dataesr/scientific-paragraphs-categorization huggingface dataset:
Acknowledgements The authors kindly acknowledge the radiation oncologists involved in coordination of the contours collection in their own center:  Georges Noel ,  Laetitia Rangeard ,  Anne Laprie ,  Philippe Quetin ,  Claire Gamelon-Bénichou ,  Philippe Coucke ,  Nicolas Jansen ,  Stéphanie Servagi-Vernat ,  Jochen Fleckenstein ,  Alexandre Coutte ,  Julian Biau ,  Sara Belkheiri ,  Anne Ducassou ,  Fatima Lopes ,  Jordan Bouter ,  Anne D'hombres ,  Eric Jadaud.
Low density microarray (LDA) analysis of RNA expression demonstrated the kinase-activated Ph-like ALL signature with positive 8-gene and 15-gene scores of 0. 739 and 0. 956, respectively,  3, 6  and moderately elevated EPOR expression (Online Supplementary Table  S1 ). ArcherDX FusionPlex (anchored multiplex polymerase chain reaction [PCR]) analysis and next-generation sequencing (NGS) detected IGH-EPOR fusion and partial deletions of IKZF1 (7p12. 2) and PAX5 (9p13. 2), respectively. The patient was treated with a four-drug induction chemotherapy regimen on the Children's Oncology Group (COG) AALL1131 phase III clinical trial (clinicaltrials gov. Identifier: NCT02883049) with end-induction flow cytometry (FC) MRD 48%, consistent with induction failure. She received post-induction chemotherapy with ruxolitinib 20 mg/m 2 twice-daily 14-days-on/14-days-off/month (DL-2) on the COG AALL1521 phase II clinical trial (clinicaltrials gov.
Identifier: NCT02723994)  7  with end-consolidation MRD 9. 5% and end-interim maintenance I MRD 7. 3%. Chemotherapy-associated complications included steroid-induced hyperglycemia and central venous catheter-associated thrombosis and infection. Given her persistently chemorefractory disease, the patient was subsequently treated with autologous CD19 chimeric antigen receptor T-cell immunotherapy tisagenlecleucel in August 2017 on an institutional phase I clinical trial (clinicaltrials gov. Identifier: NCT02906371) and achieved MRD-negative remission that was electively consolidated with a matched-sibling donor (MSD) allogeneic hematopoietic stem cell transplant (HSCT) in April 2018. HSCT complications included chronic pulmonary and skin graft-versus-host disease (GvHD). She remains in continued MRD-negative leukemia remission with 100% donor chimerism at >3 years post-HSCT.
CSF was negative for leukemia (CNS1). Cytogenetics were normal with 46,XX. RNA-sequencing identified an IGH-EPOR rearrangement with confirmed high EPOR expression by reverse transcriptase-PCR and high EPOR surface protein expression by FC (Figure  1A ). She had a poor prednisone response  8  (9730 blasts/mm 3 peripheral blood after 7 days' therapy) and was thus classified as high-risk, received a four-drug induction on the CAALL-F01 phase III trial (clinicaltrials gov. Identifier: NCT02716233), and was refractory at end-induction with MRD 15%, as measured by immunoglobulin/T-cell receptor rearrangement PCR assay (Figure  1B ). She was removed from study and received consolidation therapy with cyclophosphamide, cytarabine, 6-mercaptopurine, and ponatinib 45 mg daily Letters to the Editor 2764 haematologica | 2021; 106(10)  Ponatinib was increased to 30 mg twice-daily given persistent mid-induction 1B/consolidation MRD 3.
Interestingly, we also saw partial single-agent ponatinib and ruxolitinib activity in a third PDX model (MDACC3) established from an adult with relapsed IGH-EPOR ALL who was resistant to ruxolitinib 25 mg twice-daily and hyper-CVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone) chemotherapy on an institutional phase II/III clinical trial (clinicaltrials gov. Identifier: NCT02420717). 12 As in the de novo pediatric ALL PDX models, combined ponatinib and ruxolitinib more potently reduced leukemia burden in end-study murine spleens versus TKI monotherapy (Figure  2C ), although this relapsed adult ALL model's lack of LDA positivity or increased FC EPOR surface staining remains puzzling given our confirmation of IGH-EPOR fusion by both FISH and ArcherDX FusionPlex analyses.
