Introduction
Prostate-specific membrane antigen (PSMA)-based radioligand therapy (RLT) showed in a multicentre WARMTH (World Association of Radiopharmaceutical and Molecular Therapy) study that the ...presence of bone metastases is a negative prognosticator for the survival. The current multicentre retrospective analysis aims to evaluate the response rate to RLT, the overall survival (OS) of patients and the safety of the treatment according to the extent of bone involvement.
Methods
The study included patients with progressive metastatic castration-resistant prostate cancer (mCRPC), who underwent RLT with
177
LuLu-PSMA-617 and a follow-up of at least 6 months. Tumour burden in the bone was classified prior to RLT as follows: less than 6 lesions, 6–20 lesions, more than 20 lesions and diffuse involvement. The response rate was evaluated using changes of the prostate-specific antigen (PSA) after the first treatment cycle. Overall survival was calculated from the date of the first treatment. Haematological adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
Results
A total of 319 males were included in the analysis. The extent of bone metastases and PSA response did not correlate significantly. Any PSA decline was observed in 73% patients; 44% showed a decline of ≥50%. The median OS of patient in the different subgroups was 18 months (less than 6 lesions), 13 months (6–20 lesions), 11 months (more than 20 lesions) and 8 months (diffuse involvement), respectively (
p
< 0.0001). Patients with prior Ra-223-therapy showed longer OS in all subgroups, especially in the subgroups with 6–20 lesions (OS: 16 vs. 12 months;
p
= 0.038) as well as diffuse involvement (OS: 11 vs. 7 months;
p
= 0.034). Significant negative prognosticators of OS were the existence of liver metastases in all subgroups and prior chemotherapy in patients with <6 bone lesions. Anaemia and thrombocytopenia correlated positively with the extent of bone metastases:
p
< 0.0001 and 0.005, respectively. No patient showed a high grade leukopenia.
Conclusion
The extent of bone involvement correlated negatively with the OS after RLT; however, it showed no relevant correlation with the PSA response rate. Prior therapy with Ra-223 may have a positive impact on OS. Haematotoxicity was higher in patients with more than 20 bone lesions; nevertheless, the majority of these patients did not show a relevant haematotoxicity.
Arabidopsis thaliana L. produces flavonoid pigments, i.e. flavonols, anthocyanidins and proanthocyanidins, from dihydroflavonol substrates. A small family of putative flavonol synthase (FLS) genes ...had been recognized in
Arabidopsis, and functional activity was attributed only to FLS1. Nevertheless, other FLS activities must be present, because
A. thaliana
fls1 mutants still accumulate significant amounts of flavonols. The recombinant FLSs and leucoanthocyanidin dioxygenase (LDOX) proteins were therefore examined for their enzyme activities, which led to the identification of FLS3 as a second active FLS. This enzyme is therefore likely responsible for the formation of flavonols in the
ldox/fls1-2 double mutant. These double mutant and biochemical data demonstrate for the first time that LDOX is capable of catalyzing the
in planta formation of flavonols.
Tissue inhibitor of metalloproteinases-1 (TIMP-1) plays a crucial role in the pathogenesis of hepatic fibrosis and thus may represent an important therapeutic target in the design of anti-fibrotic ...strategies for chronic liver disease. We present an innovative therapy based on the assignment of inactivated enzymes acting as scavengers for TIMP-1. Hepatic fibrosis was induced in BALB/c mice by repetitive intraperitoneal CCl₄ injection. The animals were treated with proteolytic inactive matrix metalloproteinase-9 mutants (E402Q, H401A, E402H/H411E) using adenovirus-mediated gene transfer. Application of these MMP-9 mutants inhibited fibrogenesis, which was indicated by decreasing portal and periportal accumulation of collagen. Total hydroxyproline of liver tissue, the morphometric stage of fibrosis as well as mRNA expression of marker proteins for hepatic fibrosis in livers of E402Q- and H401A-treated mice were significantly reduced. MMP-9 mutants suppressed transdifferentiation of hepatic stellate cells to the myofibroblast like phenotype in vitro and in vivo. Moreover, adenoviral application of the mutants MMP-9-H401A and -E402Q led to increased apoptosis of activated hepatic stellate cells, thought to be the main promoters of hepatic fibrosis. Application of MMP-9 mutants as TIMP-1 scavengers may provide a new therapeutic strategy for hepatic fibrosis.--Roderfeld, M., Weiskirchen, R., Wagner, S., Berres, M.-L., Henkel, C., Grötzinger, J., Gressner, A. M., Matern, S., Roeb, E. Inhibition of hepatic fibrogenesis by matrix metalloproteinase-9 mutants in mice.
