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Meningiomas constitute the most common primary tumors of the central nervous system. Despite maximum treatment, grade 2/3 meningiomas are associated with a high risk of recurrence. Stereotactic radiosurgery is the treatment of choice as adjuvant treatment for grade 2/3 meningiomas. Currently, pharmacotherapies, including molecular targeted therapy for various growth factors, their receptors, and the associated pathways, have shown limited effectiveness for management of refractory or recurrent meningiomas. Therefore, novel systemic treatment approaches are urgently required in such cases. Recent advances in genetics and epigenetics and the identification of specific genetic alterations have led to new classifications of these tumors and the development of therapeutic targets. Identification of targeted gene mutations may lead to precision-based medicine. Other therapeutic approaches such as immune checkpoint inhibitors rarely elicit a significant response in meningiomas with a high tumor mutation burden. Combination therapies that affect these multiple targets are also considered adjuvant therapeutic options. Comprehensive/in-depth research is warranted to investigate the safety and efficacy of other treatment strategies, including chimeric antigen receptor T-cells, oncolytic virus immunotherapy, and gene therapy. In this article, we review the current evidence regarding the efficacy of systemic treatments available in the literature and discuss recent and ongoing trials for meningiomas.
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Neoplasias Meníngeas , Meningioma , Meningioma/tratamento farmacológico , Meningioma/terapia , Humanos , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/terapia , Terapia de Alvo Molecular , ImunoterapiaRESUMO
NF2-related schwannomatosis (NF2; previously termed neurofibromatosis type 2) is a tumor-prone disorder characterized by development of multiple schwannomas and meningiomas. The diagnostic criteria of NF2 have been regularly revised. Clinical criteria for NF2 were first formulated at the National Institutes of Health Consensus Conference in 1987 and revised in 1990. Revised criteria were also proposed by the Manchester group in 1992 and by the National Neurofibromatosis Foundation (NNFF) in 1997. The 2011 Baser criteria improved the sensitivity of diagnostic criteria, particularly for patients without bilateral vestibular schwannomas. Revisions to the Manchester criteria were published in 2019, with replacement of "glioma" by "ependymoma," removal of "neurofibroma," addition of an age limit of 70 years for development of vestibular schwannomas, and introduction of molecular criteria, which led to the most widely used criteria. In 2022, the criteria were reviewed and updated by the international committee of NF experts. In addition to changes in diagnostic criteria, the committee recommended the use of "schwannomatosis" as an umbrella term for conditions that predispose to schwannomas. Each type of schwannomatosis was classified by the gene containing the disease-causing pathogenic variant. Molecular data from NF2 patients led to further clarification of the diagnostic criteria for NF2 mosaic phenotypes. Given all these changes, the diagnostic criteria of NF2 may be confusing. Herein, to help healthcare professionals who diagnose NF2 conditions in the clinical setting, we review the historical development of diagnostic criteria.
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Neurilemoma , Neurofibromatoses , Neurofibromatose 2 , Neoplasias Cutâneas , Humanos , Neurilemoma/diagnóstico , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Neurofibromatoses/diagnóstico , Neurofibromatoses/história , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , História do Século XX , História do Século XXIRESUMO
PURPOSE: The humanized antivascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) is efficacious for the treatment of NF2-related schwannomatosis (NF2), previously known as neurofibromatosis type 2. This study evaluated the safety and efficacy of a VEGF receptor (VEGFR) vaccine containing VEGFR1 and VEGFR2 peptides in patients with NF2 with progressive schwannomas (jRCTs031180184). MATERIALS AND METHODS: VEGFR1 and VEGFR2 peptides were injected subcutaneously into infra-axillary and inguinal regions, once a week for 4 weeks and then once a month for 4 months. The primary end point was safety. Secondary end points included tolerability, hearing response, imaging response, and immunologic response. RESULTS: Sixteen patients with NF2 with progressive schwannomas completed treatment and were assessed. No severe vaccine-related adverse events occurred. Among the 13 patients with assessable hearing, word recognition score improved in five patients at 6 months and two at 12 months. Progression of average hearing level of pure tone was 0.168 dB/mo during the year of treatment period, whereas long-term progression was 0.364 dB/mo. Among all 16 patients, a partial response was observed in more than one schwannoma in four (including one in which Bev had not been effective), minor response in 5, and stable disease in 4. Both VEGFR1-specific and VEGFR2-specific cytotoxic T lymphocytes (CTLs) were induced in 11 patients. Two years after vaccination, a radiologic response was achieved in nine of 20 assessable schwannomas. CONCLUSION: This study demonstrated the safety and preliminary efficacy of VEGFR peptide vaccination in patients with NF2. Memory-induced CTLs after VEGFR vaccination may persistently suppress tumor progression.
