Survival modelling and cost-effectiveness analysis of treatments for newly diagnosed metastatic hormone-sensitive prostate cancer

Background In metastatic hormone-sensitive prostate cancer (mHSPC) treatment, survival benefits have been shown by adding docetaxel or recent androgen receptor axis-targeted therapies (ARATs) abiraterone, apalutamide, or enzalutamide to androgen deprivation therapy (ADT). However, the optimal treatment strategy in terms of costs and effects is unclear, not least due to high ARAT costs. Methods To assess treatment cost-effectiveness, we developed a Markov cohort model with health states of progression-free disease, progressive disease and death for men with newly diagnosed mHSPC, with a 30-year time horizon. Survival data, adverse events and utilities were informed by randomized controlled trial results, our meta-analysis of re-created individual patient survival data, and publicly available sources of unit costs. We applied a Swiss healthcare payer perspective and discounted costs and effects by 3%. Results We found a significant overall survival benefit for ADT+abiraterone versus ADT+docetaxel. The corresponding incremental cost-effectiveness ratio (ICER) was predicted to be EUR 39,814 per quality-adjusted life-year (QALY) gained. ADT+apalutamide and ADT+enzalutamide incurred higher costs and lower QALYs compared to ADT+abiraterone. For all ARATs, drug costs constituted the most substantial cost component. Results were stable except for a large univariable reduction in the pre-progression utility under ADT+abiraterone and very large variations in drug prices. Conclusions Our model projected ADT+abiraterone to be cost-effective compared to ADT+docetaxel at a willingness-to-pay threshold of EUR 70,400/QALY (CHF 100,000 applying purchasing power parities). Given lower estimated QALYs for ADT+apalutamide and ADT+enzalutamide compared to ADT+abiraterone, the former only became cost-effective (the preferred) treatment option(s) at substantial 75–80% (80–90%) price reductions

Treatments for Metastatic Hormone-sensitive Prostate Cancer: Systematic Review, Network Meta-analysis, and Benefit-harm assessment

Context: Multiple treatments for metastatic, hormone-sensitive prostate cancer (mHSPC) are available, but their effects on health-related quality of life (HRQoL) and benefit-harm balance remain unclear. Objective: To assess clinical effectiveness regarding survival and HRQoL, safety, and benefit-harm balance of mHSPC treatments. Evidence acquisition: We searched MEDLINE, EMBASE, CENTRAL, and ClinicalTrials.gov until March 1, 2022. Randomized controlled trials (RCTs) comparing docetaxel, abiraterone, enzalutamide, apalutamide, darolutamide, and radiotherapy combined with androgen deprivation therapy (ADT) mutually or with ADT alone were eligible. Three reviewers independently performed screening, data extraction, and risk of bias assessment in duplicate. Evidence synthesis: Across ten RCTs, we found relevant survival benefits for ADT + docetaxel (high certainty according to the Grading of Recommendations, Assessment, Development and Evaluation [GRADE]), ADT + abiraterone (moderate certainty), ADT + enzalutamide (low certainty), ADT + apalutamide (high certainty), and ADT + docetaxel + darolutamide (high certainty) compared with ADT alone. ADT + radiotherapy appeared effective only in low-volume de novo mHSPC. We found a short-term HRQoL decrease lasting 3-6 mo for ADT + docetaxel (moderate certainty) and a potential HRQoL benefit for ADT + abiraterone up to 24 mo of follow-up (moderate certainty) compared with ADT alone. There was no difference in HRQoL for ADT + enzalutamide, ADT + apalutamide, or ADT + radiotherapy over ADT alone (low-high certainty). Grade 3-5 adverse effect rates were increased with all systemic combination treatments. A benefit-harm assessment showed high probabilities (>60%) for a net clinical benefit with ADT + abiraterone, ADT + enzalutamide, and ADT + apalutamide, while ADT + docetaxel and ADT + docetaxel + darolutamide appeared unlikely (<40%) to be beneficial. Conclusions: Despite substantial survival benefits, no systemic combination treatment showed a clear HRQoL improvement compared with ADT alone. We found evidence for a short-term HRQoL decline with ADT + docetaxel and a higher net clinical benefit with ADT + abiraterone, ADT + apalutamide and ADT + enzalutamide. While individualized decision-making remains important and economic factors need to be considered, the evidence may support a general preference for the combination of ADT with androgen receptor axis-targeted therapies over docetaxel-containing strategies. Patient summary: We assessed different combination treatments for metastatic hormone-sensitive prostate cancer. While survival was better with all systemic combination treatments, there was no clear improvement in health-related quality of life compared with androgen deprivation therapy alone. Novel hormonal combination treatments had a more favorable benefit-harm balance than combination treatments that include chemotherapy. Keywords: Adverse effects; Benefit-harm assessment; Benefit-harm balance; Health-related quality of life; Network meta-analysis; Overall survival; Prostate cancer; Systematic revie