Fibrogenesis or scarring of the liver is a common consequence of all chronic liver diseases. Here we refine a quantitative trait locus that confers susceptibility to hepatic fibrosis by in silico ...mapping and show, using congenic mice and transgenesis with recombined artificial chromosomes, that the gene Hc (encoding complement factor C5) underlies this locus. Small molecule inhibitors of the C5a receptor had antifibrotic effects in vivo, and common haplotype-tagging polymorphisms of the human gene C5 were associated with advanced fibrosis in chronic hepatitis C virus infection. Thus, the mouse quantitative trait gene led to the identification of an unknown gene underlying human susceptibility to liver fibrosis, supporting the idea that C5 has a causal role in fibrogenesis across species.
The aim of this guideline was to find evidence on whether carrying out Doppler examinations and CTGs in low-risk cohorts of pregnant women improves outcomes.
First, a systematic search for ...guidelines was carried out. Identified guidelines were evaluated using the DELPHI instrument of the AWMF. Three guidelines were found to be suitable to evaluate CTG. Two DEGUM best practice guidelines were judged suitable to describe the methods. All studies on this issue were additionally analyzed using 8 PICO questions. A structured consensus of the participating professional societies was achieved using a nominal group process and a structured consensus conference moderated by an independent moderator.
No antepartum Doppler sonography examinations should be carried out in low-risk cohorts in the context of antenatal care. No antepartum CTG should be carried out in low-risk cohorts. NOTE: The guideline will be published simultaneously in the official journals of both professional societies (i. e.,
for the DGGG and
for the DEGUM).
Purpose
The aim of this guideline was to find evidence on whether carrying out Doppler examinations and CTGs in low-risk cohorts of pregnant women improves outcomes.
Methods
First, a systematic ...search for guidelines was carried out. Identified guidelines were evaluated using the DELPHI instrument of the AWMF. Three guidelines were found to be
suitable to evaluate CTG. Two DEGUM best practice guidelines were judged suitable to describe the methods. All studies on this issue were additionally analyzed using 8 PICO questions. A
structured consensus of the participating professional societies was achieved using a nominal group process and a structured consensus conference moderated by an independent moderator.
Recommendations
No antepartum Doppler sonography examinations should be carried out in low-risk cohorts in the context of antenatal care. No antepartum CTG should be carried out in
low-risk cohorts.
Note
The guideline will be published simultaneously in the official journals of both professional societies (i.e.,
Geburtshilfe und Frauenheilkunde
for the DGGG and
Ultraschall in der Medizin/European Journal of Ultrasound
for the DEGUM).
Abstract
Purpose The aim of this guideline was to find evidence on whether carrying out Doppler examinations and CTGs in low-risk cohorts of pregnant women improves outcomes.
Methods First, a ...systematic search for guidelines was carried out. Identified guidelines were evaluated using the DELPHI instrument of the AWMF. Three guidelines were found to be
suitable to evaluate CTG. Two DEGUM best practice guidelines were judged suitable to describe the methods. All studies on this issue were additionally analyzed using 8 PICO questions. A
structured consensus of the participating professional societies was achieved using a nominal group process and a structured consensus conference moderated by an independent moderator.
Recommendations No antepartum Doppler sonography examinations should be carried out in low-risk cohorts in the context of antenatal care. No antepartum CTG should be carried out in
low-risk cohorts.
Note The guideline will be published simultaneously in the official journals of both professional societies (i.e., Geburtshilfe und Frauenheilkunde for the DGGG and
Ultraschall in der Medizin/European Journal of Ultrasound for the DEGUM).
