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Glioblastoma is the most common malignant brain tumor in adults, the survival rate of which has not significantly improved over the past three decades. Therefore, there is an urgent need to develop novel treatment modalities. We previously reported that G1 to S phase transition 1 (GSPT1) depletion induces delayed cell cycle in primary astrocytes. Herein, we examined the potential of GSPT1 as a novel target for glioblastoma therapy. CC-885, a cereblon modulator that degrades GSPT1 by bridging GSPT1 to the CRL4 E3 ubiquitin ligase complex, was administered to nude mice with transplanted brain tumors of U87 glioblastoma cells. The survival period was significantly longer in CC-885 treated mice than in control mice. Furthermore, we generated GSPT1-knockout (KO) U87 cells and GSPT1-KO U87 cells with stable overexpression of FLAG-tagged GSPT1 (Rescued GSPT1-KO). Mice with transplanted GSPT1-KO U87 cells and Rescued GSPT1-KO U87 cells showed significantly longer and similar survival periods, respectively, as those with wild-type (WT) U87 cells. GSPT1-KO U87 cells showed enhanced apoptosis, detected by cleaved PARP1, compared to WT U87 cells. Brain tumors with transplantation of GSPT1-KO U87 cells also showed enhanced apoptosis compared to those with transplantation of WT and Rescued GSPT1-KO U87 cells. GSPT1 expression was confirmed in patients with glioblastoma. However, the clinical study using 87 glioblastoma samples showed that GSPT1 mRNA levels were not associated with overall survival. Taken together, we propose that GSPT1 is an essential protein for glioblastoma growth, but not its malignant characteristics, and that GSPT1 is a potential target for developing glioblastoma therapeutics.
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Neoplasias Encefálicas , Glioblastoma , Camundongos Nus , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Animais , Humanos , Linhagem Celular Tumoral , Camundongos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Apoptose , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
[This corrects the article DOI: 10.32604/or.2023.044085.].
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BACKGROUND: Soft tissue sarcoma (STS) has various histological types and is rare, making it difficult to evaluate the malignancy of each histological type. Thus, comprehensive histological grading is most important in the pathological examination of STS. The Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system is most commonly used in daily pathological analysis of STS. Among the FNCLCC grading system parameters, mitotic count is a key morphological parameter reflecting the proliferative activity of tumor cells, although its reproducibility may be lacking. Here, we compared the prognostic utility of the conventional and modified FNCLCC grading systems in JCOG1306. METHODS: We analyzed 140 patients with non-small round cell sarcoma. We performed Ki-67 immunostaining using open biopsy specimens before preoperative chemotherapy in all patients. We assessed histological grade in individual cases by conventional FNCLCC grading (tumor differentiation, mitotic count, and necrosis) and modified FNCLCC grading using the Ki-67 labeling index instead of mitotic count. We conducted univariable and multivariable Cox regression analyses to investigate the influence of grade on overall survival. RESULTS: In univariable analysis, prognosis was worse for patients with conventional FNCLCC Grade 3 tumors compared with Grade 1 or 2 tumors (hazard ratio [HR] 4.21, 95% confidence interval [CI] 1.47-12.05, P = 0.008). Moreover, prognosis was worse in patients with modified FNCLCC Grade 3 tumors compared with Grade 1 or 2 tumors (HR 4.90, 95% CI 1.64-14.65, P = 0.004). In multivariable analysis including both conventional and modified FNCLCC grading, the modified grading more strongly affected overall survival (HR 6.70, 95% CI 1.58-28.40, P = 0.010). CONCLUSIONS: The modified FNCLCC grading system was superior to the conventional system in predicting the prognosis of patients with non-small round cell sarcoma according to this supplementary analysis of data from the randomized controlled trial JCOG1306.
