Inequality in place-of-death among children: a Danish nationwide study.

To identify predictors for home death among children using socio-demographic factors and cause of death. It is a nationwide registry study. A cohort of children (1-17 years) who died between 1 January 2006 and 31 December 2016. It was set in Denmark, Europe. Predictors for home death were assessed: age, gender, diagnosis, region of residence, urbanicity, household income and immigrant status. Of 938 deceased children included, causes of death were solid tumours (17.3%), haematological cancers (8.5%) and non-cancerous conditions (74.2%). A total of 25% died at home. Compared to the lowest quartile, the groups with higher household income did not have a higher probability of dying at home (adjusted odds ratio (adj-OR) 0.8 (95% CI 0.5-1.2/1.3)). Dying of haematological cancers (adj-OR 0.3 (95% CI 0.2-0.7)) and non-cancerous conditions (adj-OR 0.5 (95% CI 0.3-0.7)) was associated with lower odds for home death compared to dying of solid tumours. However, being an immigrant was negatively associated with home death (adj-OR 0.6 (95% CI 0.4-0.9)). Moreover, a tendency was also found that being older, male, living outside the capital and in more urban areas were notable in relation to home death, however, not statistically significant.Conclusions: The fact that household income was not associated with dying at home may be explained by the Danish tax-financed healthcare system. However, having haematological cancers, non-cancerous conditions or being an immigrant were associated with lower odds for home death. Cultural differences along with heterogeneous trajectories may partly explain these differences, which should be considered prospectively. What is Known: • Prior studies have shown disparities in place-of-death of terminally ill children with diagnosis, ethnicity and socio-economic position as key factors. • Danish healthcare is tax-financed and in principle access to healthcare is equal; however, disparities have been found in the intensity of treatment of terminally ill children. What is New: • In a tax-financed, equal-access healthcare system, children died just as frequently at home in families with low as high household income. • Disparities in home death were related to diagnosis and immigrant status.

Four-year patient-level pooled mortality analysis of the ILLUMENATE US Pivotal and EU randomized controlled trials.

OBJECTIVE: To perform a meta-analysis of two concordant randomized controlled trials (RCTs) examining the long-term, 4-year safety profile of the Stellarex drug-coated balloon (DCB) vs percutaneous transluminal angioplasty (PTA) for the treatment of peripheral artery disease. METHODS: An independent, third-party, meta-analysis of homogeneous, patient-level data from the ILLUMENATE Pivotal and ILLUMENATE EU RCTs was performed to assess mortality (time to death) in patients treated for symptomatic femoropopliteal disease. The Kaplan-Meier (KM) methodology was used to estimate hazard rates [HRs] of all-cause mortality, and Cox proportional hazard modeling was used to assess predictors of mortality. All serious adverse events, including deaths, were adjudicated by an independent, blinded clinical events committee. RESULTS: In total, 589 (419 DCB; 170 PTA) patients were included in the pooled analysis of the ILLUMENATE Pivotal and ILLUMENATE EU RCTs. The median follow-up was 1735 days (interquartile range, 1434-1829 days), equivalent to 4.75 years. Vital status compliance was >95% in each RCT. The total number of deaths through 4 years was 81 of 589 (13.8%): 58 of 419 (13.8%) in the DCB arm and 23 of 170 (13.5%) in the PTA arm. The 1-year KM estimate of all-cause mortality was 1.9% ± 0.7% (estimate ±standard error) in those treated with DCB vs 1.2% ± 0.9% in those treated with PTA. At 2, 3, and 4 years, the respective KM estimates were 6.6% ± 1.2% vs 4.9% ± 1.7%, 9.3% ± 1.4% vs 9.9% ± 2.4%, and 14.0% ± 1.7% vs 14.4% ± 2.8% (P = .864). There were no significant differences in clinical events committee-adjudicated deaths between the two cohorts. In multivariate analysis, predictors of 4-year mortality were age (HR, 1.048; 95% confidence interval [CI], 1.026-1.071; P < .0001), renal insufficiency (HR, 2.440; 95% CI, 1.566-3.800; P < .0001), and lesion length (HR, 1.004; 95% CI, 1.000-1.008; P = .041). Neither paclitaxel exposure (DCB vs PTA; HR, 1.086; 95% CI, 0.709-1.664; P = .705) nor dose (mg; HR, 1.043; 95% CI, 0.971-1.119; P = .248) was the predictor of all-cause mortality at 4 years. CONCLUSIONS: This systematic meta-analysis of two concordant ILLUMENATE RCTs shows no difference in all-cause mortality through 4 years between Stellarex DCB and PTA, confirming the acceptable, long-term safety profile of the Stellarex DCB.

