Helen Spoudeas

Do doctors discuss fertility issues before they treat young patients with cancer

BACKGROUND Many children treated for cancer are at risk of infertility, but for girls and prepubertal boys, all fertility preservation techniques remain experimental. We have assessed UK practice relating to information provision about the effects of cancer treatment on fertility and options for fertility preservation. METHODS Paediatric oncologists prospectively completed a data form for each new patient registered over a 12 month period. RESULTS Data were available on 1030 patients (68% of total registered). The effect of cancer treatment on fertility was discussed with 63% of patients. Of these, 61% were judged to be at high or medium risk of fertility problems. Discussions took place more commonly with boys than girls; the commonest reason for discussion not occurring was young age. The majority (83%) of post-pubertal boys assessed as high/medium risk of infertility were referred for semen cryopreservation. This rate fell to 39% of those in early puberty. Only 1% (n=4) of girls were referred to an assisted conception unit. CONCLUSIONS These data indicate a high awareness of the potential adverse effects of therapy on fertility among UK paediatric oncologists. High referral rates for older boys indicate that current guidelines are followed, but there is a need for fertility preservation techniques for girls and younger boys.

Tests of adrenal insufficiency

AIM In suspected adrenal insufficiency, the ideal test for assessing the hypothalamo–pituitary–adrenal axis is controversial. Therefore, three tests were compared in patients presenting with symptoms suggestive of adrenal insufficiency. METHOD Responses to the standard short Synacthen test (SSST), the low dose Synacthen test (LDST), and the 08:00 hour serum cortisol concentration were measured in 32 patients. A normal response to the synacthen test was defined as a peak serum cortisol of ⩾ 500 nmol/l and/or incremental concentration of ⩾ 200 nmol/l. The sensitivity and specificity of the 08:00 hour serum cortisol concentration compared with other tests was calculated. RESULTS Three patients had neither an adequate peak nor increment after the SSST and LDST. All had a serum 08:00 hour cortisol concentration of < 200 nmol/l. Eight patients had abnormal responses by both criteria to the LDST but had normal responses to the SSST. Three reported amelioration of their symptoms on hydrocortisone replacement. Twenty one patients had a normal response to both tests (of these, 14 achieved adequate peak and increment after both tests and seven did not have an adequate peak after the LDST but had a normal increment). The lowest 08:00 hour serum cortisol concentration above which patients achieved normal responses to both the LDST and SSST was 500 nmol/l. At this cut off value (compared with the LDST), the serum 08:00 hour cortisol concentration had a sensitivity of 100% but specificity was only 33%. CONCLUSION The LDST revealed mild degrees of adrenal insufficiency not detected by the SSST. The value of a single 08:00 hour serum cortisol concentration is limited.

Reduction of Health Status 7 Years After Addition of Chemotherapy to Craniospinal Irradiation for Medulloblastoma: A Follow-Up Study in PNET 3 Trial Survivors—on Behalf of the CCLG (formerly UKCCSG)

PURPOSE To compare quality of survival after craniospinal irradiation (CSI) alone with survival after CSI plus chemotherapy (CT) for medulloblastoma. PATIENTS AND METHODS Follow-up study of surviving UK patients with medulloblastoma diagnosed between 1992 and 2000 treated according to one or other treatment arm of the PNET 3 controlled trial. RESULTS Seventy three percent of all 147 eligible patients ages 6.6 to 24.3 years were assessed at a mean of 7.2 years after diagnosis. Health status was significantly poorer in the group treated in the CSI plus CT arm of the trial than in the CSI alone arm, and there were also trends to poorer outcomes for behavior and quality of life scores. The CSI plus CT group were also significantly more restricted physically and needed more therapeutic and educational support. Body mass index, stature, and other endocrine outcomes were similar in the two treatment arms, except for the trend in increased frequency of medical induction of puberty in the CSI plus CT group. CONCLUSION The addition of CT to CSI for medulloblastoma was associated with a significant decrease in health status. The effect of the addition of other CT regimens to CSI on quality of survival should be evaluated.