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Antígeno Ki-67 , Gradação de Tumores , Humanos , Antígeno Ki-67/análise , Antígeno Ki-67/metabolismo , Feminino , Masculino , Prognóstico , Pessoa de Meia-Idade , Idoso , Adulto , Sarcoma/patologia , Sarcoma/mortalidade , Sarcoma/metabolismoRESUMO
An important factor in the emergence and progression of osteosarcoma (OS) is the dysregulated expression of microRNAs (miRNAs). Transcription factor 7-like 1 (TCF7L1), a member of the T cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor family, interacts with the Wnt signaling pathway regulator ß-catenin and acts as a DNA-specific binding protein. This study sought to elucidate the impact of the interaction between miR-329-3p and TCF7L1 on the growth and apoptosis of OS and analyze the regulatory expression relationship between miRNA and mRNA in osteosarcoma cells using a variety of approaches. MiR329-3p was significantly downregulated, while TCF7L1 was considerably up-regulated in all examined OS cell lines. Additionally, a clinical comparison study was performed using the TCGA database. Subsequently, the regulatory relationship between miR-329-3p and TCF7L1 on the proliferation and apoptosis of OS cells was verified through in vitro and in vivo experiments. When miR-329-3p was transfected into the OS cell line, the expression of TCF7L1 decreased, the proliferation of OS cells was inhibited, the cytoskeleton disintegrated, and the nucleus condensed to form apoptotic bodies. The expression of proteins that indicate apoptosis increased simultaneously. The cell cycle was arrested in the G0/G1 phase, and the G1/S transition was blocked. The introduction of miR-329-3p also inhibited downstream Cyclin D1 of the Wnt pathway. Xenograft experiments indicated that the overexpression of miR-329-3p significantly inhibited the growth of OS xenografts in nude mice, and the expression of TCF7L1 and c-Myc in tumor tissues decreased. MiR-329-3p was significantly reduced in OS cells and played a suppressive role in tumorigenesis and proliferation by targeting TCF7L1 both in vitro and in vivo. Osteosarcoma cell cycle arrest and pathway inhibition were observed upon the regulation of TCF7L1 by miR-329-3p. Summarizing these results, it can be inferred that miR-329-3p exerts anticancer effects in osteosarcoma by inhibiting TCF7L1.
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Neoplasias Ósseas , MicroRNAs , Osteossarcoma , Proteína 1 Semelhante ao Fator 7 de Transcrição , Via de Sinalização Wnt , Animais , Humanos , Camundongos , beta Catenina/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Osteossarcoma/patologia , Via de Sinalização Wnt/genética , Proteína 1 Semelhante ao Fator 7 de Transcrição/genéticaRESUMO
BACKGROUND: Malignant femoral soft tissue tumors are occasionally resected together with the femoral nerves, but this can cause loss of knee extensor muscle activity. To the best of our knowledge, no previous reports have detailed the gait analysis of such cases in combination with electromyography. Herein, we report the gait analysis of a patient who underwent left groin synovial sarcoma and left femoral nerve resection 12 years ago. CASE PRESENTATION: We analyzed the gait of a 38-year-old man who was able to walk unaided after the resection of a synovial sarcoma in the left groin together with the ipsilateral femoral nerve. The muscle activities of the affected medial (MH) and lateral hamstrings (LH), and lateral heads of the gastrocnemius (GL) were increased during 50-75% of the stance phase. The hip flexion angle of the affected limb was smaller, and the ankle plantar flexion angle of the affected limb was larger than that of the non-affected limb. This means that in the affected limb, the hip and ankle angles were adjusted to prevent knee collapse, and the MH, LH, and GL muscles contributed in the mid- and late-stance phases. Moreover, we found that the hamstring and gastrocnemius of the affected limb worked together to keep the ipsilateral knee extended in the mid-stance phase and slightly flexed in the late-stance phase. CONCLUSIONS: Patients capable of walking after femoral nerve resection may control their hamstrings and gastrocnemius muscles collaboratively to prevent ipsilateral knee collapse in the mid- and late-stance phases.
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Sarcoma Sinovial , Sarcoma , Masculino , Humanos , Adulto , Nervo Femoral , Análise da Marcha , Marcha/fisiologia , Caminhada/fisiologia , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/cirurgia , Articulação do Joelho/fisiologia , Músculo Esquelético/cirurgia , Músculo Esquelético/fisiologia , Sarcoma/diagnóstico por imagem , Sarcoma/cirurgia , Fenômenos BiomecânicosRESUMO
BACKGROUND: Exoscopy in neurosurgery offers various advantages, including increased freedom of the viewing axis while the surgeon maintains a comfortable upright position. However, the optimal monitor positioning to avoid interference with surgical manipulation remains unresolved. Herein, the authors describe two cases in which a three-dimensional head-mounted display (3D-HMD) was introduced into a transcranial neurosurgical procedure using an exoscope. OBSERVATIONS: Case 1 was a 50-year-old man who presented with recurrent epistaxis and was diagnosed with an olfactory neuroblastoma that extended from the nasal cavity to the anterior cranial base and infiltrated the right anterior cranial fossa. Case 2 was a 65-year-old man who presented with epistaxis and was diagnosed with a left-sided olfactory neuroblastoma. In both cases, en bloc tumor resection was successfully performed via a simultaneous exoscopic transcranial approach using a 3D-HMD and an endoscopic endonasal approach, eliminating the need to watch a large monitor beside the patient. LESSONS: This is the first report of using a 3D-HMD in transcranial surgery. The 3D-HMD effectively addressed issues with the field of vision and concentration while preserving the effectiveness of traditional microscopic and exoscopic procedures when observed on a 3D monitor. Combining the 3D-HMD with an exoscope holds the potential to become a next-generation surgical approach.
