Beishuizen, A.

Mutation analysis of the LH receptor gene in Leydig cell adenoma and hyperplasia and functional and biochemical studies of activating mutations of the LH receptor gene (Article)

2011-07-01T00:00:00Z

Context: Germline and somatic activating mutations in the LH receptor (LHR) gene have been reported. Objective: Our objective was to perform mutation analysis of the LHR gene of patients with Leydig cell adenoma or hyperplasia. Functional studies were conducted to compare the D578H-LHR mutant with the wild-type (WT)-LHR and the D578G-LHR mutant, a classic cause of testotoxicosis. The three main signal transduction pathways in which LHR is involved were studied. Patients: We describe eight male patients with gonadotropin-independent precocious puberty due to Leydig cell adenoma or hyperplasia. Results: The D578H-LHR mutation was found in the adenoma or nodule with hyperplasia in all but two patients. D578H-LHR displayed a constitutively increased but noninducible production of cAMP, led to a very high production of inositol phosphates, and induced a slight phosphorylation of p44/42 MAPK in the absence of human chorionic gonadotropin. The D578G-LHR showed a response intermediate between WT-LHR and the D578H-LHR. Subcellular localization studies showed that the WT-LHR was almost exclusively located at the cell membrane, whereas the D578HLHR showed signs of internalization. D578H-LHR was the only receptor to colocalize with early endosomes in the absence of human chorionic gonadotropin. Conclusions: Although several LHR mutations have been reported in testotoxicosis, the D578H-LHR mutation, which has been found only as a somatic mutation, appears up untilnowto be specifically responsible for Leydig cell adenomas. This is reflected by the different activation of the signal transduction pathways, when compared with the WT-LHR or D578G-LHR, which may explain the tumorigenesis in the D578H mutant. Copyright

Limited stage I disease is not necessarily indicative of an excellent prognosis in childhood anaplastic large cell lymphoma (Article)

2011-05-26T00:00:00Z

Data on incidence, characteristics, and prognosis in stage I childhood anaplastic large cell lymphoma are scarce. Of 463 patients enrolled in the international ALCL99 trial, 36 (8%) had stage I disease and were treated with a prephase chemotherapy, followed by either 3 chemotherapy courses in case of initial complete resection (6 patients) or otherwise by 6 courses of chemotherapy (30 patients). Disease localization was to the peripheral lymph nodes in 26, soft tissue mass in 8, and solitary bone and bronchial disease in 1 patient each. Of the 6 patients with complete resection, none experienced relapse, whereas of the 30 remaining stage I patients, 9 (30%) relapsed, including in all cases a new site of disease involvement and including 3 of 5 anaplastic lymphoma kinase-negative patients. In summary, the failure rate for incompletely resected stage I disease was similar to that for patients with stage II and stage III/IV disease. Whether anaplastic lymphoma kinase negativity contributed to this moderate outcome has to be proven prospectively. This study was registered at www.clinicaltrials.gov as NCT00006455.

Communicating with child patients in pediatric oncology consultations: A vignette study on child patients', parents', and survivors' communication preferences (Article)

2011-03-01T00:00:00Z

Objective: To investigate the preferences of children with cancer, their parents, and survivors of childhood cancer regarding medical communication with child patients and variables associated with these preferences. Methods: Preferences regarding health-care provider empathy in consultations, and children's involvement in information exchange and medical decision making were investigated by means of vignettes. Vignettes are brief descriptions of hypothetical situations, in which important factors are systematically varied following an experimental design. In total, 1440 vignettes were evaluated by 34 children with cancer (aged 8-16), 59 parents, and 51 survivors (aged 8-16 at diagnosis, currently aged 10-30). Recruitment of participants took place in three Dutch university-based pediatric oncology centers. Data were analyzed by multilevel analyses. Results: Patients, parents, and survivors indicated the importance of health-care providers' empathy in 81% of the described situations. In most situations (70%), the three respondent groups preferred information about illness and treatment to be given to patients and parents simultaneously. Preferences regarding the amount of information provided to patients varied. The preference whether or not to shield patients from information was mainly associated with patients' age and emotionality. In most situations (71%), the three respondent groups preferred children to participate in medical decision making. This preference was mainly associated with patients' age. Conclusions: To be able to adapt communication to parents' and patients' preferences, health-care providers should repeatedly assess the preferences of both groups. Future studies should investigate how health-care providers balance their communication between the sometimes conflicting preferences of patients and parents.

