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Chordomas, arising from notochord remnants, are rare neoplasms with aggressive growth patterns despite their histologically low-grade nature. This review explores their embryological origins, molecular markers like brachyury, and genetic alterations driving pathogenesis. Diagnosis relies on advanced imaging and biopsy confirmation due to overlapping features with chondrosarcoma. The WHO classification distinguishes conventional, dedifferentiated, and poorly differentiated chordomas, each with distinct prognostic implications. Recent genomic analyses uncovered recurrent mutations in PI3K signaling pathways and chromatin remodeling genes, informing prognostic models. Surgery remains the cornerstone of treatment, though adjuvant radiation complements surgical resection. Although chordomas are generally considered refractory to medical therapy, emerging targeted molecular strategies show potential promise in ongoing trials. This review aims to provide a concise yet comprehensive overview of chordomas, guiding clinicians in diagnosis, treatment, and prognostication for improved patient outcomes.
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Cordoma , Humanos , Cordoma/genética , Cordoma/terapia , Cordoma/patologia , Cordoma/diagnóstico , Prognóstico , Biomarcadores Tumorais/genética , Mutação , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Gerenciamento Clínico , Proteínas FetaisRESUMO
BACKGROUND: Cerebrospinal fluid leak after endoscopic skull base surgery remains a significant complication. Several investigators have suggested Hydroset cranioplasty to reduce leak rates. We investigated our early experience with Hydroset and compared the rate of nasal complications and CSF leak rates with case-controlled historic controls. METHODS: We queried a prospective database of patients undergoing first time endoscopic, endonasal resection of suprasellar meningiomas and craniopharyngiomas from 2015 to 2023. We compared cases closed with a gasket seal, Hydroset, and a nasoseptal flap with those closed with only a gasket seal and nasoseptal flap. Demographics, technical considerations and postoperative outcomes (SNOT-22) were compared. RESULTS: Seventy patients met inclusion criteria, twenty patients in the Hydroset group (meningioma n = 12; craniopharyngioma n = 8) and 50 control patients (meningioma n = 25; craniopharyngioma n = 25). CSF diversion was used in fewer Hydroset patients (75%, 15/20) compared with control group (94%, 47/50; p = 0.02). CSF leak was less frequent in the Hydroset than the control group (5% versus 12%, p = 0.38). One Hydroset patient required delayed nasal debridement. SNOT-22 responses demonstrated no significant difference in sinonasal complaints between groups (Hydroset average SNOT-22 score 22.45, control average SNOT-22 score 25.90; p = 0.58). CONCLUSIONS: We demonstrate that hydroxyapatite reconstruction leads to improved CSF leak control above that provided by the gasket-seal and nasoseptal flap, without significant associated morbidity as long as the cement is fully covered with vascularized tissue.
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Vazamento de Líquido Cefalorraquidiano , Craniofaringioma , Meningioma , Base do Crânio , Retalhos Cirúrgicos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Vazamento de Líquido Cefalorraquidiano/prevenção & controle , Vazamento de Líquido Cefalorraquidiano/etiologia , Vazamento de Líquido Cefalorraquidiano/cirurgia , Estudos de Casos e Controles , Base do Crânio/cirurgia , Craniofaringioma/cirurgia , Idoso , Meningioma/cirurgia , Adulto , Neoplasias Hipofisárias/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/etiologia , Resultado do Tratamento , Neoplasias da Base do Crânio/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Neoplasias Meníngeas/cirurgia , Septo Nasal/cirurgiaRESUMO
Transorbital neuroendoscopic surgery (TONES) is a minimally invasive approach, providing excellent access to extradural pathology of the sphenoid wing, orbital apex, Meckel's cave, and lateral cavernous sinus.1-10 Few cases of intradural pathology, such as gliomas or epileptic foci of the temporal lobe, have been described, apart from cadaveric anatomic studies.11-13 In this video, we present the case of a 63-year-old man with first time seizure. MRI demonstrated a fluid-attenuated inversion recovery hyperintense, noncontrast enhancing medial temporal lobe lesion consistent with low grade glioma. While frontotemporal craniotomy is the standard approach for this lesion, the TONES approach detailed in the video (the patient consented to the procedure and to the publication of his image) provided excellent access to the lesion, which minimized unnecessary trauma or removal of the lateral temporal lobe during the approach.4,14,15 The dura was closed primarily, overlayed with abdominal fat and fibrin glue, and a lumbar drain was left in place for 24 hours. The TONES approach avoided not only temporal lobe violation but also temporalis muscle disruption and any sort of external bone manipulation, which expedited the patient's recovery.16 The patient's eyelid incision was barely visible as early as postoperative day 7 with minimal ecchymosis. Postoperative MRI demonstrated a gross total resection. Pathology was consistent with a central nervous system World Health Organization grade 1 dysembryoplastic neuroepithelial tumor, a low-grade lesion with low risk of recurrence.17,18.
