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.

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.

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 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.

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.

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.

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.

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.

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.

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.

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.

Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial.

BACKGROUND: High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, and melphalan. METHODS: We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma at 128 institutions in 18 countries that included an open-label randomised arm in which high-dose chemotherapy regimens were compared. Patients (age 1-20 years) with neuroblastoma were eligible to be randomly assigned if they had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate disease response. Patients were randomly assigned (1:1) to busulfan and melphalan or to carboplatin, etoposide, and melphalan by minimisation, balancing age at diagnosis, stage, MYCN amplification, and national cooperative clinical group between groups. The busulfan and melphalan regimen comprised oral busulfan (150 mg/m2 given on 4 days consecutively in four equal doses); after Nov 8, 2007, intravenous busulfan was given (0·8-1·2 mg/kg per dose for 16 doses according to patient weight). After 24 h, an intravenous melphalan dose (140 mg/m2) was given. Doses of busulfan and melphalan were modified according to bodyweight. The carboplatin, etoposide, and melphalan regimen consisted of carboplatin continuous infusion of area under the plasma concentration-time curve 4·1 mg/mL per min per day for 4 days, etoposide continuous infusion of 338 mg/m2 per day for 4 days, and melphalan 70 mg/m2 per day for 3 days, with doses for all three drugs modified according to bodyweight and glomerular filtration rate. Stem-cell rescue was given after the last dose of high-dose chemotherapy, at least 24 h after melphalan in patients who received busulfan and melphalan and at least 72 h after carboplatin etoposide, and melphalan. All patients received subsequent local radiotherapy to the primary tumour site followed by maintenance therapy. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17. FINDINGS: Between June 24, 2002, and Oct 8, 2010, 1347 patients were enrolled and 676 were eligible for random allocation, 598 (88%) of whom were randomly assigned: 296 to busulfan and melphalan and 302 to carboplatin, etoposide, and melphalan. Median follow-up was 7·2 years (IQR 5·3-9·2). At 3 years, 146 of 296 patients in the busulfan and melphalan group and 188 of 302 in the carboplatin, etoposide, and melphalan group had an event; 3-year event-free survival was 50% (95% CI 45-56) versus 38% (32-43; p=0·0005). Nine patients in the busulfan and melphalan group and 11 in the carboplatin, etoposide, and melphalan group had died without relapse by 5 years. Severe life-threatening toxicities occurred in 13 (4%) patients who received busulfan and melphalan and 29 (10%) who received carboplatin, etoposide, and melphalan. The most frequent grade 3-4 adverse events were general condition (74 [26%] of 281 in the busulfan and melphalan group vs 103 [38%] of 270 in the carboplatin, etoposide, and melphalan group), infection (55 [19%] of 283 vs 74 [27%] of 271), and stomatitis (138 [49%] of 284 vs 162 [59%] of 273); 60 (22%) of 267 patients in the busulfan and melphalan group had Bearman grades 1-3 veno-occlusive disease versus 21 (9%) of 239 in the carboplatin, etoposide, and melphalan group. INTERPRETATION: Busulfan and melphalan improved event-free survival in children with high-risk neuroblastoma with an adequate response to induction treatment and caused fewer severe adverse events than did carboplatin, etoposide, and melphalan. Busulfan and melphalan should thus be considered standard high-dose chemotherapy and ongoing randomised studies will continue to aim to optimise treatment for high-risk neuroblastoma. FUNDING: European Commission 5th Framework Grant and the St Anna Kinderkrebsforschung.

Epidemiological study of paediatric germ cell tumours revealed the incidence and distribution that was expected, but a low mortality rate.

