthy children and adolescents. The aims of this systematic review and ...meta-analysis were to examine the relationship between both cardiorespiratory fitness (CRF) and muscular fitness (MF) and HRQoL in healthy subjects under 18 years of age and to describe the dimensions of HRQoL in which these relationships are more robust.
The Medline, Embase, Cochrane Library, SCIELO, SPORTDiscus and PEDro databases were systematically searched to collect observational studies that examined the relationship between CRF and HRQoL and between MF and HRQoL in participants under 18 years of age without any diagnosed medical condition. Pooled effect sizes (ES) were estimated for the associations between both CRF and MF and the various HRQoL dimensions.
The pooled ES (95% CI) estimates for the relationship between CRF and HRQoL were as follows: 0.19 (0.10 to 0.27) for physical well-being, 0.19 (0.07 to 0.32) for psychological well-being, 0.20 (- 0.14 to 0.55) for perceived health status, 0.10 (0.00 to 0.20) for self-perception/self-esteem, 0.07 (- 0.05 to 0.19) for quality of family relationship, 0.14 (0.04 to 0.25) for quality of peer relationship, 0.17 (0.04 to 0.29) for everyday functioning at school and 0.20 (0.12 to 0.28) for total HRQoL score. The pooled ES (95% CI) estimates for the relationship between MF and HRQoL were: 0.25 (0.12 to 0.37) for physical well-being, 0.11 (0.04 to 0.17) for psychological well-being, 0.08 (0.01 to 0.15) for quality of family relationship, 0.14 (0.03 to 0.25) for quality of peer relationship, and 0.09 (0.03 to 0.14) for total HRQoL score.
Our data suggest that both CRF and MF are positively associated with HRQoL, mainly in physical, psychological and peer relationships. Moreover, CRF is positively associated with school dimensions and MF is positively associated with family relationships. Trail registration Protocol PROSPERO registration number: CRD42015025823.
Ovarian cancer remains one of the leading causes of cancer deaths. Thus, new biomarkers predictive of response to the standard paclitaxel-carboplatin treatment are needed to improve chemotherapy ...strategies. MicroRNAs have the potential to modify drug outcomes. Based on this, we have demonstrated in this study that patients with a high expression of the miR-200 family show low levels of β-tubulin class III in ovarian carcinoma. In addition, we have established the clinical relevance of these microRNAs for ovarian cancer patients' treatment response and survival. In a well-characterized series of 72 ovarian carcinomas, the expressions of miR-141, miR-200a, miR-200b, miR-200c, and miR-429 were quantified by quantitative reverse transcription-PCR, and the protein content of β-tubulin isotypes I, II, and III was determined by immunohistochemistry. The relationship between these microRNAs, β-tubulin expression, response to paclitaxel-based treatment, progression-free survival (PFS) and overall survival was determined. While isotype I had constant high levels, protein expression of β-tubulins II and III was mutually exclusive. Low tumoral miR-200 expression was significantly associated with high β-tubulin III protein content (P values range, 0.047-<0.0001), and patients without complete response (CR) had lower miR-200c levels than patients with CR (hazard ratio (HR)=1.43, 95% confidence interval (CI)=1.02-1.99, P=0.037, multivariate analysis). Additionally, low miR-200 family expression had a trend toward poor PFS (HR>2.0, P values 0.051, 0.054, and 0.079 for miR-200c, miR-141, and miR-429 respectively, multivariate analysis). In conclusion, miR-200 family members affect the final β-tubulin III protein content of ovarian carcinomas. Furthermore, these microRNAs might constitute the biomarkers of response to paclitaxel-based treatments and relapse/progression of advanced stage ovarian carcinoma patients.
An association between gross motor competence (GMC) and academic achievement (AA) has been described, but the potential mechanisms behind this association are still unknown. It is not known either ...whether these mechanisms are similar for boys and girls. The aim of this study was to analyse whether the association between GMC and AA is mediated by executive functions (EFs), and to investigate whether this mediation differs by sex. This cross‐sectional study involved 451 children aged 8 to 10 (234 girls; mean age 9.95 ± 0.59). The Movement Assessment Battery for Children‐Second Edition (MABC‐2), NIH Toolbox, and grades in language and mathematics were used to test GMC, EFs, and AA, respectively. Multifactorial structural equation model (SEM) was used to evaluate a possible relation between variables, controlling for confounders. The differences by sex were examined using a multi‐group SEM approach. The results showed that EFs acted as a full mediator of the relationship between GMC and AA in boys (β = 0.14, p = 0.012) but not in girls (β = 0.10, p = 0.326). These results show that the benefit of GMC on AA is mediated by EFs in boys but not in girls. Nevertheless, these conclusions should be carefully considered due to the cross‐sectional nature of the study.
