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.

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.

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.

Primary ovarian insufficiency in children after treatment with 131I-metaiodobenzylguanidine for neuroblastoma: report of the first two cases.

BACKGROUND: Primary ovarian insufficiency (POI) is a noted late effect in childhood cancer survivors treated with alkylating agents or after radiation to a field that includes the ovaries. Gonadal failure in children with neuroblastoma (NBL) who were exposed to 131I- metaiodobenzylguanidine (MIBG) has only been reported in those who were also treated with chemotherapy. In these cases, the cause of gonadal failure was assumed to be the cytotoxic therapy. Here, we present the first two cases of POI after 131I-MIBG treatment only for NBL, indicating that 131I-MIBG treatment may have a causative role. PATIENTS: During follow-up after treatment for NBL in childhood, elevated gonadotropins were found in a 12-year-old girl and an 11-year-old girl (FSH values, 105 and 161 U/L, respectively), indicating POI. The first patient had been diagnosed at the age of 17 months with sacrally located (intraspinal) NBL. Treatment consisted of five courses of 131I-MIBG and local resection. The second patient had been diagnosed at the age of 8 months with an abdominal (intraspinal) NBL. She had been treated with acute (neuro) surgery for decompression of her intraspinal tumor causing neurological symptoms, followed by two courses of 131I-MIBG therapy. Both girls had normal karyotypes (46, XX). No other cause for the ovarian failure was found. Estrogen suppletion was started, and patients and parents were counseled regarding fertility options. CONCLUSION: These two cases suggest that exposure to 131I-MIBG may damage the female gonads. Clinicians caring for childhood cancer survivors should be aware of the risk of POI after 131I-MIBG treatment. Prospective studies are warranted to confirm our observations.

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.

No adverse effect of vincristine on handwriting in children after completion of therapy.

BACKGROUND: Long-term writing difficulties in children after treatment with vincristine for acute lymphoblastic leukemia, Wilms tumor, B non-Hodgkin lymphoma, and malignant mesenchymal tumors, were investigated. PROCEDURE: Handwriting of 33 survivors and 33 controls matched for age, sex, and grade, was assessed with the BHK-scale. The examiner was blinded for whether a child was a case or a control. RESULTS: No significant difference in writing speed was found. Mean difference in number of letters produced during 5 min was 6.4 (+/-67.1, range -103 to +169). No significant difference was found in quality of writing scores; mean difference in points was 1.5 (+/-7.7, range -19 to +22). Cumulative vincristine dose, age at diagnosis or time since completion of treatment did not affect writing speed or quality. CONCLUSION: Chemotherapy, including vincristine, does not lead to long-term problems in speed or quality of writing in children treated for cancer.

[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.

Quality of life, self-esteem and worries in young adult survivors of childhood cancer.

This study assessed quality of life, self-esteem and worries in young adult survivors of childhood cancer compared to a group of young adults with no history of cancer. The impact of demographic, medical and treatment factors and self-esteem on survivors' quality of life and worries was studied. Participants were 400 long-term survivors (LTS) of childhood cancer (age range 16-49 years, 45% female) who had completed treatment an average of 16 years previously and 560 persons (age range 16-53 years, 55% female) with no history of cancer. All participants completed the MOS-24 (Medical Outcome Study Scale), a Worry questionnaire consisting of three scales (cancer-specific concerns, general health concerns, present and future concerns), and the Rosenberg Self-Esteem Scale. Small to moderate differences were found in mean MOS-24 scores between the LTS group and controls (range effect sizes -0.36-0.22). No significant difference was found in the mean self-esteem scores between LTS and controls. Female LTS had more cancer-specific concerns than male LTS. In several related areas of general health, self-image and dying, the LTS group reported less worries than controls, but LTS worried significantly more about their fertility, getting/changing a job and obtaining insurance's. Multiple linear regression analysis revealed that female gender, unemployment, severe late effects/health problems and a low self-esteem were predictors of worse quality of life in survivors. In addition, age at follow-up, unemployment, years since completion of therapy and a low self-esteem were associated with a higher degree of survivors' worries. Quality of life and the level of self-esteem in LTS of childhood cancer is not different from their peers. Although many LTS worried not more or even less about health issues than their peers, they often are concerned about some present and future concerns. The investigated factors could explain poor quality of life and worries only to a limited extent. Further research exploring determinants and indices of quality of life and worries in LTS is warranted.