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Pituitary adenomas are slow-growing, benign intracranial tumors that can be characterized as functional (hormone-producing) or non-functional (non-hormone producing). Symptoms therefore arise from either endocrinologic abnormalities or mass effect on surrounding structures resulting in symptoms such as visual impairment and headache. In the last two decades, technical innovations have shifted surgical resection of such adenomas to endoscopic endonasal approaches. In this review, we describe the evolving approach to pituitary adenomas in the modern endoscopic era, including preoperative multidisciplinary review, relevant surgical anatomy, and a description of the technical nuances of standard and expanded approaches to the anterior skull base.
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Adenoma , Neoplasias Encefálicas , Neoplasias Hipofisárias , Humanos , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/cirurgia , Endoscopia , Adenoma/diagnóstico por imagem , Adenoma/cirurgia , CefaleiaRESUMO
Sonobiopsy is an emerging technology that combines focused ultrasound (FUS) with microbubbles to enrich circulating brain disease-specific biomarkers for noninvasive molecular diagnosis of brain diseases. Here, we report the first-in-human prospective trial of sonobiopsy in high-grade glioma patients to evaluate its feasibility and safety in enriching plasma circulating tumor biomarkers. A nimble FUS device integrated with a clinical neuronavigation system was used to perform sonobiopsy following an established clinical workflow for neuronavigation. Analysis of blood samples collected before and after FUS sonication showed that sonobiopsy enriched plasma circulating tumor DNA (ctDNA), including a maximum increase of 1.6-fold for the mononucleosome cell-free DNA (cfDNA) fragments (120-280 bp), 1.9-fold for the patient-specific tumor variant ctDNA level, and 5.6-fold for the TERT mutation ctDNA level. Histological analysis of surgically resected tumors confirmed the safety of the procedure. Transcriptome analysis of sonicated and nonsonicated tumor tissues found that FUS sonication modulated cell physical structure-related genes. Only 2 out of 17,982 total detected genes related to the immune pathways were upregulated. These feasibility and safety data support the continued investigation of sonobiopsy for noninvasive molecular diagnosis of brain diseases.
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BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is a commonly performed procedure for degenerative cervical spine disease. Rare complications of ACDF surgery include hardware failure, in the form of screw loosening and migration, or rod breakage. We present a case in which we removed a migrated screw lodged in the esophagus from a patient with a failed anterior cervical fusion. OBJECTIVE: To present a surgical technique and considerations to remove a migrated screw. METHODS: The previous ACDF incision was reopened and exposure was gained under the guidance of a head and neck surgeon. Longus coli were mobilized off the spine bilaterally with electrocautery. After dissection, the screw was found lodged in the longitudinal muscle of the esophageal wall and excised with the use of a 15-blade. The integrity of the esophageal mucosa and submucosa was maintained and subsequently checked with rigid esophagoscopy. Fluoroscopy was used to confirm that all hardware was removed, with the exception of the anterior cages. RESULTS: The dislodged screw, which was embedded in the esophagus, was successfully removed. CONCLUSIONS: Failure of an ACDF carries a risk of screw migration, which may be asymptomatic even if the screw is lodged in the esophagus. Additional considerations are required with potential violations of the adjacent viscera.
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Vértebras Cervicais , Fusão Vertebral , Humanos , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Discotomia/efeitos adversos , Discotomia/métodos , Fluoroscopia , Placas Ósseas/efeitos adversos , Fusão Vertebral/efeitos adversos , Fusão Vertebral/métodos , Parafusos Ósseos/efeitos adversosRESUMO
Many groups have reported lymphatic and glymphatic structures in animal and human brains, but tracer injection into the human brain to demonstrate real-time lymphatic drainage and mapping has not been described. We enrolled patients undergoing standard-of-care resection or stereotactic biopsy for suspected intracranial tumors. Patients received peritumoral injections of 99mTc-tilmanocept followed by planar or tomographic imaging. Fourteen patients with suspected brain tumors were enrolled. One was excluded from analysis because of tracer leakage during injection. There was no drainage of 99mTc-tilmanocept to regional lymph nodes in any of the patients. On average, after correcting for radioactive decay, 70.7% (95% CI: 59.9%, 81.6%) of the tracer in the injection site and 78.1% (95% CI: 71.1%, 85.1%) in the whole-head on the day of surgery remained the morning after, with variable radioactivity in the subarachnoid space. The retained fraction was much greater than expected based on the clearance rate from non-brain injection sites. In this pilot study, the lymphatic tracer 99mTc-tilmanocept was injected into the brain parenchyma, and there was no drainage outside the brain to the cervical lymph nodes. Our work demonstrates an inefficiency of drainage from peritumoral brain parenchyma and highlights a therapeutic opportunity to improve immunosurveillance of the brain.
