Limitations of the MELD score in predicting mortality or need for removal from waiting list in patients awaiting liver transplantation

<p>Abstract</p> <p>Background</p> <p>Decompensated cirrhosis is associated with a poor prognosis and liver transplantation provides the only curative treatment option with excellent long-term results. The relative shortage of organ donors renders the allocation algorithms of organs essential. The optimal strategy based on scoring systems and/or waiting time is still under debate.</p> <p>Methods</p> <p>Data sets of 268 consecutive patients listed for single-organ liver transplantation for nonfulminant liver disease between 2003 and 2005 were included into the study. The Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores of all patients at the time of listing were used for calculation. The predictive ability not only for mortality on the waiting list but also for the need for withdrawal from the waiting list was calculated for both scores. The Mann-Whitney-U Test was used for the univariate analysis and the AUC-Model for discrimination of the scores.</p> <p>Results</p> <p>In the univariate analysis comparing patients who are still on the waiting list and patients who died or were removed from the waiting list due to poor conditions, the serum albumin, bilirubin INR, and CTP and MELD scores as well as the presence of ascites and encephalopathy were significantly different between the groups (p < 0.05), whereas serum creatinine and urea showed no difference.</p> <p>Comparing the predictive abilities of CTP and MELD scores, the best discrimination between patients still alive on the waiting list and patients who died on or were removed from the waiting list was achieved at a CTP score of ≥9 and a MELD score of ≥14.4. The sensitivity and specificity to identify mortality or severe deterioration for CTP was 69.0% and 70.5%, respectively; for MELD, it was 62.1% and 72.7%, respectively. This result was supported by the AUC analysis showing a strong trend for superiority of CTP over MELD scores (AUROC 0.73 and 0.68, resp.; p = 0.091).</p> <p>Conclusion</p> <p>The long term prediction of mortality or removal from waiting list in patients awaiting liver transplantation might be better assessed by the CTP score than the MELD score. This might have implications for the development of new improved scoring systems.</p

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

The Stubenberg meteorite—An LL6 chondrite fragmental breccia recovered soon after precise prediction of the strewn field

On March 6, 2016 at 21:36:51 UT, extended areas of Upper Austria, Bavaria (Germany) and the southwestern part of the Czech Republic were illuminated by a very bright bolide. This bolide was recorded by instruments in the Czech part of the European Fireball Network and it enabled complex and precise description of this event including prediction of the impact area. So far six meteorites totaling 1473 g have been found in the predicted area. The first pieces were recovered on March 12, 2016 on a field close to the village of Stubenberg (Bavaria). Stubenberg is a weakly shocked (S3) fragmental breccia consisting of abundant highly recrystallized rock fragments embedded in a clastic matrix. The texture, the large grain size of plagioclase, and the homogeneous compositions of olivine (Fa31.4) and pyroxene (Fs25.4) clearly indicate that Stubenberg is an LL6 chondrite breccia. This is consistent with the data on O, Ti, and Cr isotopes. Stubenberg does not contain solar wind-implanted noble gases. Data on the bulk chemistry, IR spectroscopy, cosmogenic nuclides, and organic components also indicate similarities to other metamorphosed LL chondrites. Noble gas studies reveal that the meteorite has a cosmic ray exposure (CRE) age of 36 ± 3 Ma and that most of the cosmogenic gases were produced in a meteoroid with a radius of at least 35 cm. This is larger than the size of the meteoroid which entered the Earth's atmosphere, which is constrained to <20 cm from short-lived radionuclide data. In combination, this might suggest a complex exposure history for Stubenberg.PostprintPeer reviewe

The Sariçiçek Howardite Fall in Turkey: Source Crater of HED Meteorites on Vesta and İmpact Risk of Vestoids

