The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and ...radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants.
Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for
exonuclease domain were done to classify tumors as p53 abnormal (p53abn),
ultramutated (
mut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary end point was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis.
Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n = 93; 23%),
mut (n = 51; 12%), MMRd (n = 137; 33%), and NSMP (n = 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for
mut EC, 72% for MMRd EC, and 74% for NSMP EC (
< .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% (
= .019); 100% versus 97% for patients with
mut EC (
= .637); 68% versus 76% (
= .428) for MMRd EC; and 80% versus 68% (
= .243) for NSMP EC.
Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with
mut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients.
Standard molecular classification of endometrial cancers (EC) is now endorsed by the WHO and identifies p53-abnormal (p53abn) EC as the subgroup with the poorest prognosis and the most likely to ...benefit from adjuvant chemo(radio)therapy. P53abn EC are POLE wildtype, mismatch repair proficient and show abnormal immunohistochemical (IHC) staining for p53. Correct interpretation of routinely performed p53 IHC has therefore become of paramount importance. We aimed to comprehensively investigate abnormal p53 IHC patterns and their relation to clinicopathological and molecular features. Tumor material of 411 molecularly classified high-risk EC from consenting patients from the PORTEC-3 clinical trial were collected. p53 IHC was successful in 408 EC and was considered abnormal when the tumor showed a mutant expression pattern (including subclonal): overexpression, null or cytoplasmic. The presence of pathogenic mutations was determined by next generation sequencing (NGS). Abnormal p53 expression was observed in 131/408 (32%) tumors. The most common abnormal p53 IHC pattern was overexpression (n = 89, 68%), followed by null (n = 12, 9%) and cytoplasmic (n = 3, 2%). Subclonal abnormal p53 staining was observed in 27 cases (21%), which was frequently but not exclusively, associated with POLE mutations and/or MMRd (n = 22/27; p < 0.001). Agreement between p53 IHC and TP53 NGS was observed in 90.7%, resulting in a sensitivity and specificity of 83.6% and 94.3%, respectively. Excluding POLEmut and MMRd EC, as per the WHO-endorsed algorithm, increased the accuracy to 94.5% with sensitivity and specificity of 95.0% and 94.1%, respectively. Our data shows that awareness of the abnormal p53 IHC patterns are prerequisites for correct EC molecular classification. Subclonal abnormal p53 expression is a strong indicator for POLEmut and/or MMRd EC. No significant differences in clinical outcomes were observed among the abnormal p53 IHC patterns. Our data support use of the WHO-endorsed algorithm and combining the different abnormal p53 IHC patterns into one diagnostic entity (p53abn EC).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
3.
Vaccines for COVID‐19 Tregoning, J. S.; Brown, E. S.; Cheeseman, H. M. ...
Clinical and experimental immunology,
November 2020, Volume:
202, Issue:
2
Journal Article
Peer reviewed
Open access
The spread of the virus SARS‐CoV‐2, the cause of COVID‐19 has triggered a tidal wave of vaccine development. In the first 9 months since the virus emerged over 200 vaccines have begun pre‐clinical ...development, 36 of which have entered clinical trials. This review will cover the platforms under assessment, the immune responses underpinning the vaccines, the results so far and the considerations for the next steps.
