Re-irradiation in the treatment of patients with cerebral metastases of solid tumors: retrospective analysis

Background: Goal of this retrospective analysis was to evaluate the role of repeat whole brain radiotherapy in the palliative care of patients with brain metastases due to solid tumors. Methods: Data regarding demographic data, primary tumor, metastasis, radiotherapy and symptoms were compiled on 134 patients with cerebral metastases that received repeat whole brain radiotherapy (WBRT) in our clinic between 2002 and 2011. Results: The analyzed group consisted of 63 (47%) women and 71 (53%) men with a median age of 57 at the start of re-irradiation. Most frequent primary site was the lung (87%). Sixty patients with lung cancer received the first WBRT prophylactically. At the time of re-WBRT 81% of all patients suffered from additional extracerebral metastases. Time between first and second WBRT was a median of 13.4 months. Full dose for the first WBRT was 30 Gy in 2.0 Gy single dose, for the second 20 Gy in 2.0 Gy single dose. At the start of the Re-WBRT 81 patients (60.4%) had mild, 32 (23.9%) severe neurological symptoms, 21 patients (15.7%) were asymptomatic. The median Karnofsky performance status was 70%. Overall, re-WBRT was tolerated satisfactorily. Main side effects were fatigue, erythema and focal alopecia, 10% of patients discontinued treatment before reaching the planned dose. Median survival was 2.8 months since the end of the re-WBRT with good performance status at the start of the re-irradiation being a key indicator for longer survival. Fifty-two patients (39%) showed a clinical improvement of neurological symptoms after the therapy, 59 patients (44%) remained stable, 23 patients (17%) showed worse symptoms. Conclusions: From this large patient collective we were able to show that re-WBRT can be an important therapeutic option with low rate of acute side effects for patients in adequate general condition

Subclinical Left Ventricular Dysfunction Detected by Speckle-Tracking Echocardiography in Breast Cancer Patients Treated With Radiation Therapy:A Six-Month Follow-Up Analysis (MEDIRAD EARLY‐HEART study)

Copyright © 2022 Locquet, Spoor, Crijns, van der Harst, Eraso, Guedea, Fiuza, Santos, Combs, Borm, Mousseaux, Gencer, Frija, Cardis, Langendijk and Jacob. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background: In the case of breast cancer (BC), radiotherapy (RT) helps reduce locoregional recurrence and BC-related deaths but can lead to cardiotoxicity, resulting in an increased risk of long-term major cardiovascular events. It is therefore of primary importance to early detect subclinical left ventricular (LV) dysfunction in BC patients after RT and to determine the dose-response relationships between cardiac doses and these events. Methods: Within the frame of the MEDIRAD European project (2017-2022), the prospective multicenter EARLY-HEART study (ClinicalTrials.gov Identifier: NCT03297346) included chemotherapy naïve BC women aged 40-75 years and treated with lumpectomy and adjuvant RT. Myocardial strain analysis was provided using speckle-tracking echocardiography performed at baseline and 6 months following RT. A global longitudinal strain (GLS) reduction >15% between baseline and follow-up was defined as a GLS-based subclinical LV dysfunction. Individual patient dose distributions were obtained using multi-atlas-based auto-segmentation of the heart. Dose-volume parameters were studied for the whole heart (WH) and left ventricle (LV). Results: The sample included 186 BC women (57.5 ± 7.9 years, 64% left-sided BC). GLS-based subclinical LV dysfunction was observed in 22 patients (14.4%). These patients had significantly higher cardiac exposure regarding WH and LV doses compared to patients without LV dysfunction (for mean WH dose: 2.66 ± 1.75 Gy versus 1.64 ± 0.96 Gy, p = 0.01). A significantly increased risk of subclinical LV dysfunction was observed with the increase in the dose received to the WH [ORs from 1.13 (V5) to 1.74 (Dmean); p <0.01] and to the LV [ORs from 1.10 (V5) to 1.46 (Dmean); p <0.01]. Based on ROC analysis, the LV-V5 parameter may be the best predictor of the short-term onset of subclinical LV dysfunction. Conclusion: These results highlighted that all cardiac doses were strongly associated with the occurrence of subclinical LV dysfunction arising 6 months after BC RT. Whether measurements of GLS at baseline and 6 months after RT combined with cardiac doses can early predict efficiently subclinical events occurring 24 months after RT remains to be investigated.The European Community’s Horizon 2020 Programme supported the EARLY-HEART study conducted in the frame of the MEDIRAD - Implications of Medical Low Dose Radiation Exposure - project spanning from 2017 to 2021 granted by the Euratom Research and Training Programme 2014-2014 under agreement No. 755523.info:eu-repo/semantics/publishedVersio