Search for supersymmetry in events with photons and low missing transverse energy in pp collisions at √s=7 TeV

This is the pre-print version of the Article. The official published version can be accessed from the links below - Copyright @ 2013 Elsevier.Many models of new physics, including versions of supersymmetry (SUSY), predict production of events with low missing transverse energy, electroweak gauge bosons, and many energetic final-state particles. The stealth SUSY model yields this signature while conserving R-parity by means of a new hidden sector in which SUSY is approximately conserved. The results of a general search for new physics, with no requirement on missing transverse energy, in events with two photons and four or more hadronic jets are reported. The study is based on a sample of proton–proton collisions at √s=7 TeV corresponding to 4.96 fb−1 of integrated luminosity collected with the CMS detector in 2011. Based on good agreement between the data and the standard model expectation, the data are used to determine model-independent cross-section limits and a limit on the squark mass in the framework of stealth SUSY. With this first study of its kind, squark masses less than 1430 GeV are excluded at the 95% confidence level.This study is supported by the BMWF and FWF (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, and FAPESP (Brazil); MES (Bulgaria); CERN; CAS, MoST, and NSFC (China); COLCIENCIAS (Colombia); MSES (Croatia); RPF (Cyprus); MEYS (Czech Republic); MoER, SF0690030s09 and ERDF (Estonia); Academy of Finland, MEC, and HIP (Finland); CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Germany); GSRT (Greece); OTKA and NKTH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); NRF and WCU (Korea); LAS (Lithuania); CINVESTAV, CONACYT, SEP, and UASLP-FAI (Mexico); MSI (New Zealand); PAEC (Pakistan); MSHE and NSC (Poland); FCT (Portugal); JINR (Armenia, Belarus, Georgia, Ukraine, Uzbekistan); MON, RosAtom, RAS and RFBR (Russia); MSTD (Serbia); SEIDI and CPAN (Spain); Swiss Funding Agencies (Switzerland); NSC (Taipei); ThEP, IPST and NECTEC (Thailand); TUBITAK and TAEK (Turkey); NASU (Ukraine); STFC (United Kingdom); DOE and NSF (USA)

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Endoscopic papillectomy for ampullary lesions in patients with familial adenomatous polyposis compared with sporadic lesions:A propensity score-matched cohort

Background Familial adenomatous polyposis (FAP) is a rare inherited syndrome that predisposes the patient to cancer. Treatment of FAP-related ampullary lesions is challenging and the role of endoscopic papillectomy has not been elucidated. We retrospectively analyzed the outcomes of endoscopic papillectomy in matched cohorts of FAPrelated and sporadic ampullary lesions (SALs). Methods This retrospective multicenter study included 1422 endoscopic papillectomy procedures. Propensity score matching including age, sex, comorbidity, histologic subtype, and size was performed. Main outcomes were complete resection (R0), technical success, complications, and recurrence. Results Propensity score matching identified 202 patients (101 FAP, 101 SAL) with comparable baseline characteristics. FAP patients were mainly asymptomatic (79.2% [95 %CI 71.2-87.3] vs. 46.5% [95 %CI 36.6-56.4]); P &lt; 0.001). The initial R0 rate was significantly lower in FAP patients (63.4% [95%CI 53.8-72.9] vs. 83.2% [95%CI 75.8-90.6]; P = 0.001). After repeated interventions (mean 1.30 per patient), R0 was comparable (FAP 93.1% [95%CI 88.0-98.1] vs. SAL 97.0% [95%CI 93.7-100]; P = 0.19). Adverse events occurred in 28.7%. Pancreatitis and bleeding were the most common adverse events in both groups. Severe adverse events were rare (3.5 %). Overall, 21 FAP patients (20.8% [95%CI 12.7-28.8]) and 16 SAL patients (15.8% [95%CI 8.6-23.1]; P = 0.36) had recurrence. Recurrences occurred later in FAP patients (25 [95 %CI 18.3-31.7] vs. 2 [95 %CI CI 0.06-3.9] months). Conclusions Endoscopic papillectomy was safe and effective in FAP-related ampullary lesions. Criteria for endoscopic resection of ampullary lesions can be extended to FAP patients. FAP patients have a lifetime risk of relapse even after complete resection, and require long-time surveillance.</p

