dataesr/scientific-paragraphs-categorization huggingface dataset:
However, these studies have been limited by the low number of patients. Although molecular imaging has emerged as a promising technique for improved lymph node staging in patients with PCa, positron emission tomography (PET) tracers like F18-or C-11--choline have not proved to be superior to anatomical imaging methods  (20, 21)  and a prospective study with C-11 choline PET/CT has shown disappointing results  (22). That said, some reports have shown encouraging data with PSMA PET/CT for initial detection of LNI. Recently, Ga-68 PSMA PET/CT has been proposed for the evaluation of biochemical recurrence after primary active treatment of PCa. Several studies have shown high diagnostic performance with a higher sensitivity compared to other radiopharmaceuticals such as radiolabeled choline  (23, 24).
In addition, several current retrospective studies have criticized the impact of PLND on survival. In one of them, 20. 668 Surveillance, Epidemiology, and End results (SEER) database patients with PCa and >5% LNI risk as per Briganti´s nomogram were evaluated. This study compared radical prostatectomy with and without PLND. No significant difference of CSS and overall survival (OS) was found between groups (5-year CSS rate: 99. 4% vs. 99. 7%, p=0. 479, 5-year OS rate: 97. 3% vs. 97. 8%, p=0. 204). They concluded that neither PLND nor its extension was associated with improved survival in these patients and perhaps the cut-off point of 5% is too low to show benefits in patients who underwent PLND along with the prostatectomy (50). Preisser et al. compared oncologic outcomes of 9. 742 intermediate and highrisk patients who underwent radical prostatectomy with or without PLND.
The authors did not find significant differences in BCR  (51). Conversely, again Preisser et al. evaluated cancer specific mortality (CSM) in 28. 147 SEER database PCa patients (2004-2014) subject to eLPND or lPLND. They found a lower CSM in patients who underwent eLPND. They estimated that removal of >11 nodes during PLND improved 6-year CSS and each additional LN removed reduced CSM risk by 4. 5%  (44). In a retrospective meta-analysis involving 1. 095 intermediate and high-risk PCa patients of 3 centers in Korea, Min Soo Choo et al. (46)  suggested ePLND would provide oncological benefits by preventing biochemical relapse (BCR). The pooled analysis showed a significant reduction in BCR with ePLND compared to sPLND (HR 0. 71, 95% CI 0. 56-0. 90, p=0. 005). An additional meta-analysis on 5 retrospectives studies  (45) , found improved BCR with ePLND, although two of them also included low--risk patients.
Sood et al. recently evaluated 311. 061 patients from the National Cancer Database (NCDB). They found that patients undergoing ePLND had 9% lower risk of 10-year mortality as compared to patients undergoing none or limited PLND  (48). Recent results of the only prospective phase III trial were presented. To define the primary endpoint, the authors compared biomedical recurrence-free survival (BRFS) among 300 patients with D'Amico´s intermediate or high-risk PCa, who had received lPLND (n 150) or ePLND (n 150) during robotic prostatectomy. This trial was designed with 80% power and an alpha error of 0. 05 to detect a 15% difference in 5-year BRFS. ePLND and lPLND yielded median (mean) 17 (19. 8) and 3 (4. 1) positive nodes, respectively (p <0. 001), while ePLND resulted in five times more lymph node metastases detection (p <0.
+ Another two prospective randomized studies (NCT01555086) are being carried out to establish the impact of PLND on survival. The first of these is a German clinical trial that aims to show whether the extent of PLND could influence PSA progression over 5 years. While we continue to expect results, new data have not been presented since 2017. Currently, a second clinical trial has begun recruiting patients in Switzerland (NCT03921996), but it only comparing ePLND vs. no PLND in patients who undergo radical prostatectomy. The impact of PLND on survival is still controversial and results of others prospective studies are eagerly awaited.
oncology -High CI 0. 56-0. 90, p = 2004-2014 (46). outcomes results 0. 005) 1095 p. Preisser (2017). 28147 patients. lPLND (75%) vs. NA Gleason Median PSA Retrospective ePLND (24,8%) -≤6: 2238 (8%) (IQR) 6. 5 2004-2014 (44). -7: 19374 (68. 8) (SEER) database. -≥8: 6535 (23. 2%) Intermediate risk -18942 (67. 3%) High risk -9205 (32. 7%).
