Renal toxicity of ifosfamide in children with cancer: an exploratory study integrating aldehyde dehydrogenase enzymatic activity data and a wide-array urinary metabolomics approach.

BACKGROUND: Ifosfamide is a major anti-cancer drug in children with well-known renal toxicity. Understanding the mechanisms underlying this toxicity could help identify children at increased risk of toxicity. METHODS: The IFOS01 study included children undergoing ifosfamide-based chemotherapy for Ewing sarcoma or rhabdomyosarcoma. A fully evaluation of renal function was performed during and after chemotherapy. Proton nuclear magnetic resonance (NMR) and conventional biochemistry were used to detect early signs of ifosfamide-induced tubulopathy. The enzymatic activity of aldehyde dehydrogenase (ALDH) was measured in the peripheral blood lymphocytes as a marker of ifosfamide-derived chloroacetaldehyde detoxification capacity. Plasma and urine concentrations of ifosfamide and dechloroethylated metabolites were quantified. RESULTS: The 15 participants received a median total ifosfamide dose of 59 g/m2 (range: 24-102), given over a median of 7 cycles (range: 4-14). All children had acute proximal tubular toxicity during chemotherapy that was reversible post-cycle, seen with both conventional assays and NMR. After a median follow-up of 31 months, 8/13 children presented overall chronic toxicity among which 7 had decreased glomerular filtration rate. ALDH enzymatic activity showed high inter- and intra-individual variations across cycles, though overall activity looked lower in children who subsequently developed chronic nephrotoxicity. Concentrations of ifosfamide and metabolites were similar in all children. CONCLUSIONS: Acute renal toxicity was frequent during chemotherapy and did not allow identification of children at risk for long-term toxicity. A role of ALDH in late renal dysfunction is possible so further exploration of its enzymatic activity and polymorphism should be encouraged to improve the understanding of ifosfamide-induced nephrotoxicity.

Pediatric palliative care at home by Home Care Unit: how home nurses feel?

PURPOSE: Our Home Care Unit (HCU) undertakes close to twenty pediatric palliative care engagements per year. We investigated the factors underlying such care by independent home health nurses. METHODS: This was a retrospective, observational, single-center study. Home nurses who had provided palliative pediatric care in the past 16 months were included. RESULTS: Fifty-six questionnaires were sent out (response rate of 44.6%). Eight home nurses had never provided pediatric palliative care. Three-quarters of the home nurses (76%) acknowledged having misgivings accepting these duties. The factors that facilitated providing this care were the availability of the HCU doctor and nurses, the proactiveness of the HCU team, and house calls. In 76% of cases, the involvement of the home nurses exceeded the strictly professional setting. Forty-six percent of the home nurses were amenable to undertaking another pediatric palliative care engagement, although 48% deemed the remuneration to be somewhat lacking. CONCLUSION: The analysis allowed us to identify several prerequisites for these care engagements: the availability and the proactiveness of the HCU team, communication, and planning. This study showed the pronounced personal involvement of home nurses in complex situations, with both the child and their entire family. Home nurses appear to be skilled at using the resources available to manage the exhaustion that can arise with such an engagement. Facilitating and respecting the choice to stay home of the child and their family was meaningful to them. The personal and professional enrichment were a source of motivation despite certain limitations (availability, remuneration).

[Palliative care for children in onco-hematology: Role of a specific home-care team]. / Soins palliatifs pédiatriques et fin de vie d'enfants suivis en onco-hématologie : place de l'hospitalisation à domicile.