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Vacinas Anticâncer , Neurilemoma , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/administração & dosagem , Neurilemoma/imunologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neurofibromatose 2 , Adulto Jovem , Idoso , NeurofibromatosesRESUMO
Perampanel (PER) is an antiseizure medication (ASM) with a unique mechanism of action, which was approved in Japan for use in combination therapy in 2016 and as a monotherapy in 2020. It has exerted antitumor effects against several types of tumors in vitro. However, the efficacy of PER monotherapy for seizure control is not well-established in patients with brain tumor. In the present study, 25 patients with brain tumor treated using PER monotherapy at our institution were analyzed and compared with 45 patients treated using the most commonly prescribed ASM, levetiracetam (LEV). The PER group was younger and had a higher frequency of glioma cases. During drug administration, seizures were observed in two patients from the PER group (8.0%) and five patients from the LEV group (11.1%); however, the difference was not significant. The incidence of adverse effects did not significantly differ between the groups (12.0 and 2.2%, respectively). In the PER group, mild liver dysfunction was observed in two patients and drug rash in one. In the LEV group, a drug-induced rash was observed in one patient. PER monotherapy may be safe and effective for seizure treatment or prophylaxis in patients with brain tumor. Further large-scale clinical studies are warranted.
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PURPOSE: Chordomas are malignant tumors that destroy bones, compress surrounding nerve tissues and exhibit phenotypes that recapitulate notochordal differentiation in the axial skeleton. Chordomas recur frequently, as they resist radio-chemotherapy and are difficult to completely resect, leading to repeated bone destruction and local expansion via unknown mechanisms. Here, using chordoma specimens and JHC7 chordoma cells, we asked whether chordoma cells possess bone-dissolving activity. METHODS: CT imaging and histological analysis were performed to evaluate the structure and mineral density of chordoma-invaded bone and osteolytic marker expression. JHC7 cells were subjected to immunocytochemistry, imaging of cell fusion, calcium dynamics and acidic vacuoles, and bone lysis assays. RESULTS: In patients, we found that the skull base invaded by chordoma was highly porous, showed low mineral density and contained brachyury-positive chordoma cells and conventional osteoclasts both expressing the osteolytic markers tartrate-resistant acid phosphatase (TRAP) and collagenases. JHC7 cells expressed TRAP and cathepsin K, became multinucleated via cell-cell fusion, showed spontaneous calcium oscillation, and were partly responsive to the osteoclastogenic cytokine RANKL. JHC7 cells exhibited large acidic vacuoles, and nonregulatory bone degradation without forming actin rings. Finally, bone-derived factors, calcium ions, TGF-ß1, and IGF-1 enhanced JHC7 cell proliferation. CONCLUSION: In chordoma, we propose that in addition to conventional bone resorption by osteoclasts, chordoma cells possess bone-dissolving activity at the tumor-bone boundary. Furthermore, bone destruction and tumor expansion may occur in a positive feedback loop.