Funding This work was supported by the  Wellcome/EPSRC Centre for Medical Engineering  ( WT 203148/Z/16/Z ). SN is supported by  NIH   R01-HL152256 ,  ERC PREDICT-HF 453  ( 864055 ),  BHF  ( RG/20/4/34803 ),  EPSRC  ( EP/P01268X/1 ). This study received financial support from the  French Government  as part of the  "Investments of the Future" program  managed by the  National Research Agency (ANR)  ( ANR-10-IAHU-04 ). AN is employed by  NumeriCor GmbH, Graz, Austria.
Statistical analysis Descriptive analysis was performed and patients and treatment characteristics were recorded. T-test was used to assess for any significant relationship between the extracted data. Moreover, a correlation between these averaged differences and target volume were evaluated. A correlation between the extracted DVH parameters and the prescribed dose was studied through linear regression analysis and Pearson correlation tests by considering a statistical significance level of 0. 05 (p-value < 0. 05). Finally, correlations between DVH parameters of delineated pelvic lymph nodes and point B dose were assessed. IBM SPSS ® statistics (version 23, IBM Corp. ) software was used to perform statistical tests.
Descriptive statistics Thirty-six stage IB1-IIIB cervical cancer patients were included in the study. The median age was 60 years (range, 29-88 years), and CTV HR volume was 25. 3 ±16. 5 cm 3. The descriptive data about their target and OARs doses are presented in Table  1. The mean radiation dose and mean percentage of prescription dose on the delineated lymph nodes are shown in Table  2. The mean dose and mean percentage of the prescription dose to the left and right B points were 4. 6 ±0. 18 Gy and 82. 08 ±0. 72%, respectively. The mean prescription dose to A RF and A LF points was 26. 6 ±2. 9 Gy for the patients.
The phase 3 MIRROS (MDM2 antagonist Idasanutlin in Relapsed or Refractory acute myeloid leukemia [AML] for Overall Survival) trial (NCT02545283) evaluated the efficacy and safety of the small-molecule MDM2 antagonist idasanutlin plus cytarabine in patients with relapsed/refractory (R/R) AML. Adults (n 5 447) with R/R AML whose disease relapsed or was refractory after #2 prior induction regimens as initial treatment or following salvage chemotherapy regimen, with Eastern Cooperative Oncology Group performance status #2 were enrolled regardless of TP53 mutation status and randomly assigned 2:1 to idasanutlin 300 mg or placebo orally twice daily plus cytarabine 1 g/m 2 IV on days 1 to 5 of 28-day cycles. At primary analysis (cutoff, November 2019), 436 patients were enrolled, including 355 in the TP53 wild-type intention-to-treat (TP53WT-ITT) population.
Patients and methods Patients MIRROS (NCT02545283) enrolled patients $18 years of age who had a confirmed AML per World Health Organization classification,  24  both with R/R disease after #2 prior induction regimens (excluding HSCT) for first-line therapy, including cytarabine with an anthracycline or anthracenedione, and patients with R/R disease after a second chemotherapy regimen. Patients had an Eastern Cooperative Oncology Group performance status #2 and acceptable hepatic and renal function (serum total bilirubin #1. 5 3 upper limit of normal; aspartate aminotransferase or alanine aminotransferase #3 3 upper limit of normal; serum creatinine within laboratory ranges, or creatinine clearance [by Cockcroft Gault formula] $50 mL/min). Patients were enrolled regardless of TP53 mutation status.
Antibiotic (levofloxacin), antifungal (posaconazole), antidiarrheal (loperamide), and antiemetic (palonosetron, dexamethasone) prophylaxis during treatment cycles was mandated. The primary endpoint was OS in the predefined intention-to-treat (ITT) population of patients with TP53WT status, including patients with TP53 missense mutations with retained functionality, as listed in the International Agency for Research on Cancer database. 26 Key secondary endpoints evaluated in the TP53WT-ITT population were investigator-assessed CR rates during the induction cycle, overall response rate (CR, CR with incomplete platelet recovery [CRp], and CR with incomplete blood count recovery [CRi]), duration of remission following CR, rate of HSCT, and rate of minimal residual disease (MRD). Safety was evaluated according to the Common Terminology Criteria for Adverse Events version 4.
OS was compared between treatment groups using a stratified Cox proportional hazards regression to estimate an HR and a 95% confidence interval (CI). Additionally, due to the short survival times in this population, a reverse Kaplan-Meier analysis of potential followup time was performed that effectively measures survival time rather than time to death. In this method, alive and censoring data are treated as events, and death and event data are censored. 27 Treatment response, including CR, was assessed at the end of each cycle and summarized by the study arm along with the 2-sided 95% CI by the Pearson-Clopper method. MRD was analyzed by descriptive statistics at the 0. 1% cutoff. CD34 1 and CD117 1 cells were evaluated for MDM2 status by flow cell cytometry and correlated to treatment response at the end of induction.
