Chemotherapy followed by low dose radiotherapy in childhood Hodgkin's disease: retrospective analysis of results and prognostic factors

PURPOSE: To report the treatment results and prognostic factors of childhood patients with Hodgkin's disease treated with chemotherapy (CT) followed by low dose radiotherapy (RT). PATIENTS AND METHODS: This retrospective series analyzed 166 patients under 18 years old, treated from January 1985 to December 2003. Median age was 10 years (range 2–18). The male to female ratio was 2,3 : 1. Lymphonode enlargement was the most frequent clinical manifestation (68%), and the time of symptom duration was less than 6 months in 55% of the patients. In histological analysis Nodular Sclerosis was the most prevalent type (48%) followed by Mixed Celularity (34.6%). The staging group according Ann Arbor classification was: I (11.7%), II (36.4%), III (32.1%) and IV (19.8%). The standard treatment consisted of chemotherapy multiple drug combination according the period of treatment protocols vigent: ABVD in 39% (n-65) of the cases, by VEEP in 13 %(n-22), MOPP in 13 %(n-22), OPPA-13 %(n-22) and ABVD/OPPA in 22 %(n-33). Radiotherapy was device to all areas of initial presentation of disease. Dose less or equal than 21 Gy was used in 90.2% of patients with most part of them (90%) by involved field (IFRT) or mantle field. RESULTS: The OS and EFS in 10 years were 89% and 87%. Survival according to clinical stage as 94.7%, 91.3%, 82.3% and 71% for stages I to IV(p = 0,005). The OS was in 91.3% of patients who received RT and in 72.6% of patients who did not (p = 0,003). Multivariate analysis showed presence of B symptoms, no radiotherapy and advanced clinical stage to be associated with a worse prognosis. CONCLUSION: This data demonstrating the importance of RT consolidation with low dose and reduced volume, in all clinical stage of childhood HD, producing satisfactory ten years OS and EFS. As the disease is highly curable, any data of long term follow-up should be presented in order to better direct therapy, and to identify groups of patients who would not benefit from radiation treatment

Assessment of Outcomes Among Patients With Venous Thromboembolism With and Without Chronic Kidney Disease

