Endonasal endoscopic skullbase surgery in children.

OBJECTIVE: The role of endonasal endoscopic approach for pathologies in the paediatric population is evolving and has still not been accepted as standard of care in neurosurgery. It represents a challenge in terms of narrow access, instrument manipulation and adequate reconstruction of defects. We have described our experience in 49 cases from a single neurosurgical unit in paediatric skull base surgeries through this approach over the last 12 years. MATERIAL AND METHODS: A case series of 59 paediatric skull base surgeries in 49 children through endoscopic endonasal route over the last 12 years is presented. The age ranges from 4 months to 18 years. Out of 49 cases, 22 cases were of craniopharyngiomas, 8 cases of pituitary adenomas, 5 cases with CSF rhinorrhea, 5 cases with meningoencephalocele, 3 cases of Rathke's cleft cysts, 2 cases of odontoidectomy and 4 miscellaneous cases viz. mucocele, hypothalamic glioma, esthesioneuroblastoma and epidermoid. CSF leaks were repaired with free graft in the initial years and by vascularized flap more recently. RESULTS: The goal of surgery was achieved in all but two cases in whom the tumour excision was unsatisfactory due to failure of the cyst wall to collapse after decompression. Extent of tumour excision was not compromised by the choice of this approach. Revision surgery for CSF leak was required in three patients. Local vascularized nasoseptal flap has been possible even in very young patients and has now become the standard for reconstruction. CONCLUSION: In spite of the challenges posed by small nostrils and ill-developed sinuses in the paediatric age group, surgery from endoscopic endonasal corridor is possible to be carried out successfully in selected cases.

Immunogenicity phase II study evaluating booster capacity of nonadjuvanted AKS-452 SARS-Cov-2 RBD Fc vaccine.

AKS-452, a subunit vaccine comprising an Fc fusion of the ancestral wild-type (WT) SARS-CoV-2 virus spike protein receptor binding domain (SP/RBD), was evaluated without adjuvant in a single cohort, non-randomized, open-labelled phase II study (NCT05124483) at a single site in The Netherlands for safety and immunogenicity. A single 90 µg subcutaneous booster dose of AKS-452 was administered to 71 adults previously primed with a registered mRNA- or adenovirus-based vaccine and evaluated for 273 days. All AEs were mild and no SAEs were attributable to AKS-452. While all subjects showed pre-existing SP/RBD binding and ACE2-inhibitory IgG titers, 60-68% responded to AKS-452 via ≥2-fold increase from days 28 to 90 and progressively decreased back to baseline by day 180 (days 28 and 90 mean fold-increases, 14.7 ± 6.3 and 8.0 ± 2.2). Similar response kinetics against RBD mutant proteins (including omicrons) were observed but with slightly reduced titers relative to WT. There was an expected strong inverse correlation between day-0 titers and the fold-increase in titers at day 28. AKS-452 enhanced neutralization potency against live virus, consistent with IgG titers. Nucleocapsid protein (Np) titers suggested infection occurred in 66% (46 of 70) of subjects, in which only 20 reported mild symptomatic COVID-19. These favorable safety and immunogenicity profiles support booster evaluation in a planned phase III universal booster study of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain.

A randomized phase I/II safety and immunogenicity study of the Montanide-adjuvanted SARS-CoV-2 spike protein-RBD-Fc vaccine, AKS-452.

BACKGROUND: Previous interim data from a phase I study of AKS-452, a subunit vaccine comprising an Fc fusion of the respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor binding domain (SP/RBD) emulsified in the water-in-oil adjuvant, Montanide™ ISA 720, suggested a good safety and immunogenicity profile in healthy adults. This phase I study was completed and two dosing regimens were further evaluated in this phase II study. METHODS: This phase II randomized, open-labelled, parallel group study was conducted at a single site in The Netherlands with 52 healthy adults (18 - 72 years) receiving AKS-452 subcutaneously at one 90 µg dose (cohort 1, 26 subjects) or two 45 µg doses 28 days apart (cohort 2, 26 subjects). Serum samples were collected at the first dose (day 0) and at days 28, 56, 90, and 180. Safety and immunogenicity endpoints were assessed, along with induction of IgG isotypes, cross-reactive immunity against viral variants, and IFN-γ T cell responses. RESULTS: All AEs were mild/moderate (grades 1 or 2), and no SAEs were attributable to AKS-452. Seroconversion rates reached 100% in both cohorts, although cohort 2 showed greater geometric mean IgG titers that were stable through day 180 and associated with enhanced potencies of SP/RBD-ACE2 binding inhibition and live virus neutralization. AKS-452-induced IgG titers strongly bound mutant SP/RBD from several SARS-CoV-2 variants (including Omicrons) that were predominantly of the favorable IgG1/3 isotype and IFN-γ-producing T cell phenotype. CONCLUSION: These favorable safety and immunogenicity profiles of the candidate vaccine as demonstrated in this phase II study are consistent with those of the phase I study (ClinicalTrials.gov: NCT04681092) and suggest that a total of 90 µg received in 2 doses may offer a greater duration of cross-reactive neutralizing titers than when given in a single dose.