Patients and trial interventions From 31 December 2015 through 13 January 2020, a total of 447 patients (ITT) were enrolled at 79 sites in 17 countries. The cutoff for the primary analysis, planned as an efficacy interim analysis, was in November 2019, at which time the ITT population had enrolled a total of 436 patients, with 342 patients (78%) in Europe, 27 (6%) in Australia and New Zealand, 19 (4%) each in South Korea and Israel, 14 (3%) in the United States and Canada, 12 (3%) in Russia, and 3 (1%) in Latin America. A total of 290 patients were randomized to receive idasanutlin plus cytarabine, and 146 were randomized to receive placebo plus cytarabine. The TP53WT-ITT population excluded patients with TP53 mutations that affect protein function as listed in the IARC database and those of unknown TP53 status.
The TP53WT-ITT population included 355 patients (81%; 232 patients in the idasa-C group and 123 in the placebo-C group, including 3 and 1 patients, respectively, harboring TP53 mutations known to retain full TP53 functionality). Overall, the characteristics of the patients in the TP53WT-ITT groups at baseline were well balanced between the 2 treatment arms (Table  1 ). The numbers of patients who were still receiving the trial intervention at the time of analysis (unblinding: 10 January 2020) are shown in the Consolidated Standards of Reporting Trials diagram in Figure  1. The sponsor decided to close the study considering the outcomes of this analysis and the expected impact of the SARS-CoV-2/COVID-19 pandemic on further data collection. All participants discontinued the study by April 2020.
Also, further research is needed to clarify whether MDM2 inhibitors such as idasanutlin may still have a potential role in earlier-stage AML or other cancer settings. Conflict-of-interest disclosure: All authors received grants and nonfinancial support from F. Hoffmann-La Roche during the conduct of the study. Editorial support, funded by the sponsor, was provided by an independent medical writer under the guidance of the authors. M. Y. K. has received grants from AbbVie, Genentech, Stemline Therapeutics, Forty-Seven, Kisoji, Eli Lilly, Cellectis, Calithera, Ablynx, Agios, Ascentage, AstraZeneca, Rafael Pharmaceutical, and Sanofi; has consulted for Stemline Therapeutics, Amgen, Forty-Seven, and Kisoji; and holds stock options/royalties related to a patent for Reata Pharmaceutical. In addition, M.
Study design and population We conducted a retrospective, single-centre, cohort study including all patients who underwent LVAD implantation from January 2008 to December 2019 at Rangueil University Hospital (Toulouse, France), a tertiary cardiac centre with regional expertise in cardiac transplantation and mechanical assist device implantation. Patients with premature death, defined as death occurring within 30 days post-implantation, were excluded. The study was consistent with the principles set out in the Helsinki Declaration. After evaluation and validation by the data protection officer and in accordance with the General Data Protection Regulation, this study has met all the criteria and is registered in the retrospective study register of the Toulouse University Hospital (number's register: RnIPH 2021-87) and covered by the MR-004 (CNIL number: 2206723 v 0).
Follow-up and endpoints Follow-up data were collected up to July 2021 or the occurrence of heart transplantation or death. The primary endpoint was the occurrence of any haemorrhagic event, including GI bleeding, intracranial haemorrhage, epistaxis, or any other bleeding leading to medical consultation or hospitalization. Only events occurring more than 30 days after LVAD implantation were considered to avoid surgery-associated events. GI bleeding was defined as the occurrence of at least one of the following events: haematemesis, melaena, haematochezia or drop of haemoglobin > 2 g/dL requiring blood transfusion, and digestive explorations without extra-digestive aetiology found. GI bleeding was classified as 'upper' tract bleeding if the origin was located above the suspensory muscle of the duodenum; otherwise, it was classified as 'lower' tract bleeding.
Intracranial haemorrhage was defined as the occurrence of one of the following events: intracerebral haemorrhage, subarachnoid haemorrhage, subdural haematoma, or epidural haematoma. Collected data included demographic data such as age, gender, comorbidities, and type of cardiomyopathy; type of device and device strategy; biological values such as haemoglobin level, platelet count, and international normalized ratio (INR) before implantation and at the time of the event; long-term treatment and during event; and number of packed red blood cell transfused during event as well as the various diagnostic and therapeutic explorations carried out during event.