Summary
Since the emergence of COVID‐19, caused by the SARS‐CoV‐2 virus at the end of 2019, there has been an explosion of vaccine development. By 24 September 2020, a staggering number of vaccines (more than 200) had started preclinical development, of which 43 had entered clinical trials, including some approaches that have not previously been licensed for human vaccines. Vaccines have been widely considered as part of the exit strategy to enable the return to previous patterns of working, schooling and socializing. Importantly, to effectively control the COVID‐19 pandemic, production needs to be scaled‐up from a small number of preclinical doses to enough filled vials to immunize the world’s population, which requires close engagement with manufacturers and regulators. It will require a global effort to control the virus, necessitating equitable access for all countries to effective vaccines. This review explores the immune responses required to protect against SARS‐CoV‐2 and the potential for vaccine‐induced immunopathology. We describe the profile of the different platforms and the advantages and disadvantages of each approach. The review also addresses the critical steps between promising preclinical leads and manufacturing at scale. The issues faced during this pandemic and the platforms being developed to address it will be invaluable for future outbreak control. Nine months after the outbreak began we are at a point where preclinical and early clinical data are being generated for the vaccines; an overview of this important area will help our understanding of the next phases.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Diffusion tensor imaging (DTI) studies consistently reported abnormalities in fractional anisotropy (FA) and radial diffusivity (RD), measures of the integrity of white matter (WM), in bipolar ...disorder (BD), that may reflect underlying pathophysiologic processes. There is, however, a pressing need to identify peripheral measures that are related to these WM measures, to help identify easily obtainable peripheral biomarkers of BD. Given the high lipid content of axonal membranes and myelin sheaths, and that elevated serum levels of lipid peroxidation are reported in BD, these serum measures may be promising peripheral biomarkers of underlying WM abnormalities in BD. We used DTI and probabilistic tractography to compare FA and RD in ten prefrontal-centered WM tracts, 8 of which are consistently shown to have abnormal FA (and/or RD) in BD, and also examined serum lipid peroxidation (lipid hydroperoxides, LPH and 4-hydroxy-2-nonenal, 4-HNE), in 24 currently euthymic BD adults (BDE) and 19 age- and gender-matched healthy adults (CONT). There was a significant effect of group upon FA in these a priori WM tracts (BDE<CONT: F1,41=6.8; P=0.013) and RD (BDE>CONT: F1,41=10.3; P=0.003), and a significant between-group difference in LPH (BDE>CONT: t40=2.4; P=0.022), but not in 4-HNE. Multivariate multiple regression analyses revealed that LPH variance explained, respectively, 59 and 51% of the variance of FA and RD across all study participants. This is the first study to examine relationships between measures of WM integrity and peripheral measures of lipid peroxidation. Our findings suggest that serum LPH may be useful in the development of a clinically relevant, yet easily obtainable and inexpensive, peripheral biomarkers of BD.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Knowledge products comprise assessments of authoritative information supported by standards, governance, quality control, data, tools, and capacity building mechanisms. Considerable resources are ...dedicated to developing and maintaining knowledge products for biodiversity conservation, and they are widely used to inform policy and advise decision makers and practitioners. However, the financial cost of delivering this information is largely undocumented. We evaluated the costs and funding sources for developing and maintaining four global biodiversity and conservation knowledge products: The IUCN Red List of Threatened Species, the IUCN Red List of Ecosystems, Protected Planet, and the World Database of Key Biodiversity Areas. These are secondary data sets, built on primary data collected by extensive networks of expert contributors worldwide. We estimate that US$160 million (range: US$116-204 million), plus 293 person-years of volunteer time (range: 278-308 person-years) valued at US$ 14 million (range US$12-16 million), were invested in these four knowledge products between 1979 and 2013. More than half of this financing was provided through philanthropy, and nearly three-quarters was spent on personnel costs. The estimated annual cost of maintaining data and platforms for three of these knowledge products (excluding the IUCN Red List of Ecosystems for which annual costs were not possible to estimate for 2013) is US$6.5 million in total (range: US$6.2-6.7 million). We estimated that an additional US$114 million will be needed to reach pre-defined baselines of data coverage for all the four knowledge products, and that once achieved, annual maintenance costs will be approximately US$12 million. These costs are much lower than those to maintain many other, similarly important, global knowledge products. Ensuring that biodiversity and conservation knowledge products are sufficiently up to date, comprehensive and accurate is fundamental to inform decision-making for biodiversity conservation and sustainable development. Thus, the development and implementation of plans for sustainable long-term financing for them is critical.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
To investigate associations of sociodemographic factors—race/ethnicity, neighborhood socioeconomic status (SES), and health insurance—with survival for adolescents and young adults (AYAs) ...with invasive cancer.
Methods
Data on 80,855 AYAs with invasive cancer diagnosed in California 2001–2011 were obtained from the California Cancer Registry. We used multivariable Cox proportional hazards regression to estimate overall survival.
Results
Associations of public or no insurance with greater risk of death were observed for 11 of 12 AYA cancers examined. Compared to Whites, Blacks experienced greater risk of death, regardless of age or insurance, while greater risk of death among Hispanics and Asians was more apparent for younger AYAs and for those with private/military insurance. More pronounced neighborhood SES disparities in survival were observed among AYAs with private/military insurance, especially among younger AYAs.
Conclusions
Lacking or having public insurance was consistently associated with shorter survival, while disparities according to race/ethnicity and neighborhood SES were greater among AYAs with private/military insurance. While health insurance coverage associates with survival, remaining racial/ethnic and socioeconomic disparities among AYAs with cancer suggest additional social factors also need consideration in intervention and policy development.
