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OBJECTIVE: Patients with moderate traumatic brain injury (TBI) are under the threat of intracranial hypertension (IHT). However, it is unclear which moderate TBI patient will develop IHT and should receive intracranial pressure (ICP)-lowering treatment or invasive ICP monitoring after admission. The purpose of the present study was to develop and validate a prediction model that estimates the risk of IHT in moderate TBI patients. METHODS: Baseline data collected on admission of 296 moderate TBI patients with Glasgow Coma Scale (GCS) score of 9-11 was collected and analyzed. Multi-variable logistic regression modeling with backward stepwise elimination was used to develop a prediction model for IHT. The discrimination efficacy, calibration efficacy, and clinical utility of the prediction model were evaluated. Finally, the prediction model was validated in a separate cohort of 122 patients from 3 hospitals. RESULTS: Four independent prognostic factors for IHT were identified: GCS score, Marshall head computed tomography score, injury severity score and location of contusion. The C-statistic of the prediction model in internal validation was 84.30% (95% confidence interval [CI]: 0.794-0.892). The area under the curve for the prediction model in external validation was 82.80% (95% CI: 0.747â¼0.909). CONCLUSIONS: A prediction model based on baseline parameters was found to be highly sensitive in distinguishing moderate TBI patients with GCS score of 9-11 who would suffer IHT. The high discriminative ability of the prediction model supports its use in identifying moderate TBI patients with GCS score of 9-11 who need ICP-lowering therapy or invasive ICP monitoring.
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OBJECTIVE: The objective of this study was to evaluate the clinical effect and safety of the postauricular infratemporal fossa approach (ITFA) in resecting jugular foramen lesions. METHODS: All 25 patients undergoing microsurgery via postauricular ITFA from March 2015 to May 2023 in the Department of Neurosurgery, Tangdu Hospital, Air Force Military Medical University were included. The clinical and radiological data were retrospectively analyzed. Regular follow-up was carried out. RESULTS: The mean age of all patients was 50.5±8.9 years, and 14 of them were female and 11 were male. Among the cases, lower cranial nerve schwannoma accounted for 60â¯% (15/25) of all tumors, jugular foramen paraganglioma accounted for 20â¯% (5/25), and the remaining 20â¯% included meningioma, chondrosarcoma, plasmacytoma, and salivary gland tumors. Total tumor resection was performed in 18 cases, subtotal tumor resection in 7 cases and partial resection in 1 case. Seven patients underwent gamma knife radiotherapy after surgery. Transient lower cranial nerve dysfunction occurred in 8 patients, and permanent lower cranial nerve dysfunction occurred in 2 patients after surgery. One patient developed facial paralysis, and one patient presented hearing loss. CONCLUSIONS: The postauricular ITFA achieved a relatively high total tumor resection rate and a lower incidence of neurological functional disorders. It is an alternative and suitable surgical approach for resecting jugular foramen lesions. Maximizing the preservation of neurological function is preferred, especially when radical resection cannot be achieved. Stereotactic radiotherapy could be used for residual tumors.
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Fosa Infratemporal , Foramina Yugular , Complicaciones Posoperatorias , Neoplasias de la Base del Cráneo , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Foramina Yugular/cirugía , Neoplasias de la Base del Cráneo/cirugía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Fosa Infratemporal/cirugía , Estudios Retrospectivos , Procedimientos Neuroquirúrgicos/métodos , Procedimientos Neuroquirúrgicos/efectos adversos , Neurilemoma/cirugía , Meningioma/cirugía , Resultado del Tratamiento , Neoplasias de los Nervios Craneales/cirugía , Anciano , Microcirugia/métodos , Paraganglioma/cirugía , Paraganglioma/diagnóstico por imagenRESUMEN
Despite the development of various novel therapies, glioblastoma (GBM) remains a devastating disease, with a median survival of less than 15 months. Recently, targeted radionuclide therapy has shown significant progress in treating solid tumors, with the approval of Lutathera for neuroendocrine tumors and Pluvicto for prostate cancer by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This achievement has shed light on the potential of targeted radionuclide therapy for other solid tumors, including GBM. This review presents the current status of targeted radionuclide therapy in GBM, highlighting the commonly used therapeutic radionuclides emitting alpha, beta particles, and Auger electrons that could induce potent molecular and cellular damage to treat GBM. We then explore a range of targeting vectors, including small molecules, peptides, and antibodies, which selectively target antigen-expressing tumor cells with minimal or no binding to healthy tissues. Considering that radiopharmaceuticals for GBM are often administered locoregionally to bypass the blood-brain barrier (BBB), we review prominent delivery methods such as convection-enhanced delivery, local implantation, and stereotactic injections. Finally, we address the challenges of this therapeutic approach for GBM and propose potential solutions.
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Glioblastoma , Radioisótopos , Radiofármacos , Glioblastoma/radioterapia , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Radiofármacos/uso terapéutico , Radiofármacos/química , Radioisótopos/uso terapéutico , Radioisótopos/química , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de la radiaciónRESUMEN
The advancement of theranostics, which combines therapeutic and diagnostic capabilities in oncology, has significantly impacted cancer management. This review explores fibroblast activation protein (FAP) expression in the tumor microenvironment (TME) and its association with various malignancies, highlighting its potential as a theranostic marker for PET/CT imaging using FAP-targeted tracers and for FAP-targeted radiopharmaceutical therapy. We examine the development and clinical applications of FAP inhibitors (FAPIs) and peptides, providing insights into their diagnostic accuracy, initial therapeutic efficacy, and clinical impact across diverse cancer types, as well as the synthesis of novel FAP-targeted ligands. This review aims to showcase the promising outcomes and challenges in integrating FAP-targeted approaches into cancer management.
