Long-term androgen deprivation therapy (ADT) combined with radiotherapy (RT) is a standard treatment for patients with localized high-risk prostate cancer (HRPC). However, the optimal duration of ADT ...is not yet defined.
The aim of this superiority randomized trial was to compare outcomes of RT combined with either 36 or 18 mo of ADT.
From October 2000 to January 2008, 630 patients with HRPC were randomized, 310 to pelvic and prostate RT combined with 36 mo (long arm) and 320 to the same RT with 18 mo (short arm) of ADT.
Overall survival (OS) and quality of life (QoL) were primary end points. OS rates were compared with Cox Regression model and QoL data were analyzed through mixed linear model.
With a median follow-up of 9.4 yr, 290 patients had died (147 long arm vs 143 short arm). The 5-yr OS rates (95% confidence interval) were 91% for long arm (88–95%) and 86% for short arm (83–90%), p=0.07. QoL analysis showed a significant difference (p<0.001) in six scales and 13 items favoring 18 mo ADT with two of them presenting a clinically relevant difference in mean scores of ≥10 points.
In localized HRPC, our results support that 36 mo is not superior to 18 mo of ADT. ADT combined with RT can potentially be reduced to 18 mo in selected men without compromising survival or QoL. Thus, 18 mo of ADT appears to represent a valid option in HRPC.
In this study, we report outcomes from high-risk prostate cancer patients treated with radiotherapy and either 36 or 18 mo of androgen deprivation therapy. There was no difference in survival between the two groups, with the 18-mo group experiencing a better quality of life.
In localized high-risk prostate cancer, the use of 18 mo of androgen deprivation therapy in combination with radiotherapy represents a valid therapeutic option. Moreover, the shorter hormonal duration improves quality of life and decreases health costs.
PURPOSE Patients with hematologic malignancies are increasingly admitted to the intensive care unit (ICU) when life-threatening events occur. We sought to report outcomes and prognostic factors in ...these patients. PATIENTS AND METHODS Ours was a prospective, multicenter cohort study of critically ill patients with hematologic malignancies. Health-related quality of life (HRQOL) and disease status were collected after 3 to 6 months. Results Of the 1,011 patients, 38.2% had newly diagnosed malignancies, 23.1% were in remission, and 24.9% had received hematopoietic stem-cell transplantations (HSCT, including 145 allogeneic). ICU admission was mostly required for acute respiratory failure (62.5%) and/or shock (42.3%). On day1, 733 patients (72.5%) received life-supporting interventions. Hospital, day-90, and 1-year survival rates were 60.7%, 52.5%, and 43.3%, respectively. By multivariate analysis, cancer remission and time to ICU admission less than 24 hours were associated with better hospital survival. Poor performance status, Charlson comorbidity index, allogeneic HSCT, organ dysfunction score, cardiac arrest, acute respiratory failure, malignant organ infiltration, and invasive aspergillosis were associated with higher hospital mortality. Mechanical ventilation (47.9% of patients), vasoactive drugs (51.2%), and dialysis (25.9%) were associated with mortality rates of 60.5%, 57.5%, and 59.2%, respectively. On day 90, 80% of survivors had no HRQOL alterations (physical and mental health similar to that of the overall cancer population). After 6 months, 80% of survivors had no change in treatment intensity compared with similar patients not admitted to the ICU, and 80% were in remission. CONCLUSION Critically ill patients with hematologic malignancies have good survival, disease control, and post-ICU HRQOL. Earlier ICU admission is associated with better survival.
Tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR) transduce information from the microenvironment into the cell and activate homeostatic signaling pathways. ...Internalization and degradation of EGFR after ligand binding limits the intensity of proliferative signaling, thereby helping to maintain cell integrity. In cancer cells, deregulation of EGFR trafficking has a variety of effects on tumor progression. Here we report that sortilin is a key regulator of EGFR internalization. Loss of sortilin in tumor cells promoted cell proliferation by sustaining EGFR signaling at the cell surface, ultimately accelerating tumor growth. In lung cancer patients, sortilin expression decreased with increased pathologic grade, and expression of sortilin was strongly correlated with survival, especially in patients with high EGFR expression. Sortilin is therefore a regulator of EGFR intracellular trafficking that promotes receptor internalization and limits signaling, which in turn impacts tumor growth.
