Deep-learning-based reconstruction of undersampled MRI to reduce scan times: a multicentre, retrospective, cohort study.

BACKGROUND: The extended acquisition times required for MRI limit its availability in resource-constrained settings. Consequently, accelerating MRI by undersampling k-space data, which is necessary to reconstruct an image, has been a long-standing but important challenge. We aimed to develop a deep convolutional neural network (dCNN) optimisation method for MRI reconstruction and to reduce scan times and evaluate its effect on image quality and accuracy of oncological imaging biomarkers. METHODS: In this multicentre, retrospective, cohort study, MRI data from patients with glioblastoma treated at Heidelberg University Hospital (775 patients and 775 examinations) and from the phase 2 CORE trial (260 patients, 1083 examinations, and 58 institutions) and the phase 3 CENTRIC trial (505 patients, 3147 examinations, and 139 institutions) were used to develop, train, and test dCNN for reconstructing MRI from highly undersampled single-coil k-space data with various acceleration rates (R=2, 4, 6, 8, 10, and 15). Independent testing was performed with MRIs from the phase 2/3 EORTC-26101 trial (528 patients with glioblastoma, 1974 examinations, and 32 institutions). The similarity between undersampled dCNN-reconstructed and original MRIs was quantified with various image quality metrics, including structural similarity index measure (SSIM) and the accuracy of undersampled dCNN-reconstructed MRI on downstream radiological assessment of imaging biomarkers in oncology (automated artificial intelligence-based quantification of tumour burden and treatment response) was performed in the EORTC-26101 test dataset. The public NYU Langone Health fastMRI brain test dataset (558 patients and 558 examinations) was used to validate the generalisability and robustness of the dCNN for reconstructing MRIs from available multi-coil (parallel imaging) k-space data. FINDINGS: In the EORTC-26101 test dataset, the median SSIM of undersampled dCNN-reconstructed MRI ranged from 0·88 to 0·99 across different acceleration rates, with 0·92 (95% CI 0·92-0·93) for 10-times acceleration (R=10). The 10-times undersampled dCNN-reconstructed MRI yielded excellent agreement with original MRI when assessing volumes of contrast-enhancing tumour (median DICE for spatial agreement of 0·89 [95% CI 0·88 to 0·89]; median volume difference of 0·01 cm3 [95% CI 0·00 to 0·03] equalling 0·21%; p=0·0036 for equivalence) or non-enhancing tumour or oedema (median DICE of 0·94 [95% CI 0·94 to 0·95]; median volume difference of -0·79 cm3 [95% CI -0·87 to -0·72] equalling -1·77%; p=0·023 for equivalence) in the EORTC-26101 test dataset. Automated volumetric tumour response assessment in the EORTC-26101 test dataset yielded an identical median time to progression of 4·27 months (95% CI 4·14 to 4·57) when using 10-times-undersampled dCNN-reconstructed or original MRI (log-rank p=0·80) and agreement in the time to progression in 374 (95·2%) of 393 patients with data. The dCNN generalised well to the fastMRI brain dataset, with significant improvements in the median SSIM when using multi-coil compared with single-coil k-space data (p<0·0001). INTERPRETATION: Deep-learning-based reconstruction of undersampled MRI allows for a substantial reduction of scan times, with a 10-times acceleration demonstrating excellent image quality while preserving the accuracy of derived imaging biomarkers for the assessment of oncological treatment response. Our developments are available as open source software and hold considerable promise for increasing the accessibility to MRI, pending further prospective validation. FUNDING: Deutsche Forschungsgemeinschaft (German Research Foundation) and an Else Kröner Clinician Scientist Endowed Professorship by the Else Kröner Fresenius Foundation.

Genetics of preschool wheeze and its progression to childhood asthma.

