TY  - JOUR
AB  - 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.
AU  - Franceschi, E.*
AU  - Hofer, S.*
AU  - Brandes, A.A.*
AU  - Frappaz, D.*
AU  - Kortmann, R.D.*
AU  - Bromberg, J.*
AU  - Dangouloff-Ros, V.*
AU  - Boddaert, N.*
AU  - Hattingen, E.*
AU  - Wiestler, B.*
AU  - Clifford, S.C.*
AU  - Figarella-Branger, D.*
AU  - Giangaspero, F.*
AU  - Haberler, C.*
AU  - Pietsch, T.*
AU  - Pajtler, K.W.*
AU  - Pfister, S.M.*
AU  - Guzman, R.*
AU  - Stummer, W.*
AU  - Combs, S.E.
AU  - Seidel, C.*
AU  - Beier, D.*
AU  - McCabe, M.G.*
AU  - Grotzer, M.*
AU  - Laigle-Donadey, F.*
AU  - Stücklin, A.S.G.*
AU  - Idbaih, A.*
AU  - Preusser, M.*
AU  - van den Bent, M.*
AU  - Weller, M.*
AU  - Hau, P.*
C1  - 57538
C2  - 47825
SP  - e715-e728
TI  - EANO–EURACAN clinical practice guideline for diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma.
JO  - Lancet Oncol.
VL  - 20
IS  - 12
PY  - 2019
SN  - 1470-2045
ER  - 

TY  - JOUR
AB  - Background The prevalence of malignant pleural effusion is increasing worldwide, but prognostic biomarkers to plan treatment and to understand the underlying mechanisms of disease progression remain unidentified. The PROMISE study was designed with the objectives to discover, validate, and prospectively assess biomarkers of survival and pleurodesis response in malignant pleural effusion and build a score that predicts survival.Methods In this multicohort study, we used five separate and independent datasets from randomised controlled trials to investigate potential biomarkers of survival and pleurodesis. Mass spectrometry-based discovery was used to investigate pleural fluid samples for differential protein expression in patients from the discovery group with different survival and pleurodesis outcomes. Clinical, radiological, and biological variables were entered into least absolute shrinkage and selection operator regression to build a model that predicts 3-month mortality. We evaluated the model using internal and external validation.Findings 17 biomarker candidates of survival and seven of pleurodesis were identified in the discovery dataset. Three independent datasets (n=502) were used for biomarker validation. All pleurodesis biomarkers failed, and gelsolin, macrophage migration inhibitory factor, versican, and tissue inhibitor of metalloproteinases 1 (TIMP1) emerged as accurate predictors of survival. Eight variables (haemoglobin, C-reactive protein, white blood cell count, Eastern Cooperative Oncology Group performance status, cancer type, pleural fluid TIMP1 concentrations, and previous chemotherapy or radiotherapy) were validated and used to develop a survival score. Internal validation with bootstrap resampling and external validation with 162 patients from two independent datasets showed good discrimination (C statistic values of 0.78 [95% CI 0.72-0.83] for internal validation and 0.89 [0.84-0.93] for external validation of the clinical PROMISE score).Interpretation To our knowledge, the PROMISE score is the first prospectively validated prognostic model for malignant pleural effusion that combines biological and clinical parameters to accurately estimate 3-month mortality. It is a robust, clinically relevant prognostic score that can be applied immediately, provide important information on patient prognosis, and guide the selection of appropriate management strategies.
AU  - Psallidas, I.*
AU  - Kanellakis, N.I.*
AU  - Gerry, S.*
AU  - Thézénas, M.L.*
AU  - Charles, P.D.*
AU  - Samsonova, A.*
AU  - Schiller, H. B.
AU  - Fischer, R.*
AU  - Asciak, R.*
AU  - Hallifax, R.J.*
AU  - Mercer, R.*
AU  - Dobson, M.*
AU  - Dong, T.*
AU  - Pavord, I.D.*
AU  - Collins, G.S.*
AU  - Kessler, B.M.*
AU  - Pass, H.I.*
AU  - Maskell, N.*
AU  - Stathopoulos, G.T.
AU  - Rahman, N.M.*
C1  - 53664
C2  - 44941
CY  - 360 Park Ave South, New York, Ny 10010-1710 Usa
SP  - 930-939
TI  - Development and validation of response markers to predict survival and pleurodesis success in patients with malignant pleural effusion (PROMISE): A multicohort analysis.
JO  - Lancet Oncol.
VL  - 19
IS  - 7
PB  - Elsevier Science Inc
PY  - 2018
SN  - 1470-2045
ER  - 