Some teams have already developed a diagnostic algorithm adapted to the initial presentation of GI bleeding. 20 Their results seem to be encouraging but have to be validated on a larger scale. 21 Interestingly, 86% of patients were taking proton-pump inhibitor during GI bleeding, raising the question of the value of such systematic treatment in LVAD recipients. Invasive management was rarely performed (20%) because the bleeding source remained largely unknown and if a lesion is found, invasive management is not always possible. 3] [24]  Prospective, randomized, and larger studies are underway to confirm these results (NCT01707225). Thalidomide and danazol also seem to decrease recurrent bleeding,  [25] [26] [27] [28]  to be confirmed by prospective and larger studies. Recently, a pilot study reported a significant reduction of blood transfusions, bleeding-related hospitalizations, and endoscopy procedures in LVAD's patients with refractory GI angiodysplasia related bleeding after intravenous infusion of a humanized monoclonal antibody against VEGF (bevacizumab Avastin).
Context: Somapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in children with GH deficiency (GHD). Objective: To demonstrate efficacy and safety of somapacitan vs daily GH. Methods: REAL4 is a randomised, multinational, open-labeled, active-controlled parallel group phase 3 trial, comprising a 52-week main trial and 3-year extension (NCT03811535). Setting: Eighty-six sites across 20 countries. Patients: 200 treatment-naïve patients were randomized and exposed. Interventions: Patients were randomized 2:1 to somapacitan (0. 16 mg/kg/wk) or daily GH (Norditropin; 0. 034 mg/kg/d), administered subcutaneously. Main outcome measures: The primary endpoint was annualized height velocity (HV; cm/y) at week 52. Additional assessments included HV SD score (SDS), height SDS, bone age, IGF-I SDS, patient-reported outcomes, and safety measures.
Study Design The current trial was conducted as a randomized, multinational, open labeled, and active-controlled parallel group phase 3 trial at 86 sites in 20 countries in Asia, Europe, and North America (ClinicalTrials. gov: NCT03811535). The study was conducted in Austria, Canada, France, Germany, India, Israel, Italy, Japan, Korea, Latvia, Poland, Russia, Serbia, Slovenia, Spain, Switzerland, Thailand, Ukraine, United Kingdom, and United States. The sponsor (Novo Nordisk A/ S) designed the trial and oversaw its conduct. The trial investigated the efficacy and safety of once-weekly somapacitan treatment (0. 16 mg/kg/wk) for GHD in children compared with a control group receiving daily GH (Norditropin, Novo Nordisk; 0. 034 mg/kg/d) (Fig. 1 ). The main trial period was 52 weeks, followed by an ongoing 3-year single-group extension period.
The 52-week data reported here were collected between May 2019 and November 2021. The somapacitan dose is supported by results from a phase 2 dose-finding trial (NCT03878446) demonstrating the efficacy and safety of 0. 16 mg/kg/wk somapacitan matches that of daily treatment with 0. 034 mg/kg/d Norditropin  (10). The daily GH dose of 0. 034 mg/kg/d was chosen based on the maximum dose according to the product label for children with GHD (0. 034 or 0. 035 mg/kg/d in participating countries). Both treatments were administered subcutaneously, the approved administration route for Norditropin and intended route of somapacitan administration. The 0. 16 mg/kg/wk dose of somapacitan was provided as 5 mg/1. 5 mL, 10 mg/1. 5 mL, and 15 mg/1. 5 mL prefilled pen injectors of the FlexPro family (Novo Nordisk A/S).
Statistical Analysis Two analysis populations were defined: the full analysis set included all randomly assigned participants (used for efficacy outcome analyses) and the safety analysis set included all participants exposed to 1 or more doses of trial product (used for safety outcome analyses). Observation periods included ontreatment (the time from first administration and up until last trial contact or visit 7 or 14 days after last administration, whichever comes first) and in-trial (the time from first administration and up until visit 7 or last trial contact, whichever comes first). Two distinct estimand strategies were defined to evaluate treatment effect from different scientific perspectives. The treatment policy strategy recommended by the Food and Drug Administration and Pharmaceuticals and Medical Devices Agency evaluates data collected up to and including week 52, regardless of treatment discontinuation, or use of ancillary therapy.
The hypothetical strategy recommended by the European Medicines Agency evaluates data collected up to and including week 52, excluding data assessed after discontinuation of randomized treatment. HV was analyzed based on both the treatment policy strategy and the hypothetical strategy. HV at week 52 was analyzed using an analysis of covariance model with treatment, sex, age group, region, GH peak group and sex by age group by region interaction term as factors, and baseline height as covariate. The prespecified noninferiority threshold was -1. 8 cm/y. Changes in height SDS and HV SDS were analyzed using the same analysis model as was used for analyzing the primary endpoint for the treatment policy estimand with the exception that baseline height SDS and baseline HV SDS were used, respectively, as covariates in the model instead of baseline height.
