A case report of a blueberry muffin baby caused by congenital self-healing indeterminate cell histiocytosis.

BACKGROUND: Blueberry muffin is a descriptive term for a neonate with multiple purpuric skin lesions. Many causes are known, amongst them life-threatening diseases like congenital infections or leukemia. Indeterminate cell histiocytosis (ICH) is an exceptionally rare cause of blueberry muffin rash. ICH is a histiocytic disorder which can be limited to the skin or can present with systemic involvement. A mutation that has been described in histiocytic disorders is a MAP2K1 mutation. In ICH, this mutation has previously been described in merely one case. CASE PRESENTATION: A term male neonate was admitted to the neonatology ward directly after birth because of a blueberry muffin rash. ICH was diagnosed on skin biopsy. The lesions resolved spontaneously. The patient is currently 3 years old and has had no cutaneous lesions or systemic involvement so far. This disease course is similar to that of the Hashimoto-Pritzker variant of LCH. CONCLUSIONS: ICH can manifest in neonates as resolving skin lesions. It is limited to the skin in most cases, but systemic development is possible. Therefore, it is essential to confirm the diagnosis with a biopsy before the lesions resolve and to monitor these patients closely with routine follow-up.

Population Pharmacokinetics and Pharmacodynamics of Ciprofloxacin Prophylaxis in Pediatric Acute Lymphoblastic Leukemia Patients.

BACKGROUND: Ciprofloxacin is used as antimicrobial prophylaxis in pediatric acute lymphoblastic leukemia (ALL) to decrease infections with gram-negative bacteria. However, there are no clear guidelines concerning prophylactic dose. AIMS: To determine the pharmacokinetics and pharmacodynamics (PKPD) of ciprofloxacin prophylaxis in a pediatric ALL population. The effect of patient characteristics and antileukemic treatment on ciprofloxacin exposure, the area under the concentration time curve over minimal inhibitory concentration (AUC24/MIC) ratios, and emergence of resistance were studied. METHODS: A total of 615 samples from 129 children (0-18 years) with ALL were collected in a multicenter prospective study. A population pharmacokinetic model was developed. Microbiological cultures were collected prior to and during prophylaxis. An AUC24/MIC of ≥125 was defined as target ratio. RESULTS: A 1-compartment model with zero-order absorption and allometric scaling best described the data. No significant (P < .01) covariates remained after backward elimination and no effect of asparaginase or azoles were found. Ciprofloxacin AUC24 was 16.9 mg*h/L in the prednisone prophase versus 29.3 mg*h/L with concomitant chemotherapy. Overall, 100%, 81%, and 18% of patients at, respectively, MIC of 0.063, 0.125, and 0.25 mg/L achieved AUC24/MIC ≥ 125. In 13% of the patients, resistant bacteria were found during prophylactic treatment. CONCLUSION: Ciprofloxacin exposure shows an almost 2-fold change throughout the treatment of pediatric ALL. Depending on the appropriateness of 125 as target ratio, therapeutic drug monitoring or dose adjustments might be indicated for less susceptible bacteria starting from ≥ 0.125 mg/L to prevent the emergence of resistance and reach required targets for efficacy.

Measuring vincristine-induced peripheral neuropathy in children with cancer: validation of the Dutch pediatric-modified Total Neuropathy Score.

PURPOSE: The aims were to evaluate the construct validity and reliability of the Dutch version of the pediatric-modified Total Neuropathy Score (ped-mTNS) for assessing vincristine-induced peripheral neuropathy (VIPN) in Dutch pediatric oncology patients aged 5-18 years. METHODS: Construct validity (primary aim) of the ped-mTNS was determined by testing hypotheses about expected correlation between scores of the ped-mTNS (range: 0-32) and the Common Terminology Criteria for Adverse Events (CTCAE) (range: 0-18) for patients and healthy controls and by comparing patients and controls regarding their total ped-mTNS scores and the proportion of children identified with VIPN. Inter-rater and intra-rater reliability and measurement error (secondary aims) were assessed in a subgroup of study participants. RESULTS: Among the 112 children (56 patients and 56 age- and gender-matched healthy controls) evaluated, correlation between CTCAE and ped-mTNS scores was as expected (moderate (r = 0.60)). Moreover, as expected, patients had significantly higher ped-mTNS scores and more frequent symptoms of VIPN compared with controls (both p < .001). Reliability as measured within the intra-rater group (n = 10) (intra-class correlation coefficient (ICCagreement) = 0.64, standard error of measurement (SEMagreement) = 2.92, and smallest detectable change (SDCagreement) = 8.1) and within the inter-rater subgroup (n = 10) (ICCagreement = 0.63, SEMagreement = 3.7, and SDCagreement = 10.26) indicates insufficient reliability. CONCLUSION: The Dutch version of the ped-mTNS appears to have good construct validity for assessing VIPN in a Dutch pediatric oncology population, whereas reliability appears to be insufficient and measurement error high. To improve standardization of VIPN assessment in children, future research aimed at evaluating and further optimizing the psychometric characteristics of the ped-mTNS is needed.

