Preoperative word-finding difficulties in children with posterior fossa tumours: a European cross-sectional study.

PURPOSE: Posterior fossa tumour surgery in children entails a high risk for severe speech and language impairments, but few studies have investigated the effect of the tumour on language prior to surgery. The current crosslinguistic study addresses this gap. We investigated the prevalence of preoperative word-finding difficulties, examined associations with medical and demographic characteristics, and analysed lexical errors. METHODS: We included 148 children aged 5-17 years with a posterior fossa tumour. Word-finding ability was assessed by means of a picture-naming test, Wordrace, and difficulties in accuracy and speed were identified by cut-off values. A norm-based subanalysis evaluated performance in a Swedish subsample. We compared the demographic and medical characteristics of children with slow, inaccurate, or combined slow and inaccurate word finding to the characteristics of children without word-finding difficulties and conducted a lexical error analysis. RESULTS: Thirty-seven percent (n = 55) presented with slow word finding, 24% (n = 35) with inaccurate word finding, and 16% (n = 23) with both slow and inaccurate word finding. Children with posterior fossa tumours were twice as slow as children in the norming sample. Right-hemisphere and brainstem location posed a higher risk for preoperative word-finding difficulties, relative to left-hemisphere location, and difficulties were more prevalent in boys than in girls. The most frequent errors were lack of response and semantically related sideordinated words. CONCLUSION: Word-finding difficulties are frequent in children with posterior fossa tumours, especially in boys and in children with right-hemisphere and brainstem tumours. Errors resemble those observed in typical development and children with word-finding difficulties.

Postoperative speech impairment and cranial nerve deficits after secondary surgery of posterior fossa tumours in childhood: a prospective European multicentre study.

PURPOSE: Brain tumours constitute 25% of childhood neoplasms, and half of them are in the posterior fossa. Surgery is a fundamental component of therapy, because gross total resection is associated with a higher progression-free survival. Patients with residual tumour, progression of residual tumour or disease recurrence commonly require secondary surgery. We prospectively investigated the risk of postoperative speech impairment (POSI) and cranial nerve dysfunction (CND) following primary and secondary resection for posterior cranial fossa tumours. METHODS: In the Nordic-European study of the cerebellar mutism syndrome, we prospectively included children undergoing posterior fossa tumour resection or open biopsy in one of the 26 participating European centres. Neurological status was assessed preoperatively, and surgical details were noted post-operatively. Patients were followed up 2 weeks, 2 months and 1 year postoperatively. Here, we analyse the risk of postoperative speech impairment (POSI), defined as either mutism or reduced speech, and cranial nerve dysfunction (CND) following secondary, as compared to primary, surgery. RESULTS: We analysed 426 children undergoing primary and 78 undergoing secondary surgery between 2014 and 2020. The incidence of POSI was significantly lower after secondary (12%) compared with primary (28%, p = 0.0084) surgery. In a multivariate analysis adjusting for tumour histology, the odds ratio for developing POSI after secondary surgery was 0.23, compared with primary surgery (95% confidence interval: 0.08-0.65, p = 0.006). The frequency of postoperative CND did not differ significantly after primary vs. secondary surgery (p = 0.21). CONCLUSION: Children have a lower risk of POSI after secondary than after primary surgery for posterior fossa tumours but remain at significant risk of both POSI and CND. The present findings should be taken in account when weighing risks and benefits of secondary surgery for posterior fossa tumours.

Rare childhood hybrid histiocytosis of the central nervous system-diagnosed by stereotactic brain biopsy with marked treatment response to clofarabine.

Histiocytosis is a heterogeneous group of disease entities, comprised by two main categories, namely Langerhans and non-Langerhans cell histiocytoses. Central nervous system involvement in histiocytosis is considered very rare and is often secondary to affection of anatomically related bone structures and/or multi-organ disease. We present a never-before described case of rare childhood histiocytosis with hybrid features of Langerhans cell histiocytosis and juvenile xanthogranuloma confined to the central nervous system in a 2- and a half-year-old boy with distinct treatment response to clofarabine. The case also emphasizes the diagnostic significance of stereotactic brain biopsy.