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Proteínas de la Membrana , Péptidos , Humanos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/antagonistas & inhibidores , Serina Endopeptidasas/metabolismo , Endopeptidasas/metabolismo , Animales , Gelatinasas/metabolismo , Gelatinasas/antagonistas & inhibidores , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Neoplasias/metabolismo , Nanomedicina Teranóstica/métodos , Medicina de Precisión/métodos , Microambiente Tumoral , Radiofármacos/uso terapéuticoRESUMEN
Persistent neuroinflammation and progressive neuronal loss are defining features of acute brain injury including traumatic brain injury (TBI) and cerebral stroke. Microglia, the most abundant type of brain-resident immune cells, continuously surveil the environment and play a central role in shaping the inflammatory state of the central nervous system (CNS). In the study, we discovered that the protein expression of METTL3 (a m6A methyltransferase) was upregulated in inflammatory microglia independent of increased Mettl3 gene transcription following TBI in both human and mouse subjects. Subsequently, we identified TRIP12, a HECT-domain E3 ubiquitin ligase, as a negative regulator of METTL3 protein expression by facilitating METTL3 K48-linked polyubiquitination. Importantly, selective ablation of Mettl3 inhibited microglial pathogenic activities, diminished neutrophil infiltration, rescued neuronal loss and facilitated functional recovery post-TBI. Using MeRIP-seq and CUT&Tag sequencing, we identified that METTL3 promoted the expression of Basic Leucine Zipper Transcriptional Factor ATF-Like (BATF), which in turn directly bound to a cohort of characteristic inflammatory cytokines and chemokine genes. Enhanced activities of BATF in microglia elicited TNF-dependent neurotoxicity and can also promote neutrophil recruitment through releasing CXCL2. Pharmacological inhibition of METTL3 using a BBB-penetrating drug-loaded nano-system showed satisfactory therapeutic effects in both TBI and stroke mouse models. Collectively, our findings identified METTL3-m6A-BATF axis as a potential therapeutic target for terminating detrimental neuroinflammation and progressive neuronal loss following acute brain injury. METTL3 protein is significantly up-regulated in inflammatory microglia due to the decreased proteasomal degradation mediated by TRIP12 and ERK-USP5 pathways. METTL3 stabilized BATF mRNA stability and promoted BATF expression through the m6A-IGF2BP2-dependent mechanism. Elevated expression of BATF elicits a pro-inflammatory gene program in microglia, and aggravates neuroinflammatory response including local immune responses and peripheral immune cell infiltration. Genetic deletion or pharmaceutically targeting METTL3-BATF axis suppressed microglial pro-inflammatory activities and promoted neurological recovery following TBI and stroke.
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Fibroblast activation protein (FAP) has emerged as a highly promising target for cancer diagnostic imaging and targeted radionuclide therapy. To exploit the therapeutic potential of suitably radiolabeled FAP inhibitors (FAPIs), this study presents the design and synthesis of a series of FAPI dimers to increase tumor uptake and retention. Preclinical evaluation and a pilot clinical PET imaging study were conducted to screen the lead compound with the potential for radionuclide therapy. METHODS: Three new FAPI dimers were synthesized by linking two quinoline-based FAPIs with different spacers. The in vitro binding affinity and preclinical small animal PET imaging of the compounds were compared with their monomeric counterparts, FAPI-04 and FAPI-46. The lead compound, [68Ga]Ga -LNC1013, was then evaluated in a pilot clinical PET imaging study involving seven patients with gastrointestinal cancer. RESULTS: The three newly synthesized FAPI homodimers had high binding affinity and specificity in vitro and in vivo. Small animal PET imaging and biodistribution studies showed that [68Ga]Ga-LNC1013 had persistent tumor retention for at least 4 h, also higher uptake than the other two dimers and the monomer counterparts, making it the lead compound to enter clinical investigation. In the pilot clinical PET imaging study, seven patients were enrolled. The effective dose of [68Ga]Ga-LNC1013 was 8.24E-03 mSv/MBq. The human biodistribution of [68Ga]Ga-LNC1013 demonstrated prominent tumor uptake and good tumor-to-background contrast. [68Ga]Ga-LNC1013 PET imaging showed potential in capturing primary and metastatic lesions and outperforming 18F-FDG PET in detecting pancreatic and esophageal cancers. The SUVmax for lesions with [68Ga]Ga-FAPI-46 decreased over time, whereas [68Ga]Ga-LNC1013 exhibited persistently high tumor uptake from 1 to 4 h post-injection. CONCLUSION: Dimerization is an effective strategy to produce FAPI derivatives with favorable tumor uptake, long tumor retention, and imaging contrast over its monomeric counterpart. We demonstrated that [68Ga]Ga-LNC1013, the lead compound without any piperazine moiety, had superior diagnostic potential over [68Ga]Ga-FAPI-46 and 18F-FDG, suggesting the future potential of LNC1013 for radioligand therapy of FAP-positive cancers.