Maxillary Sinus Vascular Malformation or Metastatic Renal Cell Carcinoma: The Importance of Differential Diagnosis.

Epistaxis is a common presenting complain with varied differentials. Our case is of epistaxis due to maxillary sinus vascular malformation which could be managed with embolization and endoscopic excision. Histopathologically, the lesion had features of metastatic renal cell carcinoma (RCC). A RCC metastatic lesion masquerading as a maxillary sinus vascular malformation (VM) has been extremely rare in published literature. We present this interesting case of maxillary sinus VM and also briefly review the relevant literature.

Phase I interim results of a phase I/II study of the IgG-Fc fusion COVID-19 subunit vaccine, AKS-452.

To address the coronavirus disease 2019 (COVID-19) pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recombinant subunit vaccine, AKS-452, is being developed comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain (SP/RBD) antigen and human IgG1 Fc emulsified in the water-in-oil adjuvant, Montanide™ ISA 720. A single-center, open-label, phase I dose-finding and safety study was conducted with 60 healthy adults (18-65 years) receiving one or two doses 28 days apart of 22.5 µg, 45 µg, or 90 µg of AKS-452 (i.e., six cohorts, N = 10 subjects per cohort). Primary endpoints were safety and reactogenicity and secondary endpoints were immunogenicity assessments. No AEs ≥ 3, no SAEs attributable to AKS-452, and no SARS-CoV-2 viral infections occurred during the study. Seroconversion rates of anti-SARS-CoV-2 SP/RBD IgG titers in the 22.5, 45, and 90 µg cohorts at day 28 were 70%, 90%, and 100%, respectively, which all increased to 100% at day 56 (except 89% for the single-dose 22.5 µg cohort). All IgG titers were Th1-isotype skewed and efficiently bound mutant SP/RBD from several SARS-CoV-2 variants with strong neutralization potencies of live virus infection of cells (including alpha and delta variants). The favorable safety and immunogenicity profiles of this phase I study (ClinicalTrials.gov: NCT04681092) support phase II initiation of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain.

Transnasal Endoscopic Surgery for Suprasellar Meningiomas.

AIM: Endoscopic trans-nasal surgery has evolved a long way from the days of narrow corridors with high rates of cerebrospinal fluid (CSF) leak to the present state of HD optics with better tissue differentiation, extended approaches, and use of vascularized flaps for defect closure. Trans-nasal approach is an established technique for pituitary tumors practiced worldwide. However, trans-nasal endoscopic excision of suprasellar meningiomas provides a tougher challenge in terms of instrument manipulation, tumor excision with good visual outcome, and a robust defect closure to prevent CSF leaks. MATERIALS AND METHODS: Out of 83 cases of midline anterior cranial fossa meningiomas operated over 14 years, our experience in 12 cases of suprasellar meningiomas for radical resection via the trans-nasal endoscopic route is discussed. RESULTS: Amongst these, six were excised via primary extended endoscopic trans-sphenoidal surgery, four cases had a residual lesion or recurrence after primary transcranial surgery, and two cases involved a combined transcranial and extended endoscopic approach. Visual improvement along with resolution of headache was seen in all patients postoperatively. None of the patients had CSF leak requiring further repair. Syndrome of inappropriate antidiuretic hormone was found in one patient, which was transient and easily corrected. CONCLUSION: Trans-nasal endoscopic surgery for suprasellar meningiomas is an effective technique that provides results of tumor excision comparable to the transcranial approach in suitable cases. Visual outcome was found to be superior, and rates of CSF leak were remarkably reduced with vascularized flap. However, each case must be assessed individually and lateral extension beyond the optic canals with internal carotid artery encasement must be considered before planning surgery.

