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BACKGROUND: To improve hearing function after resection of large vestibular schwannomas, we describe a strategy of vestibular-nerve-fiber preservation. Anatomical considerations and stepwise dissection are described. METHOD: Steps include locating the vestibular nerve at the brainstem and identifying a dissection plane between nerve fibers and tumor capsule. Using this plane to mobilize and resect tumor reduced manipulation and maintained vascularity of underlying cochlear and facial nerves. CONCLUSION: Preservation of hearing function is feasible in large vestibular schwannomas with vestibular-nerve-fiber preservation. Reducing manipulation and ischemic injury of underlying cochlear and facial nerves thereby helped facilitate hearing preservation, even in large tumors.
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Neuroma Acústico , Humanos , Neuroma Acústico/cirurgia , Neuroma Acústico/patologia , Nervo Vestibular/cirurgia , Audição , Nervo Facial/cirurgia , Testes Auditivos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controleRESUMO
PURPOSE: Sinus thrombosis is a common post-operative finding after posterior fossa surgery performed in the vicinity of the dural venous sinuses. The SARS-CoV-2 virus has been shown to confer an increased risk of venous thromboembolic events owing to eliciting a hyper-inflammatory and pro-thrombotic state. In this study, we examine the incidence of post-operative venous sinus thrombosis in patients undergoing peri-sigmoid posterior fossa surgery in the pre- and post-COVID era and investigate whether COVID infection confers an increased risk of sinus thrombosis. METHODS: A retrospective review of a single institution case series of patients underwent peri-sigmoid surgery (retrosigmoid, translabyrinthine, or far lateral) approach. Relevant clinical variables were investigated that may confer an increased risk of sinus thrombosis. RESULTS: A total of 311 patients (178 in the pre-COVID era, and 133 operated on after the pandemic began in March 2020) are included in the study. The composite incidence of sinus thrombosis seen on post-operative imaging was 7.8%. The incidence of sinus thrombosis in the pre-COVID cohort was N = 12 patients (6.7%) versus N = 12 (9%) in the post-COVID cohort (p = 0.46). A history of COVID infection was not shown to confer an increased risk of post-operative sinus thrombosis (OR: 0.61; 95% CI: 0.08-4.79, p = 0.64). Only a small number of patients (N = 7, 2.3%) required either medical or surgical intervention for post-operative sinus thrombosis. CONCLUSION: The overall incidence of post-operative sinus thrombosis is similar in the pre- and post-COVID era. The findings of this study suggest that COVID infection is not associated with a higher risk of venous sinus thrombosis.
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COVID-19 , Complicações Pós-Operatórias , Trombose dos Seios Intracranianos , Humanos , COVID-19/epidemiologia , COVID-19/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Incidência , Estudos Retrospectivos , Trombose dos Seios Intracranianos/epidemiologia , Trombose dos Seios Intracranianos/etiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Idoso , Adulto , Base do Crânio/cirurgia , Procedimentos Neurocirúrgicos/efeitos adversos , Fatores de RiscoRESUMO
Introduction Penttinen premature aging syndrome is caused by mutations in the PDGFRB gene. We describe the case of a 10-year-old girl with a de novo c.1994T>C variant in PDGFRB who developed multiple cranial, intracranial, and spinal manifestations, including macrocephaly, enlarged convexity subarachnoid spaces crossed by numerous vascularized arachnoid trabeculae, hydrocephalus, spinal epidural lipomatosis, a low conus medullaris, calvarial thinning with large anterior fontanelle, and a skull fracture with bilateral epidural hematomas. Vascularized arachnoid granulations, spinal epidural lipomatosis, and low conus medullaris have not been previously described in Penttinen syndrome. Case Report A female with Penttinen syndrome diagnosed at 9 years of age initially presented as an infant with cutaneous hemangiomas and macrocephaly, later developing external hydrocephalus necessitating shunt placement. At surgery, her enlarged subarachnoid spaces were found to contain numerous abnormally thick, vascularized arachnoid trabeculae. She later developed chronic back pain and imaging revealed spinal epidural lipomatosis, a low conus medullaris, and mild scoliosis. A large anterior fontanelle which did not diminish in size led to cranioplasty with a custom implant. At 10 years of age, a fall from a chair resulted in an elevated skull fracture and bilateral parasagittal epidural hematomas. Emergency left parietal craniotomy was performed for evacuation of the left hematoma, and the patient recovered without complications. Intraoperatively, it was noted that her skull was extremely thin. Discussion This case report highlights the clinical presentation and multifaceted neurosurgical management of a patient with Penttinen syndrome. The patient exhibited characteristic features including hypertrophic skin lesions, macrocephaly, and skeletal abnormalities. Our patient's vascularized arachnoid trabeculae, spinal epidural lipomatosis, and low conus medullaris have not previously been reported in Penttinen syndrome. Her thin skull potentially contributed to the extent of her elevated skull fracture after her backwards fall and predisposed her toward developing epidural hematomas. Patients with Pentinnen syndrome can have multiple cranial, intracranial, and spinal manifestations which may need the attention of a neurosurgeon.