Infectious exposure in the first years of life and risk of central nervous system tumours in children: analysis of birth order, childcare attendance and seasonality of birth.

BACKGROUND: An infective, mostly viral basis has been found in different human cancers. To test the hypothesis of a possible infectious aetiology for central nervous system (CNS) tumours in children, we investigated the associations with proxy measures of exposure to infectious disease. METHODS: In a large case-control study nested in the populations of Denmark, Norway, Sweden, and Finland of 4.4 million children, we studied the association of birth order and seasonal variation of birth with subsequent risk for CNS tumours. We identified 3983 children from the national cancer registries, and information on exposure was obtained from the high-quality national administrative health registries. We investigated the association between childcare attendance during the first 2 years of life and the risk for CNS tumours in a subset of Danish children with CNS tumours, using information from the Danish Childcare database. RESULTS: We observed no association between birth order and risk of CNS tumours overall (odds ratio (OR) for second born or later born vs first born, 1.03; 95% confidence interval (CI), 0.96-1.10) or by histological subgroup, and children with CNS tumours did not show a seasonal variation of birth that was distinct from that of the background population. Childcare attendance compared with homecare showed a slightly increased OR (1.29; 95% CI, 0.90-1.86) for CNS tumours, with the highest risk observed in children attending a crèche. The strongest association was observed for embryonal CNS tumours. We found no effect of age at enrolment or duration of enrolment in childcare. CONCLUSION: These results do not support the hypothesis that the burden of exposure to infectious disease in early childhood has an important role in the aetiology of paediatric CNS tumours.

New evidence for the origin of intracranial germ cell tumours from primordial germ cells: expression of pluripotency and cell differentiation markers.

Primary intracranial germ cell tumours are rare neoplasms that occur in children and adolescents. This study examined both the biology and the origin of these tumours, as it has been hypothesized that they originate from a totipotent primordial germ cell. We applied recent knowledge from gonadal germ cell tumours and analysed expression of a wide panel of stem cell-related proteins (C-KIT, OCT-3/4 (POU5F1), AP-2gamma (TFAP2C), and NANOG) and developmentally regulated germ cell-specific proteins (including MAGE-A4, NY-ESO-1, and TSPY). Expression at the protein level was analysed in 21 children and young adults with intracranial germinomas and non-germinomas, contributing to a careful description of these unusual tumours and adding to the understanding of pathogenesis. Stem cell related proteins were highly expressed in intracranial germ cell tumours, and many similarities were detected with their gonadal equivalents, including a close similarity with primordial germ cells. A notable difference was the sex-specific expression of TSPY, a gene previously implicated in the origin of gonadoblastoma. TSPY was only detected in germ cell tumours in the central nervous system (CNS) from males, suggesting that it is not required for the initiation of malignant germ cell transformation. The expression of genes associated with embryonic stem cell pluripotency in CNS germ cell tumours strongly suggests that these tumours are derived from cells that retain, at least partially, an embryonic stem cell-like phenotype, which is a hallmark of primordial germ cells.

Hormonal changes during GnRH analogue therapy in children with central precocious puberty.

Gonadotropin releasing hormone analogues (GnRHa) have been used for treatment of central precocious puberty (CPP) for more than 15 years. They are generally considered safe although data on potential long-term side effects are scarce. However, GnRHa therapy has profound effects on both the hypothalamopituitary-gonadal axis as well as on growth hormone (GH) secretion. Gonadal activity is increased in children with CPP; during GnRHa therapy secretion of gonadal hormones is suppressed as reflected by measurements of LH, FSH, and estradiol/testosterone. More recently, studies of levels of inhibin A and B as well as markers of androgen action such as SHBG and prostate specific antigen have demonstrated marked suppression of gonadal function possibly to infra-physiological levels. The possible long-term consequences of these observations have yet to be determined. Detailed analyses of the GH-IGF-I axis have revealed a decrease in levels of free, biologically active IGF-I during GnRHa treatment. These findings are in accord with the observed decrease in height velocity in children with CPP under treatment with GnRHa, and may also play a role in the relatively small gain in final height in most patients.