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Linfocintigrafia , Biópsia de Linfonodo Sentinela , Humanos , Linfocintigrafia/métodos , Projetos Piloto , Biópsia de Linfonodo Sentinela/métodos , Compostos Radiofarmacêuticos , Metástase LinfáticaRESUMO
Sonobiopsy is an emerging technology that combines focused ultrasound (FUS) with microbubbles to enrich circulating brain disease-specific biomarkers for noninvasive molecular diagnosis of brain diseases. Here, we report the first-in-human prospective trial of sonobiopsy in glioblastoma patients to evaluate its feasibility and safety in enriching circulating tumor biomarkers. A nimble FUS device integrated with a clinical neuronavigation system was used to perform sonobiopsy following an established clinical workflow for neuronavigation. Analysis of blood samples collected before and after FUS sonication showed enhanced plasma circulating tumor biomarker levels. Histological analysis of surgically resected tumors confirmed the safety of the procedure. Transcriptome analysis of sonicated and unsonicated tumor tissues found that FUS sonication modulated cell physical structure-related genes but evoked minimal inflammatory response. These feasibility and safety data support the continued investigation of sonobiopsy for noninvasive molecular diagnosis of brain diseases.
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BACKGROUND: Adoptive cellular therapies with chimeric antigen receptor T cells have revolutionized the treatment of some malignancies but have shown limited efficacy in solid tumors such as glioblastoma and face a scarcity of safe therapeutic targets. As an alternative, T cell receptor (TCR)-engineered cellular therapy against tumor-specific neoantigens has generated significant excitement, but there exist no preclinical systems to rigorously model this approach in glioblastoma. METHODS: We employed single-cell PCR to isolate a TCR specific for the Imp3D81N neoantigen (mImp3) previously identified within the murine glioblastoma model GL261. This TCR was used to generate the Mutant Imp3-Specific TCR TransgenIC (MISTIC) mouse in which all CD8 T cells are specific for mImp3. The therapeutic efficacy of neoantigen-specific T cells was assessed through a model of cellular therapy consisting of the transfer of activated MISTIC T cells and interleukin 2 into lymphodepleted tumor-bearing mice. We employed flow cytometry, single-cell RNA sequencing, and whole-exome and RNA sequencing to examine the factors underlying treatment response. RESULTS: We isolated and characterized the 3×1.1C TCR that displayed a high affinity for mImp3 but no wild-type cross-reactivity. To provide a source of mImp3-specific T cells, we generated the MISTIC mouse. In a model of adoptive cellular therapy, the infusion of activated MISTIC T cells resulted in rapid intratumoral infiltration and profound antitumor effects with long-term cures in a majority of GL261-bearing mice. The subset of mice that did not respond to the adoptive cell therapy showed evidence of retained neoantigen expression but intratumoral MISTIC T cell dysfunction. The efficacy of MISTIC T cell therapy was lost in mice bearing a tumor with heterogeneous mImp3 expression, showcasing the barriers to targeted therapy in polyclonal human tumors. CONCLUSIONS: We generated and characterized the first TCR transgenic against an endogenous neoantigen within a preclinical glioma model and demonstrated the therapeutic potential of adoptively transferred neoantigen-specific T cells. The MISTIC mouse provides a powerful novel platform for basic and translational studies of antitumor T-cell responses in glioblastoma.