In contrast to carbon‐substituted isocyanates that are common building blocks, N‐substituted isocyanates remain underdeveloped and reports on their N‐acyl derivatives (i. e. amido‐isocyanates) are ...exceedingly rare. Herein, amido‐isocyanates were investigated in the context of syntheses of aza‐tripeptide and hydantoins subunits starting from simple bench‐stable precursors. A key finding is that the amido‐isocyanate formed in situ cyclized to yield an oxadiazolone, and that under suitable reaction conditions this heterocycle is a traceless blocked (masked) N‐isocyanate. Using organic bases as catalysts and upon heating, oxadiazolone formation is observed, and various nucleophiles to provide the desired aza‐dipeptides or hydantoins in moderate to high yields. Further support for an amido‐isocyanate intermediate was obtained using carboxylic acids as nucleophiles, affording N‐acylhydrazide products.
Masked synthesis: N‐isocyanates are reactive intermediates and their N‐acyl derivatives, amido‐isocyanates, are rare. Herein, their synthesis and reactivity are studied, supporting that under suitable conditions the amido‐isocyanate is in equilibrium with the parent oxadiazolone. Reactions with amino‐amides as nucleophiles form nitrogen‐rich products, either aza‐tripeptides or their parent hydantoins. Support for an isocyanate intermediate was also obtained using carboxylate ions as nucleophiles, affording N‐acylhydrazides.
Topology optimization (TO) has become an integral part of the structural design process in recent years. However, automatically deriving parametrized Computer-Aided Design (CAD) models from TO ...results still represents a great challenge. In this paper, we present a new fully automatic process aimed at converting 3D TO results that tend towards beam-like structures into solid CAD models. Our reconstruction process starts with curve-skeletonization of the optimized shape. The curve-skeleton obtained is used alongside with a boundary triangulation of the optimized shape to compute closed cross-sections along the skeleton branches and junctions at the intersection between branches. These cross-sections are interpolated with cubic B-spline fitting curves, which are used as a basis for lofting operations to generate CAD surface representations of branches and junctions of the optimized shape. Remaining openings in the optimized shape boundary are closed with filling surfaces. A solid CAD model can be built by sewing together all created surfaces and filling, by the way, the closed boundary that comes out of this process. Finite Element Analysis (FEA) is carried out on both the 3D optimal shape and the CAD solid model derived in order to validate this CAD model. Several case studies are presented to demonstrate effectiveness and usefulness of this new approach.
•Reconstruction of 3D solid models from topology optimization results.•Based on curve-skeletonization, B-spline fitting curves and lofting operations.•Applied to beam-like topology optimization results.•FEA validation of 3D models generated.
This contribution analyzes the fundamental performance limits of traditional two-step Global Navigation Satellite System (GNSS) receiver architectures, which are directly linked to the achievable ...time-delay estimation performance. In turn, this is related to the GNSS baseband signal resolution, i.e., bandwidth, modulation, autocorrelation function, and the receiver sampling rate. To provide a comprehensive analysis of standard point positioning techniques, we consider the different GPS and Galileo signals available, as well as the signal combinations arising in the so-called GNSS meta-signal paradigm. The goal is to determine: (i) the ultimate achievable performance of GNSS code-based positioning systems; and (ii) whether we can obtain a GNSS code-only precise positioning solution and under which conditions. In this article, we provide clear answers to such fundamental questions, leveraging on the analysis of the Cramér-Rao bound (CRB) and the corresponding Maximum Likelihood Estimator (MLE). To determine such performance limits, we assume no external ionospheric, tropospheric, orbital, clock, or multipath-induced errors. The time-delay CRB and the corresponding MLE are obtained for the GPS L1 C/A, L1C, and L5 signals; the Galileo E1 OS, E6B, E5b-I, and E5 signals; and the Galileo E5b-E6 and E5a-E6 meta-signals. The results show that AltBOC-type signals (Galileo E5 and meta-signals) can be used for code-based precise positioning, being a promising real-time alternative to carrier phase-based techniques.
Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is a serious complication in the ICU that results in increased mortality and risk of chronic kidney disease (CKD). Some studies ...suggest RRT modality may have an impact on long-term renal recovery after AKI. However, other predictive factors of severe long-term CKD in ICU patients with AKI requiring RRT are unknown.
We performed an ancillary study of the multicenter ELVIS trial in the population with AKI requiring RRT. Patients alive 3 months after RRT initiation were eligible. Serum creatinine levels available at 3, 6 and 12 months and 3 and 5 years were recorded. CKD stage was determined according to the glomerular filtration rate as estimated by the CKD-EPI formula. At each timepoint, two groups of patients were compared, a no/mild CKD group with normal or mildly to moderately decreased renal function (stages 1, 2 and 3 of the international classification) and a severe CKD group (stages 4 and 5). Our objective was to identify predictive factors of severe long-term CKD.