Future clinical trials could explore the potential for combinatorial efficacy of ruxolitinib and ponatinib with chemotherapy in patients with IGH-EPOR fusions and other high-risk Ph-like ALL subtypes. ALL PDX mice were randomized upon >1% peripheral blood engraftment to treatment with vehicle, ponatinib 25 mg/kg orally once daily for 5 days/week, ruxolitinib 2 g/kg chow orally ad libitum, or both ponatinib and ruxolitinib for 2-4 weeks depending upon rate of leukemia progression in control animals requiring sacrifice. 0] [11]  Combination ponatinib and ruxolitinib treatment induced superior inhibition of leukemia proliferation versus tyrosine kinase inhibitors (TKI) monotherapies in all three tested models. Flow cytometry analysis was performed in Cytobank. Statistical analysis and data display were performed in Prism (*P<0.
Acknowledgments: we gratefully acknowledge the Center for Biological Resources ('CRB-cancer') of the Robert Debré Hospital (BB-0033-00076; EL, AC-E, and HC), Drs I-Ming Chen and Richard Harvey at the University of New Mexico for performing Ph-like ALL low density microarray expression analysis of primary clinical and patient-derived xenograft (PDX) model ALL specimens, Ms Elizabeth Wagner at Nationwide Children's Hospital for clinical annotation of COG ALL specimens, Dr Marilyn Li at CHOP for performing genetic characterisation of PDX models, and Dr Matthew Stubbs at Incyte Corporation for provision of ruxolitinib rodent chow for preclinical animal studies. We also kindly thank Dr Vandana Batra  at the  Children's Hospital of Philadelphia ,  Dr Jing Chen  at  Hackensack University Medical Center , and  Dr Michael Loschi  at  CHU de Nice  for assisting in clinical patient care.
This study is dedicated in honor of  Miss Emily Herrera and Miss Ava Daisy Phillips. Funding: these studies were supported by  United States National Institutes of Health (NIH)/National Institute of Child Health and Human Development  award  T32HD043021  (LMN),  NIH/National Cancer Institute (NCI)  award  T32CA009615  (LMN),  1U01CA232486  (SKT),  U01CA243072  (SKT), the  ERA-NET TRANSCAN/Foundation ARC  (EL, AC-E, HC),  Department of Defense Translational Team Science  award  CA180683P1 , the  V Foundation for Cancer Research (SKT) , the  Sohn Monaco Foundation (PSR) , and the  PHRC program  from the  French Institut National du Cancer (PSR). Children's Oncology Group (COG)  specimen banking was supported by  NCI   U24CA114766  and  U24CA196173. Childhood IGH-EPOR ALL PDX modeling was also supported by a  Lady Tata Memorial Trust Award (II) ,  St Jude Children's Research Hospital Hematological Malignancies Program Garwood Fellowship (II) ,  Leukemia and Lymphoma Society Specialized Center of Research (CGM) ,  Stand  up to Cancer  Innovative Research Grant  (CGM),  St Baldrick's   Foundation Scholar award (CGM), NCI Outstanding Investigator Award   R35CA197695  (CGM), and  NIH Cancer Center Support  Grant  P30 CA21765  (CGM).
their COVID-19 clinical course, severity, complications and outcomes. This extensive global dataset represents an important reference for clinicians treating and managing IEIs patients in the context of the COVID-19 pandemic. J o u r n a l P r e -p r o o f Methods A retrospective study was undertaken by a web-based survey, approved by the University Hospitals Leuven Committee for Medical Ethics. The questionnaire inquired about demographic data, COVID-19 presentation, treatment and outcomes in patients with IEIs (according to current diagnostic guidelines) and documented SARS-CoV-2 infection. No identifying information was required, while physicians were given the option of providing their contact details. The survey opened on March 16 th 2020 and closed on June 30 th 2020. An invitation to participate in the survey was shared with members of various societies (European Society for Immunodeficiencies; Clinical Immunology Society; Latin American Society for Immunodeficiencies; African Society for Immunodeficiencies; Asia Pacific Society for Immunodeficiencies; Australasian Society for Clinical Immunology & Allergy), as well as via the International Patient Organization for Primary Immunodeficiencies, the Jeffrey Modell Foundation and the International Union of Immunological Societies (IUIS) Committee for Inborn Errors of Immunity, with the aid of social media alerts.