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PURPOSE: Missense mutated von Hippel Lindau (VHL) protein (pVHL) maintains intrinsic function but undergoes proteasomal degradation and tumor initiation and/or progression in VHL disease. Vorinostat can rescue missense mutated pVHL and arrest tumor growth in preclinical models. We asked whether short-term oral vorinostat could rescue pVHL in central nervous system hemangioblastomas in patients with germline missense VHL. PATIENTS AND METHODS: We administered oral vorinostat to 7 subjects (ages 46.0 ± 14.5 years) and then removed symptomatic hemangioblastomas surgically (ClinicalTrials.gov identifier NCT02108002). RESULTS: Vorinostat was tolerated without serious adverse events by all patients. pVHL expression was elevated in neoplastic stromal cells compared with untreated hemangioblastomas from same patients. We found transcriptional suppression of downstream hypoxia-inducible factor (HIF) effectors. Mechanistically, vorinostat prevented Hsp90 recruitment to mutated pVHL in vitro. The effects of vorinostat on the Hsp90-pVHL interaction, pVHL rescue, and transcriptional repression of downstream HIF effectors was independent of the location of the missense mutation on the VHL locus. We confirmed a neoplastic stromal cell-specific effect in suppression of protumorigenic pathways with single-nucleus transcriptomic profiling. CONCLUSIONS: We found that oral vorinostat treatment in patients with germline missense VHL mutations has a potent biologic effect that warrants further clinical study. These results provide biologic evidence to support the use of proteostasis modulation for the treatment of syndromic solid tumors involving protein misfolding. Proteostasis modulation with vorinostat rescues missense mutated VHL protein. Further clinical trials are needed to demonstrate tumor growth arrest.
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Produtos Biológicos , Neoplasias do Sistema Nervoso Central , Hemangioblastoma , Doença de von Hippel-Lindau , Humanos , Doença de von Hippel-Lindau/genética , Vorinostat , Proteostase , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
CONTEXT: Single ACTH measurements have limited ability to distinguish patients with Cushing's disease (CD) from those in remission or with other conditions. OBJECTIVE: To investigate the changes in ACTH levels before and after transsphenoidal surgery (TSS) to identify trends that could confirm remission from CD and help establish ACTH cutoffs for targeted clinical trials in CD. DESIGN: Retrospective analysis of CD patients who underwent TSS from 2005 to -2019. SETTING: Referral center. PATIENTS: CD patients (n = 253) with ACTH measurements before and after TSS. INTERVENTIONS: TSS for CD. MAIN OUTCOME MEASURES: Remission after TSS. RESULTS: Remission was observed in 223 patients after TSS. Those in remission had higher ACTH variability at AM (P = .02) and PM (P < .001) time points compared to nonremission. The nonremission group had a significantly narrower diurnal range compared to the remission group (P = <.0001). A decrease in plasma ACTH of ≥50% from mean preoperative levels predicted CD remission after TSS, especially when using PM values. The absolute plasma ACTH concentration and ratio of preoperative to postoperative values were significantly associated with nonremission after multivariable logistic regression (adj P < .001 and .001, respectively). CONCLUSIONS: Our findings suggest that ACTH variability is suppressed in CD, and remission from CD is associated with the restoration of this variability. Furthermore, a decrease in plasma ACTH by 50% or more may serve as a predictor of remission post-TSS. These insights could guide clinicians in developing rational outcome measures for interventions targeting CD adenomas.