Early detection of cardiovascular changes after radiotherapy for breast cancer: protocol for a European multicenter prospective cohort study (MEDIRAD EARLY HEART Study)

Background: breast cancer is the most common cancer among women, and radiotherapy plays a major role in its treatment. However, breast cancer radiotherapy can lead to incidental irradiation of the heart, resulting in an increased risk for a variety of heart diseases arising many years after radiotherapy. Therefore, identifying breast cancer patients at the highest risk for radiation-induced cardiac complications is crucial for developing strategies for primary and secondary prevention, which may contribute to healthy aging. There is still a need for precise knowledge on the relationship between radiation dose to specific cardiac structures and early subclinical cardiac changes and their occurrence over time that could finally lead to cardiac complications. Objective: the MEDIRAD EARLY HEART study aims to identify and validate new cardiac imaging and circulating biomarkers of radiation-induced cardiovascular changes arising within first 2 years of breast cancer radiotherapy and to develop risk models integrating these biomarkers combined with precise dose metrics of cardiac structures based on three-dimensional dosimetry. Methods: the EARLY HEART study is a multicenter, prospective cohort study in which 250 women treated for breast cancer and followed for 2 years after radiotherapy will be included. Women treated with radiotherapy without chemotherapy for a unilateral breast cancer and aged 40-75 years meet the inclusion criteria. Baseline and follow-up data include cardiac measurements based on two-dimensional speckle-tracking echocardiography, computed tomography coronary angiography, cardiac magnetic resonance imaging, and a wide panel of circulating biomarkers of cardiac injury. The absorbed dose will be evaluated globally for the heart and different substructures. Furthermore, the dose-response relationship will allow modeling the radiation-induced occurrence and evolution of subclinical cardiac lesions and biomarkers to develop prediction models. Results: this study details the protocol of the MEDIRAD EARLY HEART study and presents the main limits and advantages of this international project. The inclusion of patients began in 2017. Preliminary results are expected to be published in 2019, and complete analysis should be published in 2021. Conclusions: the MEDIRAD EARLY HEART study will allow identifying the main cardiac imaging and blood-based determinants of radiation-induced cardiac injuries to better propose primary and secondary preventive measures in order to contribute to enhanced patient care and quality of life

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Dosiomics and radiomics to predict pneumonitis after thoracic stereotactic body radiotherapy and immune checkpoint inhibition

IntroductionPneumonitis is a relevant side effect after radiotherapy (RT) and immunotherapy with checkpoint inhibitors (ICIs). Since the effect is radiation dose dependent, the risk increases for high fractional doses as applied for stereotactic body radiation therapy (SBRT) and might even be enhanced for the combination of SBRT with ICI therapy. Hence, patient individual pre-treatment prediction of post-treatment pneumonitis (PTP) might be able to support clinical decision making. Dosimetric factors, however, use limited information and, thus, cannot exploit the full potential of pneumonitis prediction.MethodsWe investigated dosiomics and radiomics model based approaches for PTP prediction after thoracic SBRT with and without ICI therapy. To overcome potential influences of different fractionation schemes, we converted physical doses to 2 Gy equivalent doses (EQD2) and compared both results. In total, four single feature models (dosiomics, radiomics, dosimetric, clinical factors) were tested and five combinations of those (dosimetric+clinical factors, dosiomics+radiomics, dosiomics+dosimetric+clinical factors, radiomics+dosimetric+clinical factors, radiomics+dosiomics+dosimetric+clinical factors). After feature extraction, a feature reduction was performed using pearson intercorrelation coefficient and the Boruta algorithm within 1000-fold bootstrapping runs. Four different machine learning models and the combination of those were trained and tested within 100 iterations of 5-fold nested cross validation.ResultsResults were analysed using the area under the receiver operating characteristic curve (AUC). We found the combination of dosiomics and radiomics features to outperform all other models with AUCradiomics+dosiomics, D = 0.79 (95% confidence interval 0.78-0.80) and AUCradiomics+dosiomics, EQD2 = 0.77 (0.76-0.78) for physical dose and EQD2, respectively. ICI therapy did not impact the prediction result (AUC ≤ 0.5). Clinical and dosimetric features for the total lung did not improve the prediction outcome.ConclusionOur results suggest that combined dosiomics and radiomics analysis can improve PTP prediction in patients treated with lung SBRT. We conclude that pre-treatment prediction could support clinical decision making on an individual patient basis with or without ICI therapy