Background
Stagnant outcomes for adolescents and young adults (AYAs) 15–39 years of age with cancer are partly attributed to poor enrollment onto clinical trials. Initiatives have focused on ...increasing accrual, but changes at the population‐level are unknown. We examined patterns of clinical trial participation over time in AYA patients with cancer.
Procedure
We utilized medical record data from AYAs in two population‐based National Cancer Institute Patterns of Care Studies identified through the Surveillance, Epidemiology and End Results Program. Among 3135 AYAs diagnosed with non‐Hodgkin lymphoma (NHL), Hodgkin lymphoma, acute lymphoblastic leukemia (ALL), and sarcoma, we used multivariate logistic regression to evaluate patient and provider characteristics associated with clinical trial enrollment. Interaction terms evaluated variation in clinical trial enrollment across patient and provider characteristics by year of diagnosis.
Results
From 2006 to 2012–2013, clinical trial participation increased from 14.8% to 17.9% (P < 0.01). Adjusting for patient and provider characteristics, we found lower clinical trial enrollment among those who were older at diagnosis, diagnosed with NHL vs ALL, treated by adult hematologist/oncologists only (vs pediatric hematologist/oncologists), and of non‐Hispanic Black race/ethnicity (vs non‐Hispanic White) (P < 0.05 for all). Interaction analyses indicate improved clinical trial enrollment from 2006 to 2012–2013 among young adults 25–29 years of age and the uninsured.
Conclusions
Although disparities in enrollment onto clinical trials remain for AYAs with cancer, our study identified increasing overall clinical trial participation over time. Further, we identify promising trends in enrollment uptake among AYAs 25–29 years of age and the uninsured.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Adolescent and young adult (AYA) cancer survivors experience psychological distress often because of cancer and its treatment. However, no prior studies have evaluated the additional ...medical expenditures and health care utilization associated with psychological distress in AYA cancer survivors.
Methods
AYA cancer survivors and a comparison matched group of adults with no history of cancer were identified from 2011‐2016 Medical Expenditure Panel Survey data. Medical expenditures and health care utilization were evaluated with multivariable regression models.
Results
AYA cancer survivors were more likely to have psychological distress (11.5% of 1757) than adults with no history of cancer (5.8% of 5227). The prevalence of psychological distress was found to be high many years after the diagnosis, with 11.2% reporting distress ≥20 years after their cancer diagnosis. AYA cancer survivors with psychological distress were more likely to smoke and have chronic conditions and were less likely to exercise regularly in comparison with AYAs with no history of psychological distress. AYA cancer survivors with psychological distress had additional annual medical expenses ($4415; 95% CI, $993‐$9690), office visits (2.80; 95% CI, 0.23‐6.15), and use of prescription medications/medication renewals (11.58; 95% CI, 5.70‐19.47) in comparison with AYA cancer survivors without psychological distress. Additional annual medical expenses of psychological distress were $2600 higher in AYA cancer survivors than adults without a history of cancer ($1802; 95% CI, $440‐$3791).
Conclusions
These results highlight the substantial economic burden associated with psychological distress in AYA cancer survivors. This research could inform survivorship care plans and interventions addressing the psychological needs of AYA cancer survivors.
Psychological distress in adolescent and young adult cancer survivors is associated with substantial increases in health care expenses and utilization. Using survivorship care plans that acknowledge psychological needs can mitigate the impact of psychological distress in adolescent and young adult cancer survivors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The terms micro-thermal analysis and micro-spectroscopic analysis are used to include any form of localized characterization or analysis combined with microscopy that uses a near-field thermal probe ...to exploit the benefits of using thermal excitation. We describe the state of the art of scanning microscopy that uses resistive thermal probes, followed by an account of the various techniques of micro-thermal analysis. Modern materials technology is increasingly concerned with the control of materials at the mesoscale. The ability to add an extra dimension of, say, chemical composition information to high-resolution microscopy, or microscopic information to spectroscopy, plays an increasingly useful part in applied research. Micro-thermal analysis is now being used commercially to visualize the spatial distribution of phases, components and contaminants in polymers, pharmaceuticals, foods, biological materials, and electronic materials. This review outlines various applications that have been described in the literature to date, topics ranging from multi-layer packaging materials and interphase regions in composites, to the use of the technique as a means of surface treatment. (Author)
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