BACKGROUND/OBJECTIVE: Our home-care unit (HCU) is specialized for pediatric cancer patients and has a strong palliative care activity. We believe that the introduction of home-care services can influence the place of palliative care and of death as well as the length of hospitalization. We aimed at describing characteristics and care course of patients treated in our HCU, and tried to identify some factors contributing to home care at the end of life. DESIGN/METHODS: We conducted a retrospective, observational, monocentric study about patients in pediatric onco-hematology, treated at least one day in our home-care unit, who died between July 1st 2013 and December 31st 2015. Statistical analysis was descriptive and analytic. RESULTS: A total of 74 patients known by our HCU died during study period. Eight were excluded. Forty-three out of 66 patients died at home. During the last 3 months of life, oncology patients have significantly less classical hospitalization, when compared to hematology patients. The implication of general physicians (GP) and nurses and information given to the family increase the possibility for home death. No significant association was found between ages at death, distance between home and hospital, other life conditions and place of death. CONCLUSIONS: Our HCU has a strong palliative care activity and a high rate of children dying at home. Good collaborations between our pediatric onco-hematology team and our HCU as well as between our HCU and caregivers optimize palliative care.

[Intravenous chemotherapy at home: A pediatric monocentric experience]. / Chimiothérapie intraveineuse à domicile en cancérologie pédiatrique : une expérience monocentrique.

INTRODUCTION: Our home care unit (HCU) developed the administration of IV chemotherapy at home for some pediatric oncologic patients. METHODS: We conducted a retrospective monocentric analysis, leading to identify patients with at least one sequence of chemotherapy at home in 2015. RESULTS: Two hundred and forty four sequences of home chemotherapy have been administered in 2015. We identified two situations for home IV chemotherapy. Pediatric oncologist of day hospital prescribes the sequence. The chemotherapy is delivered at hospital for the first day. HCU takes over for the next days at home. For a sequence replacing a conventional hospitalization, the attending physician examines the patient, and confirm the clinical validation. The pediatric oncologist of HCU checks lab exams, and prescribes the chemotherapy. For both situations, IV chemotherapy is prepared by our hospital pharmacy, delivers at home or at day hospital, and HCU team manages home material and organizes hospitalization. CONCLUSIONS: This kind of organization allows setting up home IV CT for more and more patients. It allows to limit daily hospitalization for some patients living far from the hospital, and whose therapies lead to several hospitalizations.

Assessment of informal caregiver's needs by self-administered instruments: a literature review.

Background: Clinicians, researchers and politicians are seeking to better assess caregiver's needs. Challenges exist in broadly implementing this so as to provide appropriate support. The aim of this review was to compile self-administered instruments for assessment of caregiver's needs that are deemed to be scientifically robust. Methods: The Medline database was searched for publications reporting self-administered instruments assessing caregiver's needs with acceptable psychometric properties. These instruments were analyzed in terms of the development context, target population, concept, purpose, structure, content and psychometric properties. The dimensions of the needs were listed and categorized. Results: A total of nine self-administered instruments were analyzed. They averaged 32 items, they were specifically developed for a targeted subpopulation of caregivers and dedicated to epidemiological research. Response devices were based on Likert scales. The main dimensions of the needs identified were 'Health and Care', 'Psychological - Emotional Support', 'Information-Knowledge', 'Social Life-Work-Finance'. None was specifically geared toward caregivers for the elderly, children or teenagers. In the absence of transcultural validation, no instrument was directly usable in Europe. Conclusions: Assessing caregivers' needs is a key part in providing caregivers with appropriate support. The development of self-administered instruments constitutes a complex field that is still underexplored at the international level; strict specifications with psychometric validation are essential. To be efficient, the instrument should be integrated in a larger process including: upstream, recognition, identification and assessment of the overall situation of the caregiver; and downstream, guidance, establishment and follow-up of a suitable action plan.

[The "do-not-resuscitate order" in paediatric palliative home care: why should the emergency team be involved ?]. / L'anticipation de la non-réanimation en soins palliatifs pédiatrique à domicile : le Samu comme partenaire de soins ?