Randomized Trial of Two Induction Therapy Regimens for High-Risk Neuroblastoma: HR-NBL1.5 International Society of Pediatric Oncology European Neuroblastoma Group Study.

PURPOSE: Induction therapy is a critical component of the therapy of high-risk neuroblastoma. We aimed to assess if the Memorial Sloan Kettering Cancer Center (MSKCC) N5 induction regimen (MSKCC-N5) would improve metastatic complete response (mCR) rate and 3-year event-free survival (EFS) compared with rapid COJEC (rCOJEC; cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C]). PATIENTS AND METHODS: Patients (age 1-20 years) with stage 4 neuroblastoma or stage 4/4s aged < 1 year with MYCN amplification were eligible for random assignment to rCOJEC or MSKCC-N5. Random assignment was stratified according to national group and metastatic sites. Following induction, therapy comprised primary tumor resection, high-dose busulfan and melphalan, radiotherapy to the primary tumor site, and isotretinoin with ch14.18/CHO (dinutuximab beta) antibody with or without interleukin-2 immunotherapy. The primary end points were mCR rate and 3-year EFS. RESULTS: A total of six hundred thirty patients were randomly assigned to receive rCOJEC (n = 313) or MSKCC-N5 (n = 317). Median age at diagnosis was 3.2 years (range, 1 month to 20 years), and 16 were younger than 1 year of age with MYCN amplification. mCR rate following rCOJEC induction (32%, 86/272 evaluable patients) was not significantly different from 35% (99/281) with MSKCC-N5 (P = .368), and 3-year EFS was 44% ± 3% for rCOJEC compared with 47% ± 3% for MSKCC-N5 (P = .527). Three-year overall survival was 60% ± 3% for rCOJEC compared with 65% ± 3% for MSKCC-N5 (P = .379). Toxic death rates with both regimens were 1%. However, nonhematologic CTC grade 3 and 4 toxicities were higher with MSKCC-N5: 68% (193/283) versus 48% (129/268) (P < .001); infection 35% versus 25% (P = .011); stomatitis 25% versus 3% (P < .001); nausea and vomiting 17% versus 7% (P < .001); and diarrhea 7% versus 3% (P = .011). CONCLUSION: No difference in outcome was observed between rCOJEC and MSKCC-N5; however, acute toxicity was less with rCOJEC, and therefore rCOJEC is the preferred induction regimen for International Society of Pediatric Oncology European Neuroblastoma Group.

Disparities in intensity of treatment at end-of-life among children according to the underlying cause of death.

AIM: To compare indicators of high-intensity treatment at end-of-life (HI-EOL) among children according to causes of death. METHODS: We conducted a nationwide registry study in Denmark among 938 children of 1-17 years of age who died from natural causes from 2006 to 2016. We identified and compared indicators of HI-EOL within the last month of life across diagnoses. Indicators were hospital admissions, days in hospital, intensive care unit admission, mechanical ventilation, and hospital death. RESULTS: Proportions of each indicator of HI-EOL ranged from 27% to 75%. The most common indicators were hospital death (75%) and ICU admission (39%). Compared to children with solid tumours, children with non-cancerous conditions had an adjusted odds ratio of 3.5 (95% CI 2.1-5.9) of having ≥3 indicators of HI-EOL within the last month of life and children with haematological cancer had an odds ratio of 11.8 (95% CI 6.1-23.0). CONCLUSION: The underlying diagnosis was strongly associated with HI-EOL. Children who died from solid tumours experienced substantially less intensive treatment than both children with haematological cancer and non-cancerous conditions did. Across non-cancerous diagnoses, the intensity of treatment appeared consistent, which may indicate, that the awareness of palliative care is higher among oncologists than within other paediatric fields.

Paclitaxel-Coated Balloon Angioplasty for the Treatment of Infrainguinal Arteries: 24-Month Outcomes in the Full Cohort of BIOLUX P-III Global Registry.