Correlation between delivered radiation doses to the brainstem or vestibular organ and nausea & vomiting toxicity in patients with head and neck cancers – an observational clinical trial

Abstract Objective Today intensity modulated radiation therapy (IMRT) can be considered the standard of care in patients with head and neck tumors. IMRT treatment plans are proven to reduce acute treatment related side effects by optimal sparing of organs at risk (OAR). At the same time, areas that were out of the former 3D fields now receive low radiation doses. Amongst those areas the brainstem (BS) and the vestibular system (VS) are known to be physiologically connected to nausea and vomiting (NV). In our study we tried to find out, if doses to these areas are linked to NV. Material & Methods NV were assessed at different time points during treatment in 26 patients leading to 98 documented toxicity scores that were later correlated to dose deposition in the described areas. Patients were either treated with normo-fractionated or simultaneously integrated boost IMRT plans in a curative approach. Subareas of the BS as well as the VS were delineated. Toxicity was rated based on the common toxicity criteria (CTCAE Version 4.0). Other factors such as age, gender, chemotherapy, location of the tumor, irradiated volume and unilateral dose to the VS were taken into account and analyzed also. Results The majority (65.4%) of our patients experienced an episode of NV at least once during treatment. NV was more frequent when treating the oropharyngeal region compared to the hypopharyngeal region, as well as when patients were female and/ or of a younger age. Nevertheless, upon statistical analysis (ROC analysis, ‘within/ between analysis’) no significant association between delivered doses to subareas and toxicity could be demonstrated. Conclusion In our analysis, no significant correlation between radiation dose to the BS or the VS and the occurrence of NV could be found. Therefore, until conclusive data are available, we recommend to rely on the published data regarding OAR tolerance within the BS and not to compromise on dose coverage

Early subclinical cardiovascular changes after radiotherapy for breast cancer detected by echocardiography: contribution of the MEDIRAD EARLY-HEART cohort

International audienceBackground: Breast cancer (BC) represents a major public health burden worldwide. Significant advances in treatments have been made in recent decades. Among them, radiotherapy (RT) allows reducing local recurrence and deaths resulting from BC. However, RT for BC can lead to cardiotoxicity, resulting in an increased risk of long-term major cardiovascular adverse events (MACE). Consequently, to detect early subclinical cardiac alterations is of primary importance.Objective: One of the aims of the MEDIRAD EARLY-HEART study is to determine the short-term impact of BC RT on subclinical cardiac function by means of echocardiography and to explore the dose-response relationship. Methods: Launched in 2017, the ongoing EARLY-HEART study is a prospective multicenter cohort study including women with BC aged 40 to 75 years and treated by RT in the Netherlands, Germany, France, Portugal and Spain. All women were chemotherapy naive. Echocardiographic exams after the RT+6-month follow-up (FU) will be available in September 2021 to determine if significant subclinical cardiac function alterations occurred. A RT+24-month FU is currently ongoing to determine if eventual previous alterations persist. Myocardial deformation analysis was provided by the 2D-speckle-tracking echocardiography. The global longitudinal strain (GLS), its worsening > 10% and the global longitudinal strain rate (GLSR) will be considered to evaluate subclinical cardiac dysfunction. Results: The EARLY-HEART cohort included 258 women with BC, with a mean age of 58.2±8.1 years, 63.5% with left-sided BC. Presence of pre-existing cardiovascular (CV) risk factors were recorded to allow adjustments in further analyses: obesity was present in 21.0% of the sample (mean body mass index of 26.3±4.6 kg/m²), hypertension in 48.2%, diabetes in 5.4% and 47.8% were current or former smoker. RT total dose varied from 40.05 Gray (Gy) to 50.40 Gy, and 46.1% received a boost (mean boost dose of 11.9±1.9 Gy). Among the 258 patients, 63.9% received concomitant hormonotherapy. Regarding subclinical cardiac investigations at baseline (before RT), 242 patients (93.8%) performed echocardiography exams, yielding a mean GLS of -19.3±3.3%. Full echocardiography analyses after the 6-month FU will be available soon to explore potential alterations of myocardial function between pre-RT time-point, 6-month and 24-month post-RT time-points using paired t tests. Future EARLY-HEART analyses will also provide accurate absorbed dose of cardiac structures (whole heart, right and left ventricles, right and left atrium) based on 3D-dosimetry to explore dose-response relationships using multivariate regressions. Subgroup and sensitivity analyses will be performed. Results of analyses of the relationship between radiation dose and subclinical cardiac function will be presented.Conclusion: Using strain analysis from echocardiography, the impact of RT on subclinical cardiac function in patients with BC are being explored within the MEDIRAD EARLY-HEART project. Epidemiological data regarding early alteration of GLS could contribute to adaptions in clinical practice about CV monitoring