The impact of maintenance therapy on sleep-wake rhythms and cancer-related fatigue in pediatric acute lymphoblastic leukemia.

PURPOSE: To assess the impact of maintenance therapy and the additional impact of dexamethasone treatment on cancer-related fatigue and sleep-wake rhythms in pediatric acute lymphoblastic leukemia (ALL) patients and to determine the association between these outcomes. METHODS: A national cohort of pediatric ALL patients (≥ 2 years) was included (± 1 year post-diagnosis). Patients receiving dexamethasone were assessed twice (assessment with and without dexamethasone). Actigraphy assessments were used to calculate sleep-wake outcomes with nonparametric methods. Cancer-related fatigue was assessed with the PedsQL Multidimensional Fatigue Scale. Sleep-wake rhythms and cancer-related fatigue were compared between patients participating in the assessment without dexamethasone and healthy children (linear regression) and between assessments with and without dexamethasone (mixed models). Using linear regression, associations between sleep-wake outcomes and cancer-related fatigue were determined during assessments with and without dexamethasone. RESULTS: Responses were collected for 125 patients (113 assessments with and 81 without dexamethasone). The sleep-wake rhythm was less stable (p = 0.03) and less robust (p = 0.01), with lower physical activity levels (p < 0.001) and higher cancer-related fatigue levels (p < 0.001) in ALL patients compared to healthy children. Physical activity was lower (p = 0.001) and cancer-related fatigue more severe (p ≤ 0.001) during assessments with dexamethasone compared to without dexamethasone. Sleep-wake outcomes were significantly associated with cancer-related fatigue during periods without dexamethasone, but not during periods with dexamethasone. CONCLUSION: Sleep-wake rhythms are disturbed, physical activity levels lower, and cancer-related fatigue levels higher during maintenance therapy. Interventions aimed to enhance sleep-wake rhythms during maintenance therapy could improve cancer-related fatigue. Families should be supported in coping with the additional burden of dexamethasone treatment to improve well-being of ALL patients.

Psychiatric symptoms causing delay in diagnosing childhood cancer: two case reports and literature review.

INTRODUCTION: A somatic disorder may initially be overlooked when a child presents with psychiatric symptoms. We report two children with anorexia nervosa as initial diagnosis and in whom there was a delay in the final diagnosis of the underlying malignancy. A literature survey was performed including patients under 18 years of age with psychiatric symptoms in whom later on an oncological diagnosis became evident as an explanation. RESULTS: We have found 30 additional cases, with a median delay of 12 months until the diagnosis of the tumour. Overall, 16 boys and 16 girls had a solid tumour: 26 central nervous system tumours, 3 tumours of the gastrointestinal tract and 3 others. In 25 out of 32 patients anorexia nervosa was assumed, although it always appeared to be atypical. Patients younger than 7 years had a significantly longer delay until final diagnosis, while no other patient characteristics correlated with such delay. DISCUSSION: In addition to careful physical (including full neurological) examination, we advise additional neuroimaging especially in each case of atypical presentation of anorexia nervosa, in order to avoid a delay in diagnosis of a possible malignancy. Furthermore, it is desirable to perform a re-examination when a psychiatric disorder does not respond to therapy, in order not to overlook an underlying oncological disease.

Development of a national protocol to screen Dutch cancer survivors on late cancer treatment effects.