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Glioblastoma multiforme (GBM) acquires resistance to bevacizumab (Bev) treatment. Bev affects angiogenic factors other than vascular endothelial growth factor (VEGF), which are poorly understood. We investigated changes in angiogenic factors under and after Bev therapy, including angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), placental growth factor (PLGF), fibroblast growth factor 2, and ephrin A2 (EphA2). Fifty-four GBM tissues, including 28 specimens from 14 cases as paired specimens from the same patient obtained in three settings: initial tumor resection (naïve Bev), tumors resected following Bev therapy (effective Bev), and recurrent tumors after Bev therapy (refractory Bev). Immunohistochemistry assessed their expressions in tumor vessels and its correlation with recurrent MRI patterns. PLGF expression was higher in the effective Bev group than in the naïve Bev group (p = 0.024) and remained high in the refractory Bev group. ANGPT2 and EphA2 expressions were higher in the refractory Bev group than in the naïve Bev group (p = 0.047 and 0.028, respectively). PLGF expression was higher in the refractory Bev group compared with the naïve Bev group for paired specimens (p = 0.036). PLGF was more abundant in T2 diffuse/circumscribe patterns (p = 0.046). This is the first study to evaluate angiogenic factors other than VEGF during effective and refractory Bev therapy in patient-derived specimens.
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Inibidores da Angiogênese , Angiopoietina-2 , Bevacizumab , Neoplasias Encefálicas , Glioblastoma , Neovascularização Patológica , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/cirurgia , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neovascularização Patológica/tratamento farmacológico , Adulto , Angiopoietina-2/metabolismo , Inibidores da Angiogênese/uso terapêutico , Fator de Crescimento Placentário/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Angiopoietina-1/metabolismo , Recidiva Local de NeoplasiaRESUMO
OBJECTIVES: To determine the natural history of hearing loss and tumor volume in patients with untreated neurofibromatosis type 2 (NF2)-related schwannomatosis. Moreover, we statistically examined the factors affecting hearing prognosis. METHODS: This retrospective cohort study was conducted on 37 ears of 24 patients with NF2-related vestibular schwannomatosis followed up without treatment for more than 1 year. We obtained detailed chronological changes in the PTA and tumor volume in each case over time, and the rate of change per year was obtained. Multivariate analysis was also conducted to investigate factors associated with changes in hearing. RESULTS: The average follow-up period was approximately 9 years, and hearing deteriorated at an average rate of approximately 4 dB/year. The rate of maintaining effective hearing decreased from 30 ears (81%) at the first visit to 19 ears (51%) at the final follow-up. The average rate of change in tumor growth for volume was approximately 686.0 mm3/year. This study revealed that most patients with NF2 experienced deterioration in hearing acuity and tumor growth during the natural course. A correlation was observed between an increase in tumor volume and hearing loss (r = 0.686; p < 0.001). CONCLUSIONS: Although the hearing preservation rate in NF2 cases is poor with the current treatment methods, many cases exist in which hearing acuity deteriorates, even during the natural course. Patients with an increased tumor volume during the follow-up period were more likely to experience hearing deterioration. Trial registration number 20140242 (date of registration: 27 October 2014).