PURPOSE: After promising small randomized trials, the aim of BIOLUX P-III was to further investigate the safety and performance of the Passeo-18 lx drug-coated balloon in infrainguinal arteries under real-world conditions. METHODS: BIOLUX P-III is a global prospective single-arm study with follow-up at 6, 12 and 24 months. The primary safety endpoint was freedom from major adverse events (MAE) within 6 months. The primary performance endpoint was freedom from clinically driven target lesion revascularization (TLR) within 12 months. RESULTS: 877 patients/1084 lesions were enrolled. Diabetes mellitus was present in 47.7%, and 42.1% had critical limb ischemia (CLI). The mean lesion length was 89.0 mm with 76.1% of calcified lesions, and 24.9% occluded. At 24 months, freedom from MAE was 83.1% in the full cohort; 84.9% in the femoropopliteal population (592 patients, 691 lesions); 77.7% for long lesions (187 subjects/192 lesions); and 72.5% in the in-stent restenosis (ISR) subgroup (103 subjects/116 lesions). Twenty-four-month freedom from clinically driven TLR was 88.1% in the full cohort; 88.9% in the femoropopliteal population; 80.3% for the long lesions; and 78.4% for ISR. Twenty-four-month all-cause mortality was 12.0% in the full cohort, 10.2% in the femoropopliteal population, 14.8% for the long lesions and 12.0% for ISR. There was no device- or procedure-related death up to 24-month follow-up. CONCLUSION: The BIOLUX P-III 24-month outcomes confirm the safety and performance of Passeo-18 lx in infrainguinal arteries in a large population treated under real-world conditions with low complication rates and good clinical outcomes (NCT02276313).

Supraspinatus and deltoid muscle fiber composition in rotator cuff tear conditions.

BACKGROUND: Rotator cuff (RC) tears are associated with RC muscle atrophy and changes in composition that are crucial to the prognosis of RC repair. The aim of this study was to characterize muscle fiber composition in the supraspinatus (SS) muscle under tear conditions. METHODS: Muscle biopsies were obtained from 21 patients undergoing surgery for an RC tendon tear. Biopsies were obtained from the musculotendinous junction of the SS muscle, and control biopsies were harvested from the deltoid muscle (DT). Biopsies were immunohistochemically processed for detection of type 1 (slow type) and type 2 (fast type) fibers and analyzed using unbiased, stereological principles. We counted the total numbers of type 1 and 2 muscle fibers/mm2, and fiber diameter was used to estimate muscle fiber atrophy and hypertrophy. RESULTS: We found significantly more type 2 cells/mm2 in the SS compared with the DT (P < .01). In addition, we found a significantly higher fraction of type 1 fibers than type 2 fibers in the DT (P < .01), whereas both fiber types were equally present in the SS. The diameters of SS cells were generally smaller than those of DT cells. Atrophy of especially SS type 2 fibers was also demonstrated. Fiber atrophy was more pronounced in men than women. CONCLUSION: The changes in the composition of SS muscle cell types suggest a shift from type 1 to type 2 muscle fibers and atrophy of both type 1 and 2 fibers. This composition indicates loss of endurance and rapid fatigue of the SS muscle under RC tear conditions.

Predictors for place of death among children:A systematic review and meta-analyses of recent literature.

Through a systematic review and meta-analyses, we aimed to determine predictors for place of death among children. We searched online databases for studies published between 2008 and 2019 comprising original quantitative data on predictors for place of death among children. Data regarding study design, population characteristics and results were extracted from each study. Meta-analyses were conducted using generic inverse variance method with random effects. Fourteen cohort studies met the inclusion criteria, comprising data on 106,788 decedents. Proportions of home death varied between countries and regions from 7% to 45%. Lower age was associated with higher odds of hospital death in eight studies (meta-analysis was not possible). Children categorised as non-white were less likely to die at home compared to white (pooled OR 0.6; 95% CI 0.5-0.7) as were children of low socio-economic position versus high (pooled OR 0.7; 95% CI 0.6-0.9). Compared to patients with cancer, children with non-cancer diagnoses had lower odds of home death (pooled OR 0.5; 95% CI 0.5-0.5).Conclusion: Country and region of residence, older age of the child, high socio-economic position, 'white' ethnicity and cancer diagnoses appear to be independent predictors of home death among children. What is Known: • Home is often considered an indicator of quality in end-of-life care. • Most terminally ill children die in hospitals. What is New: • Through a systematic review and meta-analyses, this study examined predictors for place of death among children. • Country and region of residence, older age of the child, high socio-economic position, white ethnicity and having a cancer diagnosis appear to be independent predictors of home death among terminally ill children.

Influence of Surgical Excision on the Survival of Patients With Stage 4 High-Risk Neuroblastoma: A Report From the HR-NBL1/SIOPEN Study.