PURPOSES: The development of a national protocol to formalize the screening of Dutch cancer survivors on potential late cancer treatment effects and the medical terminology used in describing the patient follow up procedures. METHODS: A combined evidence-based and qualitative approach, the Glaser's State of the Art Strategy, was used to reach consensus on how to screen Dutch cancer survivors on late cancer treatment effects. A core working group set up a first proposal of a screening protocol and a handbook of medical term definitions by incorporating available research evidence (1980-2003), clinical expertise and definitions from Dutch medical dictionaries and textbooks. External experts reviewed this proposal in a cycle of two postal and two discussion rounds. The follow-up procedures and medical term definitions described in the draft screening protocol were to be accepted if consensus among external experts was > or =50%. RESULTS: A protocol for screening cancer survivors on late cancer treatment effects was developed describing the follow-up procedures for cancer survivors according to previous therapeutic exposures. Four hundred and twenty one medical terms were used in describing these follow-up procedures. One hundred and fifteen of these terms were classified as multi-interpretable and 101 of these terms were defined. No definitions could be found for the remaining 14 medical terms. CONCLUSIONS: We succeeded in reaching consensus throughout The Netherlands on a protocol to screen cancer survivors on late cancer treatment effects. This protocol is now in use by all Dutch outpatient clinics and warrants that the screening of cancer survivors is consistent across The Netherlands. The screening protocol specifies in detail how screening of cancer survivors should take place and can therefore be used by clinicians who were not involved in the consensus study.

[A boy with acute cerebellar ataxia without opsoclonus caused by neuroblastoma]. / Een jongen met acute cerebellaire ataxie zonder opsoclonus, door een neuroblastoom.

A 2-year-old boy presented with acute cerebellar ataxia without opsoclonus. The ataxia was assumed to be post-viral. After a period of years a neuroblastoma was detected. Treatment with a curative intent was successful and consisted of metaiodobenzylguanidine I 131, chemotherapy, tumour resection, chemotherapy again and follow-up treatment with isotretinoin after irradiation. In the literature, 5 other children have been described with acute cerebellar ataxia without opsoclonus in whom neuroblastoma was detected eventually. The mean age of these children at initial presentation was 26 months. The mean time between initial presentation and diagnosis ofneuroblastoma or ganglioneuroblastoma was 12 months. Urine concentrations of catecholamine metabolites were normal in 5 of the 6 total children; concentrations were elevated in 1 child. The tumour was located paravertebrally in 5 of the 6 children. Ataxia resolved following resection of the neuroblastoma in all patients. Each child with prolonged or recurrent acute cerebellar ataxia should be extensively investigated for the presence of neuroblastoma, even in the absence of opsoclonus.

Loss of long-term repopulating ability in long-term bone marrow culture.

We have studied the maintenance of stem cells with long-term multilineage repopulating ability from murine bone marrow, cultured on a pre-established bone marrow-derived stromal cell layer, both in a qualitative and quantitative way. Female bone marrow cells were cultured for a period of 1-4 weeks and compared with uncultured cells for their ability to establish and maintain a level of 50% chimerism in a sex-mismatched bone marrow transplantation model. Chimerism was determined in nucleated cells using fluorescence in situ hybridization with a murine Y-chromosome-specific probe. We observed a rapid decline in the ability of cultured marrow cells to repopulate the blood, bone marrow, spleen, and thymus of sublethally irradiated male recipients. After 4 weeks of culture only 5% of the long-term repopulating ability of the inoculated bone marrow cells remained. The remaining long-term repopulating cells, however, had similar qualities to establish and maintain long-term engraftment compared to fresh bone marrow, as judged from their ability to give stable chimerism over a period of 6 months. These observations are relevant for the therapeutic applications of long-term bone marrow cultures in purging protocols prior to autologous bone marrow transplantation of acute and chronic myeloid leukemic patients, and for the use of long-term marrow cultures when introducing foreign genetic material in hematopoietic stem cells.

Pharmacokinetic basis for optimal hemopoietic effectiveness of homologous IL-3 administered to rhesus monkeys.