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Neurofibromatoses , Neurofibromatose 2 , Neuroma Acústico , Neoplasias Cutâneas , Humanos , Masculino , Estudos Retrospectivos , Feminino , Neurofibromatose 2/complicações , Neurofibromatose 2/patologia , Pessoa de Meia-Idade , Adulto , Neuroma Acústico/patologia , Neuroma Acústico/complicações , Neuroma Acústico/fisiopatologia , Neurofibromatoses/complicações , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/complicações , Neurilemoma/complicações , Neurilemoma/patologia , Neurilemoma/cirurgia , Seguimentos , Idoso , Carga Tumoral , Perda Auditiva/etiologia , Adulto Jovem , Progressão da Doença , Adolescente , Audiometria de Tons Puros , PrognósticoRESUMO
PURPOSE: This multi-institutional phase I/II study was conducted to confirm the safety and explore the clinical utility of preoperative Bevacizumab (Bev) for newly diagnosed glioblastoma (GB). METHODS: Patients were enrolled based on magnetic resonance imaging (MRI) findings typically suggestive of GB. Preoperative Bev and temozolomide (TMZ) were administered at doses of 10 mg/kg on day 0 and 150 mg/m2 on days 1-5, respectively. Surgical resection was performed between days 21 and 30, inclusive. The safety and efficacy were evaluated in a total of 15 cases by progression-free survival (PFS), changes in tumor volume, Karnofsky Performance Scale (KPS) and Mini-Mental State Examination (MMSE) scores after preoperative therapy. RESULTS: Tumor resection was performed on a mean of day 23.7. Pathological diagnosis was GB, isocitrate dehydrogenase (IDH)-wildtype in 14 cases and GB, IDH-mutant in 1 case. Severe adverse events possibly related to preoperative Bev and TMZ were observed in 2 of the 15 patients, as wound infection and postoperative hematoma and thrombocytopenia. KPS and MMSE scores were significantly improved with preoperative therapy. Tumor volume was decreased in all but one case on T1-weighted imaging with contrast-enhancement (T1CE) and in all cases on fluid-attenuated inversion recovery, with mean volume decrease rates of 36.2% and 54.0%, respectively. Median PFS and overall survival were 9.5 months and 16.5 months, respectively. CONCLUSION: Preoperative Bev and TMZ is safe as long as the instructions are followed. The strategy might be useful for GB in some patients, not only reducing tumor burden, but also improving patient KPS preoperatively. TRIAL REGISTRATION NUMBER: UMIN000025579, jRCT1031180233 https://jrct.niph.go.jp/latest-detail/jRCT1031180233 . Registration Date: Jan. 16, 2017.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Terapia Neoadjuvante , Estudos Prospectivos , Temozolomida/uso terapêuticoRESUMO
Introduction: Glioblastomas can manifest as multiple, simultaneous, noncontiguous lesions. We genetically analyzed multiple glioblastomas and discuss their etiological origins in this report. Case Presentation: We present the case of a 47-year-old woman who presented with memory impairment and left partial paralysis. Radiographic imaging revealed three apparently noncontiguous lesions in the right temporal and parietal lobes extending into the corpus callosum, leading to diagnosis of multicentric glioblastomas. All three lesions were excised. Genetic analysis of the lesions revealed a TERT promoter C228T mutation, a roughly equivalent amplification of EGFR, and homozygous deletion of CDKN2A/B exclusively in the two contrast-enhanced lesions. Additionally, the contrast-enhanced lesions exhibited the same two-base pair mutations of PTEN, whereas the non-enhanced lesion showed a partially distinct 13-base pair mutation. The other genetic characteristics were consistent. Rather than each having arisen de novo, we believe that they had developed by infiltration and are therefore best classified as multifocal glioblastomas. Conclusion: Our findings underscore anew the possibility of infiltration by glioblastomas, even within regions devoid of signal alterations on T2-weighted images or fluid-attenuated inversion recovery images. Genetic analysis can play a crucial role in differentiating whether multiple glioblastomas are multifocal or multicentric.
