BC-Monitor: Towards a Routinely Accessible Circulating Tumor DNA-Based Tool for Real-Time Monitoring Breast Cancer Progression and Treatment Effectiveness.

Circulating tumor DNA (ctDNA) is increasingly employed in the screening, follow-up, and monitoring of the continuously evolving tumor; however, most ctDNA assays validated for clinical use cannot maintain the right balance between sensitivity, coverage, sample requirements, time, and cost. Here, we report our BC-monitor, a simple, well-balanced ctDNA diagnostic approach using a gene panel significant in breast cancer and an optimized multiplex PCR-based NGS protocol capable of identifying allele variant frequencies below 1% in cell-free plasma DNA. We monitored a cohort of 45 breast cancer patients prospectively enrolled into our study receiving neoadjuvant chemotherapy or endocrine therapy or palliative therapy for metastatic diseases. Their tumor mutation status was examined in the archived tumor samples and plasma samples collected before and continuously during therapy. Traceable mutations of the used 38-plex NGS assay were found in approximately two-thirds of the patients. Importantly, we detected new pathogenic variants in follow-up plasma samples that were not detected in the primary tumor and baseline plasma samples. We proved that the BC-monitor can pre-indicate disease progression four-six months earlier than conventional methods. Our study highlights the need for well-designed ctDNA monitoring during treatment and follow-up, integrated into a real-time treatment assessment, which could provide information on the active tumor DNA released into the blood.

Dose escalation can maximize therapeutic potential of sunitinib in patients with metastatic renal cell carcinoma.

BACKGROUND: In patients with metastatic renal cell cancer, based on limited evidence, increased sunitinib exposure is associated with better outcome. The survival and toxicity data of patients receiving individualized dose escalated sunitinib therapy as compared to standard management were analyzed in this study. METHODS: From July 2013, the data of metastatic renal cell cancer patients with slight progression but still a stable disease according to RECIST 1.1 criteria treated with an escalated dose of sunitinib (first level: 62.5 mg/day in 4/2 or 2 × 2/1 scheme, second level: 75 mg/day in 4/2 or 2 × 2/1 scheme) were collected prospectively. Regarding characteristics, outcome, and toxicity data, an explorative retrospective analysis of the register was carried out, comparing treatments after and before July 1, 2013 in the study (selected patients for escalated dose) and control (standard dose) groups, respectively. RESULTS: The study involved 103 patients receiving sunitinib therapy with a median overall and progression free survival of 25.36 ± 2.62 and 14.2 ± 3.22 months, respectively. Slight progression was detected in 48.5% of them. First and second-level dose escalation were indicated in 18.2% and 4.1% of patients, respectively. The dosing scheme was modified in 22.2%. The median progression free survival (39.7 ± 5.1 vs 14.2 ± 1.3 months (p = 0.037)) and the overall survival (57.5 ± 10.7 vs 27.9 ± 2.5 months (p = 0.044)) were significantly better in the study group (with dose escalation) than in the control group. Patients with nephrectomy and lower Memorial Sloan Kettering Cancer Center (MSKCC) scores showed more favorable outcomes. After dose escalation, the most common adverse events were worsening or development of fatigue, hypertension, stomatitis, and weight loss of over 10%. CONCLUSIONS: Escalation of sunitinib dosing in selected patients with metastatic renal cell cancer, especially in case of slight progression, based on tolerable toxicity is safe and improves outcome. Dose escalation in 12.5 mg steps may be recommended for properly educated patients.

The Expression of Checkpoint and DNA Repair Genes in Head and Neck Cancer as Possible Predictive Factors.

