HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an ...important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22-1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04-1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35-1.73, p < 0.001), microvascular (HR = 2.37, 95%-CI, 1.87-2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41-4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29-2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54-3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.
Gridded bottom-up inventories of CO2 emissions are needed in global CO2 inversion schemes as priors to initialize transport models and as a complement to top-down estimates to identify the ...anthropogenic sources. Global inversions require gridded datasets almost in near-real time that are spatially and methodologically consistent at a global scale. This may result in a loss of more detailed information that can be assessed by using regional inventories because they are built with a greater level of detail including country-specific information and finer resolution data. With this aim, a global mosaic of regional, gridded CO2 emission inventories, hereafter referred to as CoCO2-MOSAIC 1.0, has been built in the framework of the CoCO2 project.CoCO2-MOSAIC 1.0 provides gridded (0.1∘ × 0.1∘) monthly emissions fluxes of CO2 fossil fuel (CO2ff, long cycle) and CO2 biofuel (CO2bf, short cycle) for the years 2015–2018 disaggregated in seven sectors. The regional inventories integrated are CAMS-REG-GHG 5.1 (Europe), DACCIWA 2.0 (Africa), GEAA-AEI 3.0 (Argentina), INEMA 1.0 (Chile), REAS 3.2.1 (East, Southeast, and South Asia), and VULCAN 3.0 (USA). EDGAR 6.0, CAMS-GLOB-SHIP 3.1 and CAMS-GLOB-TEMPO 3.1 are used for gap-filling. CoCO2-MOSAIC 1.0 can be recommended as a global baseline emission inventory for 2015 which is regionally accepted as a reference, and as such we use the mosaic to inter-compare the most widely used global emission inventories: CAMS-GLOB-ANT 5.3, EDGAR 6.0, ODIAC v2020b, and CEDS v2020_04_24. CoCO2-MOSAIC 1.0 has the highest CO2ff (36.7 Gt) and CO2bf (5.9 Gt) emissions globally, particularly in the USA and Africa. Regional emissions generally have a higher seasonality representing better the local monthly profiles and are generally distributed over a higher number of pixels, due to the more detailed information available. All super-emitting pixels from regional inventories contain a power station (CoCO2 database), whereas several super-emitters from global inventories are likely incorrectly geolocated, which is likely because regional inventories provide large energy emitters as point sources including regional information on power plant locations. CoCO2-MOSAIC 1.0 is freely available at zenodo (10.5281/zenodo.7092358; Urraca et al., 2023) and at the JRC Data Catalogue (https://data.jrc.ec.europa.eu/dataset/6c8f9148-ce09-4dca-a4d5-422fb3682389, last access: 15 May 2023; Urraca Valle et al., 2023).
Abstract G-protein-coupled receptors (GPCRs) exist both as monomers and also as dimers or higher-order oligomers, representing assemblies either with their peers or with other classes of GPCR ...(“heterodimers”). The pharmacological profiles of heterodimers often differ from the corresponding monomers or homodimers. Heterodimerization of dopamine receptors has been shown for both the D1 /D5 and D2 /D3 /D4 receptor families, which couple positively and negatively, respectively, to adenylyl cyclase. Notably, heterodimers are formed by: D1 and adenosine A1 receptors; D2 or D3 and adenosine A2 receptors; and D2 and somatostatin SST5 receptors. Further, D1 ,D2 and D3 receptors physically assemble into functional D1 /D2 ,D1 /D3 and D2 /D3 heterodimers possessing binding and coupling profiles distinct from the respective monomers. This article reviews data on dopamine D3 /D2 and D3 /D1 heterodimers, including observations that some antiparkinsonian agents – such as the preferential high-efficacy D3 versus D2 receptor agonists, pramipexole and ropinirole –show amplified potency at D3 /D2 heterodimers versus constituent monomers, and others in contrast, such as the D3 /D2 receptor agonist pergolide, show no difference. This article also discusses allosteric modulation amongst heterodimeric dopamine receptors, whereby agonist actions at one member of a heterodimer influence functional coupling at the other protomer. Finally, it presents data showing that, in cells co-transfected with D3 and D1 receptors, long-term exposure to pramipexole and ropinirole (which possess negligible affinities for D1 sites) elicits supersensitivity of D1 receptor-activated adenylyl cyclase, and conversely, D3 /D2 receptor agonists such as apomorphine and bromocriptine (which also act as D1 receptor agonists) do not. A hypothetical relationship between these observations and the exacerbation of gambling in Parkinson's disease by antiparkinsonian agents is discussed.
