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A major limitation of chimeric antigen receptor (CAR) T cell therapies is the poor persistence of these cells in vivo1. The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy2-6, suggesting that memory programs may underpin durable CAR T cell function. Here we show that the transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells. Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo. By contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells. Notably, FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy. Our results show that overexpressing FOXO1 can increase the antitumour activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states.
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Proteína Forkhead Box O1 , Memória Imunológica , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Linfócitos T , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Cromatina/metabolismo , Cromatina/genética , Proteína Forkhead Box O1/metabolismo , Edição de Genes , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/citologiaRESUMO
Minimally invasive surgical approaches to the spine that leverage indirect decompression are gaining increasing popularity. While there is excellent literature on the value of indirect decompression, there are limitations to this procedure. Specifically, in patients with severe stenosis and neurogenic claudication, there is a concern among many surgeons regarding the adequacy of indirect decompression alone. In these cases, the lateral approach is often abandoned in favor of an open posterior or posterior minimally invasive approach. Unfortunately, some of the distinct benefits of the direct lateral approach are then lost. Here, we present the case of a 58-year-old male who underwent an L4-L5 lateral interbody fusion with an endoscopic ipsi-contra decompression to achieve both direct and indirect treatment of severe neuroforaminal and central stenosis. From this strategy, this patient had complete pre-operative symptom resolution and was able to return to work immediately after surgery without significant restriction. Combining the benefits of direct and indirect using an ultra-minimally invasive decompressive approach offers a potential solution.
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Vertebral osteomyelitis/discitis is a relatively rare disease but is a known potential complication of spinal surgical intervention. In general, the first-line treatment for this condition is targeted antibiotic therapy with surgical intervention only utilized in refractory cases with evidence of extensive damage, structural instability, or abscess formation. However, surgical best practices have not been established for osteomyelitis, including indications for anterior lateral interbody fusion (ALIF), posterior lateral interbody fusion (PLIF), or direct lateral interbody fusion (DLIF). This case provides a discussion of the indications that led to a direct lateral approach in the setting of refractory osteomyelitis/discitis, supporting factors that led to its success, and the efficacy of utilizing intraoperative neuromonitoring in cases of infection.
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BACKGROUND: Prompt diagnosis and treatment of vertebral artery dissection (VAD) is critical for preventing stroke. The use of emboli detection studies (EDS) using Doppler ultrasonography is an emerging method that has been proposed to predict stroke risk and guide subsequent treatment. Limited data exists on the predictive value of this emerging modality in the posterior circulation. This study aims to assess the predictive value of emboli detection studies (EDS) in forecasting inpatient stroke in VAD patients and identify associated risk factors. Patients were recruited between January 2009 and January 2018. METHODS: We performed a retrospective analysis of 104 consecutive patients with VAD who underwent EDS at our institution. Patients underwent transcranial ultrasonography for detection of microemboli and were followed clinically and radiographically thereafter for evidence of stroke. RESULTS: A total of 104 patients with spontaneous (58 %), traumatic (39 %) or iatrogenic (4 %) VAD were included in our analysis. Stroke occurred more frequently in patients with spontaneous VAD compared to traumatic VAD (p < 0.001). Microemboli were detected in 17 patients (16 %), including 18.3 % of spontaneous VAD, 12.5 % of traumatic VAD, and 25 % of iatrogenic VAD. 61 patients (59 %) suffered a posterior circulation stroke, however there was no significant association between detection of microemboli and stroke events (60 % of patients without microemboli vs. 53 % of patients with ≥ 1 HITS during EDS; p = 0.6). Similarly, no microemboli were detected in any of the patients who went on to develop a delayed stroke. CONCLUSIONS: In our single-institution retrospective analysis of patients with VAD, the detection of microemboli on EDS was not associated with stroke nor was it predictive of delayed stroke. Additionally, patients with spontaneous VAD may be at higher risk for stroke compared to traumatic VAD.