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RATIONALE: Precision medicine and tumor-agnostic treatment strategies have recently been promoted for clinical use. One of the most successful treatments in patients with neurotrophic tyrosine receptor kinase (NTRK) fusion-positive tumors is targeting the tropomyosin receptor kinase (TRK) with an inhibitor. The TRK inhibitors, larotrectinib, and entrectinib, have been approved in many countries. Nevertheless, the most effective administration regimen for these TRK inhibitors is uncertain. To date, no reports have shown the efficacy of sequential treatment with larotrectinib and entrectinib in patients with NTRK fusion-positive tumors. In this report, we present a patient with NTRK fusion-positive sarcoma arising from the anterior mediastinum, with tumor progression after 4 months of entrectinib use. The patient took larotrectinib subsequently and maintained disease control for more than 21 months. PATIENT CONCERNS: A 48-year-old female visited a physician because she experienced difficulty in breathing and chest and back pain with no obvious cause 2 months ago. Computed tomography (CT)-guided biopsy was performed at a district general hospital, and histopathological examination revealed a small round cell tumor. She was referred to our hospital, and a second CT-guided biopsy was performed to confirm the pathological diagnosis. Considering the results of the histopathological examination, Ewing sarcoma was suspected, but a specific fusion gene was not detected due to poor quality specimens. DIAGNOSES: After 3 regimens of cytotoxic chemotherapy, biopsy was repeated, and specimens were analyzed using next-generation sequencing. The PHF20-NTRK1 fusion gene was detected, and the tumor was finally diagnosed as an NTRK fusion-positive sarcoma. INTERVENTIONS: She was administered the TRK inhibitor entrectinib, but the tumor started to grow after 4 months of medication, and she stopped taking entrectinib. After 1 cycle of cytotoxic chemotherapy, another TRK inhibitor, larotrectinib, was administered. OUTCOMES: Her stable disease was maintained for more than 21 months. Here, we have shown that sequential administration of both drugs can be effective. LESSONS: In the treatment of NTRK fusion-positive tumors, there are cases in which 2 approved first-generation TRK inhibitors can be used sequentially.
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Antineoplásicos , Neoplasias , Sarcoma , Neoplasias de Tecidos Moles , Feminino , Humanos , Pessoa de Meia-Idade , Antineoplásicos/efeitos adversos , Benzamidas/uso terapêutico , Indazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/uso terapêutico , Receptor trkA/antagonistas & inibidores , Sarcoma/tratamento farmacológico , Sarcoma/genética , Sarcoma/patologia , Neoplasias de Tecidos Moles/tratamento farmacológico , /uso terapêuticoRESUMO
We elucidated the mechanism through which the reduced expression of miR-152 leads to the overexpression of its target cyclin-dependent kinase-5 activator 1 (CDK5R1) in Ewing's sarcoma (ES) cells and the role of this mechanism in the proliferation of ES cells. To explore possible oncogenic factors in ES, we conducted microarray-based investigation and profiled the changes in miRNA expression and their effects on downstream mRNAs in five ES cell lines and human mesenchymal stem cells (hMSCs). miR-152 was significantly downregulated, while cyclin-dependent kinase-5 activator 1 (CDK5R1) expression was significantly upregulated in all tested ES cells as compared to hMSCs. The overexpression of CDK5R1 led to the activation of CDK5, enabling the phosphorylation of retinoblastoma protein and persistent overexpression of CCNE. Moreover, miR-152 suppressed cell proliferation via cell cycle retardation, and its upregulation reduced tumor size and CCNE expression in tumor tissues. The overexpression of cyclin E (CCNE) has been detected in ES cells, but the detailed mechanisms have not been previously elucidated. These findings identify the miR152-CDK5R1 signaling axis as a critical mechanism for tumorigenesis that may serve as a new therapeutic target in Ewing's sarcoma. We believe that our results will aid in the development of effective treatment strategies for patients with ES.