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OBJECTIVE: The authors report on the anterior transpetrosal approach (ATPA) and the results of surgeries performed over a 33-year period for petroclival tumors, including meningioma, trigeminal schwannoma, chordoma, and epidermoid tumor. They analyze early postoperative neurological changes, surgical complications, and trends over the decades. METHODS: A retrospective analysis of 274 surgical cases that had undergone the ATPA from January 1984 to March 2017 was conducted. Data were collected from charts, clinical summaries, operative records, and operative videos. The analyzed parameters included patient diagnosis, tumor size, disease location, operation date, tumor removal rate, pre- and postoperative neurological symptoms (consciousness level, motor and sensory deficits of the limbs, sensory aphasia, and cranial nerve III-VIII injuries), surgical deaths, and radiologically recognized brain injuries after the operation (contusion, infarction, hemorrhage). RESULTS: Gross-total resection (GTR) was achieved in 53.5% of the 243 tumors with available data. The GTR rate for meningiomas (148 cases) was 54.1%. Trigeminal schwannomas had a high GTR rate of 87.1%, whereas chordomas had a low GTR rate of 14.3%. The rate of early neurological deterioration immediately after the ATPA, referred to as "early neurological change," was as follows: consciousness disturbance in 1.9% of cases (5 cases), improvement of hemiparesis in 45.0% of cases but deterioration in 8.1% of cases, sensory aphasia in 2.3% of cases due to temporal lobe injury, improvement of cerebellar symptoms in 39.3% of cases with rare deterioration (1.9% of cases), worsening of preoperative diplopia in 49.4% of patients and rarely improving, improvement of trigeminal symptoms in 19.1% of cases (mostly trigeminal neuralgia) among the 43.7% of patients who had them preoperatively, and deterioration of facial hypesthesia and/or paresthesia in 27.4% of cases. Early neurological deterioration was monitored in 183 patients for 6 months to determine the surgical complications of ATPA. Consciousness disturbance recovered in half of the cases but persisted in 3 (1.5%). Hemiparesis fully recovered in 63.2% of cases, resulting in a complication rate of 3.0%. The most frequent complication was diplopia (36.4%), with a complete remission rate of 26.4%. The second most frequent complication was facial hypesthesia (24.0%), with a recovery rate of 16.1%. Facial nerve palsy improved in 63.0% of cases and had a complication rate of 4.9%. Cerebellar symptoms showed complete recovery in all cases. CONCLUSIONS: The ATPA allows the removal of petroclival tumors extending into Meckel's cave and the middle fossa, making it preferred for dumbbell trigeminal schwannomas and meningiomas. However, the ATPA's aggressive tumor removal can risk a lower recovery of cranial nerve IV-VI deficits. For benign meningiomas, initial observation with regular follow-up is recommended. Surgery is appropriate for high-growth cases aiming for total removal, accompanied by a thorough explanation of the risks. If the risks are not accepted, subtotal removal can be considered, and radiosurgery is suggested for residual tumor.
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Procedimentos Neurocirúrgicos , Complicações Pós-Operatórias , Humanos , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Adulto , Idoso , Procedimentos Neurocirúrgicos/métodos , Procedimentos Neurocirúrgicos/efeitos adversos , Adulto Jovem , Adolescente , Meningioma/cirurgia , Neoplasias da Base do Crânio/cirurgia , Idoso de 80 Anos ou mais , Criança , Neoplasias Meníngeas/cirurgia , Resultado do Tratamento , Cordoma/cirurgia , Neurilemoma/cirurgiaRESUMO
Transcranial direct current stimulation (tDCS) is increasingly being used for Parkinson's disease (PD); however, the evaluation of its clinical impact remains complex owing to the heterogeneity of patients and treatments. Therefore, we used a unilateral 6-hydroxydopamine-induced PD rat model to investigate whether anodal tDCS of the primary motor cortex (M1) alleviates PD motor deficits. Before tDCS treatment, unilateral PD rats preferentially used the forelimb ipsilateral to the lesion in the exploratory cylinder test and showed reduced locomotor activity in the open field test. In addition, PD-related clumsy forelimb movements during treadmill walking were detected using deep learning-based video analysis (DeepLabCut). When the 5-day tDCS treatment began, the forelimb-use asymmetry was ameliorated gradually, and locomotor activity increased to pre-lesion levels. tDCS treatment also normalized unnatural forelimb movement during walking and restored a balanced gait. However, these therapeutic effects were rapidly lost or gradually disappeared when the tDCS treatment was terminated. Histological analysis at the end of the experiment revealed that the animals had moderately advanced PD, with 40-50% of dopamine neurons and fibers preserved on the injured side compared with those on the intact side. Although it remains a challenge to elucidate the neural mechanisms of the transient improvement in motor function induced by tDCS, the results of this study provide evidence that tDCS of the M1 produces positive behavioral outcomes in PD animals and provides the basis for further clinical research examining the application of tDCS in patients with PD.