To design an interleukin-3 (IL-3) administration schedule for optimal hemopoietic effectiveness, serum half-life (t1/2) was determined after intravenous (i.v) and subcutaneous (s.c.) bolus injections. The initial t1/2 in serum after i.v. injection was about 10 minutes and the terminal t1/2 close to 2 hours. Subcutaneous administration resulted in plateau levels after 2 to 4 hours, while the apparent terminal t1/2 was similar to that after i.v. infusion. The bioavailability of IL-3 following subcutaneous administration was only about 40% of that following i.v. administration. Hemopoietic effects of continuous i.v. infusion of IL-3 was then compared to s.c. administration in either one, two, or three daily injections. Doses chosen ranged from 1 to 30 micrograms/kg per day. In agreement with the more limited bioavailability of IL-3 following s.c. administration, continuous i.v. infusion was much more effective in stimulating hemopoiesis than s.c. administration. Two or three daily s.c. injections did not improve the hemopoietic response compared to a single s.c. injection, which is in agreement with the apparent terminal t1/2 of 101 min. It is concluded that IL-3 is more effective by continuous i.v. infusion than by subcutaneous administration.

Facilitated engraftment of human hematopoietic cells in severe combined immunodeficient mice following a single injection of Cl2MDP liposomes.

Transplantation of normal and malignant human hematopoietic cells into severe combined immunodeficient (SCID) mice allows for evaluation of long-term growth abilities of these cells and provides a preclinical model for therapeutic interventions. However, large numbers of cells are required for successful engraftment in preirradiated mice due to residual graft resistance, that may be mediated by cells from the mononuclear phagocytic system. Intravenous (i.v.) injection of liposomes containing dichloromethylene diphosphonate (Cl2MDP) may eliminate mouse macrophages in spleen and liver. In this study outgrowth of acute myeloid leukemia (AML) cells and umbilical cord blood (UCB) cells in SCID mice conditioned with a single i.v. injection of Cl2MDP liposomes in addition to sublethal total body irradiation (TBI) was compared to outgrowth of these cells in SCID mice that had received TBI alone. A two- to 10-fold increase in outgrowth of AML cells was observed in four cases of AML. Administration of 10(7) UCB cells reproducibly engrafted SCID mice that had been conditioned with Cl2MDP liposomes and TBI, whereas human cells were not detected in mice conditioned with TBI alone. As few as 2 x 10(4) purified CD34+ UCB cells engrafted in all mice treated with Cl2MDP liposomes. In SCID mice treated with macrophage depletion unexpected graft failures were not observed. Histological examination of the spleen showed that TBI and Cl2MDP liposomes i.v. resulted in a transient elimination of all macrophage subsets in the spleen, whereas TBI had a minor effect. Cl2MDP liposomes were easy to use and their application was not associated with appreciable side-effects. Cl2MDP liposome pretreatment in combination with TBI allows for reproducible outgrowth of high numbers of human hematopoietic cells in SCID mice.

Compensatory splenic hemopoiesis in beta-thalassemic mice.

beta-Thalassemic mice, homozygous for the deletion of the beta major-globin gene, were investigated for compensatory hemopoiesis in bone marrow and spleen. Apart from characteristic severe anemia, these mice have a marked granulocytosis, monocytosis and lymphocytosis. A large compensatory expansion of late (CFU-E) erythroid progenitor cells was demonstrated, predominantly in the spleen. Immature hemopoietic cells (CFU-S) were also expanded, as were early progenitor cells of erythroid (BFU-E), as well as granulocyte/macrophage (GM-CFU) and megakaryocytic (CFU-Meg) lineages. It is concluded that the persistent erythropoietic stress results in a selective expansion of immature hemopoietic cells and inappropriate production of nonerythroid blood cells from excess production of progenitor cells.

Selective advantage of normal erythrocyte production after bone marrow transplantation of alpha-thalassemic mice.

Anemia resulting from alpha-thalassemia in mice was corrected by transplantation of normal bone marrow cells following sublethal total body irradiation, resulting in partial hematopoietic chimerism with a preponderance of normal peripheral blood red cells. Peripheral blood red cell chimerism in recipients of graded numbers of bone marrow cells from sex-mismatched donors, determined by cytometric analysis, was directly compared with immature hematopoietic cell (CFU-S) chimerism and peripheral blood white cell chimerism. The latter two were assessed by fluorescent in situ hybridization with a murine Y-chromosome-specific probe. Peripheral blood white cell chimerism consistently corresponded with immature hematopoietic cell chimerism, emphasizing the selective advantage of normal red cell production in partially chimeric alpha-thalassemic mice.