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Radioisótopos de Galio , Humanos , Animales , Ratones , Radioisótopos de Galio/química , Línea Celular Tumoral , Femenino , Distribución Tisular , Tomografía de Emisión de Positrones/métodos , Masculino , Dimerización , Radiofármacos/farmacocinética , Radiofármacos/química , Persona de Mediana Edad , Investigación Biomédica Traslacional , Anciano , Proteínas de la Membrana , Endopeptidasas , QuinolinasRESUMEN
Background: Studies have been inconclusive on the risk for hemorrhage in patients with a history of aspirin use who underwent emergency external ventricular drainage (EVD)/intracranial pressure (ICP) probe placement. The aim of this study was to explore hemorrhage-related risk factors in order to reduce the risk for hemorrhage in these patients. Methods: Between July 2014 and July 2020, patients were retrospectively divided into EVD/ICP-related hemorrhage and non-hemorrhage groups. The collected data included age, gender, major diagnosis, medical history, imaging examinations, conventional coagulation test data, thromboelastography with platelet mapping (TEG-PM), surgical procedures and discharge conditions. Results: In total 94 patients, 21 in the hemorrhage group (15 males, 6 females) and 73 in the non-hemorrhage group (52 males, 21 females) were included. The majority of hemorrhages were recorded in EVD patients (19/21; 90.5%). Platelet AA pathway inhibition rate of ≥75% (sensitivity: 79.45% specificity: 52.38%) (P = 0.014) and SBP ≥125 mmHg (P = 0.006) were significantly related to hemorrhage. When the platelet AA pathway inhibition rate was ≥75% and the during-procedure SBP was ≥125 mmHg, the hemorrhage rate was significantly higher (83.3%) than with SBP <125 mmHg (6.7%) (P < 0.001). When the inhibition rate was <75%, there were no significant differences in the hemorrhage rates between the during-procedure SBP ≥125 mmHg group (17.2%) and the SBP <125 mmHg group (13.2%) (P > 0.05). Multivariate logistic regression analysis revealed that a platelet AA pathway inhibition rate ≥75% (OR = 5.183, 95% CI: 1.683-15.960) and during-procedure SBP ≥125 mmHg (OR = 4.609, 95% CI: 1.466-14.484) were independent risk factors for EVD/ICP-related hemorrhage. Conclusion: Patients with long-term aspirin therapy, a platelet AA pathway inhibition rate ≥75% and during-procedure SBP ≥125 mmHg had a significantly higher risk of hemorrhage, which could be reduced by adjusting the SBP to <125 mmHg.
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PURPOSE: Vascular endothelial growth factor receptor 3 (VEGFR-3) plays a critical role in tumor lymphangiogenesis and metastasis, holding promise as a promising therapeutic target for solid tumors. TMVP1 (LARGR) is a 5-amino acid peptide previously identified in our laboratory from bacterial peptide display system that specifically targets VEGFR-3. Radiolabeled TMVP1 can be used for non-invasive imaging of VEGFR-3 expressing tumors. Homodimeric peptides have better targeting ability than monomeric peptides, and it is worth exploring whether homodimers of TMVP1 ((TMVP1)2) can achieve better imaging effects. This study aimed to explore the peptide properties and tumor assessment value of [68Ga]Ga-labeled (TMVP1)2. METHODS: In this study, we developed a TMVP1 homodimer that was conjugated with 1,4,7-triazacyclononane-N, N', Nâ³-triacetic acid (NOTA) via tetraethyleneglycol (PEG4) and triglyicine (Gly3) spacer, and labeled with 68Ga, to construct [68Ga]Ga-NOTA-(TMVP1)2. Binding of VEGFR-3 by TMVP1 and (TMVP1)2, respectively, was modeled by molecular docking. The affinity of [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 and its ability to bind to cells were evaluated. MicroPET imaging and biodistribution studies of [68Ga]Ga-NOTA-(TMVP1)2 were performed in subcutaneous C33A cervical cancer xenografts. Five healthy volunteers and eight patients with cervical cancer underwent whole-body PET/CT acquisition 30-45 min after intravenous injection of [68Ga]Ga-NOTA-(TMVP1)2. RESULTS: Both molecular docking and cellular experiments showed that homodimeric TMVP1 had a higher affinity for VEGFR-3 than monomeric TMVP1. [68Ga]Ga-NOTA-(TMVP1)2 was excreted mainly through the renal route and partly through the liver route. In mice bearing C33A xenografts, [68Ga]Ga-NOTA-(TMVP1)2 specifically localized in the tumor (2.32 ± 0.10% ID/g). Pretreatment of C33A xenograft mice with the unlabeled peptide NOTA-(TMVP1)2 reduced the enrichment of [68Ga]Ga-NOTA-(TMVP1)2 in tumors (0.58 ± 0.01% ID/g). [68Ga]Ga-NOTA-(TMVP1)2 proved to be safe in all healthy volunteers and recruited patients, with no side effects or allergies noted. In cervical cancer patients, a majority of the [18F]-FDG identified lesions (18/22, 81.8%) showed moderate to high signal intensity on [68Ga]Ga-NOTA-(TMVP1)2. SUVmax and SUVmean were 2.32 ± 0.77 and 1.61 ± 0.48, respectively. With normal muscle (gluteus maximus) as background, tumor-to-background ratios were 3.49 ± 1.32 and 3.95 ± 1.64 based on SUVmax and SUVmean, respectively. CONCLUSION: The favorable characterizations of [68Ga]Ga-NOTA-(TMVP1)2 such as convenient synthesis, high specific activity, and high tumor uptake enable the evaluation of VEGFR-3 in cervical cancer patients and warrant further clinical studies. TRIAL REGISTRATION: ChiCTR-DOD-17012458. Registered August 23, 2017 (retrospectively registered).
