Pharmazeutische Betreuung onkologischer Patienten unter Therapie mit Capecitabin

Die in dieser Arbeit beschriebene Studie hatte das Ziel, den Einfluss einer intensivierten Pharmazeutischen Betreuung auf verschiedene Endpunkte einer onkologischen Therapie mit dem per os applizierbaren Zytostatikum Capecitabin zu untersuchen. Capecitabin ist ein Prodrug des in der Onkologie seit vielen Jahren verbreitet eingesetzten, intravenös verabreichten Fluorouracil und ist in Deutschland als Monotherapie oder in Kombination mit anderen Substanzen zur Behandlung von Mamma- und Kolorektalkarzinoma zugelassen. Nach Abschluss einer Pilotphase mit dem primären Ziel einer Machbarkeitsuntersuchung des geplanten Studienablaufs begann die Hautphase der Studie mit dem Einschluss des ersten Patienten im Mai 2006. Die Studie wurde multizentrisch und prospektiv im „zeitlich versetzten Kontrollgruppendesign“ durchgeführt. Gemäß der Einschlusskriterien wurden in die Studie Mamma- und Kolorektalkarzinompatienten aufgenommen, die mit einer ambulant durchgeführten Chemotherapie mit Capecitabin begannen und zuvor noch nie mit einem per os applizierbaren Zytostatikum therapiert worden waren. Aus drei onkologischen Krankenhausambulanzen und drei Praxen niedergelassener Onkologen wurden insgesamt 69 Patienten für die Studie gemeldet, von denen jeweils 24 Patienten in die Auswertung der Kontroll- und Interventionsgruppe eingingen. Die Ergebnisse zeigten in Bezug auf die Compliance, die mittels MEMS®-Technologie gemessen wurde, eine signifikante Verbesserung hinsichtlich des primären Endpunkts tägliche Compliance von 93,80 % in der Kontroll- auf 98,45 % in der Interventionsgruppe (Medianwerte, p = 0,029, Mann-Whitney U). Auch hinsichtlich der täglichen Compliance ohne therapiefreie Tage war die erzielte Verbesserung (91,35 % vs. 97,95 %) statistisch signifikant (p = 0,037), in Bezug auf die Gesamtcompliance wurde das geforderte Signifikanzniveau knapp verfehlt (96,15 % vs. 99,00 %, p = 0,069). In der intensiv pharmazeutisch betreuten Interventionsgruppe wies kein Patient eine tägliche Compliance 14 Stunden zu finden, war in der Interventionsgruppe halb so groß wie in der Kontrollgruppe. Die Number Needed to Treat zur Verhinderung eines solchen Intervalls durch Pharmazeutische Betreuung lag bei 6. Dies entspricht im Fall von Capecitabin einer Therapiedauer von drei Tagen. Die Lebensqualitätsmessungen mit dem krankheitsspezifischen EORTC QLQ-C30-Fragebogen ergaben insgesamt keine signifikanten Unterschiede zwischen der Kontroll- und Interventionsgruppe. Lediglich bezüglich der Funktionalitätsskala Rollenfunktion ergab sich hier ein signifikanter Vorteil für die Interventionsgruppe. Auch das Auftreten bzw. der Schweregrad des Hand-Fuß-Syndroms ließ sich durch die Intervention nicht signifikant verbessern. Bezüglich der Patientenzufriedenheit mit der Information, die mit einer für diese Studie angepassten Version der deutschen Übersetzung des PS-CaTE-Fragebogens erfasst wurde, ließ sich am Ende der Studie in allen Skalen eine signifikante Überlegenheit der Interventionsgruppe feststellen. Die Befragung der Patienten der Interventionsgruppe ergab sehr hohe Zufriedenheitswerte mit der erhaltenen Pharmazeutischen Betreuung. Alle befragten Patienten würden sich in Zukunft wieder für die Inanspruchnahme dieser Dienstleistung entscheiden. Die Studie zeigte, dass Pharmazeutische Betreuung einen signifikanten Beitrag zur Complianceförderung von Patienten unter per os applizierbarer Chemotherapie leisten kann. Wahrscheinlich bedingt durch die geringe Fallzahl und die Heterogenität des Patientenkollektivs konnte dieser Effekt nicht für den sekundären Endpunkt Lebensqualität gezeigt werden. Zum Management des Hand-Fuß-Syndrom bedarf es weiterhin der Entwicklung effektiver Maßnahmen zu Prophylaxe und Therapie, die dann auch im Rahmen der Pharmazeutischen Betreuung eingesetzt werden könnten

Segregation and mixing of granular material in industrial processes

Within the EU-funded PARDEM network mixing and segregation are studied in silos and heaps, agitated mixers and fluidized beds. A method is presented with which mixing and segregation can be characterized, adapted for quasi-static to dynamic systems and applied at the global system level as well as at the local level. This paper attempts to give an overview of the applicability of this analysis by providing three instances, being chute flow representing flow down a heap, agitated mixing and fluidization, in which the method is applied