PURPOSE: To evaluate the impact of surgeon-assessed extent of primary tumor resection on local progression and survival in patients in the International Society of Pediatric Oncology Europe Neuroblastoma Group High-Risk Neuroblastoma 1 trial. PATIENTS AND METHODS: Patients recruited between 2002 and 2015 with stage 4 disease > 1 year or stage 4/4S with MYCN amplification < 1 year who had completed induction without progression, achieved response criteria for high-dose therapy (HDT), and had no resection before induction were included. Data were collected on the extent of primary tumor excision, severe operative complications, and outcome. RESULTS: A total of 1,531 patients were included (median observation time, 6.1 years). Surgeon-assessed extent of resection included complete macroscopic excision (CME) in 1,172 patients (77%) and incomplete macroscopic resection (IME) in 359 (23%). Surgical mortality was 7 (0.46%) of 1,531. Severe operative complications occurred in 142 patients (9.7%), and nephrectomy was performed in 124 (8.8%). Five-year event-free survival (EFS) ± SE (0.40 ± 0.01) and overall survival (OS; 0.45 ± 0.02) were significantly higher with CME compared with IME (5-year EFS, 0.33 ± 0.03; 5-year OS, 0.37 ± 0.03; P < .001 and P = .004). The cumulative incidence of local progression (CILP) was significantly lower after CME (0.17 ± 0.01) compared with IME (0.30 ± 0.02; P < .001). With immunotherapy, outcomes were still superior with CME versus IME (5-year EFS, 0.47 ± 0.02 v 0.39 ± 0.04; P = .038); CILP was 0.14 ± 0.01 after CME and 0.27 ± 0.03 after IME (P < .002). A hazard ratio of 1.3 for EFS associated with IME compared with CME was observed before and after the introduction of immunotherapy (P = .030 and P = .038). CONCLUSION: In patients with stage 4 high-risk neuroblastoma who have responded to induction therapy, CME of the primary tumor is associated with improved survival and local control after HDT, local radiotherapy (21 Gy), and immunotherapy.

Paclitaxel-Coated Balloon vs Uncoated Balloon Angioplasty for Treatment of In-Stent Restenosis in the Superficial Femoral and Popliteal Arteries: The COPA CABANA Trial.

Purpose: To investigate the efficacy and sustainability of drug-coated balloon (DCB) treatment of femoropopliteal in-stent restenosis (ISR). Materials and Methods: An investigator-initiated, prospective, multicenter, 1:1 randomized study enrolled 88 patients for treatment of ISR with DCB (n=47; mean age 68.3±9.6 years; 26 men) or uncoated balloon (n=41; mean age 67.6±10.2 years; 26 men) angioplasty (ClinicalTrials.gov identifier NCT01594684). Additionally, the protocol provided for an observational arm composed of patients from either randomized arm who experienced recurrent ISR ≥30 days after the index treatment. Redo treatment consisted of 2 DCBs sequentially inflated at the same location (double dose therapy). The majority of patients (66, 78%) had Rutherford category 3 ischemia. The mean lesion length was 140 mm; a third (27, 31%) were total occlusions. The primary endpoint was angiographic late lumen loss (LLL) at 6 months evaluated by an independent core laboratory. Results: Twenty-two patients (7 DCB +15 uncoated) were treated for recurrence with fully overlapping double DCB angioplasty. Six-month LLL was lower after DCB (0.34±1.12 mm) treatment than after angioplasty with an uncoated balloon (1.58±1.10 mm, p<0.001). At the 12-month follow-up, target lesion revascularization (TLR) was performed in 18 (49%) of 37 patients in the uncoated group, 6 (14%) of 43 patients in the single-dose DCB group (p=0.001), and no patients from the recurrent ISR group. At ~2 years after treatment, a remarkable number (14/27, 52%) of TLRs were recorded in the single-dose DCB group. Conclusion: Treatment with DCBs resulted in significantly less 6-month LLL and fewer TLRs up to 24 months than treatment with uncoated balloons. The double dose for treating recurrent ISR did not cause recognizable adverse events or require TLR up to 24 months.

Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1).

To explore the effects of immunotherapy in the International Society of Paediatric Oncology Europe Neuroblastoma Group SIOPEN high-risk neuroblastoma 1 trial (HR-NBL1 trial), two cohorts were studied: one prior to and one after the introduction of dinutuximab beta. All patients received standard induction and high-dose therapy (HDT) with autologous stem cell rescue (ASCR); the local control comprised surgery and radiotherapy to the primary tumour site, followed by isotretinoin. A landmark timepoint of 109 days, resulting from the median time between ASCR and initiation of immunotherapy, was used to define patients' eligibility in the pre-immunotherapy analysis cohort. Median follow-up was 5.8 years (inter-quartile range (IQR): 4.2-8.2 years) for 844 eligible patients balanced for risk factors, such as age, sex, stage 4, MYCN amplification and response prior to HDT. The five-year event-free and overall survival (95% confidence interval (CI) of 466 patients not receiving immunotherapy was 42% (38-47%) and 50% (46-55%) but was 57% (51-62%) and 64% (59-69%) for 378 patients receiving immunotherapy (p < 0.001). A multivariate analysis identified absence of immunotherapy (p = 0.0002, hazard ratio (HR) 1.573); type of HDT (p = 0.0029, HR 1.431); less than complete response prior to maintenance therapy (p = 0.0043, HR 1.494) and >1 metastatic compartment at diagnosis (p < 0.001, HR 2.665) as risk factors for relapse or progression. Results suggest an important role for dinutuximab beta-based immunotherapy within the treatment concepts applied in HR-NBL1/SIOPEN.