The South East European International Institute for Sustainable Technologies (SEEIIST) was proposed in 2016 at the World Academy of Art and Science, with the objective of building a facility for ...charged particle cancer therapy for the South Eastern European countries. SEEIIST will offer the world-class research needed to reduce or even revert the brain drain that is causing a shortage of talent and economic losses in South East Europe. There is no particle therapy in South-East Europe in spite of a growing number of cancers being diagnosed. The facility beam time will be shared 50:50 between treating patients and performing research with a wide spectrum of different light ions beyond the presently used protons and carbon ions, which will make the facility unique in the world. SEEIIST Project is presently in a Conceptual to a Design Phase, implemented with the support of the EU and the involvement of CERN and GSI. The next phase of the project realization will include a final technical design for the facility, a structure and a business plan for the organization and the definition of conditions for the site selection.
Despite widespread cervical screening, an estimated 13,800 women will be diagnosed with cervical cancer in the United States in 2020. To inform improvements, the screening histories of women ...diagnosed with cervical cancer in New Mexico were assessed.
Data were collected on all cervical screening, diagnostic tests and treatment procedures for all women diagnosed with cervical cancer aged 25-64 yrs. in New Mexico from 2006 to 2016. Women were categorized by their screening attendance in the 5–40 months (screening interval) and 1–4 months (peri-diagnostic interval) prior to cancer diagnosis.
Of the 504 women diagnosed between May 2009–December 2016, 64% were not screened or had only inadequate screening tests in the 5–40 months prior to diagnosis, and 90 of 182 screened women (49%) had only negative screens in this period. Only 32% (N = 162) of cervical cancers were screen-detected. Women with adenocarcinomas were more likely to have had a recent negative screen (41/57 = 72%) than women with squamous cancers (50/112 = 45%). Both older women (aged 45–64 years) and women with more advanced cancers were less likely to have been screened, and if screened, were more likely to have a false-negative outcome. Only 9% of cancers were diagnosed in women who did not attend biopsy or treatment after positive tests requiring clinical management. Screening currently prevents 35% of cancers, whereas full screening coverage could prevent 61% of cervical cancers.
Improved screening coverage has the largest potential for reducing cervical cancer incidence, though there is also a role for improved recall procedures and screening sensitivity.
•64% of women diagnosed with cervical cancer aged 25-64y had not been screened in the 3-years prior to diagnosis.•Screening currently prevents 35% of cancers; full screening coverage could prevent 61% of cancers.•One-third of cervical cancers were screen-detected (i.e. diagnosed within 4 months of a positive screen).•72% of the adenocarcinomas had a negative screen in a 3-yr period prior to diagnosis.•9% of cancers were associated with a failure to receive recommended diagnostic biopsy or treatment (failsafe failure).
Cardiac computed tomography (CCT) was recently validated to measure extracellular volume (ECV) in the setting of cardiac amyloidosis, showing good agreement with cardiovascular magnetic resonance ...(CMR). However, no evidence is available with a whole-heart single source, single energy CT scanner in the clinical context of newly diagnosed left ventricular dysfunction. Therefore, the aim of this study was to test the diagnostic accuracy of ECVCCT in patients with a recent diagnosis of dilated cardiomyopathy, having ECVCMR as the reference technique.
39 consecutive patients with newly diagnosed dilated cardiomyopathy (LVEF <50%) scheduled for clinically indicated CMR were prospectively enrolled. Myocardial segment evaluability assessment with each technique, agreement between ECVCMR and ECVCCT, regression analysis, Bland-Altman analysis and interclass correlation coefficient (ICC) were performed.
Mean age of enrolled patients was 62 ± 11 years, and mean LVEF at CMR was 35.4 ± 10.7%. Overall radiation exposure for ECV estimation was 2.1 ± 1.1 mSv. Out of 624 myocardial segments available for analysis, 624 (100%) segments were assessable by CCT while 608 (97.4%) were evaluable at CMR. ECVCCT demonstrated slightly lower values compared to ECVCMR (all segments, 31.8 ± 6.5% vs 33.9 ± 8.0%, p < 0.001). At regression analysis, strong correlations were described (all segments, r = 0.819, 95% CI: 0.791 to 0.844). On Bland-Altman analysis, bias between ECVCMR and ECVCCT for global analysis was 2.1 (95% CI: −6.8 to 11.1). ICC analysis showed both high intra-observer and inter-observer agreement for ECVCCT calculation (0.986, 95%CI: 0.983 to 0.988 and 0.966, 95%CI: 0.960 to 0.971, respectively).