Human mesenchymal stem cells promote human osteoclast differentiation from CD34+ bone marrow hematopoietic progenitors.

Interactions between osteoclast progenitors and stromal cells derived from mesenchymal stem cells (MSCs) within the bone marrow are important for osteoclast differentiation. In vitro models of osteoclastogenesis are well established in animal species; however, such assays do not necessarily reflect human osteoclastogenesis. We sought to establish a reproducible coculture model of human osteoclastogenesis using highly purified human marrow-derived MSCs (hMSCs) and CD34+ hematopoietic stem cells (HSCs). After 3 weeks, coculture of hMSCs and HSCs resulted in an increase in hematopoietic cell number with formation of multinucleated osteoclast-like cells (Ocls). Coculture of hMSCs with HSCs, transduced with a retroviral vector that expresses enhanced green fluorescent protein, produced enhanced green fluorescent protein+ Ocls, further demonstrating that Ocls arise from HSCs. These Ocls express calcitonin and vitronectin receptors and tartrate-resistant acid phosphatase and possess the ability to resorb bone. Ocl formation in this assay is cell contact dependent and is independent of added exogenous factors. Conditioned medium from the coculture contained high levels of interleukin (IL)-6, IL-11, leukemia inhibitory factor (LIF), and macrophage-colony stimulating factor. IL-6 and LIF were present at low levels in cultures of hMSCs but undetectable in cultures of HSCs alone. These data suggest that coculture with HSCs induce hMSCs to secrete cytokines involved in Ocl formation. Addition of neutralizing anti-IL-6, IL-11, LIF, or macrophage-colony stimulating factor antibodies to the coculture inhibited Ocl formation. hMSCs seem to support Ocl formation as undifferentiated progenitor cells, because treatment of hMSCs with dexamethasone, ascorbic acid, and beta-glycerophosphate (to induce osteogenic differentiation) actually inhibited osteoclastogenesis in this coculture model. In conclusion, we have developed a simple and reproducible assay using culture-expanded hMSCs and purified HSCs with which to study the mechanisms of human osteoclastogenesis.

No excess fatigue in young adult survivors of childhood cancer.

Clinical reports suggest that many survivors of childhood cancer experience fatigue as a long-term effect of their treatment. To investigate this issue further, we assessed the level of fatigue in young adult survivors of childhood cancer. We compared the results with a group of young adults with no history of cancer. The impact of demographic, medical and treatment factors and depressive symptoms on survivors' fatigue was studied. Participants were 416 long-term survivors of childhood cancer (age range 16-49 years, 48% of whom were female) who had completed treatment an average of 15 years previously and 1026 persons (age range 16-53 years, 55% female) with no history of cancer. All participants completed the Multidimensional Fatigue Inventory (MFI-20), a self-report instrument consisting of five scales (general fatigue, physical fatigue, mental fatigue, reduced activity, reduced motivation) and the Center for Epidemiologic Studies Depression Scale (CES-D). Small differences were found in the mean scores for the different dimensions of fatigue between the long-term survivors and controls (range effect sizes -0.34 to 0.34). Women experienced more fatigue than men. Logistic regression revealed that being female and unemployed were the only demographic characteristics explaining the various dimensions of fatigue. With regard to medical and treatment factors, diagnosis and severe late effects/health problems were associated with fatigue. Finally, depression was significantly associated with fatigue on all subscales. Our clinical practice suggests a difference in fatigue in young adult childhood cancer survivors and their peers. This could not be confirmed in this study using the MFI-20. The well known correlation between fatigue and depression was confirmed in our study. Further research is needed to clarify the undoubtedly complex somatic and psychological mechanisms responsible for the development, maintenance and treatment of fatigue in childhood cancer survivors.

Frequent adverse events after treatment for childhood-onset differentiated thyroid carcinoma: a single institute experience.

