Bei verschiedenen Schmerztypen besteht eine nicht vorhersehbare Sensibilität gegenüber Opioiden, selbst bei gleicher Schmerzpathogenese variierte die Opioidsensibilität. Klinisch wird der Morphintest ...empfohlen. Unter monitorgestützter Überwachung wird Morphin kontinuierlich i.v. verabreicht und Schmerzreduktion wie Nebenwirkung registriert. Retrospektiv wurde die Reaktion auf eine ärztlich kontrollierte nasale Fentanylgabe ausgewertet und in Bezug auf den Erfolg einer anschließenden Ein- oder Umstellung nach WHO III gesetzt.
Methodik:
Patienten, die im Rahmen der SAPV Betreuung einen dringenden Hausbesuch aufgrund von Schmerzen anforderten, erhielten unter SO2- Überwachung 0,1mg Fentanyl nasal vom Arzt. Bei fehlender Reaktion Wiederholung nach 5 Minuten. Bei erfolgreicher Schmerzreduktion wurde die Dosis des retardierten Opioids bedarfsadaptiert angepasst. Die Schmerzstärke wurde nach VAS bestimmt.
Ergebnis:
Ausgewertet wurden die Besuche bei 21 Patienten mit starken Schmerzen. Die Schmerzstärke lag vor Applikation im Schnitt bei 8 (Median, 4–10). Nur bei einer Patientin führten auch 0,2mg Fentanyl zu keiner Schmerzreduktion, auch die anschließende ambulante Einstellung gelang nicht. Bei allen anderen Patienten kam es zu einer deutlichen Schmerzreduktion zumindest in Teilbereichen (2 Patienten unterschieden verschiedene Schmerzen, ein brennender Schmerztyp verblieb). Alle Patienten profitierten in der Folge von einer adaptierten Einstellung nach WHO III.
Fazit:
Mittels Morphintest kann die Opioidsensibilität von Schmerzen ermittelt werden Schauberger 1999. Bei Morphin sind jedoch verzögerte Opioidwirkungen möglich, eine Überwachung daher für Stunden notwendig. Dies ist bei häuslicher Betreuung kaum durchführbar. Im Rahmen der hier durchgeführten Pilotuntersuchung wurde die Wirkung mittels 0,1–0,2mg Fentanyl nasal bei fast allen Patienten eine Schmerzreduktion erzielt, diese Patienten profitierten gleichsam von einer anschließenden Erhöhung des Retardopioids.
Bei Patienten in spezialisierter ambulanter Palliativversorgung (SAPV) sind depressive Verstimmungen ein häufiges Problem. In einer fragebogengestützten Pilotuntersuchung im Rahmen der SAPV sollte ...die Korrelation zwischen Beck'schem Depressionsinventar (BDI) und einer Symptomliste untersucht werden.
Methodik:
Zur Auswertung kam ein routinemäßig verwendeter Symptomfragebogen aus dem Palliativnetz Bochum e.V.. Die aus der Selbsteinschätzung mit Werten von 0 (nicht vorhanden) bis 10 (maximal vorhanden) angegebene Symptomschwere wurde in Bezug zur Auswertung des BDI gebracht.
Ergebnis:
55 Patienten oder ihre Angehörigen füllten den Bogen aus, bei 50 war das BDI auswertbar, welches im Median bei 28,5 lag. Bei den 25 Patienten unterhalb des Medians (in Klammern Symptomschwere bei den übrigen mit höheren Depressionswerten) lag die Symptomschwere im Mittel bei: max Schmerz 7,8 (8,0), Übelkeit 1,6 (3,6), Erbrechen 0,9 (2,4), Obstipation 0,8 (4,3), Dyspnoe 3 (4,2), Fatigue 4,7 (8), Ängste 3,5 (4,3), gefühlte Belastung 4,1 (6,5 alles n.s.).
Diskussion:
Das Beck'sche Depressionsinventar ist ein valides Instrument zur Einschätzung einer möglichen depressiven Stimmungslage Beck 1996. Im Mittel lagen die Patienten vor SAPV Betreuung auf einer 70% Perzentile im Vergleich zur Normalbevölkerung und waren somit insgesamt depressiver nach diesem Screening. Wenngleich aufgrund der geringen Studiengröße kein Signifikanzniveau erreicht wurde, so zeigten sich durchgehend höhergradige Symptomschweren bei den depressiven Patienten, vor allem bei Übelkeit, Erbrechen, Obstipation, Fatigue und Angst.
