Respective roles of Pik3ca mutations and cyproterone acetate impregnation in mouse meningioma tumorigenesis.

Despite their rarity, PIK3CA mutations in meningiomas have raised interest as potentially targetable, ubiquitous mutations owing to their presence in sporadic benign and malignant tumors but also in hormone-related cases. Using new genetically engineered mouse models, we here demonstrate that Pik3ca mutations in postnatal meningeal cells are sufficient to promote meningioma formation but also tumor progression in mice. Conversely, hormone impregnation, whether alone or in association with Pik3ca and Nf2 mutations, fails to induce meningioma tumorigenesis while promoting breast tumor formation. We then confirm in vitro the effect of Pik3ca mutations but not hormone impregnation on the proliferation of primary cultures of mouse meningeal cells. Finally, we show by exome analysis of breast tumors and meninges that hormone impregnation promotes breast tumor formation without additional somatic oncogenic mutation but is associated with an increased mutational burden on Pik3ca-mutant background. Taken together, these results tend to suggest a prominent role of Pik3ca mutations over hormone impregnation in meningioma tumorigenesis, the exact effect of the latter is still to be discovered.

GAB1 as a Marker of Recurrence in Anterior Skull Base Meningioma.

BACKGROUND: About one-third of anterior skull base meningiomas show Hedgehog pathway activation. We have recently identified GAB1 as a surrogate marker for Hedgehog pathway-activated meningiomas. OBJECTIVE: To determine the reproducibility and prognostic value of GAB1 marker in anterior skull base meningiomas. METHODS: A retrospective bicentric cohort of anterior skull base meningiomas, operated from 2005 to 2015, was constituted. GAB1 immunohistochemistry was performed in 2 centers, and the GAB1 score was assessed. Clinical and pathological data were reviewed to determine the prognostic value of the GAB1 score, along with classical factors of recurrence. RESULTS: One hundred forty-eight patients were included (median follow-up of 72 ± 46 months). 78% of patients had gross total resection. Eighty-four percentage of patients harbored grade 1 meningiomas. GAB1 immunohistochemistry was positive (ie, GAB1 staining score was >250) in 53 cases (35%). GAB1-positive cases were mainly at olfactory groove, of meningothelial grade 1 subtype, and showed greater recurrence (36% vs 14%, P = .002), greater requirement for multiple surgeries (17% vs 4.2%, P = .014), and more likely evolution toward diffuse skull base infiltration (15% vs 3%, P = .0017). By multivariable Cox regression analysis, incomplete surgical resection (hazard ratios [HR] = 8.3, 95% IC [3.7-18.2], P < .001), male sex (HR = 5.4, 95% IC [2.2-13.5], P < .001), GAB1 positivity (HR = 3.2, 95% CI [1.5-6.9], P = .004), and Ki67 index >4 (HR = 2.2, 95% IC [1.2-4.6], P = .035) were independent prognostic factors for recurrence. CONCLUSION: GAB1 marker is an independent prognostic factor for anterior skull base meningioma and could be useful for both prognostic evaluation and identification of Hedgehog-activated meningiomas.

Roles and outcomes of stereotactic biopsy for adult patients with brainstem lesion.

