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Additional file 2: Table 2. Summary of paired t-tests comparing values between the defined times of LDH and hemoglobin.

Additional file 1: Table 1. Mean value of all analyzed parameters, including range and standard deviation [SD] at all time points (Baseline, begin durvalumab, 3 months follow up [FU], 6 months FU, 9 months FU, 12 months FU).

Head and neck squamous cell carcinomas (HNSCCs) have poor clinical outcome owing to therapy resistance and frequent recurrences that are among others attributable to tumor cells in partial epithelial‐to‐mesenchymal transition (pEMT). We compared side‐by‐side software‐based and visual quantification of immunohistochemistry (IHC) staining of epithelial marker EpCAM and EMT regulator Slug in n = 102 primary HNSCC to assess optimal analysis protocols. IHC scores incorporated expression levels and percentages of positive cells. Digital and visual evaluation of membrane‐associated EpCAM yielded correlating scorings, whereas visual evaluation of nuclear Slug resulted in significantly higher overall scores. Multivariable Cox proportional hazard analysis defined the median EpCAM expression levels resulting from visual quantification as an independent prognostic factor of overall survival. Slug expression levels resulting from digital quantification were an independent prognostic factor of recurrence‐free survival, locoregional recurrence‐free survival, and disease‐specific survival. Hence, we propose to use visual assessment for the membrane‐associated EpCAM protein, whereas nuclear protein Slug assessment was more accurate following digital measurement., Epithelial‐to‐mesenchymal transition (EMT) impacts on the clinical outcome of head and neck squamous cell carcinomas (HNSCC). Here, we compared visual and digital scoring of epithelial marker EpCAM and EMT marker Slug in HNSCC for routine quantification of EMT. We propose to use visual assessment for membrane‐associated EpCAM, whereas nuclear protein Slug assessment was more accurate following digital measurement.

Deep learning models based on medical images play an increasingly important role for cancer outcome prediction. The standard approach involves usage of convolutional neural networks (CNNs) to automatically extract relevant features from the patient’s image and perform a binary classification of the occurrence of a given clinical endpoint. In this work, a 2D-CNN and a 3D-CNN for the binary classification of distant metastasis (DM) occurrence in head and neck cancer patients were extended to perform time-to-event analysis. The newly built CNNs incorporate censoring information and output DM-free probability curves as a function of time for every patient. In total, 1037 patients were used to build and assess the performance of the time-to-event model. Training and validation was based on 294 patients also used in a previous benchmark classification study while for testing 743 patients from three independent cohorts were used. The best network could reproduce the good results from 3-fold cross validation [Harrell’s concordance indices (HCIs) of 0.78, 0.74 and 0.80] in two out of three testing cohorts (HCIs of 0.88, 0.67 and 0.77). Additionally, the capability of the models for patient stratification into high and low-risk groups was investigated, the CNNs being able to significantly stratify all three testing cohorts. Results suggest that image-based deep learning models show good reliability for DM time-to-event analysis and could be used for treatment personalisation.

We examined the prognostic role of PD-1+ and CD8+ tumor infiltrating lymphocytes (TILs), and PD-L1+ cells in patients with squamous cell carcinoma of the head and neck (SCCHN) treated with surgery and postoperative chemoradiotherapy (CRT). FFPE samples from 161 patients were immunohistochemically stained for PD-1, CD8 and PD-L1. The immune marker expression was correlated with clinicopathologic characteristics, and overall survival (OS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of HPV16 DNA/p16 status. The median follow-up was 48 months (range: 4-100). The 2-year-OS was 84.1% for the entire cohort. High PD-1 and PD-L1 expression were more common in patients with positive HPV16 DNA (p

