Ellen Ruud

Low‐dose warfarin for the prevention of central line‐associated thromboses in children with malignancies—a randomized, controlled study

Background: Central venous lines (CVLs) are essential in the care of children with malignancies, but are associated with venous thromboembolism (VTE) and infections. Effective and safe prophylactic approaches are deficient. Aim: To perform a study of adjusted low‐dose warfarin for the prevention of CVL‐related VTE in children with malignancies. Methods: Children with newly diagnosed cancer, a CVL in a jugular vein and an expected treatment period of over 6 mo were eligible for the study. Participants were randomized to low‐dose warfarin, with intended international normalized ratio (INR) 1.3–1.9, or to a control group. Primary outcome was VTE in a jugular vein diagnosed by ultrasonography at 1, 3 and 6 mo after inclusion. Secondary outcome was CVL‐related infections, mainly measured as days on antibiotics or positive blood cultures. Results: The study enrolled 73 children, and 62 completed it fully. Asymptomatic CVL‐related VTE was frequent (42%), but often transient. Regardless of severity, timing and duration, CVL‐related VTE was equally frequent among children on warfarin as compared to controls (p=0.44). Low‐dose warfarin (p=0.59) or jugular CVL‐related VTE (p=0.91) did not have any impact on days on antibiotics, but we observed a tendency towards an association between CVL‐related VTE and positive blood cultures (p=0.15).

Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification.

PURPOSE On the assumption that most infants with disseminated neuroblastoma without MYCN amplification (MYCNA) have a favorable prognosis, two concomitant prospective trials were started in which chemotherapy was limited to patients presenting life- or organ-threatening symptoms or overt metastases to skeleton, lung, or CNS. Surgery was to be performed only in the absence of surgical risk factors. PATIENTS AND METHODS One hundred seventy infants with disseminated neuroblastoma without MYCNA, diagnosed between June 1999 and June 2004 in nine European countries were eligible for either of the two studies. Trial 99.2 included all stage 4S infants and those with stage 4 with a primary tumor infiltrating across the midline or positive skeletal scintigraphy who were to be observed in absence of symptoms. Trial 99.3 included infants with overt metastases to the skeleton, lung, and CNS to be treated with a minimum of four chemotherapy courses. RESULTS The 125 infants treated on trial 99.2 had a 2-year overall survival (OS) of 97.6% with no difference between asymptomatic and symptomatic patients (97.7% v 97.3%), patients without or with unresectable primary tumors (96.8% v 100%), and patients without or with positive skeletal scintigraphy without radiologic abnormalities (97.2% v 100%). The 45 infants treated on trial 99.3 had a 2-year OS of 95.6%. No patients died of surgery- or chemotherapy-related complications. CONCLUSION Infants with disseminated disease without MYCNA have excellent survival with minimal or no treatment. Asymptomatic infants with an unresectable primary tumor or positive skeletal scintigraphy without radiologic abnormalities may undergo observation alone.

Randomized trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: The European HR-NBL1/SIOPEN study

PURPOSE To reduce the incidence of febrile neutropenia during rapid COJEC (cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide given in a rapid delivery schedule) induction. In the High-Risk Neuroblastoma-1 (HR-NBL1) trial, the International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) randomly assigned patients to primary prophylactic (PP) versus symptom-triggered granulocyte colony-stimulating factor (GCSF; filgrastim). PATIENTS AND METHODS From May 2002 to November 2005, 239 patients in 16 countries were randomly assigned to receive or not receive PPGCSF. There were 144 boys with a median age of 3.1 years (range, 1 to 17 years) of whom 217 had International Neuroblastoma Staging System (INSS) stage 4 and 22 had stage 2 or 3 MYCN-amplified disease. The prophylactic arm received a single daily dose of 5 microg/kg GCSF, starting after each of the eight COJEC chemotherapy cycles and stopping 24 hours before the next cycle. Chemotherapy was administered every 10 days regardless of hematologic recovery, provided that infection was controlled. RESULTS The PPGCSF arm had significantly fewer febrile neutropenic episodes (P = .002), days with fever (P = .004), hospital days (P = .017), and antibiotic days (P = .001). Reported Common Toxicity Criteria (CTC) graded toxicity was also significantly reduced: infections per cycle (P = .002), fever (P < .001), severe leucopenia (P < .001), neutropenia (P < .001), mucositis (P = .002), nausea/vomiting (P = .045), and constipation (P = .008). Severe weight loss was reduced significantly by 50% (P = .013). Protocol compliance with the rapid induction schedule was also significantly better in the PPGCSF arm shown by shorter time to completion (P = .005). PPGCSF did not adversely affect response rates or success of peripheral-blood stem-cell harvest. CONCLUSION Following these results, PPG-GSF was advised for all patients on rapid COJEC induction.

Gonadal function and parenthood 20 years after treatment for childhood lymphoma: A cross-sectional study†

Gonadal function decades after treatment for childhood lymphoma (CL) is not well described. This cross‐sectional study had two aims: (1) describe long‐term gonadal function and fertility in childhood lymphoma survivors (CLSs), and (2) explore anti‐Mullerian hormone (AMH) as a measure of ovarian function in CLSs.