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Radioisótopos de Galio , Compuestos Heterocíclicos con 1 Anillo , Neoplasias del Cuello Uterino , Receptor 3 de Factores de Crecimiento Endotelial Vascular , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/metabolismo , Humanos , Femenino , Animales , Ratones , Compuestos Heterocíclicos con 1 Anillo/química , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 3 de Factores de Crecimiento Endotelial Vascular/química , Radioisótopos de Galio/química , Línea Celular Tumoral , Compuestos Heterocíclicos/química , Distribución Tisular , Péptidos/química , Péptidos/farmacocinética , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Radiofármacos/química , Persona de Mediana Edad , Multimerización de Proteína , Trazadores RadiactivosRESUMEN
BACKGROUND: Watertight duraplasty is essential for surgical management of traumatic anterior skull base (ASB) dural defect but challenging in the deep and narrow operative corridor. Here, the authors report a trans-defect underlay watertight duraplasty (TDUWD) technique for traumatic ASB dural defect. METHODS: TDUWD was performed by inserting a free pericranium graft under the dural defect. The diameter of the pericranium graft was larger than the dural defect. The pericranium graft was sutured to the dural defect watertightly in an "inside-to-outside" direction, with the needle not penetrating the inner layer of pericranium graft. The pedicled pericranium flap was used as a second layer of reconstruction. The characteristics, complications, and outcomes of patients who received TDUWD are reported. RESULTS: A total of 29 patients received TDUWD. Immediate postoperative cessation of cerebrospinal fluid (CSF) leak occurred in 28 patients. One patient recovered after lumber drainage. No patient needed a second operation or reported delayed recurrence of CSF leak. No complication related to the surgical technique was observed. CONCLUSIONS: Use of TDUWD for traumatic ASB dural defect results in an immediate, 1-stage, and definitive correction of CSF leak and seems to be simple, safe, and reliable for large and deeply located dural defects.
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Pérdida de Líquido Cefalorraquídeo , Duramadre , Procedimientos de Cirugía Plástica , Base del Cráneo , Humanos , Duramadre/cirugía , Duramadre/lesiones , Masculino , Femenino , Adulto , Persona de Mediana Edad , Base del Cráneo/cirugía , Base del Cráneo/lesiones , Procedimientos de Cirugía Plástica/métodos , Pérdida de Líquido Cefalorraquídeo/cirugía , Pérdida de Líquido Cefalorraquídeo/etiología , Adulto Joven , Anciano , Adolescente , Colgajos Quirúrgicos , Procedimientos Neuroquirúrgicos/métodos , Resultado del TratamientoRESUMEN
Due to the heterogeneity of tumors, strategies to improve the effectiveness of dual-targeting tracers in tumor diagnostics have been intensively practiced. In this study, the radiolabeled [18F]AlF-NOTA-FAPI-RGD (denoted as [18F]AlF-LNC1007), a dual-targeting heterodimer tracer targeting both fibroblast activation protein (FAP) and integrin αvß3 to enhance specific tumor uptake and retention, was synthesized and evaluated. The tracer was compared with [68Ga]Ga-LNC1007 in preclinical and clinical settings. METHODS: The preparation of [18F]AlF- and 68Ga-labeled FAPI-RGD was carried out with an optimized protocol. The stability was tested in PBS and fetal bovine serum (FBS). Cellular uptake and in vivo distribution of the two products were compared and carried out on the U87MG cell line and its xenograft model. The safety and dosimetry of [18F]AlF-LNC1007 PET/CT scan were evaluated in six patients with malignant tumors. RESULTS: Two radiolabeling protocols of [18F]AlF-/[68Ga]Ga-LNC1007 were developed and optimized to give a high yield of tracers with good stability. In vivo microPET images showed that the two tracers exhibited comparable pharmacokinetic characteristics, with high tumor uptake and prolonged tumor retention. In vivo distribution data showed that the target-to-non-target ratios of [18F]AlF-LNC1007 were similar to[68Ga]Ga-LNC1007. A total of six patients underwent [18F]AlF-LNC1007 PET/CT evaluation while two had head-to-head [18F]FDG PET/CT scans. The total body effective dose was 9.94E-03 mSv/MBq. The biodistribution curve showed optimal normal organ uptake with high tumor uptake and long retention of up to 3h p.i., and notably, the tumor-to-background ratio increased over time. CONCLUSION: We successfully prepared an [18F]AlF-LNC1007 dual-targeting PET probe with comparable performances as [68Ga]Ga-LNC1007. With prolonged tumor retention and tumor specificity, it produced good imaging quality in preclinical and clinical translational studies, indicating that [18F]AlF-LNC1007 is a promising non-invasive tracer for detecting tumors expressing FAP and/or integrin avß3, with the prospect of clinical implementation.