Importance: Patients with venous thromboembolism (VTE) and concomitant chronic kidney disease (CKD) have been reported to have a higher risk of thrombosis and major bleeding complications compared with patients without concomitant CKD. The use of anticoagulation therapy is challenging, as many anticoagulant medications are excreted by the kidney. Large-scale data are needed to clarify the impact of CKD for anticoagulant treatment strategies and clinical outcomes of patients with VTE. Objective: To compare clinical characteristics, treatment patterns, and 12-month outcomes among patients with VTE and concomitant moderate to severe CKD (stages 3-5) vs patients with VTE and mild to no CKD (stages 1-2) in a contemporary international registry. Design, Setting, and Participants: The Global Anticoagulant Registry in the Field-Venous Thromboembolism (GARFIELD-VTE) study is a prospective noninterventional investigation of real-world treatment practices. A total of 10 684 patients from 415 sites in 28 countries were enrolled in the GARFIELD-VTE between May 2014 and January 2017. This cohort study included 8979 patients (6924 patients with mild to no CKD and 2055 patients with moderate to severe CKD) who had objectively confirmed VTE within 30 days before entry in the registry. Chronic kidney disease stages were defined by estimated glomerular filtration rates. Data were extracted from the study database on December 8, 2018, and analyzed between May 1, 2019, and July 30, 2020. Exposure: Moderate to severe CKD vs mild to no CKD. Main Outcomes and Measures: The primary outcomes were all-cause mortality, recurrent VTE, and major bleeding. Event rates and 95% CIs were calculated and expressed per 100 person-years. Hazard ratios (HRs) were estimated with Cox proportional hazards regression models and adjusted for relevant confounding variables. All-cause mortality was considered a competing risk for other clinical outcomes in the estimation of cumulative incidences. Results: Of the 10 684 patients with objectively confirmed VTE, serum creatinine data were available for 8979 patients (84.0%). Of those, 4432 patients (49.4%) were female and 5912 patients (65.8%) were White; 6924 patients (77.1%; median age, 57 years; interquartile range [IQR], 44-69 years) were classified as having mild to no CKD, and 2055 patients (22.9%; median age, 70 years; IQR, 59-78 years) were classified as having moderate to severe CKD. Calculations using the equation from the Modification of Diet in Renal Disease study indicated that, among the 6924 patients with mild to no CKD, 2991 patients had stage 1 CKD, and 3933 patients had stage 2 CKD; among the 2055 patients with moderate to severe CKD, 1650 patients had stage 3 CKD, 190 patients had stage 4 CKD, and 215 patients had stage 5 CKD. The distribution of VTE presentation was comparable between groups. In total, 1171 patients (57.0%) with moderate to severe CKD and 4079 patients (58.9%) with mild to no CKD presented with deep vein thrombosis alone, 547 patients (26.6%) with moderate to severe CKD and 1723 patients (24.9%) with mild to no CKD presented with pulmonary embolism alone, and 337 patients (16.4%) with moderate to severe CKD and 1122 patients (16.2%) with mild to no CKD presented with both pulmonary embolism and deep vein thrombosis. Compared with patients with mild to no CKD, patients with moderate to severe CKD were more likely to be female (3259 women [47.1%] vs 1173 women [57.1%]) and older than 65 years (2313 patients [33.4%] vs 1278 patients [62.2%]). At baseline, the receipt of parenteral therapy alone was comparable between the 2 groups (355 patients [17.3%] with moderate to severe CKD vs 1253 patients [18.1%] with mild to no CKD). Patients with moderate to severe CKD compared with those with mild to no CKD were less likely to be receiving direct oral anticoagulant therapy, either alone (557 patients [27.1%] vs 2139 patients [30.9%]) or in combination with parenteral therapy (319 patients [15.5%] vs 1239 patients [17.9%]). Patients with moderate to severe CKD had a higher risk of all-cause mortality (adjusted hazard ratio [aHR], 1.44; 95% CI, 1.21-1.73), major bleeding (aHR, 1.40; 95% CI, 1.03-1.90), and recurrent VTE (aHR, 1.40; 95% CI, 1.10-1.77) than patients with mild to no CKD. Conclusions and Relevance: In this study of patients with VTE, the presence of moderate to severe CKD was associated with increases in the risk of death, VTE recurrence, and major bleeding compared with the presence of mild to no CKD

Net clinical benefit of dabigatran vs. warfarin in venous thromboembolism: analyses from RE-COVER®, RE-COVER™ II, and RE-MEDY™

The direct oral anticoagulants, e.g., dabigatran etexilate (DE), are effective and well tolerated treatments for venous thromboembolism (VTE). Net clinical benefit (NCB) is a useful concept in weighing potential benefits against potential harm of comparator drugs. The NCB of DE vs. warfarin in VTE treatment was compared. Post-hoc analyses were performed on pooled data from the 6-month RE-COVER® and RE-COVER™ II trials, and data from the RE-MEDY™ trial (up to 36 months), to compare the NCB of DE (150 mg twice daily) and warfarin [target international normalized ratio (INR) 2.0-3.0]. Patients (≥18 years old) had symptomatic proximal deep vein thrombosis and/or pulmonary embolism. NCB was the composite of cardiovascular endpoints (non-fatal events of recurrent VTE, myocardial infarction, stroke or systemic embolism), all-cause death, and bleeding outcomes, all weighted equally. A broad definition of NCB included major bleeding events (MBE) and clinically relevant non-major bleeding events as bleeding outcomes, while a narrow definition included just MBE. The pooled dataset totalled 5107 patients from RE-COVER/RE-COVER II and 2856 patients from RE-MEDY. When NCB was narrowly defined, NCB was similar between DE and warfarin. When broadly defined, NCB was superior with DE vs. warfarin [RE-COVER/RE-COVER II, hazard ratio (HR) 0.80; 95% confidence interval (CI), 0.68-0.95 and RE-MEDY, HR 0.73; 95% CI 0.59-0.91]. These findings were unaffected by warfarin time in therapeutic range. The NCB of DE was similar or superior to warfarin, depending on the NCB definition used, regardless of the quality of INR control

Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility : a randomized trial

Q1Q18-18BACKGROUND: Extended-duration low-molecular-weight heparin has been shown to prevent venous thromboembolism (VTE) in high-risk surgical patients. OBJECTIVE: To evaluate the efficacy and safety of extended-duration enoxaparin thromboprophylaxis in acutely ill medical patients. DESIGN: Randomized, parallel, placebo-controlled trial. Randomization was computer-generated. Allocation was centralized. Patients, caregivers, and outcome assessors were blinded to group assignment. (ClinicalTrials.gov registration number: NCT00077753) SETTING: 370 sites in 20 countries across North and South America, Europe, and Asia. PATIENTS: Acutely ill medical patients 40 years or older with recently reduced mobility (bed rest or sedentary without [level 1] or with [level 2] bathroom privileges). Eligibility criteria for patients with level 2 immobility were amended to include only those who had additional VTE risk factors (age >75 years, history of VTE, or active or previous cancer) after interim analyses suggested lower-than-expected VTE rates. INTERVENTION: Enoxaparin, 40 mg/d subcutaneously (2975 patients), or placebo (2988 patients), for 28 +/- 4 days after receiving open-label enoxaparin for an initial 10 +/- 4 days. MEASUREMENTS: Incidence of VTE up to day 28 and of major bleeding events up to 48 hours after the last study treatment dose. RESULTS: Extended-duration enoxaparin reduced VTE incidence compared with placebo (2.5% vs. 4%; absolute risk difference favoring enoxaparin, -1.53% [95.8% CI, -2.54% to -0.52%]). Enoxaparin increased major bleeding events (0.8% vs. 0.3%; absolute risk difference favoring placebo, 0.51% [95% CI, 0.12% to 0.89%]). The benefits of extended-duration enoxaparin seemed to be restricted to women, patients older than 75 years, and those with level 1 immobility. LIMITATION: Estimates of efficacy and safety for the overall trial population are difficult to interpret because of the change in eligibility criteria during the trial. CONCLUSION: Use of extended-duration enoxaparin reduces VTE more than it increases major bleeding events in acutely ill medical patients with level 1 immobility, those older than 75 years, and women. PRIMARY FUNDING SOURCE: Sanofi-aventis

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

GARFIELD-AF: risk profiles, treatment patterns and 2-year outcomes in patients with atrial fibrillation in Germany, Austria and Switzerland (DACH) compared to 32 countries in other regions worldwide.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is a worldwide non-interventional study of stroke prevention in patients with non-valvular AF. METHODS AND RESULTS: 52,080 patients with newly diagnosed AF were prospectively enrolled from 2010 to 2016. 4121 (7.9%) of these patients were recruited in DACH [Germany (n = 3567), Austria (n = 465) and Switzerland (n = 89) combined], and 47,959 patients were from 32 countries in other regions worldwide (ORW). Hypertension was most prevalent in DACH and ORW (85.3% and 75.6%, respectively). Diabetes, hypercholesterolaemia, carotid occlusive disease and vascular disease were more prevalent in DACH patients vs ORW (27.6%, 49.4%, 5.8% and 29.0% vs 21.7%, 40.9%, 2.8% and 24.5%). The use of non-vitamin K antagonist oral anticoagulants (NOACs) increased more in DACH over time. Management of vitamin K antagonists was suboptimal in DACH and ORW (time in therapeutic range of INR ≥ 65% in 44.6% and 44.4% of patients or ≥ 70% in 36.9% and 36.0% of patients, respectively). Adjusted rates of cardiovascular mortality and MI/ACS were higher in DACH while non-haemorrhagic stroke/systemic embolism was lower after 2-year follow-up. CONCLUSIONS: Similarities and dissimilarities in AF management and clinical outcomes are seen in DACH and ORW. The increased use of NOAC was associated with a mismatch of risk-adapted anticoagulation (over-and-undertreatment) in DACH. Suboptimal control of INR requires educational activities in both regional groups. Higher rates of cardiovascular death in DACH may reflect the higher risk profile of these patients and lower rates of non-haemorrhagic stroke could be associated with increased NOAC use