Paclitaxel-Coated Balloon for the Treatment of Infrainguinal Disease: 12-Month Outcomes in the All-Comers Cohort of BIOLUX P-III Global Registry.

Purpose: To further investigate the safety and performance of the Passeo-18 Lux drug-coated balloon (DCB) for the treatment of atherosclerotic infrainguinal disease under real-world conditions. Materials and Methods: BIOLUX P-III is an international, prospective, observational registry (ClinicalTrials.gov identifier NCT02276313) conducted at 41 centers in Europe, Asia, and Australia with follow-up visits at 6, 12, and 24 months. Of 700 patients (mean age 70.0±10.2 years; 439 men) with 863 lesions in the all-comers cohort, 330 (47.1%) patients had diabetes and 234 (37.7%) had chronic limb-threatening ischemia. The majority (79.3%) of lesions were in the femoropopliteal segment; of all lesions, 645 (74.9%) were calcified and 99 (11.5%) had in-stent restenosis (ISR). The mean lesion length was 84.7±73.3 mm. The primary clinical endpoint was major adverse events (MAEs) within 6 months, a composite of device- and procedure-related mortality through 30 days, major target limb amputation, and clinically-driven target lesion revascularization (TLR). The primary performance endpoint was clinically-driven TLR within 12 months. Results: At 6 and 12 months, freedom from MAEs was 94.0% and 89.5% in the all-comers cohort: 95.0% and 91.2% in the femoropopliteal group and 95.3% and 88.0% in the ISR subgroup, respectively. Freedom from clinically-driven TLR at 12 months was 93.1% in the all-comers cohort, 93.9% in the femoropopliteal lesions, and 89.4% for ISR lesions. All-cause mortality was 6.1% in the all-comers cohort: 5.9% in both the femoropopliteal and ISR subgroups. There were no device- or procedure-related deaths at up to 12 months. The Rutherford category improved in >80% of all subgroups at 12 months. Conclusion: In a real-world patient population, the safety and performance of the Passeo-18 Lux DCB for the treatment of atherosclerotic infrainguinal lesions are maintained, with good performance outcomes and low complication rates at 12 months.

Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia: A Danish population-based study.

BACKGROUND: Severely delayed elimination of methotrexate (MTX) is difficult to predict in patients treated with high-dose MTX (HD-MTX), but it may cause life-threatening toxicity. It has not been defined how an increase in plasma creatinine can be best used as a predictor for severely delayed MTX elimination, thus providing a guide for therapeutic interventions to minimize renal toxicity. METHODS: Pharmacokinetic data were retrospectively collected on 218 Danish children with acute lymphoblastic leukemia treated with HD-MTX 5 or 8 g/m2 on the NOPHO2000 protocol. Moderately delayed MTX elimination was defined as 42-hour plasma MTX ≥ 4.0-9.9 µM, and severely delayed elimination was defined as 42-hour plasma MTX ≥ 10 µM. RESULTS: Median 42-hour plasma MTX was 0.61 µM (interquartile range, 0.4-1.06 µM). Of 1295 MTX infusions with 5 g/m2 (n = 140 patients) or 8 g/m2 (n = 78 patients), 5.1% were severely (1.5%) or moderately (3.6%) delayed. The risk of having delayed elimination was highest in the first of eight infusions with MTX 5 g/m² (7.4% vs 0.0 to 4.1% for subsequent MTX infusions) (P < 0.02). A 25 µM increase or a 1.5-fold increase in plasma creatinine within 36 hours from start of the MTX infusion had a sensitivity of 92% (95% CI, 82%-97%) and a specificity of 85% (95% CI, 83%-87%) for predicting 42-hour MTX ≥4.0 µM. CONCLUSIONS: A 25 µM increase or a 1.5-fold in plasma creatinine within 36 hours after start of an HD-MTX infusion can predict delayed MTX elimination, thus allowing intensification of hydration and alkalization to avoid further renal toxicity and promote the elimination of MTX.

Mesenchymal stem cells isolated from both distal femurs of patients with unilateral trauma or osteoarthritis of the knee exhibit similar in-vitro ability of bone formation.