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Neoplasias Ósseas , MicroRNAs , Tumores Neuroectodérmicos Primitivos Periféricos , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Proliferação de Células/genética , Fatores de Transcrição , Quinases Ciclina-Dependentes , Linhagem Celular Tumoral , Neoplasias Ósseas/patologiaRESUMO
Alveolar soft part sarcoma is a rare neoplasm of uncertain histogenesis that belongs to a newly defined category of ultra-rare sarcomas. The neoplasm is characterized by a specific chromosomal translocation, der (17) t(X; 17)(p11.2;q25), that results in ASPSCR1-TFE3 gene fusion. The natural history of alveolar soft part sarcoma describes indolent behaviour with slow progression in deep soft tissues of the extremities, trunk and head/neck in adolescents and young adults. A high rate of detection of distant metastasis at presentation has been reported, and the most common metastatic sites in decreasing order of frequency are the lung, bone and brain. Complete surgical resection remains the standard treatment strategy, whereas radiotherapy is indicated for patients with inadequate surgical margins or unresectable tumours. Although alveolar soft part sarcoma is refractory to conventional doxorubicin-based chemotherapy, monotherapy or combination therapy using tyrosine kinase inhibitors and immune checkpoint inhibitors have provided antitumor activity and emerged as new treatment strategies. This article provides an overview of the current understanding of this ultra-rare sarcoma and recent advancements in treatments according to the clinical stage of alveolar soft part sarcoma.
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Sarcoma Alveolar de Partes Moles , Neoplasias de Tecidos Moles , Adolescente , Adulto Jovem , Humanos , Sarcoma Alveolar de Partes Moles/genética , Sarcoma Alveolar de Partes Moles/terapia , Sarcoma Alveolar de Partes Moles/diagnóstico , Proteínas de Fusão Oncogênica/genética , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/genética , Translocação Genética , Terapia CombinadaRESUMO
Heat shock protein (HSP) 90 plays a crucial role in correcting the misfolded three-dimensional structure of proteins, assisting them in folding into proper conformations. HSP90 is critical in maintaining the normal functions of various proteins within cells, as essential factors for cellular homeostasis. Contrastingly, HSP90 simultaneously supports the maturation of cancer-related proteins, including mesenchymal epithelial transition factor (MET) within tumor cells. All osteosarcoma cell lines had elevated MET expression in the cDNA array in our possession. MET, a tyrosine kinase receptor, promotes proliferation and an anti-apoptotic state through the activation of the MET pathway constructed by HSP90. In this study, we treated osteosarcoma cells with an HSP90 inhibitor, 17-demethoxygeldanamycin hydrochloride (17-DMAG), and assessed the changes in the MET signaling pathway and also the antitumor effect of the drug. The cell cycle in osteosarcoma cells administered 17-DMAG was found to be halted at the G2/M phase. Additionally, treatment with 17-DMAG inhibited cell proliferation and induced apoptosis. Inhibition of tumor cell proliferation was also observed in an in vivo model system, mice that were treated with 17-DMAG. Based on the results of this study, we were able to confirm that 17-DMAG promotes inhibition of osteosarcoma cell proliferation and induction of apoptosis by inhibition of MET, a protein highly expressed in osteosarcoma cells. This approach may be useful for the establishment of a new treatment strategy for patients resistant to the standard treatment for osteosarcoma.
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Antineoplásicos , Neoplasias Ósseas , Osteossarcoma , Humanos , Animais , Camundongos , Benzoquinonas/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células , Apoptose , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Linhagem Celular Tumoral , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Proteínas de Choque Térmico HSP90RESUMO
Clear cell sarcoma (CCS) is a rare melanocytic soft tissue sarcoma with a high propensity for lymphatic metastasis and poor prognosis. It is characterized by the translocation of t (12;22), resulting in the rearrangement of the EWSR1 gene and overexpression of MET. Despite improvements in the diagnosis and treatment of soft tissue sarcomas, the management of CCSs remains challenging owing to their rarity, unique biological behaviour and limited understanding of their molecular pathogenesis. The standard treatment for localized CCSs is surgical excision with negative margins. However, there is an ongoing debate regarding the role of adjuvant chemotherapy, radiotherapy and lymphadenectomy in the management of this disease. CCSs are usually resistant to conventional chemotherapy. Targeted therapies, such as sunitinib and MET inhibitors, may provide promising results. Immunotherapy, particularly immune checkpoint inhibitors, is currently under investigation as a potential treatment option for CCSs. Further research is needed to better understand the biology of CCSs and develop effective therapeutic strategies. The purpose of this review is to provide a comprehensive overview of current knowledge and advances in the diagnosis and treatment of CCSs.
