Expert survey on coverage and characteristics of pediatric palliative care in Europe - a focus on home care.

BACKGROUND: For children with life-limiting conditions home care is a key component of pediatric palliative care. However, poor information is available on service coverage and in particular on country-specific pediatric palliative home care characteristics. The aim of the study was therefore to describe the association between pediatric palliative care coverage and national activities and obtain detailed information on the pediatric palliative home care structure in different European countries. METHODS: Online survey with in-country experts from N = 33 European countries. RESULTS: Pediatric palliative home care (65.6%) represented the most pediatric palliative care units (15.6%) and the least common services. National documents constituted the most widespread national pediatric palliative care activity (59.4%) and were associated with available services. Pediatric palliative home care could be mostly accessed as a service free of charge to families (95.2%) from the time of a child's diagnosis (85.7%). In most countries, oncological and non-oncological patients were cared for in pediatric palliative home care. Only a minority of home care teams covered home-ventilated children. Pediatric palliative home care usually comprised medical care (81.0%), care coordination (71.4%), nursing care (75.0%) and social support (57.1%). Most countries had at least two professional groups working in home care teams (81.0%), mostly physicians and nurses. In many countries, pediatric palliative home care was not available in all regions and did not offer a 24 h-outreach service. CONCLUSIONS: Pediatric palliative care provision in Europe is heterogeneous. Further work on country-specific structures is needed.

No pain, no gain? Children with cerebral palsy and their experience with physiotherapy.

OBJECTIVES: Recent studies have shown that physiotherapy can induce pain in children and young adults with cerebral palsy (CP). There is a lack of knowledge of children's pain experiences during therapy sessions and the specific causes of pain. The main objective of this study was to better understand the experience of children and young adults with CP during physiotherapy sessions and to analyse the coping strategies used by children and therapists. METHODS: Qualitative study with focus groups. Eighteen children/young adults with CP who experienced pain during physiotherapy were interviewed, using focus groups as a source of data collection in a phenomenological perspective. Data collection and analysis were consecutive to ensure that the data saturation point was reached. The transcripts were coded manually using thematic analysis. First, interesting features of the verbatim were coded, then codes were collated into potential themes and then the themes were checked to ensure they worked in relation to the coded extracts. Multiple coding was performed by 3 different researchers, and results were merged at each step. RESULTS: This study confirmed that among the 18 children interviewed (mean [SD] age 13.17 [4.02] years, 10 girls), physiotherapy, particularly stretching, induced pain. Participants reported that the experience of pain led to a dislike of physiotherapy, although some believed that the pain was necessary to show that the treatment was effective. The use of distraction techniques and the relationship with the physiotherapist were key elements associated with the perception and experience of pain. CONCLUSIONS: This study confirmed that patients with CP experience pain during physiotherapy. Stretching seems to be the main source of pain. Beliefs and practices regarding the concept of pain show that physiotherapists need training in this field.

Should We Pay Attention to the Delay Before Admission to a Pediatric Intensive Care Unit for Children With Cancer? Impact on 1-Month Mortality. A Report From the French Children's Oncology Study Group, GOCE.

Acute complications requiring admission to pediatric intensive care unit (PICU) are frequent for children with cancer. Our objective was to determine early prognostic factors of mortality in a cohort of children with cancer hospitalized in PICU for acute complications and particularly to assess whether the delay before admission to a PICU is an early predictor of mortality. We conduct a retrospective multicenter analysis. All patients transferred in PICU for acute complications between January 2002 and December 2012 were included. One-month mortality of the 224 patients analyzed was 24.5%. Delay before PICU admission was a significant prognostic factor of 1-month mortality with nonsurvivors experiencing a longer median delay than survivors (24 vs. 12 h, respectively, P<0.05). Time from diagnosis to PICU admission (P<0.001), hematopoietic stem cell transplant (P<0.05), the duration of neutropenia (P<0.01), infection type (P<0.001), number of organ dysfunctions (P<0.001), and reaching any grade 4 toxicity before PICU admission (P<0.001) also affected mortality rate at 1-month post-PICU discharge. In the multivariate analysis, only reaching any grade 4 toxicity before PICU admission influenced 1-month mortality (odds ratio, 2.30; 95% confidence interval, 1.07-4.96; P<0.05). These results suggest that PICU admission before severe impairment leads to a better outcome for children with cancer.

