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BACKGROUND: Neuroendocrine carcinoma of the bladder (NEC-bladder) is a rare disease with poor outcomes and variable treatment approaches. MATERIALS AND METHODS: Patients with localized NEC-bladder treated with surgery or radiation between 2001-2021 were retrospectively identified. Rates of pathologic complete response (pCR) and downstaging were evaluated following NAC in surgically-treated patients. Progression-free survival (PFS) and overall survival (OS) were analyzed with univariable (log-rank) and multivariable (MVA; Cox regression) methods. RESULTS: Sixty-five patients were identified having a median age of 73. The tumor histology distribution was small cell (64.6%) or urothelial with NE differentiation (35.4%). Most patients (69.2%) received NAC. Patients received local therapy by surgery (78.5%) or chemoradiation (21.5%). The majority (62.7%) of surgical patients had ≥ pT2 with 37.3% having nodal involvement (pN+). The pCR and downstaging rates were 21.6% and 35.1%, respectively. At a median follow-up of 60 months (m), the median PFS and OS were 16.4m and 25.9m, respectively. NAC improved PFS (p=0.04) and downstaging improved PFS (p=0.012) and OS (p<0.001). Patients receiving NAC with ypN0 vs. ypN+ had median OS of 69.9m vs 15.3m, respectively (p<0.001). MVA identified receipt of NAC and pN as predictors of PFS; pN was predictive of OS. No differences in PFS or OS were seen between histology of primary tumor. The brain metastasis rate was 10.8% with all patients having small cell histology. CONCLUSIONS: Optimized therapy in NEC-bladder includes NAC followed by local consolidation. Ascertainment of ypN0 is associated with long term survival, while pN+ remains associated with poor outcomes.
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BACKGROUND: Brain metastasis from prostate adenocarcinoma (PCa) is rare, often leading to death within a year. Its infrequent occurrence and atypical histopathologic features contribute to lower consideration in the differential diagnosis of tumor brain metastasis. This study aims to assess the clinical characteristics and distinctive histopathologic features of metastatic PCa in the brain for timely and enhanced diagnostic accuracy. DESIGN: A retrospective search spanning 20 years (2003-2022) was conducted on our archives and identified 21 cases diagnosed as "metastatic prostate adenocarcinoma (mPCa)" in brain biopsies and resections. All existing slides were thoroughly reviewed to evaluate the histopathology of the mPCa. RESULT: The mean age at presentation for brain metastasis was 70 years. Of 21 cases, 5 were dural-based lesions, 16 were true intraparenchymal metastases, including 2 sellar/suprasellar masses, 3 frontal, 3 temporal, 3 occipital, 1 cerebellum, and 4 involving multiple brain lobes. The average interval between initial diagnosis and brain metastasis was 90.75 months. Notably, brain metastasis was the initial presentation for one patient, while another patient, initially diagnosed with prognostic grade group (GG) 2 PCa in 1/12 cores, presented with isolated brain metastasis two years later. Architecturally, tumor cells were arranged in sheets or nests in most cases; however, four cases showed histologic cribriform patterns, and five displayed papillary architecture. Cytohistology varied from uniform monomorphic to highly pleomorphic cells with prominent nucleoli (8/19) and high mitotic activity. Interestingly, 1 case showed small round blue cell morphology, another had focal areas of rhabdoid and spindle cell differentiation, and 6 had cytoplasmic clearing. Almost half of the cases (47%) showed necrosis. CONCLUSION: mPCa to the brain can present with variable histomorphology. Therefore, consideration of mPCa in the differential diagnosis of metastatic brain lesions, even with non-suggestive imaging, is imperative in male patients with or without a history of primary disease. Accurate and prompt diagnosis is crucial, given the recent advancements in treatment that have improved survival rates.