Of the 287 eligible patients, 183 had follow-up at 3 months, 136 (74.3%) from the no/mild CKD group and 47 (25.7%) from the severe CKD group, and 122 patients at 5 years comprising 96 (78.7%) from the no/mild CKD group and 26 (21.3%) from the severe CKD group. Multivariate analysis showed that a long RRT period was associated with severe CKD up to 12 months (OR
= 1.03 95% CI 1.02-1.05 per day) and that a high SOFA score at the initiation of RRT was not associated with severe CKD up to 5 years (OR
= 0.85 95% CI 0.77-0.93 per point).
Severe long-term CKD was found in 21% of ICU survivors who underwent RRT for AKI. The duration of the RRT in AKI patients was identified as a new predictive factor for severe long-term CKD. This finding should be taken into consideration in future studies on the prognosis of ICU patients with AKI requiring RRT. Trial registration ELVIS trial was registered with ClinicalTrials.gov, number: NCT00875069 (June 16, 2014), and this ancillary study was registered with ClinicalTrials.gov, number: NCT03302624 (October 6, 2017).
By using photo‐redox catalysis in flow the newly marketed drug entrectinib (referred to by the brand name Rozlytrek) was synthesized in 6 linear steps from readily available building blocks under ...mild conditions. Evaluation of multiple intermediates for their use in the critical C−N amination step in flow led to the finding that more electron deficient aryl‐halides achieve higher conversion to the desired product. Data supports that more electron rich aryl‐halides undergo a significant amount of hydro‐dehalogenation compared to the productive C−N bond formation. Through evaluating various entry points into the synthesis of entrectinib, shorter routes were identified albeit in low yields. The modularity of this route will allow chemists to rapidly synthesize a diverse library of compounds through this route. Via different synthetic intermediates, a scale‐up route was discovered for the synthesis of entrectinib using photo‐redox in flow in less steps than previously reported, highlighting the utility of flow chemistry in the pharmaceutical industry.
The newly marketed drug entrectinib was synthesized in 6 steps using photo‐redox in flow as the key C−N bond forming step. Through investigating various substrates for the C−N coupling in flow it was discovered that more electron‐poor aryl halides perform optimally in the coupling step. Through varying residence time, temperature, and catalyst loadings tools to reduce hydro‐dehalogenation were discovered.
Global Navigation Satellite Systems (GNSS) are the main source of position, navigation, and timing (PNT) information and will be a key player in the next-generation intelligent transportation systems ...and safety-critical applications, but several limitations need to be overcome to meet the stringent performance requirements. One of the open issues is how to provide precise PNT solutions in harsh propagation environments. Under nominal conditions, the former is typically achieved by exploiting carrier phase information through precise positioning techniques, but these methods are very sensitive to the quality of phase observables. Another option that is gaining interest in the scientific community is the use of large bandwidth signals, which allow obtaining a better baseband resolution, and therefore more precise code-based observables. Two options may be considered: (i) high-order binary offset carrier (HO-BOC) modulations or (ii) the concept of GNSS meta-signals. In this contribution, we assess the time-delay and phase maximum likelihood (ML) estimation performance limits of such signals, together with the performance translation into the position domain, considering single point positioning (SPP) and RTK solutions, being an important missing point in the literature. A comprehensive discussion is provided on the estimators’ behavior, the corresponding ML threshold regions, the impact of good and bad satellite constellation geometries, and final conclusions on the best candidates, which may lead to precise solutions under harsh conditions. It is found that if the receiver is constrained by the receiver bandwidth, the best choices are the L1-M or E6-Public Regulated Service (PRS) signals. If the receiver is able to operate at 60 MHz, it is recommended to exploit the full-bandwidth Galileo E5 signal. In terms of robustness and performance, if the receiver can operate at 135 MHz, the best choice is to use the GNSS meta-signals E5 + E6 or B2 + B3, which provide the best overall performances regardless of the positioning method used, the satellite constellation geometry, or the propagation conditions.
Behind the mask: Nitrogen‐substituted isocyanates are rare and their synthetic potential is virtually untapped. Simple masked precursors can form amphoteric amino isocyanate intermediates in situ, ...and allows the synthesis of complex hydrazine derivatives upon addition with amines. This reactivity was used in a cascade substitution/hydroamination sequence, and in the assembly of azadipeptide analogues.
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