Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations.

Orbital cavernous venous malformation (OCVM) is a sporadic vascular anomaly of uncertain etiology characterized by abnormally dilated vascular channels. Here, we identify a somatic missense mutation, c.121G > T (p.Gly41Cys) in GJA4, which encodes a transmembrane protein that is a component of gap junctions and hemichannels in the vascular system, in OCVM tissues from 25/26 (96.2%) individuals with OCVM. GJA4 expression was detected in OCVM tissue including endothelial cells and the stroma, through immunohistochemistry. Within OCVM tissue, the mutation allele frequency was higher in endothelial cell-enriched fractions obtained using magnetic-activated cell sorting. Whole-cell voltage clamp analysis in Xenopus oocytes revealed that GJA4 c.121G > T (p.Gly41Cys) is a gain-of-function mutation that leads to the formation of a hyperactive hemichannel. Overexpression of the mutant protein in human umbilical vein endothelial cells led to a loss of cellular integrity, which was rescued by carbenoxolone, a non-specific gap junction/hemichannel inhibitor. Our data suggest that GJA4 c.121G > T (p.Gly41Cys) is a potential driver gene mutation for OCVM. We propose that hyperactive hemichannel plays a role in the development of this vascular phenotype.

Targeted deep sequencing of DNA from multiple tissue types improves the diagnostic rate and reveals a highly diverse phenotype of mosaic neurofibromatosis type 2.

BACKGROUND: Although 60% of patients with de novo neurofibromatosis type 2 (NF2) are presumed to have mosaic NF2, the actual diagnostic rate of this condition remains low at around 20% because of the existing difficulties in detecting NF2 variants with low variant allele frequency (VAF). Here, we examined the correlation between the genotype and phenotype of mosaic NF2 after improving the diagnostic rate of mosaic NF2. METHODS: We performed targeted deep sequencing of 36 genes including NF2 using DNA samples from multiple tissues (blood, buccal mucosa, hair follicle and tumour) of 53 patients with de novo NF2 and elucidated their genotype-phenotype correlation. RESULTS: Twenty-four patients (45.2%) had the NF2 germline variant, and 20 patients with NF2 (37.7%) had mosaic NF2. The mosaic NF2 phenotype was significantly different from that in patients with NF2 germline variant in terms of distribution of NF2-related disease, tumour growth rate and hearing outcome. The behaviour of schwannoma correlated to the extent of VAF with NF2 variant in normal tissues unlike meningioma. CONCLUSION: We have improved the diagnostic rate of mosaic NF2 compared with that of previous studies by targeted deep sequencing of DNA from multiple tissues. Many atypical patients with NF2 diagnosed with 'unilateral vestibular schwannoma' or 'multiple meningiomas' presumably have mosaic NF2. Finally, we suggest that the highly diverse phenotype of NF2 could result not only from the type and location of NF2 variant but also the extent of VAF in the NF2 variant within normal tissue DNA.

The mini-combined transpetrosal approach: an anatomical study and comparison with the combined transpetrosal approach.

BACKGROUND: The combined transpetrosal approach (CTPA) is a versatile technique suitable for challenging skull base pathologies. Despite the advantages provided by a wide surgical exposure, the soft tissue trauma, complex and time-consuming bony work, and cosmetic issues make it far from patient expectations. In this study, the authors describe a less invasive modification of the CTPA, the mini-combined transpetrosal approach (mini-CTPA), and perform a quantitative comparison between these two approaches. METHODS: Five human specimens were used for this study. CTPA was performed on one side and mini-CTPA on the opposite side. The surgical freedom, petroclival and brainstem area of exposure, and maneuverability for 6 anatomical targets, provided by the CTPA and mini-CTPA, were calculated and statistically compared. The bony volumes corresponding to each anterior petrosectomy were also measured and compared. Three clinical cases with an operative video are also reported to illustrate the effectiveness of the approach. RESULTS: The question-mark skin incision done along the muscle attachments permits an optimal cosmetic result. Even though the limited incision, the smaller craniotomy, and the less extensive bone drilling of mini-CTPA provide a smaller area of surgical freedom, the areas of exposure of petroclival region and brainstem were not statistically different between the two approaches. The antero-posterior maneuverability for the oculomotor foramen (OF), Meckel's cave (MC) and the REZ of trigeminal nerve, and the supero-inferior maneuverability for OF, MC, Dorello's canal, and REZ of CN VII are significantly reduced by the smaller opening. The bony volume of anterior petrosectomy resulted similar among the approaches. CONCLUSIONS: The mini-CTPA is an interesting alternative to the CTPA, providing comparable surgical exposure both for petroclival region and for brainstem. Although the lesser soft tissue dissection and bony opening decrease the surgical maneuverability, the mini-CTPA may reduce surgical time, potential approach-related morbidities, and improve cosmetic and functional outcomes for the patients.

