Development and Application of an Open Tool for Sharing and Analyzing Integrated Clinical and Environmental Exposures Data: Asthma Use Case.

Background: The Integrated Clinical and Environmental Exposures Service (ICEES) serves as an open-source, disease-agnostic, regulatory-compliant framework and approach for openly exposing and exploring clinical data that have been integrated at the patient level with a variety of environmental exposures data. ICEES is equipped with tools to support basic statistical exploration of the integrated data in a completely open manner.

Objective: This study aims to further develop and apply ICEES as a novel tool for openly exposing and exploring integrated clinical and environmental data.

Translator Exposure APIs: Open Access to Data on Airborne Pollutant Exposures, Roadway Exposures, and Socio-Environmental Exposures and Use Case Application.

Environmental exposures have profound effects on health and disease. While public repositories exist for a variety of exposures data, these are generally difficult to access, navigate, and interpret. We describe the research, development, and application of three open application programming interfaces (APIs) that support access to usable, nationwide, exposures data from three public repositories: airborne pollutant estimates from the US Environmental Protection Agency; roadway data from the US Department of Transportation; and socio-environmental exposures from the US Census Bureau's American Community Survey.

Correlating Dose Variables with Local Tumor Control in Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer: A Modeling Study on 1500 Individual Treatments.

Background: Large variation regarding prescription and dose inhomogeneity exists in stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer. The aim of this modeling study was to identify which dose metric correlates best with local tumor control probability to make recommendations regarding SBRT prescription.

Methods And Materials: We combined 2 retrospective databases of patients with non-small cell lung cancer, yielding 1500 SBRT treatments for analysis.

Dose-volume predictors of early esophageal toxicity in non-small cell lung cancer patients treated with accelerated-hyperfractionated radiotherapy.

Background And Purpose: Early radiation-induced esophageal toxicity (RIET) is one of the major side effects in patients with non-small cell lung cancer (NSCLC) and can be a reason for treatment interruptions. As the age of patients with NSCLC and corresponding comorbidities continue to increase, primary radiotherapy alone is a commonly used alternative treatment in these cases. The aim of the present study is to compare dosimetric and clinical parameters from the previously reported CHARTWEL trial for their ability to predict esophagitis and investigate potential differences in the accelerated and conventional fractionation arm.

Estimation of the α/β ratio of non-small cell lung cancer treated with stereotactic body radiotherapy.

Background: High-dose hypofractionated radiotherapy should theoretically result in a deviation from the typical linear-quadratic shape of the cell survival curve beyond a certain threshold dose, yet no evidence for this hypothesis has so far been found in clinical data of stereotactic body radiotherapy treatment (SBRT) for early-stage non-small cell lung cancer (NSCLC). A pragmatic explanation is a larger α/β ratio than the conventionally assumed 10 Gy. We here attempted an estimation of the α/β ratio for NSCLC treated with SBRT using individual patient data.

Inter-observer variability in target delineation increases during adaptive treatment of head-and-neck and lung cancer.

Inter-observer variability (IOV) in target volume delineation is a well-documented source of geometric uncertainty in radiotherapy. Such variability has not yet been explored in the context of adaptive re-delineation based on imaging data acquired during treatment. We compared IOV in the pre- and mid-treatment setting using expert primary gross tumour volume (GTV) and clinical target volume (CTV) delineations in locoregionally advanced head-and-neck squamous cell carcinoma (HNSCC) and (non-)small cell lung cancer [(N)SCLC].

Reduced diffusion in normal appearing white matter of glioma patients following radio(chemo)therapy.

Background And Purpose: Standard treatment of high grade gliomas includes gross tumour resection followed by radio(chemo)therapy. Radiotherapy inevitably leads to irradiation of normal brain tissue. The goal of this prospective, longitudinal study was to use MRI to quantify normal appearing white and grey matter changes following radiation treatment as a function of dose and time after radiotherapy.

Independent validation of tumour volume, cancer stem cell markers and hypoxia-associated gene expressions for HNSCC after primary radiochemotherapy.

Objective: To independently validate the impact of tumour volume, p16 status, cancer stem cell (CSC) marker expression and hypoxia-associated gene signatures as potential prognostic biomarkers for patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who underwent primary radiotherapy or radiochemotherapy (RCTx). These markers have previously been reported in a study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG) (Linge et al., 2016).

Comparison of subjective evaluation versus objective algorithm in the interpretation of follow-up FDG-PET/CT scans after radiochemotherapy in head and neck cancer patients.