Major challenge in paediatric palliative home care is to anticipate management of future events. In our opinion, one of major approach is to avoid medical futility especially resuscitation attempts in terminally-ill children especially if home care will be organized. We therefore prospectively discussed with proxi what should be attempted (e.g. treat symptoms of pain or discomfort) and what should be avoided for the sake of the child. A crucial part of the discussion included anticipating non resuscitation of the terminally-ill child. We informed in writing local emergency unit coordinator on results of the discussion with care takers and suggested a procedure in case of an emergency call. To include the local emergency unit is now a standard in our paediatric oncology department since two situations may occur: 1) Parental panic while facing difficult terminal symptoms. We recommend that the local emergency unit coordinator dispatches an emergency team to the child's home in order to manage symptoms (seizures, pain, etc.) but avoid any futile resuscitation attempt. Parental decision to maintain the child at home should be re-evaluated regularly. 2) Parents who wish to stay at home as long as possible, refusing home-based death of their terminally-ill child. We recommend that the family doctor decides whether or not to refer the child to the hospital. Emergency team may be called upon based on the child's status and need for medicalised transport. Even if it should be rather rare that parents contact directly the emergency unit and not as usually the home care coordinator, such situation may occur and should be anticipated. Therefore, the anticipation of non-resuscitation recommendations is a key approach in paediatric palliative home care. This complex discussion should not be avoided as parental/medical panic may induce unrealistic requests for futile medical procedures.

A positioning pillow to improve lumbar puncture success rate in paediatric haematology-oncology patients: a randomized controlled trial.

BACKGROUND: Lumbar punctures (LPs) are common in children with cancer. Although pain management during the lumbar puncture has been well standardized, dealing with stress and anxiety is not well addressed yet. Our objective was to evaluate the potential improvement of the LP success rate using a positioning pillow, to ensure maximum lumbar flexion, and allow paravertebral muscles to relax, in children who are awake, with either conscious sedation or no sedation. METHODS: Children aged 2-18 years undergoing LP were randomly assigned to a positioning pillow or no intervention. The primary outcome was the rate of success, i.e. achieving the LP (sampling or injection) at the first attempt, without bleeding (RBC < 50/mm3). The secondary outcomes included: the child's pain, assessed by a self-administered visual analogical scales (VAS) for children over 6 years of age; the parents' and caregivers' perception of the child's pain; the satisfaction of the children, the parents, the caregivers and the physician. The child's cooperation and the occurrence of post-LP syndrome were also evaluated. RESULTS: 124 children (62 in each group) were included. The LP pillow tended to increase the success rate of LPs (67% vs. 57%, p = 0.23), and decreased the post-LP syndromes (15% vs. 24%, p = 0.17) but the differences were not statistically significant. In children over 6-year of age (n = 72), the rate of success was significantly higher in the pillow group (58.5% vs. 41.5%, p = 0.031), with a tendency to feel less pain (median VAS 25 vs. 15 mm, p = 0.39) and being more satisfied (84.4% vs. 75.0%, p = 0.34). CONCLUSION: Overall results do not demonstrate a benefit in using this pillow for lumbar punctures. This study results also suggest a benefit in the sub group of children over 6-year of age; this result needs confirmation.

A phase II study of irinotecan in children with relapsed or refractory neuroblastoma: a European cooperation of the Société Française d'Oncologie Pédiatrique (SFOP) and the United Kingdom Children Cancer Study Group (UKCCSG).

PURPOSE: To evaluate the efficacy and safety of irinotecan in paediatric recurrent or refractory neuroblastoma. PATIENTS AND METHODS: Thirty seven patients aged between 6 months and < or = 20 years, with relapsed or refractory neuroblastoma, received irinotecan at 600 mg/m(2) administered as a 60-min infusion, every 3 weeks. Tumour response was evaluated by conventional radiological and mIBG scans every two cycles. RESULTS: No objective response was observed during the study. Stable disease was observed in 13% of evaluable patients. Median times to progression and survival were 1.4 months (range, 1.2-1.5 months) and 8.8 months (range, 6.7-11.3 months), respectively. One forty two cycles were administered, with a median of two cycles per patient (range, 1-17 cycles). The most common grade 3-4 toxicities were neutropenia (65% of patients), anaemia (43%), thrombocytopenia (38%), vomiting (14%), abdominal pain or cramping (8%), and nausea (5%). CONCLUSION: Irinotecan administered intravenously as a single agent every 3 weeks induced no objective response in relapsed or refractory neuroblastoma.

