Molecular pathogenesis of craniopharyngioma: switching from a surgical approach to a biological one

Craniopharyngioma has long been considered a benign tumor because of its pathological aspect. This primordial view of craniopharyngioma fit with the primitive treatment attempts based on blind resection of the tumor each time it recurred. The limits of this management strategy were proven early by the high morbidity related to the resection and recurrence risk despite radical lesion removal. Nowadays, craniopharyngioma must be considered a complex molecular disease, and a detailed explanation of the mechanisms underlying its aggressive biological and clinical behavior, despite some benign pathological features, would be the first step toward defining the best management of craniopharyngioma. Indeed, advances in the knowledge of the molecular mechanisms at the base of craniopharyngioma oncogenesis will lead to comprehension of the critical checkpoints involved in neoplastic transformation. The final research target will be the definition of new biological agents able to reverse the neoplastic process by acting on these critical checkpoints. This biological approach will lead to a refined therapy combining higher efficacy and safety with lower morbidity. In this paper the authors reveal state-of-the-art comprehension of the molecular biology of craniopharyngioma and the consequent therapeutic implications

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. KEYWORDS: Craniopharyngioma; IL1-β; Inflammasome; MAPK/ERK pathway; Odontogenesis; Paracrine signalling; Trametini

Hydrocephalus in prematurity: does valve choice make a difference?

Abstract Purpose Extremely premature neonates diagnosed with post-haemorrhagic hydrocephalus (PHH) are recognised to have particularly poor outcomes. This study assessed the impact of a number of variables on outcomes in this cohort, in particular the choice of shunt valve mechanism. Methods Electronic case notes were retrospectively reviewed of all premature neonates admitted to our centre for management of hydrocephalus between 2012 and 2021. Data included (i) gestational age, (ii) birth weight, (iii) hydrocephalus aetiology, (iv) surgical intervention, (v) shunt system, (vi) ‘surgical burden’ and (vii) wound failure and infection rate. Data was handled in Microsoft Excel and statistical analysis performed in SPSS v27.0 Results N = 53 premature hydrocephalic patients were identified (n = 28 (52.8%) female). Median gestational age at birth was 27 weeks (range: 23–36 + 6 weeks), with n = 35 extremely preterm patients and median birth weight of 1.9 kg (range: 0.8–3.6 kg). Total n = 99 programmable valves were implanted (n = 28 (28.3%) de novo, n = 71 (71.2%) revisions); n = 28 (28.3%) underwent n ≥ 1 pressure alterations, after which n = 21 (75%) patients had symptoms improve. In n = 8 patients exchanged from fixed to programmable valves, a mean reduction of 1.9 revisions per patient after exchange was observed (95%CI: 0.36–3.39, p = 0.02). Mean overall shunt survival was 39.5 weeks (95%CI: 30.6–48.5); 33.2 weeks (95%CI: 25.2–41.1) in programmable valves and 35.1 weeks (95%CI: 19.5–50.6) in fixed pressure (p = 0.22) with 12-month survival rates of 25.7% and 24.7%, respectively (p = 0.22). Shorter de novo shunt survival was associated with higher operation count overall (Pearson’s R: − 0.54, 95%CI: − 0.72 to − 0.29, p &lt; 0.01). Wound failure, gestational age and birth weight were significantly associated with shorter de novo shunt survival in a Cox regression proportional hazards model; gestational age had the greatest impact on shunt survival (Exp(B): 0.71, 95%CI: 0.63–0.81, p &lt; 0.01). Conclusion Hydrocephalus is especially challenging in extreme prematurity, with a shorter de novo shunt survival associated with higher number of future revisions. Programmable valves provide flexibility with regard to pressure setting, with the potential for fewer shunt revisions in this complex cohort. </jats:sec