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Compuestos de Aluminio , Endopeptidasas , Fluoruros , Radioisótopos de Flúor , Proteínas de la Membrana , Oligopéptidos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Humanos , Animales , Ratones , Radioisótopos de Flúor/química , Línea Celular Tumoral , Oligopéptidos/química , Oligopéptidos/farmacocinética , Femenino , Distribución Tisular , Radioisótopos de Galio , Proyectos Piloto , Masculino , Marcaje Isotópico , Neoplasias/diagnóstico por imagen , Persona de Mediana Edad , Radiofármacos/farmacocinética , Radiofármacos/químicaRESUMEN
This study aimed to investigate the effects of G1-activated G protein-coupled estrogen receptor 1 (GPER1) on neurological impairments and neuroinflammation in traumatic brain injury (TBI) mice. The controlled cortical impingement (CCI) method was used to establish the TBI model. The mice were subjected to ovariectomy (OVX) for two weeks prior to modeling. GPER1 agonist G1 was administered by intracerebroventricular injection. Brain tissue water content was detected by wet/dry method, and blood-brain barrier damage was detected by Evans blue extravasation. The neurological impairments in mice were evaluated by open field test, Y-maze test, nest-building test, object location memory test and novel object recognition test. Ionized calcium-binding adapter molecule 1 (Iba1) staining was used to indicate the activation of microglia. Expression of M1/M2-type microglia markers and inflammatory factors were evaluated by ELISA and qRT-PCR. The G1 administration significantly reduced cerebral edema and Evans blue extravasation at injury ipsilateral cortex and basal ganglia in TBI mice. Activation of GPER1 by G1 improved the anxiety behavior and the cognitive dysfunction of mice induced by TBI. G1 administration significantly decreased Iba1-positive staining cells and the mRNA levels of CD86, macrophage cationic peptide 1 (Mcp-1), nitric oxide synthase 2 (Nos2), interleukin 1 beta (IL-1ß), and macrophage inflammatory protein-2 (MIP-2), while increased the mRNA levels of interleukin 10 (IL-10), arginase1 (Arg-1) and CD206. Activation of GPER1 through G1 administration has the potential to ameliorate cognitive dysfunction induced by TBI in mice. It may also inhibit the activation of M1 microglia in cortical tissue resulting from TBI, while promoting the activation of M2 microglia and contributing to the regulation of inflammatory responses.
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Lesiones Traumáticas del Encéfalo , Microglía , Receptores Acoplados a Proteínas G , Animales , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Receptores Acoplados a Proteínas G/metabolismo , Ratones , Femenino , Microglía/metabolismo , Microglía/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Barrera Hematoencefálica/efectos de los fármacos , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Ratones Endogámicos C57BL , Enfermedades del Sistema Nervioso/etiología , Edema Encefálico/metabolismo , Edema Encefálico/etiologíaRESUMEN
In the swine industry, meat quality, color, and texture are influenced by the excessive differentiation of fat cells. miRNAs have emerged as integral regulators of adipose development. This study delves into the influence of miR-10a-5b on the proliferation and differentiation of pig preadipocytes. Our findings reveal that miR-10a-5b is prevalent across various tissues. It hinders preadipocyte proliferation, amplifies the expression of adipogenic genes, promotes lipid accumulation, and, as a result, advances preadipocyte differentiation. We predict that KLF11 is the target gene of miRNA. A dual-fluorescence reporter assay was conducted to validate the binding sites of miR-10a-5b on the 3'UTR of the KLF11 mRNA. Results showed that miR-10a-5b targeted KLF11 3'UTR and reduced the fluorescence activity of the dual-fluorescent reporter vector. Our research also indicates that miR-10a-5b targets and downregulates the expression of both mRNA and the protein levels of KLF11. During the differentiation of the preadipocytes, KLF11 inhibited adipose differentiation and was able to suppress the promotion of adipose differentiation by miR-10a-5b. This underscores miR-10a-5b's potential as a significant regulator of preadipocyte behavior by modulating KLF11 expression, offering insights into the role of functional miRNAs in fat deposition.
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Rationale: Peptide receptor radionuclide therapy (PRRT) for the treatment of neuroendocrine tumors (NETs) has been explored for more than two decades, but there are only limited data on the treatment of NETs of unknown primary site (CUP-NETs). This study aimed to analyze the long-term outcome, efficacy, and safety of PRRT in patients with CUP-NETs. Methods: Patients with pathologically confirmed metastatic CUP-NET who received lutetium-177 (177Lu) and/or yttrium-90 (90Y) labeled somatostatin analogs between March 2001 and March 2019 were retrospectively reviewed; those patients were referred as cCUP-NETs (clinical CUP-NETs). Eighty-one patients had unknown primary tumors even after [68Ga]Ga-SSTR and [18F]FDG PET/CT and were classified as pCUP-NETs (PET CUP-NETs). Treatment response was assessed according to RECIST 1.1 and PERCIST. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier analysis, and adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Results: A total of 575 PRRT cycles were administered to 156 patients (76 men and 80 women) evaluable for analysis: these patients were monitored for a median period of 92.3 mo (range, 4.0-169.1 mo). The disease control rate was 41.4% (43.4%) by RECIST and 40.2% (40.8%) by PERCIST in cCUP-NENs (pCUP-NETs). The objective response rate (ORR) with PRRT was 29.4% and 32.2% in cCUP-NENs and pCUP-NETs, respectively. The median PFS and OS for the entire cohort were 17.4 mo (95% confidence interval [95% CI], 11.4-23.4) and 67.4 mo (95% CI, 47.2-87.2) for all patients, respectively. The median OS for G3 tumors was significantly lower (15 mo) than for patients with G1 NET (85.5 mo), G2 (71.7 mo), and for patients with unknown grade (63.3 mo) NETs (P = 0.186, HR: 10.6, 95% CI: 3.87, 28.97, P = 0.09). PRRT was well tolerated by all patients. During treatment and long-term follow-up, CTCAE grade 3 and grade 4 thrombocytopenia and leukocytopenia were observed in only 3 patients (1.9%); there was no evidence of renal or hepatic toxicity. Conclusion: In a large cohort of patients with advanced CUP-NETs treated with PRRT in a real-world scenario and followed up to 14 years after the commencement, PRRT has demonstrated favorable and clinically significant efficacy and survival with minimal and acceptable side effects. Our results indicate that PRRT is a well-tolerated and effective treatment option for patients with metastatic CUP-NETs expressing somatostatin receptors.
