How VEGF-A and its splice variants affect breast cancer development – clinical implications

Background: Altered expression levels and structural variations in the vascular endothelial growth factor (VEGF) have been found to play important roles in cancer development and to be associated with the overall survival and therapy response of cancer patients. Particularly VEGF-A and its splice variants have been found to affect physiological and pathological angiogenic processes, including tumor angiogenesis, correlating with tumor progression, mostly caused by overexpression. This review focuses on the expression and impact of VEGF-A splice variants under physiologic conditions and in tumors and, in particular, the distribution and role of isoform VEGF(165)b in breast cancer. Conclusions and perspectives: Many publications already highlighted the importance of VEGF-A and its splice variants in tumor therapy, especially in breast cancer, which are summarized in this review. Furthermore, we were able to demonstrate that cytoplasmatic VEGFA/(165)b expression is higher in invasive breast cancer tumor cells than in normal tissues or stroma. These examples show that the detection of VEGF splice variants can be performed also on the protein level in formalin fixed tissues. Although no quantitative conclusions can be drawn, these results may be the starting point for further studies at a quantitative level, which can be a major step towards the design of targeted antibody-based (breast) cancer therapies

PRO B: evaluating the effect of an alarm-based patient-reported outcome monitoring compared with usual care in metastatic breast cancer patients—study protocol for a randomised controlled trial

Background: Despite the progress of research and treatment for breast cancer, still up to 30% of the patients afflicted will develop distant disease. Elongation of survival and maintaining the quality of life (QoL) become pivotal issues guiding the treatment decisions. One possible approach to optimise survival and QoL is the use of patient-reported outcomes (PROs) to timely identify acute disease-related burden. We present the protocol of a trial that investigates the effect of real-time PRO data captured with electronic mobile devices on QoL in female breast cancer patients with metastatic disease. Methods: This study is a randomised, controlled trial with 1:1 randomisation between two arms. A total of 1000 patients will be recruited in 40 selected breast cancer centres. Patients in the intervention arm receive a weekly request via an app to complete the PRO survey. Symptoms will be assessed by study-specific optimised short forms based on the EORTC QLQ-C30 domains using items from the EORTC CAT item banks. In case of deteriorating PRO scores, an alarm is sent to the treating study centre as well as to the PRO B study office. Following the alarm, the treating breast cancer centre is required to contact the patient to inquire about the reported symptoms and to intervene, if necessary. The intervention is not specified and depends on the clinical need determined by the treating physician. Patients in the control arm are prompted by the app every 3 months to participate in the PRO survey, but their response will not trigger an alarm. The primary outcome is the fatigue level 6 months after enrolment. Secondary endpoints include among others hospitalisations, use of rescue services and overall QoL. Discussion: Within the PRO B intervention group, we expect lower fatigue levels 6 months after intervention start, higher levels of QoL, less unplanned hospitalisations and less emergency room visits compared to controls. In case of positive results, our approach would allow a fast and easy transfer into clinical practice due to the use of the already nationwide existing IT infrastructure of the German Cancer Society and the independent certification institute OnkoZert

Immunohistochemical detection of lymph node metastases pN0 (i+) in patients with prostate cancer after radical prostatectomy and their significance for recurrences