TY  - JOUR
AB  - Background Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Methods Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest—namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trial—ENTHUSE M1—in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone. Findings 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0·791; Bayes factor >5) and surpassed the reference model (iAUC 0·743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3·32, 95% CI 2·39–4·62, p<0·0001; reference model: 2·56, 1·85–3·53, p<0·0001). The new model was validated further on the ENTHUSE M1 cohort with similarly high performance (iAUC 0·768). Meta-analysis across all methods confirmed previously identified predictive clinical variables and revealed aspartate aminotransferase as an important, albeit previously under-reported, prognostic biomarker. Interpretation Novel prognostic factors were delineated, and the assessment of 50 methods developed by independent international teams establishes a benchmark for development of methods in the future. The results of this effort show that data-sharing, when combined with a crowdsourced challenge, is a robust and powerful framework to develop new prognostic models in advanced prostate cancer. Funding Sanofi US Services, Project Data Sphere.
AU  - Guinney, J.*
AU  - Wang, T.*
AU  - Laajala, T.D.*
AU  - Kanigel-Winner, K.*
AU  - Bare, C.*
AU  - Neto, E.C.*
AU  - Khan, S.*
AU  - Peddinti, K.*
AU  - Airola, A.*
AU  - Pahikkala, T.*
AU  - Mirtti, T.*
AU  - Yu, T.*
AU  - Bot, B.M.*
AU  - Shen, L.*
AU  - Abdallah, K.*
AU  - Norman, T.*
AU  - Friend, S.*
AU  - Stolovitzky, G.*
AU  - Soule, H.*
AU  - Sweeney, C.J.*
AU  - Ryan, C.J.*
AU  - Scher, H.I.*
AU  - Sartor, O,*
AU  - Xie, Y.*
AU  - Aittokallio, T.*
AU  - Zhou, F.L.*
AU  - Costello, J.C.*
AU  - Prostate Cancer Challenge DREAM Community (Kondofersky, I.
AU  - Krautenbacher, N.
AU  - Laimighofer, M.
AU  - Scherb, H.
AU  - Kurz, C.F.
AU  - Fuchs, C.
AU  - Söllner, J.)
C1  - 49973
C2  - 41945
SP  - 132-142
TI  - Prediction of overall survival for patients with metastatic castration-resistant prostate cancer: Development of a prognostic model through a crowdsourced challenge with open clinical trial data.
JO  - Lancet Oncol.
VL  - 18
IS  - 1
PY  - 2017
SN  - 1470-2045
ER  - 

TY  - JOUR
AB  - BACKGROUND: Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. METHODS: We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5-9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7-7·6). FINDINGS: We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31-57·95) versus 77·21% (95% CI 69·21-86·14) for the low-risk group (hazard ratio [HR] 4·14, 95% CI 2·47-6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10-6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%, respectively, with a C-index of 0·80 (95% CI 0·71-0·89). In the validation cohort, m7-FLIPI again defined a high-risk group (22%, 24/107) with 5-year failure-free survival of 25·00% (95% CI 12·50-49·99) versus 68·24% (58·84-79·15) in the low-risk group (HR 3·58, 95% CI 2·00-6·42; p<0.0001). The positive predictive value for 5-year failure-free survival was 72% and 68% for negative predictive value, with a C-index of 0·79 (95% CI 0·69-0·89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2·18, 95% CI 1·21-3·92), and FLIPI combined with ECOG performance status (HR 2·03, 95% CI 1·12-3·67). INTERPRETATION: Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. FUNDING: Deutsche Krebshilfe, Terry Fox Research Institute.
AU  - Pastore, A.*
AU  - Jurinovic, V.*
AU  - Kridel, R.*
AU  - Hoster, E.*
AU  - Staiger, A.M.*
AU  - Szczepanowski, M.*
AU  - Pott, C.*
AU  - Kopp, N.*
AU  - Murakami, M.*
AU  - Horn, H.*
AU  - Leich, E.*
AU  - Moccia, A.A.*
AU  - Mottok, A.*
AU  - Sunkavalli, A.*
AU  - van Hummelen, P.*
AU  - Ducar, M.*
AU  - Ennishi, D.*
AU  - Shulha, H.P.*
AU  - Hother, C.*
AU  - Connors, J.M.*
AU  - Sehn, L.H.*
AU  - Dreyling, M.*
AU  - Neuberg, D.*
AU  - Möller, P.*
AU  - Feller, A.C.*
AU  - Hansmann, M.L.*
AU  - Stein, H.*
AU  - Rosenwald, A.*
AU  - Ott, G.
AU  - Klapper, W.*
AU  - Unterhalt, M.*
AU  - Hiddemann, W.
AU  - Gascoyne, R.D.*
AU  - Weinstock, D.M.*
AU  - Weigert, O.
C1  - 46558
C2  - 37710
SP  - 1111-1122
TI  - Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: A retrospective analysis of a prospective clinical trial and validation in a population-based registry.
JO  - Lancet Oncol.
VL  - 16
IS  - 9
PY  - 2015
SN  - 1470-2045
ER  - 