Early stages are under-represented in studies on the molecular and immune features of high-grade serous ovarian carcinoma (HGSOC), and specific studies focused on early-stage HGSOC are required for a ...better prognostic stratification and to personalize chemotherapy. The aim of this study was to determine the prognostic significance of CD8+ and CD4+ tumor-infiltrating lymphocytes (TILs), tumoral cell PD-L1 expression,
mutational status and tumor mutation burden (TMB) in early-stage HGSOC. A retrospective study was performed on stage I and II HGSOC from the Molecular Reclassification of Early Stages of Ovarian Cancer (RECLAMO) cohort from the Spanish Group of Ovarian Cancer Research (GEICO). Centralized histological typing was performed based on morphological and immunohistochemical features. Intraepithelial (i) and stromal (s) CD8+ and CD4+ T cells and PD-L1 were evaluated on tissue microarrays by immunohistochemistry.
and
mutation status and TMB were analyzed in tumor DNA using next-generation sequencing. The study included 124 tumors. High iCD8+ (>20 TILs/core), low/intermediate CD4+ (<20 TILs/core) and high CD8+/CD4+ ratio (>35/core) were associated with favorable outcomes. Tumor cell PD-L1 expression (TPS ≥ 1) was present in only 8% of tumors. In total, 11 (16%) and 6 (9%) out of 69 HGSOC tested carried pathogenic or likely pathogenic
or
mutations, respectively. Median TMB of 40 tumors analyzed was 5.04 mutations/Mb and only 6 tumors had 10 or more mutations/Mb.
status and TMB were not associated with TILs or prognosis. When compared with studies on advanced HGSOC, our results suggested that prognostic variables differed according to stage and that more studies focused on early stages of HGSOC are needed to better stratify these tumors.
To report updated long-term efficacy and safety from the double-blind, placebo-controlled, phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016).
Patients with newly diagnosed advanced ovarian cancer ...with complete or partial response (CR or PR) to first-line platinum-based chemotherapy received niraparib or placebo once daily (2:1 ratio). Stratification factors were best response to first-line chemotherapy regimen (CR/PR), receipt of neoadjuvant chemotherapy (yes/no), and homologous recombination deficiency (HRD) status (deficient HRd/proficient HRp or not determined). Updated (ad hoc) progression-free survival (PFS) data (as of November 17, 2021) by investigator assessment (INV) are reported.
In 733 randomised patients (niraparib, 487; placebo, 246), median PFS follow-up was 3.5years. Median INV-PFS was 24.5 versus 11.2months (hazard ratio, 0.52; 95% confidence interval CI, 0.40–0.68) in the HRd population and 13.8 versus 8.2months (hazard ratio, 0.66; 95% CI, 0.56–0.79) in the overall population for niraparib and placebo, respectively. In the HRp population, median INV-PFS was 8.4 versus 5.4months (hazard ratio, 0.65; 95% CI, 0.49–0.87), respectively. Results were concordant with the primary analysis. Niraparib-treated patients were more likely to be free of progression or death at 4years than placebo-treated patients (HRd, 38% versus 17%; overall, 24% versus 14%). The most common grade ≥ 3 treatment-emergent adverse events in niraparib patients were thrombocytopenia (39.7%), anaemia (31.6%), and neutropenia (21.3%). Myelodysplastic syndromes/acute myeloid leukaemia incidence rate (1.2%) was the same for niraparib- and placebo-treated patients. Overall survival remained immature.
Niraparib maintained clinically significant improvements in PFS with 3.5years of follow-up in patients with newly diagnosed advanced ovarian cancer at high risk of progression irrespective of HRD status. No new safety signals were identified.
•Updated long-term efficacy and safety data from PRIMA/ENGOT-OV26/GOG-3012 study.•Niraparib first-line maintenance therapy extended progression-free survival (PFS).•Durable PFS benefit observed in overall population and across biomarker subgroups.•The most common grade ≥ 3 adverse events in niraparib patients were haematologic.•No new safety signals were identified.
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