The tetrahydroisoquinoline trabectedin is a marine compound with approved activity against human soft-tissue sarcoma. It exerts anti-proliferative activity mainly by specific binding to the DNA and inducing DNA double-strand breaks (DSB). Since homologous recombination repair (HRR) deficient tumors are more susceptible to trabectedin, hyperthermia mediated on-demand induction of HRR deficiency represents a novel and promising strategy to boost trabectedin treatment. For the first time, we demonstrate enhancement of trabectedin effectiveness in human sarcoma cell lines by heat and characterize cellular events and molecular mechanisms related to heat-induced effects. Hyperthermic temperatures (41.8°C or 43°C) enhanced significantly trabectedin-related clonogenic cell death and G2/M cell cycle arrest followed by cell type dependent induction of apoptosis or senescence. Heat combination increased accumulation of γH2AX foci as key marker of DSBs. Expression of BRCA2 protein, an integral protein of the HRR machinery, was significantly decreased by heat. Consequently, recruitment of downstream RAD51 to γH2AX positive repair foci was almost abolished indicating relevant impairment of HRR by heat. Accordingly, enhancement of trabectedin effectiveness was significantly augmented in BRCA2-proficient cells by hyperthermia and alleviated in BRCA2 knockout or siRNA transfected BRCA2 knockdown cells. In peripheral blood mononuclear cells isolated from sarcoma patients, increased numbers of nuclear γH2AX foci were detected after systemic treatment with trabectedin and hyperthermia of the tumor region. The findings establish BRCA2 degradation by heat as a key factor for a novel treatment strategy that allows targeted chemosensitization to trabectedin and other DNA damaging antitumor drugs by on-demand induction of HRR deficiency.

PURPOSE To compare the accuracy of lesion detection and characterization and to determine the agreement of observers, methods and timing of mammography (MX), ultrasound (US) and MR imaging (MRI) during the first year after breast conserving therapy. MATERIALS AND METHODS The study included 20 patients diagnosed with breast cancer of stages equal or inferior to T2 N1bi M0 after breast conserving therapy and subsequent radiotherapy. Patients with any history of breast diseases in the affected or contralateral breast were excluded. Patients were examined before and at 3, 6 and 12 months after adjuvant radiotherapy with MX, US and dynamic MR mammography. Additional US and MRI were performed 3 months after radiotherapy. All 220 examinations were retrospectively read in a randomized order by two independent readers, blinded for the results of the other examinations. The outcome after 2.5 years of follow-up was used as gold standard. Histological examination was available in one case. Lesion detection and specificity were assessed including kappa values for different reliabilities between observers, timing and methods. The kappa values were used to characterize the degree of agreement as follows: > 0.8 very good; 0.6 - 0.8 good; 0.4 - 0.6 fair; 0.2 - 0.4 minimal; and < 0.2 negligible. RESULTS Based on the interpretation of all available findings (clinical examination, MX, US, MRT and histology in one case), 20 patients observed for a mean period of 2.5 years had no evidence of intramammary recurrence. Therefore the sensitivity of the various methods could not be assessed. The reading of certainly no lesion was given by MRI in 43 %, by MX in 30 % and by US in 5 % of all examinations (p < 0.05). True negative findings were observed by MRI in 94.4 %, by MX in 90.4 % and by US in 82.5 %. Reliability between observers, timing and imaging methods was 0.496, 0.411, and 0.215 for lesion detection and 0.303, 0.282, and 0.030 for lesion characterization. CONCLUSION Within the first year after breast conserving therapy, MRI was the most confident method for the exclusion of lesions and presented the highest true negative rate. The assessment of dignity of a particular lesion was difficult by all imaging methods, reflected by the weak agreement between observers, methods and timing. The difference between times of readings were marginal in the first year after therapy. Agreement between the different diagnostics methods was minimal to negligible.