Activation of cAMP signaling inhibits DNA damage-induced apoptosis in BCP-ALL cells through abrogation of p53 accumulation

In lymphocytes, the second messenger cyclic adenosine monophosphate (cAMP) plays a well-established antiproliferative role through inhibition of G(1)/S transition and S-phase progression. We have previously demonstrated that, during S-phase arrest, cAMP inhibits the action of S phase-specific cytotoxic compounds, leading to reduction in their apoptotic response. In this report, we provide evidence that cAMP can also inhibit the action of DNA-damaging agents independently of its effect on S phase. Elevation of cAMP in B-cell precursor acute lymphoblastic leukemia cells is shown to profoundly inhibit the apoptotic response to ionizing radiation, anthracyclins, alkylating agents, and platinum compounds. We further demonstrate that this effect depends on the ability of elevated cAMP levels to quench DNA damage-induced p53 accumulation by increasing the p53 turnover, resulting in attenuated Puma and Bax induction, mitochondrial outer membrane depolarization, caspase activation, and poly(ADP-ribose) polymerase cleavage. On the basis of our findings, we suggest that cAMP levels may influence p53 function in malignant cells that retain wild-type p53, potentially affecting p53 both as a tumor suppressor during cancer initiation and maintenance, and as an effector of the apoptotic response to DNA-damaging agents during anticancer treatment.

Reduced Neuroanatomic Volumes in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia

PURPOSE To compare regional brain volumes in adult long-term survivors of childhood acute lymphoblastic leukemia (ALL) and healthy controls. PATIENTS AND METHODS We investigated 130 survivors of childhood ALL diagnosed between 1970 and 2002 with magnetic resonance imaging (MRI) and neuropsychological testing at a median of 22.5 years after diagnosis. Morphometric analyses including whole-brain segmentation were performed using a validated automated procedure; 130 healthy adults served as controls. RESULTS Compared with healthy controls, ALL survivors showed significantly smaller volumes of cortical gray matter, cerebral white matter, amygdala, caudate, hippocampus, thalamus, and estimated intracranial volume. Effect sizes ranged from small to medium. The strongest effect was found for the caudate, which on average was 5.2% smaller in ALL survivors. Caudate volumes were also smaller when controlling for intracranial volume, suggesting a specific effect. Neither age at diagnosis nor treatment variables such as radiation therapy or drug dose had a major impact on neuroanatomic volumes. Neuropsychological assessment revealed reduced processing speed, executive function, and verbal learning/memory in survivors compared with controls but no difference in estimated general intellectual ability. In ALL survivors, but not in controls, neuropsychological test results correlated with volumes of cortical gray matter, caudate, and thalamus as well as intracranial volume. CONCLUSION Structural MRI of long-term survivors of childhood ALL demonstrated smaller volumes of multiple brain structures compared with healthy controls. Because of possible selection biases, these results must be interpreted with caution. Future studies are required to clarify the significance of these findings and the neurobiologic mechanisms involved.

Factors associated with poor quality of life in survivors of childhood acute lymphoblastic leukemia and lymphoma

Previous studies of health‐related quality of life (QoL) in childhood cancer survivors have hardly focused on factors associated with poor QoL. The aims of our study were: (1) to assess QoL in long‐term survivors (LTSs) of childhood acute lymphoblastic leukemia (ALL) and lymphomas compared to age‐matched controls from the general population (NORMs). (2) To investigate factors associated with poor QoL in LTSs.

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.

Central line-associated venous late effects in children without prior history of thrombosis

Background: The frequency of asymptomatic central line‐associated thromboses is high and well recognized among children with cancer, while the long‐term consequences are mainly unknown. Aim: In a cross‐sectional study, we evaluated clinical and radiological venous outcome in children with previous long‐standing intravascular catheters. Methods: The study enrolled 71 children previously treated for malignant or haematological diseases, 4–180 (median 37) mo after removal of their central lines. Inclusion criteria were a prior central line in a jugular vein for a minimum of 6 mo and no previous history of thrombosis. The children had clinical examination for post‐thrombotic syndrome (PTS) and Doppler ultrasonography of the central neck veins. Twelve children had additional venous magnetic resonance imaging (MRI). But no kind of venography was performed in the remaining. Results: We observed mild PTS with increased superficial collaterals in four children (6%), but no cases of more severe PTS. None complained of symptoms related to venous late effects. By ultrasonography, post‐thrombotic venous alterations were detected in 17 children (24%), and five of these had complete occlusion of the veins. The sensitivity for pathologically increased collaterals to identify occlusive thrombosis was 0.6, while the specificity was 0.98. Occlusive venous thromboembolism was associated with the total number of central venous lines (CVLs; p=0.002), previous severe CVL‐associated infections (p=0.001) and duration of central line in place (p=0.042).

Diagnostic value of family histories of thrombosis to identify children with thrombophilia.

Thrombophilia screening is a time-consuming and expensive procedure. Information about thromboembolism among relatives may be a simple method to identify those at risk of having thrombophilia. In a cross-sectional clinical study the authors have investigated the role of such family histories to detect children with thrombophilia. In 202 children a family history of venous or arterial thromboembolism was recorded. The participants were either children with congenital heart defects at the time of a scheduled cardiac catheterization (n = 134) or children with newly diagnosed cancer (n = 68). Questions were answered, on the spot, by the parents, at the same time as blood samples for thrombophilia screening were taken. Questions about family history of thromboembolism were completed in 184 children, of whom 114 children (62%) were positive, and 35 of these had relatives with venous thromboembolic events. Only one child had an affected first-degree relative. Thrombophilic alterations were observed in 60 children (30%), and 25 of these were defined as inherited. A positive family history of venous origin increased the relative risk of a child having inherited thrombophilia to 2.35 (95% confidence interval 1.1–5.2). Information about familial arterial thromboembolism was not useful in spotting children with prothrombotic risk factors. These results indicate that questioning about family history of venous thromboembolism may identify children with genetic thrombophilia, but the association is not strong. The authors encourage similar larger-scale studies to enlighten the issue fully.