Fazit:
Die Untersuchung gibt Hinweise, dass depressive Patienten in palliativer Situation eine höhere Symptomschwere haben. Depression und Symptomlast kommen wechselseitig als Ursache und Wirkung in Frage. In der Praxis sollten vor einer langsam wirkenden und nebenwirkungsträchtigen antidepressiven Therapie adäquate symptomkontrollierende Maßnahmen erwogen werden.
Abstract This paper describes the experience with the calibration, reconstruction and evaluation of the timing capabilities of the CMS HGCAL prototype in the beam tests in 2018. The calibration ...procedure includes multiple steps and corrections ranging from tens of nanoseconds to a few hundred picoseconds. The timing performance is studied using signals from positron beam particles with energies between 20 GeV and 300 GeV. The performance is studied as a function of particle energy against an external timing reference as well as standalone by comparing the two different halves of the prototype. The timing resolution is found to be 60 ps for single-channel measurements and better than 20 ps for full showers at the highest energies, setting excellent perspectives for the HGCAL calorimeter performance at the HL-LHC.
Mice lacking c-fos develop osteopetrosis due to a block in osteoclast differentiation. Carboxy-terminal phosphorylation of Fos on serine 374 by ERK1/2 and serine 362 by RSK1/2 regulates Fos stability ...and transactivation potential in vitro. To assess the physiological relevance of Fos phosphorylation in vivo, serine 362 and/or serine 374 was replaced by alanine (Fos362A, Fos374A and FosAA) or by phospho-mimetic aspartic acid (FosDD). Homozygous mutants were healthy and skeletogenesis was largely unaffected. Fos C-terminal phosphorylation, predominantly on serine 374, was found important for osteoclast differentiation in vitro and affected lipopolysaccharide (LPS)-induced cytokine response in vitro and in vivo. Importantly, skin papilloma development was delayed in FosAA, Fos362A and Rsk2-deficient mice, accelerated in FosDD mice and unaffected in Fos374A mutants. Furthermore, the related Fos protein and putative RSK2 target Fra1 failed to substitute for Fos in papilloma development. This indicates that phosphorylation of serines 362 and 374 exerts context-dependent roles in modulating Fos activity in vivo. Inhibition of Fos C-terminal phosphorylation on serine 362 by targeting RSK2 might be of therapeutic relevance for skin tumours.
Hairy cell leukemia (HCL) comprises the clonal malignancies classical and variant hairy cell leukemia (vHCL). Classical HCL (cHCL) is characterized by a near 100% frequency of the BRAFV600E mutations ...while ~50% of vHCL have MAP2K1 mutations. However, recurrent genetic alterations cooperating with BRAFV600E or MAP2K1 mutations in HCL, as well as those in MAP2K1 - wild type vHCL are not well defined. Therefore, we performed deep targeted mutational and copy number (CN) analysis of cHCL (n=53) and vHCL (n=8) to gain additional insights into the pathogenesis and mechanisms of therapeutic resistance in HCL.
Diagnostic bone marrow (BM) or peripheral blood (PB) mononuclear cells (MNCs) were obtained from 53 cHCL and 8 vHCL patients from multiple centers. Mutational and CN analysis of MNCs (and FACS-purified HCL cells for some cases) was performed using a targeted next-generation sequencing assay, which sequences all coding regions of 585 genes recurrently mutated in leukemias, lymphomas, and solid tumors.
Of the 53 cHCL patients, 100% were marked by BRAFV600E mutations, and the next most commonly mutated genes were the histone methyltransferase KMT2C (MLL3) and CDKN1B occurring in 15% (8/53) and 11% (6/53) of patients, respectively. Other recurrent mutations in cHCL affected genes involved in transcriptional regulation (BRD4, CEBPA, CREBBP, RUNX1, EP300, and MED12), Notch signaling (NOTCH1 and NOTCH2), and DNA repair (RAD50) (Fig. A). The most recurrent copy alterations in cHCL were deletions of chromosome 7q and 13q and gains of chromosome 5. Chromosome 7q and 13q deletions were confirmed by FISH. While recurrent 7q deletions have previously been reported in cHCL, genes in the minimally deleted region of 7q were not known and identified here to include SMO (7q32) and BRAF (7q34). Recurrent 13q deletions in cHCL include the tumor suppressor RB1 and the miR-15a and miR-16-1 microRNA cluster at 13q14.3 (Fig. B-D).