The Sariçiçek howardite meteorite shower consisting of 343 documented stones occurred on 2 September 2015 in Turkey and is the first documented howardite fall. Cosmogenic isotopes show that Sariçiçek experienced a complex cosmic ray exposure history, exposed during ~12–14 Ma in a regolith near the surface of a parent asteroid, and that an ~1 m sized meteoroid was launched by an impact 22 ± 2 Ma ago to Earth (as did one third of all HED meteorites). SIMS dating of zircon and baddeleyite yielded 4550.4 ± 2.5 Ma and 4553 ± 8.8 Ma crystallization ages for the basaltic magma clasts. The apatite U-Pb age of 4525 ± 17 Ma, K-Ar age of ~3.9 Ga, and the U,Th-He ages of 1.8 ± 0.7 and 2.6 ± 0.3 Ga are interpreted to represent thermal metamorphic and impact-related resetting ages, respectively. Petrographic, geochemical and O-, Cr- and Tiisotopic studies confirm that Sariçiçek belongs to the normal clan of HED meteorites. Petrographic observations and analysis of organic material indicate a small portion of carbonaceous chondrite material in the Sariçiçek regolith and organic contamination of the meteorite after a few days on soil. Video observations of the fall show an atmospheric entry at 17.3 ± 0.8 kms-1 from NW, fragmentations at 37, 33, 31 and 27 km altitude, and provide a pre-atmospheric orbit that is the first dynamical link between the normal HED meteorite clan and the inner Main Belt. Spectral data indicate the similarity of Sariçiçek with the Vesta asteroid family (V-class) spectra, a group of asteroids stretching to delivery resonances, which includes (4) Vesta. Dynamical modeling of meteoroid delivery to Earth shows that the complete disruption of a ~1 km sized Vesta family asteroid or a ~10 km sized impact crater on Vesta is required to provide sufficient meteoroids ≤4 m in size to account for the influx of meteorites from this HED clan. The 16.7 km diameter Antonia impact crater on Vesta was formed on terrain of the same age as given by the 4He retention age of Sariçiçek. Lunar scaling for crater production to crater counts of its ejecta blanket show it was formed ~22 Ma ago

Regulation and function of CD70 and its clinical relevance in clear cell renal cell carcinoma