PURPOSE: This study aimed to assess the benefit-risk ratio by determining diagnostic yield and safety of brainstem biopsies in adult patients. The secondary objectives were (i) to compare brainstem biopsy safety and postbiopsy patients' outcomes and survival with those of patients biopsied for a brain or cerebellar lesion, and (ii) to assess the impact of brainstem biopsy on final diagnosis and further therapeutic management. METHODS: Among 1784 stereotactic biopsies performed in adult patients at a tertiary center between April 2009 and October 2020, we retrospectively examined 50 consecutive brainstem biopsies. We compared variables regarding diagnostic yield, safety and post-biopsy outcomes between brainstem biopsy patients and brain/cerebellum biopsy patients. RESULTS: Brainstem biopsy led to a diagnosis in 86% of patients (94.6% in patients with suspected tumor). Lesion contrast enhancement on imaging was the sole predictor of obtaining a diagnosis. Rates of symptomatic complications and mortality were significantly higher in brainstem biopsy patients compared to brain/cerebellum biopsy patients (20% vs 0%; p < 0.001 and 6% vs 0%; p = 0.01, respectively). Transfrontal trajectory and prebiopsy swallowing disorders were predictors of brainstem biopsy-related symptomatic complications. Brainstem biopsy findings led to diagnostic change in 22% of patients. CONCLUSIONS: Stereotactic biopsy in adult patients with brainstem lesion has a high diagnostic yield. Although stereotactic brainstem biopsy is associated with more functional and fatal complications than biopsies targeting the brain/cerebellum, its safety profile appears acceptable. Thus, the benefit-risk ratio of stereotactic biopsy in patients with brainstem lesion is favorable but should nevertheless be carefully weighted on a case-by-case basis.

Severity, timeline, and management of complications after stereotactic brain biopsy.

OBJECTIVE: The literature shows discrepancies in stereotactic brain biopsy complication rates, severities, and outcomes. Little is known about the timeline of postbiopsy complications. This study aimed to analyze 1) complications following brain biopsies, using a graded severity scale, and 2) a timeline of complication occurrence. The secondary objectives were to determine factors associated with an increased risk of complications and to assess complication-related management and extra costs. METHODS: The authors retrospectively examined 1500 consecutive stereotactic brain biopsies performed in adult patients at their tertiary medical center between April 2009 and April 2019. RESULTS: Three hundred eighty-one biopsies (25.4%) were followed by a complication, including 88.2% of asymptomatic hemorrhages. Symptomatic complications involved 3.0% of the biopsies, and 0.8% of the biopsies were fatal. The severity grading scale had a 97.6% interobserver reproducibility. Twenty-three (51.1%) of the 45 symptomatic complications occurred within the 1st hour following the biopsy, while 75.6% occurred within the first 6 hours. Age ≥ 65 years, second biopsy procedures, gadolinium-enhanced lesions, glioblastomas, and lymphomas were predictors of biopsy-related complications. Brainstem biopsy-targeted lesions and cerebral toxoplasmosis were predictive of mortality. Asymptomatic hemorrhage was associated with delayed (> 6 hours) symptomatic complications. Symptomatic complications led to extended hospitalization in 86.7% of patients. The average extra cost for management of a patient with postbiopsy symptomatic complication was $35,702. CONCLUSIONS: Symptomatic complications from brain biopsies are infrequent but associated with substantial adverse effects and cost implications for the healthcare system. The use of a severity grading scale, as the authors propose in this article, helps to classify complications according to the therapeutic consequences and the patient's outcome. Because this study indicates that most complications occur within the first few hours following the biopsy, postbiopsy monitoring can be tailored accordingly. The authors therefore recommend systematic monitoring for 2 hours in the recovery unit and a CT scan 2 hours after the end of the biopsy procedure. In addition, they propose a modern algorithm for optimal postoperative management of patients undergoing stereotactic biopsy.

Angiographic Anatomy of the Middle Meningeal Artery in Relation to Chronic Subdural Hematoma Embolization.