DNA damage response failure may influence the efficacy of DNA-damaging treatments. We determined the expression of 16 genes involved in distinct DNA damage response pathways, in association with the response to standard therapy. Twenty patients with locoregionally advanced, squamous cell head and neck carcinoma were enrolled. The treatment included induction chemotherapy (iChT) with docetaxel, cisplatin and 5-fluorouracil followed by concomitant chemoradiotherapy (ChRT) or radiotherapy (RT) alone. The volumetric metabolic therapeutic response was determined by [18F]FDG-PET/CT. In the tumor and matched normal tissues collected before treatment, the gene expressions were examined via the quantitative real-time polymerase chain reaction (qRT-PCR). The down-regulation of TP53 was apparently associated with a poor response to iChT, its up-regulation with complete regression in 2 cases. 7 cases with down-regulated REV1 expression showed complete regression after ChRT/RT, while 1 case with REV1 overexpression was resistant to RT. The overexpression of WRN was an independent predictor of tumor relapse. Our results suggest that an altered expression of REV1 predicts sensitivity to RT, while WRN overexpression is an unfavorable prognostic factor.

[Therapeutic significance of sunitinib-induced "off-target" side effects]. / Sunitinib indukálta "off-target" mellékhatások terápiás jelentõsége.

Sunitinib is a basic medicine in the therapy of metastatic clear cell renal carcinoma. Our aim was to retrospectively evaluate the efficacy of sunitinib in the everyday clinical practice taking the most common side effects and clinical features into consideration. Data of ninety-four patients with metastatic, clear cell renal carcinoma, receiving sunitinib therapy were analyzed retrospectively, regarding efficacy and toxicity. Factors potentially influencing progression-free survival (PFS) and overall survival (OS) [age, nephrectomy, "off-target" side effects that are not connected to vascular endothelial growth factor receptor (VEGFR)] were studied. Complete remission, partial remission and stable disease occurred in 8 (8.5%), 30 (31.9%) and 50 (53.1%) patients, respectively. Objective tumor response developed in 38 (40.4%) cases. Median PFS and OS were 18.3 (95% CI 14.45-22.14) and 27.9 (95% CI 20.95-34.85) months, respectively. PFS and OS were more favorable in case of hypothyreosis (pPFS=0.005, pOS=0.043), hand-foot syndrome (pPFS=0.006, pOS=0.008), grade ≥2 neutropenia (pPFS=0.003, pOS=0.008) and thrombocytopenia (pPFS=0.01, pOS=0.011). Effective therapy of manageable side effects (most of which have potential predictive effect) is important for favorable survival results. Maintenance of dose intensity is also essential in order to compare the daily routine with the efficacy and safety results of clinical trials.

A pilot ontological model of public health indicators.

UNLABELLED: There are various public health databases in the world aiming to provide data to compare health conditions in different countries. Their data sets are more or less overlapping but data from different databases and different countries are hard to compare due to different definitions and interpretations. Our aim was to create a core ontological model that is able to represent public health indicators. We assumed, that by such representation comparability and quality of data could be improved. METHOD: Three sets of indicators were taken, and a core ontology was built from information objects describing their top level entities. The Protégé ontology editor with RDF backend was used for building the ontology. The used indicator sets were the indicators of the Health for All Database of the World Health Organisation (HFA), the OECD Health Data, and the set of indicators proposed by the European Community Health Indicators (ECHI) European project. Then 19 indicators selected from HFA was represented using the core ontology. Strength and weaknesses of the descriptive capability of the model was studied. RESULT: The drafted core model seems to be useful in representing many of the public health indicators. In some cases it really helps improve comparability. However, some of the semantic details cannot be sufficiently expressed by the used ontology representation language. There is a need of merging other domain ontologies to represent indicators related to other domains, such as economy, social and environmental sciences.

Conceptual framework of health indicators: the IDA model.

This paper presents a flexible conceptual framework for pub-lic health indicator databases. The model is a multidimensional-hierarchical representation of statistical data describing health and health influencing factors. The main characteristics of the IDA model are the strong discrimination of concepts (categories of entities enumerated in statistical systems) and dimensions (aspects that divide categories). Top level concepts of known data sources (WHO HFA database, OECD Health Data and ECHI) have been compared and a generalized structure had been created which can represent easily and consistently all the top level concepts of the known data sources. The model has been implemented in a prototype system, which demonstrates the feasibility of the approach.