AIM: Germ cell tumours (GCTs) are a rare heterogeneous tumour group derived from primordial germ cells, which can be benign or malignant and occur in the gonads or extragonadally. This study mapped the paediatric GCTs in Denmark from 1984 to 2013 to study the incidence and outcome. METHODS: We identified paediatric GCTs from the Danish Childhood Cancer and National Pathology Registries and reviewed the case records for patient characteristics, tumour characteristics and clinical outcome. RESULTS: We identified 403 (71% female) paediatric GCTs and the crude incidence was 1.43 per 100 000. Of these, 79 (20%) were malignant, 39 (10%) were potentially malignant and 285 (70%) were benign. Extragonadal GCTs (39%) were mainly observed in early childhood and were predominately sacrococcygeal teratomas. Gonadal GCTs (61%) in late childhood were most frequently mature teratomas in the ovaries. Nearly all patients underwent surgery. Of the malignant tumours, 62% were treated with chemotherapy. Radiotherapy was only administered to intracranial GCTs. In the cohort, 12 patients died (3%). CONCLUSION: Paediatric GCTs in Denmark were mainly benign and mortality was low, even for malignant tumours. We identified a peak of extragonadal GCTs in early childhood and a peak of gonadal GCTs in late childhood, which was comparable to previous reports.

Maintenance therapy of childhood acute lymphoblastic leukemia revisited-Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?

BACKGROUND: 6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines. PROCEDURE: To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5-3.5 × 109 /l. RESULTS: After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 109 /l rise [1.00-1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 109 /l rise [1.3-2.4], P = 0.0007), and Ery thiopurine methyltransferase activity (HR = 2.7 per IU/ml rise [1.1-6.7], P = 0.03). WBC was significantly related to ANC (Spearman correlation coefficient, rs  = 0.77; P < 0.001), and only a borderline significant risk factor for relapse (HR = 1.28 [95% CI: 1.00-1.64], P = 0.046) when ANC was excluded from the Cox model. CONCLUSIONS: This study indicates that a low neutrophil count is likely to be the best hematological target for dose adjustments of maintenance therapy.

Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: outcomes from the ILLUMENATE first-in-human study.

OBJECTIVES: To assess the safety and effectiveness of the Stellarex™ drug-coated angioplasty balloon (DCB) to inhibit restenosis in the superficial femoral and/or popliteal artery. BACKGROUND: Treatment of peripheral arterial disease is challenged by restenosis, requiring revascularization procedures to maintain patency. DCBs are designed to deliver an anti-proliferative drug to the vessel wall to diminish smooth muscle cell proliferation and maintain patency. METHODS: This prospective, single-arm, multicenter study enrolled 50 patients with 58 lesions in the first cohort that required pre-dilatation with an uncoated angioplasty balloon prior to inflation of the DCB. The primary effectiveness endpoint was 6-month late lumen loss (LLL). The major secondary endpoint was major adverse event (MAE) rate at 6 months, defined as cardiovascular death, amputation, and/or ischemia-driven target lesion revascularization. RESULTS: The mean lesion length was 7.2 cm and baseline stenosis was 75.1%. Calcification was present in 62.1% of lesions and 12.1% were occluded. Both endpoints met their prespecified performance goals; at 6 months, the MAE rate was 4% and the mean LLL was 0.54 mm. The primary patency rate was 89.5% at 12 months and 80.3% at 24 months. The freedom from clinically-driven target lesion revascularization rate, per Kaplan-Meier estimate, was 90.0% at 12 months and 85.8% at 24 months. Additionally, there were no amputations or cardiovascular deaths reported through 24 months. CONCLUSIONS: The Stellarex DCB provides safe and durable clinical outcomes for treatment of femoropopliteal artery disease through 24 months.

Extended duration of prehydration does not prevent nephrotoxicity or delayed drug elimination in high-dose methotrexate infusions: a prospectively randomized cross-over study.