As treatment response for advanced renal cell carcinoma (RCC) is still limited, biomarkers to diagnose and predict the applicability of drugs are needed. The deregulation of the Von HippelLindau protein (pVHL)/hypoxiainducible factor (HIF) axis is a hallmark of clear cell RCC (ccRCC). Consequently, protein products of HIFregulated genes are considered potential therapeutic targets of this tumor type. In a previous work mass spectrometry analysis of RCC cell lines was used to define the ccRCC protein surfaceome. The expression pattern of these proteins was further validated on mRNA level. The overall objective of my PhD project was to select and analyse potential candidates of the RCC surfaceome for clinical applications. We focused our interest on the mechanism of the aberrant and frequent upregulation of CD70 in ccRCC. Since the discovery of the frequent overexpression of CD70 ccRCC in 2005, therapeutic antibodies targeting CD70 were developed, which are already under clinical evaluation. However, studies elucidating the regulation of the CD70 expression in RCC and the consequences of the constant interaction of CD70 with its unique receptor CD27 within the tumor microenvironment, are lacking. Immunohistochemical analyses of 667 RCC revealed elevated CD70 protein expression in 80% of primary tumors and metastases of ccRCC and in 32% of papillary RCC. We have found that in ccRCC abundant and frequent CD70 expression is directly driven by HIF. By analyzing VHL mutations, mRNA and protein expression patterns of pVHL, HIFα and several HIF targets in RCC tissues and cell lines, we found that CD70 upregulation is linked to the inactivation of pVHL. Reexpression of pVHL in pVHLdeficient cell lines as well as silencing of HIFα lead to attenuated CD70 expression, whereas transient overexpression of HIFα and hypoxia lead to increased CD70. Gene promoter analyses revealed that HIF directly binds to specific hypoxia response elements within the promoter of CD70 thereby activating its transcription. Furthermore, CD27+ lymphocytes preferentially infiltrate CD70expressing ccRCCs, which seems to be linked to a more aggressive biological behavior. Coculturing of RCC cell lines with peripheral blood mononuclear cells induced significant increase of soluble CD27 levels in the presence of CD70. This may explain the high soluble CD27 levels observed in the sera of patients with CD70expressing ccRCC infiltrated by CD27+ lymphocytes, thus suggesting soluble CD27 as diagnostic tool for ccRCC patient monitoring 2 Zusammenfassung Aufgrund des begrenzten Behandlungserfolgs von fortgeschrittenem Nierenzellkarzinom (NZK), bedarf es Biomarkern zur Diagnose und Prognose der Anwendbarkeit von Medikamenten. Die Aufhebung der „Von Hippel‐Lindau‐Protein (pVHL)/ Hypoxie‐ induzierbarer Faktor (HIF)“‐Achse ist ein Merkmal des klarzelligen NZK (kzNZK). Daraus ergibt sich die Möglichkeit, dass Gene, die von HIF gesteuert werden als therapeutische Ziele für diese Tumorart genutzt werden können. In einer früheren Arbeit wurde das Oberflächenproteom des kzNZK durch eine massenspektrometrische Analyse definiert. Das Expressionsmuster dieser Proteine wurde weiterhin auf mRNA‐Ebene validiert. Das Hauptanliegen meines PhD‐Projektes lag in der Auswahl und Analyse potentieller Kandidaten des NZK‐Oberflächenproteoms für deren klinische Anwendbarkeit. Wir richteten unser Interesse auf die Ursache der häufigen und fehlgeleiteten Überexpression von CD70 im kzNZK. Seit der Entdeckung der hohen und häufigen CD70‐Expression im kzNZK im Jahre 2005 wurden CD70‐zielgerichtete therapeutische Antikörper entwickelt, die schon klinisch getestet werden. Dennoch gibt es keine Studien, die veranschaulichen, wodurch die kontinuierliche Hochregulierung von CD70 im NZK gesteuert wird und was die Folgen der konstanten Interaktion von CD70 mit seinen einzig bekannten Rezeptor CD27 für die nahe Umgebung des Tumors sind. Immunhistochemische Analysen von 667 NZK ergaben eine erhöhte CD70‐ Expression in 80% der Primärtumoren und Metastasen des kzNZK und in 32% des papillären NZK. Wir haben herausgefunden, dass die hohe und häufige Expression von CD70 im kzNZK direkt durch HIF angetrieben wird. Durch die Analyse der VHL‐Mutationen, der mRNA‐ und Protein‐Expressionsmuster von pVHL, HIFα und verschiedener HIF‐gesteuerter Gene in NZK‐ Gewebe und ‐Zelllinien, haben wir entdeckt, dass CD70 mit der Inaktivierung von pVHL verknüpft ist. Die Wiederexpression von pVHL in pVHL‐defizienten Zelllinien als auch das Gen‐ Silencing von HIFα führten zu einer Abschwächung der CD70‐Expression, wohingegen eine vorübergehende Überexpression von HIFα und Hypoxie CD70 erhöhten. Genepromoter‐ Analysen legten dar, dass HIF direkt an spezifische Hypoxie‐Antwort‐Elemente innerhalb des Promoters von CD70 bindet und dadurch dessen Transkription auslöst. Des Weiteren infiltrieren CD27+ Lymphozyten bevorzugt CD70‐expreimierende kzNZK, was mit einem vermehrt aggressiven biologischen Verhalten zusammenzuhängen scheint. Kokultivierung von NZK‐Zelllinien mit mononukleären Zellen des periphären Blutes induzierten einen signifikanten Anstieg der gelösten CD27‐Menge an Anwesenheit von CD70. Dies könnte die Ursache der erhöhten gelösten CD27‐Mengen im Blutserum von Patienten mit CD70‐ exprimierenden NZK, die von CD27+ Lymphozyten infiltriert sind, sein. Deshalb ist der Einsatz von gelöstem CD27 als diagnostisches Instrument für die kzNZK‐Patientenbeobachtung denkbar

Interaction of tumor cells with infiltrating lymphocytes via CD70 and CD27 in clear cell renal cell carcinoma

