Hans Delye

Experimental treatment of NRAS-mutated neurocutaneous melanocytosis with MEK162, a MEK-inhibitor

Neurocutaneous melanosis (NCM) is a rare congenital disorder characterized by the association of large and/or multiple congenital melanocytic nevi (CMN) of the skin with melanocytic lesions of the leptomeninges, including melanocytosis. Leptomeningeal melanocytosis carries a poor prognosis once neurological symptoms develop. Despite surgery, which is often not radical, few other treatment options exist. Recently, it was demonstrated that early embryonic, post-zygotic somatic mutations in the NRAS gene are implicated in the pathogenesis of NCM.In this report, we present a 13-year-old boy with NCM and progressive symptomatic leptomeningeal melanocytosis. A somatic NRASQ61K mutation was present in both CMN as well as the melanocytosis. Despite repeated surgery, the patient showed clinical progression. Therefore, treatment with MEK162, a MEK inhibitor, was started on compassionate use base. The patient died only five days later, i.e. too early to expect a clinical effect of MEK162 therapy. We therefore studied the effect of MEK162 at the protein level in the leptomeningeal tumor by immunohistochemical and Western Blot analyses using Ki67 and pERK antibodies. We observed lower MIB-1 expression and lower pERK expression in the post-treatment samples compared to pre-treatment, suggesting a potential effect of MEK inhibiting therapy. Further studies are needed to determine whether MEK inhibitors can effectively target NRAS-mutated symptomatic NCM, a rare but potentially fatal disease.

Increase of prevalence of craniosynostosis

INTRODUCTIONnCraniosynostosis represents premature closure of cranial sutures. Prevalence is approximately 3.1-6.4 in 10.000 live births, which is reportedly rising. This epidemiologic study aims to provide insight into this rise through an accurate description of the prevalence, exploring regional variation and change over time.nnnMETHODSnThe Dutch Association for Cleft Palate and Craniofacial Anomalies was consulted to identify patients with craniosynostosis born between 2008 and 2013. Data were verified using data provided by all hospitals that treated these patients. The following data were collected: date of birth, gender, diagnosis and postal code. Previously reported data from 1997 until 2007 were included to assess for change in prevalence over the years.nnnRESULTSnBetween 2008 and 2013 759 patients with craniosynostosis were born in the Netherlands. Prevalence of craniosynostosis was 7.2 per 10.000 live births. Sagittal synostosis was the most common form (44%). Poisson regression analysis showed a significant mean annual increase of prevalence of total craniosynostosis (+12.5%), sagittal (+11.7%) and metopic (+20.5%) synostosis from 1997 to 2013.nnnCONCLUSIONnThe prevalence of craniosynostosis is 7.2 per 10.000 live born children in the Netherlands. Prevalence of total craniosynostosis, sagittal and metopic suture synostosis has risen significantly from 1997 until 2013, without obvious cause.

Intraoperative and postoperative complications in the surgical treatment of craniosynostosis: minimally invasive versus open surgical procedures