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Adenocarcinoma , Neoplasias Encefálicas , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/patologia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/patologia , Idoso , Adenocarcinoma/secundário , Adenocarcinoma/patologia , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Diagnóstico DiferencialRESUMO
BACKGROUND: Lung cancer brain metastasis has a devastating prognosis, necessitating innovative treatment strategies. While chimeric antigen receptor (CAR) T-cell show promise in hematologic malignancies, their efficacy in solid tumors, including brain metastasis, is limited by the immunosuppressive tumor environment. The PD-L1/PD-1 pathway inhibits CAR T-cell activity in the tumor microenvironment, presenting a potential target to enhance therapeutic efficacy. This study aims to evaluate the impact of anti-PD-1 antibodies on CAR T-cell in treating lung cancer brain metastasis. METHODS: We utilized a murine immunocompetent, syngeneic orthotopic cerebral metastasis model for repetitive intracerebral two-photon laser scanning microscopy, enabling in vivo characterization of red fluorescent tumor cells and CAR T-cell at a single-cell level over time. Red fluorescent EpCAM-transduced Lewis lung carcinoma cells (EpCAM/tdtLL/2 cells) were implanted intracranially. Following the formation of brain metastasis, EpCAM-directed CAR T-cell were injected into adjacent brain tissue, and animals received either anti-PD-1 or an isotype control. RESULTS: Compared to controls receiving T-cell lacking a CAR, mice receiving EpCAM-directed CAR T-cell showed higher intratumoral CAR T-cell densities in the beginning after intraparenchymal injection. This finding was accompanied with reduced tumor growth and translated into a survival benefit. Additional anti-PD-1 treatment, however, did not affect intratumoral CAR T-cell persistence nor tumor growth and thereby did not provide an additional therapeutic effect. CONCLUSION: CAR T-cell therapy for brain malignancies appears promising. However, additional anti-PD-1 treatment did not enhance intratumoral CAR T-cell persistence or effector function, highlighting the need for novel strategies to improve CAR T-cell therapy in solid tumors.
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Neoplasias Encefálicas , Molécula de Adesão da Célula Epitelial , Imunoterapia Adotiva , Neoplasias Pulmonares , Receptor de Morte Celular Programada 1 , Receptores de Antígenos Quiméricos , Animais , Camundongos , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Imunoterapia Adotiva/métodos , Molécula de Adesão da Célula Epitelial/imunologia , Molécula de Adesão da Célula Epitelial/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/terapia , Carcinoma Pulmonar de Lewis/patologia , Feminino , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/imunologiaRESUMO
Brain metastasis, a serious complication of cancer, hinges on the initial survival, microenvironment adaptation, and outgrowth of disseminated cancer cells. To understand the early stages of brain colonization, we investigated two prevalent sources of cerebral relapse, triple-negative (TNBC) and HER2+ (HER2BC) breast cancers. Using mouse models and human tissue samples, we found that these tumor types colonize the brain, with a preference for distinctive tumor architectures, stromal interfaces, and autocrine programs. TNBC models tend to form perivascular sheaths with diffusive contact with astrocytes and microglia. In contrast, HER2BC models tend to form compact spheroids driven by autonomous tenascin C production, segregating stromal cells to the periphery. Single-cell transcriptomics of the tumor microenvironment revealed that these architectures evoke differential Alzheimer's disease-associated microglia (DAM) responses and engagement of the GAS6 receptor AXL. The spatial features of the two modes of brain colonization have relevance for leveraging the stroma to treat brain metastasis.