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Sarcoma de Células Claras , Neoplasias de Tecidos Moles , Humanos , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/terapia , Sarcoma de Células Claras/patologia , Translocação Genética , Metástase Linfática , Excisão de Linfonodo , Neoplasias de Tecidos Moles/patologiaRESUMO
INTRODUCTION: Multidrug chemoimmunotherapy with rituximab, high-dose methotrexate, procarbazine and vincristine (R-MPV) is a standard therapy for younger patients with primary central nervous system lymphoma (PCNSL); however, prospective data regarding its use in elderly patients are lacking. This multi-institutional, non-randomised, phase II trial will assess the efficacy and safety of R-MPV and high-dose cytarabine (HD-AraC) for geriatric patients with newly diagnosed PCNSL. METHODS AND ANALYSIS: Forty-five elderly patients will be included. If R-MPV does not achieve complete response, the patients will undergo reduced-dose, whole-brain radiotherapy comprising 23.4 Gy/13 fractions, followed by local boost radiotherapy comprising 21.6 Gy/12 fractions. After achieving complete response using R-MPV with or without radiotherapy, the patients will undergo two courses of HD-AraC. All patients will undergo baseline geriatric 8 (G8) assessment before HD-AraC and after three, five and seven R-MPV courses. Patients with screening scores of ≥14 points that decrease to <14 points during subsequent treatment, or those with screening scores <14 points that decrease from the baseline during subsequent treatment are considered unfit for R-MPV/HD-AraC. The primary endpoint is overall survival, and the secondary endpoints are progression-free survival, treatment failure-free survival and frequency of adverse events. The results will guide a later phase III trial and provide information about the utility of a geriatric assessment for defining chemotherapy ineligibility. ETHICS AND DISSEMINATION: This study complies with the latest Declaration of Helsinki. Written informed consent will be obtained. All participants can quit the study without penalty or impact on treatment. The protocol for the study, statistical analysis plan and informed consent form have been approved by the Certified Review Board at Hiroshima University (CRB6180006) (approval number: CRB2018-0011). The study is ongoing within nine tertiary and two secondary hospitals in Japan. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION: jRCTs061180093.
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Neoplasias do Sistema Nervoso Central , Linfoma , Idoso , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Encéfalo/patologia , Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/patologia , Ensaios Clínicos Fase II como Assunto , Citarabina/uso terapêutico , Linfoma/terapia , Metotrexato/uso terapêutico , Estudos Multicêntricos como Assunto , Estudos Prospectivos , Rituximab , Resultado do Tratamento , VincristinaRESUMO
BACKGROUND: Soft tissue sarcomas (STS) are a rare type of malignancy comprising a variety of histological diagnoses. Chemotherapy constitutes the standard treatment for advanced STS. Doxorubicin-based regimens, which include the administration of doxorubicin alone or in combination with ifosfamide or dacarbazine, are widely accepted as first-line chemotherapy for advanced STS. Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD), which is the empirical standard therapy in Japan, are major candidates for second-line chemotherapy for advanced STS, although clear evidence of the superiority of any one regimen is lacking. The Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group (JCOG) conducts this trial to select the most promising regimen among trabectedin, eribulin, and pazopanib for comparison with GD as the test arm regimen in a future phase III trial of second-line treatment for patients with advanced STS. METHODS: The JCOG1802 study is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 intravenously, every 3 weeks), eribulin (1.4 mg/m2 intravenously, days 1 and 8, every 3 weeks), and pazopanib (800 mg orally, every day) in patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. The principal eligibility criteria are patients aged 16 years or above; unresectable and/or metastatic STS; exacerbation within 6 months prior to registration; histopathological diagnosis of STS other than Ewing sarcoma, embryonal/alveolar rhabdomyosarcoma, well-differentiated liposarcoma and myxoid liposarcoma; prior doxorubicin-based chemotherapy for STS, and Eastern Cooperative Oncology Group performance status 0 to 2. The primary endpoint is progression-free survival, and the secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. The total planned sample size to correctly select the most promising regimen with a probability of > 80% is 120. Thirty-seven institutions in Japan will participate at the start of this trial. DISCUSSION: This is the first randomized trial to evaluate trabectedin, eribulin, and pazopanib as second-line therapies for advanced STS. We endeavor to perform a subsequent phase III trial comparing the best regimen selected by this study (JCOG1802) with GD. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials ( jRCTs031190152 ) on December 5, 2019.