Endoscopic papillectomy for ampullary lesions in patients with familial adenomatous polyposis compared with sporadic lesions:A propensity score-matched cohort

Background Familial adenomatous polyposis (FAP) is a rare inherited syndrome that predisposes the patient to cancer. Treatment of FAP-related ampullary lesions is challenging and the role of endoscopic papillectomy has not been elucidated. We retrospectively analyzed the outcomes of endoscopic papillectomy in matched cohorts of FAPrelated and sporadic ampullary lesions (SALs). Methods This retrospective multicenter study included 1422 endoscopic papillectomy procedures. Propensity score matching including age, sex, comorbidity, histologic subtype, and size was performed. Main outcomes were complete resection (R0), technical success, complications, and recurrence. Results Propensity score matching identified 202 patients (101 FAP, 101 SAL) with comparable baseline characteristics. FAP patients were mainly asymptomatic (79.2% [95 %CI 71.2-87.3] vs. 46.5% [95 %CI 36.6-56.4]); P &lt; 0.001). The initial R0 rate was significantly lower in FAP patients (63.4% [95%CI 53.8-72.9] vs. 83.2% [95%CI 75.8-90.6]; P = 0.001). After repeated interventions (mean 1.30 per patient), R0 was comparable (FAP 93.1% [95%CI 88.0-98.1] vs. SAL 97.0% [95%CI 93.7-100]; P = 0.19). Adverse events occurred in 28.7%. Pancreatitis and bleeding were the most common adverse events in both groups. Severe adverse events were rare (3.5 %). Overall, 21 FAP patients (20.8% [95%CI 12.7-28.8]) and 16 SAL patients (15.8% [95%CI 8.6-23.1]; P = 0.36) had recurrence. Recurrences occurred later in FAP patients (25 [95 %CI 18.3-31.7] vs. 2 [95 %CI CI 0.06-3.9] months). Conclusions Endoscopic papillectomy was safe and effective in FAP-related ampullary lesions. Criteria for endoscopic resection of ampullary lesions can be extended to FAP patients. FAP patients have a lifetime risk of relapse even after complete resection, and require long-time surveillance.</p

X-ray crystal spectrometer upgrade for ITER-like wall experiments at JET

The high resolution X-Ray crystal spectrometer at the JET tokamak has been upgraded with the main goal of measuring the tungsten impurity concentration. This is important for understanding impurity accumulation in the plasma after installation of the JET ITER-like wall (main chamber: Be, divertor: W). This contribution provides details of the upgraded spectrometer with a focus on the aspects important for spectral analysis and plasma parameter calculation. In particular, we describe the determination of the spectrometer sensitivity: important for impurity concentration determination

CTA Contributions to the 34th International Cosmic Ray Conference (ICRC2015)

List of contributions from the CTA Consortium presented at the 34th International Cosmic Ray Conference, 30 July - 6 August 2015, The Hague, The Netherlands.Comment: Index of CTA conference proceedings at the ICRC2015, The Hague (The Netherlands). v1: placeholder with no arXiv links yet, to be replaced once individual contributions have been all submitted; v2: final with arXiv links to all CTA contributions and full author lis