Childhood immune thrombocytopenia: A nationwide cohort study on condition management and outcomes.

OBJECTIVES: Nationwide prospective cohort study exploring (i) the factors associated with treatment initiation (vs. watchful waiting) in children with primary immune thrombocytopenia (ITP) followed in routine clinical practice and (ii) the predictors of chronicity at 12 months. PROCEDURE: Between 2008 and 2013, 23 centers throughout France consecutively included 257 children aged 6 months-18 years and diagnosed with primary ITP over a 5-year period. Data on ITP clinical features along with medical management were collected at baseline and 12 months. Multivariate logistic regressions were used to determine (i) and (ii) as defined above, providing odds ratio (OR) with 95% confidence interval (95% CI). RESULTS: One hundred thirty-seven (53%) children were males, median age was 4.6 years, median platelet count was 7 × 109/l, and 214 (81%) patients initiated medication. Factors independently associated with treatment initiation included platelet counts <10 × 109/l (P < 0.0001) and mucocutaneous bleeding symptoms at baseline (P < 0.001). At 12 months, data were available for 211 (82%) children, of whom 160 (74%) had recovered. Predictors of chronicity included female gender (OR = 2.2; 95% CI = 1.0-4.8), age ≥10 years (OR = 2.6; 95% CI = 1.1-6.0), and platelet counts ≥10 × 109 /l (OR = 3.2; 95% CI = 1.5-6.9). CONCLUSIONS: In routine clinical practice, the decision to apply a watchful waiting strategy seems to be driven by platelet counts even in the absence of bleeding symptoms, resulting in treatment being initiated in more than 80% of the children surveyed. Overall, younger children with ITP showed good prognosis, with lower platelet counts and, to a lesser extent, male gender predicting more favorable outcomes.

Care-related pain and discomfort in children with motor disabilities in rehabilitation centres.

BACKGROUND: Pain is one of the symptoms reported most by children with motor disabilities particularly during daily living activities in institutions and during rehabilitation. Despite the care and consideration of professionals, a wide range of motor and cognitive disabilities, limited communication skills, the presence of chronic pain and frequent care interventions place such children at high risk of experiencing induced pain. OBJECTIVES: We aimed to identify care-related pain and discomfort in children with motor disabilities in rehabilitation centres and the characteristics of children at risk of induced pain. A further aim was to evaluate the validity of a method for the continuous assessment of care-related pain. METHODS: Patients were recruited from 2 paediatric rehabilitation centres. The level of pain or discomfort experienced during each daily care activity was evaluated for 5 days and 1 night by using the FLACC-r scale and a visual analog scale (VAS) rated by the caregiver (VAS caregiver) and the patient (VAS patient). RESULTS: We included 32 children (mean age: 8.5±5 years, range: 1-15 years) with 1302 care activities evaluated. Overall, 3.6% of the activities were rated as painful and 11% uncomfortable. The most frequent painful activities were mouth care, transfers standing and dressing. The most frequent uncomfortable activities were passive limb mobilisation, dressing and transfers. Children with neurological disorders were at increased risk of induced pain. CONCLUSIONS: Children with motor disabilities experienced pain during daily care activities. The methodology we propose is valid and can be used in any type of institution for children with motor disability to evaluate and reduce the frequency of care-related pain.

HEDEN Pain Scale: A Shortened Behavioral Scale for Assessment of Prolonged Cancer or Postsurgical Pain in Children Aged 2 to 6 Years.