Utility of systemic voriconazole in equine keratomycosis based on pharmacokinetic-pharmacodynamic analysis of tear fluid following oral administration.

OBJECTIVE: To clarify the detailed pharmacokinetics (PK) of orally administered voriconazole in tear fluid (TF) of horses for evaluating the efficacy of voriconazole secreted into TF against equine keratomycosis. ANIMALS STUDIED: Five healthy Thoroughbred horses. PROCEDURES: Voriconazole was administrated through a nasogastric tube to each horse at a single dose of 4.0 mg/kg. TF and blood samples were collected before and periodically throughout the 24 hours after administration. Voriconazole concentrations in plasma and TF samples were analyzed using liquid chromatography-electrospray tandem-mass spectrometry. The predicted voriconazole concentration in both samples following multiple dosing every 24 hours was simulated by the superposition principle. RESULTS: The mean maximum voriconazole concentrations in plasma and TF were 3.3 µg/mL at 1.5 h and 1.9 µg/mL at 1.6 h, respectively. Mean half-life in both samples were 16.4 and 25.2 h, respectively. The ratio of predicted AUC0-24 at steady state in TF (51.3 µg∙h/mL) to previously published minimum inhibitory concentration (MIC) of Aspergillus and Fusarium species was >100 and 25.7, respectively. CONCLUSIONS: This study demonstrated the detailed single-dose PK of voriconazole in TF after oral administration and simulated the predicted concentration curves in a multiple oral dosing. Based on the analyses of PK-PD, the simulation results indicated that repeated oral administration of voriconazole at 4.0 mg/kg/d achieves the ratio of AUC to MIC associated with treatment efficacy against Aspergillus species. The detailed PK-PD analyses against pathogenic fungi in TF can be used to provide evidence-based medicine for equine keratomycosis.

The effectiveness of microsurgical fenestration for middle fossa arachnoid cysts in children.

OBJECTIVE: Although middle fossa arachnoid cysts (MFACs) are common, the optimal surgical treatment for these lesions remains controversial. In this study, we present our experiences of treating MFACs by microsurgical fenestration and evaluate its effectiveness. METHODS: We performed retrospective review of 28 patients who underwent microsurgical fenestration for MFACs between May 2003 and December 2014. We reviewed patient characteristics and treatment outcomes including age, sex, symptoms, complicating hydrocephalus, Gallasi classification, change in cyst size after surgery, complicating subdural hygroma, symptom resolution, regrowth of the cyst, and reoperation (including additional CSF diversion). RESULTS: Twenty-eight MFACs in 28 patients were investigated. The average age at the time of surgery was 61.6 months. The average follow-up duration was 53.5 months. After surgery, 19 (90.5 %) of 21 patients with symptomatic MFACs experienced improvements. The cysts decreased in size in all cases (100 %, 28/28) and disappeared in three cases (11 %, 3/28). None of the cases experienced regrowth of the cyst. Subdural hygroma was identified in 23 cases (82.1 %) at the immediate postoperative period. Hygroma was asymptomatic in all cases but one. Hygroma disappeared in 19 cases (83 %) and decreased in size in three cases (13 %) in the long term. Only one case (4 %) required an additional subdural-peritoneal shunt. The rate of CSF diversion after the fenestration was significantly higher in patients with preoperative ventricular dilation (p = 0.0002). CONCLUSION: Microsurgical fenestration for pediatric MFACs was considered to be safe and effective. Although subdural hygroma developed in significant number of patients at the immediate postoperative period, it was mostly asymptomatic and disappeared or decreased in size in the long term.