BACKGROUND: Bone fractures are a common cause of hospital admission. Currently, treatment consists of conservative regimens or operation. However, regenerative medicine introduces a possible new addition to established treatments. Evidence suggests that application of autologous mesenchymal stem cells can enhance bone regeneration, by differentiating into osteoblasts. This study investigates whether mesenchymal stem cells, isolated from bone marrow in sites of trauma or osteoarthritis, exhibit reduced proliferation and osteogenic differentiation in-vitro, compared to stem cells isolated from non-traumatic and non-osteoarthritic sites. If these pathologies are detrimental to the quality, clinicians should prioritize bone marrow from unafflicted sites. METHODS: 17 patients were enrolled. 7 had recent unilateral trauma to the knee, requiring arthroscopy. 10 had x-ray verified unilateral osteoarthritis of the knee and were scheduled for arthroplasty. Stem cells were isolated from bone marrow aspirated perioperatively from both distal femurs. In-vitro osteogenic activity was assessed through alkaline phosphatase measurement, RNA-expression and alizarin red staining. Proliferation was measured using a growth curve. RESULTS: 29 out of 34 primary cultures were successful, forming colonies with characteristic stem cell-morphology. There was no difference in mononuclear cell yield of aspirates or stem cell-yield from primary culture between non-osteoarthritic and arthritic knees or non-traumatic and traumatic knees. There was no significant difference in in-vitro osteogenic capability or proliferation. CONCLUSION: Our findings suggest that stem cells from sites afflicted by osteoarthritis or trauma can be utilized for bone regeneration with identical results as MSCs isolated from non-traumatic and non-osteoarthritic sites. However, clinical studies are needed to confirm this assumption.

Sustainable Antirestenosis Effect With a Low-Dose Drug-Coated Balloon: The ILLUMENATE European Randomized Clinical Trial 2-Year Results.

OBJECTIVES: The aim of this study was to assess the safety and effectiveness of a next-generation low-dose drug-coated balloon (DCB) designed to optimize the amount of drug transferred into the vessel wall and to maximize the amount of time the drug resides in the vessel wall. BACKGROUND: Several randomized controlled studies evaluating various DCBs have demonstrated a significantly higher patency rate compared with noncoated percutaneous transluminal angioplasty balloons at 1 year. However, the data are limited and vary by DCB at longer follow-up time points. An earlier generation low-dose DCB failed to demonstrate significant treatment effect at 2 years, raising questions regarding the durability of low-dose DCBs. METHODS: In this prospective, multicenter trial, 294 patients were randomized (3:1) to treatment with a DCB or an uncoated percutaneous transluminal angioplasty balloon. Assessments at 2 years included primary patency with duplex ultrasonography, clinically driven target lesion revascularization, and functional outcomes. RESULTS: Primary patency at 2 years was significantly higher in the DCB cohort (75.9% vs. 61.0%; p = 0.025), and the rate of clinically driven target lesion revascularization was significantly lower (12.1% vs. 30.5%; p < 0.001). There were no major limb amputations in either group. The rates of all-cause (6.5% vs. 5.1%; p = 1.00) and cardiovascular-related (1.6% vs. 1.7%; p = 1.00) mortality were similar between groups. Functional improvements over baseline were sustained in both groups, with 60% fewer reinterventions in the DCB group. CONCLUSIONS: A sustained treatment effect is achievable with a low-dose DCB with an optimized coating formulation. This trial demonstrated for the first time a statistically significantly higher primary patency rate for a low-dose DCB versus PTA at 2 years. (CVI Drug Coated Balloon European Randomized Clinical Trial; NCT01858363).

Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial.