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Adenoma , Hipersecreção Hipofisária de ACTH , Humanos , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/cirurgia , Resultado do Tratamento , Estudos Retrospectivos , Adenoma/cirurgia , Hormônio AdrenocorticotrópicoRESUMO
BACKGROUND: Retroperitoneal nerve sheath tumors present a surgical challenge. Despite potential advantages, robotic surgery for these tumors has been limited. Identifying and sparing functional nerve fascicles during resection can be difficult, increasing the risk of neurological morbidity. OBJECTIVE: To review the literature regarding robotic resection of retroperitoneal nerve sheath tumors and retrospectively analyze our experience with robotic resection of these tumors using a manual electromyographic probe to identify and preserve functional nerve fascicles. METHODS: We retrospectively analyzed the clinical courses of 3 patients with retroperitoneal tumors treated at the National Institutes of Health by a multidisciplinary team using the da Vinci Xi system. Parent motor nerve fascicles were identified intraoperatively with a bipolar neurostimulation probe inserted through a manual port, permitting tumor resection with motor fascicle preservation. RESULTS: Two patients with neurofibromatosis type 1 underwent surgery for retroperitoneal neurofibromas located within the iliopsoas muscle, and 1 patient underwent surgery for a pelvic sporadic schwannoma. All tumors were successfully resected, with no complications or postoperative neurological deficits. Preoperative symptoms were improved or resolved in all patients. CONCLUSION: Resection of retroperitoneal nerve sheath tumors confers an excellent prognosis, although their deep location and proximity to vital structures present unique challenges. Robotic surgery with intraoperative neurostimulation mapping is safe and effective for marginal resection of histologically benign or atypical retroperitoneal nerve sheath tumors, providing excellent visibility, increased dexterity and precision, and reduced risk of neurological morbidity.
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Neoplasias de Bainha Neural , Neurilemoma , Procedimentos Cirúrgicos Robóticos , Humanos , Neoplasias de Bainha Neural/patologia , Neoplasias de Bainha Neural/cirurgia , Neurilemoma/cirurgia , Procedimentos Neurocirúrgicos , Estudos Retrospectivos , Estados UnidosRESUMO
The unique acute effects of the large fractional doses that characterize stereotactic radiosurgery (SRS) or radiotherapy (SRT), specifically in terms of antitumor immune cellular processes, vascular damage, tumor necrosis, and apoptosis on brain metastasis have yet to be empirically demonstrated. The objective of this study is to provide the first in-human evaluation of the acute biological effects of SRS/SRT in resected brain metastasis. Tumor samples from patients who underwent dose-escalated preoperative SRT followed by resection with available non-irradiated primary tumor tissues were retrieved from our institutional biorepository. All primary tumors and irradiated metastases were evaluated for the following parameters: tumor necrosis, T-cells, natural killer cells, vessel density, vascular endothelial growth factor, and apoptotic factors. Twenty-two patients with irradiated and resected brain metastases and paired non-irradiated primary tumor samples met inclusion criteria. Patients underwent a median preoperative SRT dose of 18 Gy (Range: 15-20 Gy) in 1 fraction, with 3 patients receiving 27-30 Gy in 3-5 fractions, followed by resection within median interval of 67.8 h (R: 18.25-160.61 h). The rate of necrosis was significantly higher in irradiated brain metastases than non-irradiated primary tumors (p < 0.001). Decreases in all immunomodulatory cell populations were found in irradiated metastases compared to primary tumors: CD3 + (p = 0.003), CD4 + (p = 0.01), and CD8 + (p = 0.01). Pre-operative SRT is associated with acute effects such as increased tumor necrosis and differences in expression of immunomodulatory factors, an effect that does not appear to be time dependent, within the limited intervals explored within the context of this analysis.