OBJECTIVE To compare minimally invasive endoscopic and open surgical procedures, to improve informed consent of parents, and to establish a baseline for further targeted improvement of surgical care, this study evaluated the complication rate and blood transfusion rate of craniosynostosis surgery in our department. METHODS A prospective complication registration database that contains a consecutive cohort of all pediatric neurosurgical procedures in the authors neurosurgical department was used. All pediatric patients who underwent neurosurgical treatment for craniosynostosis between February 2004 and December 2014 were included. In total, 187 procedures were performed, of which 121 were endoscopically assisted minimally invasive procedures (65%). Ninety-three patients were diagnosed with scaphocephaly, 50 with trigonocephaly, 26 with plagiocephaly, 3 with brachycephaly, 9 with a craniosynostosis syndrome, and 6 patients were suffering from nonsyndromic multisutural craniosynostosis. RESULTS A total of 18 complications occurred in 187 procedures (9.6%, 95% CI 6.2-15), of which 5.3% (n = 10, 95% CI 2.9-10) occurred intraoperatively and 4.2% (n = 8, 95% CI 2.2-8.2) occurred postoperatively. In the open surgical procedure group, 9 complications occurred: 6 intraoperatively and 3 postoperatively. In the endoscopically assisted procedure group, 9 complications occurred: 4 intraoperatively and 5 postoperatively. Blood transfusion was needed in 100% (n = 66) of the open surgical procedures but in only 21% (n = 26, 95% CI 15-30) of the endoscopic procedures. One patient suffered a transfusion reaction, and 6 patients suffered infections, only one of which was a surgical site infection. A dural tear was the most common intraoperative complication that occurred (n = 8), but it never led to postoperative sequelae. Intraoperative bleeding from a sagittal sinus occurred in one patient with only minimal blood loss. There were no deaths, permanent morbidity, or neurological sequelae. CONCLUSIONS Complications during craniosynostosis surgery were relatively few and minor and were without permanent sequelae in open and in minimally invasive procedures. The blood transfusion rate was significantly reduced in endoscopic procedures compared with open procedures.

Endoscopically assisted craniosynostosis surgery (EACS): The craniofacial team Nijmegen experience.

INTRODUCTIONnAn evaluation of our first 111 consecutive cases of non-syndromic endoscopically assisted craniosynostosis surgery (EACS) followed by helmet therapy.nnnMETHODSnRetrospective analysis of a prospective registration database was performed. Age, duration of surgery, length of hospital stay, blood loss, transfusion rate, cephalic index and duration of helmet therapy were evaluated. An online questionnaire was used to evaluate the burden of the helmet therapy for the child and parents.nnnRESULTSn111 EAC procedures were performed: 64 for scaphocephaly, 34 for trigonocephaly and13 for anterior plagiocephaly. The mean age at the time of surgery was 3.9 (±1) months, mean surgical time was 58 (±18) minutes, mean blood loss was 34 (±28) ml, transfusion rate was 22% (nxa0=xa026), mean duration of postoperative helmet therapy was 10 (±2.5) months, mean preoperative and postoperative CI were respectively 0.67(±0.057) and 0.72 (±0.062) in scaphocephalic patients and the mean length of hospital stay was 2.6 (±1) days. The burden of the helmet therapy for the child and his family was deemed very low.nnnCONCLUSIONnEACS for non-syndromic patients shows low morbidity rates, short surgical time, short length of hospital stay, little blood loss and low need for blood transfusion and is associated with satisfying cosmetic results.

A new method for three-dimensional evaluation of the cranial shape and the automatic identification of craniosynostosis using 3D stereophotogrammetry

Craniosynostosis is a congenital defect which can result in abnormal cranial morphology. Three dimensional (3D) stereophotogrammetry is potentially an ideal technique for the evaluation of cranial morphology and diagnosis of craniosynostosis because it is fast and harmless. This study presents a new method for objective characterization of the morphological abnormalities of scaphocephaly and trigonocephaly patients using 3D photographs of patients and healthy controls. Sixty 3D photographs of healthy controls in the age range of 3-6 months were superimposed and scaled. Principal component analysis (PCA) was applied to find the mean cranial shape and the cranial shape variation in this normal population. 3D photographs of 20 scaphocephaly and 20 trigonocephaly patients were analysed by this PCA model to test whether cranial deformities of scaphocephaly and trigonocephaly patients could be objectively identified. PCA was used to find the mean cranial shape and the cranial shape variation in the normal population. The PCA model was able to significantly distinguish scaphocephaly and trigonocephaly patients from the normal population. 3D stereophotogrammetry in combination with the presented method can be used to objectively identify and classify the cranial shape of healthy newborns, scaphocephaly and trigonocephaly patients.