Serum inhibin A and inhibin B in healthy prepubertal, pubertal, and adolescent girls and adult women: relation to age, stage of puberty, menstrual cycle, follicle-stimulating hormone, luteinizing hormone, and estradiol levels.

Biochemical assessment of gonadal function during maturation in girls and in adult women can be troublesome. With the recent advent of specific assays for the gonadal peptides inhibin A and inhibin B, it might be possible to achieve a clearer picture of events. We therefore determined serum levels of inhibin A, inhibin B, FSH, LH and estradiol in a cross-sectional study of 403 healthy schoolgirls (aged 6 -20 yr) in relation to age and stage of puberty and in 181 healthy nonpregnant women (aged 20-32 yr) in relation to stage of the menstrual cycle. In addition, inhibin A and inhibin B were measured daily throughout the menstrual cycle in 10 healthy adult women. Levels of inhibin B are low or undetectable in prepubertal girls (median, 26.5 pg/mL; 95% prediction interval, <20-100 pg/mL), increase sharply through pubertal stage II to peak in stage III (median, 84 pg/mL; 95% prediction interval, 28-227 pg/mL) and thereafter decline through pubertal stages IV and V. These changes presumably reflect increasing ovarian stimulation through early puberty, resulting in an increased number of developing follicles, follicles reaching a later stage of development before undergoing atresia, or both. Declining levels in late puberty and adulthood probably reflect the onset of the menstrual cycle and the subsequent appearance of the luteal phase, where inhibin B levels are low. Inhibin A levels are undetectable or very low in early puberty (median, <7 pg/mL; 95% prediction interval, <7-14) pg/mL), increasing gradually through pubertal stages to reach their highest values in adult women (median, 21.5 pg/mL; 95% prediction interval, <7-129 pg/mL). Levels of inhibin A greater than 19 pg/mL are only seen in postmenarcheal girls in puberty and in adult women, again consistent with inhibin A being primarily produced by the corpus luteum. Determining cut-off levels of serum inhibin B regarding whether a girl had entered puberty resulted in similar (low) sensitivities and specificities as those found for cut-off levels of LH or estradiol due to the large overlap between serum values in Tanner stages I and II. Correlations between inhibin A and inhibin B and FSH, LH, and estradiol within pubertal stages are presented. In early puberty both inhibin A and inhibin B correlated positively with LH and FSH. In late puberty inhibin A correlated negatively with FSH and did not correlate with LH; inhibin B still correlated positively with both FSH and LH, now most strongly with FSH. In adult women during the menstrual cycle, serum inhibin B levels increased during the follicular phase, indicating the greatest production by follicles in early stages of development. In contrast, serum inhibin A levels peaked during the luteal phase, indicating the greatest production by the corpus luteum. In conclusion, serum inhibin A and inhibin B levels in normal puberty in girls show consistency with our knowledge of the manner in which these hormones are secreted within the menstrual cycle in adult women. The presented reference values may be of use in the clinical evaluation of pubertal development in girls.

Serum inhibin A and inhibin B in central precocious puberty before and during treatment with GnRH agonists.