GATEKEEPER’s Strategy for the Multinational Large-Scale Piloting of an eHealth Platform: Tutorial on How to Identify Relevant Settings and Use Cases

Background: The World Health Organization’s strategy toward healthy aging fosters person-centered integrated care sustained by eHealth systems. However, there is a need for standardized frameworks or platforms accommodating and interconnecting multiple of these systems while ensuring secure, relevant, fair, trust-based data sharing and use. The H2020 project GATEKEEPER aims to implement and test an open-source, European, standard-based, interoperable, and secure framework serving broad populations of aging citizens with heterogeneous health needs. Objective: We aim to describe the rationale for the selection of an optimal group of settings for the multinational large-scale piloting of the GATEKEEPER platform. Methods: The selection of implementation sites and reference use cases (RUCs) was based on the adoption of a double stratification pyramid reflecting the overall health of target populations and the intensity of proposed interventions; the identification of a principles guiding implementation site selection; and the elaboration of guidelines for RUC selection, ensuring clinical relevance and scientific excellence while covering the whole spectrum of citizen complexities and intervention intensities. Results: Seven European countries were selected, covering Europe’s geographical and socioeconomic heterogeneity: Cyprus, Germany, Greece, Italy, Poland, Spain, and the United Kingdom. These were complemented by the following 3 Asian pilots: Hong Kong, Singapore, and Taiwan. Implementation sites consisted of local ecosystems, including health care organizations and partners from industry, civil society, academia, and government, prioritizing the highly rated European Innovation Partnership on Active and Healthy Aging reference sites. RUCs covered the whole spectrum of chronic diseases, citizen complexities, and intervention intensities while privileging clinical relevance and scientific rigor. These included lifestyle-related early detection and interventions, using artificial intelligence–based digital coaches to promote healthy lifestyle and delay the onset or worsening of chronic diseases in healthy citizens; chronic obstructive pulmonary disease and heart failure decompensations management, proposing integrated care management based on advanced wearable monitoring and machine learning (ML) to predict decompensations; management of glycemic status in diabetes mellitus, based on beat to beat monitoring and short-term ML-based prediction of glycemic dynamics; treatment decision support systems for Parkinson disease, continuously monitoring motor and nonmotor complications to trigger enhanced treatment strategies; primary and secondary stroke prevention, using a coaching app and educational simulations with virtual and augmented reality; management of multimorbid older patients or patients with cancer, exploring novel chronic care models based on digital coaching, and advanced monitoring and ML; high blood pressure management, with ML-based predictions based on different intensities of monitoring through self-managed apps; and COVID-19 management, with integrated management tools limiting physical contact among actors. Conclusions: This paper provides a methodology for selecting adequate settings for the large-scale piloting of eHealth frameworks and exemplifies with the decisions taken in GATEKEEPER the current views of the WHO and European Commission while moving forward toward a European Data Space

Incomplete echocardiographic recovery at 6\ua0months predicts long-term sequelae after intermediate-risk pulmonary embolism. A post-hoc analysis of the Pulmonary Embolism Thrombolysis (PEITHO) trial

Introduction: Symptoms and functional limitation are frequently reported by survivors of acute pulmonary embolism (PE). However, current guidelines provide no specific recommendations on which patients should be followed after acute PE, when follow-up should be performed, and which tests it should include. Definition and classification of late PE sequelae are evolving, and their predictors remain to be determined. Methods: In a post hoc analysis of the Pulmonary Embolism Thrombolysis (PEITHO) trial, we focused on 219 survivors of acute intermediate-risk PE with clinical and echocardiographic follow-up 6 months after randomisation as well as over the long term (median, 3 years after acute PE). The primary outcome was a composite of (1) confirmed chronic thromboembolic pulmonary hypertension (CTEPH) or (2) \u2018post-PE impairment\u2019 (PPEI), defined by echocardiographic findings indicating an intermediate or high probability of pulmonary hypertension along with New York Heart Association functional class II\u2013IV. Results: Confirmed CTEPH or PPEI occurred in 29 (13.2%) patients, (6 with CTEPH and 23 with PPEI). A history of chronic heart failure at baseline and incomplete or absent recovery of echocardiographic parameters at 6 months predicted CTEPH or PPEI at long-term follow-up. Conclusions: CTEPH or PPEI occurs in almost one out of seven patients after acute intermediate-risk PE. Six-month echocardiographic follow-up may be useful for timely detection of late sequelae