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Lipossarcoma Mixoide , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Adulto , Trabectedina/uso terapêutico , Japão , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Doxorrubicina/uso terapêutico , Gencitabina , Docetaxel/uso terapêutico , Oncologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
OBJECTIVE: Carotid stenosis can lead to both cognitive impairment (CI) and ischemic stroke. Although carotid revascularization surgery, which includes carotid endarterectomy (CEA) and carotid artery stenting (CAS), can prevent future strokes, its effect on cognitive function is controversial. In this study, the authors examined resting-state functional connectivity (FC) in carotid stenosis patients with CI undergoing revascularization surgery, with a particular focus on the default mode network (DMN). METHODS: Twenty-seven patients with carotid stenosis who were scheduled to undergo CEA or CAS between April 2016 and December 2020 were prospectively enrolled. A cognitive assessment, including the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and Japanese version of the Montreal Cognitive Assessment (MoCA), as well as resting-state functional MRI, was performed 1 week preoperatively and 3 months postoperatively. For FC analysis, a seed was placed in the region associated with the DMN. The patients were divided into two groups according to the preoperative MoCA score: a normal cognition (NC) group (MoCA score ≥ 26) and a CI group (MoCA score < 26). The difference in cognitive function and FC between the NC and CI groups was investigated first, and then the change in cognitive function and FC after carotid revascularization was investigated in the CI group. RESULTS: There were 11 and 16 patients in the NC and CI groups, respectively. The FC of the medial prefrontal cortex with the precuneus and that of the left lateral parietal cortex (LLP) with the right cerebellum were significantly lower in the CI group than in the NC group. In the CI group, significant improvements were found in MMSE (25.3 vs 26.8, p = 0.02), FAB (14.4 vs 15.6, p = 0.01), and MoCA scores (20.1 vs 23.9, p = 0.0001) after revascularization surgery. Significantly increased FC of the LLP with the right intracalcarine cortex, right lingual gyrus, and precuneus was observed after carotid revascularization. In addition, there was a significant positive correlation between the increased FC of the LLP with the precuneus and improvement in the MoCA score after carotid revascularization. CONCLUSIONS: These findings suggest that carotid revascularization, including CEA and CAS, might improve cognitive function based on brain FC in the DMN in carotid stenosis patients with CI.
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Estenose das Carótidas , Disfunção Cognitiva , Endarterectomia das Carótidas , Humanos , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/cirurgia , Projetos Piloto , Testes Neuropsicológicos , Stents , Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Cognição , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/cirurgia , Artérias CarótidasRESUMO
OBJECTIVE: Adult brainstem gliomas (BSGs) are rare tumors of the CNS that are poorly understood. Upregulation of the oncometabolite 2-hydroxyglutarate (2HG) in the tumor indicates the mutation of isocitrate dehydrogenase (IDH), which can be detected by magnetic resonance spectroscopy (MRS). Although histological examination is required for the definitive diagnosis of BSG, 2HG-optimized MRS (2HG-MRS) may be useful, considering the difficult nature of brainstem lesion biopsy. The aim of this study was to evaluate the utility of 2HG-MRS for diagnosing IDH-mutant adult BSG. METHODS: Patients with a radiographically confirmed brainstem tumor underwent 3T MRS. A single voxel was set in the lesion with reference to the T2 or fluid-attenuated inversion recovery image and analyzed according to the 2HG-tailored MRS protocol (point-resolved spectroscopic sequence; echo time 35 msec). All patients underwent intraoperative navigation-guided or CT-guided stereotactic biopsy for histopathological diagnosis. The status of IDH and H3K27M mutations was confirmed by immunohistochemistry and direct DNA sequencing. In addition, the authors examined the relationship between patients' 2HG concentrations and survival time. RESULTS: Ten patients (7 men, 3 women; median age 33.5 years) underwent 2HG-MRS and biopsy. Four patients had an H3K27M mutation and 4 had an IDH1 mutation (1 R132H canonical IDH mutation, 2 R132S and 1 R132G noncanonical IDH mutations). Two had neither H3K27M nor IDH mutations. The H3K27M and IDH mutations were mutually exclusive. Most tumors were located in the pons. There was no significant radiological difference between mutant H3K27M and IDH on a conventional MRI sequence. A 2HG concentration ≥ 1.8 mM on MRS demonstrated 100% (95% CI 28%-100%) sensitivity and 100% (95% CI 42%-100%) specificity for IDH-mutant BSG (p = 0.0048). The median overall survival was 10 months in IDH-wild-type BSG patients (n = 6) and could not be estimated in IDH-mutant BSG patients (n = 4) due to the small number of deaths (p = 0.008). CONCLUSIONS: 2HG-MRS demonstrated high sensitivity and specificity for the prediction of IDH-mutant BSG. In addition, 2HG-MRS may be useful for predicting the prognosis of adult BSG patients.