Aim: Retrospective evaluation of serial FDG-PET/CT scans in head and neck squamous cell cancer (HNSCC) patient's follow-up after primary radiochemotherapy (RCTx), to assess the diagnostic accuracy of an experienced observer vs. an objective classification compared to standard clinical follow-up examinations.

Methods: Sixty-nine patients with locally advanced HNSCC were included, who received curative RCTx.

Correlation between FMISO-PET based hypoxia in the primary tumour and in lymph node metastases in locally advanced HNSCC patients.

Purpose: This secondary analysis of the prospective study on repeat [F]fluoromisonidazole (FMISO)-PET in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) assessed the correlation of hypoxia in the primary tumour and lymph node metastases (LN) prior to and during primary radiochemotherapy.

Methods: This analysis included forty-five LN-positive HNSCC patients having undergone FMISO-PET/CTs at baseline, and at week 1, 2 and 5 of radiochemotherapy. The quantitative FMISO-PET/CT parameters maximum standardised uptake value (SUV, corrected for partial volume effect) and peak tumour-to-background ratio (TBR) were estimated in the primary tumour as well as in index and large LN, respectively.

Retrospective investigation of the prognostic value of the β1 integrin expression in patients with head and neck squamous cell carcinoma receiving primary radio(chemo)therapy.

This retrospective study evaluated the expression of β1 integrins and associated proteins as prognostic markers for primary radio(chemo)therapy outcome of patients with locally advanced head and neck squamous cell carcinomas (HNSCC). Tissue microarrays were prepared from 224 HNSCC patients undergoing curative primary radio(chemo)therapy from 1996 to 2005. Staining intensities of β1 integrin and its downstream-proteins FAK, phosphorylated FAK as well as the β1 integrin ECM ligands fibronectin and collagen type-I were determined.

FMISO-PET-based lymph node hypoxia adds to the prognostic value of tumor only hypoxia in HNSCC patients.

Purpose: This secondary analysis of the prospective study on repeat [F]fluoromisonidazole (FMISO)-PET in patients with locally advanced head and neck squamous cell carcinomas (HNSCC) assessed the prognostic value of synchronous hypoxia in primary tumor (Tu) and lymph node metastases (LN), and evaluated whether the combined reading was of higher prognostic value than that of primary tumor hypoxia only.

Methods: This analysis included forty-five LN-positive HNSCC patients. FMISO-PET/CTs were performed at baseline, weeks 1, 2 and 5 of radiochemotherapy.

Sites of recurrent disease and prognostic factors in SCLC patients treated with radiochemotherapy.

Objectives: Concurrent radiochemotherapy (RCHT) is standard treatment in locally advanced small cell lung cancer (SCLC) patients. Due to conflicting results on elective nodal irradiation (ENI) or selective node irradiation (SNI) there is no clear evidence on optimal target volumes. Therefore, the purposes of this study were to assess the sites of recurrent disease in SCLC and to evaluate the feasibility of SNI ENI.

Intratumoral heterogeneity and promoter mutations in progressive/higher-grade meningiomas.

Background: Recent studies have reported mutations in the telomerase reverse transcriptase promoter (p) in meningiomas. We sought to determine the frequency, clonality and clinical significance of telomere gene alterations in a cohort of patients with progressive/higher-grade meningiomas.

Methods: We characterized 64 temporally- and regionally-distinct specimens from 26 WHO grade III meningioma patients.

Development and Validation of a Gene Signature for Patients with Head and Neck Carcinomas Treated by Postoperative Radio(chemo)therapy.

The aim of this study was to identify and independently validate a novel gene signature predicting locoregional tumor control (LRC) for treatment individualization of patients with locally advanced HPV-negative head and neck squamous cell carcinomas (HNSCC) who are treated with postoperative radio(chemo)therapy (PORT-C). Gene expression analyses were performed using NanoString technology on a multicenter training cohort of 130 patients and an independent validation cohort of 121 patients. The analyzed gene set was composed of genes with a previously reported association with radio(chemo)sensitivity or resistance to radio(chemo)therapy.

Long-term quality of life in inoperable non-small cell lung cancer patients treated with conventionally fractionated compared to hyperfractionated accelerated radiotherapy - Results of the randomized CHARTWEL trial.

Background And Purpose: To evaluate the quality of life (QoL) of patients with inoperable non-small cell lung cancer treated with conventionally fractionated radiotherapy (CF) vs. continuous hyperfractionated accelerated radiotherapy weekend-less (CHARTWEL).

Material And Methods: The largest monocentric subgroup of the phase III CHARTWEL trial was analyzed up to three years after randomization.