PK/PD Modeling IGF-I SDS profiles and weekly IGF-I average SDS at steadystate week 52 were estimated by population PK/PD modeling. Models were fitted to PK and IGF-I data from this study and previous phase 1 and 2 data in children with GHD (9, 10) using models developed from full PK and IGF-I profiles obtained in phase 1 healthy adults, and adults and children with GHD  (26, 27). Weekly average IGF-I levels were calculated from the estimated IGF-I area under the curve in a dosing interval for each individual treated with somapacitan.
Acknowledgments The authors thank the patients and their families, nurses and study coordinators, and all investigators involved in this study, including members of the REAL4 Study Group*, without whom the study would not have been possible. The authors thank  Kai Wai Lee  and  Sebastian Roerich  of  Novo Nordisk  for critically assessing the manuscript. Medical writing and editorial support were provided by  Ryan Ard ,  Novo Nordisk. Disclosures B. S. M. : Consultant: Abbvie,  Ascendis Pharma ,  BioMarin ,  Bristol Myers Squibb ,  EMD Serono ,  Endo Pharmaceuticals ,  Novo Nordisk ,  Orchard Therapeutics ,  Pfizer , Tolmar, and Vertice; Research support:  Alexion ,  Abbvie ,  Aeterna Zentaris ,  Amgen ,  Amicus ,  Lumos Pharma ,  Lysogene ,  Novo Nordisk ,  OPKO Health Pfizer ,  Prevail Therapeutics , and  Sangamo Therapeutics.
J. C. B. : Advisory boards:  Novo Nordisk ; Speaker fees from  Novo Nordisk  and  Ipsen ; Financial support to attend scientific meetings: Novo Nordisk. M. H. R. : Employee, stockholder:  Novo Nordisk. A. M. : Principal Investigator:  Novo Nordisk , Ascendis,  OPKO , and  Pfizer. RJK: Employee, stockholder:  Novo Nordisk. J. M. : Nothing to disclose. M. P. : Advisory boards:  Ipsen ,  Novo Nordisk ,  Pfizer ; Speaker fees:  Novo Nordisk , and  Ipsen ; Research support:  Ipsen ,  Novo Nordisk ,  Pfizer ,  Sandoz ,  Merck , and  Sanofi , as well as  French  institutional grants (PHRC and ANR). R. B. B. : Employee, stockholder:  Novo Nordisk. V. B. : Advisory boards:  Merck ; Speaker fees:  Novo Nordisk  and  Merck ; Financial support to attend scientific meetings:  Ferring ,  Lilly ,  Merck ,  Novo Nordisk.
Data Management & Analysis All data were collected through standardized questionnaires, double entered into a specially designed database and veri ed. Analysis was conducted using Microsoft Excel and Stata software (version 14, College Station, Texas, USA). All questionnaires were labeled with the pregnant woman's unique identity number and date of collection, thus ensuring anonymity. Costs were reported in local currencies. Costs were then converted to US dollars using the average exchange rate across the time of the study, speci cally August 2014-December 2015 (OANDA)  [25] ). Costs were broken down into both direct and indirect costs. Direct costs (out-of-pocket expenses) were further broken down into medical (such as admission fees, drug charges, and laboratory fees), and nonmedical (such as transportation and food).
Funding The research is funded by the  European Union Seventh Framework Programme  ( FP7/2002-2016 ) under grant agreement n°  305662-COSMIC  (Project: Community-based scheduled screening and treatment of malaria in pregnancy for improved maternal and infant health: a cluster-randomized trial 'COSMIC'). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We acknowledge joint funding from the  UK Medical Research Council and Department for International Development. MR/R015600/1.
Patients Of the 12 patients, 9 were foetuses referred for abnormal ultrasound screening results and 3 were new-born babies who died shortly after birth (of whom 2 had abnormal prenatal ultrasound results). All the patients in this study will be referred to hereafter by the term "foetus," to avoid confusion with data from the literature. Among the 9 pregnancies, two women had chosen to terminate the pregnancy (termination of pregnancy, TOP) following a cytogenetic diagnosis, 2 foetuses died in utero and 5 pregnancies led to a live birth. Standardized autopsy procedures were performed on all deceased foetuses or new-born babies, including skeletal X-rays, macroscopic examinations and histology analyses. For all the patients, written informed consent for genetic testing and possible publication of this anonymized data were obtained from their legal representative(s).