A great deal of effort has been dedicated to the revision of the standard values in connection with the neutron interaction for some actinides. While standard data compilation are available for ...decades nuclear data evaluations included in existing nuclear data libraries (ENDF, JEFF, JENDL, etc.) do not follow the standard recommended values. Indeed, the majority of evaluations for major actinides do not conform to the standards whatsoever. In particular, for the n + 235U interaction the only value in agreement with the standard is the thermal fission cross section. A resonance re-evaluation of the n + 235U interaction has been performed to address the issues regarding standard values in the energy range from 10−5 eV to 2250 eV. Recently, 235U fission cross-section measurements have been performed at the CERN Neutron Time-of-Flight facility (TOF), known as n_TOF, in the energy range from 0.7 eV to 10 keV. The data were normalized according to the recommended standard of the fission integral in the energy range 7.8 eV to 11 eV. As a result, the n_TOF averaged fission cross sections above 100 eV are in good agreement with the standard recommended values. The n_TOF data were included in the 235U resonance analysis that was performed with the code SAMMY. In addition to the average standard values related to the fission cross section, standard thermal values for fission, capture, and elastic cross sections were also included in the evaluation. This paper presents the procedure used for re-evaluating the 235U resonance parameters including the recommended standard values as well as new cross section measurements.
We aimed to compare the efficacy and safety of maintaining or withdrawing abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer who had ...experienced cancer progression to this treatment and were beginning a docetaxel-based therapy.
Phase II, randomised, open-label study conducted in patients with metastatic castration-resistant prostate cancer who were asymptomatic or mildly symptomatic. After open-label treatment with AAP, patients who had experienced cancer progression to AAP were randomised to 75 mg/m2 of docetaxel plus AAP or to receive 75 mg/m2 of docetaxel plus 10 mg of prednisone orally daily. The primary outcome was the radiographic progression-free survival rate at 12 months as evaluated by the investigators in all randomised patients.
A total of 148 patients were included in open-label treatment with AAP, and of them, 94 patients were randomised to receive either docetaxel plus AAP (intervention group; n = 47) or docetaxel plus prednisone (control group; n = 47). The 12-month radiographic progression-free survival rates did not differ between the intervention group (34.9%; 95% CI 20.7–49.2) and the control group (33.9%; 95% CI 19.5–48.3). There were no significant differences in the time to radiographic progression and the overall survival between the intervention and control groups. Grade 3–5 neutropenia with the combination of docetaxel plus prednisone and AA was more frequent than with docetaxel plus prednisone (59.6% versus 27.7%).
Our results indicate that the therapeutic strategy of maintaining AAP added to docetaxel in chemotherapy-naïve patients who have experienced cancer progression to AAP treatment should not be further evaluated and should be avoided in clinical practice.
NCT02036060 https://clinicaltrials.gov/ct2/show/NCT02036060.
•Docetaxel plus abiraterone acetate plus prednisone (AAP) versus docetaxel plus prednisone after progression to AAP in metastatic castration-resistant prostate cancer.•The 12-month radiographic progression-free survival rates did not differ (34.9% versus 33.9%).•No differences in the time to radiographic progression and overall survival.•Higher frequency of grade 3–5 and serious adverse events with the intervention.•Maintaining AAP added to docetaxel after progression to AAP is not an option.
In the current era of personalized medicine, liquid biopsy has acquired a relevant importance in patient management of advanced stage non-small cell lung cancer (NSCLC). As a matter of fact, liquid ...biopsy may supplant the problem of inadequate tissue for molecular testing. The term 'liquid biopsy' refers to a number of different biological fluids, but is most clearly associated with plasma-related platforms. It must be taken into account that pre-analytical processing and the selection of the appropriate technology according to the clinical context may condition the results obtained. In addition, novel clinical applications beyond the evaluation of the molecular status of predictive biomarkers are currently under investigation.
This review summarizes the available evidence on pre-analytical issues and different clinical applications of liquid biopsies in NSCLC patients.
Liquid biopsy should be considered not only as a valid alternative but as complementary to tissue-based molecular approaches. Careful attention should be paid to the optimization and standardization of all phases of liquid biopsy samples management in order to determine a significant improvement in either sensitivity or specificity, while significant reducing the number of 'false negative' or 'false positive' molecular results.