BACKGROUND: Alkalized hydration is used as supportive care to prevent renal toxicity during infusions with high-dose methotrexate (HDMTX). In children with acute lymphoblastic leukemia (ALL), the hydration is commonly initiated 4 hours before start of the methotrexate (MTX) infusion. To test if longer duration of prehydration would prevent MTX-induced renal toxicity, we preformed a randomized cross-over study comparing 12-4 hours of hydration before the infusion of HDMTX. PROCEDURES: Children with ALL and non-Hodgkin lymphoma that were treated with infusions of HDMTX 5 or 8 g/m(2) were randomized to receive intravenous prehydration 12 or 4 hours before the first HDMTX infusion. Patients alternated between 12 and 4 hours of prehydration in the subsequent HDMTX infusions. Renal toxicity was defined as 50% increase in plasma creatinine after the HDMTX infusion. The plasma MTX concentration was measured during and after the HDMTX infusion to determine if the duration of prehydration would influence the systemic MTX clearance. RESULTS: A total of 47 patients (224 HDMTX infusions) with a median age of 4.9 years were included in the study. The duration of prehydration had no effect on MTX induced renal toxicity that occurred in 18.5% of all HDMTX 5 g/m(2) infusions and in 40.0% of all HDMTX 8 g/m(2) infusions. Similar the duration of prehydration had no impact on the systemic clearance of MTX. CONCLUSION: Extending prehydration beyond 4 hours does not reduce the risk of renal toxicity or delayed MTX clearance after infusions with HDMTX 5-8 g/m(2).

The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number.

The reduced folate carrier (RFC) is involved in the transport of methotrexate (MTX) across the cell membrane. The RFC gene (SLC19A1) is located on chromosome 21, and we hypothesized that the RFC80 G>A polymorphism would affect outcome and toxicity in childhood leukemia and that this could interact with chromosome 21 copy number in the leukemic clone. A total of 500 children with acute lymphoblastic leukemia treated according to the common Nordic treatment protocols were included, and we found that the RFC AA variant was associated with a 50% better chance of staying in remission compared with GG or GA variants (P = .046). Increased copy numbers of chromosome 21 appear to improve outcome also in children with GA or GG variant. In a subset of 182 children receiving 608 high-dose MTX courses, we observed higher degree of bone marrow toxicity in patients with the RFC AA variant compared with GA/GG variants (platelet 73 vs 99/105 x 10(9)/L, P = .004, hemoglobin 5.6 vs 5.9/6.0 mmol/L, P = .004) and a higher degree of liver toxicity in patients with RFC GG variant (alanine aminotransferase 167 vs 127/124 U/L, P = .05). In conclusion, the RFC 80G>A polymorphism interacts with chromosome 21 copy numbers and affects both efficacy and toxicity of MTX.

Palonosetron for the prevention of nausea and vomiting in children with acute lymphoblastic leukemia treated with high dose methotrexate.

BACKGROUND: High dose methotrexate (HD-MTX), used in the treatment of children with acute lymphoblastic leukemia (ALL), is moderately emetogenic. First generation 5-HT(3) receptor antagonists are effective prophylactic agents but require multiple administrations. Palonosetron has a half life of 36-42 hours and has higher affinity and selectivity to the 5-HT(3) receptor. Adult studies have demonstrated that palonosetron is both more effective and require fewer administrations than first generation 5-HT(3) receptor antagonists. The purpose of this study was to examine the effect of a single dose of palonosetron (5 µg/kg) for the prevention of chemotherapy-induced nausea and vomiting in children 18 years of age with ALL treated with HD-MTX, 5 g/m(2). PROCEDURE: Between January 2010 and December 2010, 138 courses, originating from 53 children, were included from four Danish Childhood Cancer Centers. Information regarding emetic episodes, rescue therapy, and nausea were recorded prospectively on questionnaires. RESULTS: Complete response (no emesis and no rescue therapy) was achieved in 84.1% of courses during the acute (0-24 hours post-chemotherapy) and in 60.1% during the delayed phase (24-66 hours post-chemotherapy). 92.0% of courses were free of emesis during the acute, and 86.2% were free of emesis during the delayed phase. 76.8% of courses were free of nausea during the acute, and 78.3% were free of nausea during the delayed phase. CONCLUSIONS: A single dose of palonosetron--without concomitant corticosteroid--was effective in preventing both acute and delayed phase CINV in majority of children with ALL treated with HD-MTX.