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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS German Medical Science; VOL: 9; DOC26 /20110927/
    Publication Date: 2011-09-28
    Description: Purpose: Introduction of lenalidomide has expanded the therapeutic options for refractory and recurrent multiple myeloma (MM) patients. However, the application of the approved doses may be difficult in some patients due to adverse effects. Experimental design: Therefore, we evaluated the efficacy and safety of lenalidomide in 10 patients with relapsed and refractory MM who received a reduced dose due to leukopenia (4), polyneuropathy (1), muscle cramps (1), thrombocytopenia (1), renal insufficiency (1), at the request of patient (1), as continuous therapy (1), either from the beginning (2) or during treatment (8). They received lenalidomide at a mean (median) daily dose of 14 (15) mg/d once a day (days 1-21 every <TextGroup> 28 days </TextGroup>) in combination with dexamethasone at a mean (median) dose of 17.6 (28) mg per day (4-40 mg) on days 1-4, 9-12 and 17-20. Results: Mean (median) duration of treatment with lenalidomide was 15.1 (15) months. Partial response or better was reported in seven and minimal response or better was reported in eight patients. Mean (median) values for time-to-progression (TTP) and for progression-free survival (PFS) were 8.7 (4) months. Mean overall survival (OS) has not been reached, all patients are still alive. Conclusion: In conclusion, dose-reduced lenalidomide is an effective and well tolerated treatment for patients with recurrent or refractory MM who cannot tolerate full doses.
    Description: Hintergrund: Die Einführung von Lenalidomid hat die therapeutischen Möglichkeiten für Patienten mit refraktärem oder rezidiviertem Multiplen Myelom (MM) erweitert. Allerdings ist die Anwendung der zugelassenen Dosierung bei einigen Patienten aufgrund unerwünschter Wirkungen schwierig. Experimentelles Design: Deshalb haben wir die Wirksamkeit und Sicherheit von Lenalidomid bei 10 Patienten mit rezidiviertem und refraktärem MM ausgewertet, die eine reduzierte Dosis erhielten wegen Leukopenie (4), Polyneuropathie (1), Muskelkrämpfen (1), Thrombozytopenie (1), Niereninsuffizienz (1), auf Wunsch des Patienten (1), als Dauertherapie (1), entweder von Anfang an (2) oder während der Behandlung (8). Sie erhielten Lenalidomid mit einer mittleren (medianen) Tagesdosis von 14 (15) mg/d. einmal pro Tag (Tag 1-21 alle 28 Tage) in Kombination mit Dexamethason in einer mittleren (medianen) Dosis von 17,6 (28) mg pro Tag (4-40 mg) an den Tagen 1-4, 9-12 und 17-20. Ergebnisse: Die mittlere (mediane) Dauer der Behandlung mit Lenalidomid betrug 15,1 (15) Monate. Partielles Ansprechen oder besser wurde in sieben, minimales Ansprechen oder besser wurde bei acht Patienten berichtet. Mittel-/(Median)werte für das Fortschreiten der Erkrankung (time to progression; TTP) und für das progressionsfreie Überleben lagen bei 8,7 (4) Monaten. Die mittlere Überlebenszeit wurde nicht erreicht: Alle Patienten leben noch. Fazit: Zusammenfassend ist Lenalidomid eine wirksame und gut verträgliche Behandlung auch für Patienten mit rezidiviertem oder refraktärem MM, die die volle Dosierung nicht tolerieren können.
    Keywords: myeloma ; lenalidomide ; dexamethasone ; lymphoma ; treatment ; Myelom ; Lenalidomid ; Dexamethason ; Lymphom ; Behandlung ; ddc: 610
    Language: English
    Type: article
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  • 2
    Abstract: Histopathological subtyping of non-small cell lung cancer (NSCLC) into adenocarcinoma (ADC), and squamous cell carcinoma (SqCC) is of utmost relevance for treatment stratification. However, current immunohistochemistry (IHC) based typing approaches on biopsies are imperfect, therefore novel analytical methods for reliable subtyping are needed. We analyzed formalin-fixed paraffin-embedded tissue cores of NSCLC by Matrix-assisted laser desorption/ionization (MALDI) imaging on tissue microarrays to identify and validate discriminating MALDI imaging profiles for NSCLC subtyping. 110 ADC and 98 SqCC were used to train a Linear Discriminant Analysis (LDA) model. Results were validated on a separate set of 58 ADC and 60 SqCC. Selected differentially expressed proteins were identified by tandem mass spectrometry and validated by IHC. The LDA classification model incorporated 339 m/z values. In the validation cohort, in 117 cases (99.1%) MALDI classification on tissue cores was in accordance with the pathological diagnosis made on resection specimen. Overall, three cases in the combined cohorts were discordant, after reevaluation two were initially misclassified by pathology whereas one was classified incorrectly by MALDI. Identification of differentially expressed peptides detected well-known IHC discriminators (CK5, CK7), but also less well known differentially expressed proteins (CK15, HSP27). In conclusion, MALDI imaging on NSCLC tissue cores as small biopsy equivalents is capable to discriminate lung ADC and SqCC with a very high accuracy. In addition, replacing multislide IHC by an one-slide MALDI approach may also save tissue for subsequent predictive molecular testing. We therefore advocate to pursue routine diagnostic implementation strategies for MALDI imaging in solid tumor typing.