Functional ability and physical activity in children and young adults after limb-salvage or ablative surgery for lower extremity bone tumors (Article)

2011-03-01T00:00:00Z

Background: Aim of our study was to compare functional ability and physical activity in children and young adults who underwent surgery for a malignant bone tumor that was located around the knee. Methods: This cross-sectional study included 82 patients aged 8-25 years with a follow-up of 1-5 years. The functional ability and the amount of physical activity were evaluated by means of questionnaires and objective instruments. Results: Thirty nine patients underwent limb-salvage surgery (24 allograft and 15 endoprosthesis) and 43 underwent ablative surgery (27 amputations and 16 rotationplasty). Patients in the limb-salvage group were significantly older at the time of surgery than patients in the ablative group (mean age 15.2 years vs. 13.2 years, P = 0.03). Apart from significantly better scores for the timed up and down stairs and various walking activities in the limb-salvage group as compared to the ablative surgery group, no significant differences were seen for any of the outcome measures. Conclusions: One to 5 years after limb-salvage and ablative surgery due to a malignant bone tumor children and young adults do, apart from a few activities involving walking and climbing stairs, not differ with respect to overall functional ability and physical activity.

Long-term survival after significant treatment reduction in a patient with CBF-AML (Article)

2011-02-01T00:00:00Z

Factors influencing parental readiness to let their child with cancer die (Article)

2010-07-01T00:00:00Z

Background. One in four cases of childhood cancer is incurable. In these cases death can usually be anticipated and therefore preceded by a phase of palliative care. For parents, preparing to let their child die is an extraordinarily painful process. Most struggle to preserve their child. This study identified, from a parental perspective, the main factors that influence the transition from preserving life to letting go. Procedure. Amulti-centre, qualitative research, study was undertaken during the end-of-life (EoL) phase, comprising single or repeated interviews with 44 parents of 23 children with incurable cancer. Results. We discovered that uncertainty, fragmentation and anxiety underpin the preserving life perspective. Aperspecti ve of letting go could be supported by a variety of factors. These included: Certainty that the child cannot be cured, postponed grief, the perception of suffering, the ability to disentangle needs and the ability to parent meaningfully. Hope, creating a peaceful parent - child relationship, and the attitude of professionals, could support movements in either direction. Of these, certainty, and in most cases postponed grief, were pre-conditions for the transition towards letting go. Strategies such as not challenging the parents' suppression of grief, creating certainty about the child's condition and supporting parents in efforts to redefine their parental role, supported progress towards accepting a letting go perspective. Conclusions. Parents' internal struggle between a preserving frame of mind and one of letting go is influenced by a combination of factors. However, professionals can influence some of these factors in order to facilitate this transition.

Quality of life in young patients after bone tumor surgery around the knee joint and comparison with healthy controls (Article)