Cardiorespiratory and anesthetic effects of combined alfaxalone, butorphanol, and medetomidine in Thoroughbred horses.

This study evaluated induction of anesthesia and cardiorespiratory and anesthetic effects during maintained anesthesia with the combination of alfaxalone, medetomidine, and butorphanol. Alfaxalone (1.0 mg/kg) was administered to induce anesthesia after premedication with medetomidine (7.0 µg/kg), butorphanol (25 µg/kg), and midazolam (50 µg/kg) in six Thoroughbred horses. Intravenous general anesthesia was maintained with alfaxalone (2.0 mg/(kg∙hr)), medetomidine (5.0 µg/(kg∙hr)), and butorphanol (30 µg/(kg∙hr)) for 60 min. Electrical stimulation of the upper oral mucosa was used to assess anesthetic depth at 10 min intervals during anesthesia. Heart rate (HR), respiratory rate (RR), and mean arterial pressure (MAP) were measured. All horses became recumbent within 1 min after alfaxalone administration. Induction scores were 5 (best) in five horses and 4 in one horse. During the 60-min anesthesia, average HR, RR, and MAP were 35.8 ± 2.6 beat/min, 4.7 ± 0.6 breath/min, and 129 ± 3 mmHg, respectively. No horse moved with electrical stimulation; however, two horses experienced apnea (no respiration for 1 to 3 min). Recovery scores were 5 (best) in two horses and 3 in four horses. These results suggest that alfaxalone is effective for induction and maintenance of anesthesia and analgesia when combined with butorphanol and medetomidine for 60 min in Thoroughbreds. However, respiratory depression might require support.

Validation of the bispectral index as an indicator of anesthetic depth in Thoroughbred horses anesthetized with sevoflurane.

To evaluate the bispectral index (BIS) as an indicator of anesthetic depth in Thoroughbred horses, BIS values were measured at multiple stages of sevoflurane anesthesia in five horses anesthetized with guaifenesin and thiopental following premedication with xylazine. There was no significant difference between the BIS values recorded at end-tidal sevoflurane concentrations of 2.8% (median 60 ranging from 47 to 68) and 3.5% (median 71 ranging from 49 to 82) in anesthetized horses. These BIS values during anesthesia were significantly lower (P<0.01) than those in awake horses (median 98 ranging from 98 to 98) or sedated horses (median 92 ranging from 80 to 93). During the recovery phase, the BIS values gradually increased over time but did not significantly increase until the horses showed movement. In conclusion, the BIS value could be useful as an indicator of awakening during the recovery period in horses, as previous reported.

Effects of an extended photoperiod on gonadal function and condition of hair coats in Thoroughbred colts and fillies.

The effects of an extended photoperiod (EP) in Thoroughbreds colts and fillies from winter at one year old to spring at two years old on the gonadal functions, coat condition, and endocrine changes were investigated. Sixty-two Thoroughbreds (31 colts and 31 fillies) reared in the Hidaka Training and Research Center (Hidaka), Japan Racing Association were used. Thirty of them (15 colts and 15 fillies) were reared under EP conditions from December 20 to April 10, and the remaining 32 horses were reared under natural light alone as a control group. For EP, a 100-watt white bulb was set near the ceilings of stalls, and lighting conditions of 14.5-hr light and 9.5-hr dark periods were established. Blood was collected from the jugular vein once a month from October at one year old to February at two years old in both colts and fillies, and then twice a month in colts and weekly in fillies after March, and the coat condition was evaluated in January and April in 56 horses. To investigate endocrine changes, the plasma concentrations of prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), immunoreactive (ir-) inhibin, testosterone, estradiol-17ß and progesterone were measured. No significant difference was noted in the coat condition between the two groups in January, but they changed from winter to summer coats (molting of winter coats) in April in the EP group compared with the control group. Regarding endocrine changes, the plasma concentrations of prolactin, FSH, ir-inhibin and testosterone were significantly higher in the EP colts than in the control group from January to April. The plasma concentrations of LH tended to rise in the EP colts from January to April compared with the control group. In the EP fillies, the plasma concentrations of prolactin, LH, ir-inhibin, estradiol-17ß and progesterone were significantly higher during January and April, but a significantly high level of FSH was noted in the control than EP group in January. The ovulation day was advanced in the EP fillies compared with the control group. The present study clearly demonstrated that EP treatment during rearing advanced the molting of winter coats in both colts and fillies. These results suggested to be due to the action of prolactin being increased by EP treatment. In addition, EP treatment stimulated the hypothalamus-pituitary-gonadal axis even in yearlings, and advanced ovulation in fillies. Since EP treatment-induced changes in the yearlings were within the physiological range, and the method is safe and simple, EP treatment may be an effective technique in horse husbandry.