PORTAF - postoperative radiotherapy of non-small cell lung cancer: accelerated versus conventional fractionation - study protocol for a randomized controlled trial.

Background: In early-stage non-small cell lung cancer (NSCLC) without affected lymph nodes detected at staging, surgical resection is still the mainstay of treatment. However, in patients with metastatic mediastinal lymph nodes (pN2) or non-radically resected primary tumors (R1/R2), postoperative radiotherapy (possibly combined with chemotherapy) is indicated. So far, investigations about time factors affecting postoperative radiotherapy have only examined the waiting time defined as interval between surgery and start of radiotherapy, but not the overall treatment time (OTT) itself.

FDG uptake in normal tissues assessed by PET during treatment has prognostic value for treatment results in head and neck squamous cell carcinomas undergoing radiochemotherapy.

Background And Purpose: Pronounced early side effects have been suggested to be a positive prognostic factor in patients undergoing chemo-radio-therapy (CRT) for head and neck squamous cell carcinomas (HNSCC). We assessed the utility of positron emission tomography (PET) during treatment to analyze the correlation of 18F-fluorodeoxyglucose (FDG) uptake in off target structures within the irradiated volume with outcome.

Material And Methods: Two independent cohorts of patients with locally advanced HNSCC, both treated within prospective clinical imaging trials with curatively intended CRT were retrospectively analyzed.

Independent validation of the prognostic value of cancer stem cell marker expression and hypoxia-induced gene expression for patients with locally advanced HNSCC after postoperative radiotherapy.

Objective: To validate the impact of HPV status, cancer stem cell (CSC) marker expression and tumour hypoxia status in patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who received postoperative radiotherapy. The results of the exploration cohort have previously been reported by the German Cancer Consortium Radiation Oncology Group (DKTK-ROG; Lohaus et al., 2014; Linge et al.

PRONTOX - proton therapy to reduce acute normal tissue toxicity in locally advanced non-small-cell lung carcinomas (NSCLC): study protocol for a randomised controlled trial.

Background: Primary radiochemotherapy with photons is the standard treatment for locally advanced-stage non-small cell lung cancer (NSCLC) patients. Acute radiation-induced side effects such as oesophagitis and radiation pneumonitis limit patients' quality of life, and the latter can be potentially life-threatening. Due to its distinct physical characteristics, proton therapy enables better sparing of normal tissues, which is supposed to translate into a reduction of radiation-induced side effects.

Spatial distribution of FMISO in head and neck squamous cell carcinomas during radio-chemotherapy and its correlation to pattern of failure.

Background: Tumour hypoxia can be measured by FMISO-PET and negatively impacts local tumour control in patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy. The aim of this post hoc analysis of a prospective clinical trial was to investigate the spatial variability of FMISO hypoxic subvolumes during radio-chemotherapy and the co-localisation of these volumes with later recurrences as a basis for individualised dose prescription trials with dose escalation defined by FMISO-PET.

Methods: Sequential FMISO scans of 12 (of 25) patients presenting residual hypoxia taken before (FMISOpre) and during (FMISOw1-FMISOw5) radio-chemotherapy were analysed regarding the stability of the FMISO subvolumes and, in case of local failure, their correlation to local relapse.

The mean lung dose (MLD) : predictive criterion for lung damage?

Aim: The purpose of this work was to prove the validity of the mean lung dose (MLD), widely used in clinical practice to estimate the lung toxicity of a treatment plan, by reevaluating experimental data from mini pigs.

Materials And Methods: A total of 43 mini pigs were irradiated in one of four dose groups (25, 29, 33, and 37 Gy). Two regimens were applied: homogeneous irradiation of the right lung or partial irradiation of both lungs-including parts with lower dose-but with similar mean lung doses.

Radiochemotherapy-induced changes of tumour vascularity and blood supply estimated by dynamic contrast-enhanced CT and fractal analysis in malignant head and neck tumours.

Objective: To investigate radiochemotherapy (RChT)-induced changes of transfer coefficient (K(trans)) and relative tumour blood volume (rTBV) estimated by dynamic contrast-enhanced CT (DCE-CT) and fractal analysis in head and neck tumours (HNTs).

Methods: DCE-CT was performed in 15 patients with inoperable HNTs before RChT, and after 2 and 5 weeks. The dynamics of K(trans) and rTBV as well as lacunarity, slope of log(lacunarity) vs log(box size), and fractal dimension were compared with tumour behaviour during RChT and in the 24-month follow-up.