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.

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.

Decreasing the number of MOPP courses reduces gonadal damage in survivors of childhood Hodgkin disease.

BACKGROUND: Children treated for Hodgkin disease are at risk for gonadal damage. Since most children were treated with radiotherapy (RT) in combination with chemotherapy, the presumed detrimental effect of MOPP (mustine, vincristine, procarbazine, and prednisone) (in contrast to schemes with less or without alkylating agents) could not be discerned completely from the effects of RT. PROCEDURES: Children with Hodgkins disease treated without RT were included in sequential protocols containing six courses of MOPP (n = 24), six courses of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (n = 17), or three courses of MOPP/ABVD (n = 35). Of these 76 patients, 48, who had completed treatment and had reached puberty, were investigated for gonadal damage. RESULTS: Of the male patients, 81% of MOPP treated patients had increased follicular stimulating hormone (FSH) values, in 23% luteinizing hormone (LH) values were abnormal. In ABVD treated patients, no elevated levels of FSH or LH were noted. In 30% of patients treated with MOPP/ABVD, FSH values were abnormal, but no abnormal LH values were found. Median testicular volume per group decreased in relation to a higher number of MOPP courses. Sperm analysis revealed azoospermia in nearly all MOPP treated patients. In ABVD and MOPP/ABVD treated patients both oligospermia and azoospermia were noted. The number of sperm samples were too less to make any sound conclusions. Menarche occurred in all females, however in some at a relatively later age. One female patient treated with MOPP/ABVD had a normal pregnancy. CONCLUSIONS: Limitation of MOPP therapy to three courses, in children treated without any RT, results in less gonadal damage as compared with six MOPP courses. From our data, MOPP damages Sertoli cells and may also damage Leydig cells as suggested by the higher LH values in conjunction with normal testosterone levels.

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.

[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.

The use of cognitive methods in analyzing clinicians' task behavior.

To ensure the acceptance and routine use of information systems in healthcare tight coupling is required between the work practices of potential endusers and the systems functionalities and presentation of these functionalities via the user interface. The application of methods from cognitive engineering during requirement analysis may contribute to the support of healthcare work practice by computer systems. We applied the think aloud method in combination with video analysis during the requirement analysis phase in designing a user interface for a patient information retrieval system. These methods provided a detailed insight in the information needs of physicians and the way in which they search through this information in preparing a patient visit. Using these insights in endusers work practices in the early phase of user interface development may lead to a better fit between physicians' work practices and the supporting computer system.

Mutation at the CK2 phosphorylation site on Cdc28 affects kinase activity and cell size in Saccharomyces cerevisiae.

We have recently reported that protein kinase CK2 phosphorylates both in vivo and in vitro residue serine-46 of the cell cycle regulating protein Cdc28 of budding yeast Saccharomyces cerevisiae, confirming a previous observation that the same site is phosphorylated in Cdc2/Cdk1, the human homolog of Cdc28. In addition, S. cerevisiae in which serine-46 of Cdc28 has been mutated to alanine show a decrease of 33% in both cell volume and protein content, providing the genetic evidence that CK2 is involved in the regulation of budding yeast cell division cycle, and suggesting that this regulation may be brought about in G1 phase of the mammalian cell cycle. Here, we extended this observation reporting that the mutation of serine-46 of Cdc28 to glutamic acid doubles, at least in vitro, the H1-kinase activity of the Cdc28/cyclin A complex. Since this mutation has only little effects on the cell size of the cells, we hypothesize multiple roles of yeast CK2 in regulating the G1 transition in budding yeast.