BACKGROUND: Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma. METHODS: We did an international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma at 104 institutions in 12 countries. Eligible patients were aged 1-20 years and had MYCN-amplified neuroblastoma with stages 2, 3, or 4S, or stage 4 neuroblastoma of any MYCN status, according to the International Neuroblastoma Staging System. Patients were eligible if they had been enrolled at diagnosis in the HR-NBL1/SIOPEN trial, had completed the multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, with or without topotecan, vincristine, and doxorubicin), had achieved a disease response that fulfilled prespecified criteria, had received high-dose therapy (busulfan and melphalan or carboplatin, etoposide, and melphalan) and had received radiotherapy to the primary tumour site. In this component of the trial, patients were randomly assigned (1:1) to receive dinutuximab beta (20 mg/m2 per day as an 8 h infusion for 5 consecutive days) or dinutuximab beta plus subcutaneous IL-2 (6 × 106 IU/m2 per day on days 1-5 and days 8-12 of each cycle) with the minimisation method to balance randomisation for national groups and type of high-dose therapy. All participants received oral isotretinoin (160 mg/m2 per day for 2 weeks) before the first immunotherapy cycle and after each immunotherapy cycle, for six cycles. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17, and recruitment to this randomisation is closed. FINDINGS: Between Oct 22, 2009, and Aug 12, 2013, 422 patients were eligible to participate in the immunotherapy randomisation, of whom 406 (96%) were randomly assigned to a treatment group (n=200 to dinutuximab beta and n=206 to dinutuximab beta with subcutaneous IL-2). Median follow-up was 4·7 years (IQR 3·9-5·3). Because of toxicity, 117 (62%) of 188 patients assigned to dinutuximab beta and subcutaneous IL-2 received their allocated treatment, by contrast with 160 (87%) of 183 patients who received dinutuximab beta alone (p<0·0001). 3-year event-free survival was 56% (95% CI 49-63) with dinutuximab beta (83 patients had an event) and 60% (53-66) with dinutuximab beta and subcutaneous IL-2 (80 patients had an event; p=0·76). Four patients died of toxicity (n=2 in each group); one patient in each group while receiving immunotherapy (n=1 congestive heart failure and pulmonary hypertension due to capillary leak syndrome; n=1 infection-related acute respiratory distress syndrome), and one patient in each group after five cycles of immunotherapy (n=1 fungal infection and multi-organ failure; n=1 pulmonary fibrosis). The most common grade 3-4 adverse events were hypersensitivity reactions (19 [10%] of 185 patients in the dinutuximab beta group vs 39 [20%] of 191 patients in the dinutuximab plus subcutaneous IL-2 group), capillary leak (five [4%] of 119 vs 19 [15%] of 125), fever (25 [14%] of 185 vs 76 [40%] of 190), infection (47 [25%] of 185 vs 64 [33%] of 191), immunotherapy-related pain (19 [16%] of 122 vs 32 [26%] of 124), and impaired general condition (30 [16%] of 185 vs 78 [41%] of 192). INTERPRETATION: There is no evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8 h infusion, improved outcomes in patients with high-risk neuroblastoma who had responded to standard induction and consolidation treatment. Subcutaneous IL-2 with dinutuximab beta was associated with greater toxicity than dinutuximab beta alone. Dinutuximab beta and isotretinoin without subcutaneous IL-2 should thus be considered the standard of care until results of ongoing randomised trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available. FUNDING: European Commission 5th Frame Work Grant, St. Anna Kinderkrebsforschung, Fondation ARC pour la recherche sur le Cancer.

A polymer-coated, paclitaxel-eluting stent (Eluvia) versus a polymer-free, paclitaxel-coated stent (Zilver PTX) for endovascular femoropopliteal intervention (IMPERIAL): a randomised, non-inferiority trial.

BACKGROUND: The clinical effect of a drug-eluting stent in the femoropopliteal segment has not been investigated in a randomised trial with a contemporary comparator. The IMPERIAL study sought to compare the safety and efficacy of the polymer-coated, paclitaxel-eluting Eluvia stent with the polymer-free, paclitaxel-coated Zilver PTX stent for treatment of femoropopliteal artery segment lesions. METHODS: In this randomised, single-blind, non-inferiority study, patients with symptomatic lower-limb ischaemia manifesting as claudication (Rutherford category 2, 3, or 4) with atherosclerotic lesions in the native superficial femoral artery or proximal popliteal artery were enrolled at 65 centres in Austria, Belgium, Canada, Germany, Japan, New Zealand, and the USA. Patients were randomly assigned (2:1) with a site-specific, web-based randomisation schedule to receive treatment with Eluvia or Zilver PTX. All patients, site personnel, and investigators were masked to treatment assignment until all patients had completed 12 months of follow-up. The primary efficacy endpoint was primary patency (defined as a peak systolic velocity ratio ≤2·4, without clinically driven target lesion revascularisation or bypass of the target lesion) and the primary safety endpoint was major adverse events (ie, all causes of death through 1 month, major amputation of target limb through 12 months, and target lesion revascularisation through 12 months). We set a non-inferiority margin of -10% at 12 months. Primary non-inferiority analyses were done when the minimum sample size required for adequate statistical power had completed 12 months of follow-up. The primary safety non-inferiority analysis included all patients who had completed 12 months of follow-up or had a major adverse event through 12 months. This trial is registered with ClinicalTrials.gov, number NCT02574481. FINDINGS: Between Dec 2, 2015, and Feb 15, 2017, 465 patients were randomly assigned to Eluvia (n=309) or to Zilver PTX (n=156). Non-inferiority was shown for both efficacy and safety endpoints at 12 months: primary patency was 86·8% (231/266) in the Eluvia group and 81·5% (106/130) in the Zilver PTX group (difference 5·3% [one-sided lower bound of 95% CI -0·66]; p<0·0001). 259 (94·9%) of 273 patients in the Eluvia group and 121 (91·0%) of 133 patients in the Zilver PTX group had not had a major adverse event at 12 months (difference 3·9% [one-sided lower bound of 95% CI -0·46]; p<0.0001). No deaths were reported in either group. One patient in the Eluvia group had a major amputation and 13 patients in each group required target lesion revascularisation. INTERPRETATION: The Eluvia stent was non-inferior to the Zilver PTX stent in terms of primary patency and major adverse events at 12 months after treatment of patients for femoropopliteal peripheral artery disease. FUNDING: Boston Scientific.