Effects of contrast-enhanced ultrasound treatment on neoadjuvant chemotherapy in breast cancer

Purpose: Preclinical and clinical data indicate that contrast-enhanced ultrasound can enhance tumor perfusion and vessel permeability, thus, improving chemotherapy accumulation and therapeutic outcome. Therefore, we investigated the effects of high mechanical index (MI) contrast-enhanced Doppler ultrasound (CDUS) on tumor perfusion in breast cancer. Methods: In this prospective study, breast cancer patients were randomly assigned to receive either 18 minutes of high MI CDUS during chemotherapy infusion (n = 6) or chemotherapy alone (n = 5). Tumor perfusion was measured before and after at least six chemotherapy cycles using motion-model ultrasound localization microscopy. Additionally, acute effects of CDUS on vessel perfusion and chemotherapy distribution were evaluated in mice bearing triple-negative breast cancer (TNBC). Results: Morphological and functional vascular characteristics of breast cancer in patients were not significantly influenced by high MI CDUS. However, complete clinical tumor response after neoadjuvant chemotherapy was lower in high MI CDUS-treated (1/6) compared to untreated patients (4/5) and size reduction of high MI CDUS treated tumors tended to be delayed at early chemotherapy cycles. In mice with TNBC high MI CDUS decreased the perfused tumor vessel fraction (p < 0.01) without affecting carboplatin accumulation or distribution. Higher vascular immaturity and lower stromal stabilization may explain the stronger vascular response in murine than human tumors. Conclusion: High MI CDUS had no detectable effect on breast cancer vascularization in patients. In mice, the same high MI CDUS setting did not affect chemotherapy accumulation although strong effects on the tumor vasculature were detected histologically. Thus, sonopermeabilization in human breast cancers might not be effective using high MI CDUS protocols and future applications may rather focus on low MI approaches triggering microbubble oscillations instead of destruction. Furthermore, our results show that there are profound differences in the response of mouse and human tumor vasculature to high MI CDUS, which need to be further explored and considered in clinical translation

Minimising treatment-associated risks in systemic cancer therapy

Aim of the review To review the consequences of drug-related problems (DRP) in systemic cancer therapy and identify specific contributions of the pharmacist to minimise treatment-associated risks. Method Searches in PubMed, Embase and the Cochrane Library were conducted. Bibliographies of retrieved articles were examined for additional references. Only papers in English between 1980 and 2007 were included. Results In systemic cancer therapy there is an enormous potential for DRP due to the high toxicity and the complexity of most therapeutic regimens. The most frequently reported DRP can be classified into adverse effects, drug–drug interactions, medication errors, and non-adherence. Pharmacists have enhanced efforts to assure quality and safety in systemic cancer therapy together with other health care providers. In consequence, oncology pharmacy has evolved as a novel specialist discipline. The endeavour to merge and co-ordinate individual activities and services of the pharmacist has led to pharmaceutical care concepts which aim at offering novel solutions to the various DRP. Conclusion Pharmaceutical care for cancer patients should be developed within research projects and integrated into disease management programs in order to ensure broad implementation

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Vulnerability of Polarised Intestinal Porcine Epithelial Cells to Mycotoxin Deoxynivalenol Depends on the Route of Application

BACKGROUND AND AIMS: Deoxynivalenol (DON) is a Fusarium derived mycotoxin, often occurring on cereals used for human and animal nutrition. The intestine, as prominent barrier for nutritional toxins, has to handle the mycotoxin from the mucosa protected luminal side (apical exposure), as well as already absorbed toxin, reaching the cells from basolateral side via the blood stream. In the present study, the impact of the direction of DON exposure on epithelial cell behaviour and intestinal barrier integrity was elucidated. METHODS: A non-transformed intestinal porcine epithelial cell line (IPEC-J2), cultured in membrane inserts, serving as a polarised in vitro model to determine the effects of deoxynivalenol (DON) on cellular viability and tight junction integrity. RESULTS: Application of DON in concentrations up to 4000 ng/mL for 24, 48 and 72 hours on the basolateral side of membrane cultured polarised IPEC-J2 cells resulted in a breakdown of the integrity of cell connections measured by transepithelial electrical resistance (TEER), as well as a reduced expression of the tight junction proteins ZO-1 and claudin 3. Epithelial cell number decreased and nuclei size was enlarged after 72 h incubation of 4000 ng/mL DON from basolateral. Although necrosis or caspase 3 mediated apoptosis was not detectable after basolateral DON application, cell cycle analysis revealed a significant increase in DNA fragmentation, decrease in G0/G1 phase and slight increase in G2/M phase after 72 hours incubation with DON 2000 ng/mL. CONCLUSIONS: Severity of impact of the mycotoxin deoxynivalenol on the intestinal epithelial barrier is dependent on route of application. The epithelium appears to be rather resistant towards apical (luminal) DON application whereas the same toxin dose from basolateral severely undermines barrier integrity