Acknowledgements We thank all the patients and clinicians involved in the care for these patients. We also thank the  European Society for Immunodeficiencies (ESID) ,  Clinical Immunology Society (CIS) ,  Latin American Society for Immunodeficiencies (LASID) ,  African Society for Immunodeficiencies (ASID) ,  Asia Pacific Society for Immunodeficiencies (APSID) ,  Australasian Society for Clinical Immunology & Allergy (ASCIA) , the  International Patient Organization for Primary Immunodeficiencies (IPOPI) , and the  Jeffrey Modell Foundation  for distributing and promoting the e-survey to their members.
Background: An accurate and comprehensive assessment of harms is a fundamental part of an accurate weighing of benefits and harms of an intervention when making treatment decisions; however, harms are known to be underreported in journal publications. Therefore, we sought to compare the completeness of reporting of harm data, discrepancies in harm data reported, and the delay to access results of oncological clinical trials between three sources: clinical study reports (CSRs), clinical trial registries and journal publications. Methods: We used the EMA clinical data website to identify all trials submitted to the EMA between 2015 and 2018. We retrieved all CSRs and included all phase II, II/III or III randomised controlled trials (RCTs) assessing targeted therapy and immunotherapy for cancer.
We then identified related records in clinical trial registries and journals. We extracted harms data for eight pre-specified variables and determined the completeness of reporting of harm data in each of the three sources. Results: We identified 42 RCTs evaluating 13 different drugs. Results were available on the EMA website in CSRs for 37 (88%) RCTs, ClinicalTrials. gov for 36 (86%), the European Clinical Trials Register (EUCTR) for 20 (48%) and in journal publications for 32 (76%). Harms reporting was more complete in CSRs than other sources. We identified marked discrepancies in harms data between sources, e. g. the number of patients discontinuing due to adverse events differed in CSRs and clinical trial registers for 88% of trials with data in both sources. For CSRs and publications, the corresponding number was 90%.
However, no study has systematically compared reporting of harms in trial registries and publications with a large sample of recent CSRs from oncological trials. Targeted therapy and immunotherapy for cancer have revolutionised the care of most patients with cancer. Several of these specific oncologic drugs have recently been approved by the US Food and Drug Administration and EMA. Evaluating the harms of these new drugs is essential. Thus, we aimed to compare the delay to access results of oncological RCTs, the completeness of reporting harm data and discrepancies in harm data reported between the three sources: CSRs available on the EMA Website, clinical trial registries and journal publications.
Identification of trials In November 2019, we used the EMA's clinical data website (https://clinicaldata. ema. europa. eu) to identify all submissions for marketing authorisation or extension of indication under the EMA policy 0070. We updated the search in June 2020 and identified no new submissions. For all submissions, we extracted the product name, active substance, marketing authorisation holder and Anatomical Therapeutic Chemical (ATC) code. We selected the ATC codes for monoclonal antibodies (L01XC) and protein kinase inhibitors (L01XE) corresponding to targeted therapy and immunotherapy. Once we had identified all eligible active substances, we downloaded all documents from the EMA website (i. e. , CSRs and related documents) and used these to create a list of all trials submitted to the EMA.
Identification of related clinical-trial registry records for the identified RCTs One reviewer (ASP-M) systematically searched Clinical-Trials. gov and the European Clinical Trials Register (EUCTR) by using (1) the trial registry identifier or ID number if mentioned in the CSR or (2) the name of the experimental drug (or its international non-proprietary name). If we were still unable to identify the corresponding trial, we used other keywords (e. g. treatment comparator and indication). The records identified were systematically checked by a second reviewer (PC). Then we checked whether results were posted on the trial registries identified. If the study was registered in both registries, we extracted data from both.
Identification of results publications for identified RCTs We first searched for citations listed in trial registries. For ClinicalTrials. gov, the only registry to give access to citations, we used the citations listed under "publication of results" and "publications automatically indexed to this study by ClinicalTrials. gov identifier (NCT Number)". We included all publications reporting results for the trial identified. We did not include publications of reviews or publications that presented pooled analyses of several trials and did not include data from the individual trial. If no publications were indexed in the registry record, we searched MEDLINE and EMBASE by using the name of the experimental drug, treatment comparator, indication and name of the principal investigator.