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Neoplasias Primarias Desconocidas , Tumores Neuroendocrinos , Compuestos Organometálicos , Masculino , Humanos , Femenino , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias Primarias Desconocidas/radioterapia , Neoplasias Primarias Desconocidas/inducido químicamente , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Estudios Retrospectivos , Tumores Neuroendocrinos/radioterapia , Radioisótopos/uso terapéutico , Receptores de Somatostatina , Octreótido , Compuestos Organometálicos/uso terapéuticoRESUMEN
PURPOSE: This translational study aimed to determine the maximum tolerated dose (MTD), safety, dosimetry, and therapeutic efficacy of 177Lu-PSMA-EB-01 (denoted as [177Lu]Lu-LNC1003) in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: A total of 13 patients with mCRPC were recruited in this study. A standard 3 + 3 dose escalation protocol was performed. The following dose levels were ultimately evaluated: 1.11, 1.85, and 2.59 GBq/cycle. Patients received [177Lu]Lu-LNC1003 therapy for up to two cycles at a 6-week interval. RESULTS: Patients received fractionated doses of [177Lu]Lu-LNC1003 ranging from 1.11 to 2.59 GBq per cycle. Myelosuppression was dose-limiting at 2.59 GBq, and 1.85 GBq was determined to be the MTD. The total-body effective dose for 177Lu-LNC1003 was 0.35 ± 0.05 mSv/MBq. The salivary glands were found to receive the highest estimated radiation dose, which was calculated to be 3.61 ± 2.83 mSv/MBq. The effective doses of kidneys and red bone marrow were 1.88 ± 0.35 and 0.22 ± 0.04 mSv/MBq, respectively. The tumor mean absorbed doses for bone and lymph node metastases were 8.52 and 9.51 mSv/MBq. Following the first treatment cycle, PSA decline was observed in 1 (33.3%), 4 (66.7%), and 2 (50.0%) patients at dose levels 1 (1.11 GBq), 2 (1.85 GBq), and 3 (2.59 GBq), respectively. Compared with the baseline serum PSA value, 1 (33.3%) at dose level 1 and 4 (66.6%) patients at dose level 2, presented a PSA decline after the second treatment cycle. CONCLUSION: This phase 1 trial revealed that the MTD of [177Lu]Lu-LNC1003 is 1.85 GBq. The treatment with multiple cycles at the dose of 1.11 GBq /cycle and 1.85 GBq /cycle was well tolerated. [177Lu]Lu-LNC1003 has higher tumor effective doses in bone and lymph nodes metastases while the absorbed dose in the red bone marrow should be closely monitored in future treatment studies with higher doses and multiple cycles. The frequency of administration also needs to be further explored to assess the efficacy and side effects of [177Lu]Lu-LNC1003 treatment. TRIAL REGISTRATION: 177Lu-PSMA-EB-01 in patients with metastatic castration-resistant prostate cancer (NCT05613738, Registered 14 November 2022). URL of registry https://classic. CLINICALTRIALS: gov/ct2/show/NCT05613738.
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Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Antígeno Prostático Específico , Dosis Máxima Tolerada , Dipéptidos/uso terapéutico , Radiofármacos/uso terapéutico , Metástasis Linfática , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Lutecio/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: The authors aimed to explore the clinical outcomes and risk factors related to recurrence of and survival from solitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs) that were reclassified according to the 2021 WHO classification of central nervous system (CNS) tumors. METHODS: The authors retrospectively collected and analyzed the clinical and pathological data of SFTs and HPCs recorded from January 2007 to December 2021. Two neuropathologists reassessed pathological slides and regraded specimens on the basis of the 2021 WHO classification. The prognostic factors related to progression-free survival (PFS) and overall survival (OS) were statistically assessed with univariate and multivariate Cox regression analyses. RESULTS: A total of 146 patients (74 men and 72 women, mean ± SD [range] age 46.1 ± 14.3 [3-78] years) were reviewed, and 86, 35, and 25 patients were reclassified as having grade 1, 2, and 3 SFTs on the basis of the 2021 WHO classification, respectively. The median PFS and OS of the patients with WHO grade 1 SFT were 105 months and 199 months after initial diagnosis; for patients with WHO grade 2 SFT, 77 months and 145 months; and for patients with WHO grade 3 SFT, 44 months and 112 months, respectively. Of the entire cohort, 61 patients experienced local recurrence and 31 died, of whom 27 (87.1%) died of SFT and relevant complications. Ten patients had extracranial metastasis. In multivariate Cox regression analysis, subtotal resection (STR) (HR 4.648, 95% CI 2.601-8.304, p < 0.001), tumor located in the parasagittal or parafalx region (HR 2.105, 95% CI 1.099-4.033, p = 0.025), tumor in the vertebrae (HR 3.352, 95% CI 1.228-9.148, p = 0.018), WHO grade 2 SFT (HR 2.579, 95% CI 1.343-4.953, p = 0.004), and WHO grade 3 SFT (HR 5.814, 95% CI 2.887-11.712, p < 0.001) were significantly associated with shortened PFS, whereas STR (HR 3.217, 95% CI 1.435-7.210, p = 0.005) and WHO grade 3 SFT (HR 3.433, 95% CI 1.324-8.901, p = 0.011) were significantly associated with shortened OS. In univariate analyses, patients who received adjuvant radiotherapy (RT) after STR had longer PFS than patients who did not receive RT. CONCLUSIONS: The 2021 WHO classification of CNS tumors better predicted malignancy with different pathological grades, and in particular WHO grade 3 SFT had worse prognosis. Gross-total resection (GTR) can significantly prolong PFS and OS and should serve as the most important treatment method. Adjuvant RT was helpful for patients who underwent STR but not for patients who underwent GTR.