2010-05-01T00:00:00Z

Background. This study aimed to compare the health related quality of life (HRQoL) of children and adolescents after malignant bone tumor surgery of the leg with healthy controls. Procedure. Patients between 8 and 25 years old were cross-sectional recruited. Patients under 16 years of age received the TNO (Netherlands Organization for Applied Scientific Research) and AZL (Leiden University Medical Center) Children's Quality of Life Questionnaire (TACQOL), patients aged 16 years and older received the TNO-AZL Questionnaire for Adult's Quality of Life (TAAQOL) and the Short Form-36 (SF-36). Three age- and sex-matched normative random samples, drawn from large, nationwide studies, were used for the comparison with healthy controls. Patients were interviewed regarding their most important problems related to the disease and its treatment. Results. Eighty-one patients with a mean age of 16.9 years (SD 4.2) were included (41 female). Limb sparing surgery was executed in 38 patients, ablative surgery in 43 patients. In comparison with healthy controls, patients had significantly poorer HRQoL within the domains autonomy and motor function of the TACQOL, gross motor function, cognitive functioning, daily functioning and sexuality of the TAAQOL, and physical functioning, role physical, general health, and the physical and mental component summary scales of the SF-36. Patients reported limitations in physical activities, participation in sports, and cosmetic aspects as the most detrimental consequences of their disease and its treatment. Conclusion. In children and adolescents who underwent surgery for a malignant tumor of the leg physical, functioning was significantly impaired as compared to healthy controls.

PAS-positive lymphocyte vacuoles can be used as diagnostic screening test for Pompe disease (Article)

2010-04-01T00:00:00Z

Screening of blood films for the presence of periodic acid-Schiff (PAS)-positive lymphocyte vacuoles is sometimes used to support the diagnosis of Pompe disease, but the actual diagnostic value is still unknown. We collected peripheral blood films from 65 untreated Pompe patients and 51 controls. Lymphocyte vacuolization was quantified using three methods: percentage vacuolated lymphocytes, percentage PAS-positive lymphocytes, and a PAS score depending on staining intensity. Diagnostic accuracy of the tests was assessed using receiver operating characteristic (ROC) curves. All three methods fully discerned classic infantile patients from controls. The mean values of patients with milder forms of Pompe disease were significantly higher than those of controls, but full separation was not obtained. The area under the ROC curve was 0.98 for the percentage vacuolated lymphocytes (optimal cutoff value 3; sensitivity 91%, specificity 96%) and 0.99 for the percentage PAS-positive lymphocytes and PAS score (optimal cutoff value 9; sensitivity 100%, specificity 98%). Our data indicate that PAS-stained blood films can be used as a reliable screening tool to support a diagnosis of Pompe disease. The percentage of PAS-positive lymphocytes is convenient for use in clinical practice but should always be interpreted in combination with other clinical and laboratory parameters.

Familial adenomatous polyposis coli in childhood [Familiaire adenomateuze polyposis coli op de kinderleeftijd] (Article)

2010-01-01T00:00:00Z

Familial adenomatous polyposis coli (FAP) is an inherited predisposition to develop hundreds to thousands adenomatous colorectal polyps leading to colorectal cancer, and is caused by germline mutations in the APC-gene. Polyps generally develop in childhood and are often asymptomatic or give aspecific symptoms. However, other extra-intestinal manifestations of FAP may well become manifest in childhood. Here we present a child with hepatoblastoma as the first manifestation of FAP and describe the genetic testing and counseling of him and his brother. An overview of the medical, genetic and psychosocial aspects of FAP in childhood is given. The genetic testing and counseling for FAP in children requires specific expertise and should be provided in a multidisciplinary setting.

Clinical Aspects of Diffuse Cutaneous Mastocytosis in Children: Two Variants (Article)

2009-11-01T00:00:00Z

Objective: This paper describes two different clinical presentations of diffuse cutaneous mastocytosis (DCM), based on the largest series published to date. As far as we are aware, these two variants of clinical presentations have not yet been reported. Design: We undertook a case controlled analysis of 8 children with DCM. Results of laboratory testing including mast cell mediator levels, and clinical symptoms on presentation and during follow-up were analyzed. Results: The levels of relevant mast cell mediators were initially high in all cases but declined sharply later on. There was a reduction of 20% in 2 of the 7 cases, whereas there was a reduction of 80% in the remaining 5. No reduction occurred in 1 case. Clinical improvement followed the same pattern. Conclusions: DCM is a rare variant of cutaneous childhood onset mastocytosis. Various forms show the same or overlapping features at various times. It appears to follow a course similar to that in other types of childhood onset mastocytosis, taking into account the decreased symptoms and the levels of mast cell mediators during follow-up. Obtaining a bone marrow biopsy should be considered only in those cases where there is no improvement or even worsening of signs or symptoms and persistent elevated levels of mast cell mediators.