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Neoplasias Encefálicas , Neoplasias do Tronco Encefálico , Glioma , Masculino , Adulto , Humanos , Feminino , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Glioma/diagnóstico por imagem , Glioma/genética , Espectroscopia de Ressonância Magnética/métodos , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/genética , Biópsia Guiada por Imagem , Isocitrato Desidrogenase/genética , MutaçãoRESUMO
BACKGROUND: Among tandem occlusions, atherosclerotic cervical internal carotid artery occlusion (ACICAO) can be technically challenging and associated with its unique complications. We evaluated our experience with endovascular treatment (EVT) of ACICAO in the setting of acute ischemic stroke. METHODS: In total, 154 consecutive patients who underwent EVT for acute anterior circulation stroke at our institute were retrospectively reviewed. Patients with tandem ACICAO were analyzed in this study. Procedures, recanalization rates, complications, and prognoses were evaluated. RESULTS: Ten patients (6%) of all 154 patients had ACICAO. In nine (90%) of the 10 patients, cervical lesions were successfully crossed and intervened upon. Four patients underwent stenting and five underwent angioplasty alone, followed by intracranial procedure. Eight patients (80%) achieved successful recanalization following mechanical thrombectomy for intracranial occlusion. However, one patient had massive subarachnoid hemorrhage during the procedure and another patient developed massive intracranial hemorrhage after EVT, both after stenting. Four of the five patients who initially underwent angioplasty alone subsequently underwent staged endarterectomy or stenting for residual stenosis on or after the next day. The single patient in whom the cervical lesion could not be crossed and another with reocclusion after EVT underwent a rescue bypass procedure due to persistent ischemic symptoms. After 90 days, four patients (40%) were functionally independent (modified Rankin scale score 0-2). CONCLUSIONS: Our experience suggests that EVT for ACICAO is technically feasible; however, it involves the potential risk of several significant complications. To avoid serious hemorrhagic complications, cervical lesions may be better treated with angioplasty alone first.