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Ultrassonografia Doppler Transcraniana , Dissecação da Artéria Vertebral , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Dissecação da Artéria Vertebral/epidemiologia , Dissecação da Artéria Vertebral/diagnóstico por imagem , Dissecação da Artéria Vertebral/complicações , Adulto , Ultrassonografia Doppler Transcraniana/métodos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/diagnóstico por imagem , Idoso , Fatores de Risco , Pacientes Internados/estatística & dados numéricos , Embolia Intracraniana/epidemiologia , Embolia Intracraniana/diagnóstico por imagem , Embolia Intracraniana/etiologiaRESUMO
We present a rare case of an intraparenchymal chordoma in the brain stem of a 69-year-old male with a history of multiple chordoma recurrences. Chordomas are uncommon tumors that originate from notochordal remnants, with intraparenchymal presentations in the brain stem being particularly rare. A 69-year-old male with a history of clival chordoma three years after primary endoscopic resection and adjuvant proton-beam radiotherapy and a recurrence one year postoperatively for which he underwent a second surgery, presented with severe headaches, weakness, diaphoresis, and difficulty ambulating. Head CT in the ER revealed a 2.7 x 3.5 cm hyperdense lesion in the pons, indicating acute hemorrhage. Magnetic resonance imaging (MRI) suggested a hemorrhagic radiation-induced cavernoma. A right retrosigmoid craniotomy was performed, and the lesion was resected without major complications. Final pathology reported an intraparenchymal hemorrhagic chordoma. To our knowledge, this is the first case of intra-axial chordoma, particularly in the brain stem. It highlights the importance of considering intraparenchymal chordoma on the differential when evaluating for recurrence versus other treatment-induced pathologies and changes. This may prompt the neurosurgeon to reconsider treatment options and weigh the risks of watchful waiting versus biopsy or even aggressive surgical management.
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BACKGROUND: Adjacent segment disease (ASD) is a known sequela of thoracolumbar instrumented fusions. Various surgical options are available to address ASD in patients with intractable symptoms who have failed conservative measures. However, the optimal treatment strategy for symptomatic ASD has not been established. We examined several clinical outcomes utilizing different surgical interventions for symptomatic ASD. METHODS: A retrospective review was performed for a consecutive series of patients undergoing revision surgery for thoracolumbar ASD between October 2011 and February 2022. Patients were treated with endoscopic decompression (N = 17), microdiscectomy (N = 9), lateral lumbar interbody fusion (LLIF; N = 26), or open laminectomy and fusion (LF; N = 55). The primary outcomes compared between groups were re-operation rates and numeric pain scores for leg and back at 2 weeks, 10 weeks, 6 months, and 12 months postoperation. Secondary outcomes included time to re-operation, estimated blood loss, and length of stay. RESULTS: Of the 257 patients who underwent revision surgery for symptomatic ASD, 107 patients met inclusion criteria with a minimum of 1-year follow-up. The mean age of all patients was 67.90 ± 10.51 years. There was no statistically significant difference between groups in age, gender, preoperative American Society of Anesthesiologists scoring, number of previously fused levels, or preoperative numeric leg and back pain scores. The re-operation rates were significantly lower in LF (12.7%) and LLIF cohorts (19.2%) compared with microdiscectomy (33%) and endoscopic decompression (52.9%; P = 0.005). Only LF and LLIF cohorts experienced significantly decreased pain scores at all 4 follow-up visits (2 weeks, 10 weeks, 6 months, and 12 months; P < 0.001 and P < 0.05, respectively) relative to preoperative scores. CONCLUSION: Symptomatic ASD often requires treatment with revision surgery. Fusion surgeries (either stand-alone lateral interbody or posterolateral with instrumentation) were most effective and durable with respect to alleviating pain and avoiding additional revisions within the first 12 months following revision surgery. CLINICAL RELEVANCE: This study emphasizes the importance of risk-stratifying patients to identify the least invasive approach that treats their symptoms and reduces the risk of future surgeries.