Wheezing is a common and heterogeneous condition in preschool children. In some countries, the prevalence can be as high as 30% and up to 50% of all children experience wheezing before the age of 6. Asthma often starts with preschool wheeze, but not all wheezing children will develop asthma at school age. At this moment, it is not possible to accurately predict which wheezing children will develop asthma. Recently, studying the genetics of wheeze and the childhood-onset of asthma have grown in interest. Childhood-onset asthma has a stronger heritability in comparison with adult-onset asthma. In early childhood asthma exacerbations, CDHR3, which encodes the receptor for Rhinovirus C, was identified, as well as IL33, and the 17q locus that includes GSDMB and ORMDL3 genes. The 17q locus is the strongest wheeze and childhood-onset asthma locus, and was shown to interact with many environmental factors, including smoking and infections. Finally, ANXA1 was recently associated with early-onset, persistent wheeze. ANXA1 may help resolve eosinophilic inflammation. Overall, despite its complexities, genetic approaches to unravel the early-onset of wheeze and asthma are promising, since these shed more light on mechanisms of childhood asthma-onset. Implicated genes point toward airway epithelium and its response to external factors, such as viral infections. However, the heterogeneity of wheeze phenotypes complicates genetic studies. It is therefore important to define accurate wheezing phenotypes and forge larger international collaborations to gain a better understanding of the pathways underlying early-onset asthma.

Mitochondrial modulation with leriglitazone as a potential treatment for Rett syndrome.

BACKGROUND: Rett syndrome is a neuropediatric disease occurring due to mutations in MECP2 and characterized by a regression in the neuronal development following a normal postnatal growth, which results in the loss of acquired capabilities such as speech or purposeful usage of hands. While altered neurotransmission and brain development are the center of its pathophysiology, alterations in mitochondrial performance have been previously outlined, shaping it as an attractive target for the disease treatment. METHODS: We have thoroughly described mitochondrial performance in two Rett models, patients' primary fibroblasts and female Mecp2tm1.1Bird-/+ mice brain, discriminating between different brain areas. The characterization was made according to their bioenergetics function, oxidative stress, network dynamics or ultrastructure. Building on that, we have studied the effect of leriglitazone, a PPARγ agonist, in the modulation of mitochondrial performance. For that, we treated Rett female mice with 75 mg/kg/day leriglitazone from weaning until sacrifice at 7 months, studying both the mitochondrial performance changes and their consequences on the mice phenotype. Finally, we studied its effect on neuroinflammation based on the presence of reactive glia by immunohistochemistry and through a cytokine panel. RESULTS: We have described mitochondrial alterations in Rett fibroblasts regarding both shape and bioenergetic functions, as they displayed less interconnected and shorter mitochondria and reduced ATP production along with increased oxidative stress. The bioenergetic alterations were recalled in Rett mice models, being especially significant in cerebellum, already detectable in pre-symptomatic stages. Treatment with leriglitazone recovered the bioenergetic alterations both in Rett fibroblasts and female mice and exerted an anti-inflammatory effect in the latest, resulting in the amelioration of the mice phenotype both in general condition and exploratory activity. CONCLUSIONS: Our studies confirm the mitochondrial dysfunction in Rett syndrome, setting the differences through brain areas and disease stages. Its modulation through leriglitazone is a potential treatment for this disorder, along with other diseases with mitochondrial involvement. This work constitutes the preclinical necessary evidence to lead to a clinical trial.

The Fundamental Role of Oxime and Oxime Ether Moieties in Improving the Physicochemical and Anticancer Properties of Structurally Diverse Scaffolds.

The present review explores the critical role of oxime and oxime ether moieties in enhancing the physicochemical and anticancer properties of structurally diverse molecular frameworks. Specific examples are carefully selected to illustrate the distinct contributions of these functional groups to general strategies for molecular design, modulation of biological activities, computational modeling, and structure-activity relationship studies. An extensive literature search was conducted across three databases, including PubMed, Google Scholar, and Scifinder, enabling us to create one of the most comprehensive overviews of how oximes and oxime ethers impact antitumor activities within a wide range of structural frameworks. This search focused on various combinations of keywords or their synonyms, related to the anticancer activity of oximes and oxime ethers, structure-activity relationships, mechanism of action, as well as molecular dynamics and docking studies. Each article was evaluated based on its scientific merit and the depth of the study, resulting in 268 cited references and more than 336 illustrative chemical structures carefully selected to support this analysis. As many previous reviews focus on one subclass of this extensive family of compounds, this report represents one of the rare and fully comprehensive assessments of the anticancer potential of this group of molecules across diverse molecular scaffolds.

Immune-checkpoint inhibitors in pituitary malignancies.