The pathogenesis of intracranial growing teratoma syndrome: proliferation of tumor cells or formation of multiple expanding cysts? Two case reports and review of the literature.

PURPOSE: Growing teratoma syndrome (GTS) is a rare clinical phenomenon defined as the paradoxical growth of mature teratoma components during or after chemotherapy. The mechanism of this phenomenon is not well understood. We present two cases of pineal mixed germ cell tumors that exhibited the similar course to GTS and speculate its pathogenesis. CASE REPORT: The first case was accompanied by slightly elevated alpha-fetoprotein (8.8 ng/ml; normal <6.6 ng/ml). The tumor rapidly grew from 1.5 to 2.7 cm in diameter within 4 weeks. Despite this rapid preoperative growth, thorough pathological investigation found only mature teratoma components along with multiple micro- and macro-cysts. The other case was diagnosed as a pure germinoma based on biopsy and serological examinations. During three courses of chemotherapy, this tumor presented a honeycomb-like appearance on magnetic resonance (MR) images and an exceptionally rapid enlargement. Second-look surgery confirmed the histological diagnosis of a mature teratoma. In both cases, meticulous pathological examination of all whole tumor sections revealed no malignant histological features, and the MIB-1 labeling indices were too low to account for the extremely rapid tumor growth. Instead, both MR images and histological findings demonstrated a predominant formation of multiple cysts. CONCLUSION: We speculate that this paradoxical growth might not be tumorous proliferation but instead the formation and expansion of multiple cysts inside mature teratoma components and that the presence or absence of growth might be a subsidiary phenomenon. Our hypothesis appears consistent with the characteristic radiological findings of GTS reported in the literature.

Analysis of risk factors for chronic subdural haematoma recurrence after burr hole surgery: optimal management of patients on antiplatelet therapy.

OBJECTIVE. Not much is known about surgical management of patients with chronic subdural haematoma (CSDH) treated with antiplatelet or anticoagulant therapy. The aims of this study were to review the surgical outcomes of patients with CSDH and assess the risks of antiplatelet in their surgical management. METHODS. We retrospectively analysed 448 consecutive patients with CSDH treated by one burr hole surgery at our institution. Among them, 58 patients had been on antiplatelet therapy. We discontinued the antiplatelet agents before surgery for all 58 patients. For 51 of these 58 patients (87.9%), early surgery was performed within 0-2 days from admission. We analysed the association between recurrence and patient characteristics, including history of antiplatelet or anticoagulant therapy; age (< 70 years or ≥ 70 years); side; history of angiotensin receptor II blocker, angiotensin converting enzyme blocker, or statin therapy; and previous medical history of head trauma, infarction, hypertension, diabetes mellitus, haemodialysis, seizure, cancer, or liver cirrhosis. RESULTS. Recurrence occurred in 40 patients (8.9%), which was one of the lowest rates in the literature. Univariate analysis showed that only the presence of bilateral haematomas was associated with increased recurrence rate while antiplatelet or anticoagulant therapy did not significantly increase recurrence risk. Also, the recurrence rate from early surgery (0-2 days from drug cessation) for patients on antiplatelet therapy was not significantly higher than that from elective surgery (5 days or more after drug cessation). However, multivariate analysis revealed that previous history of cerebral infarction was an independent risk factor for CSDH recurrence. CONCLUSIOns. Our overall data support the safety of early surgery for patients on the preoperative antiplatelet therapy without drug cessation or platelet infusion. Patients with a previous history of infarction may need to be closely followed regardless of antiplatelet or anticoagulant therapy.