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BACKGROUND: Treatment of brain metastases (BMs) in non-small cell lung cancer (NSCLC) patients, especially those with non-sensitive genetic mutations, is hindered by limited drug delivery through the blood-brain barrier (BBB). This retrospective study explores the efficacy of systemic treatments during brain metastasis to radiotherapy evaluation window in improving patient survival. METHODS: In this retrospective cohort study, we evaluated 209 NSCLC patients with non-sensitive mutations and BMs, treated between 2016 and 2023 at two tertiary medical centers (Chongqing University Cancer Hospital and Guangxi Medical University Cancer Hospital). The patients were divided into three groups, namely chemotherapy alone (C; n = 95), chemotherapy plus immune checkpoint inhibitors (ICIs) (C + I; n = 62), and chemotherapy with ICIs and antiangiogenic therapy (A) (C + I + A; n = 52). Statistical analyses were performed using R software, version 4.3.3. Categorical variables were compared using Fisher's exact test, and survival curves were estimated with the Kaplan-Meier method and compared via the log-rank test. Univariate and multivariate Cox regression models were used to assess factors associated with overall survival (OS). Bayesian model averaging (BMA) was employed to address model uncertainty and improve result robustness. Subgroup analyses evaluated treatment-related mortality risk. RESULTS: From an initial cohort of 658 NSCLC patients with BMs, 209 were analyzed with a median age of 59; the majority were male (80.9%) and diagnosed with adenocarcinoma (78.9%). Univariate analysis identified significant variables influencing outcomes, including BMs radiotherapy EQD2, BMs count, local thoracic treatment, BMs radiotherapy field, intracranial response, and systemic treatment post-BMs diagnosis. The C + I + A regimen significantly improved median OS to 23.6 months compared to 11.4 months with C and 16.2 months with C + I, with a hazard ratio (HR) of 0.60 (95% CI: 0.43-0.82; P < 0.0001). The two-year OS rate was highest in the C + I + A group at 38.5%, versus 10.5% in C and 20.4% in C + I (P < 0.001). Cox regression and BMA analyses confirmed the stability of BMA in providing HR estimates, yielding area under the curve (AUC) values of 0.785 for BMA and 0.793 for the Cox model, with no significant difference in predictive performance. Subgroup analysis revealed a 71% mortality risk reduction with C + I + A (HR: 0.29; 95% CI: 0.18-0.47; P < 0.0001), showing consistent benefits regardless of patient sex, BMs count, extracranial metastases presence, and local thoracic treatments. Treatment sequence analysis indicated a median OS of 33.4 months for patients starting with A, though not statistically significant (HR: 0.59; P = 0.36). The overall incidence of radiation-induced brain injury was low at 3.3%, with rates in the C, C + I, and C + I + A groups being 3.2%, 4.8%, and 1.9%, respectively (P = 0.683). CONCLUSION: Our study demonstrates the significant benefit of the C + I + A combination therapy in improving OS and reducing mortality risk in NSCLC patients with non-sensitive gene-mutated BMs. The sequential administration of A followed by ICIs shows a promising synergistic effect with cranial radiotherapy, highlighting the potential for optimized treatment sequencing. These findings emphasize the efficacy of tailored combination therapies in complex oncological care and suggest that our approach could lead to meaningful improvements in clinical outcomes for this challenging patient population.
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Inibidores da Angiogênese , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos Retrospectivos , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/tratamento farmacológico , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Inibidores da Angiogênese/uso terapêutico , Idoso , Inibidores de Checkpoint Imunológico/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , AdultoRESUMO
Clonal MAPK-pathway activating mutations in the MAP2K1 (MEK1) gene are present in approximately 9% of cutaneous melanomas. These mutations are divided into three classes: RAF-dependent, RAF-regulated, RAF-independent. Cell lines with class-2 or RAF-regulated MAP2K1-mutations are most responsive to MEK-inhibitors. We present a patient with a class-2 MAP2K1-mutant stage IV-M1d melanoma who experienced extra- and intracranial progressive disease following treatment with immune-checkpoint inhibitors. The patient was treated with the MEK-inhibitor trametinib (2 mg OD) to which a low-dose of dabrafenib (50 mg BID) was added to mitigate skin-toxicity. Following documentation of a partial response (PR), she developed one new, and increase in volume of two pre-existing brain metastases that were treated with stereotactic radiosurgery (SRS) while continuing trametinib and dabrafenib. Thereafter, a deep partial radiologic and metabolic response both extra-and intra-cranially was achieved and is ongoing 88 weeks after initiating trametinib. She experienced no grade > 2 adverse events. Focal post-radiation necrosis at site of an irradiated brain metastasis developed 9 months after SRS and is successfully being treated with low-dose bevacizumab. This is the first published case of a durable intracranial disease control with the MEK-inhibitor trametinib of a stage IV-M1d class-2 MAP2K1-mutant melanoma. This illustrates the utility of NGS profiles that include class-1/2 MAP2K1-mutations in patients with melanoma and other malignancies to provide valuable information on a potentially active individualized treatment option. A prospective clinical trial that further evaluates the efficacy of MEK-inhibitor therapies in MAP2K1-mutated tumors is justified.
