Kristian Aquilina

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.

Selective dorsal rhizotomy: an old treatment re-emerging

Selective dorsal rhizotomy (SDR) is a neurosurgical technique developed to reduce spasticity and improve mobility in children with cerebral palsy (CP) and lower extremity spasticity. It involves the selective division of lumbosacral afferent (sensory) rootlets at the conus or at the intervertebral foramina under intraoperative neurophysiological guidance. First described in 1908, early procedures were effective at reducing spasticity but were associated with significant morbidity. Technical advancements over the last two decades have reduced the invasiveness of the procedure, typically from a five-level laminoplasty to a single-level laminotomy at the conus. As practised today, SDR is an effective treatment for young patients with bilateral spastic CP who are rigorously selected for surgery and for whom realistic objectives are set. SDR has therefore re-emerged as a valuable management option for spastic CP. In this article, the authors review the single-level SDR technique and its role in the management of bilateral spastic CP, with particular emphasis on patient selection and outcomes.

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.

Surgical decision-making in the management of childhood tumors of the CNS disseminated at presentation

OBJECTIVE It is relatively unusual for pediatric CNS tumors to be disseminated at presentation, and the literature on the clinical features, management, and outcomes of this specific group is scarce. Surgical management in this population is often challenging, particularly in the presence of hydrocephalus. The authors present their recent experience of treating pediatric CNS tumors that were disseminated at presentation, and they compare these lesions with focal tumors. METHODS The authors performed a retrospective review of prospectively collected data on children presenting to a tertiary center between 2003 and 2016 inclusive. RESULTS Of 361 children with CNS tumors, the authors identified 53 patients with disease dissemination at presentation (male/female ratio 34:19, median age 3.8 years, age range 7 days to 15.6 years) and 308 without dissemination at presentation (male/female ratio 161:147, median age 5.8 years, age range 1 day to 16.9 years). Five tumor groups were studied: medulloblastoma (disseminated n = 29, focal n = 74), other primitive neuroectodermal tumor (n = 8, n = 17), atypical teratoid rhabdoid tumor (n = 8, n = 22), pilocytic astrocytoma (n = 6, n = 138), and ependymoma (n = 2, n = 57). The median follow-up duration in survivors was not significantly different between those with disease dissemination at presentation (64.0 months, range 5.2-152.0 months) and those without it (74.5 months, range 4.7-170.1 months) (p > 0.05). When combining data from all 5 tumor groups, dissemination status at presentation was significantly associated with a higher risk of requiring CSF diversion, a higher surgical complication rate, and a reduced likelihood of achieving gross-total resection of the targeted lesion (all variables p < 0.05). Differences between the 5 tumor groups were evident. No factors that predicted the need for permanent CSF diversion following temporary external ventricular drainage were identified on multivariate analysis, and there was no clear superiority of either ventriculoperitoneal shunt surgery or endoscopic third ventriculostomy as a permanent CSF diversion procedure. CONCLUSIONS Tumor type and dissemination status at initial presentation significantly affect outcomes across a range of measures. The management of hydrocephalus in patients with CNS tumors is challenging, and further prospective studies are required to identify the optimal CSF diversion strategy in this population.

Early Wound Site Seeding in a Patient with Central Nervous System High-Grade Neuroepithelial Tumor with BCOR Alteration

BACKGROUND Advances in molecular profiling have facilitated the emergence of newly defined entities of central nervous system (CNS) tumor, including CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR). Relatively little is known about the clinical behavior of these newly characterized tumors. CASE DESCRIPTION We describe a pediatric male patient with CNS HGNET-BCOR, who developed seeding of the tumor into the site of the surgical wound within months of surgery and who underwent resection of a residual posterior fossa tumor. CONCLUSIONS This case emphasizes 3 important points. First, CNS HGNET-BCOR can be aggressive tumors that necessitate close clinical and radiologic surveillance. Second, surveillance imaging in such cases should incorporate the surgical incision site into the field of view, and this should be closely scrutinized to ensure the timely detection of wound site seeding. Third, wound site seeding may still occur despite the use of meticulous surgical techniques.