Effects of an extended photoperiod on body composition of young Thoroughbreds in training.

The effects of an extended photoperiod (EP) on body composition of Thoroughbreds colts and fillies from December at one year old to April at two years old were investigated. Seventy-three Thoroughbreds reared and trained in Hidaka Training and Research Center, Japan Racing Association, Hokkaido were used. Forty-one horses were under the EP conditions from December 20 to April 15, and the 32 horses were under natural light alone as the control group. Body weight (BW), rump fat thickness (RFT), fat free mass (FFM) and percentage of fat (%F) were used as parameters of body composition. The present study revealed that BW and FFM increased with age in the EP group in colts. In fillies, BW increased with age in both the EP and the control group, however FFM increased with age only in the EP group. From December to April, only colts had a higher rate of increase in both BW and FFM in the EP group than in the control group. However, according to the mean rates of increase in FFM from January to March, the EP group was significantly higher than the control group in both sexes. Furthermore, monthly increase rate of FFM in March was significantly higher in the EP group than in the control group in both sexes. These results suggests that EP treatment to young Thoroughbreds in training at Hokkaido, which is shorter daylength in winter, accelerate the increase of FFM, representing muscle mass.

POLR2A Mutation is a Poor Prognostic Marker of Cerebellopontine Angle Meningioma.

BACKGROUND AND OBJECTIVES: Recent molecular analyses have shown that the driver genetic mutations of meningiomas were associated with the anatomic location. Among these, POLR2A mutation is common among lesions in the skull base, mainly in the cerebellopontine angle (CPA). The objective of this study was to investigate the efficacy of POLR2A mutation as a prognostic marker for CPA meningiomas. METHODS: We retrospectively analyzed the clinical data of 70 patients who had World Health Organization grade I CPA meningiomas. Somatic DNA was analyzed by Sanger sequencing and microsatellite array to examine for NF2, AKT1, KLF4, SMO, and POLR2A mutations and 22q loss. Genetic and clinical parameters were analyzed to identify the factors related with tumor recurrence. RESULTS: We detected clearly the clinical features of the CPA cases with POLR2A mutation. Compared with cases without POLR2A mutation, cases with POLR2A mutation had more meningothelial type (P = 6.9 × 10-4), and higher rate of recurrence (P = .04). We found that the poor prognostic factors associated with the recurrence of CPA meningiomas were POLR2A mutation (P = .03, hazard ratio [HR] 9.38, 95% CI 1.26-70.0) and subtotal resection (STR) (P = 5.1 × 10-4, HR 63.1, 95% CI 6.09-655.0). In addition, in the group that underwent STR, POLR2A mutation was a poor prognostic factor associated with tumor recurrence (P = .03, HR 11.1, 95% CI 1.19-103.7). CONCLUSION: POLR2A mutation and STR were the poor prognostic markers associated with the recurrence of CPA meningioma. For CPA meningioma cases that underwent STR, only POLR2A mutation was a poor prognostic factor. Detecting POLR2A mutation may be a cost-effective, easy, and useful marker for prognostication.

Significance of radical resection for pilomyxoid astrocytoma of the cerebellum: a case report and review of the literature.