Data extraction For each trial, we extracted information from the CSR available on the EMA Website, the clinical trial registry records (both ClinicalTrials. gov and EUCTR) and all related publications. The extracted information was entered in a data extraction spreadsheet. Two reviewers (ASP and PC) independently extracted data for 10% of trials. Because of only minor disagreements, one reviewer (ASP-M) extracted the data for the remaining trials. All extractions were then checked by a second reviewer (PC). All discrepancies were resolved by discussion. We extracted the following information for each trial: 1) General characteristics: name of trial, name of studied drug, clinical development phase, condition; number of centres, number of arms, number of participants randomised, whether the trial was a non-inferiority trial, the primary outcome, funding and whether the trial was blinded.
2) Delay in access to trial results: The CSRs included in this project are released under the EMA policy 0070  [21] , which dictates that clinical data submitted to the EMA as part of a marketing authorisation application or a post-authorisation procedure shall be released once the concerned procedure (hereafter EMA procedure) has been finalised. We recorded the date of finalisation of the procedure for all included submissions by using the European Commission's register  [22]  and determined the delay between the finalisation of the procedure and publication of CSRs on the EMA website. To determine the time between completion of the study and release of results in each source, we recorded the primary trial completion date (i. e. the date of the last participant's final follow-up visit for measurement of the primary outcome) from ClinicalTrials.
gov. If this was not available, we checked the other sources (CSRs, publications, and EUCTR) for a primary completion date. We also recorded for each source the date when the results were released and available. For trials with multiple publications, we used the earliest publication date. We then calculated the delay between primary trial completion date and availability of results for each source. 3) Completeness of reporting harm data and discrepancies in harm data: We extracted the following information from all three sources of data for each trial: number of patients randomised, whether a definition of safety population was provided, number of patients in the safety population, threshold for reporting adverse events (e. g. 10%, 5% or none), number of patients experiencing at least one adverse event, total number of adverse events, number of patients experiencing at least one serious adverse event, total number of serious adverse events, number of patients experiencing at least one adverse event judged to be grade 3-5 according to the Common Terminology Criteria for Adverse Events (CTCAE), total number of adverse events judged to be grade 3-5 according to the CTCAE, number of patients discontinuing the trial due to adverse events, number of deaths due to adverse events, and whether a description of the process of determining whether a death was due to adverse events, including whether the person(s) making the judgement were blinded, was provided.
Analysis We compared reporting of the different variables defined above in CSRs with that in clinical trial registries and publications, separately. We performed Kaplan-Meier analysis on the delay from primary trial completion date to the publication of the CSR, the first publication of results in trial registries, and a publication in a medical journal. If a trial had not been published in a source, we calculated the delay between the primary completion date and June 29, 2020 and considered the trial right censored. For numerical variables reported in at least two of the data sources, we examined whether the numbers reported were the same. For this analysis, we pooled results from Clinical-Trials. gov and EUCTR. If results were available from both registries, we used the data from ClinicalTrials.
Selection of trials We identified 142 submissions through the EMA clinical data Website. These submissions corresponded to 124 unique substances: 22 concerned oncology drugs and 13 of these corresponded to targeted therapy and immunotherapy (Additional file 1). For these 13 drugs included in the study, we identified 164 unique trials, of which 42 met our eligibility criteria (phase II, II/III or III RCTs). The inclusion process is shown in Fig. 1. The drugs included and the number of trials for each drug are in Table  1. The median number of randomised patients in the included trials was 364 (range 142-666) (Table  2 ). The primary outcome was progression-free survival for 27 of the 42 (64%) included trials, overall survival for eight (19%) and both for three (7%). The remaining four trials (7%) had other primary outcomes.
Availability of sources The EMA's Website had complete CSRs for 37 of the 42 (88%) included trials. For the remaining five (12%) trials, the EMA Website did not contain full CSRs and only documents such as summaries, pharmacokinetic data or periodic safety reports were available; the EMA Website did not explain why full CSRs are not available for these trials, but three trials were ongoing at the time of the application for marketing authorisation. Among the 42 included trials, trial results were posted on ClinicalTrials. gov for 36 (86%) and on the EUCTR for 20 (48%). We were able to identify publications with results for 32 of the 42 (76%) included trials (all included publications are in the Additional file 1). Trial results were available in the three sources for 25 (60%) trials and in two sources for 13 (31%) (i.