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Glioblastoma , Imunoterapia Adotiva , Camundongos , Humanos , Animais , Antígenos de Neoplasias , Linfócitos T CD8-Positivos , Receptores de Antígenos de Linfócitos TRESUMO
The central nervous system (CNS) antigen-presenting cell (APC) that primes antitumor CD8+ T-cell responses remains undefined. Elsewhere in the body, the conventional dendritic cell 1 (cDC1) performs this role. However, steady-state brain parenchyma cDC1 are extremely rare; cDCs localize to the choroid plexus and dura. Thus, whether the cDC1 play a function in presenting antigen derived from parenchymal sources in the tumor setting remains unknown. Using preclinical glioblastoma (GBM) models and cDC1-deficient mice, we explored the presently unknown role of cDC1 in CNS antitumor immunity. We determined that, in addition to infiltrating the brain tumor parenchyma itself, cDC1 prime neoantigen-specific CD8+ T cells against brain tumors and mediate checkpoint blockade-induced survival benefit. We observed that cDC, including cDC1, isolated from the tumor, the dura, and the CNS-draining cervical lymph nodes harbored a traceable fluorescent tumor antigen. In patient samples, we observed several APC subsets (including the CD141+ cDC1 equivalent) infiltrating glioblastomas, meningiomas, and dura. In these same APC subsets, we identified a tumor-specific fluorescent metabolite of 5-aminolevulinic acid, which fluorescently labeled tumor cells during fluorescence-guided GBM resection. Together, these data elucidate the specialized behavior of cDC1 and suggest that cDC1 play a significant role in CNS antitumor immunity.
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Células Dendríticas , Neoplasias , Animais , Camundongos , Linfócitos T CD8-Positivos , Antígenos de Neoplasias , EncéfaloRESUMO
[This corrects the article DOI: 10.3389/fonc.2022.851758.].
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BACKGROUND: Glioblastoma is a fatal disease despite aggressive multimodal therapy. PD-1 blockade, a therapy that reinvigorates hypofunctional exhausted CD8 T cells (Tex) in many malignancies, has not shown efficacy in glioblastoma. Loss of CD4 T cells can lead to an exhausted CD8 T-cell phenotype, and terminally exhausted CD8 T cells (Tex term) do not respond to PD-1 blockade. GL261 and CT2A are complementary orthotopic models of glioblastoma. GL261 has a functional CD4 T-cell compartment and is responsive to PD-1 blockade; notably, CD4 depletion abrogates this survival benefit. CT2A is composed of dysfunctional CD4 T cells and is PD-1 blockade unresponsive. We leverage these models to understand the impact of CD4 T cells on CD8 T-cell exhaustion and PD-1 blockade sensitivity in glioblastoma. METHODS: Single-cell RNA sequencing was performed on flow sorted tumor-infiltrating lymphocytes from female C57/BL6 mice implanted with each model, with and without PD-1 blockade therapy. CD8+ and CD4+ T cells were identified and separately analyzed. Survival analyses were performed comparing PD-1 blockade therapy, CD40 agonist or combinatorial therapy. RESULTS: The CD8 T-cell compartment of the models is composed of heterogenous CD8 Tex subsets, including progenitor exhausted CD8 T cells (Tex prog), intermediate Tex, proliferating Tex, and Tex term. GL261 is enriched with the PD-1 responsive Tex prog subset relative to the CT2A and CD4-depleted GL261 models, which are composed predominantly of the PD-1 blockade refractory Tex term subset. Analysis of the CD4 T-cell compartments revealed that the CT2A microenvironment is enriched with a suppressive Treg subset and an effector CD4 T-cell subset that expresses an inhibitory interferon-stimulated (Isc) signature. Finally, we demonstrate that addition of CD40 agonist to PD-1 blockade therapy improves survival in CT2A tumor-bearing mice. CONCLUSIONS: Here, we describe that dysfunctional CD4 T cells are associated with terminal CD8 T-cell exhaustion, suggesting CD4 T cells impact PD-1 blockade efficacy by controlling the severity of exhaustion. Given that CD4 lymphopenia is frequently observed in patients with glioblastoma, this may represent a basis for resistance to PD-1 blockade. We demonstrate that CD40 agonism may circumvent a dysfunctional CD4 compartment to improve PD-1 blockade responsiveness, supporting a novel synergistic immunotherapeutic approach.