Several studies with different Large Area Avalanche Photo-Diodes (LAAPDs) coupled to ad-hoc bi-frustum shaped CsI(Tl) crystals have been carried out as a part of the R&D program for the CALIFA ...R3B/FAIR calorimeter. CALIFA, which is designed for the detection of light charged particles and gamma-rays in a wide energetic domain, has very stringent requirements. We report in this work our studies on the energy resolution for gamma-rays using LAAPDs as photosensors. One of the factors affecting the energy resolution is the matching between the APD active area and the crystal exit face. We present in this paper a procedure for characterizing APDs based on the measurement of their contribution to the energy resolution. The results obtained are very promising and suggest that a solution based on CsI(Tl) crystals coupled to LAAPDs could be suitable for, at least, part of the CALIFA calorimeter.
Clinical variables may correlate with lack of response to treatment (primary resistance) or clinical benefit in patients with clear cell renal cell carcinoma (ccRCC) treated with anti-programmed ...death 1/ligand one antibodies.
In this multi-institutional collaboration, clinical characteristics of patients with primary resistance (defined as progression on initial computed tomography scan) were compared to patients with clinical benefit using Two sample t-test and Chi-square test (or Fisher's Exact test). The Kaplan-Meier method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS) in all patients and the subsets of patients with clinical benefit or primary resistance. Cox's regression model was used to evaluate the correlation between survival endpoints and variables of interest. To explore clinical factors in a larger, independent patient sample, The Cancer Genome Atlas (TCGA) was analyzed. RNAseq gene expression data as well as demographic and clinical information were downloaded for primary tumors of 517 patients included within TCGA-ccRCC.
Of 90 patients, 38 (42.2%) had primary resistance and 52 (57.8%) had clinical benefit. Compared with the cohort of patients with initial benefit, primary resistance was more likely to occur in patients with worse ECOG performance status (p = 0.03), earlier stage at diagnosis (p = 0.04), had no prior nephrectomy (p = 0.04) and no immune-related adverse events (irAE) (p = 0.02). In patients with primary resistance, improved OS was significantly correlated with lower International Metastatic RCC Database Consortium risk score (p = 0.02) and lower neutrophil:lymphocyte ratio (p = 0.04). In patients with clinical benefit, improved PFS was significantly associated with increased BMI (p = 0.007) and irAE occurrence (p = 0.02) while improved OS was significantly correlated with overweight BMI (BMI 25-30; p = 0.03) and no brain metastasis (p = 0.005). The cohort TCGA-ccRCC was examined for the correlations between gene expression patterns, clinical factors, and survival outcomes observing associations of T-cell inflammation and angiogenesis signatures with histologic grade, pathologic stage and OS.
Clinical characteristics including performance status, BMI and occurrence of an irAE associate with outcomes in patients with ccRCC treated with immunotherapy. The inverse association of angiogenesis gene signature with ccRCC histologic grade highlight opportunities for adjuvant combination VEGFR2 tyrosine kinase inhibitor and immune-checkpoint inhibition.
Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the ...anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane.
In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436.
Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 58% of 289), anaemia (156 54%), and vomiting (111 38%); the most common grade 3 or worse events were haematological (anaemia in 95 33% of 289; thrombocytopenia in 47 16%; and neutropenia in 28 10%). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 6% and anaemia in 13 4%). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment.
Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations.
Janssen Research & Development.
Enadenotucirev is a chimeric adenovirus with demonstrated preclinical tumor-selective cytotoxicity and a short half-life. Further clinical mechanism of action data showed that enadenotucirev can gain ...access to and replicate within different types of epithelial tumors. This phase 1 dose escalation study assessed intravenous (IV) dose escalation with enadenotucirev to establish the maximum tolerated dose (MTD) and subsequently identify a suitable schedule for repeated cycles.
Sixty-one patients with advanced epithelial tumors unresponsive to conventional therapy were enrolled and received enadenotucirev monotherapy as part of this study. During the phase 1a dose escalation (n = 22) and expansion (n = 9), delivery of enadenotucirev between 1 × 10
and 1 × 10
viral particles (vp) on days 1, 3, and 5 (single cycle) was used to determine an appropriate MTD. Subsequent treatment cohorts (phase 1a, n = 6 and phase 1b, n = 24) examined the feasibility of repeated dosing cycles in either 3-weekly or weekly dosing regimens.
Enadenotucirev displayed a predictable and manageable safety profile at doses up to the MTD of 3 × 10
vp, irrespective of infusion time or dosing schedule. The most commonly reported treatment-emergent adverse events (TEAEs) of grade 3 or higher were hypoxia, lymphopenia, and neutropenia. The frequency of all TEAEs (notably pyrexia and chills) was highest within 24 h of the first enadenotucirev infusion and decreased upon subsequent dosing. Additionally, delivery of three doses of enadenotucirev over 5 days optimized pharmacokinetic and chemokine profiles in the circulation over time.