Purpose: To quantify therapy related effects after breast conservation therapy (BCT) with dynamic MRI of the breast. Methods: Twenty patients (median age 51 years) with breast conserving tumor excision were included. Contrast enhanced dynamic MRI was performed before and 3, 6 and 12 months after adjuvant radiation therapy (RT) with a total dose of 50.0 0 to 50.4 Gy. The following sequences were applied: axial fat-suppressed T 2 -weighted; coronal contrast enhanced 3D spoiled gradient-echo (first measurement prior to the administration of 0.16 mmol/kg Gd-DTPA, six repetitive measurements); sagittal T 1 -weighted Flash3D. Enhancement data were obtained using a computer software with automated segmentation of regions of interest (ROIs). After defining ROIs for skin, parenchyma and pectoral muscle of each breast the early enhancement after the first post contrast measurement (E 1 ) and the slope of enhancement between the second and last postcontrast measurement (SE 2-L ) were calculated. The edema was quantified by assessing the signal intensities (SI) in the T 2 -weighted images. The thickness of the skin was measured in the sagittal T 1 -weighted images. Results: Three months after RT statistically significant increases between 51 and 179% of the SI and E 1 quotients were detected for all tissues compared to the examinations prior to RT. Six months after RT the skin still presented a by 102% significantly higher E 1 quotient, and a by 140% significantly increased SI quotient. No significant differences for SI and E 1 quotients could be observed 12 months after RT compared to the examinations prior to RT. A significant increase of the SE 2-L difference for the skin from 0.0225 to 0.0691 and 0.0665 was found 3 and 6 months after RT, respectively. No significant differences between the initial MR examination and the follow-up examinations 3, 6 and 12 months could be detected for the SE 2-L differences of the parenchyma. Conclusion: Early therapy related effects after BCT can be exactly quantified with dynamic MRI using an automated ROI-segmentation and whole breast analysis software. Both edema formation and early enhancement show peaks 3 months after RT, and after 12 months there is no statistically significant difference compared with baseline.

6006 Background: The genetic landscape of SCCHN is currently being unravelled, but the role of distinct mutations for treatment outcome remains largely unknown. We compared mutational patterns of H...

Radiotherapy is the single most effective therapy for malignant gliomas. Targeting the CD95 apoptotic pathway is a promising experimental approach to these neoplasms. Here, we asked whether irradiation modulates CD95-mediated apoptosis of human malignant glioma cells in vitro.LN-18, LN-229 and T98G human malignant glioma cell lines were irradiated with dosages from 0-8 Gy and treated with CD95L (CD95 ligand). CD95 expression was assessed by flow cytometry. Caspase activity was determined by DEVD cleavage. Cytotoxic effects were assessed by crystal violet staining of cells in a 96-well plate assay. Clonogenic cell death was determined by a standard colony forming assay.We find that (i) CD95L-induced apoptosis, but not irradiation-induced clonogenic cell death, involves caspase 3 activation and is blocked by the viral caspase inhibitor, crm-A. (ii) Irradiation does not modulate CD95 expression either in p53 wild-type or in p53 mutant glioma cell lines, and does not enhance CD95L-evoked caspase 3 activity or CD95L-induced clonogenic cell death.We conclude that endogenous CD95/CD95L interactions are not involved in radiation-induced clonogenic cell death and that the killing cascades of CD95L and irradiation are independent in human malignant glioma cells.

The European SocieTy for Radiation and Oncology -Advisory Committee on Radiation Oncology Practice (ESTRO-ACROP) endorsed a project to provide guidelines (GL) for the identification and delineation of clinically negative lymph-nodal stations (LNs) involved in upper gastrointestinal clinical scenarios. The presented GL is focused on preoperative (or definitive) setting. The project aim is to improve the consistency of clinical target volume (CTV) delineation by providing: a description of the anatomical boundaries of the LNs; a radiological computed tomography-based atlas depicting the LNs areas; a free, web-based, interactive example case for independent training of radiation oncologists on LNs delineation according to the presented GL, by both qualitative and quantitative analysis (through the FALCON EduCase platform). This project was carried out with the intention to facilitate and improve uniformity of future upper gastrointestinal guidelines on nodal CTV delineation. We report methodology and results from the collaboration of a working group panel selected by the ESTRO-ACROP. ispartof: RADIOTHERAPY AND ONCOLOGY vol:164 pages:92-97 ispartof: location:Ireland status: published