PORTEC-2 was a randomised trial for women with high-intermediate risk (HIR) endometrial cancer, comparing pelvic external beam radiotherapy (EBRT) with vaginal brachytherapy (VBT). We evaluated ...long-term outcomes combined with the results of pathology review and molecular analysis.
427 women with HIR endometrial cancer were randomised between 2002-2006 to VBT or EBRT. Primary endpoint was vaginal recurrence (VR). Pathology review was done in 97.4%, combined with molecular analysis.
Median follow-up was 116 months; 10-year VR was 3.4% versus 2.4% for VBT vs. EBRT (p = 0.55). Ten-year pelvic recurrence (PR) was more frequent in the VBT group (6.3% vs. 0.9%, p = 0.004), mostly combined with distant metastases (DM). Ten-year isolated PR was 2.5% vs. 0.5%, p = 0.10, and DM 10.4 vs. 8.9% (p = 0.45). Overall survival for VBT vs. EBRT was 69.5% vs. 67.6% at 10 years (p = 0.72). L1CAM and p53-mutant expression and substantial lymph-vascular space invasion were risk factors for PR and DM. EBRT reduced PR in cases with these risk factors.
Long-term results of the PORTEC-2 trial confirm VBT as standard adjuvant treatment for HIR endometrial cancer. Molecular risk assessment has the potential to guide adjuvant therapy. EBRT provided better pelvic control in patients with unfavourable risk factors.
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).
Co-digestion changes slurry characteristics and is supposed to increase short-term nitrogen (N) uptake by crops after application. A higher N uptake from slurry reduces the need for additional ...mineral N fertilizer. If farmers apply co-digested slurry (CS), a higher N recovery has to be taken into account to prevent losses to the environment. Since data on the effects of co-digestion on N recovery by crops are scarce, a pot experiment was performed. The apparent N recovery (ANR) of five different co-digested pig slurries was compared with their raw source slurries (RS) during 105 d after a single fertilization of ryegrass (Lolium perenne L.), grown under controlled conditions. Slurry was mixed with sandy soil and grass was cut every 35 d. The results show that co-digestion increased (p < 0.05) the ANR at first cut on average from 39 to 50%, at second cut from 7 to 9% (p < 0.05), and had no effect on ANR at third cut (3%). The ANR increase at first cut was likely due to an increase of the NH4-N/total N ratio along with a decrease of the organic C/total N ratio of slurry during co-digestion. Field application may under certain circumstances decrease N fertilizer value of CS, due to a higher NH3 emission compared to RS. A potential ANR increase may then be reduced, absent, or even become a decrease. Under comparable NH3 emissions, however, CS can in the short term be more valuable as an N fertilizer than RS, and fertilizer savings can likely be realized.
The Miocene: The Future of the Past Steinthorsdottir, M.; Coxall, H. K.; de Boer, A. M. ...
Paleoceanography and Paleoclimatology,
April 2021, Letnik:
36, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The Miocene epoch (23.03–5.33 Ma) was a time interval of global warmth, relative to today. Continental configurations and mountain topography transitioned toward modern conditions, and many flora and ...fauna evolved into the same taxa that exist today. Miocene climate was dynamic: long periods of early and late glaciation bracketed a ∼2 Myr greenhouse interval—the Miocene Climatic Optimum (MCO). Floras, faunas, ice sheets, precipitation, pCO2, and ocean and atmospheric circulation mostly (but not ubiquitously) covaried with these large changes in climate. With higher temperatures and moderately higher pCO2 (∼400–600 ppm), the MCO has been suggested as a particularly appropriate analog for future climate scenarios, and for assessing the predictive accuracy of numerical climate models—the same models that are used to simulate future climate. Yet, Miocene conditions have proved difficult to reconcile with models. This implies either missing positive feedbacks in the models, a lack of knowledge of past climate forcings, or the need for re‐interpretation of proxies, which might mitigate the model‐data discrepancy. Our understanding of Miocene climatic, biogeochemical, and oceanic changes on broad spatial and temporal scales is still developing. New records documenting the physical, chemical, and biotic aspects of the Earth system are emerging, and together provide a more comprehensive understanding of this important time interval. Here, we review the state‐of‐the‐art in Miocene climate, ocean circulation, biogeochemical cycling, ice sheet dynamics, and biotic adaptation research as inferred through proxy observations and modeling studies.