Predicting bacterial infections among pediatric cancer patients with febrile neutropenia: External validation of the PICNICC model.

INTRODUCTION: The Predicting Infectious Complications in Neutropenic Children and Young People with Cancer (PICNICC) model was recently developed for antibiotic stewardship among pediatric cancer patients, but limited information is available about its clinical usefulness. We aimed to assess the performance of the PICNICC model for predicting microbiologically documented bacterial infections among pediatric cancer patients with febrile neutropenia. MATERIALS AND METHODS: We used data for febrile neutropenia episodes at a pediatric cancer center in Aarhus, Denmark between 2000 and 2016. We assessed the area under the receiver operating characteristic curve (AUC), calibration, and clinical usefulness (i.e., net benefit). We also recalibrated the model using statistical updating methods. RESULTS: We observed 306 microbiologically documented bacterial infections among 1,892 episodes of febrile neutropenia. The AUC of the model was 0.73 (95% confidence limits [CL]: 0.71-0.75). The calibration intercept (calibration-in-the-large) was -0.69 (95% CL: -0.86 to -0.51) and the slope was 0.77 (95% CL: 0.65-0.89). Modest net benefit was observed at a decision threshold of 5%. Recalibration improved calibration but did not improve net benefit. CONCLUSIONS: The PICNICC model has potential for reducing unnecessary antibiotic exposure for pediatric cancer patients with febrile neutropenia, but continued validation and refinement is necessary to optimize clinical usefulness.

Low-Dose Paclitaxel-Coated Versus Uncoated Percutaneous Transluminal Balloon Angioplasty for Femoropopliteal Peripheral Artery Disease: One-Year Results of the ILLUMENATE European Randomized Clinical Trial (Randomized Trial of a Novel Paclitaxel-Coated Percutaneous Angioplasty Balloon).

BACKGROUND: Numerous studies have reported favorable outcomes using drug-coated balloons (DCBs) for treatment of symptomatic peripheral artery disease of the superficial femoral and popliteal arteries. However, the treatment effect compared with an uncoated balloon has differed greatly among the randomized trials, with better outcomes observed with higher-dose DCBs. This European trial was designed to assess the safety and effectiveness of a next-generation low-dose (2-µg/mm2 surface dose of paclitaxel) DCB. METHODS: This was a prospective, randomized, multicenter, single-blinded trial. Patients were randomized (3:1) to treatment with a low-dose DCB or an uncoated percutaneous transluminal angioplasty (PTA) balloon. The primary safety end point was a composite of freedom from device- and procedure-related death through 30 days after the procedure and freedom from target limb major amputation and clinically driven target lesion revascularization through 12 months after the procedure. The primary effectiveness end point was primary patency at 12 months. RESULTS: Patients were randomized to treatment with a DCB (222 patients, 254 lesions) or uncoated PTA balloon (72 patients, 79 lesions) after successful predilatation. Mean lesion length was 7.2 and 7.1 cm, and 19.2% and 19.0% of lesions represented total occlusions, respectively. The primary safety end point was met, and superiority was demonstrated; freedom from a primary safety event was 94.1% (193 of 205) with DCB and 83.3% (50 of 60) with PTA, for a difference of 10.8% (95% confidence interval, 0.9%-23.0%). The primary effectiveness end point was met, and superiority of DCB over PTA was achieved (83.9% [188 of 224] versus 60.6% [40 of 66]; P<0.001). Outcomes with DCB were also superior to PTA per the Kaplan-Meier estimate for primary patency (89.0% versus 65.0% at 365 days; log-rank P<0.001) and for rates of clinically driven target lesion revascularization (5.9% versus 16.7%; P=0.014). CONCLUSIONS: Superiority with a low-dose DCB for femoropopliteal interventions was demonstrated over PTA for both the safety and effectiveness end points. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01858363.