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Neoplasias del Sistema Nervioso Central , Hemangiopericitoma , Síndrome de Trombocitopenia Febril Grave , Tumores Fibrosos Solitarios , Masculino , Humanos , Femenino , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Hemangiopericitoma/cirugía , Hemangiopericitoma/patología , Tumores Fibrosos Solitarios/cirugía , Tumores Fibrosos Solitarios/patología , Pronóstico , Neoplasias del Sistema Nervioso Central/cirugía , Sistema Nervioso Central/patología , Factores de Riesgo , Organización Mundial de la Salud , Recurrencia Local de Neoplasia/epidemiologíaRESUMEN
With the inherent antitumor function and unique "off-the-shelf" potential, genetically engineered human natural killer (NK) cells with chimeric antigen receptors (CARs) bear great promise for the treatment of multiple hematological malignancies and solid tumors. Current methods of producing large-scale CAR-NK cells mainly rely on mRNA transfection and viral vector transduction. However, mRNA CAR-NK cells were not stable in CAR expression while viral vector transduction mostly ended up with low efficiency. In this chapter, we described an optimized protocol to generate CAR-NK cells by using the piggyBac transposon system via electroporation and to further expand these engineered CAR-NK cells in a large scale together with artificial antigen-presenting feeder cells. This method can stably engineer human primary NK cells with high efficiency and supply sufficient scale of engineered CAR-NK cells for the future possible clinical applications.
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Neoplasias , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Células Asesinas Naturales , Neoplasias/patología , Vectores Genéticos/genética , ARN Mensajero/metabolismo , Inmunoterapia Adoptiva/métodosRESUMEN
PURPOSE: Fibroblast activation protein (FAP) is a promising target for tumor treatment. In this study, we aimed to investigate the safety and efficacy of the albumin binder-conjugated FAP-targeted radiopharmaceutical, 177Lu-EB-FAPI (177Lu-LNC1004), in patients with metastatic radioiodine-refractory thyroid cancer (mRAIR-TC). PATIENTS AND METHODS: This open-label, non-randomized, first-in-human, dose-escalation, investigator-initiated trial had a 3+3 design and involved a 6-week 177Lu-LNC1004 treatment cycle in patients with mRAIR-TC at 2.22 GBq initially, with subsequent cohorts receiving an incremental 50% dose increase until dose-limiting toxicity (DLT) was observed. RESULTS: 177Lu-LNC1004 administration was well tolerated, with no life-threatening adverse events observed. No patients experienced DLT in Group A (2.22 GBq/cycle). One patient experienced grade 4 thrombocytopenia in Group B (3.33 GBq/cycle); hence, another three patients were enrolled, none of whom experienced DLT. Two patients experienced grade 3 and 4 hematotoxicity in Group C (4.99 GBq/cycle). The mean whole-body effective dose was 0.17 ± 0.04 mSv/MBq. Intense 177Lu-LNC1004 uptake and prolonged tumor retention resulted in high mean absorbed tumor doses (8.50 ± 12.36 Gy/GBq). The mean effective half-lives for the whole-body and tumor lesions were 90.20 ± 7.68 and 92.46 ± 9.66 hours, respectively. According to RECIST, partial response, stable disease, and progressive disease were observed in 3 (25%), 7 (58%), and 2 (17%) patients, respectively. The objective response and disease control rates were 25% and 83%, respectively. CONCLUSIONS: FAP-targeted radioligand therapy with 177Lu-LNC1004 at 3.33 GBq/cycle was well tolerated in patients with advanced mRAIR-TC, with high radiation dose delivery to the tumor lesions, encouraging therapeutic efficacy, and acceptable side effects.