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Neoplasias Encefálicas , Glioblastoma , Feminino , Camundongos , Animais , Linfócitos T CD4-Positivos , Receptor de Morte Celular Programada 1 , Glioblastoma/tratamento farmacológico , Exaustão das Células T , Linfócitos T CD8-Positivos , Neoplasias Encefálicas/tratamento farmacológico , Microambiente TumoralRESUMO
Pituitary tumor apoplexy (PTA) classically comprises sudden-onset headache, loss of vision, ophthalmoparesis, and decreased consciousness. It typically results from hemorrhage and/or infarction within a pituitary adenoma. Presentation is heterologous, and optimal management is debated. The time course of recovery of cranial nerve deficits (CNDs) and headaches is not well established. In this study, a retrospective series of consecutive patients with PTA managed at a single academic institution over a 22-year period is presented. Headaches at the time of surgery were more severe in the early and subacute surgical cohort and improved significantly within 72 h postoperatively (p < 0.01). At one year, 90% of CNDs affecting cranial nerves (CNs) 3, 4, and 6 had recovered, with no differences between early (<4 d), subacute (4−14 d), and delayed (>14 d) time-to-surgery cohorts. Remarkably, half recovered within three days. In total, 56% of CN2 deficits recovered, with the early surgery cohort including more severe deficits and recovering at a lower rate (p = 0.01). No correlation of time-to-surgery and rapidity of recovery of CNDs was observed (p = 0.65, 0.72). Surgery for PTA is associated with rapid recovery of CNDs in the early, subacute, and delayed time frames, and with rapid headache improvement in the early and subacute time frames in 50% or more of patients.
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Apoplexia Hipofisária , Neoplasias Hipofisárias , Acidente Vascular Cerebral , Nervos Cranianos/patologia , Cefaleia/complicações , Cefaleia/cirurgia , Humanos , Apoplexia Hipofisária/complicações , Apoplexia Hipofisária/patologia , Apoplexia Hipofisária/cirurgia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/cirurgia , Estudos Retrospectivos , Acidente Vascular Cerebral/complicaçõesRESUMO
BACKGROUND: Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples. METHODS: Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers. RESULTS: In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples. CONCLUSIONS: Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura.
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Neoplasias Meníngeas , Meningioma , Animais , Células Endoteliais/patologia , Humanos , Imunidade , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Meninges/patologia , Meningioma/genética , Meningioma/patologia , Camundongos , Microambiente TumoralRESUMO
Meningiomas are common primary central nervous system tumors derived from the meninges, with management most frequently entailing serial monitoring or a combination of surgery and/or radiation therapy. Although often considered benign lesions, meningiomas can not only be surgically inaccessible but also exhibit aggressive growth and recurrence. In such cases, adjuvant radiation and systemic therapy may be required for tumor control. In this review, we briefly describe the current WHO grading scale for meningioma and provide demonstrative cases of treatment-resistant meningiomas. We also summarize frequently observed molecular abnormalities and their correlation with intracranial location and recurrence rate. We then describe how genetic and epigenetic features might supplement or even replace histopathologic features for improved identification of aggressive lesions. Finally, we describe the role of surgery, radiotherapy, and ongoing systemic therapy as well as precision medicine clinical trials for the treatment of recurrent meningioma.
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Though surgical biopsies provide direct access to tissue for genomic characterization of brain cancer, they are invasive and pose significant clinical risks. Brain cancer management via blood-based liquid biopsies is a minimally invasive alternative; however, the blood-brain barrier (BBB) restricts the release of brain tumor-derived molecular biomarkers necessary for sensitive diagnosis. Methods: A mouse glioblastoma multiforme (GBM) model was used to demonstrate the capability of focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) to improve the diagnostic sensitivity of brain tumor-specific genetic mutations compared with conventional blood-based liquid biopsy. Furthermore, a pig GBM model was developed to characterize the translational implications of sonobiopsy in humans. Magnetic resonance imaging (MRI)-guided FUS sonication was performed in mice and pigs to locally enhance the BBB permeability of the GBM tumor. Contrast-enhanced T1-weighted MR images were acquired to evaluate the BBB permeability change. Blood was collected immediately after FUS sonication. Droplet digital PCR was used to quantify the levels of brain tumor-specific genetic mutations in the circulating tumor DNA (ctDNA). Histological staining was performed to evaluate the potential for off-target tissue damage by sonobiopsy. Results: Sonobiopsy improved the detection sensitivity of EGFRvIII from 7.14% to 64.71% and TERT C228T from 14.29% to 45.83% in the mouse GBM model. It also improved the diagnostic sensitivity of EGFRvIII from 28.57% to 100% and TERT C228T from 42.86% to 71.43% in the porcine GBM model. Conclusion: Sonobiopsy disrupts the BBB at the spatially-targeted brain location, releases tumor-derived DNA into the blood circulation, and enables timely collection of ctDNA. Converging evidence from both mouse and pig GBM models strongly supports the clinical translation of sonobiopsy for the minimally invasive, spatiotemporally-controlled, and sensitive molecular characterization of brain cancer.