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Doenças das Artérias Carótidas , Estenose das Carótidas , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/etiologia , AVC Isquêmico/terapia , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/terapia , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/complicações , Doenças das Artérias Carótidas/complicações , Trombectomia/efeitos adversos , Trombectomia/métodos , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/métodos , Stents/efeitos adversosRESUMO
Ror1 plays a crucial role in cancer progression by regulating cell proliferation and migration. Ror1 is expressed abundantly in various types of cancer cells and cancer stem-like cells. However, the molecular mechanisms regulating expression of Ror1 in these cells remain largely unknown. Ror1 and its putative ligand Wnt5a are expressed highly in malignant gliomas, especially in glioblastomas, and the extents of Ror1 expression are correlated positively with poorer prognosis in patients with gliomas. We show that Ror1 expression can be upregulated in glioblastoma cells under spheroid culture, but not adherent culture conditions. Notch and hypoxia signaling pathways have been shown to be activated in spheroid-forming glioblastoma stem-like cells (GSCs), and Ror1 expression in glioblastoma cells is indeed suppressed by inhibiting either Notch or hypoxia signaling. Meanwhile, either forced expression of the Notch intracellular domain (NICD) in or hypoxic culture of glioblastoma cells result in enhanced expression of Ror1 in the cells. Consistently, we show that both NICD and hypoxia-inducible factor 1 alpha bind to upstream regions within the Ror1 gene more efficiently in GSCs under spheroid culture conditions. Furthermore, we provide evidence indicating that binding of Wnt5a to Ror1, upregulated by Notch and hypoxia signaling pathways in GSCs, might promote their spheroid-forming ability. Collectively, these findings indicate for the first time that Notch and hypoxia signaling pathways can elicit a Wnt5a-Ror1 axis through transcriptional activation of Ror1 in glioblastoma cells, thereby promoting their stem cell-like property.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/metabolismo , Glioma/patologia , Transdução de Sinais , Hipóxia/patologia , Células-Tronco Neoplásicas/metabolismo , Linhagem Celular Tumoral , Neoplasias Encefálicas/patologia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismoRESUMO
Treatment of malignant tumors, such as rhabdomyosarcoma (RMS), can improve overall survival (OS). It is time-consuming and expensive for patients to obtain benefits from randomized controlled trials (RCTs) with OS as the primary end-point. Therefore, another surrogate end-point is necessary; however, there is no report on the surrogacy analysis of RMS. In this study, we performed a systematic review of RCTs, involving patients with newly diagnosed RMS, and 11 RCTs were identified. We performed a meta-analysis to assess the surrogacy of intermediate end-points for OS. The correlations between surrogate end-points and OS were investigated using Spearman's rank correlation coefficient (ρ). The coefficient of determination (R2) was employed to measure the strength of the association. A total of 5183 patients were randomly allocated to 34 treatment groups. A marginal correlation (R2 = 0.281, ρ = 0.445) between the hazard ratios (HRs) for event-free survival (EFS) and OS was observed. In patients with localized RMS, the EFS HR had a weaker correlation with OS HR in the sensitivity analysis than that in the primary analysis. Overall, the surrogacy of EFS for OS cannot be confirmed.
Assuntos
Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Rabdomiossarcoma/terapia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Intervalo Livre de Doença , Análise de SobrevidaRESUMO
There is an unmet need to develop effective and tolerable treatments for pediatric patients with malignant central nervous system tumors. This is especially essential for pediatric patients with aggressive brain tumors such as high-grade gliomas, which have a typical survival rate of under 2 years. Tumor Treating Fields (TTFields) are locoregional, noninvasive electric fields that produce an antimitotic effect on cancerous cells when applied to the skin via arrays. TTFields therapy (200 kHz) is currently approved in adult patients with newly diagnosed glioblastoma (GBM), with temozolomide, and recurrent GBM as monotherapy. Positive preclinical and clinical data have encouraged off-label use of TTFields therapy in pediatric patients with brain tumors, and this study aims to explore the safety of TTFields therapy in pediatric patients (0-18 years of age) based on data from an unsolicited post-marketing surveillance safety database. The real-world data reported here demonstrate that TTFields therapy has a favorable safety profile for pediatric patients with brain tumors, with no new safety signals observed. Findings from this study warrant further research into the efficacy of TTFields therapy, as well as its potential impact on the quality of life in pediatric patients.
RESUMO
Chromosome translocation (TL) is an important mode of genomic changes underlying human tumorigenesis, the detailed mechanisms of which are, however, still not well understood. The two major modalities of DNA double strand break repair, i.e. homologous recombination (HR) and non-homologous end-joining (NHEJ), have been hypothesized. In a typical TL+ human neoplasm, Ewing sarcoma, which is frequently associated with t(11;22) TL encoding the EWS-FLI1 fusion gene, NHEJ has been regarded as a model to explain the disease-specific TL. Using comprehensive microarray approaches, we observed that expression of the HR genes, particularly of RAD51, is upregulated in TL+ Ewing sarcoma cell lines, WE-68 and SK-N-MC, as in the other TL+ tumor cell lines and one defective in DNA mismatch repair (MMR). The upregulated RAD51 expression indeed lead to frequent focus formation, which may suggest an activation of the HR pathway in these cells. Furthermore, sister chromatid exchange was frequently observed in the TL+ and MMR-defective cells. Intriguingly, ionizing irradiation revealed that the decrease of 53BP1 foci was significantly retarded in the Ewing sarcoma cell lines, suggesting that the NHEJ pathway may be less active in the cells. These observations may support an HR involvement, at least in part, to explain TL in Ewing sarcoma.