Serum levels of the gonadal hormones inhibin A and inhibin B are undetectable or low in prepubertal girls, and rise during puberty. In girls with central precocious puberty (CPP) the hypothalamic-pituitary-gonadal axis is prematurely activated, if the girl is thereafter treated with GnRH agonists both gonadotropins and estradiol levels become suppressed. We therefore investigated serum levels of inhibin A and inhibin B in girls with CPP at diagnosis and during treatment in order to test the hypothesis that inhibin secretion would increase and decrease in parallel with the activation and suppression of the hypothalamic-pituitary-gonadal axis. Serum levels of inhibin A and inhibin B were significantly (p < 0.0005) elevated in 42 girls at diagnosis of CPP (inhibin A: 7 pg/ml (<7--139), inhibin B: 80 pg/ml (<20--294) (median, range)) compared to levels in age-matched healthy schoolgirls (inhibin A: all values <7 pg/ml, inhibin B: 21 pg/ml (<20--122) (median, range)), but were appropriate for Tanner stage. During treatment with GnRH agonist (intranasal buserelin and oral cyproterone acetate, treatment group 1, n = 23, or triptorelin depot injections, treatment group 2, n = 19) levels of both hormones fell significantly (p = 0.002). There was a significantly (p = 0.003) greater fall in inhibin B levels during treatment in group 2 compared to group 1, with inhibin B levels now lying below (group 2: <20 pg/ml (<20--68)) rather than within (group 1: 34.5 pg/ml (<20--93)) the age-appropriate range. It is concluded that levels of inhibin A and inhibin B are elevated and suppressed in concert with activation and suppression of the hypothalamo-pituitary-gonadal axis in girls with CPP, supporting the concept that ovarian inhibin secretion is dynamically regulated by gonadotropin stimulation.

Preoperative prediction model of outcome after cholecystectomy for symptomatic gallstones.

BACKGROUND: After cholecystectomy for symptomatic gallstone disease 20%-30% of the patients continue to have abdominal pain. The aim of this study was to investigate whether preoperative variables could predict the symptomatic outcome after cholecystectomy. METHODS: One hundred and two patients were referred to elective cholecystectomy in a prospective study. Median age was 45 years; range, 20-81 years. A preoperative questionnaire on pain, symptoms, and history was completed, and the questions on pain and symptoms were repeated 1 year postoperatively. Preoperative cholescintigraphy and sonography evaluated gallbladder motility, gallstones, and gallbladder volume. Preoperative variables in patients with or without postcholecystectomy pain were compared statistically, and significant variables were combined in a logistic regression model to predict the postoperative outcome. RESULTS: Eighty patients completed all questionnaires. Twenty-one patients continued to have abdominal pain after the operation. Patients with pain 1 year after cholecystectomy were characterized by the preoperative presence of a high dyspepsia score, 'irritating' abdominal pain, and an introverted personality and by the absence of 'agonizing' pain and of symptoms coinciding with pain (P < 0.000001). In a constructed logistic regression model 15 of 18 predicted patients had postoperative pain (PVpos = 0.83). Of 62 patients predicted as having no pain postoperatively, 56 were pain-free (PVneg = 0.90). Overall accuracy was 89%. CONCLUSION: From this prospective study a model based on preoperative symptoms was developed to predict postcholecystectomy pain. Since intrastudy reclassification may give too optimistic results, the model should be validated in future studies.

Long-term follow-Up of an infant with thyrotoxicosis due to germline mutation of the TSH receptor gene (Met453Thr).

UNLABELLED: A 18-year clinical follow-up period in a male patient with a germline TSH-R gene mutation (Met453Thr) is described. Nonautoimmune thyrotoxicosis was diagnosed at the age of 7 months. The patient had exophthalmus, failure to thrive, advanced bone age and no goiter. Long-term antithyroid drug treatment (ATD) was necessary during childhood. At the age of 7 years he developed a goiter. Subtotal thyroidectomy was performed at the age of 9 years, followed by repeated ablative radiotherapy at the age of 9.5-13 years due to a toxic multinodular goiter. After 13 years ATD could be discontinued and the patient was euthyroid until 16 years of age, where L-thyroxine substitution had to be started. The exophthalmus diminished, and had disappeared at the age of 18 years, when CT scan of the orbit was performed. CONCLUSION: TSH-R mutation must be considered in early nonautoimmune thyrotoxicosis. A very aggressive treatment strategy is necessary.