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Neoplasias Encefálicas , DNA Tumoral Circulante/metabolismo , Glioblastoma , Biópsia Líquida/métodos , Sonicação/métodos , Animais , Barreira Hematoencefálica , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Camundongos , SuínosRESUMO
Since the late 19th century, the immune system has increasingly garnered interest as a novel avenue for cancer therapy, particularly given scientific breakthroughs in recent decades delineating the fundamental role of the immune system in tumorigenesis. The immunoediting hypothesis has articulated this role, describing three phases of the tumor-immune system interaction: Elimination, Equilibrium, and Escape wherein tumors progress from active immunologic surveillance and destruction through dynamic immunologic stasis to unfettered growth. The primary goals of immunotherapy are to restrict and revert progression through these phases, thereby improving the immune system's ability to control tumor growth. In this review, we detail the development and foundation of the cancer immunoediting hypothesis and apply this hypothesis to the dynamic immunotherapy field that includes checkpoint blockade, vaccine therapy, and adoptive cell transfer.
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Suscetibilidade a Doenças/imunologia , Sistema Imunitário , Neoplasias/etiologia , Animais , Humanos , Vigilância Imunológica , Imunoterapia , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Microambiente TumoralRESUMO
The Gamma Knife Center of St. Louis has established itself as a key facility offering stereotactic radiosurgery (SRS) for a variety of neuro-oncologic disorders. Since the Gamma Knife unit was first brought to Washington University in 1997, we have treated 5,696 patients. In this review, we discuss the effective role of Gamma Knife SRS in the treatment strategies for patients with neuro-oncologic disorders including brain metastases, meningiomas, pituitary adenomas, and acoustic neuromas. While there is active ongoing research evaluating the most effective treatment for patients with these disorders, it is clear that best management practices may be tailored for individual patients utilizing SRS either alone or in conjunction alternative treatment strategies including open neurosurgical procedures, laser thermos-ablative surgery, and even new medical oncological treatment strategies.
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Neoplasias Encefálicas/cirurgia , Meningioma/cirurgia , Neuroma Acústico/cirurgia , Neurocirurgia/métodos , Neoplasias Hipofisárias/cirurgia , Radiocirurgia/métodos , Neoplasias Encefálicas/secundário , Humanos , Neurocirurgia/tendências , Radiocirurgia/tendências , Resultado do TratamentoRESUMO
Unfortunately, the first author surname was incorrectly published as "Harrison Farber" instead of "Farber" in original publication.
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PURPOSE: Chimeric antigen receptor (CAR) T cells have shown promise against solid tumors, but their efficacy has been limited, due in part, to immunosuppression by CD4+FoxP3+ regulatory T cells (Tregs). Although lymphodepletion is commonly used to deplete Tregs, these regimens are nonspecific, toxic, and provide only a narrow window before Tregs repopulate hosts. Importantly, CARs have also been shown to inadvertently potentiate Tregs by providing a source of IL2 for Treg consumption. We explored whether disruption of the IL2 axis would confer efficacy against solid tumors without the need for lymphodepletion. EXPERIMENTAL DESIGN: We developed second- (CD28z) and third- (CD28-4-1BBz) generation CARs targeting EGFRvIII. To eliminate secretion of IL2, 2 amino acid substitutions were introduced in the PYAP Lck-binding motif of the CD28 domain (ΔCD28). We evaluated CARs against B16 melanomas expressing EGFRvIII. RESULTS: CD28z CARs failed to engraft in vivo. Although 4-1BB addition improved expansion, CD28-4-1BBz CARs required lymphodepletion to treat solid tumors. CARs deficient in Lck signaling, however, significantly retarded tumor growth without a need for lymphodepletion and this was dependent on inclusion of 4-1BB. To evaluate CAR vulnerability to Tregs, we lymphodepleted mice and transferred CARs alone or with purified Tregs. Cotransfer with Tregs abrogated the efficacy of CD28-4-1BBz CARs, whereas the efficacy of ΔCD28-4-1BBz CARs remained unperturbed. CONCLUSIONS: In the absence of lymphodepletion, CARs targeting solid tumors are hindered by Treg immunosuppression and poor persistence. Here, CARs were modified to circumvent Treg suppression and to simultaneously improve in vivo engraftment. Modified CARs treated solid tumors without a need for lymphodepletion.