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Neoplasias Encefálicas , Radiocirurgia , Biomarcadores , Neoplasias Encefálicas/patologia , Humanos , Necrose/etiologia , Radiocirurgia/efeitos adversos , Estudos Retrospectivos , Fator A de Crescimento do Endotélio VascularRESUMO
Sporadic pituitary adenomas occur in over 10% of the population. Hormone-secreting adenomas, including those causing Cushing's disease (CD), cause severe morbidity and early mortality. Mechanistic studies of CD are hindered by a lack of in vitro models and control normal human pituitary glands. Here, we surgically annotate adenomas and adjacent normal glands in 25 of 34 patients. Using single-cell RNA sequencing (RNA-seq) analysis of 27594 cells, we identify CD adenoma transcriptomic signatures compared with adjacent normal cells, with validation by bulk RNA-seq, DNA methylation, qRT-PCR, and immunohistochemistry. CD adenoma cells include a subpopulation of proliferating, terminally differentiated corticotrophs. In CD adenomas, we find recurrent promoter hypomethylation and transcriptional upregulation of PMAIP1 (encoding pro-apoptotic BH3-only bcl-2 protein noxa) but paradoxical noxa downregulation. Using primary CD adenoma cell cultures and a corticotroph-enriched mouse cell line, we find that selective proteasomal inhibition with bortezomib stabilizes noxa and induces apoptosis, indicating its utility as an anti-tumor agent.
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Adenoma , Hipersecreção Hipofisária de ACTH , Neoplasias Hipofisárias , Adenoma/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Animais , Apoptose , Humanos , Camundongos , Hipersecreção Hipofisária de ACTH/genética , Hipersecreção Hipofisária de ACTH/patologia , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologiaRESUMO
PFKFB3 is a bifunctional enzyme that modulates and maintains the intracellular concentrations of fructose-2,6-bisphosphate (F2,6-P2), essentially controlling the rate of glycolysis. PFKFB3 is a known activator of glycolytic rewiring in neoplastic cells, including central nervous system (CNS) neoplastic cells. The pathologic regulation of PFKFB3 is invoked via various microenvironmental stimuli and oncogenic signals. Hypoxia is a primary inducer of PFKFB3 transcription via HIF-1alpha. In addition, translational modifications of PFKFB3 are driven by various intracellular signaling pathways that allow PFKFB3 to respond to varying stimuli. PFKFB3 synthesizes F2,6P2 through the phosphorylation of F6P with a donated PO4 group from ATP and has the highest kinase activity of all PFKFB isoenzymes. The intracellular concentration of F2,6P2 in cancers is maintained primarily by PFKFB3 allowing cancer cells to evade glycolytic suppression. PFKFB3 is a primary enzyme responsible for glycolytic tumor metabolic reprogramming. PFKFB3 protein levels are significantly higher in high-grade glioma than in non-pathologic brain tissue or lower grade gliomas, but without relative upregulation of transcript levels. High PFKFB3 expression is linked to poor survival in brain tumors. Solitary or concomitant PFKFB3 inhibition has additionally shown great potential in restoring chemosensitivity and radiosensitivity in treatment-resistant brain tumors. An improved understanding of canonical and non-canonical functions of PFKFB3 could allow for the development of effective combinatorial targeted therapies for brain tumors.