PURPOSE: Middle meningeal artery (MMA) embolization is emerging as a potential treatment of chronic subdural hematomas (CSDHs). The purpose of this study is to describe MMA angiographic anatomy in relation to CSDH embolization. METHODS: This retrospective monocentric study was performed on imaging data of MMA embolization procedures for CSDH treatment performed between March 15, 2018 and April 30, 2020. Imaging data, including digital subtraction angiography (DSA) were reviewed independently by two physicians. Discrepancies were resolved by consensus. The MMA bifurcation pattern was analyzed according to an extended Adachi classification. Relations of the MMA with the ophthalmic artery (OA) were also analyzed. RESULTS: In this study, 140 MMAs were analyzed. Dominance of the anterior branch (type I) was observed in only 57/140 (41%) MMAs with a moderate interobserver agreement for classifying MMA into type I against all other (κ = 0.53, 95% confidence interval, CI 0.39-0.67). The posterior branch presented a proximal origin (type A), at the point of emergence of the MMA from the foramen spinosum or its immediate vicinity, in 48/135 (36%) MMAs with a very good interobserver agreement for classifying MMAs into type A against all other (κ = 0.82, 95% CI 0.72-0.92). An angiographic relationship with the OA was observed in 26 MMAs (19%). CONCLUSION: In the majority of CSDH patients both anterior and posterior branches of the MMA should be targeted to achieve extensive convexity devascularization. Frequent anatomical variations of the MMA with respect to emergence of the posterior branch and MMA orbital branches are expected to impact CSDH embolization strategy.

Outpatient stereotactic brain biopsies.

Outpatient neurosurgery is rising popularity leading to patients' satisfaction and cost-savings. Although several North-American teams have shown the safety of outpatient stereotactic brain biopsies, few data from other countries with different health care systems are available. We therefore conducted a feasibility and safety study on the outpatient stereotactic brain biopsies. We prospectively examined all the consecutive stereotactic brain biopsies performed in an outpatient setting at our tertiary medical center, between June 2018 and September 2020. Among the 437 patients who underwent stereotactic brain biopsy during the study period, 40 (9.2%) patients were enrolled for an outpatient management. The sex ratio was 1 and the median age on biopsy day was 55 [41-66] years. The median distance from patients' home to hospital was 17 km [3-47]. 95% of patients had pre-biopsy ASA score of 1 or 2 and mRs equal to 2 or less. The rate of same-day discharge was 100%. No patient experienced post-biopsy symptomatic complication necessitating readmission within the month following the biopsy. One patient (2.5%) resorted to an unplanned consultation. Histological findings obtained from brain biopsy led to a diagnosis in all patients; the most frequently found were neoplastic lesions (77.5%). Stereotactic brain biopsies can therefore be safely achieved on an outpatient setting in carefully selected patients. This process could be more widely adopted in other neurosurgical centers, without affecting the quality of patient's health care and safety. In this article, we propose management guidelines and pre-biopsy checklist for performing ambulatory stereotactic brain biopsies.

Somatic PIK3CA Mutations in Sporadic Cerebral Cavernous Malformations.

BACKGROUND: Cerebral cavernous malformations (CCMs) are common sporadic and inherited vascular malformations of the central nervous system. Although familial CCMs are linked to loss-of-function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3), the genetic cause of sporadic CCMs, representing 80% of cases, remains incompletely understood. METHODS: We developed two mouse models harboring mutations identified in human meningiomas with the use of the prostaglandin D2 synthase (PGDS) promoter. We performed targeted DNA sequencing of surgically resected CCMs from patients and confirmed our findings by droplet digital polymerase-chain-reaction analysis. RESULTS: We found that in mice expressing one of two common genetic drivers of meningioma - Pik3ca H1047R or AKT1 E17K - in PGDS-positive cells, a spectrum of typical CCMs develops (in 22% and 11% of the mice, respectively) instead of meningiomas, which prompted us to analyze tissue samples from sporadic CCMs from 88 patients. We detected somatic activating PIK3CA and AKT1 mutations in 39% and 1%, respectively, of lesion tissue from the patients. Only 10% of lesions harbored mutations in the CCM genes. We analyzed lesions induced by the activating mutations Pik3ca H1074R and AKT1 E17K in mice and identified the PGDS-expressing pericyte as the probable cell of origin. CONCLUSIONS: In tissue samples from sporadic CCMs, mutations in PIK3CA were represented to a greater extent than mutations in any other gene. The contribution of somatic mutations in the genes that cause familial CCMs was comparatively small. (Funded by the Fondation ARC pour la Recherche contre le Cancer and others.).