TY  - JOUR
AB  - BACKGROUND: The optimum treatment for high-risk soft-tissue sarcoma (STS) in adults is unclear. Regional hyperthermia concentrates the action of chemotherapy within the heated tumour region. Phase 2 studies have shown that chemotherapy with regional hyperthermia improves local control compared with chemotherapy alone. We designed a parallel-group randomised controlled trial to assess the safety and efficacy of regional hyperthermia with chemotherapy. METHODS: Patients were recruited to the trial between July 21, 1997, and November 30, 2006, at nine centres in Europe and North America. Patients with localised high-risk STS (> or = 5 cm, Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep to the fascia) were randomly assigned to receive either neo-adjuvant chemotherapy consisting of etoposide, ifosfamide, and doxorubicin (EIA) alone, or combined with regional hyperthermia (EIA plus regional hyperthermia) in addition to local therapy. Local progression-free survival (LPFS) was the primary endpoint. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT 00003052. FINDINGS: 341 patients were enrolled, with 169 randomly assigned to EIA plus regional hyperthermia and 172 to EIA alone. All patients were included in the analysis of the primary endpoint, and 332 patients who received at least one cycle of chemotherapy were included in the safety analysis. After a median follow-up of 34 months (IQR 20-67), 132 patients had local progression (56 EIA plus regional hyperthermia vs 76 EIA). Patients were more likely to experience local progression or death in the EIA-alone group compared with the EIA plus regional hyperthermia group (relative hazard [RH] 0.58, 95% CI 0.41-0.83; p=0.003), with an absolute difference in LPFS at 2 years of 15% (95% CI 6-26; 76% EIA plus regional hyperthermia vs 61% EIA). For disease-free survival the relative hazard was 0.70 (95% CI 0.54-0.92, p=0.011) for EIA plus regional hyperthermia compared with EIA alone. The treatment response rate in the group that received regional hyperthermia was 28.8%, compared with 12.7% in the group who received chemotherapy alone (p=0.002). In a pre-specified per-protocol analysis of patients who completed EIA plus regional hyperthermia induction therapy compared with those who completed EIA alone, overall survival was better in the combined therapy group (HR 0.66, 95% CI 0.45-0.98, p=0.038). Leucopenia (grade 3 or 4) was more frequent in the EIA plus regional hyperthermia group compared with the EIA-alone group (128 of 165 vs 106 of 167, p=0.005). Hyperthermia-related adverse events were pain, bolus pressure, and skin burn, which were mild to moderate in 66 (40.5%), 43 (26.4%), and 29 patients (17.8%), and severe in seven (4.3%), eight (4.9%), and one patient (0.6%), respectively. Two deaths were attributable to treatment in the combined treatment group, and one death was attributable to treatment in the EIA-alone group. INTERPRETATION: To our knowledge, this is the first randomised phase 3 trial to show that regional hyperthermia increases the benefit of chemotherapy. Adding regional hyperthermia to chemotherapy is a new effective treatment strategy for patients with high-risk STS, including STS with an abdominal or retroperitoneal location. FUNDING: Deutsche Krebshilfe, Helmholtz Association (HGF), European Organisation of Research and Treatment of Cancer (EORTC), European Society for Hyperthermic Oncology (ESHO), and US National Institute of Health (NIH).
AU  - Issels, R.D.
AU  - Lindner, L.H.
AU  - Verweij, J.*
AU  - Wust, P.*
AU  - Reichardt, P.*
AU  - Schem, B.C.*
AU  - Abdel-Rahman, S.*
AU  - Daugaard, S.*
AU  - Salat, C.*
AU  - Wendtner, C.M.*
AU  - Vujaskovic, Z.*
AU  - Wessalowski, R.*
AU  - Jauch, W.*
AU  - Dürr, H.R.*
AU  - Ploner, F.*
AU  - Baur-Melnyk, A.*
AU  - Mansmann, U.*
AU  - Hiddemann, W.*
AU  - Blay, J.Y.*
AU  - Hohenberger, P.*
C1  - 1206
C2  - 27343
SP  - 561-570
TI  - Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study.
JO  - Lancet Oncol.
VL  - 11
IS  - 6
PB  - Elsevier
PY  - 2010
SN  - 1470-2045
ER  - 

TY  - JOUR
AU  - Landi, M.T.*
AU  - Chatterjee, N.*
AU  - Caporaso, N.E.*
AU  - Rotunno, M.*
AU  - Albanes, D.*
AU  - Thun, M.*
AU  - Wheeler, W.*
AU  - Rosenberger, A.*
AU  - Bickeböller, H.*
AU  - Risch, A.*
AU  - Wang, Y.F.*
AU  - Gaborieau, V.*
AU  - Thorgeirsson, T.*
AU  - Gudbjartsson, D.*
AU  - Sulem, P.*
AU  - Spitz, M.R.*
AU  - Wichmann, H.-E.
AU  - Rafnar, T.*
AU  - Stefansson, K.*
AU  - Houlston, R.S.*
AU  - Brennan, P.*
C1  - 5157
C2  - 27471
SP  - 714-716
TI  - GPC5 rs2352028 variant and risk of lung cancer in never smokers.
JO  - Lancet Oncol.
VL  - 11
IS  - 8
PB  - Elsevier
PY  - 2010
SN  - 1470-2045
ER  -