Hintergrund: 10% bis 30% der Patienten mit einem Prostatakarzinom (PCa), die nach radikaler Prostatektomie (RPE) als Lymphknotenmetastasen frei und damit als geheilt bezeichnet werden, entwickeln im Verlauf einen erneuten Anstieg des prostataspezifischen Antigens (PSA), ein sogenanntes biochemisches Rezidiv (BCR). Die Bedeutung von isolierten Tumorzellen (ITC) und Mikrometastasen im Hinblick auf das Auftreten eines BCR ist nicht abschließend geklärt. Ziel: Die vorliegende Arbeit weist mittels immunhistochemischer Färbungen Lymphknotenmetastasen (N0(i+)) bei Prostatakarzinomen nach radikaler Prostatektomie mit R0-Resektion und initialer N0-Klassifizierung nach und untersucht deren Bedeutung für Rezidive. Methodik: 1924 Patienten mit PCaaus der Datenbank der Klinik für Urologie des Universitätsklinikum Charité, die zwischen 1999 und 2014 mittels RPE therapiert wurden, wurden nach Lymphknotenstatus (N0), Zustand der Resektionsränder bei RPE (R0) und Vorhandensein von Metastasen (M0) selektiert. Die Lymphknotenpräparate von 197 Patienten wurden mittels immunhistochemischer Färbung (MNF116), bei positivem Ergebnis zusätzlich mittels PSMA-Färbung bearbeitet. Statistische Signifikanz wurde bei p<0,05 angenommen. Mithilfe von bivariaten Korrelationsanalysen, t-Test, Mann-Whitney-U-Test,Kruskal-Wallis-Testsowie Kreuztabellen, Chi- Quadrat-Test bzw. dem Fisher-Exakt-Testwurden metrische und kategoriale Variablen analysiert und in Q-Q-, Streu-, Balkendiagrammen oder Box Plots dargestellt. Die Kaplan-Meier-Methode dient der Berechnung des rezidivfreien Überlebens (RFS). Abschließend wurden Testgütekriterien berechnet um einen Überblick über den Nutzen der untersuchten immunhistochemischen Färbungen zu erhalten. Ergebnisse: Insgesamt wurden 2352 Lymphknoten (LK) von 197 Patienten (12 LK pro Patient) mit PCa mittels HE-Färbung und Immunhistochemie (IHC) untersucht. Mittels IHC konnten in den Präparaten von 17 Patienten (8,6%) positive Reaktionen erkannt werden. In10 Fällen waren ausschließlich ITC, in 3 Fällen Mikrometastasen und in 4 Fällen sowohl ITC als auch Mikrometastasen zu erkennen. Ein positiver Lymphknotenstatus war signifikant assoziiert mit einem höheren Gleason Score (p=0,009) und einer größeren Tumorfläche (p<0,001). Die Korrelationen mit dem T-Stadium (p=0,143) sowie mit dem präoperativen PSA-Wert (p=0,369)waren statistisch nicht signifikant. Ein BCR trat bei 45 von 195 Patienten (23,1%) auf. Das Auftreten eines BCR war signifikant mit einem positiven Lymphknotenstatus (p<0,001) und größerer Tumorfläche (p=0,042) assoziiert. Auch die Kaplan-Meier-Analyse beschreibt ein deutlich verringertes rezidivfreies Überleben für Patienten mit positivem Lymphknotenstatus (p<0,001). Die Zeit bis zum Auftreten eines BCR unterscheidet sich nicht signifikant (p=0,925). Schlussfolgerungen: Der Lymphknotenstatus zeigt prognostische Bedeutung für das Auftreten eines BCR. Ein Teil der BCR kann durch die Existenz von ITC und Mikrometastasen in Lymphknoten erklärt werden. Die zusätzliche Anwendung von immunhistochemischen Färbungen scheint daher insbesondere bei Patienten mit höherem Gleason Score (≥8), höherem T-Stadium (≥pT3a) undgrößerer Tumorfläche (≥10cm) einen diagnostischen Zugewinn zu erbringen.Background: 10% - 30% of patients with prostate cancer (PCa) treated by radical prostatectomy (RPE) and diagnosed as lymph node (LN) negative will have a biochemical recurrence (BCR). Although the BCR etiology is multifactorial, a significant proportion of these recurrences might be attributed to LNmetastases undetected by routine pathologic examination. The significance of isolated tumor cells (ITC) and micrometastasis remains unclear. Purpose: The purpose of this study is to determine the incidence and clinical significance of occult LN metastasis (N0(i+)) in patients with PCa who are initially considered node negative (N0) by histological evaluation. Methods: Data comes from the department of urology at Charité - University Hospital Berlin with data of 1,924 patients diagnosed with PCa and treated with RPE between 1999 and 2014. The databasewas searched for cases with node negative status (N0), negative surgical margins (R0) and the absence of metastasis (M0). 197 patients´ RPE specimenwere stained with antibodies against cytokeratines (MNF 116) and if positive against prostate specific membrane antigen (PSMA). Statistical significance was accepted at the p<0,05 level. Bivariate correlation analyses, t-test, Mann-Whitney-U-test or Kruskal- Wallis-test, cross tables, chi-square-test or Fisher-exact test were used to analyse metric and categorical variables. Graphs were completed using Q-Q-diagrams, scatterplots, box plots and bar graphs. The biochemical free survival (RFS) rates were calculatedwith the Kaplan-Meier method. Test quality criteria were calculated to get an overview of the diagnostic gain of immunohistochemistry (IHC). Results: A total of 2352 LN obtained from 197 patients (12 LN per patient) with PCa were analysed histologically and by IHC. LN of 17 Patients (8,6%) were found positive. In 10 casesonly ITC and in 3 cases micrometastasis were present, both were present in 4 cases. Positive LNs were significantly associated with a higher Gleason Score (p=0,009) and a bigger tumor area (p<0,001). Correlation with T-stage (p=0,143) and preoperative PSA-level (p=0,369) was not significant. BCR was diagnosed in 45 of 195 patients (23,1%) and wassignificantassociatedwith positive LN(p<0,001) and higher tumor area (p=0,042). Kaplan-Meier analysis showed decreased recurrence free survival for patients with positive LN (p<0,001). Conclusion:Lymph node status has a prognostic significance for developing a BCR. Some of the cases with BCR can be explained by ITC and micrometastasis. The additional use of IHC for patients with higher Gleason Score (≥8), higher T-stade (≥pT3a) and bigger tumor area adds an important diagnostic gain to a routine histological evaluation

Examining the Feasibility of an Application-Based Patient-Reported Outcome Monitoring for Breast Cancer Patients: A Pretest for the PRO B Study