BACKGROUND: Pilomyxoid astrocytoma (PMA) was recently classified as a variant of pilocytic astrocytoma (PA) with significantly more aggressive clinical features than those of PA. Like PAs, PMAs frequently arise in the chiasmatic/hypothalamic regions. The cerebellum is also a common site of occurrence for PAs but not for PMAs. CASE DESCRIPTION: We present the case of a 31-month-old boy with cerebellar PMA that showed rapid regrowth during the 3 months following the first subtotal resection. Gross total resection was achieved in the second surgery, followed by radiation to the tumor bed. RESULTS: During follow-up over the next 12 years, there has been no evidence of recurrence on magnetic resonance imaging. CONCLUSIONS: Although the prognosis of cerebellar PMAs remains unknown because of the paucity of cases, the relevant literature reports a more favorable outcome for cerebellar PMAs than for PMAs occurring at other locations. The results of this case study and a review of the relevant literature advocate radical resection, sometimes involving multiple surgeries, for cerebellar PMAs because gross total or near total resection is more feasible in the cerebellum than in other locations.

Beneficial effect of selective intra-arterial infusion of fasudil hydrochloride as a treatment of symptomatic vasospasm following SAH.

INTRODUCTION: We envisage the efficacy and safety of intra-arterial infusion of fasudil hydrochloride (IAF) for symptomatic vasospasm (SVS) after subarachnoid hemorrhage (SAH). We compared results obtained from the groups that received selective IAF (a microcatheter inserted in intracranial arteries) and nonselective IAF (a microcatheter inserted in the cervical arteries). Glasgow Outcome Scale (GOS) value and computed tomographic (CT) score were used to evaluate clinical outcome and the extent of infarction due to delayed vasospasm. MATERIAL AND METHODS: Over 2 years, 113 patients with SAH underwent clipping or coiling. Among them, 31 patients (27.4%) developed SVS. We performed nonselective IAF in 10 patients and selective IAF in 10 other patients. Eleven patients with SVS were treated without IAF. The data were statistically analyzed. RESULT: By univariate linear regression analysis, IAF negatively correlated with CT score (p = 0.016), but IAF was significantly correlated with GOS (p = 0.035). By multiple regression analysis, Hunt and Kosnik grade and CT score significantly correlated with GOS. DISCUSSION: CT score significantly correlated with functional outcome. Although IAF, both selective and nonselective, was significantly effective for the treatment of delayed vasospasm, the former seemed to be more beneficial.

Probable Sporadic Creutzfeldt-Jakob Disease Presenting as Refractory Status Epilepticus in a Poststroke Epilepsy Patient: A Case Report.

In this study, we report on a case of probable sporadic Creutzfeldt-Jakob disease (sCJD) diagnosed after a difficult course of status epilepticus (SE) in a patient with poststroke epilepsy. The patient was admitted with progressive cognitive decline and convulsive SE; therefore, it was initially thought that the patient had developed SE due to nonadherence to antiseizure medication (ASM) use, but despite treatment with ASMs after admission, no improvement was noted in consciousness disturbance or lateralized periodic discharges (LPDs) on electroencephalogram (EEG) examination. After a refractory course, the progression of LPDs to generalized periodic discharges (GPDs) on EEG and abnormal magnetic resonance imaging (MRI) findings met the diagnostic criteria of sCJD. Even if the patient had epilepsy, such as poststroke epilepsy, as in this case, it is essential to consider other underlying causes, including CJD in cases of superrefractory SE.

Surgical morbidity of the extradural anterior petrosal approach: the Lariboisière experience.