CD70 upregulation by hypoxia-inducible factor and CD27(+) lymphocyte tumor infiltration are associated with worse survival in von Hippel-Lindau gene (VHL) mutated clear cell renal cell carcinoma (ccRCC). CD70/CD27 interaction is accompanied by high soluble CD27 levels in the sera of ccRCC patients suggesting that soluble CD27 is a potential predictive tool for anti-CD70 therapy

Early PSA Change after [177Lu]PSMA-617 Radioligand Therapy as a Predicator of Biochemical Response and Overall Survival

Purpose: Radioligand therapy with [177Lu]PSMA-617 (PSMA-RLT) is a promising therapeutic option for metastatic castration-resistant prostate cancer (mCPRP). This study assessed the prognostic value of early PSA measurements during PSMA-RLT. Methods: 27 patients with mCRPC scheduled for PSMA-RLT were prospectively enrolled for a serial short-interval PSA-assessment. Change in PSA (&#8710;%PSA) during two treatment cycles was correlated with biochemical response (BR) and change in tumor volume on PET (TV) after 16 weeks (w16), as well as overall survival (OS). PCWG3 criteria and the recently recommended threshold of &#8710;%PSA &le; &minus;30% were assessed for their predictive value. Results: &#8710;%PSA first correlated with BR, TV and OS after 4 weeks (c1w4). At c1w4, &#8710;%PSA &le; &minus;30% was associated with the biochemical response at w16 (p = 0.003) and a longer median OS (p = 0.025), whereas the PCWG3-derived threshold of &#8710;%PSA &le; &minus;50% showed no such correlation. In contrast, &#8710;%PSA &ge; 25% at c1w4 was associated with biochemical progression at w16 (p = 0.003) and a shorter median OS (p &lt; 0.001). Conclusion: PSA changes as early as four weeks after PSMA-RLT allow a significant prediction of later biochemical and PET-based imaging response, as well as OS. At this early time point, a more lenient threshold for a PSA decrease of at least 30% appears better-suited for the prediction of a positive biochemical response and longer OS. In contrast, the PCWG3-derived threshold for PSA increase (+25%) reliably anticipates biochemical progression and shorter OS

pVHL/HIF-regulated CD70 expression is associated with infiltration of CD27+ lymphocytes and increased serum levels of soluble CD27 in clear cell renal cell carcinoma

PURPOSE: CD70, a member of the TNF ligand superfamily, has been shown frequently overexpressed in clear cell renal cell carcinoma (ccRCC). The mechanisms of CD70's upregulation and its role in ccRCC are unknown. EXPERIMENTAL DESIGN: CD70 expression was immunohistochemically analyzed in 667 RCCs and RCC metastases. Von Hippel-Lindau gene (VHL) mutations, expression patterns of VHL protein (pVHL), hypoxia-inducible factor (HIF) α, and several HIF targets were studied in tissues and cell lines and correlated with CD70 overexpression. Gene promoter analysis was performed to confirm CD70 as HIF target gene. Consecutive tissue sections were immunostained to reveal the relation between CD70-expressing RCCs and tumor-infiltrating lymphocytes positive for the CD70 receptor (CD27). CD70-mediated release of soluble CD27 in RCC was assessed by coculture experiments and sera analysis of patients with RCC. RESULTS: Elevated CD70 expression was seen in 80% of primary tumors and metastases of ccRCC and correlated with dysregulation of the pVHL/HIF pathway. In vitro analyses demonstrated that CD70 upregulation is driven by HIF. Furthermore, CD27(+) lymphocytes preferentially infiltrate CD70-expressing ccRCCs. CD70-dependent release of soluble CD27 in cocultures may explain the high CD27 levels observed in sera of patients with CD70-expressing ccRCC. The combination of lymphocyte infiltration and CD70 expression in RCC was associated with worse patient outcome. CONCLUSION: Our findings demonstrate that in ccRCC, CD70 expression is regulated by HIF as a consequence of pVHL inactivation. Increased serum levels of CD27 suggest the existence of CD70-expressing ccRCC, thus representing a potential serum marker for patients suffering from this disease