Sequencing across 8 additional vHCL patients identified change-of-function mutations in both CCND3 and U2AF1, each in 13% (1/8) of vHCL patients and hotspot mutations in TP53 (38%; 3/8) (Fig. E). The CCND3 and U2AF1 mutations were absent in cHCL suggesting additional genetic differences between cHCL and vHCL. These findings may have therapeutic relevance as CCND3 mutations are thought to confer sensitivity to CDK4/CDK6 inhibitors while those in U2AF1 confer sensitivity to spliceosome inhibitors. Other mutations affecting genes involved in transcriptional regulation (CEBPA, CREBBP, DDX3X, and PBRM1) and chromatin remodeling (KMT2C, KDM6A, and KDM5C) were also identified (Fig. E). As with cHCL, chromosome 7q deletions were also present in vHCL and always included BRAF (7q34). Additionally, we identified recurrent 3p deletions in vHCL, which include a critical tumor suppressor locus encoding VHL, SETD2, BAP1, and PBRM1 (Fig. F).
Prior studies have identified acquired KRAS mutations as driving vemurafenib resistance in HCL. Here we identified an activating mutation in NRAS in a treatment naïve cHCL patient. In addition, genomic analysis of the pre-treatment sample from a patient that developed de novo vemurafenib resistance uncovered a clonal hemizygous BRAFV600E mutation, as well as heterozygous deletions of BRAF, NF1, NF2, and TP53 (Fig. G). Consistent with the heterozygous deletion of NF1 and NF2, the de novo vemurafenib-resistant patient showed decreased expression of both NF1 and NF2 while vemurafenib-sensitive patients without NF1 or NF2 copy loss did not demonstrate decreased expression of NF1/NF2 by qRT-PCR. To understand the functional role of Nf1 and Nf2 loss and the potential contribution to RAF inhibitor resistance in the hematological system, we performed shRNA-mediated downregulation of Nf1 or Nf2 in Ba/F3 cells stably expressing BRAFV600E. Silencing of either Nf1 or Nf2 alone or concomitant downregulation of Nf1 and Nf2 simultaneously conferred vemurafenib resistance in vitro (Fig. H).
Combined, these data identify several novel drivers of HCL. While activating MAPK mutations are critical for both cHCL and vHCL, our data suggest additional shared cooperating alterations, as well as disease-specific alterations targeting BRAF, KMT2C, and CDKN1B in cHCL and MAP2K1, CCND3, U2AF1, TP53, and KMT2C in vHCL. Finally, these data nominate several novel potential therapeutic approaches for vHCL and identify a novel mechanism of vemurafenib resistance seen clinically.
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Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
Introduction:
About one third of all patients with Chronic Lymphocytic Leukemia (CLL) have quasi-identical, so-called stereotyped B-cell receptors (BCR) that can be divided into subsets ...(Agathangelidis et al. Blood 2012). At present, 19 major subsets have been described that account for approximately 12% of all patients with CLL. Of these, subsets #1 and #2 are associated with a poor prognosis (Baliakas et al. Lancet Hematology 2014). The HOVON68 trial compared fludarabine and cyclophosphamide (FC) chemotherapy to chemo-immunotherapy with low-dose alemtuzumab (FCA) as a first line treatment in selected high risk patients defined as either harboring 17p deletion, 11q deletion, trisomy 12, having unmutated mmunoglobulin heavy variable genes (IGHV) and/or VH3-21. The study showed a benefit of adding low-dose alemtuzumab to FC (Geisler et al. Blood 2014). Here, we studied the impact of BCR stereotypy subsets on the primary outcome progression free survival (PFS) and overall survival (OS).
Methods:
Sequences from IGHV mutational analyses were collected from participating centers in Sweden, Norway, Finland, Denmark, and the Netherlands. Subsets were assigned based on the ARResT/AssignSubsets software (Bystry et al. Bioinformatics 2015). Analysis for recurrent mutations were performed by next generation sequencing by a 454 based platform (Roche Diagnostics Corporation, Indianapolis, USA). All other clinical data were extracted from the HOVON database as of November 2016. Kaplan-Meier curves, log-rank tests, and Cox regression models were used for survival analysis. Fisher's exact test was used for contingency table analysis. P-values < 0.05 were considered statistically significant.