To date, there are no standardized systemic treatment options for patients with metastatic pituitary carcinoma progressed to chemo and radiation therapy. Immune-checkpoint inhibitors (ICIs) have been successfully assessed in other solid malignancies and could be a concrete hope for these patients. We performed a critical review of the literature aimed to evaluate studies assessing ICIs in pituitary malignancies. We also conducted research about published translational data assessing immune-contexture in these malignancies. Some preliminary reports reported a successful administration of pembrolizumab or the combination between nivolumab and ipilimumab in patients with metastatic ACTH-secreting pituitary carcinomas. Translational data suggest that adenomas secreting growth hormone and ACTH have a suppressed immune-microenvironment, which could be more likely to benefit from ICIs. Immune-checkpoint inhibitors can be an effective treatment in patients with pituitary carcinoma and maybe also recurrent adenoma. Tumors secreting growth hormone and ACTH are more likely to benefit from ICIs due to a different immune-microenvironment.

An American lineage of Helicobacter pylori prophages found in Colombia.

BACKGROUND: Helicobacter pylori is a human gastric carcinogen that is highly prevalent in Latin American. The prophages of H. pylori show a structured population and contribute to the diversity of this bacterium. However, H. pylori prophages present in American strains have not been described to date. In this study, we identified, characterized, and present the phylogenetic analysis of the prophages present in Colombian H. pylori strains. METHODS: To characterize Colombian H. pylori strains and their prophages, a Multilocus Sequences Typing (MLST) and a Prophage Sequences Typing (PST), using the integrase and holin genes, were performed. Furthermore, five Colombian H. pylori had their full genome sequenced, and six Colombian H.pylori retrieved from databases, allowing to determine the prophage complete genome and insertion site. RESULTS: The integrase gene frequency was 12.6% (27/213), while both integrase and holin genes were present in 4.2% (9/213) of the samples analyzed. The PST analysis showed that Colombian prophages belong to different populations, including hpSWEurope, hpNEurope, hpAfrica1, and a new population, named hpColombia. The MLST analysis classified most of the Colombia strains in the hpEurope population. CONCLUSIONS: The new H. pylori prophage population revealed that Colombian prophages follow a unique evolutionary trajectory, contributing to bacterial diversity. The global H. pylori prophage phylogeny highlighted five phylogenetic groups, one more than previously reported. After the arrival of Europeans, the Colombian H. pylori bacteria and their prophages formed an independent evolutionary line to adapt to the new environment and new human hosts.

Response assessment in paediatric high-grade glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Response criteria for paediatric high-grade glioma vary historically and across different cooperative groups. The Response Assessment in Neuro-Oncology working group developed response criteria for adult high-grade glioma, but these were not created to meet the unique challenges in children with the disease. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric high-grade glioma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric high-grade gliomas to various treatments. For areas in which scientific investigation was scarce, consensus was reached through an iterative process. RAPNO response assessment recommendations include the use of MRI of the brain and the spine, assessment of clinical status, and the use of corticosteroids or antiangiogenics. Imaging standards for brain and spine are defined. Compared with the recommendations for the management of adult high-grade glioma, for paediatrics there is inclusion of diffusion-weighted imaging and a higher reliance on T2-weighted fluid-attenuated inversion recovery. Consensus recommendations and response definitions have been established and, similar to other RAPNO recommendations, prospective validation in clinical trials is warranted.

Response assessment in paediatric low-grade glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Paediatric low-grade gliomas (also known as pLGG) are the most common type of CNS tumours in children. In general, paediatric low-grade gliomas show clinical and biological features that are distinct from adult low-grade gliomas, and the developing paediatric brain is more susceptible to toxic late effects of the tumour and its treatment. Therefore, response assessment in children requires additional considerations compared with the adult Response Assessment in Neuro-Oncology criteria. There are no standardised response criteria in paediatric clinical trials, which makes it more difficult to compare responses across studies. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop consensus recommendations for response assessment in paediatric low-grade gliomas. Final recommendations were based on literature review, current practice, and expert opinion of working group members. Consensus recommendations include imaging response assessments, with additional guidelines for visual functional outcomes in patients with optic pathway tumours. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.

A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation.