Plain Language Summary
During the Miocene time period (∼23–5 million years ago), Planet Earth looked similar to today, with some important differences: the climate was generally warmer and highly variable, while atmospheric CO2 was not much higher. Continental‐sized ice sheets were only present on Antarctica, but not in the northern hemisphere. The continents drifted to near their modern‐day positions, and plants and animals evolved into the many (near) modern species. Scientists study the Miocene because present‐day and projected future CO2 levels are in the same range as those reconstructed for the Miocene. Therefore, if we can understand climate changes and their biotic responses from the Miocene past, we are able to better predict current and future global changes. By comparing Miocene climate reconstructions from fossil and chemical data to climate simulations produced by computer models, scientists are able to test their understanding of the Earth system under higher CO2 and warmer conditions than those of today. This helps in constraining future warming scenarios for the coming decades. In this study, we summarize the current understanding of the Miocene world from data and models. We also identify gaps in our understanding that need further research attention in the future.
Key Points
Miocene floras, faunas, and paleogeography were similar to today and provide plausible analogs for future climatic warming
The Miocene saw great dynamism in biotic and climate systems, but the reasons for these shifts are still not well understood
The pCO2‐temperature‐ice relationships during major Miocene climate oscillations and transitions warrant further research
Although the flavonol quercetin is intensively investigated, our knowledge about its bioavailability and possible target organs is far from being complete. The aim of this study was to check the ...potential of quercetin to accumulate in various tissues after long-term dietary treatment compared with a single treatment with flavonol. Pigs ingested either a single dose of quercetin aglycone (25 mg/kg body weight; Expt. 1) or received the flavonol twice a day at the same dose mixed into their regular meals (i.e 50 mg·kg⁻¹·d⁻¹) for 4 wk (Expt. 2). In both experiments, we took plasma and tissue samples 90 min after the final meal and analyzed them using HPLC. Additionally, the specific activity of the enzyme β-glucuronidase was measured in selected tissues. Higher flavonol concentrations than in plasma were found in only the liver (Expt. 1) or the intestinal wall and kidneys (Expt. 2). All tissues except blood plasma contained a variable amount of deconjugated quercetin in the range of 30-100% of total flavonols. However, the specific β-glucuronidase activity was not correlated with the proportions of deconjugated flavonols in the various tissues. Long-term dietary intake of the flavonol did not lead to a greater accumulation in any tissue compared with the single treatment. Flavonol concentrations only exceeded the plasma concentration within organs involved in its metabolism and excretion, including liver, small intestine, and kidneys.
Myxoid soft-tissue tumours are mesenchymal neoplasms, which are characterised by the production of abundant extracellular myxoid matrix. Imaging plays an important role in the diagnosis of these ...tumours as well as treatment planning. The imaging features as well as the clinical course for these lesions are highly variable, depending on both the anatomical location of the tumour and the histopathological subtype. This article, illustrated by histopathologically proven cases from our tertiary referral soft-tissue sarcoma centre, reviews the spectrum of imaging findings and characteristic signs seen with different types of benign and malignant myxoid soft-tissue neoplasms.
Background
Minimally invasive distal pancreatectomy decreases time to functional recovery compared with open distal pancreatectomy, but the cost‐effectiveness and impact on disease‐specific quality ...of life have yet to be established.
Methods
The LEOPARD trial randomized patients to minimally invasive (robot‐assisted or laparoscopic) or open distal pancreatectomy in 14 Dutch centres between April 2015 and March 2017. Use of hospital healthcare resources, complications and disease‐specific quality of life were recorded up to 1 year after surgery. Unit costs of hospital healthcare resources were determined, and cost‐effectiveness and cost–utility analyses were performed. Primary outcomes were the costs per day earlier functional recovery and per quality‐adjusted life‐year.
Results
All 104 patients who had a distal pancreatectomy (48 minimally invasive and 56 open) in the trial were included in this study. Patients who underwent a robot‐assisted procedure were excluded from the cost analysis. Total medical costs were comparable after laparoscopic and open distal pancreatectomy (mean difference €–427 (95 per cent bias‐corrected and accelerated confidence interval €–4700 to 3613; P = 0·839). Laparoscopic distal pancreatectomy was shown to have a probability of at least 0·566 of being more cost‐effective than the open approach at a willingness‐to‐pay threshold of €0 per day of earlier recovery, and a probability of 0·676 per additional quality‐adjusted life‐year at a willingness‐to‐pay threshold of €80 000. There were no significant differences in cosmetic satisfaction scores (median 9 (i.q.r. 5·75–10) versus 7 (4–8·75); P = 0·056) and disease‐specific quality of life after minimally invasive (laparoscopic and robot‐assisted procedures) versus open distal pancreatectomy.