Preradiation chemotherapy may improve survival in pediatric diffuse intrinsic brainstem gliomas: final results of BSG 98 prospective trial.

Radiation therapy remains the only treatment that provides clinical benefit to children with diffuse brainstem tumors. Their median survival, however, rarely exceeds 9 months. The authors report a prospective trial of frontline chemotherapy aimed at delaying radiation until time of clinical progression. The aim was to investigate the possibility that radiotherapy would maintain its activity in children whose disease progressed after chemotherapy. Twenty-three patients took part in this protocol, the BSG 98 protocol, which consisted of frontline chemotherapy alternating hematotoxic and nonhematotoxic schedules. Each cycle included three courses delivered monthly; the first course was 1,3-bis(2-chloroethyl)-1-nitrosoureacisplatin, and the second and third were high-dose methotrexate. Three patients underwent one cycle; 5 patients each, two and three cycles; and 10 patients, four cycles. Twenty of the 23 patients eventually received local radiation therapy. A historical cohort of 14 patients who received at least local radiation therapy served as controls. Four patients experienced severe iatrogenic infections, and 11 patients required platelet transfusions. Median survival increased significantly in patients participating in the protocol compared to that in the historical controls (17 months, 95% confidence interval [CI], 10-23 months, vs. 9 months, 95% CI, 8-10 months; p = 0.022), though hospitalization was prolonged (57 vs. 25 days, p = 0.001). Although frontline chemotherapy alternating hematotoxic and nonhematotoxic schedules significantly increases overall median survival, its cost from infection and hospitalization deserves honest discussion with the children and their parents.

Osteosarcoma metastatic to the kidney and iatrogenic hemorrhage.

A 16-year old female presented painful masses in the lumbar region 5 years after the initial diagnosis of a localized osteosarcoma of the tibia. Abdominal X-ray revealed calcified masses. A bone scan confirmed an increased uptake in the renal areas. An ultrasound-guided fine needle biopsy confirmed the diagnosis of metastases. The procedure was complicated by subcapsular hemorrhage and gross hematuria. Renal metastases from osteosarcoma are usually asymptomatic and invisible on abdominal X-rays. The diagnosis is generally established by radionuclide bone scan or abdominal CT-scan. Our observation suggests that histological documentation of these unusual clinical presentations should be carefully weighed against the risk of the procedure.

[Specificities in the therapeutic management of children with cancer]. / Particularités thérapeutiques des cancers de l'enfant.

Treatment and supportive care of children with cancer differ significantly from that of adult oncology with specificities of the initial diagnostic talk, of the therapeutic strategies at diagnosis, relapse or during palliative care, as well as the particularities of chemotherapy administration, surgical procedures and radiation therapy in paediatric oncology.

[An interactive and evolutive software program to personalize treatment schedule : implication on daily life: the Centre Léon Bérard experience]. / Approche informatisée évolutive et interactive du programme personnalisé de soin: une expérience du centre Léon-Bérard.

The second plan against cancer, initiated by the French President in 2003, has introduced a two-step procedure to announce cancer to the patient. During initial visit, the doctor tells the patient about his disease. On the second visit, the doctor elaborates the treatment strategy and proposes an individualized treatment plan for each patient. The objective of this plan is to offer to patients and caregivers an accurate, precise and personalized treatment schedule. The Centre Léon Bérard (Regional Cancer Center) has implemented a computerized model to manage all different treatment schedules. We developed a software program based on two different steps. Firstly, standard treatment schedules are programmed for each type of disease. To offer a better view of the influence of treatment on daily life, we added information such as place of treatment (ambulatory, inpatient, outpatient) impact on well being (side effects, risk of aplasia...), future evaluations and medical acts (CT scan, MRI, lumbar puncture...) as well as actions the patient should take (blood cell count, to have eaten nothing...). Secondly, it tailors these standard treatments as well as all complementary information's to the specific needs of each patient, based on the medical information available in their computerized records. This personalized plan may be modified and adjusted at any time including therefore more and more real details and insights for each patient (delay of chemotherapy, dates of CT scan....). This would help patients and caregivers to better understand the different phases of the treatment and, thus, improve patient follow-up and information at every step of patient management. This tool is currently being tested at the Centre Léon Bérard.