BACKGROUND: In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer. METHODS: We derived a combined prognostic model using retrospective clinical-pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1-105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data. FINDINGS: From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1-2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3-99·9), 88·9% (83·2-95·0), and 73·9% (66·0-82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0-0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4-5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1-0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0-98·3%) and in the high-risk group was 81·1% (71·5-92·1). INTERPRETATION: The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting. FUNDING: Instituto Salud Carlos III, Save the Mama, Pas a Pas, Fundación Científica, Asociación Española Contra el Cáncer, Fundación SEOM, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, and the Veneto Institute of Oncology, and Italian Association for Cancer Research.

Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma.

BACKGROUND: Glioblastoma is associated with a poor prognosis in the elderly. Survival has been shown to increase among patients 70 years of age or younger when temozolomide chemotherapy is added to standard radiotherapy (60 Gy over a period of 6 weeks). In elderly patients, more convenient shorter courses of radiotherapy are commonly used, but the benefit of adding temozolomide to a shorter course of radiotherapy is unknown. METHODS: We conducted a trial involving patients 65 years of age or older with newly diagnosed glioblastoma. Patients were randomly assigned to receive either radiotherapy alone (40 Gy in 15 fractions) or radiotherapy with concomitant and adjuvant temozolomide. RESULTS: A total of 562 patients underwent randomization, 281 to each group. The median age was 73 years (range, 65 to 90). The median overall survival was longer with radiotherapy plus temozolomide than with radiotherapy alone (9.3 months vs. 7.6 months; hazard ratio for death, 0.67; 95% confidence interval [CI], 0.56 to 0.80; P<0.001), as was the median progression-free survival (5.3 months vs. 3.9 months; hazard ratio for disease progression or death, 0.50; 95% CI, 0.41 to 0.60; P<0.001). Among 165 patients with methylated O6-methylguanine-DNA methyltransferase (MGMT) status, the median overall survival was 13.5 months with radiotherapy plus temozolomide and 7.7 months with radiotherapy alone (hazard ratio for death, 0.53; 95% CI, 0.38 to 0.73; P<0.001). Among 189 patients with unmethylated MGMT status, the median overall survival was 10.0 months with radiotherapy plus temozolomide and 7.9 months with radiotherapy alone (hazard ratio for death, 0.75; 95% CI, 0.56 to 1.01; P=0.055; P=0.08 for interaction). Quality of life was similar in the two trial groups. CONCLUSIONS: In elderly patients with glioblastoma, the addition of temozolomide to short-course radiotherapy resulted in longer survival than short-course radiotherapy alone. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00482677 .).

Lomustine and Bevacizumab in Progressive Glioblastoma.

BACKGROUND: Bevacizumab is approved for the treatment of patients with progressive glioblastoma on the basis of uncontrolled data. Data from a phase 2 trial suggested that the addition of bevacizumab to lomustine might improve overall survival as compared with monotherapies. We sought to determine whether the combination would result in longer overall survival than lomustine alone among patients at first progression of glioblastoma. METHODS: We randomly assigned patients with progression after chemoradiation in a 2:1 ratio to receive lomustine plus bevacizumab (combination group, 288 patients) or lomustine alone (monotherapy group, 149 patients). The methylation status of the promoter of O6-methylguanine-DNA methyltransferase (MGMT) was assessed. Health-related quality of life and neurocognitive function were evaluated at baseline and every 12 weeks. The primary end point of the trial was overall survival. RESULTS: A total of 437 patients underwent randomization. The median number of 6-week treatment cycles was three in the combination group and one in the monotherapy group. With 329 overall survival events (75.3%), the combination therapy did not provide a survival advantage; the median overall survival was 9.1 months (95% confidence interval [CI], 8.1 to 10.1) in the combination group and 8.6 months (95% CI, 7.6 to 10.4) in the monotherapy group (hazard ratio for death, 0.95; 95% CI, 0.74 to 1.21; P=0.65). Locally assessed progression-free survival was 2.7 months longer in the combination group than in the monotherapy group: 4.2 months versus 1.5 months (hazard ratio for disease progression or death, 0.49; 95% CI, 0.39 to 0.61; P<0.001). Grade 3 to 5 adverse events occurred in 63.6% of the patients in the combination group and 38.1% of the patients in the monotherapy group. The addition of bevacizumab to lomustine affected neither health-related quality of life nor neurocognitive function. The MGMT status was prognostic. CONCLUSIONS: Despite somewhat prolonged progression-free survival, treatment with lomustine plus bevacizumab did not confer a survival advantage over treatment with lomustine alone in patients with progressive glioblastoma. (Funded by an unrestricted educational grant from F. Hoffmann-La Roche and by the EORTC Cancer Research Fund; EORTC 26101 ClinicalTrials.gov number, NCT01290939 ; Eudra-CT number, 2010-023218-30 .).