ECV estimation with a whole-heart single source, single energy CT scanner is feasible and accurate. Integration of ECV measurement in a comprehensive CCT evaluation of patients with newly diagnosed dilated cardiomyopathy can be performed with a small increase in overall radiation exposure.
TOC Summary: Extracellular volume estimation with cardiovascular magnetic resonance (ECVCMR) has been shown to be a reliable estimation of myocardial fibrosis, common endpoint in the majority of pathological mechanisms affecting cardiac muscle. However, cardiac computed tomography (CCT) with the latest generation single source, single energy CT scanner has several potential advantages over CMR for measuring the interstitium. In this study we found that ECVCCT is feasible and accurate compared to ECVCMR in the setting of recently diagnosed dilated cardiomyopathy, with only a small increase in overall radiation exposure. These results strengthen the concept of comprehensive cardiac assessment with CCT beyond coronary anatomy evaluation.
Systems pharmacology is a novel framework for drug research that models traditional and innovative pharmacological parameters and provides the overall efficacy and safety profile of a drug across ...body systems and complex, non-linear, molecular interactions. Lithium chloride, a pharmacological compound approved for the therapy of psychiatric disorders, represents a poorly explored compound for the treatment of Alzheimer's disease (AD). Lithium has been shown to reduce downstream effects associated with the aberrant overactivation of certain molecular pathways, such as glycogen synthase kinase 3 subunit β (GSK3-β)-related pathways, involved in AD-related pathophysiology. It seems that overactivation and overexpression of GSK3-β lead to an impairment of long-term potentiation and amyloid-β induced neurotoxicity that can be normalized using lithium. Moreover, a growing body of evidence has demonstrated that lithium's GSK3-β inhibitory effect prevents tau phosphorylation in mouse models of tauopathies. Clinical data have been inconclusive, partly due to methodological limitations. The lack of studies exploring the dynamics of protein misfolding in AD and investigating the specific tau-isoforms appearing prior to the accumulation of neurofibrillary tangles calls for new and optimized clinical trials. Advanced computer modeling based on a formal implementation of quantitative parameters and basic enzymatic insights into a mechanism-based model would present a good start to tackle these non-linear interactions. This innovative approach will pave the way for developing "molecularly" biomarker-guided targeted therapies, i.e., treatments specifically adapted ("tailored") to the individual, consistently with the primary objectives and key conceptual points of precision medicine and precision pharmacology.
Abstract Our objective was to determine if the All-Patient Refined Diagnosis-Related Groups (APR-DRGs) and other comorbidity scores correlate with pain level, functional abilities, and hospital cost ...after primary total joint arthroplasty (TJA). Three hundred three patients having TJA were evaluated with average follow-up of 21 months. Western Ontario and McMaster Universities osteoarthritis index, Short-Form 36, and Quality of Well-Being index were administered before and after surgery. The APR-DRG subclassification including severity of illness (SOI) subclass scores and risk of mortality (ROM), Charlson index, American Society of Anesthesiologist (ASA), Charnley score, length of stay, and hospital costs were reported. Patients in a higher SOI and ROM subclasses had a statistically significant decrease in functional outcomes scores, longer length of stay, and greater hospitals costs than those in lower subclasses. However, correlations of comorbidity categories with outcome scores were poor. The APR-DRG classification helps identify those individuals with worse function and is specially suited in identifying those patients who incur a higher hospital cost.
Molecular imaging is increasingly used to guide treatment decisions and planning in prostate cancer. We aimed to evaluate the role of
F-fluciclovine-PET/CT in improving cancer control compared with ...conventional imaging (bone scan and either CT or MRI) alone for salvage postprostatectomy radiotherapy.
In EMPIRE-1, a single-centre, open-label, phase 2/3 randomised controlled trial, patients with prostate cancer with detectable PSA after prostatectomy and negative conventional imaging (no extrapelvic or bone findings) were randomly assigned in a 1:1 ratio to radiotherapy directed by conventional imaging alone or to conventional imaging plus
F-fluciclovine-PET/CT. Computer-generated randomisation was stratified by PSA concentration, adverse pathology indicators, and androgen deprivation therapy intent. In the
F-fluciclovine-PET/CT group, radiotherapy decisions were rigidly determined by PET findings, which were also used for target delineation. The primary endpoint was 3 year event-free survival, with events defined as biochemical or clinical recurrence or progression, or initiation of systemic therapy, using univariate and multivariable analyses in patients who received radiotherapy. This trial is registered with ClinicalTrials.gov, NCT01666808 and is closed to new participants.