Conclusion
Laparoscopic distal pancreatectomy was at least as cost‐effective as open distal pancreatectomy in terms of time to functional recovery and quality‐adjusted life‐years. Cosmesis and quality of life were similar in the two groups 1 year after surgery.
Laparoscopic distal pancreatectomy decreases time to functional recovery compared with open distal pancreatectomy, but the cost‐effectiveness has yet to be established. A cost‐effectiveness study was performed showing that laparoscopic distal pancreatectomy was at least as cost‐effective as the open approach in terms of time to functional recovery and quality‐adjusted life‐years.
Similar cost utility and quality of life
Ischemia/reperfusion injury (IRI) remains a major problem in renal transplantation. Clinical studies have identified that high serum levels of Mannan‐binding lectin (MBL), the initiator of the lectin ...pathway of complement activation, are associated with inferior renal allograft survival. Using a rat model, we identified an entirely novel role for MBL in mediating renal IRI. Therapeutic inhibition of MBL was protective against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. Following reperfusion, exposure of tubular epithelial cells to circulation‐derived MBL resulted in internalization of MBL followed by the rapid induction of tubular epithelial cell death. Interestingly, this MBL‐mediated tubular injury was completely independent of complement activation since attenuation of complement activation was not protective against renal IRI. Our identification that MBL‐mediated cell death precedes complement activation strongly suggests that exposure of epithelial cells to MBL immediately following reperfusion is the primary culprit of tubular injury. In addition, also human tubular epithelial cells in vitro were shown to be susceptible to the cytotoxic effect of human MBL. Taken together, these data reveal a crucial role for MBL in the early pathophysiology of renal IRI and identify MBL as a novel therapeutic target in kidney transplantation.
The authors find that the therapeutic inhibition of mannan‐binding lectin protects against renal ischemia/reperfusion injury, and that following reperfusion, mannan‐binding lectin is cytotoxic to tubular cells independent of complement activation.
Quercetin is a dietary polyphenolic compound with potentially beneficial effects on health. Claims that quercetin has biological effects are based mainly on in vitro studies with quercetin aglycone. ...However, quercetin is rapidly metabolized, and we have little knowledge of its availability to tissues. To assess the long-term tissue distribution of quercetin, 2 groups of rats were given a 0.1 or 1% quercetin diet approximately50 or 500 mg/kg body weight (wt) for 11 wk. In addition, a 3-d study was done with pigs fed a diet containing 500 mg quercetin/kg body wt. Tissue concentrations of quercetin and quercetin metabolites were analyzed with an optimized extraction method. Quercetin and quercetin metabolites were widely distributed in rat tissues, with the highest concentrations in lungs (3.98 and 15.3 nmol/g tissue for the 0.1 and 1% quercetin diet, respectively) and the lowest in brain, white fat, and spleen. In the short-term pig study, liver (5.87 nmol/g tissue) and kidney (2.51 nmol/g tissue) contained high concentrations of quercetin and quercetin metabolites, whereas brain, heart, and spleen had low concentrations. These studies have for the first time identified target tissues of quercetin, which may help to understand its mechanisms of action in vivo.
The transmission cycles of the foodborne pathogens Campylobacter and Salmonella are not fully elucidated. Knowledge of these cycles may help reduce the transmission of these pathogens to humans.
The ...presence of campylobacters and salmonellas was examined in 631 fresh fecal samples of wild insectivorous bats using a specially developed method for the simultaneous isolation of low numbers of these pathogens in small-sized fecal samples (≤ 0.1 g). Salmonella was not detected in the feces samples, but thermotolerant campylobacters were confirmed in 3% (n = 17) of the bats examined and these pathogens were found in six different bat species, at different sites, in different ecosystems during the whole flying season of bats. Molecular typing of the 17 isolated strains indicated C. jejuni (n = 9), C. coli (n = 7) and C. lari (n = 1), including genotypes also found in humans, wildlife, environmental samples and poultry. Six strains showed unique sequence types.
This study shows that insectivorous bats are not only carriers of viral pathogens, but they can also be relevant for the transmission of bacterial pathogens. Bats should be considered as carriers and potential transmitters of Campylobacter and, where possible, contact between bats (bat feces) and food or feed should be avoided.
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