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BACKGROUND: Brain metastases from esophageal cancer (BMEC) are rare and aggressive, with limited literature on optimal treatment modalities and a standard of care yet to be established. The objective of this study was to systematically review existing literature and perform a retrospective analysis of our institution's patients to evaluate the influence of different treatment modalities on patient outcomes. METHODS: A systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines and a retrospective review of our institutional experience with BMEC were both conducted. Data based on mean survival,histology, metastasis location, and treatment modality were abstracted. RESULTS: A total of 48 studies representing 136 patients with BMEC were identified, in addition to the 11 patients treated at our institution. There were a total of 100 males (12 unreported), with a median age of 62.2 at diagnosis in our systematic review, along with 8 males with a median age of 62 in our institutional review. Collectively, survival rates observed based on histology were not similar (squamous cell carcinoma: 9.2 months, adenocarcinoma: 13.4 months), however, based on treatment modalities (surgery: 11.6 months, radiation: 10.4 months, chemotherapy: 12.3 months), and metastasis location (supratentorial: 10.5 months, infratentorial: 9.9 months), the survival times were comparable. CONCLUSIONS: Our review suggests that causes of death were often independent of brain metastases highlighting the need for further studies on early detection and prevention of primary esophageal cancer, as well as improved treatment modalities for BMECs.
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Neoplasias Encefálicas , Neoplasias Esofágicas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Adenocarcinoma/terapia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/cirurgia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Procedimentos Neurocirúrgicos/métodos , Estudos RetrospectivosRESUMO
Background: Colloid cysts are intracranial lesions originating from abnormalities in the primitive neuroepithelium folding of the third ventricle. Various surgical approaches have been explored for the management of colloid cysts, each carrying its own set of advantages and limitations. Tubular retractors developed recently alleviate retraction pressure through radial distribution, potentially offering benefits for colloid cyst resection. This study aims to introduce and assess a modified microsurgical method utilizing the tubular retractor for addressing colloid cysts. Methods: The study included a retrospective assessment of patients who had colloid cysts and who were treated between 2015 and 2023 by one experienced surgeon. The demographic, clinical, radiological, histological, and surgical data regarding these patients were evaluated. The patients were assessed using the colloid cyst risk score, indicating a risk for obstructive hydrocephalus. Results: The minimally invasive microsurgical approach was successfully applied to all 22 identified patients. No postoperative surgical complications were reported. Gross total resection was achieved in 21 (95.5%) patients. The early complication rate was 22.7% (n = 5). There were no postoperative seizures, permanent neurological deficits, or venous injuries. The average hospital stay was 3 days. There was no evidence of recurrence at an average follow-up length of 25.9 months. Conclusion: The transtubular approach is an effective, safe method for treating colloid cysts. It achieves complete cyst removal with minimal complications, offering the benefits of less invasiveness, improved visualization, and reduced tissue disruption, strengthening its role in colloid cyst surgery.
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BACKGROUND AND OBJECTIVES: Smartphone activity data recorded through high-fidelity accelerometry can provide accurate postoperative assessments of patient mobility. The "big data" available through smartphones allows for advanced analyses, yielding insight into patient well-being. This study compared rate of change in functional activity data between lumbar fusion (LF) and lumbar decompression (LD) patients to determine preoperative and postoperative course differences. METHODS: Twenty-three LF and 18 LD patients were retrospectively included. Activity data (steps per day) recorded in Apple Health, encompassing over 70 000 perioperative data points, was classified into 6 temporal epochs representing distinct functional states, including acute preoperative decline, immediate postoperative recovery, and postoperative decline. The daily rate of change of each patient's step counts was calculated for each perioperative epoch. RESULTS: Patients undergoing LF demonstrated steeper preoperative declines than LD patients based on the first derivative of step count data (P = .045). In the surgical recovery phase, LF patients had slower recoveries (P = .041), and LF patients experienced steeper postoperative secondary declines than LD patients did (P = .010). The rate of change of steps per day demonstrated varying perioperative trajectories that were not explained by differences in age, comorbidities, or levels operated. CONCLUSION: Patients undergoing LF and LD have distinct perioperative activity profiles characterized by the rate of change in the patient daily steps. Daily steps and their rate of change is thus a valuable metric in phenotyping patients and understanding their postsurgical outcomes. Prospective studies are needed to expand upon these data and establish causal links between preoperative patient mobility, patient characteristics, and postoperative functional outcomes.