GAB1 overexpression identifies hedgehog-activated anterior skull base meningiomas.

AIMS: Mutations activating the hedgehog (Hh) signalling pathway have been described in anterior skull base meningiomas, raising hope for the use of targeted therapies. However, identification of Hh-activated tumours is hampered by the lack of a reliable immunohistochemical marker. We report the evaluation of GAB1, an immunohistochemical marker used to detect Hh pathway activation in medulloblastoma, as a potential marker of Hh-activated meningiomas. METHODS: GAB1 staining was compared to SMO mutation detection with Sanger and NGS techniques as well as Hh pathway activation study through mRNA expression level analyses in a discovery set of 110 anterior skull base meningiomas and in a prospective validation set of 21 meningiomas. RESULTS: Using an expression score ranging from 0 to 400, we show that a cut-off score of 250 lead to excellent detection of Hh pathway mutations (sensitivity 100%, specificity 86%). The prospective validation set confirmed the excellent negative predictive value of GAB1 to exclude Hh-independent meningiomas. We describe a large series of 32 SMO-mutant meningiomas and define multiple ways of Hh activation, either through somatic mutations or associated with mutually co-exclusive sonic hedgehog (SHH) or Indian hedgehog (IHH) overexpression independent of the mutations. CONCLUSION: The assessment of GAB1 expression by an immunohistochemical score is a fast and cost-efficient tool to screen anterior skull base meningiomas for activation of the Hh pathway. It could facilitate the identification of selected cases amenable to sequencing for Hh pathway genes as predictive markers for targeted therapy.

Sustained growth of intraosseous hormone-associated meningiomas after cessation of progestin therapy.

Hormone-associated meningiomas tend to stop growing or decrease in size after cessation of certain progestins, mainly cyproterone acetate. We report three observations on the natural history of hormone-associated intraosseous meningiomas, showing in a first patient that those tumors may grow rapidly under nomegestrol. We then demonstrate the sustained growth of intraosseous hormone-associated meningiomas after cessation of promesgestone and nomegestrol, independently of the intracranial portion, which concurrently decreased in size in the second case or was resected at the time of nomegestrol withdrawal in the third case, thus giving new insights into the tumorigenesis mechanisms of hormone-associated intraosseous meningiomas.

Custom surgical management of invasive malignant tumors of the scalp.

BACKGROUND: There is no universal management protocol concerning invasive malignant tumors of the scalp with bone and dura mater invasion. The aims of this study were to report and discuss our experience in the management of these forms of tumors. METHODS: We retrospectively reviewed all consecutive patients of microsurgical scalp reconstruction performed after resection of invasive cutaneous malignancies of the scalp, calvarium, and dura mater from 2017 to 2019, at Pitié-Salpêtrière University Hospital (Paris, France). RESULTS: Five patients met inclusion criteria. There were three squamous cell carcinomas and two sarcomas. Mean age at surgery was 63.6 years. The sex ratio male/female was 4. Two received radiation prior to resection and two patients had a history of prior scalp tumor surgery. All the patients underwent craniectomy and the mean cranial defect size was 41 cm2. Cranioplasty was performed in one patient. Soft tissue coverage was provided by free tissue transfer of latissimus dorsi muscle in all patients. In four patients, split thickness skin graft was performed in a second surgical stage few weeks later. There were no intraoperative complications and no complications into the donor site for the tissue transfer or the skin graft. Two patients had flap necrosis that healed after a new free flap of latissimus dorsi. CONCLUSIONS: Wide resection with craniectomy and reconstruction with microvascular free tissue transfer provides safe and reliable treatment of recalcitrant invasive scalp skin cancers. The surgical management of these complex patients is a challenge that must be conducted by trained, experienced, and multidisciplinary teams.