Temozolomide and seizure outcomes in a randomized clinical trial of elderly glioblastoma patients.

INTRODUCTION: Tumor-related epilepsy may respond to chemotherapy. In a previously-published multi-centre randomized clinical trial of 562 elderly glioblastoma patients, temozolomide plus short-course radiotherapy conferred a survival benefit over radiotherapy alone. Seizure outcomes were not reported. METHODS: We performed an unplanned secondary analysis of this trial's data. The trial design has been previously reported. Seizures were recorded by clinicians as adverse events and by patients in quality of life questionnaires. A Chi-square test of seizure rates between the two groups (α = 0.05) and a Kaplan-Meier estimator of time-to-first self-reported seizure were planned. RESULTS: Almost all patients were followed until they died. In the radiotherapy alone group, 68 patients (24%) had a documented or self-reported seizure versus 83 patients (30%) in the temozolomide plus radiotherapy group, Chi-square analysis showed no difference (p = 0.15). Patients receiving radiotherapy alone tended to develop seizures earlier than those receiving temozolomide plus radiotherapy (p = 0.054). Patients with seizures had shorter overall survival than those without seizures (hazard ratio 1.24, p = 0.02). CONCLUSIONS: This study was not powered to detect differences in seizure outcomes, but temozolomide seemed to have minimal impact on seizure control in elderly patients with glioblastoma. CLINICAL TRIAL REGISTRATION: NCT00482677 2007-06-05.

Fighting cancer in coronavirus disease era: organization of work in medical oncology departments in Emilia Romagna region of Italy.

Aim: To assess the measures applied to reduce the spread of coronavirus disease (COVID-19) and the timing of their application in medical oncology departments. Materials & methods: We surveyed all medical oncology departments from the Italian Emilia Romagna region via a multidomain questionnaire. The questions covered items on patients, healthcare workers, risk reduction measure and clinical trials. Results: A total of 12 centers involving 861 healthcare members joined the survey. The measures applied to patients and health workers partially converged in all the departments while major divergences were found in the clinical trials domain. High rate of COVID-19 infection occurred among medical doctors (21/208, 10.1%) and social care workers (13/110, 11.8%). Rate of infection among nurses was 5.7% (24/418). Conclusion: All measures able to reduce risk of COVID-19 infection must be applied in medical oncology departments. Early introduction of risk reduction measures may be a critical issue.

EANO-EURACAN clinical practice guideline for diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma.

The European Association of Neuro-Oncology (EANO) and EUropean RAre CANcer (EURACAN) guideline provides recommendations for the diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma. The guideline is based on the 2016 WHO classification of tumours of the CNS and on scientific developments published since 1980. It aims to provide direction for diagnostic and management decisions, and for limiting unnecessary treatments and cost. In view of the scarcity of data in adults with medulloblastoma, we base our recommendations on adult data when possible, but also include recommendations derived from paediatric data if justified. Our recommendations are a resource for professionals involved in the management of post-pubertal and adult patients with medulloblastoma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.

Postsurgical Approaches in Low-Grade Oligodendroglioma: Is Chemotherapy Alone Still an Option?