Toward Holographic-Guided Surgery

The implementation of augmented reality (AR) in image-guided surgery (IGS) can improve surgical interventions by presenting the image data directly on the patient at the correct position and in the actual orientation. This approach can resolve the switching focus problem, which occurs in conventional IGS systems when the surgeon has to look away from the operation field to consult the image data on a 2-dimensional screen. The Microsoft HoloLens, a head-mounted AR display, was combined with an optical navigation system to create an AR-based IGS system. Experiments were performed on a phantom model to determine the accuracy of the complete system and to evaluate the effect of adding AR. The results demonstrated a mean Euclidean distance of 2.3 mm with a maximum error of 3.5 mm for the complete system. Adding AR visualization to a conventional system increased the mean error by 1.6 mm. The introduction of AR in IGS was promising. The presented system provided a solution for the switching focus problem and created a more intuitive guidance system. With a further reduction in the error and more research to optimize the visualization, many surgical applications could benefit from the advantages of AR guidance.

Cranial shape comparison for automated objective 3D craniosynostosis surgery planning

Virtual planning of open cranial vault reconstruction is used to simulate and define an pre-operative plan for craniosynostosis surgery. However, virtual planning techniques are subjective and dependent on the experience and preferences of the surgical team. To develop an objective automated 3D pre-operative planning technique for open cranial vault reconstructions, we used curvature maps for the shape comparison of the patient’s skull with an age-specific reference skull. We created an average skull for the age-group of 11–14 months. Also, we created an artificial test object and selected a cranial CT-scan of an 11 months old trigonocephaly patient as test case. Mesh data of skulls were created using marching cubes and raycasting. Curvature maps were computed using quadric surface fitting. The shape comparison was tested for the test object and the average skull. Finally, shape comparison was performed for the trigonocephalic skull with the average skull. Similar shapes and the area on the patient’s skull that maximally corresponded in shape with the reference shape were correctly identified. This study showed that curvature maps allow the comparison of craniosynostosis skulls with age-appropriate average skulls and a first step towards an objective user-independent pre-operative planning technique for open cranial vault reconstructions is made.

Evaluation of anesthesia in endoscopic strip craniectomy: A review of 121 patients

The aim of this study was to evaluate pre‐, intra‐, and postoperative anesthetic parameters in endoscopic strip craniectomy in order to improve anesthesiological care.

Radiation-free 3D head shape and volume evaluation after endoscopically assisted strip craniectomy followed by helmet therapy for trigonocephaly

INTRODUCTIONnRadiation-free 3D post-operative sequential follow-up in craniosynostosis is hindered by the lack of consistent markers restricting evaluation to subjective comparison. However, using the computed cranial focal point (CCFP), it is possible to perform correct sequential image superposition and objective evaluation. We used this technique for mean volume and shape change evaluation of the head utilizing 3D photos after endoscopically assisted trigonocephaly surgery.nnnMETHODSnWe performed a mean head shape and volume evaluation on age grouped 3D photos (nxa0=xa086) of children who underwent endoscopically assisted strip craniectomy with helmet therapy. We used CT-scans of healthy children as reference. We performed a mean shape evolution analysis and calculated the anterior fossa to total volume ratio (A/T-ratio). The volume- and A/T-ratio pattern were compared with the reference group.nnnRESULTSnThe mean anterior fossa volume evolved from 336xa0ml (33.4% A/T-ratio) pre-surgery to 664xa0ml (36.0% A/T-ratio) at 37-48 months post-surgery. Both groups have a near similar volume- and A/T-ratio pattern over time. The first 18 months show a predominant growth around the resected metopic suture. Between 18 and 24 months we observed mostly anterior orbital rim growth. From 24 months till 36-48 months the head grows predominantly at the temporal area. The least outward growth was observed at the temporal bones.nnnCONCLUSIONnUsing a novel technique we were able to objectively evaluate head shape and volume using stereophotogrammetry after endoscopically assisted strip craniectomy. The A/T-ratio and volume growth pattern of endoscopically treated patients is near identical to that of the normal reference group.