OBJECTIVE: Concerns about the approach-related morbidity of the extradural anterior petrosal approach (EAPA) have been raised, especially regarding temporal lobe and venous injuries, hearing impairment, facial nerve palsy, cerebrospinal fluid fistula, and seizures. There is lack in the literature of studies with detailed analysis of surgical complications. The authors have presented a large series of patients who were treated with EAPA, focusing on complications and their avoidance. METHODS: The authors carried out a retrospective review of patients who underwent EAPA at their institution between 2012 and 2021. They collected preoperative clinical characteristics, operative reports, operative videos, findings on neuroimaging, histological diagnosis, postoperative course, and clinical status at last follow-up. For pathologies without petrous bone invasion, the amount of petrous apex drilling was calculated and classified as low (< 70% of the volume) or high (≥ 70%). Complications were dichotomized as approach related and resection related. RESULTS: This study included 49 patients: 26 with meningiomas, 10 brainstem cavernomas, 4 chondrosarcomas, 4 chordomas, 2 schwannomas, 1 epidermoid cyst, 1 cholesterol granuloma, and 1 osteoblastoma. The most common approach-related complications were temporal lobe injury (6.1% of patients), seizures (6.1%), pseudomeningocele (6.1%), hearing impairment (4.1%), and dry eye (4.1%). Approach-related complications occurred most commonly in patients with a meningioma (p = 0.02) and Meckel's cave invasion (p = 0.02). Gross-total or near-total resection was correlated with a higher rate of tumor resection-related complications (p = 0.02) but not approach-related complications (p = 0.76). Inferior, lateral, and superior tumoral extension were not correlated with a higher rate of tumor resection-related complications. No correlation was found between high amount of petrous bone drilling and approach- or resection-related complications. CONCLUSIONS: EAPA is a challenging approach that deals with critical neurovascular structures and demands specific skills to be safely performed. Contrary to general belief, its approach-related morbidity seems to be acceptable at dedicated skull base centers. Morbidity can be lowered with careful examination of the preoperative neuroradiological workup, appropriate patient selection, and attention to technical details.

Transuncal Selective Amygdalohippocampectomy by an Inferolateral Preseptal Endoscopic Approach Through Inferior Eyelid Conjunctival Incision: An Anatomic Study.

BACKGROUND: Transorbital endoscopic approaches have been described for pathologies of anterior and middle fossae. Standard lateral orbitotomy gives access to mesial temporal lobe, but the axis of work is partially obscured by the temporal pole and working corridor is limited. OBJECTIVE: To evaluate the usefulness of an inferolateral orbitotomy to provide a more direct corridor to perform a transuncal selective amygdalohippocampectomy. METHODS: Three adult cadaveric specimens were used for a total of 6 dissections. A step-by-step description and illustration of the transuncal corridor for a selective amygdalohippocampectomy were performed using the inferolateral orbitotomy through an inferior eyelid conjunctival incision. The anatomic landmarks were demonstrated in detail. Orbitotomies and angles of work were measured from computed tomography scans, and the area of resection was illustrated by postdissection MRI. RESULTS: Inferior eyelid conjunctival incision was made for exposure of the inferior orbital rim. Inferolateral transorbital approach was performed to access the transuncal corridor. Endoscopic selective amygdalohippocampectomy was performed through the entorhinal cortex without damage to the temporal neocortex or Meyer's loop. The mean horizontal diameter of the osteotomy was 14.4 mm, and the vertical one was 13.6 mm. The mean angles of work were 65° and 35.5° in the axial and sagittal planes, respectively. Complete amygdalohippocampectomy was achieved in all 6 dissections. CONCLUSION: Transuncal selective amygdalohippocampectomy was feasible in cadaveric specimens using the inferolateral transorbital endoscopic approach avoiding damage to the temporal neocortex and Meyer's loop. The inferior eyelid conjunctival incision may result in an excellent cosmetic outcome.

Long-Term Outcomes of Stereotactic Radiosurgery for Postoperative World Health Organization Grade I Skull Base Meningioma: Utility of Ki-67 Labeling Index as a Prognostic Indicator.

BACKGROUND: Gross total resection, without causing neurological deficits, is challenging in skull base meningioma (SBM). Therefore, stereotactic radiosurgery (SRS) is an important approach for SBMs; however, it is difficult to predict the long-term prognosis. OBJECTIVE: To identify the predictive factors for tumor progression after SRS for World Health Organization (WHO) grade I SBMs, focusing on the Ki-67 labeling index (LI). METHODS: In this single-center retrospective study, factors affecting progression-free survival rates (PFSs) and neurological outcomes in patients undergoing SRS for postoperative SBMs were evaluated. Based on the Ki-67 LI, patients were classified into 3 groups: low (<4%), intermediate (4%-6%), and high LI (>6%). RESULTS: In the 112 patients enrolled, the cumulative 5- and 10-year PFSs were 93% and 83%, respectively. The PFSs were significantly higher in the low LI group (95% at 10 years) compared with the other groups (intermediate LI, 60% at 10 years, P = .007; high LI, 20% at 10 years, P = .001). Multivariable Cox proportional hazard analysis demonstrated that the Ki-67 LI was significantly associated with the PFSs (low vs intermediate LI; hazard ratio, 6.00; 95% CI, 1.41-25.54; P = .015; low vs high LI; hazard ratio, 31.90; 95% CI, 5.59-181.77; P = .001). CONCLUSION: Ki-67 LI may be a useful predictor of long-term prognosis in SRS for postoperative WHO grade I SBM. SRS provides excellent long- and mid-term PFSs in SBMs with Ki-67 LIs <4% or 4% to 6%, with a low risk of radiation-induced adverse events.