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Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado generation. Here, we sought to enhance CAR-T cell potency by knocking out CD39, CD73, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness and enhanced CAR-T functionality. Similarly, CAR-T cell exposure to INO augmented function and induced features of stemness. INO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.
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Inosina , Linfócitos T , Humanos , Linfócitos T/metabolismoRESUMO
Improvements in navigation technology have enabled surgeons to safely offer single-position fusion surgeries, demonstrating shorter operating times and reduced length of stay (LOS) as compared to traditional lateral and prone dual-position surgeries. However, no studies to date describe revision thoracolumbar corpectomy with simultaneous posterior rod removal and replacement in the lateral position. Furthermore, this is the first reported complication of delayed ipsilateral kidney atrophy following lateral lumbar surgery. A 56-year-old male patient with history of metastatic hepatocellular carcinoma and complex surgical history for a prior T12 pathologic fracture presented to the clinic for follow-up. Computed tomography (CT) demonstrated bilateral broken rods and subsidence of the T12 interbody cage, for which he underwent revision T12 corpectomy and posterior instrumentation revision via a single-position, left-sided lateral approach. Simultaneous exposure and removal of the broken rods enabled the placement of two short temporary rods between the T11-L1 screws posteriorly, allowing for rod distraction and the placement of the expandable corpectomy cage into the appropriate position. On follow-up cancer surveillance imaging, the left kidney became progressively atrophic within six months after surgery. According to a review of PubMed, Scopus, and Embase databases, we describe the first reported case of a single-position thoracolumbar revision corpectomy with simultaneous rod replacement. Of particular importance in this technique is the use of temporary rod placement for distraction across the index level to facilitate interbody cage placement. Furthermore, we discussed the first reported complication of delayed ipsilateral kidney atrophy following lateral lumbar fusion.
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Epidural abscesses can be caused by a number of different organisms, including atypical Mycobacterium. This is a rare case report of an atypical Mycobacterium epidural abscess requiring surgical decompression. Here, we present Mycobacterium abscessus causing a nonpurulent epidural collection surgically treated with laminectomy and washout and discuss clinical clues and radiologic characteristics associated with this condition. A 51-year-old male with a past medical history of chronic intravenous (IV) drug use presented with a three-day history of falls and three-month history of progressively worsening bilateral lower extremity radiculopathy, paresthesias, and numbness. MRI demonstrated an enhancing collection at L2-3 ventral and to the left of the spinal canal causing severe compression of the thecal sac, along with heterogenous contrast enhancement of the L2-3 vertebral bodies and intervertebral disc. The patient was taken for an L2-3 laminectomy and left medial facetectomy, where a fibrous, nonpurulent mass was discovered. Cultures ultimately demonstrated Mycobacterium abscessus subspecies massiliense, and the patient was discharged on IV levofloxacin, azithromycin, and linezolid with complete symptomatic relief. Unfortunately, despite surgical washout and antibiotic coverage, the patient presented twice more, the first time with a recurrent epidural collection requiring repeat drainage and the second time with a recurrent epidural collection with discitis and osteomyelitis with pars fractures requiring repeat epidural drainage and interbody fusion. It is important to recognize that atypical Mycobacterium abscessus can cause a nonpurulent epidural collection, especially in high-risk patients such as those with a history of chronic IV drug use. Additionally, our initial intraoperative findings of a fibrous, adherent mass suggest that in cases where this entity is suspected, surgical decompression should be carefully considered. To this end, the radiologic findings associated with this condition, namely, an enhancing ventral epidural mass involving the disc space, should also be recognized. The notable postoperative course consisting of recurrent collections and osteomyelitis with a pars fracture suggests that early fusion should be considered as an option in these patients. This case report presents clinical and radiologic findings associated with an atypical Mycobacterium discitis and osteomyelitis. The clinical course described herein suggests that early fusion in these patients may provide superior results to decompression alone.