The Bt-DUX: Development of a subjective measure of health-related quality of life in patients who underwent surgery for lower extremity malignant bone tumor (Article)

2009-09-01T00:00:00Z

Background. To examine the practical applicability, internal consistency, and validity of the Bt-DUX, a disease-specific Health Related Quality of Life (HRQoL) instrument. The Bt-Dux was developed to examine patients' individual values of their life after a malignant bone tumor of the lower extremity at four domains (cosmetic, social, emotional, and functional). Procedure. Patients were eligible for this cross-sectional, multicenter study if they underwent surgery for a malignant tumor of the leg in a period ranging between 12 and 60 months before the recruitment. Assessments included: Bt-DUX, Toronto Extremity Salvage Score (TESS) Short Form (SF)-36, TNO-AZL Questionnaire for Adult's Quality of Life (TAAQOL), and TNO-AZL Children's Quality of Life Questionnaire (TACQOL). Results. Seventy-two patients (35 male, 37 female), mean age 17 (SD 4) years were included. Limb sparing surgery took place in 32 patients and ablative surgery in 40 patients. The Bt-DUX was completed in less than 5 min and easy to comprehend. The mean Bt-DUX score was 69.8 (SD 15.5), with Cronbach's alpha being 0.92. Domain-total correlations ranged between 0.84 and 0.88 (P<0.01). Correlations between Bt-DUX Total score and TESS, SF-36 Physical and Mental Component Summary scales and selected TACQOL and TAAQOL scores were statistically significant (P<0.05), except for the social scale of the TACQOL. The Bt-DUX was able to discriminate between patients with higher and lower TESS scores (P<0.05). Conclusion. The Bt-DUX was found to be a practical and valid instrument. Its added value compared with existing HRQoL measures needs to be further established.

Serum tryptase and SCORMA (SCORing MAstocytosis) Index as disease severity parameters in childhood and adult cutaneous mastocytosis (Article)

2009-06-01T00:00:00Z

Skin lesions are the predominant clinical feature of the commonest form of mastocytosis. Mastocytosis is classified according to World Health Organization criteria. Determination of the levels of mast-cell mediators or their metabolites reflects the mast-cell burden. The extent of cutaneous mastocytosis can be assessed clinically using a scoring system (SCORing MAstocytosis; SCORMA Index) that we have developed. Objective. Serum tryptase levels were compared with the SCORMA Index in a large group of paediatric and adult patients to investigate whether there was any correlation between the two. Methods. The SCORMA Index in 64 patients (31 children and 33 adults) was compared with serum tryptase levels. The results of the first visit at which SCORMA and tryptase were evaluated were analysed. Results. There was a positive correlation between the SCORMA Index and serum tryptase levels, indicating the value of the SCORMA Index in the assessment of mastocytosis with skin involvement. Conclusion. The results of this study showed that the SCORMA Index is a useful tool for evaluating the severity of cutaneous mastocytosis. The correlation between the SCORMA Index and serum tryptase levels underlines the benefit of the SCORMA Index as a clinical tool. Repeated SCORMA Index measurements can provide a rapid impression of changes in the clinical state of mastocytosis. This is particularly relevant in children, because taking blood samples from this group is much more difficult. The well-established methods for evaluation of disease severity may be expanded by the rapid SCORMA Index method.