Case report and literature review: exploration of molecular therapeutic targets in recurrent malignant meningioma through comprehensive genetic analysis with Todai OncoPanel.

Background: Despite accumulating research on the molecular characteristics of meningiomas, no definitive molecularly targeted therapy for these tumors has been established to date. Molecular mechanisms underlying meningioma progression also remain unclear. Comprehensive genetic testing approaches can reveal actionable gene aberrations in meningiomas. However, there is still limited information on whether profiling the molecular status of subsequent recurrent meningiomas could influence the choice of molecular-targeted therapies. Case presentation: We report a case of meningioma with malignant progression and multiple recurrences. We performed matched tumor pair analysis using the Todai OncoPanel to investigate the possibility of additional standard treatments. The loss of several chromosomal regions, including NF2 and CDKN2A, which is associated with aggressive meningiomas, was considered a significant driver event for malignant progression. Using additional matched tumor pair analysis, mutations in TRAF7, ARID1A, and ERBB3 were identified as subclonal driver events at the time of recurrence. No genetic aberrations were found for which evidence-based targeted therapy was applicable. We also reviewed previous reports of molecular therapies in meningioma to discuss issues with the current molecular testing approach. Conclusion: Gene panel testing platforms such as the Todai OncoPanel represent a powerful approach to elucidate actionable genetic alterations in various types of tumors, although their use is still limited to the diagnosis and prediction of prognosis in meningiomas. To enable targeted molecular therapy informed by gene-panel testing, further studies including matched tumor pair analyses are required to understand the molecular characteristics of meningiomas and develop treatments based on genetic abnormalities.

Meningiomas in patients with neurofibromatosis type 2 predominantly comprise 'immunogenic subtype' tumours characterised by macrophage infiltration.

Although recent molecular analyses revealed that sporadic meningiomas have various genetic, epigenetic, and transcriptomic profiles, meningioma in patients with neurofibromatosis type 2 (NF2) have not been fully elucidated. This study investigated meningiomas' clinical, histological, and molecular characteristics in NF2 patients. A long-term retrospective follow-up (13.5 ± 5.5 years) study involving total 159 meningiomas in 37 patients with NF2 was performed. Their characteristics were assessed using immunohistochemistry (IHC), bulk-RNA sequencing, and copy number analysis. All variables of meningiomas in patients with NF2 were compared with those in 189 sporadic NF2-altered meningiomas in 189 patients. Most meningiomas in NF2 patients were stable, and the mean annual growth rate was 1.0 ± 1.8 cm3/year. Twenty-eight meningiomas (17.6%) in 25 patients (43.1%) were resected during the follow-up period. WHO grade I meningiomas in patients with NF2 were more frequent than in sporadic NF2-altered meningiomas (92.9% vs. 80.9%). Transcriptomic analysis for patients with NF2/sporadic NF2-altered WHO grade I meningiomas (n = 14 vs. 15, respectively) showed that tumours in NF2 patients still had a higher immune response and immune cell infiltration than sporadic NF2-altered meningiomas. Furthermore, RNA-seq/IHC-derived immunophenotyping corroborated this enhanced immune response by identifying myeloid cell infiltration, particularly in macrophages. Clinical, histological, and transcriptomic analyses of meningiomas in patients with NF2 demonstrated that meningiomas in NF2 patients showed less aggressive behaviour than sporadic NF2-altered meningiomas and elicited a marked immune response by identifying myeloid cell infiltration, particularly of macrophages.