Since the mortality rate for childhood differentiated thyroid carcinoma is nearly zero, the focus must be to minimise morbidity following treatment. Our aim was to analyse early and late adverse events. Twenty-five of 26 children treated between 1962 and 2002 were evaluated. Median follow-up was 14.2 years (range 0.9-39.4 years). All underwent total thyroidectomy, 15 (60%) with lymph node dissection and 15 (60%) with adjuvant radio-iodide therapy. Mortality was zero. Seven developed recurrent disease, two developed a third recurrence. Twenty-one (84%) had > or =1 adverse event. Eight had permanent hypoparathyroidism (PH), six permanent recurrent nerve paralysis (PRNP) and two Horner's syndrome. Risk factors for PH and PRNP were total thyroidectomy with lymph node dissection (RR: 6.45, P = 0.015) and recurrent nerve tumour encasement (RR: 8.00, P = 0.001), respectively. Other adverse events were fatigue (n = 5), scar problems (n = 4) and chronic myeloid leukaemia (n = 1). These results emphasise the need to improve treatment strategies.

Correction of murine beta-thalassemia by partial bone marrow chimerism: selective advantage of normal erythropoiesis.

beta-Thalassemic mice were transplanted with normal congeneic BM cells after sublethal total body irradiation, which resulted in partial RBC chimerism and correction of anemia. Enumeration of donor-type early hemopoietic progenitor cells (CFU-S) demonstrated that the correction of anemia originated from a minority of normal immature BM cells. It is concluded that successful BMT in beta-thalassemia does not necessarily require ablation of endogenous BM.

Screening for late effects in survivors of childhood cancer: growth hormone deficiency from a pediatric oncologist's point of view.

At the Emma Kinderziekenhuis/Academic Medical Center in Amsterdam, survivors of childhood cancer are screened annually or biennially for the occurrence of late treatment effects. The screening procedures are based on previously used treatment modalities. The data gathered at the outpatient clinic are registered in the database PLEKsys. Evaluation of the data concerning over 1000 cancer survivors screened since the start of the clinic once more illustrated the relation between cranial irradiation and the development of central endocrine abnormalities. Surprisingly, at least a proportion of the growth hormone (GH)-deficient cancer survivors were registered as not being on a replacement therapy regimen. The reasons for survivors not to be on replacement therapy are currently being evaluated. The late-effects outpatient clinic and the PLEKsys database provide a platform for additional research in fields including endocrinology, which should be aimed at improving the care for and the health status of the survivors of childhood cancer.

Human mesenchymal stem cells respond to fibroblast growth factors.

Human mesenchymal stem cells can be isolated from bone marrow aspirates, purified and cultured for many passages without losing their unique properties. One of the hallmarks of stem cells is pluripotency, and human mesenchymal stem cells can be induced to assume phenotypes of mesenchymal tissues including, but not limited to, those of osteocytes, chondrocytes and adipocytes. Due to their ability to form cartilage, bone, fat and other connective tissue, human mesenchymal stem cells have great potential in regenerating diseased or injured tissues. Successful growth of human mesenchymal stem cells is essential to this process, and we have examined the response of human mesenchymal stem cells towards FGF1 and FGF2, two potent growth factors for human tissues. We provide evidence that: 1) human mesenchymal stem cells produce mRNA for receptors for FGF1 and FGF2; 2) these receptors can be detected on the surface of human mesenchymal stem cells; 3) FGF1 and FGF2 increase the rate at which human mesenchymal stem cells proliferate.

[Children with fever peaks and bone and joint pain: systemic juvenile idiopathic arthritis or acute lymphoblastic leukemia after all?]. / Kinderen met koortspieken en bot- en gewrichtspijnen: systemische juveniele idiopathische artritis of toch acute lymfatische leukemie?

In two 3-year-old infants, a girl and a boy, systemic juvenile idiopathic arthritis was suspected because of daily fever peaks, signs of polyarthritis and general malaise. Drug treatment was unsuccessful, and after extensive laboratory investigation acute lymphoblastic leukaemia (ALL) was diagnosed and treated adequately. ALL is the most common malignancy in childhood. About one-third of the patients present with joint or bone pain and fever. In this group of children, it can be difficult to identify ALL because it may mimic the clinical picture of systemic juvenile idiopathic arthritis and because of the possibility of a normal blood count at presentation. ALL should always be considered in the differential diagnosis in children with musculoskeletal pain and fever, even in the face of a normal blood count. In any case, a bone-marrow examination should be done before steroid treatment is given.