From Sept 18, 2012, to March 4, 2019, 165 patients were randomly assigned, with median follow-up of 3·52 years (95% CI 2·98-3·95). PET findings resulted in four patients in the
F-fluciclovine-PET/CT group having radiotherapy aborted; these patients were excluded from survival analyses. Median survival was not reached (95% CI 35·2-not reached; 33% of 81 patients had events) in the conventional imaging group compared with not reached (95% CI not reached-not reached; 20% of 76 patients) in the
F-fluciclovine-PET/CT group, and 3 year event-free survival was 63·0% (95% CI 49·2-74·0) in the conventional imaging group versus 75·5% (95% CI 62·5-84·6) for
F-fluciclovine-PET/CT (difference 12·5; 95% CI 4·3-20·8; p=0·0028). In adjusted analyses, study group (hazard ratio 2·04 95% CI 1·06-3·93, p=0·0327) was significantly associated with event-free survival. Toxicity was similar in both study groups, with the most common adverse events being late urinary frequency or urgency (37 46% of 81 patients in the conventional imaging group and 31 41% of 76 in the PET group), and acute diarrhoea (11 14% in the conventional imaging group and 16 21% in the PET group).
Inclusion of
F-fluciclovine-PET into postprostatectomy radiotherapy decision making and planning significantly improved survival free from biochemical recurrence or persistence. Integration of novel PET radiotracers into radiotherapy decisions and planning for prostate cancer patients warrants further study.
National Institutes of Health/National Cancer Institute, Blue Earth Diagnostics, and Winship Cancer Institute of Emory University.
Molecular imaging is increasingly used to guide treatment decisions and planning in prostate cancer. We aimed to evaluate the role of 18F-fluciclovine-PET/CT in improving cancer control compared with ...conventional imaging (bone scan and either CT or MRI) alone for salvage postprostatectomy radiotherapy.
In EMPIRE-1, a single-centre, open-label, phase 2/3 randomised controlled trial, patients with prostate cancer with detectable PSA after prostatectomy and negative conventional imaging (no extrapelvic or bone findings) were randomly assigned in a 1:1 ratio to radiotherapy directed by conventional imaging alone or to conventional imaging plus 18F-fluciclovine-PET/CT. Computer-generated randomisation was stratified by PSA concentration, adverse pathology indicators, and androgen deprivation therapy intent. In the 18F-fluciclovine-PET/CT group, radiotherapy decisions were rigidly determined by PET findings, which were also used for target delineation. The primary endpoint was 3 year event-free survival, with events defined as biochemical or clinical recurrence or progression, or initiation of systemic therapy, using univariate and multivariable analyses in patients who received radiotherapy. This trial is registered with ClinicalTrials.gov, NCT01666808 and is closed to new participants.
From Sept 18, 2012, to March 4, 2019, 165 patients were randomly assigned, with median follow-up of 3·52 years (95% CI 2·98–3·95). PET findings resulted in four patients in the 18F-fluciclovine-PET/CT group having radiotherapy aborted; these patients were excluded from survival analyses. Median survival was not reached (95% CI 35·2–not reached; 33% of 81 patients had events) in the conventional imaging group compared with not reached (95% CI not reached–not reached; 20% of 76 patients) in the 18F-fluciclovine-PET/CT group, and 3 year event-free survival was 63·0% (95% CI 49·2–74·0) in the conventional imaging group versus 75·5% (95% CI 62·5–84·6) for 18F-fluciclovine-PET/CT (difference 12·5; 95% CI 4·3–20·8; p=0·0028). In adjusted analyses, study group (hazard ratio 2·04 95% CI 1·06–3·93, p=0·0327) was significantly associated with event-free survival. Toxicity was similar in both study groups, with the most common adverse events being late urinary frequency or urgency (37 46% of 81 patients in the conventional imaging group and 31 41% of 76 in the PET group), and acute diarrhoea (11 14% in the conventional imaging group and 16 21% in the PET group).
Inclusion of 18F-fluciclovine-PET into postprostatectomy radiotherapy decision making and planning significantly improved survival free from biochemical recurrence or persistence. Integration of novel PET radiotracers into radiotherapy decisions and planning for prostate cancer patients warrants further study.
National Institutes of Health/National Cancer Institute, Blue Earth Diagnostics, and Winship Cancer Institute of Emory University.
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