This study provides key clinical data in patients with solid epithelial tumors following treatment with IV enadenotucirev monotherapy and supports further investigation of enadenotucirev in combination with other therapeutic agents at doses up to the MTD of 3 × 10
vp.
( ClinicalTrials.gov Identifier: NCT02028442 ). Trial registration date: 07 January 2014 - Retrospectively registered.
Abstract Castration-resistant prostate cancer (CRPC) is partially characterised by overexpression of antiapoptotic proteins, such as survivin. In this phase 2 study, patients with metastatic CRPC ( n ...= 154) were randomly assigned (1:2 ratio) to receive standard first-line docetaxel/prednisone (control arm) or the combination of LY2181308 with docetaxel/prednisone (experimental arm). The primary objective was to estimate progression-free survival (PFS) for LY2181308 plus docetaxel. Secondary efficacy measures included overall survival (OS), several predefined prostate-specific antigen (PSA)–derived end points, and Brief Pain Inventory (BPI) and Functional Assessment of Cancer Therapy–Prostate (FACT-P) scores. The median PFS of treated patients for the experimental arm ( n = 98) was 8.64 mo (90% confidence interval CI, 7.39–10.45) versus 9.00 mo (90% CI, 7.00–10.09) in the control arm ( n = 51; p = 0.755). The median OS for the experimental arm was 27.04 mo (90% CI, 19.94–33.41) compared with 29.04 mo (90% CI, 20.11–39.26; p = 0.838). The PSA responses (≥50% PSA reduction), BPI, and FACT-P scores were similar in both arms. In the experimental arm, patients had a numerically higher incidence of grades 3–4 neutropenia, anaemia, thrombocytopenia, and sensory neuropathy. In conclusion, this study failed to detect a difference in efficacy between the two treatment groups.
Purpose
Genitourinary (GU) multidisciplinary tumour boards (GUMTBs) are key components of patient care, as they might lead to changes in treatment plan, improved survival, and increased adherence to ...guidelines. However, there are no guidelines on how GUMTBs should operate or how to assess their quality of performance.
Methods
A systematic literature review was conducted to identify criteria and indicators to evaluate quality in GUMTBs. A scientific committee—comprising 12 GU cancer specialists from seven disciplines—proposed a list of criteria and developed indicators, evaluated in two rounds of Delphi method. Appropriateness and utility of indicators were scored using a 9-point Likert scale. Consensus was defined as at least two-thirds of Delphi respondents selecting a score sub-category that encompassed the median score of the group.
Results
Forty-five criteria were selected to evaluate the quality of GUMTBs covering five dimensions: organisation, personnel, protocol and documentation, resources, and interaction with patients. Then, 33 indicators were developed and evaluated in the first round of Delphi, leading to a selection of 26 indicators in two dimensions: function, governance and resources, and GUMTB sessions. In the second round, consensus was reached on the appropriateness of all 26 indicators and on the utility of 24 of them. Index cards for criteria and indicators were developed to be used in clinical practice.
Conclusions
Criteria and indicators were developed to evaluate the quality of GUMTBs, aiming to serve as a guide to improve quality of care and health outcomes in patients with GU cancer.
The acoustic and entropy transfer functions of quasi-one-dimensional nozzles are studied analytically for both subsonic and choked flows with and without shock waves. The present analytical study ...extends both the compact nozzle solution obtained by Marble & Candel (J. Sound Vib., vol. 55, 1977, pp. 225–243) and the effective nozzle length proposed by Stow, Dowling & Hynes (J. Fluid Mech., vol. 467, 2002, pp. 215–239) and by Goh & Morgans (J. Sound Vib., vol. 330, 2011, pp. 5184–5198) to non-zero frequencies for both modulus and phase through an asymptotic expansion of the linearized Euler equations. It also extends the piecewise-linear approximation of the velocity profile in the nozzle proposed by Moase, Brear & Manzie (J. Fluid Mech., vol. 585, 2007, pp. 281–304) to any arbitrary profile or equivalently any nozzle geometry. The equations are written as a function of three variables, namely the dimensionless mass, total temperature and entropy fluctuations, yielding a first-order linear system of differential equations with varying coefficients, which is solved using the Magnus expansion. The solution shows that both the modulus and the phase of the transfer functions of the nozzle have a strong dependence on the frequency. This holds for both choked flows and subsonic converging–diverging nozzles. The method is used to compare two different nozzle geometries with the same inlet and outlet Mach numbers, showing that, even if the compact solution predicts no differences between the transfer functions of the two nozzles, significant differences are found at non-zero frequencies. A parametric study is finally performed to calculate the indirect to direct noise ratio for a model combustor, showing that this ratio decreases at higher frequencies.
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