Selective dorsal rhizotomy: current state of practice and the role of imaging

Spastic diplegic cerebral palsy (CP) is the most common form of CP. A specific goal-oriented approach, tailored to the child, is essential to management in all forms of CP. Selective dorsal rhizotomy (SDR) is a neurosurgical procedure that permanently reduces lower limb spasticity in children with spastic diplegic CP. The current technique is performed through a single level laminectomy at the level of the conus and, with the aid of intraoperative electromyography (EMG), allows selective division of the afferent lumbosacral nerve roots. In carefully selected children, reduction in spasticity has positive effects on the growing child. SDR is associated with minimal complications and good long-term outcomes. This article describes the surgical technique and patient selection, including the importance of medical imaging, and discusses the long-term outcomes of SDR.

Intracranial Neoplasms in the First Year of Life: Results of a Third Cohort of Patients From a Single Institution

BACKGROUND Brain tumors in the first year of life are rare and their management remains challenging. OBJECTIVE To report on the contemporary management of brain tumors in infants with reference to previous series from our institution. METHODS Retrospective cohort study design. Electronic/paper case note review of all brain tumors diagnosed at our institution in children aged <1 yr since the publication of our previous series. RESULTS Ninety-eight patients were seen. The most common presentations were with vomiting and macrocrania, at a median age of 184 d. Sixty-two percent of tumors were supratentorial. Ninety-one patients underwent 230 procedures; 7 patients had no surgery. One hundred eighteen operations were directly on brain tumors (biopsy 37, subtotal resection 47, gross total resection 34). Ninety-one cerebrospinal fluid diversions, 9 endoscopic procedures, and 13 preoperative embolizations were performed. Operative mortality was 4.4%. Tumor types in order of frequency were choroid plexus papillomas (CPP, 17), primitive neuroectodermal tumor (12), atypical teratoid/rhabdoid tumor (10), high-grade glioma (9), optic glioma (9), ependymoma (8), low-grade glioma (6), pilocytic astrocytoma (6), choroid plexus carcinoma (5), and teratoma (5), with 11 miscellaneous tumors. Survival was 93% at 1 mo (91/98), 64% at 1 yr (61/95), 44% at 5 yr (32/73), 28% at 10 yr (16/58). No patients with CPP or low-grade glioma died. Five-year survival rates were lowest for anaplastic ependymoma, primitive neuroectodermal tumor, and atypical teratoid/rhabdoid tumor. Seventy-seven percent of children reaching school age were in mainstream schooling. CONCLUSION Overall survival from neonatal brain tumors remains similar to previous series; analysis of tumor subtypes reveals improvements for CPP and gliomas. Despite increasing operative intervention, operative mortality continues to decline for this group of challenging patients.

Quantitative MRI in post-operative paediatric cerebellar mutism syndrome

Post-operative paediatric cerebellar mutism syndrome (pCMS) occurs in around 25% of children undergoing surgery for cerebellar and fourth ventricular tumours. Reversible mutism is the hallmark of a syndrome which comprises severe motor, cognitive and linguistic deficits. Recent evidence from advanced neuroimaging studies has led to the current theoretical understanding of the condition as a form of diaschisis contingent on damage to efferent cerebellar circuitry. Tractography data derived from diffusion MRI studies have shown disruption of the dentato-rubro-thalamo-cortical tract in patients with pCMS, and perfusion studies have indicated widespread supratentorial regions which may give rise to the florid signs and symptoms of pCMS. Given the difficulties in predicting pCMS from standard structural MRI, this review discusses findings from quantitative MRI modalities which have contributed to our understanding of this debilitating syndrome, and considers the goals and challenges which lie ahead in the field.

Surgical Treatment of Human ACP

Adamantinomatous craniopharyngiomas are complex cystic-solid lesions, typically located within the suprasellar cistern. Their growth causes symptoms by pressure and distortion of the optic nerves and chiasm, the hypothalamus and the pituitary gland. Involvement of the third ventricle causes hydrocephalus. Initial management is surgical and directed towards preservation of vision and control of raised intracranial pressure. Further surgical management is dictated by the extent of hypothalamic involvement, evident on clinical presentation and magnetic resonance imaging. Limited surgery, followed by radiotherapy, is as effective at long-term local control as aggressive surgery aimed at complete resection. The former approach is superior at protecting hypothalamic function and is preferable whenever hypothalamic involvement by the tumour is significant.