Growth and endocrine function after chemotherapy and radiotherapy in childhood

85% of childhood cancer survivors, particularly those treated youngest, most intensively or for central nervous system (CNS) tumours, face cognitive, neuropsychological and endocrine impairment. Future challenges include the prevention of premature mortality from treatmentinduced second tumours, cardiac, pulmonary and renal toxicity, and morbidity from hypopituitarism, obesity and their metabolic consequences. Improving quality of life (QoL) by early hormone replacement, preservation of fertility and neuropsychological rehabilitation will enable these young people to achieve employment, independence and successful peer relationships.

Neuroendocrine Morbidity After Pediatric Optic Gliomas: A Longitudinal Analysis of 166 Children Over 30 Years

CONTEXT Fifty percent of pediatric low-grade gliomas affect the optic pathway, hypothalamus, and suprasellar areas (OP/HSGs), resulting in significant long-term neuroendocrinopathy. OBJECTIVE This study aimed to dissect tumor- from treatment-related risk factors for OP/HSG-associated neuroendocrinopathy. DESIGN This was a retrospective case notes analysis of 166 children with newly diagnosed OP/HSGs at our quaternary center between 1980 and 2010 by multivariate Cox, linear, and logistic regression. RESULTS Patients were of median (range) age 4.9 (0.2-15.4) years at diagnosis and followed up for 8.3 (0.04-26.8) years. Despite high 20-year overall survival (81.0%), progression-free and endocrine event-free survival (EEFS) were 47.2 and 20.8%, respectively. EEFS declined up to 15 years post-diagnosis, with hypothalamic involvement (P < .001) being implicated more than radiotherapy (P = .008) in earlier endocrinopathy; the reverse being true of its density (radiotherapy P < .001; hypothalamic involvement P = .006). GH deficiency (GHD) was most common (40.3%), followed by central precocious puberty (CPP, 26.0%), gonadotropin (GnD; 20.4%), TSH (13.3%), and ACTH (13.3%) deficiencies. GHD increased with later treatment eras (P < .01), but replacement did not increase progression. CPP was associated with future GnD (P < .05). Posterior pituitary dysfunction (PPD; 7.2%) occurred in 57.9% after only biopsies or shunt procedures, and was associated with 6/13 deaths; 50.2% became obese. Tumor extent, surgery, and increased endocrinopathy, rather than radiotherapy, predicted visuocognitive morbidity. CONCLUSIONS This first longitudinal OP/HSG-specific study demonstrates that hypothalamo-pituitary dysfunction evolves hierarchically over decades. Tumor location predicts its speed of onset and radiotherapy its density. GnD can evolve from previous CPP, whereas life-threatening PPD can occur after any surgery. Our data suggest that recent radiation-avoiding chemotherapeutic strategies have increased GHD without improving survival.

The role of the sonic hedgehog signalling pathway in patients with midline defects and congenital hypopituitarism

The Gli family of zinc finger (GLI) transcription factors mediates the sonic hedgehog signalling pathway (HH) essential for CNS, early pituitary and ventral forebrain development in mice. Human mutations in this pathway have been described in patients with holoprosencephaly (HPE), isolated congenital hypopituitarism (CH) and cranial/midline facial abnormalities. Mutations in Sonic hedgehog (SHH) have been associated with HPE but not CH, despite murine studies indicating involvement in pituitary development.

The neuroendocrine sequelae of paediatric craniopharyngioma: a 40-year meta-data analysis of 185 cases from three UK centres