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INTRODUCTION: Metastatic spine tumors affect over 30% of patients who have been diagnosed with cancer. While techniques in surgical intervention have undoubtedly evolved, there are some pitfalls when spinal instrumentation is required for stabilization following tumor resection. However, the use of carbon fiber-reinforced polyetheretherketone (CFR-PEEK) implants has become increasingly popular due to improved radiolucency and positive osteobiologic properties. Here, we present a systematic review describing the use of CFR-PEEK-coated instrumentation in the oncologic population while identifying advantages and potential shortcomings of these devices. METHODS: In accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic review was conducted in March 2022 to identify articles detailing the use of CFR-PEEK implants for spinal instrumentation in patients with primary and secondary spine tumors. The search was performed using the PubMed, Scopus, and Embase databases. RESULTS: An initial search returned a total of 85 articles among the three databases used. After the exclusion of duplicates and screening of abstracts, 21 full-text articles were examined for eligibility. Eleven articles were excluded due to not fitting our inclusion and exclusion criteria. Ten articles were subsequently eligible for full-text review. CONCLUSIONS: CFR-PEEK possesses a similar safety and efficacy profile to titanium implants but has distinct advantages. It limits artifact, increases early detection of local tumor recurrence, increases radiotherapy dose accuracy, and is associated with low complication rates (9.96%)-making it a promising alternative for the demands unique to the treatment/outcome of spinal oncologic patients.
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Neoplasias do Sistema Nervoso Central , Neoplasias da Medula Espinal , Neoplasias da Coluna Vertebral , Humanos , Fibra de Carbono , Polímeros , Benzofenonas , Polietilenoglicóis , Cetonas , Neoplasias da Coluna Vertebral/cirurgia , CarbonoRESUMO
Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR T cells mediate Ado-induced immunosuppression through CD39/73-dependent Ado production. Knockout of CD39, CD73 or A2aR had modest effects on exhausted CAR T cells, whereas overexpression of Ado deaminase (ADA), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced functionality. Similarly, and to a greater extent, exposure of CAR T cells to INO augmented CAR T cell function and induced hallmark features of T cell stemness. INO induced a profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and modulated the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR T cell products meeting criteria for clinical dosing. These data identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.
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Poor CAR T persistence limits CAR T cell therapies for B cell malignancies and solid tumors1,2. The expression of memory-associated genes such as TCF7 (protein name TCF1) is linked to response and long-term persistence in patients3-7, thereby implicating memory programs in therapeutic efficacy. Here, we demonstrate that the pioneer transcription factor, FOXO1, is responsible for promoting memory programs and restraining exhaustion in human CAR T cells. Pharmacologic inhibition or gene editing of endogenous FOXO1 in human CAR T cells diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype, and impaired antitumor activity in vitro and in vivo. FOXO1 overexpression induced a gene expression program consistent with T cell memory and increased chromatin accessibility at FOXO1 binding motifs. FOXO1-overexpressing cells retained function, memory potential, and metabolic fitness during settings of chronic stimulation and exhibited enhanced persistence and antitumor activity in vivo. In contrast, TCF1 overexpression failed to enforce canonical memory programs or enhance CAR T cell potency. Importantly, endogenous FOXO1 activity correlated with CAR T and TIL responses in patients, underscoring its clinical relevance in cancer immunotherapy. Our results demonstrate that memory reprogramming through FOXO1 can enhance the persistence and potency of human CAR T cells and highlights the utility of pioneer factors, which bind condensed chromatin and induce local epigenetic remodeling, for optimizing therapeutic T cell states.