A tailored approach to the management of post-haemorrhagic hydrocephalus

Abstract Purpose Neuro-endoscopic lavage (NEL) is an increasingly popular intervention for intraventricular haemorrhage (IVH) and post-haemorrhagic hydrocephalus (PHH), with considerable variation in technique dependent on clinician and clinical circumstances. Whilst efforts to standardise the technique are ongoing, this work describes a tertiary centre experience utilising NEL, highlighting potential caveats to standardisation. Methods A retrospective review of electronic case notes for patients undergoing temporising surgical intervention for IVH between 2012 and 2021 at our centre was performed. Data collected included (i) gestational age, (ii) aetiology of hydrocephalus, (iii) age at time of intervention, (iv) intervention performed, (v) need for permanent CSF diversion, (vi) ‘surgical burden’, i.e. number of procedures following primary intervention, and (vii) wound failure and infection rate. Data was handled in Microsoft Excel and statistical analysis SPSS v27.0 Results 49 neonates (n = 25 males) were included. Overall mean gestational age was 27 weeks and at intervention 35 + 3 weeks. IVH was the predominant cause of hydrocephalus (93.8%) and primary surgical interventions included insertion of a ventriculosubgaleal shunt (VSGS) in n = 41 (83.6%) patients, NEL in n = 6 (12.2%) patients and insertion of an EVD in n = 2 (4.1%). N = 9 (18.4%) patients underwent NEL at some point during the time interval reviewed; n = 4 (8.2%) received NEL monotherapy and n = 5 (10.2%) also received a VSGS. Rate of conversion to definitive CSF diversion between NEL (n = 8, 88.9%) and VSGS cohorts (n = 37, 92.5%) was not significantly different (p = 0.57), nor between NEL alone (n = 3, 75%) and NEL + VSGS (n = 5, 100%) (p = 0.44). None of the patients that underwent NEL monotherapy had any wound issues or CNS infection as a result of the initial intervention, compared to n = 3 (60%) of those that underwent NEL and implantation of VSGS (p = 0.1). Conclusion Both NEL and VSGS are effective in temporising hydrocephalus in neonates, occasionally offering a definitive solution in and of themselves. The benefit of dual therapy however remains to be seen, with the addition of VSGS potentially increasing the risk of wound failure in an already vulnerable cohort. </jats:sec

Decompressive craniectomy for traumatic brain injury: patient age and outcome

The overall degree by which different patients may benefit from decompressive craniectomy (DC) remains controversial. In particular, the prognostic value of age has been investigated by very few studies. Many authors state there is no significant benefit in performing a DC in severe head injury after a certain age limit, with most placing the limit at 30-50 years of age. Between 1994 and 2004, 55 patients underwent DC at our institution. Advanced age did not constitute a contraindication to surgery for both ethical and cultural reasons. Thus, the data obtained were not biased by a selection of patients based on age. We analyzed potential predictors of outcome after DC, including sex, age, Glasgow Coma Scale (GCS), and presence of mass lesion. Chi-square test was used to compare categorical variables. The independent contribution of predictive factors to outcome was studied using logistic regression analysis. Initial GCS score was found to be an independent predictor of outcome (p = 0.001). No difference in the outcome was observed between patients with GCS 6-8 and GCS 9-15. These two groups have a better prognosis than patients with GCS 3-5. Logistic regression analysis showed age as an independent predictive factor to outcome (p = 0.005). A difference in outcome exists among patients over 65 and patients aged <or=65, while groups aged <40 and 40-65 showed no difference in outcome. Based on these findings, we believe that the age limit for performing DC should be revised

Efficacy and safety of the Miethke programmable differential pressure valve (proGAV®2.0): a single-centre retrospective analysis

Abstract Purpose Achieving decompression without CSF over-drainage remains a challenge in hydrocephalus. Differential pressure valves are a popular treatment modality, with evidence suggesting that incorporation of gravitational units helps minimise over-drainage. This study seeks to describe the utility of the proGAV®2.0 programmable valve in a paediatric population. Methods Clinical records and imaging of all patients fitted with proGAV®2.0 valves and Miethke fixed-pressure valves between 2014 and 2019 at our tertiary centre were analysed. Patient demographics, indication for shunt and valve insertion/revision and time to shunt/valve revision were collected. Ventricular linear metrics (fronto-occipital horn ratio (FOHR) and fronto-occipital horn width ratio (FOHWR)) were collected pre- and post-valve insertion. Microsoft Excel and SPSS v24 were used for data collection and statistical analysis. Results Eighty-eight proGAV®2.0 valves were inserted in a population of 77 patients (n = 45 males (58%), mean age 5.1 years (IQR: 0.4–11.0 years)). A total of 102 Miethke fixed-pressure valves were inserted over the same time period. Median follow-up was 17.5 months (1.0–47.3). One (1.1%) proGAV®2.0 was revised due to over-drainage, compared to 2 (1.9%) fixed-pressure valves (p &gt; 0.05). ProGAV®2.0 insertion resulted in a significant decrease in the mean number of revisions per patient per year (1.77 vs 0.25; p = 0.01). Overall shunt system survival with the proGAV®2.0 was 80.4% at 12 months, and mean time to revision was 37.1 months, compared to 31.0 months (95%CI: 25.7–36.3) and 58.3% in fixed-pressure valves (p &lt; 0.01). Significant decreases were seen following proGAV®2.0 insertion in both FOHR and FOHWR, by 0.014 (95%CI: 0.006–0.023, p = 0.002) and 0.037 (95%CI: 0.005–0.069, p = 0.024) respectively. Conclusion The proGAV®2.0 provides effective decompression of hydrocephalic patients, significantly reduces the number of valve revisions per patient and had a significantly greater mean time to revision than fixed-pressure valves. </jats:sec