Development of an IgG-Fc fusion COVID-19 subunit vaccine, AKS-452.

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.

Surgical Management of Rathke Cleft Cysts.

BACKGROUND: The diagnosis of Rathke cleft cysts (RCC) has increased in recent times as a result of improvements in imaging techniques; however, symptomatic patients are uncommon and accurate preoperative diagnosis may sometimes be difficult. The indications of surgical management protocol are evolving. We aim to provide a comprehensive review of clinical, imaging, and histopathologic features with operative management strategies along with outcome and prognosis in RCC. METHODS: A retrospective analysis (2003-2015) was performed of 58 consecutive cases of RCC seen in a surgical unit. Twenty-seven surgically treated symptomatic RCCs were further evaluated for their clinical presentation, imaging characteristics, surgical approaches, and intraoperative findings. RESULTS: Headache was the most common presenting complaint followed by visual deficit. Hormonal abnormality was observed in 13 patients. On magnetic resonance imaging, the characteristic intracystic nodule was identified in 6 patients. Transsphenoidal surgery for cyst excision was performed in all 27 patients with an endoscopic route in 25 patients and radical excision was performed in 17 patients. The pituitary stalk and the normal gland were preserved in all patients. Headache improved in 96% of patients and visual field defect resolved in all. Around 46% had improvement of the anterior pituitary axis. New permanent hormone deficiency was not observed. The recurrence rate was 3.7% after a minimum of 18 months follow-up. CONCLUSIONS: RCCs are an uncommon disease with a wide spectrum of clinical and radiologic features. Endonasal endoscopic transsphenoidal surgery provides excellent clinical and endocrinologic improvement. We believe that radical excision does not necessarily result in endocrinologic impairment and may have a better impact on recurrence and cyst resolution.

Endoscopic approaches to the craniovertebral junction and odontoid process.

BACKGROUND: The microsurgical transoral approach has traditionally been the preferred access for ventral decompression of the craniovertebral junction. This natural corridor, although direct, may be a challenging approach because of potential morbidities. The evolution of endoscopic methods in skull base surgeries has reduced morbidity and improved results. Endoscopic approaches are also being used for ventral decompression at the craniovertebral junction. Some technical modifications in this approach are described. METHODS: An endoscope is inserted endonasally for a panoramic view of the entire area of interest, from the sphenoid to second cervical vertebra. Image guidance systems are used in all cases to guide the resection. The soft palate is retracted away with a rubber catheter sling when both nasal and oral corridors are being used. Various mucosal flaps are raised for access and reconstruction. Actual decompression can be done through the nasal or oral corridors based on the relationship of the pathology to the palate. Reconstruction is done using standard principles with the vascularized flaps, fat, and fibrin glue. RESULTS: Reduced surgical morbidity by avoiding palatal split and good postoperative healing are some of the advantages of this modified endoscopic technique. Better surgical exposure and a wide perspective facilitate the decompression. However, as with all newer perspectives, a learning curve exists. CONCLUSIONS: Used judiciously, this modified endoscopic approach to the craniovertebral junction and odontoid process is minimally invasive and adds to the surgeon's armamentarium.

Endoscopic pituitary surgery - a. beginner's guide.

Endonasal endoscopic surgery is now the preferred technique to tackle pituitary tumours. Our paper describes the stepwise endoscopic approach for surgeons embarking on pituitary surgery. It also highlights the common pitfalls encountered during surgery and the ways to avoid them. One must proceed in a gradual step- wise manner starting from simple exposure of the sphenoid sinus to complete endoscopic tumour removal so us to gain the neurosurgeon's confidence as well as develop our own skills, confidence and ability to tackle complications. We use the endonasal paraseptal trans- sphenoidal approach. Surgery begins with gentle packing between the middle turbinate and septum to expose the anterior sphenoid wall and expose the sphenoid astium. The ostitum is then widened inferiorly and onto the opposite side to expose both sphenoid sinuses. The inter- sphenoid sinus and necessary mucosa is removed to expose the sella. We then use a bone flap technique or punches to open the sella. After incising the dura, tumour is removed with a suction curette. An endoscope holder facilitates the operation. The bone flap is replaced at the end of surgery to reconstruct the sella. This is especially important if a CSF leak is present. Nasal packing is usually not required.