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BACKGROUND: Minimally invasive surgery bases many of its benefits on decreasing tissue disruption. Endoscopic spine surgery has continued to push the boundaries to accomplish successful clinical outcomes through the evolution of the endoscope and working channel. As the indications for endoscopic spine surgery increase, a more profound discussion of cannula size selection for endoscopic spine surgery is required. The intimate relationship between the working channel, the endoscope and how these choices affect workflow and visualization are paramount to maximize outcomes. METHODS: The authors review the nuances of the endoscopic approaches to the various regions of the spine as it relates to the selection of the working channel. The advantages and limitations of various endoscopic working channels were analyzed as to how they address anatomic regional considerations as well as ultimate goals of surgery. RESULTS: In addition to anatomic regional differences and the goals of the surgery other key elements in endoscopic working channel selection included the amount of tissue disruption, regional risk to the neural elements, impact on visualization, optical physics, and the implications for surgical maneuverability/dexterity. CONCLUSION: Understanding the role and use of the endoscope-working channel combination with its effects on visualization is essential for any surgeon aspiring to perform safe and efficient full endoscopic spine surgery.
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Endoscópios , Endoscopia , Humanos , Procedimentos Cirúrgicos Minimamente Invasivos , Coluna Vertebral/cirurgiaRESUMO
T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)-T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction of rest through enforced down-regulation of the CAR protein using a drug-regulatable system or treatment with the multikinase inhibitor dasatinib resulted in the acquisition of a memory-like phenotype, global transcriptional and epigenetic reprogramming, and restored antitumor functionality in exhausted CAR-T cells. This work demonstrates that rest can enhance CAR-T cell efficacy by preventing or reversing exhaustion, and it challenges the notion that exhaustion is an epigenetically fixed state.
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Dasatinibe/farmacologia , Epigênese Genética , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigenoma , Feminino , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Humanos , Memória Imunológica , Ativação Linfocitária , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Masculino , Camundongos , Neoplasias Experimentais/terapia , Domínios Proteicos , Estabilidade Proteica , Receptores de Antígenos Quiméricos/química , Receptores de Antígenos Quiméricos/imunologia , Transdução de Sinais , Linfócitos T/metabolismo , Transcrição Gênica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: Radiofrequency catheter ablation is a common treatment for atrial fibrillation (AF), during which thermal esophageal injury may rarely occur and lead to an atrio-esophageal fistula. Therefore, we studied the utility of the Circa S-Cath™ multi-sensor luminal esophageal temperature (LET) probe to prevent esophageal thermal injury. METHODS AND RESULTS: Thirty-six patients, enrolled prospectively, underwent circumferential or segmental pulmonary vein isolation for treatment of AF. A maximum ablation electrode temperature of 42ºC was programmed for automatic power delivery cutoff. In addition, energy delivery was manually discontinued when the maximum LET on any sensor of the probe rose abruptly (i.e. Ë0.2ºC) or exceeded 39º C. Esophagoscopy was performed immediately after ablation in 18 patients (with the temperature probe still in place) and at approximately 24 hours after ablation in 18 patients. Esophageal lesions were classified as likely traumatic or thermally related. Of the 36 patients enrolled in the study, 21 had persistent and 15 had paroxysmal AF, average LVEF 57±16% and CHA2DS2VASc score 1.6±1.2 (range 0-4). Average maximum LET was 37.8±1.4ºC, power delivery 31.1±8 watts and ablation electrode temperature 36.4±4.1ºC. Average maximum contact force was 44.5±20.5 grams where measured. Only 1 patient (<3%) had an esophageal lesion that could potentially represent thermal injury and 4 patients (11.1%) had minor traumatic mechanical injury. CONCLUSIONS: LET guided titration of power and duration of energy application, using an insulated multi-sensor esophageal temperature probe, is associated with a low risk of esophageal thermal injury during AF ablation. In only rare cases, LET monitoring resulted in the need to manipulate the esophagus to avoid unacceptable temperature rises, that could not be achieved by adjustment of power and duration of energy application.