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Doença de Parkinson , Transtornos Parkinsonianos , Estimulação Transcraniana por Corrente Contínua , Humanos , Ratos , Animais , Estimulação Transcraniana por Corrente Contínua/métodos , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/terapia , LocomoçãoRESUMO
Glioblastoma is characterized by diffuse infiltration into the normal brain. Invasive glioma stem cells (GSCs) are an underlying cause of treatment failure. Despite the use of multimodal therapies, the prognosis remains dismal. New therapeutic approach targeting invasive GSCs is required. Here, we show that neural stem cells (NSCs) derived from CRISRP/Cas9-edited human-induced pluripotent stem cell (hiPSC) expressing a suicide gene had higher tumor-trophic migratory capacity compared with mesenchymal stem cells (MSCs), leading to marked in vivo antitumor effects. High migratory capacity in iPSC-NSCs was related to self-repulsive action and pathotropism involved in EphB-ephrinB and CXCL12-CXCR4 signaling. The gene insertion to ACTB provided higher and stable transgene expression than other common insertion sites, such as GAPDH or AAVS1. Ferroptosis was associated with enhanced antitumor immune responses. The thymidylate synthase and dihydroprimidine dehydrogenase expressions predicted the treatment efficacy of therapeutic hiPSC-NSCs. Our results indicate the potential benefit of genome-edited iPS cells based gene therapy for invasive GSCs. Furthermore, the present research concept may become a platform to promote clinical studies using hiPSC.
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BACKGROUND: Postoperative trigeminal neuropathy may be seen after surgery for middle and posterior cranial fossa lesions. Although neuropathic pain is a cause of reduced quality of life, global consensus on postoperative pain management is lacking. Mirogabalin besylate is a selective ligand for the α2δ subunit of voltage-gated calcium channels. Although mirogabalin has been used for patients with postherpetic neuralgia and painful diabetic peripheral neuropathy, few reports have assessed the effect on postsurgical neuropathy. In this report, we describe a clinical effectiveness of mirogabalin for trigeminal neuropathy after skull base surgery. CASE DESCRIPTION: Case 1: A 51-year-old female with right trigeminal schwannoma was operated on via the anterior transpetrosal approach. She had tingling and numb feelings in the right face postoperatively. Mirogabalin was orally administered after the operation. Her continuous facial numbness immediately improved. Case 2: A 55-year-old female with left middle fossa base meningioma extending into the infratemporal fossa was operated on via the infratemporal fossa approach. She had a tingling feeling in the left face postoperatively. Mirogabalin was orally administered for this symptom after the operation, which gradually improved. CONCLUSIONS: Mirogabalin may show significant pain relief for patients with trigeminal neuropathy after skull base surgery. Further studies using a larger number of patients are warranted to confirm these findings.
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Drug repositioning (DR) is the process of identifying novel therapeutic potentials for already-approved drugs and discovering new therapies for untreated diseases. DR can play an important role in optimizing the pre-clinical process of developing novel drugs by saving time and cost compared with the process of de novo drug discovery. Although the number of publications related to DR has rapidly increased, most therapeutic approaches were reported for malignant tumors. Surgical resection represents the definitive treatment for benign tumors of the central nervous system (BTCNS). However, treatment options remain limited for surgery-, chemotherapy- and radiation-refractory BTCNS, as well as malignant tumors. Meningioma, pituitary neuroendocrine tumor (PitNET), and schwannoma are the most common BTCNS. The treatment strategy using DR may be applied for refractory BTCNS, such as Grade 2 meningiomas, neurofibromatosis type 2-related schwannomatosis, and PitNETs with cavernous sinus invasion. In the setting of BTCNS, stable disease can provide significant benefit to the patient. DR may provide a longer duration of survival without disease progression for patients with refractory BTCNS. This article reviews the utility of DR for refractory BTCNS.