In preparation for the PRO B study which aims to examine the effects of an app-based intensified patient-reported outcome (PRO) monitoring for metastatic breast cancer patients, prior assessment of its feasibility was carried out. Sixteen breast cancer patients visiting the breast cancer unit at Charit&eacute; were recruited and downloaded an app connected to an ePRO system. They received electronic questionnaires on two occasions (baseline and the following week) and were subsequently contacted for a semi-structured phone interview for evaluation. Eleven participants answered at least one questionnaire. Some participants did not receive any or only a part of the questionnaires due to technical problems with the app. Participants who completed the evaluation questionnaire (n = 6) were overall satisfied with the weekly PRO questionnaire. All interviewed (n = 11) participants thought it was feasible to answer the PRO questionnaires on a weekly basis for one year, as planned in the PRO B study. The pretest revealed a need for major technical adjustments to the app because push notifications about the receipt of new questionnaires were not displayed on some smartphone models. Due to the low number of participants, generalization of the findings is limited to our specific context and study. Nevertheless, we could conclude that if technical aspects of the app were improved, the PRO B study could be implemented as planned. The ePRO questionnaire was considered feasible and adequate from the patients&rsquo; perspectives

Improving shared decision-making about cancer treatment through design-based data-driven decision-support tools and redesigning care paths : an overview of the 4D PICTURE project

Background:: Patients with cancer often have to make complex decisions about treatment, with the options varying in risk profiles and effects on survival and quality of life. Moreover, inefficient care paths make it hard for patients to participate in shared decision-making. Data-driven decision-support tools have the potential to empower patients, support personalized care, improve health outcomes and promote health equity. However, decision-support tools currently seldom consider quality of life or individual preferences, and their use in clinical practice remains limited, partly because they are not well integrated in patients’ care paths. Aim and objectives:: The central aim of the 4D PICTURE project is to redesign patients’ care paths and develop and integrate evidence-based decision-support tools to improve decision-making processes in cancer care delivery. This article presents an overview of this international, interdisciplinary project. Design, methods and analysis:: In co-creation with patients and other stakeholders, we will develop data-driven decision-support tools for patients with breast cancer, prostate cancer and melanoma. We will support treatment decisions by using large, high-quality datasets with state-of-the-art prognostic algorithms. We will further develop a conversation tool, the Metaphor Menu, using text mining combined with citizen science techniques and linguistics, incorporating large datasets of patient experiences, values and preferences. We will further develop a promising methodology, MetroMapping, to redesign care paths. We will evaluate MetroMapping and these integrated decision-support tools, and ensure their sustainability using the Nonadoption, Abandonment, Scale-Up, Spread, and Sustainability (NASSS) framework. We will explore the generalizability of MetroMapping and the decision-support tools for other types of cancer and across other EU member states. Ethics:: Through an embedded ethics approach, we will address social and ethical issues. Discussion:: Improved care paths integrating comprehensive decision-support tools have the potential to empower patients, their significant others and healthcare providers in decision-making and improve outcomes. This project will strengthen health care at the system level by improving its resilience and efficiency

Improving shared decision-making about cancer treatment through design-based data-driven decision-support tools and redesigning care paths: an overview of the 4D PICTURE project

Background: Patients with cancer often have to make complex decisions about treatment, with the options varying in risk profiles and effects on survival and quality of life. Moreover, inefficient care paths make it hard for patients to participate in shared decision-making. Data-driven decision-support tools have the potential to empower patients, support personalized care, improve health outcomes and promote health equity. However, decision-support tools currently seldom consider quality of life or individual preferences, and their use in clinical practice remains limited, partly because they are not well integrated in patients’ care paths. Aim and objectives: The central aim of the 4D PICTURE project is to redesign patients’ care paths and develop and integrate evidence-based decision-support tools to improve decision-making processes in cancer care delivery. This article presents an overview of this international, interdisciplinary project. Design, methods and analysis: In co-creation with patients and other stakeholders, we will develop data-driven decision-support tools for patients with breast cancer, prostate cancer and melanoma. We will support treatment decisions by using large, high-quality datasets with state-of-the-art prognostic algorithms. We will further develop a conversation tool, the Metaphor Menu, using text mining combined with citizen science techniques and linguistics, incorporating large datasets of patient experiences, values and preferences. We will further develop a promising methodology, MetroMapping, to redesign care paths. We will evaluate MetroMapping and these integrated decision-support tools, and ensure their sustainability using the Nonadoption, Abandonment, Scale-Up, Spread, and Sustainability (NASSS) framework. We will explore the generalizability of MetroMapping and the decision-support tools for other types of cancer and across other EU member states. Ethics: Through an embedded ethics approach, we will address social and ethical issues. Discussion: Improved care paths integrating comprehensive decision-support tools have the potential to empower patients, their significant others and healthcare providers in decision-making and improve outcomes. This project will strengthen health care at the system level by improving its resilience and efficiency