Enoxaparin for symptomatic COVID-19 managed in the ambulatory setting: An individual patient level analysis of the OVID and ETHIC trials.

BACKGROUND: Antithrombotic treatment may improve the disease course in non-critically ill, symptomatic COVID-19 outpatients. METHODS: We performed an individual patient-level analysis of the OVID and ETHIC randomized controlled trials, which compared enoxaparin thromboprophylaxis for either 14 (OVID) or 21 days (ETHIC) vs. no thromboprophylaxis for outpatients with symptomatic COVID-19 and at least one additional risk factor. The primary efficacy outcome included all-cause hospitalization and all-cause death within 30 days from randomization. Both studies were prematurely stopped for futility. Secondary efficacy outcomes were major symptomatic venous thromboembolic events, arterial cardiovascular events, or their composite occurring within 30 days from randomization. The same outcomes were assessed over a 90-day follow-up. The primary safety outcome was major bleeding (ISTH criteria). RESULTS: A total of 691 patients were randomized: 339 to receive enoxaparin and 352 to the control group. Over 30-day follow-up, the primary efficacy outcome occurred in 6.0 % of patients in the enoxaparin group vs. 5.8 % of controls for a risk ratio (RR) of 1.05 (95%CI 0.57-1.92). The incidence of major symptomatic venous thromboembolic events and arterial cardiovascular events was 0.9 % vs. 1.8 %, respectively (RR 0.52; 95%CI 0.13-2.06). Most cardiovascular thromboembolic events were represented by symptomatic venous thromboembolic events, occurring in 0.6 % vs. 1.5 % of patients, respectively. A similar distribution of outcomes between the treatment groups was observed over 90 days. No major bleeding occurred in the enoxaparin group vs. one (0.3 %) in the control group. CONCLUSIONS: We found no evidence for the clinical benefit of early administration of enoxaparin thromboprophylaxis in outpatients with symptomatic COVID-19. These results should be interpreted taking into consideration the relatively low occurrence of events

Outcome of a risk-related therapeutic strategy used prospectively in a population-based study of Hodgkin's lymphoma in adolescents

The aim was to assess outcome in a population-based cohort of adolescents with Hodgkin's lymphoma (HL) diagnosed in the UK's northern region over a 10-year period. Among a population of 3.09 million, 55 of 676 patients (8%) diagnosed with HL were aged 13–19. Seven had nodular lymphocyte-predominant HL, 48 classical HL (cHL). Of the latter, 36 were ⩾16 years. Application of the Scottish and Newcastle Lymphoma Group (SNLG) prognostic index meant 21 patients were considered high risk (index ⩾0.5). They received PVACEBOP multi-agent chemotherapy as primary therapy. Standard risk patients (SNLG index <0.5) were treated with standard ChlVPP or ABVD chemotherapy±radiotherapy. Scottish and Newcastle Lymphoma Group indexing is not valid for patients under 16. Twelve patients therefore received UKCCSG protocols (n=8), ABVD plus radiotherapy (n=2), or PVACEBOP (n=2). Forty-six patients with cHL (96%) achieved complete remission. Seven patients relapsed but all entered complete remission after salvage therapy. Five patients died: three of HL, one in an accident and one of disseminated varicella complicating cystic fibrosis. Five- and 10-year overall survival was 93 and 86%, respectively; disease-specific survival was 95 and 92%. The data suggest that older adolescents with high-risk HL require intensive protocols as primary therapy to secure optimal outcome