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Neoplasias Meníngeas , Meningioma , Neurilemoma , Neoplasias Hipofisárias , Humanos , Reposicionamento de Medicamentos , Sistema Nervoso Central , Meningioma/tratamento farmacológico , Neurilemoma/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológicoRESUMO
Despite developing neurosurgical procedures, few treatment options have achieved functional recovery from traumatic brain injury (TBI). Neural stem/progenitor cells (NS/PCs) may produce a long-term effect on neurological recovery. Although induced pluripotent stem cells (iPSCs) can overcome ethical and practical issues of human embryonic or fetal-derived tissues in clinical applications, the tumorigenicity of iPSC-derived populations remains an obstacle to their safe use in regenerative medicine. We herein established a novel treatment strategy for TBI using iPSCs expressing the enzyme-prodrug gene yeast cytosine deaminase-uracil phosphoribosyl transferase (yCD-UPRT). NS/PCs derived from human iPSCs displayed stable and high transgene expression of yCD-UPRT following CRISPR/Cas9-mediated genome editing. In vivo bioluminescent imaging and histopathological analysis demonstrated that NS/PCs concentrated around the damaged cortex of the TBI mouse model. During the subacute phase, performances in both beam walking test and accelerating rotarod test were significantly improved in the treatment group transplanted with genome-edited iPSC-derived NS/PCs compared with the control group. The injury area visualized by extravasation of Evans blue was smaller in the treatment group compared with the control group, suggesting the prevention of secondary brain injury. During the chronic phase, cerebral atrophy and ventricle enlargement were significantly less evident in the treatment group. Furthermore, after 5-fluorocytosine (5-FC) administration, 5-fluorouracil converted from 5-FC selectively eliminated undifferentiated NS/PCs while preserving the adjacent neuronal structures. NS/PCs expressing yCD-UPRT can be applied for safe regenerative medicine without the concern for tumorigenesis.
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Lesões Encefálicas Traumáticas , Células-Tronco Pluripotentes Induzidas , Células-Tronco Neurais , Fármacos Neuroprotetores , Camundongos , Animais , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Fármacos Neuroprotetores/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/terapiaRESUMO
Objective: Endoscopic endonasal surgery (EES) for deep intracranial lesions has gained popularity following recent developments in endoscopic technology. The operability of invasive pituitary neuroendocrine tumors (PitNETs) depends on the anatomy of the nasal cavity and paranasal sinus. This study aimed to establish a simple volume reconstruction algorithm of the nasal cavity and paranasal sinus. Additionally, this is the first study to demonstrate the relationship between the segmentation method and the clinical significance in patients with PitNET. Methods: Pre-and postoperative tumor volumes were analyzed in 106 patients with primary (new-onset) PitNETs (80 nonfunctioning and 26 functioning) who underwent EES. The efficiency and accuracy of the semiautomatic segmentation with manual adjustments (SSMA) method was compared with other established segmentation methods for volumetric analysis in the nasal cavity and paranasal sinuses. Correlations between the measured nasal cavity and paranasal sinus volumes and the extent of tumor removal were evaluated. Results: The SSMA method yielded accurate and time-saving results following the volumetric analyses of nasal cavity and paranasal sinuses with complex structures. Alternatively, the manual and semiautomatic segmentation methods proved time-consuming and inaccurate, respectively. The sphenoid sinus volume measured by SSMA was significantly correlated with the extent of tumor removal in patients with nonfunctioning Knosp grade 3 and 4 PitNET (r = 0.318; p = 0.015). Conclusion: The volume of sphenoid sinus potentially could predict the extent of resection due to better visualization of the tumor for PitNETs with CS invasion.