Few observational scales are available for assessing chronic or recurrent pain in children with cancer because overt behavioral signs of chronic pain dissipate as time passes, making them difficult to detect reliably. The Douleur Enfant Gustave Roussy (DEGR) scale developed by Gauvain-Piquard to monitor prolonged pain in children with cancer aged 2-6 years is currently the only validated tool available for this purpose, but is time consuming and difficult to use in daily clinical practice. To shorten composite measurement scales, we developed the Hétero Evaluation Douleur Enfant (HEDEN) scale from the DEGR scale. We present here the process and validation of this scale. Expert consensus was used for the elaboration of HEDEN: 5/10 DEGR items were chosen with three rating levels. Concurrent validity was tested in a first cohort with correlation analysis between HEDEN and DEGR. The HEDEN scale was then validated in a second cohort. In the first step, the study (59 children) showed acceptable correlation between DEGR and HEDEN (r = 0.5), with good reliability (α = 0.61), and interrater agreement (r = 0.62). Subsequent validation in 48 children showed a significant correlation between DEGR and HEDEN (r = 0.6). Reliability was good (α = 0.75), with excellent interrater agreement [r = 0.67 (95% CI: 0.48-0.79)]. On average, the evaluation took 23 minutes (SD = 10.4) for DEGR versus 4.42 minutes (SD = 5.9) for HEDEN. This study shows a good correlation between HEDEN and DEGR scales. HEDEN allows accurate assessment of prolonged pain in young children with cancer.

[Pain in newborns in the delivery room and in a maternity hospital]. / La douleur du nouveau-né en salle de naissance et en maternité.

A study was carried out by Brest regional teaching hospital to analyse practices in relation to non procedural pain in newborns in the delivery room and in a maternity hospital. It highlighted the fact that written transmissions are limited to recording newborns' clinical pain. The newborn pain and discomfort assessment scale is rarely used either because it is not known about, or because it is unavailable or too time-consuming. Pain management can be improved through the use of drugs, traceability and the implementation of other techniques.

Determining the technical and clinical factors associated with pain for children undergoing botulinum toxin injections under nitrous oxide and anesthetic cream.

AIMS: To determine technical and clinical factors associated with pain when using an analgesic protocol with 50% nitrous oxide/oxygen and anesthetic cream (lidocaine and prilocaine, Emla(®)) for children with cerebral palsy undergoing botulinum toxin injections. METHODS: Monocentric prospective study including 50 children newly injected with a mean age of 6.6 years (± 4.32, range 1-18) and 199 injected muscles. Pain was evaluated using the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS). The following variables were noted: gender, age, weight, Gross Motor Function Classification System, type of cerebral palsy (hemiplegic, diplegic, tetraplegic), muscles injected and severe cognitive impairment. The procedure was broken down into three phases for the purpose of pain evaluation: puncture, muscle localization using electrostimulation and injection of botulinum toxin. RESULTS: The mean CHEOPS score was 8.16 (± 3.5) and 38% of scores were above the therapeutic threshold of 9. The injection phase was significantly more painful (6.77 ± 3.30) than the puncture (4.88 ± 2.03) and localization (5.46 ± 2.68) phases. The adductor muscles were less painful than other muscles. Children with more severe cognitive impairment seemed to perceive higher levels of pain than the others. Other clinical factors were not associated with pain score. CONCLUSION: Clinical characteristics seem not strongly correlated to the success or failure of the 50% nitrous oxide/oxygen-Emla(®) protocol and this pain treatment protocol does not prevent equally all phases of botulinum toxin injections. Future research on the products and its dilution might help to reduce pain level.

Osteoclast-gene expression profiling reveals osteoclast-derived CCR2 chemokines promoting myeloma cell migration.