OBJECTIVES The management of paediatric craniopharyngiomas was traditionally complete resection (CR), with better reported tumour control compared to that by partial resection (PR) or limited surgery (LS). The subsequent shift towards hypothalamic sparing, conservative surgery with adjuvant radiotherapy (RT) to any residual tumour aimed at reducing neuroendocrine morbidity, has not been systematically studied. Hence, we reviewed the sequelae of differing management strategies in paediatric craniopharyngioma across three UK tertiary centres over four decades. METHODS Meta-data was retrospectively reviewed over two periods before (1973-2000 (Group A: n = 100)) and after (1998-2011 (Group B: n = 85)) the introduction of the conservative strategy at each centre. RESULTS Patients had CR (A: 34% and B: 19%), PR (A: 48% and B: 46%) or LS (A: 16% and B: 34%), with trends reflecting the change in surgical approach over time. Overall recurrence rates between the two periods did not change (A: 38% vs B: 32%). More patients received RT in B than A, but recurrence rates were similar: for A, 28% patients received RT with 9 recurrences (32%); for B, 62% received RT with 14 recurrences (26%). However, rates of diabetes insipidus (P = 0.04), gonadotrophin deficiency (P < 0.001) and panhypopituitarism (P = 0.001) were lower in B than those in A. In contrast, post-operative obesity (BMI SDS >+2.0) (P = 0.4) and hypothalamic (P = 0.1) and visual (P = 0.3) morbidity rates were unchanged. CONCLUSION The shift towards more conservative surgery has reduced the prevalence of hormone deficiencies, including diabetes insipidus, which can be life threatening. However, it has not been associated with reduced hypothalamic and visual morbidities, which remain a significant challenge. More effective targeted therapies are necessary to improve outcomes.

Thyroid Surgery in Children: Clinical Outcomes

AIM The aim of this study was to review the outcomes of thyroid surgery in children operated for both benign and malignant conditions. PATIENTS AND METHOD Demography, clinical features, and surgical outcomes were noted retrospectively for operations performed during the last 23 years. Results were analyzed using Fisher exact test and Woolf (logit) method with p value < 0.05 considered as significant. RESULTS In total, 61 children (43 girls and 18 boys) underwent thyroidectomy for benign (70%) and malignant (30%) conditions. Median follow-up period was 1.4 years. In the benign group, 84% children had Graves disease and 16% had other conditions. In this study, 42% children had total, 22% had near-total, 27% had subtotal, and 9% had type 2 hemithyroidectomy. In the malignant group, 50% had multiple endocrine neoplasia, 33% had papillary, 11% had follicular cancer, and 6% had B-cell lymphoma. Fifty percent children had prophylactic thyroidectomy, 44% had total thyroidectomy plus lymphadenectomy, and 6% had hemithyroidectomy. At the time of surgery, children with benign conditions were older than those with malignancy (median, 12 vs. 7.5 years). There were no incidents of postoperative bleeding or infection. Hypocalcemia was significantly more frequent in the malignant group (39 vs. 9%, p value = 0.01). The type of recurrent laryngeal nerve (RLN) injury was more serious in the benign group (one bilateral and one unilateral permanent injury) than in the malignant group (transient hoarseness in three). Overall rate of complications was higher for operations for malignancy (56 vs. 28%, p value = 0.07). In Graves disease, the subtotal thyroidectomies had a recurrence of 30% but no recurrence was seen following total or near-total thyroidectomy group (p value = 0.01). There was no recurrence in the malignant group. Children operated after 2000 were younger than those operated before 2000 (median age, 9 vs. 14 years). Malignant conditions were more common in children operated after 2000 in comparison to before 2000 (55 vs. 10%). CONCLUSION Benign conditions are commonest indications for thyroid surgery in children but the incidence of surgery for malignant conditions is rising. Overall rate of complications, especially hypocalcemia, is higher after surgery for malignancy but all cases of permanent RLN injury were in benign group. Total or near total thyroidectomy prevents recurrence of thyrotoxicosis and is an operation of choice for Graves disease.

Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target

Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP.

Medical management and antiepileptic drugs in hypothalamic hamartoma

Hypothalamic hamartoma may present with epilepsy, specifically gelastic or dacrystic seizures, or endocrine dysfunction, commonly precocious puberty. The epilepsy in many patients is drug resistant, and has a high association with progressive cognitive, learning and behavioral difficulty. Medical treatment of seizures remains problematic, with many resistant to drug treatment. Surgical resection, or disconnection of the hamartoma provides the optimal chance of seizure control but with a relatively high risk of endocrine dysfunction, the result of interference with the hypothalamic‐pituitary axis in many. Careful assessment and monitoring by specialist centers with discussion of optimal intervention is required for individual cases.