BACKGROUND: Patients with low-grade gliomas (LGGs) with isocitrate dehydrogenase (IDH) mutation (mut) and 1p19q codeletion (codel) have a median overall survival of longer than 10 years. The aim of this study is to assess the role of postsurgical treatments. SUBJECTS, MATERIALS, AND METHODS: We evaluated patients with LGGs with IDH mut and 1p19q codel; IDH1/2 was performed by immunohistochemistry and quantitative polymerase chain reaction. In all wild-type cases, we performed next-generation sequencing. 1p19 codel analysis was performed by fluorescence in situ hybridization. RESULTS: Among the 679 patients, 93 with LGGs with IDH mutation and 1p19q codel were included. Median follow-up (FU) was 96.1 months. Eighty-four patients (90.3%) were high risk according to Radiation Therapy Oncology Group criteria. After surgery, 50 patients (53.7%) received only FU, 17 (18.3%) chemotherapy (CT), and 26 (30.1%) radiotherapy (RT) with (RT + CT, 8 patients, 8.6%) or without (RT, 18 patients, 19.4%) chemotherapy. Median progression-free survival (mPFS) was 46.3 months, 50.8 months, 103.6 months, and 120.2 months in patients with FU alone, with CT alone, with RT alone, or with RT + CT, respectively. Median PFS was significantly longer in patients who received postsurgical treatment (79.5 months, 95% confidence interval [CI]: 66.4-92.7) than patients who received FU (46.3 months, 95% CI: 36.0-56.5). Moreover, mPFS was longer in patients who received RT (alone or in combination with CT, n = 26, 113.8 months, 95% CI: 57.2-170.5) than those who did not (n = 67, 47.3 months, 95% CI: 36.4-58.2). In particular, temozolomide alone did not improve PFS with respect to FU. CONCLUSION: RT with or without chemotherapy, but not temozolomide alone, could extend PFS in IDH mut 1p19q codel LGGs. IMPLICATIONS FOR PRACTICE: Low-grade gliomas with high-risk features, defined according to Radiation Therapy Oncology Group criteria, receive radiotherapy and/or chemotherapy as postsurgical treatments. Radiotherapy, however, has serious long-term effects (cognitive impairment), which are to be taken into account in these young patients. Moreover, low-grade gliomas with isocitrate dehydrogenase mutation and 1p19q codeletion (oligodendrogliomas) have an extremely long survival and a better prognosis. This study suggests that postsurgical treatments prolong the time before tumor progression in patients with good prognosis as well as those with oligodendroglioma. Moreover, temozolomide alone might not be effective in prolonging progression-free survival.

A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma.

BACKGROUND: We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. PATIENTS AND METHODS: TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. RESULTS: Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69-1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48-1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37-1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52-1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo). CONCLUSION: There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. IMPLICATIONS FOR PRACTICE: Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.

Validation of the AJCC prognostic stage for HER2-positive breast cancer in the ShortHER trial.

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging has introduced prognostic stage based on anatomic stage combined with biologic factors. We aimed to validate the prognostic stage in HER2-positive breast cancer patients enrolled in the ShortHER trial. METHODS: The ShortHER trial randomized 1253 HER2-positive patients to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Patients were classified according to the anatomic and the prognostic stage. Distant disease-free survival (DDFS) was calculated from randomization to distant relapse or death. RESULTS: A total of 1244 patients were included. Compared to anatomic stage, the prognostic stage downstaged 41.6% (n = 517) of patients to a more favorable stage category. Five-year DDFS based on anatomic stage was as follows: IA 96.6%, IB 94.1%, IIA 92.4%, IIB 87.3%, IIIA 81.3%, IIIC 70.5% (P < 0.001). Five-year DDFS according to prognostic stage was as follows: IA 95.7%, IB 91.4%, IIA 86.9%, IIB 85.0%, IIIA 77.6%, IIIC 67.7% (P < 0.001). The C index was similar (0.69209 and 0.69249, P = 0.975). Within anatomic stage I, the outcome was similar for patients treated with 9 weeks or 1 year trastuzumab (5-year DDFS 96.2% and 96.6%, P = 0.856). Within prognostic stage I, the outcome was numerically worse for patients treated with 9 weeks trastuzumab (5-year DDFS 93.7% and 96.3%, P = 0.080). CONCLUSIONS: The prognostic stage downstaged 41.6% of patients, while maintaining a similar prognostic performance as the anatomic stage. The prognostic stage is valuable in counseling patients and may serve as reference for a clinical trial design. Our data do not support prognostic stage as guidance to de-escalate treatment. TRIAL REGISTRATION: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

Prescription of statins in suspected non-alcoholic fatty liver disease and high cardiovascular risk, a population-based study.