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NF2-related schwannomatosis (NF2) is an autosomal dominant genetic disorder caused by variants in the NF2 gene. Approximately 50% of NF2 patients inherit pathogenic variants, and the remainder acquire de novo variants. NF2 is characterized by development of bilateral vestibular schwannomas. The genetic background of Japanese NF2 cases has not been fully investigated, and the present report performed a genetic analysis of 14 Japanese NF2 cases and examined genotype-phenotype correlations. DNA samples collected from peripheral blood were analyzed by next-generation sequencing, multiplex ligation-dependent probe amplification analysis, and in vitro electrophoresis. Ten cases had pathogenic or likely pathogenic variants in the NF2 gene, with seven truncating variants and three non-truncating variants. The age of onset in all seven cases with truncating variants was < 20 years. The age of onset significantly differed among cases with truncating NF2 variants, non-truncating NF2 variants, and no NF2 variants. However, the clinical course of tumor growth and hearing deterioration were not predicted only by germline pathogenic NF2 variants. The rate of truncating variants was higher in the present study than that of previous reports. Genotype-phenotype correlations in the age of onset were present in the analyzed Japanese NF2 cases.
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População do Leste Asiático , Genes da Neurofibromatose 2 , Audição , Humanos , Idade de Início , População do Leste Asiático/genética , Genótipo , Audição/genética , Fenótipo , MutaçãoRESUMO
Pilocytic astrocytomas (PAs) are benign tumors. However, clinically aggressive PAs despite benign histology have been reported, and histological and molecular risk factors for prognosis have not been elucidated. 38 PAs were studied for clinical, histological, and molecular factors, including tumor location, extent of resection, post-operative treatment, glioma-associated molecules (IDH1/2, ATRX, BRAF, FGFR1, PIK3CA, H3F3A, p53, VEGF, Nestin, PD-1/PD-L1), CDKN2A/B deletion, and chromosomal number aberrations, to see if there is any correlation with patient's progression-free survival (PFS). Brainstem/spinal location, extent of resection and post-operative treatment, and VEGF-A, Nestin and PD-L1 expression, copy number gain of chromosome 7q or 19, TP53 mutation were significantly associated with shorter PFS. None of the histological parameters was associated with PFS. Multivariate analyses demonstrated that high Nestin expression, gain of 7q or 19, and extent of removal were independently predictive for early tumor recurrence. The brainstem/spinal PAs appeared distinct from those in the other sites in terms of molecular characteristics. Clinically aggressive PAs despite benign histology exhibited high Nestin expression. Brainstem/spinal location, extent of resection and some molecular factors including Nestin expression and gains of 7q and 19, rather than histological parameters, may be associated with early tumor recurrence in PAs.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Humanos , Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/patologia , Recidiva Local de Neoplasia/genética , Nestina/genética , Nestina/metabolismo , Astrocitoma/patologia , Tronco Encefálico/metabolismo , Tronco Encefálico/patologiaRESUMO
BACKGROUND: There has been no known serum biomarker to predict the prognosis of atypical meningioma. OBJECTIVE: To investigate the prognostic impact of serum biomarkers in patients newly diagnosed with resected intracranial atypical meningiomas. METHODS: This study enrolled 523 patients with atypical meningioma who underwent surgical resection between 1998 and 2018 from 5 Asian institutions. Serum laboratory data within 1 week after surgery were obtained for analysis. Optimal cutoffs were calculated for each serum marker using the maxstat package of R. RESULTS: Of 523 patients, 19.5% underwent subtotal resection and 29.8% were treated with adjuvant radiation therapy (ART). Among the 523 patients, 454 were included in the multivariate analysis for the progression/recurrence (P/R) rate excluding patients with incomplete histopathologic or laboratory data. On multivariate analysis, tumor size >5 cm, subtotal resection, and postoperative aspartate aminotransferase/alanine transaminase (De Ritis) ratio >2 were associated with higher P/R rates, whereas ART and postoperative platelet count >137 × 10 3 /µL were associated with lower P/R rates. In the subgroup of patients treated with ART, tumor size >5 cm and postoperative neutrophil-to-lymphocyte ratio >21 were associated with higher P/R rates. By contrast, postoperative De Ritis ratio >2 remained an adverse prognosticator in patients not treated with ART. CONCLUSION: Postoperative De Ritis ratio, platelet count, and neutrophil-to-lymphocyte ratio were revealed as a novel serum prognosticator in newly diagnosed atypical meningiomas. Additional studies are warranted to validate its clinical significance and biological background.