[Immunotherapy of poor-prognosis neuroblastoma in children: from bench to bedside]. / Immunothérapie des neuroblastomes de mauvais pronostic chez l'enfant: depuis les concepts fondamentaux jusqu'aux essais cliniques de phase I-II.

During the last two decades, improvements in the induction and consolidation treatment phases in patients with high-risk neuroblastoma have not translated into significant increases in survival rates. Efforts to improve outcome have used high-dose chemotherapy with stem cell rescue and more recently, differentiating (retinoids) and antiangiogenic agents. In parallel, immunotherapy has become an increasingly important part of the treatment of high-risk neuroblastoma. We review here the biological concepts underlying these new approaches and their clinical applications, with a particular emphasis on applications that manipulate the immune system, including monoclonal antibodies, gene-modified tumor cells (vaccines) or immune effectors.

Risk model predictive of severe anemia requiring RBC transfusion after chemotherapy in pediatric solid tumor patients.

PURPOSE: Severe anemias requiring RBC transfusions is a frequent complication of chemotherapy. A model elaborated by Ray-Coquard et al in adults pointed to three independent risk factors for RBC transfusion: performance status (PS) more than 1, hemoglobin less than 12 g/dL, and prechemotherapy absolute lymphocyte count (ALC) < or = 700/microL. This model is tested on a pediatric population. PATIENTS AND METHODS: One hundred nineteen children with solid tumors consecutively admitted for conventional chemotherapy throughout 1 year were included. The study end point was the RBC-transfusion risk in the month following chemotherapy. Only one course was considered for each patient. Age, sex, number of courses, platinum-containing regimens, PS, and hemoglobin and lymphocyte count at day 1 were tested in univariate and multivariate analyses. RESULTS: Thirty-one (26%) of 119 children required RBC transfusion within 31 days of chemotherapy. Three factors correlated to transfusion risk in the univariate analysis: PS more than 1 (P <.001), hemoglobin less than 12 g/dL (P =.007), and pretreatment ALC < or = 700/microL (P <.001). In the multivariate analysis, hemoglobin less than 12 g/dL, PS more than 1, and ALC < or = 700/microL were identified as independent factors predicting RBC transfusion. The calculated probability of receiving RBC transfusion within 31 days of chemotherapy was high with three risk factors (96%), intermediate with two risk factors (53% to 77%), low with one risk factor (10% to 26%), and very low when no risk factor was present (2%). The difference of transfusion needs was significant (P <.001). CONCLUSION: The risk model elaborated for adults may also segregate children at high risk of postchemotherapy RBC transfusion, thus facilitating assessment of risk of transfusion and/or prophylactic erythropoietin support.

Circulating MYCN DNA as a tumor-specific marker in neuroblastoma patients.

MYCN oncogene amplification is an established indicator of the aggressiveness of neuroblastomas; it is used internationally for stratifying patients for therapy. The present study shows that high levels of MYCN DNA sequences are present in the peripheral blood of patients with MYCN-amplified neuroblastomas. Circulating MYCN DNA may be a powerful and noninvasive prognostic marker at the time of diagnosis. Furthermore, preliminary data strongly suggest that the release of MYCN sequences in the peripheral blood is an early process in disease progression, permitting us to propose this novel marker for the follow-up of patients after chemotherapy.