Results:
A total of 187 sequences were available. Of these, 176 were suitable for analysis. We found a total of 37 patients (21%) that could be assigned to one of the 19 major subsets: Subset #2 was the most frequent (n=12, 6.8%), thereafter subset #8 (n=7, 4.0%), subset #6 (n=6, 3.4%), and subset #1 (n=5, 2.8%). The median follow-up time for patients still alive was 78.6 months. By November 2016, 148 patients (84%) had had an event (no response to treatment, progression, or death) and 77 patients (44%) had died.
Compared to patients belonging to other major subsets, patients with subset #2 did not differ significantly as to: age group above 65 years, gender, treatment arm, cytogenetic aberrations by FISH, WHO performance status, beta2microglobulin level>3.5 mg/L, or in complete response rates, However, patients with subset #2 had more advanced disease (Binet stage C 83% vs. 52%, p=0.04) and as expected less often unmutated IGHV genes (67% vs. 100%, p=0.01). Nineteen of 37 patients (51%) was analyzed for recurrent mutations: Only SF3B1 mutations was found in patients with subset #2, and the frequency was slightly higher compared to other major subsets (57% vs. 17%, p=0.13), in whom also KRAS2 (17%) and BRAF15 (8%) mutations was found.
Unexpectedly, patients with subset #2 had a longer PFS compared to patients with other major subsets (median PFS #2: 51.2 months vs. other major #: 31.1 months, p=0.002, Figure), or compared to patients with usage of the same IGHV gene (e.g. median PFS for 7 patients with VH3-21/non #2: 15.4 months, p<0.05, data not shown). Furthermore, by Cox regression analysis, belonging to subset #2 was favorable for PFS compared to other major subsets, also when adjusting for treatment arm in the analysis (subset #2 HR: 0.22 0.08-0.57, p=0.002; FCA HR=0.37 0.17-0.78, p=0.01). Generally, patients belonging to a major subset did not differ as to PFS compared to other patients (median PFS major subset: 37.1 months vs. non major subset: 37.2 months, p=0.46). As to OS, no significant differences between groups were found.
Discussion and conclusions:
As expected, stereotypy was found more frequently in the HOVON68 trial that selected for high risk patients as compared to patients from large multi-institutional studies (Stamatopoulos at al. Leukemia 2017). Surprisingly, patients belonging to subset #2 had a better PFS after chemo-(immuno) therapy compared to other major subsets, albeit the numbers are small. Our data suggest that, chemo-(immuno) therapy may still have a place for patients otherwise assessed as ‘high risk’ such as patients with B-cell receptor stereotypy subset #2. Thus, selection of patients for trials as well as the exact treatment regimen may have major impact on the significance of biomarkers.
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Vojdeman:Roche: Other: Travel support in 2015; Gilead: Other: Travel support. Kimby:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Celgene: Research Funding; Pfizer: Research Funding. Van Oers:Roche: Consultancy; ISA therapeutics: Consultancy; Novartis: Consultancy; Immunicum: Consultancy. Kater:Celgene: Consultancy, Research Funding; Johnson & Johnson: Research Funding; Abbvie: Research Funding. Niemann:Roche: Consultancy, Other: Travel grant; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Novo Nordisk Foundation: Research Funding; The Danish Cancer Society: Research Funding; Novartis: Other: Travel grant; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding.
The clinical staging systems by Rai and Binet have remained the mainstay for clinical decision-making in patients with chronic lymphocytic leukemia (CLL). However, there is substantial heterogeneity ...of the disease within the clinical stage groups. In recent years, molecular and cellular markers have helped to predict the prognosis of CLL patients. The mutation status of the variable region of the Ig heavy chain (VH status) and genomic aberrations subdivide CLL into distinct clinical subgroups. Fluorescence in situ hybridization (FISH) can identify genomic aberrations in approximately 80% of CLL cases. Although the FISH technique is used most widely, other approaches (array-CGH, SNP-arrays or CD40 or CpG-stimulated metaphase cytogenetics) show similar results, but assess all chromosomal regions. The most frequent aberrations are deletions in 13q, 11q or 17p, and trisomy 12. Apart from providing insights into the pathogenesis, genomic aberrations identify subgroups of patients with distinct clinical pictures (lymphadenopathy (11q-) or chemotherapy resistance (17p-)). Deletions at 11q and particularly 17p are associated with rapid disease progression or inferior survival and patients with these genetic abnormalities are candidates for clinical trials investigating alternative treatments and stem cell transplantation. Similarly, abnormalities associated with good prognosis may benefit from de-escalation of current treatment approaches.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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