Multiple myeloma is characterized by the clonal expansion of malignant plasma cells (multiple myeloma cells [MMCs]), in the bone marrow. Osteolytic bone lesions are detected in 80% of patients because of increased osteoclastic bone resorption and reduced osteoblastic bone formation. MMCs are found closely associated with sites of increased bone resorption. Osteoclasts strongly support MMC survival in vitro. To further elucidate the mechanisms involved in osteoclast/MMC interaction, we have identified 552 genes overexpressed in osteoclasts compared with other bone marrow cell subpopulations. Osteoclasts express specifically genes coding for 4 CCR2-targeting chemokines and genes coding for MMC growth factors. An anti-CCR2 monoclonal antibody blocked osteoclast chemoattractant activity for MMC, and CCR2 chemokines are also MMC growth factors, promoting mitogen-activated protein kinase activation in MMC. An anti-insulin growth factor-1 receptor monoclonal antibody completely blocked the osteoclast-induced survival of MMC suppressing both osteoclast and MMC survival. Specific a proliferation-inducing ligand or IL-6 inhibitors partially blocked osteoclast-induced MMC survival. These data may explain why newly diagnosed patients whose MMC express high levels of CCR2 present numerous bone lesions. This study displays additional mechanisms involved in osteoclast/MMC interaction and suggests using CCR2 and/or insulin growth factor-1 targeting strategies to block this interaction and prevent drug resistance.

APRIL and TACI interact with syndecan-1 on the surface of multiple myeloma cells to form an essential survival loop.

BLyS and APRIL share two receptors - transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA) - and BLyS binds to a third receptor, BAFF-R. We previously reported that TACI gene expression is a good indicator of a BLyS-binding receptor in human multiple myeloma cell lines (HMCLs), unlike BCMA, which is expressed by all HMCLs or BAFF-R which is typically not expressed by late-stage B cells. We hypothesised a link between APRIL and TACI through syndecan-1, similar to the situation reported for FGF and FGFR. We observed very strong binding of APRIL, but not BLyS, at the surface of all syndecan-1(+) HMCLs and primary multiple myeloma cells (MMC). All syndecan-1(+) HMCLs and MMC could also bind TACI-Fc, but not BCMA-Fc or BAFF-R-Fc molecules. Binding of APRIL or TACI-Fc was abrogated by heparin or cell pretreatment with heparitinase, which cleaves heparan sulfate chains. The growth factor activity of APRIL on MMC was also inhibited by heparin. Our data identify syndecan-1 as a co-receptor for APRIL and TACI at the cell surface of MMC, promoting the activation of an APRIL/TACI pathway that induces survival and proliferation in MMC.

TACI expression is associated with a mature bone marrow plasma cell signature and C-MAF overexpression in human myeloma cell lines.

BACKGROUND AND OBJECTIVES: BAFF and APRIL stimulate the growth of multiple myeloma (MM) cells. BAFF and APRIL share two receptors--TACI and BCMA--and BAFF binds to a third receptor, BAFF-R. We previously reported that TACI gene expression is bimodal in 18 human MM cell lines (HMCL), being either present or absent, unlike BCMA that is expressed on all HMCL. BAFF-R is lacking. TACI expression is a good indicator of a BAFF-binding receptor in HMCL. In primary MM cells, the level of TACI expression correlates with a characteristic phenotypic pattern: TACIhighMM cells resemble bone marrow plasma cells and TACIlow resemble plasmablasts. The aim of this study was to further characterize the role of TACI expression in MM DESIGN AND METHODS: Using gene expression profiling, we investigated whether these patterns are kept in TACI+ or TACI- HMCL. RESULTS: Eighty genes/EST interrogated by Affymetrix microarrays were differentially expressed between TACI+ and TACI- HMCL, particularly c-maf, cyclin D2, and integrin beta7. Triggered by the finding that TACI and c-maf expressions correlate in TACI+ HMCL, we demonstrated that TACI activation influences c-maf expression: (i) activation of TACI by BAFF or APRIL increases c-maf, cyclin D2, and integrin beta7 gene expressions in TACI+ HMCL, (ii) blocking of autocrine BAFF/APRIL stimulation in some TACI+ HMCL by the TACI-Fc fusion protein reduces c-maf, cyclin D2, and integrin beta7 gene expression, (iii) nucleofection of siRNA to c-maf decreases c-maf mRNA levels and reduces the expression of cyclin D2 and integrin beta7 gene expressions, without affecting TACI expression INTERPRETATION AND CONCLUSIONS: We conclude that TACI activation can upregulate c-maf expression which, in turn, controls cyclin D2, and integrin beta7 gene expression.

CD200 is a new prognostic factor in multiple myeloma.