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Radioisótopos de Yodo , Neoplasias de la Tiroides , Humanos , Masculino , Radioisótopos de Yodo/uso terapéutico , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/tratamiento farmacológico , Radiofármacos/efectos adversos , Antígeno Prostático Específico , FibroblastosRESUMEN
Intracranial chondrosarcoma is a rare tumor with limited reports. We reviewed the clinical outcomes, imaging findings, and pathological characteristics at three centers to improve the diagnosis and treatment of intracranial chondrosarcoma. We retrospectively analyzed 26 patients with intracranial chondrosarcoma who had undergone surgical treatment at Tangdu Hospital of Air Force Military Medical University, Mianyang Central Hospital, and Nanchong Central Hospital from January 2010 to July 2022. Clinical manifestations, imaging features, surgical treatment, prognosis, and overall survival (OS) were analyzed. All 26 chondrosarcomas were located at the skull base. Gross total resection (GTR), subtotal resection (STR), and partial resection (PR) were performed in 14, 10, and 2 cases, respectively. Four cases underwent endoscopic transnasal surgery, while the remaining cases underwent craniotomy. The clinical symptoms were evaluated 1 week after surgery, and 15 cases were relieved to varying degrees. Postoperative complications included pulmonary infection, subcutaneous hydrops, dysphagia and choking, facial numbness, abducens paralysis, and intracranial infection (ICI). Fifteen cases received postoperative adjuvant radiotherapy. Seven cases showed recurrence: two with PR, four with STR, and one with GTR. Six cases received reoperation or radiotherapy after tumor progression, and one untreated patient died 5 months after tumor recurrence. The extent of tumor resection (HR 21.74, 95% CI 1.25-376.6, P = 0.03) and pathological grading (HR 131.99, 95% CI 4.05-4300.5, P = 0.006) were associated with improved OS. We presented our experience in the treatment of intracranial chondrosarcoma at three centers in the past 12 years. Intracranial chondrosarcoma lacked typical imaging features and are difficult to differentiate from other skull base lesions. Maximum extent of tumor resection with minimal injury to neurological function remains the most important treatment strategy. The extent of surgical resection and pathological grading were found to be predictors for OS.
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Neoplasias Óseas , Condrosarcoma , Humanos , Estudios Multicéntricos como Asunto , Recurrencia Local de Neoplasia , Reoperación , Estudios RetrospectivosRESUMEN
Background: Glioma is the most common primary brain tumor. Traditional treatments for glioma include surgical resection, radiotherapy, chemotherapy, and bevacizumab therapy, but their efficacies are limited. Immunotherapy provides a new direction for glioma treatment. This study aimed to summarize the knowledge structure and research hotspots of glioma immunotherapy through a bibliometric analysis. Method: Publications pertaining to glioma immunotherapy published during the period from 1st January 1990 to 27th March 2023 were downloaded from the Web of Science Core Collection (WoSCC). Bibliometric analysis and visualization were performed using the CiteSpace, VOSviewer, Online Analysis Platform of Literature Metrology, and R software. The hotspots and prospects of glioma immunotherapy research were illustrated via analyzing the countries, institutions, journals, authors, citations and keywords of eligible publications. Results: A total of 1,929 publications pertaining to glioma immunotherapy in 502 journals were identified as of 27th March 2023, involving 9,505 authors from 1,988 institutions in 62 countries. Among them were 1,285 articles and 644 reviews. Most of publications were produced by the United States. JOURNAL OF NEURO-ONCOLOGY published the majority of publications pertaining to glioma immunotherapy. Among the authors, Lim M contributed the largest number of publications. Through analyzing keyword bursts and co-cited references, immune-checkpoint inhibitors (ICIs) were identified as the research focus and hotspot. Conclusion: Using a bibliometric analysis, this study provided the knowledge structure and research hotspots in glioma immunotherapy research during the past 33 years, with ICIs staying in the current and future hotspot. Our findings may direct the research of glioma immunotherapy in the future.
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OBJECTIVES: This head-to-head comparison study was designed to investigate the radiotracer uptake and clinical feasibility of using 68Ga-LNC1007, to detect the primary and metastatic lesions in patients with various types of cancer, and to compare the results with those of 2-18F-FDG PET/CT and 68Ga-FAPI-02 PET/CT. PATIENTS AND METHODS: Sixty-one patients with 10 different kinds of cancers were enrolled in this study. Among them, 50 patients underwent paired 68Ga-LNC1007 and 2-18F-FDG PET/CT, and the other 11 patients underwent paired 68Ga-LNC1007 and 68Ga-FAPI-02 PET/CT. The final diagnosis was based on histopathological results and diagnostic radiology. Immunohistochemistry for FAP and integrin αvß3 was performed in 24 primary tumors. RESULTS: 68Ga-LNC1007 PET/CT detected all 55 primary tumors, whereas 2-18F-FDG PET/CT was visually positive for 45 primary tumors (P = 0.002). Furthermore, subgroup analysis showed that 68Ga-LNC1007 PET/CT was superior to 2-18F-FDG PET/CT in diagnosing renal cell carcinomas and hepatocellular carcinomas. For metastatic tumors, 68Ga-LNC1007 PET/CT revealed more PET-positive lesions and higher SUVmax for skeletal metastases and peritoneal metastases compared with 2-18F-FDG. The SUVmax and tumor-to-background ratio of primary tumors on 68Ga-LNC1007 PET/CT were much higher than those on 68Ga-FAPI-02 PET/CT, the same was also observed for metastatic tumors. Immunohistochemical results showed that the SUVmean quantified from 68Ga-LNC1007 PET was correlated with FAP expression level (r = 0.564, P = 0.005). CONCLUSIONS: 68Ga-LNC1007 is a promising new diagnostic PET tracer for imaging of various kinds of malignant lesions. It may be a better alternative to 2-18F-FDG for diagnosing renal cell carcinoma, hepatocellular carcinoma, skeletal metastases, and peritoneal metastases.