Zusammenfassung
Ziel Das Ziel dieser LL ist die Etablierung der Evidenz dafür, ob in einem Low-Risk-Schwangerschaftskollektiv die Durchführung des Dopplers oder CTGs das Outcome verbessert.
Methoden Es wurde zunächst eine systematische Suche nach Leitlinien durchgeführt. Die aufgefundenen Leitlinien wurden mithilfe des DELPHI-Instruments der AWMF bewertet. Es wurden 3
LL für eine Adaptation für das CTG als grundsätzlich geeignet befunden. Es wurden 2 DEGUM Best Practice Guidelines für die Methodenbeschreibung als grundsätzlich geeignet befunden.
Zusätzlich wurden alle Studien zur Fragestellung anhand von 8 PICO-Fragen untersucht. Die strukturierte Konsensfindung zwischen den Fachgesellschaften erfolgte im Rahmen eines nominalen
Gruppenprozesses und einer strukturierten Konsenskonferenz unter unabhängiger Moderation.
Empfehlungen Im Low-Risk-Kollektiv sollte keine antepartuale Doppler-Sonografie im Rahmen der Überwachung durchgeführt werden. Im Low-Risk-Kollektiv sollte kein antepartuales CTG
geschrieben werden.
Hinweis Die Leitlinie wird gleichzeitig in den offiziellen Zeitschriften beider Fachgesellschaften (d. h. Geburtshilfe und Frauenheilkunde für die DGGG und Ultraschall in der
Medizin/European Journal of Ultrasound für die DEGUM) veröffentlicht.
: Background: Chronic hepatitis C is frequently associated with increased hepatic iron stores. It remains controversial whether heterozygous mutations of hemochromatosis genes affect fibrosis ...progression. Therefore our aim was to assess associations between HFE mutations and hepatic inflammation and stage of fibrosis in German hepatitis C patients.
Methods: Liver biopsies from 166 patients were scored for inflammatory activity (A0–4) and hepatic fibrosis (F0–4). Gene mutations were determined by LightCycler, restriction fragment length polymorphism analysis, or direct sequencing.
Results: The frequencies of common HFE mutations C282Y and H63D are 4.2% and 21.3%, whereas the recently described S65C substitution and the Y250X mutation in the transferrin receptor 2 gene are very rare. In regression analysis, heterozygous carriers of C282Y or H63D mutations display significantly (P<0.05) higher inflammatory activities and more advanced fibrosis than patients without mutations. For C282Y heterozygous patients, the odds ratios for marked inflammatory activity (A2–4) and advanced liver fibrosis or cirrhosis (F2–4) are 4.9 and 4.6, respectively, compared with patients carrying homozygous wild‐type alleles. C282Y mutations are associated with significantly (P<0.05) increased serum iron and aminotransferase levels, whereas H63D heterozygotes display higher transferrin saturation, serum iron, and ferritin concentrations compared to wild‐type (P<0.01).
Conclusions: Common heterozygous hemochromatosis mutations are associated with higher grades of inflammation and more severe hepatic fibrosis. Our findings support a role of HFE mutations as primary risk factors for fibrogenesis and disease progression in chronic hepatitis C.
AIM: To report a patient with C282Y homozygocity, depleted body iron and intestinal atrophy caused by celiac disease (CD) who experienced resolution of the enteropathy with subsequent normalization ...of iron metabolism upon glutenfree diet.METHODS: To obtain information on the tissue distribution and quantitative expression of proteins in volved induodenal iron trafficking, we determined the expression of divalent-metal transporter 1 (DMT1), ferroportin 1 (FP1) and transferrin receptor (TfR1) by means of immunohistochemistry and real-time PCR in duodenal biopsies of this patient.RESULTS: Whereas in hereditary hemochromatosis patients without CD, DMT1 expression was up-regulated leading to excessive uptake of iron, we identified a significant reduction in protein anti mRNA expression of DMT1 as a compensatory mechanism in this patient with HH and CD.CONCLUSION: Occult CD may compensate for increased DMT1 expression in a specific subset of individuals with homozygous C282Y mutations in the hemochromatosis(HFE) gene, thus contributing to the low penetrance of HH.
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