Delay in access to trial results The median delay between finalisation of the EMA procedure and availability of CSRs was 1. 21 years (range 0. 91-1. 78). The median (interquartile range) delay between primary completion data and result availability was 4. 34 (3. 09-7. 22) years for CSRs, 2. 94 (1. 16-4. 52) years for ClinicalTrials. gov, 5. 39 (4. 18-7. 33) years for the EUCTR and 2. 15 (0. 64-5. 04) years for publications. Figure  2  shows Kaplan-Meier curves for the delay between primary trial completion dates and publication of the different sources.
Reports of harms in each source Table  3  shows the proportion of trials for which we could obtain data on our pre-specified variables from each of the four sources of data. For most variables, results were more frequently reported in CSRs than both trial registries and publications. The number of patients with at least one serious adverse event was reported for all trials in both CSRs and Clinical-Trials. gov and in 19/20 (95%) trials in the EUCTR but only 16/32 (50%) trials with publications. The number of patients with any adverse events was reported in all CSRs but was not available for any trials or registries because the number of patients with serious and non-serious adverse events are reported separately. The number of patients with any adverse events was available for only 13/32 (41%) trials with publications.
The number of patients with CTCAE grade 3-5 events was available in 36/37 (97%) CSRs but only 14/32 (44%) publications. The CTCAE grade was not reported in either of the trial registries. The total number of serious adverse events, any adverse events, and CTCAE grade 3-5 events was available in 9/37 (24%), 12/37 (32%) and 6/37 (16%) CSRs, respectively; 10/36 (28%), 10/36 (28%) and 0/36 (0%) records at ClinicalTrials. gov; and 17/20 (85%), 17/20 (85%) and 0/20 (0%) records at the EUCTR. For publications, only 1/32 (3%) reports gave the total number of serious adverse events. The number of total adverse events and grade 3-5 adverse events was not available in publications for any trial. The number of deaths due to adverse events was available in CSRs for 34/37 (92%) trials, from ClinicalTrials.
Discussion Our study shows that data on harms in RCTs evaluating targeted therapy and immunotherapy for cancer are reported more frequently and in more detail in CSRs than in registries and publications. However, reporting is not perfect. CSRs were missing for five (12%) trials. Three of these trials were ongoing at the time of submission of documents to the EMA which might explain the missing CSRs. The two remaining trials were completed before the submission and it is unclear why CSRs were missing for these trials. Furthermore, important data were incompletely reported; for example, the total number of serious adverse events and all adverse events was available in only 9/37 (24%) and 12/37 (32%) CSRs. Although data should be available at the date the EMA procedure is completed, we showed a median of 1.
21 years between the finalisation of the procedure and publication of CSRs on the website. Additionally, the delay from primary completion of a trial until results were available was longer for CSRs than for other sources. We also demonstrated discrepancies in harms data between CSRs and other sources. One possible explanation for such discrepancies could be different selection criteria for which events to include in which reports, e. g. , clinicaltrials. gov use a 5% threshold for non-serious adverse events and similar thresholds are also commonly used in journal publications. Routinely reporting all events, without thresholds, would both improve reporting and potentially solve some discrepancies. Our results are consistent with other findings. In 2013, Wieseler et al. examined a sample of 86 trials with both a CSR and a publicly available source of data and found that serious adverse events, adverse events and withdrawals due to adverse events were more frequently reported in CSRs than another source  [16].
Several teams have highlighted the need to access trial results through posting on trial registries. For example, a report from TranspariMED states that in a 2013 cohort of cancer drug trials, two thirds of trials had not posted results to ClinicalTrials. gov 3 years after completion  [117]. Interventions have been proposed to improve access to results  [118]  and similar strategies to increase access and reduce delays for CSRs should be developed. Our study is the first to compare reporting of harms in CSRs released under EMA policy 0070 with publications and trial registries for oncological trials. The automatic release of the CSRs might have led to better reporting of harms in other sources of data, but this does not seem to be the case. Additionally, we systematically examined predefined variables in a relatively large sample of trials.