Mastocytosis in children: A protocol for management (Article)

2008-07-01T00:00:00Z

Mastocytosis is characterized by an increased number of mast cells with an abnormal growth and accumulation in one or more organs. In most children mastocytosis is limited to the skin (cutaneous mastocytosis) and often transient as compared with that in adults in whom mastocytosis is usually progressive and systemic. Generally, we recognize three more common forms of cutaneous mastocytosis: maculopapulous mastocytosis (formerly urticaria pigmentosa), mastocytoma of skin, and diffuse cutaneous mastocytosis. Childhood mastocytosis can further be divided into cutaneous mastocytosis (nonpersisting and persisting) and systemic mastocytosis (extremely rare). An approach to management using a set protocol is described in table form. In most cases of mastocytosis, only yearly checkups are necessary and no treatment is required; preventive recommendations are warranted in those individuals with systemic disease and constitutional symptoms. Symptomatic therapy is advised in only a minority of cases. This article is meant as a guideline for physicians involved in the care of children with mastocytosis and their parents.

T-cell receptor Vβ CDR3 oligoclonality frequently occurs in childhood refractory cytopenia (MDS-RC) and severe aplastic anemia (Article)

2008-06-01T00:00:00Z

(Very) severe acquired aplastic anemia ((v)SAA) and myelodysplastic syndrome (MDS) are rare diseases in childhood. (V)SAA is a bone marrow (BM) failure syndrome characterized by immune-mediated destruction of hematopoietic progenitors. MDS is a malignant clonal stem cell disorder, of which the hypoplastic variant is, in case of absence of a cytogenetic clone, difficult to separate from (v)SAA. Recently, studies provided a molecular signature of autoimmunity in adult (v)SAA, by showing oligoclonality based on the length of the TCR Vβ CDR3 region. We investigated retrospectively the frequency and the discriminative value of TCR Vβ CDR3 oligoclonality in pediatric (v)SAA and MDS patients. Peripheral blood (PB) and/or BM mononuclear cell samples of pediatric patients with (v)SAA (n=38), refractory cytopenia (MDS-RC) (n=28) and 18 controls were analysed via TCR Vβ heteroduplex PCR analysis of extracted RNA. A skewed TCR Vβ CDR3 repertoire was found in 21/38 (v)SAA and in 17/28 RC patients in contrast to 2/18 in the control group. These data suggest an overlapping group of RC and SAA patients that may share a common immune-mediated pathogenesis. Prospective studies are required to establish the clinical value of TCR Vβ CDR3 repertoire analysis to predict the clinical response in these patients.

Dexamethasone in the maintenance phase of acute lymphoblastic leukaemia treatment: Is the risk of lethal infections too high? (Article)

2007-11-01T00:00:00Z

We report an increased incidence of infectious deaths during maintenance treatment of the ninth protocol for acute lymphoblastic leukaemia of the Dutch Childhood Oncology Group (DCOG-ALL-9). The main difference in maintenance treatment between DCOG-ALL-9 and the DCOG-ALL-7 and DCOG-ALL-8 protocols is the interruption of methotrexate and 6-mercaptopurine by vincristine (2 mg/m2weekly) and dexamethasone (6 mg/m2daily) for 14 days every 7 weeks in the DCOG-ALL-9 protocol. The 1107 children treated with the DCOG-ALL-7, DCOG-ALL-8 or DCOG-ALL-9 protocol were included and screened for infectious death during maintenance treatment (July 1988-July 2002). Seven of the 510 children died of severe infections during the maintenance phase of DCOG-ALL-9, compared to none of the 597 patients during the DCOG-ALL-7 and DCOG-ALL-8 protocols (1.37% versus 0.0%; p = 0.013). Results from the current study suggest that repeated, prolonged exposure to dexamethasone results in an increase of lethal infections from 0% to 1.37%. In the dosing-schedule used, the advantage of dexamethasone may not outweigh the higher risk of infectious death.

Immunogenetic studies in childhood acute lymphoblastic leukemia : analysis at diagnosis and relapse (Doctoral Thesis)

1994-09-28T00:00:00Z