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Neoplasias Encefálicas/enzimologia , Fosfofrutoquinase-2/metabolismo , Animais , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/imunologia , Carcinogênese/patologia , Humanos , Imunomodulação , Neovascularização Patológica/enzimologia , Hipóxia TumoralRESUMO
BACKGROUND: Conus medullaris tumors are rare, as the majority of all spinal cord tumors occur in the cervical and thoracic regions. Hemangioblastomas of the spinal cord account for 3%-4% of all intramedullary spinal cord tumors and can be sporadic or associated with von Hippel-Lindau disease. There are only fourteen cases of conus medullaris hemangioblastomas published in the literature, herein we present the fifteenth. CASE DESCRIPTION: A 44-year old male with von Hippel Lindau disease presented with worsening bilateral lower extremity weakness, gait imbalance as well as absent perineal and genital sensation with weak voluntary anal contraction. MRI demonstrated multiple stable spinal tumors and a 6 mm conus medullaris hemangioblastoma with growth and a new peri-tumoral cyst. The patient underwent uncomplicated surgical resection with appreciable improvement in perineal sensation and sphincteric control during post-operative course. CONCLUSIONS: Timely resection of conus medullaris tumors can provide symptomatic relief and prevent the progression of devastating neurological deficits. Careful microsurgical dissection with appropriate patient selection allows for safe resection of conus medullaris tumors.
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BACKGROUND: Providing the standard of care to patients with glioblastoma (GBM) during the novel coronavirus of 2019 (COVID-19) pandemic is a challenge, particularly if a patient tests positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Further difficulties occur in eloquent cortex tumors because awake speech mapping can theoretically aerosolize viral particles and expose staff. Moreover, microscopic neurosurgery has become difficult because the use of airborne-level personal protective equipment (PPE) crowds the space between the surgeon and the eyepiece. However, delivering substandard care will inevitably lead to disease progression and poor outcomes. OBSERVATIONS: A 60-year-old man with a left insular and frontal operculum GBM was found to be COVID-19 positive. Treatment was postponed pending a negative SARS-CoV-2 result, but in the interim, he developed intratumoral hemorrhage with progressive expressive aphasia. Because the tumor was causing dominant hemisphere language symptomatology, an awake craniotomy was the recommended surgical approach. With the use of airborne-level PPE and a surgical drape to protect the surgeon from the direction of potential aerosolization, near-total gross resection was achieved. LESSONS: Delaying the treatment of patients with GBM who test positive for COVID-19 will lead to further neurological deterioration. Optimal and timely treatment such as awake speech mapping for COVID-19-positive patients with GBM can be provided safely.
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BACKGROUND: Retrobulbar hemangioblastomas involving the optic apparatus in patients with von Hippel-Lindau disease (VHL) are rare, with only 25 reported cases in the literature. OBJECTIVE: To analyze the natural history of retrobulbar hemangioblastomas in a large cohort of VHL patients in order to define presentation, progression, and management. METHODS: Clinical history and imaging of 250 patients with VHL in an ongoing natural history trial and 1774 patients in a neurosurgical protocol were reviewed. The clinical course, magnetic resonance images, treatment, and outcomes were reviewed for all included patients. RESULTS: A total of 18 patients with retrobulbar hemangioblastoma on surveillance magnetic resonance imaging met the inclusion criteria for this study. Of the 17 for whom clinical information was available, 10 patients presented with symptoms related to the hemangioblastoma, and 7 were asymptomatic. The mean tumor volume was larger for symptomatic (810.6 ± 545.5 mm3) compared to asymptomatic patients (307.6 ± 245.5 mm3; P < .05). A total of 5 of the symptomatic patients were treated surgically and all experienced improvement in their symptoms. All 3 symptomatic patients that did not undergo intervention had continued symptom progression. Long-term serial imaging on asymptomatic patients showed that these tumors can remain radiographically stable and asymptomatic for extended periods of time (101.43 ± 71 mo). CONCLUSION: This study suggests that retrobulbar hemangioblastomas may remain stable and clinically asymptomatic for long durations. Recent growth and larger tumor volume were associated with symptom occurrence. Surgical treatment of symptomatic retrobulbar hemangioblastomas can be safe and may reverse the associated symptoms.