BACKGROUND & AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing, with concomitant high incidence of lipoprotein abnormalities. Cardiovascular disease (CVD) is the main cause of death in subjects with NAFLD and management of dyslipidaemia is pivotal for prevention. We aimed to determine cardiovascular risk and indication for statin therapy in subjects with NAFLD. METHODS: A cross-sectional analysis of the population-based Lifelines Cohort Study of 34 240 adult individuals. Subjects with reported use of lipid-lowering drugs were excluded. Suspected NAFLD was defined as Fatty Liver Index (FLI) ≥60 and advanced hepatic fibrosis as NAFLD fibrosis score (NFS) >0.676. Cardiovascular risk and indication for statin therapy were defined according to the European Society of Cardiology and European Atherosclerosis Society Guideline for the Management of Dyslipidaemias. RESULTS: FLI ≥ 60 was present in 7067 (20.6%) participants and coincided with increased prevalence of type 2 diabetes mellitus, metabolic syndrome, CVD and impaired renal function (all P < 0.001). 10-year predicted cardiovascular risk was significantly increased in subjects with elevated FLI and NFS (both P < 0.001). Indication for statin use was significantly increased in subjects with FLI ≥ 60 (31.0% vs 15.6%, P < 0.001) and NFS > 0.676 (73.2% vs 30.6%, P < 0.001). In multivariable analyses, FLI ≥ 60 (OR 1.26, 95%CI: 1.13-1.41, P < 0.001) and NFS > 0.676 (OR 5.03, 95%CI: 2.76-9.17, P < 0.001) were independent predictors for indication regarding statin therapy. CONCLUSIONS: Because of increased cardiovascular risk, substantial proportions of subjects with suspected NAFLD and/or fibrosis have an indication for lipid-lowering treatment and could benefit from statin therapy.

Medulloblastoma and central nervous system germ cell tumors in adults: is pediatric experience applicable?

Medulloblastoma and central nervous system (CNS) germ cell tumors are very rare in adults, while they account for 25% and 5% of brain tumors in children, respectively (Pastore et al. Eur J Cancer 42:2064-208, 2006). Pediatric experiences, mostly from randomized and controlled clinical trials, have led to different tailored treatments, based on various risk factors, including histology, and extent of disease. For medulloblastoma, biological features have recently emerged that enable therapies to be scaled down in some cases, or pursued more aggressively in the event of chromosomal and/or genetic alterations (Massimino et al. Crit Rev Oncol Hematol 105:35-51, 2016). Such refinements are still impossible for adult patients due to the lack of similar clinical trials that might provide the same or a different understanding regarding patients' prognosis, long-term survival, quality of life, and acute and late toxicities. This review aims to contribute to the debate on the treatment of adults with these two diseases and promote the creation of broad-based, national and international trials to advance our knowledge in this area and to share the skills between pediatric and adult oncologists as adolescent and young adults (AYA) brain tumor national boards are currently requiring.

The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033.

The optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk-adjusted treatments are required for optimizing outcome and quality of life. We aim at identifying mechanisms and associated molecular markers predictive for benefit from radiotherapy (RT) or temozolomide (TMZ) in LGG patients treated in the randomized phase III trial EORTC 22033. As candidate biomarkers for these genotoxic treatments, we considered the DNA methylome of 410 DNA damage response (DDR) genes. We first identified 62 functionally relevant CpG sites located in the promoters of 24 DDR genes, using the LGG data from The Cancer Genome Atlas. Then we tested their association with outcome [progression-free survival (PFS)] depending on treatment in 120 LGG patients of EORTC 22033, whose tumors were mutant for isocitrate dehydrogenase 1 or 2 (IDHmt), the molecular hallmark of LGG. The results suggested that seven CpGs of four DDR genes may be predictive for longer PFS in one of the treatment arms that comprised MGMT, MLH3, RAD21, and SMC4. Most interestingly, the two CpGs identified for MGMT are the same, previously selected for the MGMT-STP27 score that is used to determine the methylation status of the MGMT gene. This score was higher in the LGG with 1p/19q codeletion, in this and other independent LGG datasets. It was predictive for PFS in the TMZ, but not in the RT arm of EORTC 22033. The results support the hypothesis that a high score predicts benefit from TMZ treatment for patients with IDHmt LGG, regardless of the 1p/19q status. This MGMT methylation score may identify patients who benefit from first-line treatment with TMZ, to defer RT for long-term preservation of cognitive function and quality of life.