Using Affymetrix microarrays, we identified the expression of the CD200 gene in multiple myeloma cells (MMCs) of 112 patients with newly diagnosed multiple myeloma (MM). The CD200 gene was either absent or present (Affymetrix call) in 22% and 78% of MMCs, respectively. The CD200 gene is not expressed in cells of the patients' bone marrow (BM). CD200 is a membrane glycoprotein that imparts an immunoregulatory signal through CD200R, leading to the suppression of T-cell-mediated immune responses. Patients with CD200(absent) MMCs have an increased event-free survival (EFS; 24 months) compared with patients with CD200(present) MMCs (14 months), after high-dose therapy and stem cell transplantation. In a Cox proportional-hazard model, the absence or presence of CD200 expression in MMCs is predictive for EFS for patients independently of ISS stage or beta2M serum levels. Thus, CD200 is an independent prognosis factor for patients with MM that could represent a new therapeutic target in MM.

BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone.

Identification of growth factors in neoplasias may be a target for future therapies by blocking either growth factor receptor interaction or the induced pathway. Using gene expression profiling, we identified overexpression of 2 receptors for a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) in malignant plasma cells compared with normal plasma cells. APRIL and BAFF are involved in a variety of tumor and autoimmune diseases, including B-cell malignancies. We confirmed the expression of BAFF and APRIL receptors (B-cell maturation antigen [BCMA], transmembrane activator and calcium modulator and cyclophilin ligand interactor [TACI], and BAFF-R) in a majority of 13 myeloma cell lines and in the purified primary myeloma cells of 11 patients. APRIL and BAFF were potent survival factors for exogenous cytokine-dependent myeloma cell lines and were autocrine growth factors for the RPMI8226 and L363 autonomously growing cell lines. These factors activated nuclear factor (NF)-kappaB, phosphatidylinositol-3 (PI-3) kinase/AKT, and mitogen-activated protein kinase (MAPK) kinase pathways and induced a strong up-regulation of the Mcl-1 and Bcl-2 antiapoptotic proteins in myeloma cells. BAFF or APRIL was also involved in the survival of primary myeloma cells cultured with their bone-marrow environment, and protected them from dexamethasone (DEX)-induced apoptosis. Finally, the serum levels of BAFF and APRIL were increased about 5-fold in patients with multiple myeloma (MM) as compared with healthy donors. Altogether, these data suggest that APRIL/BAFF inhibitors may be of clinical value in MM.

Kasabach-merritt phenomenon: a retrospective study of treatment with vincristine.

PURPOSE: Kasabach-Merritt phenomenon (KMP) is characterized by profound thrombocytopenia, microangiopathic hemolytic anemia, a consumptive coagulopathy, and an enlarging vascular lesion. The syndrome develops in infancy and is associated with a high morbidity and mortality rate. The purpose of this study was to assess the effectiveness of vincristine in the treatment of KMP. METHODS: We retrospectively reviewed the clinical and laboratory data of 15 patients with KMP treated with vincristine at 9 institutions across the United States, South America, and Europe. RESULTS: All 15 patients had profound thrombocytopenia and consumption of fibrinogen at presentation. Ten patients had biopsies of their lesions, and results included five (33.3%) kaposiform hemangioendotheliomas, three (20%) tufted angiomas, one lesion (6.7%) with features of both kaposiform hemangioendothelioma and tufted angioma, and one (6.7%) unclassified vascular tumor. All 15 patients had an increase in platelet count of at least 20,000 with an average response time of 4.0 weeks after initiation of vincristine therapy. Thirteen patients had an increase in fibrinogen level of 50 mg/dL with an average response time of 3.4 weeks. In 13 patients there was a significant decrease in the size of the vascular lesion. The average duration of treatment was 21.5 (+/-12.6) weeks. Four patients (26%) relapsed. All four were successfully treated with a second course of vincristine. Complications included one patient with abdominal pain, one patient with transient loss of deep tendon reflexes, and one patient with irritability. CONCLUSION: Vincristine presents a safe and sometimes effective treatment option in the management of KMP.