    Type of Publication: Journal article published
    PubMed ID: 27473201
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  • 3
    Abstract: Proteomic approaches are of growing importance in the biologist's toolbox. It greatly benefited from past and recent advances in sampling, chemical processing, mass spectrometry (MS) instrumentation, and data processing. MS-based analysis of proteins is now in the process of being translated in pathology for objective diagnoses. In this viewpoint, we present the workflows that we think are the most promising for applications in pathology. We also comment what we think are prerequisites for a successful translational implementation.
    Type of Publication: Journal article published
    PubMed ID: 29236356
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  • 4
    Abstract: PURPOSE: Matrix assisted laser desorption/ionization time-of-flight mass spectrometry imaging (MALDI MSI) is a powerful tool to analyze the spatial distribution of peptides in tissues. Digital polymerase chain reaction (dPCR) is a method to reliably detect genetic mutations. Biopsy material is often limited due to minimally invasive techniques, but information on diagnosis, prognosis and prediction is required for subsequent clinical decision making. Thus, saving tissue material during diagnostic workup is highly warranted for best patient care. We evaluated the possibility to combine proteomic analysis by MALDI MSI and mutational analysis by dPCR from the same tissue section. EXPERIMENTAL DESIGN: Ten 0.5 x 0.5 cm formalin-fixed paraffin embedded tissue samples of pulmonary adenocarcinomas with known EGFR or KRAS mutations were analyzed by MALDI MSI. Subsequently, DNA was extracted from the analyzed tissue material and tested for the respective driver mutation by dPCR. RESULTS: Detection of driver gene mutations after MALDI MSI analysis was successful in all analyzed samples. Determined mutant allele frequencies were in good agreement with values assessed from untreated serial tissue sections with a mean absolute deviation of 0.16. CONCLUSION AND CLINICAL RELEVANCE: We demonstrate that MALDI MSI can be combined with genetic analysis, like dPCR. Workflows enabling the subsequent analysis of proteomic and genetic markers are particularly promising for the analysis of limited sample material such as biopsy specimen. This article is protected by copyright. All rights reserved.
    Type of Publication: Journal article published
    PubMed ID: 30216696
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  • 5
    Abstract: BACKGROUND: In matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) standardized sample preparation is important to obtain reliable results. Herein, we investigated the impact of section thickness in formalin-fixed paraffin embedded (FFPE) tissue microarrays (TMA) on spectral intensities. PATIENTS AND METHODS: TMAs consisting of 10 different tissues represented by duplicates of 10 patients (n = 200 cores) were cut at 1, 3 and 5 mum. MSI analysis was performed and mean intensities of all evaluable cores were extracted. Measurements were merged and mean m/z intensities were compared. RESULTS: Visual inspection of spectral intensities between 1, 3 and 5 mum revealed generally higher intensities in thinner tissue sections. Specifically, higher intensities were observed in the vast majority of peaks (98.6%, P〈0.01) in 1 compared with 5 mum sections. 28.4% and 2.1% of m/z values exhibited a 〉/=2 and 〉/=3-fold intensity difference (P〈0.01) in 1 compared to 5 mum sections, respectively. CONCLUSION: A section thickness of 1 mum resulted in higher spectral intensities compared with 5 mum. Our results highlight the importance of standardized protocols in light of recent efforts to identify clinically relevant biomarkers using MSI. The use of TMAs for comparative analysis seems advantageous, as section thickness displays less variability. This article is protected by copyright. All rights reserved.
    Type of Publication: Journal article published
    PubMed ID: 30216687
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  • 6
    Keywords: CANCER ; CELLS ; SURVIVAL ; MALIGNANCIES ; INVOLVEMENT ; microenvironment ; AUTOLOGOUS TRANSPLANTATION ; BONE-DISEASE ; FDG PET/CT ; CXCR4/SDF-1
    Abstract: CXCR4 is a G-protein-coupled receptor that mediates recruitment of blood cells toward its ligand SDF-1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination and poor prognosis. We evaluated the novel CXCR4 probe [(68)Ga]Pentixafor for in vivo mapping of CXCR4 expression density in mice xenografted with human CXCR4-positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [(68)Ga]Pentixafor PET provided images with excellent specificity and contrast. In 10 of 14 patients with advanced MM [(68)Ga]Pentixafor PET/CT scans revealed MM manifestations, whereas only nine of 14 standard [(18)F]fluorodeoxyglucose PET/CT scans were rated visually positive. Assessment of blood counts and standard CD34(+) flow cytometry did not reveal significant blood count changes associated with tracer application. Based on these highly encouraging data on clinical PET imaging of CXCR4 expression in a cohort of MM patients, we conclude that [(68)Ga]Pentixafor PET opens a broad field for clinical investigations on CXCR4 expression and for CXCR4-directed therapeutic approaches in MM and other diseases.
    Type of Publication: Journal article published
    PubMed ID: 25736399
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