Early subclinical cardiovascular changes after radiotherapy for breast cancer detected by echocardiography: contribution of the MEDIRAD EARLY-HEART cohort

International audienceBackground: Breast cancer (BC) represents a major public health burden worldwide. Significant advances in treatments have been made in recent decades. Among them, radiotherapy (RT) allows reducing local recurrence and deaths resulting from BC. However, RT for BC can lead to cardiotoxicity, resulting in an increased risk of long-term major cardiovascular adverse events (MACE). Consequently, to detect early subclinical cardiac alterations is of primary importance.Objective: One of the aims of the MEDIRAD EARLY-HEART study is to determine the short-term impact of BC RT on subclinical cardiac function by means of echocardiography and to explore the dose-response relationship. Methods: Launched in 2017, the ongoing EARLY-HEART study is a prospective multicenter cohort study including women with BC aged 40 to 75 years and treated by RT in the Netherlands, Germany, France, Portugal and Spain. All women were chemotherapy naive. Echocardiographic exams after the RT+6-month follow-up (FU) will be available in September 2021 to determine if significant subclinical cardiac function alterations occurred. A RT+24-month FU is currently ongoing to determine if eventual previous alterations persist. Myocardial deformation analysis was provided by the 2D-speckle-tracking echocardiography. The global longitudinal strain (GLS), its worsening > 10% and the global longitudinal strain rate (GLSR) will be considered to evaluate subclinical cardiac dysfunction. Results: The EARLY-HEART cohort included 258 women with BC, with a mean age of 58.2±8.1 years, 63.5% with left-sided BC. Presence of pre-existing cardiovascular (CV) risk factors were recorded to allow adjustments in further analyses: obesity was present in 21.0% of the sample (mean body mass index of 26.3±4.6 kg/m²), hypertension in 48.2%, diabetes in 5.4% and 47.8% were current or former smoker. RT total dose varied from 40.05 Gray (Gy) to 50.40 Gy, and 46.1% received a boost (mean boost dose of 11.9±1.9 Gy). Among the 258 patients, 63.9% received concomitant hormonotherapy. Regarding subclinical cardiac investigations at baseline (before RT), 242 patients (93.8%) performed echocardiography exams, yielding a mean GLS of -19.3±3.3%. Full echocardiography analyses after the 6-month FU will be available soon to explore potential alterations of myocardial function between pre-RT time-point, 6-month and 24-month post-RT time-points using paired t tests. Future EARLY-HEART analyses will also provide accurate absorbed dose of cardiac structures (whole heart, right and left ventricles, right and left atrium) based on 3D-dosimetry to explore dose-response relationships using multivariate regressions. Subgroup and sensitivity analyses will be performed. Results of analyses of the relationship between radiation dose and subclinical cardiac function will be presented.Conclusion: Using strain analysis from echocardiography, the impact of RT on subclinical cardiac function in patients with BC are being explored within the MEDIRAD EARLY-HEART project. Epidemiological data regarding early alteration of GLS could contribute to adaptions in clinical practice about CV monitoring

Neurocognitive functioning and health-related quality of life in adult medulloblastoma patients: long-term outcomes of the NOA-07 study

BACKGROUND Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult medulloblastoma patients. Here we investigated the long-term impact of this treatment, focusing on neurocognitive functioning and health-related quality of life (HRQoL). METHODS Neurocognitive functioning and HRQoL scores over time were determined, and differences between the post-treatment and follow-up assessments were calculated up to 18 months for neurocognition and 60 months for HRQoL. RESULTS 28/30 patients were analyzed. The three preselected HRQoL scales (role, social and cognitive functioning) showed improved scores, to a clinically relevant extent (≥ 10 points), compared to post-treatment levels up to 30 months, but decreased afterwards. Z-scores for verbal working memory were worse during follow-up compared to post-treatment scores and remained impaired during 18 months follow-up (i.e. z-score below - 1 standard deviation). Attention was impaired post-treatment, and remained impaired to a clinically relevant extent during follow-up. Coordination/processing speed and lexical verbal fluency improved compared to post-treatment scores, and remained within the normal range thereafter. Other tests of verbal fluency were stable over time, with z-scores within the normal range. CONCLUSIONS This long-term follow-up study showed that the NOA-07 treatment regimen was not associated with a deterioration in HRQoL in the post-treatment period. Verbal working memory deteriorated, while other neurocognitive domains did not seem to be impacted negatively by the treatment