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Introduction In linac-based stereotactic radiosurgery (SRS) leveraging a multileaf collimator (MLC) for brain metastasis (BM), volumetric-modulated arcs (VMAs) enable the generation of a suitable dose distribution with efficient planning and delivery. However, the arc arrangement, including the number of arcs, allocation, and rotation ranges, varies substantially among devices and facilities. Some modalities allow coplanar arc(s) (CA(s)) or beam(s) alone, and some facilities only use them intentionally despite the availability of non-coplanar arcs (NCAs). The study was conducted to examine the significance of NCAs and the optimal arc rotation ranges in VMA-based SRS for a single BM. Materials and methods This was a planning study for the clinical scenario of a single BM, including 20 clinical cases with a gross tumor volume (GTV) of 0.72-44.30 cc. Three different arc arrangements were compared: 1) reciprocating double CA alone of each 360º rotation with different collimator angles of 0 and 90º, 2) one CA and two NCAs of each 120º rotation with the shortest beam path lengths to the irradiation isocenter (NCA_L), and 3) one CA of 360º rotation and two NCAs of each 180º rotation (NCA_F). The three arcs were allocated similarly to equally divide the cranial hemisphere with different collimator angles of 0, 45, and 90º. Three VMA-based SRS plans were generated for each GTV using a 5 mm leaf-width MLC with the identical optimization method that prioritized the steepness of dose gradient outside the GTV boundary without any constraints to the GTV internal dose. A prescribed dose was uniformly assigned to the GTV D V-0.01 cc, the minimum dose of GTV minus 0.01 cc. The GTV dose conformity, the steepness of dose gradients both outside and inside the GTV boundary, the degree of concentric lamellarity of the dose gradients, and the appropriateness of the dose attenuation margin outside the GTV boundary were evaluated using metrics appropriate for each. Results The arc arrangements including NCAs showed significantly steeper dose gradients both outside and inside the GTV boundary with smaller dose attenuation margins than the CAs alone, while NCAs showed no significant advantage on the GTV dose conformity. In the NCA-involved arc arrangements, the NCA_F was significantly superior to the NCA_L in terms of the GTV dose conformity, the steepness of dose gradient outside the GTV, the degree of concentric lamellarity of the dose gradients outside and inside the GTV boundary, and the appropriateness of dose attenuation margin. However, the NCA_F showed no significant advantage on the steepness of dose increase inside the GTV boundary over the NCA_L. The dose increase just inside the prescribed isodose surface to the GTV boundary was significantly steeper with the NCA_L than the NCA_F. Conclusions In VMA-based SRS for a single BM, an arc arrangement including NCAs is indispensable, and sufficient arc rotations are suitable for achieving a dose distribution that maximizes therapeutic efficacy and safety in comparison to limited ones which are appropriate for dynamic conformal arcs. Although VMA with CAs alone can provide a non-inferior GTV dose conformity to NCAs, CA(s) alone should be applied only to situations where shorter irradiation time is prioritized over efficacy and safety.
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Neurotropic viruses have been implicated in altering the central nervous system microenvironment and promoting brain metastasis of breast cancer through complex interactions involving viral entry mechanisms, modulation of the blood-brain barrier, immune evasion, and alteration of the tumour microenvironment. This narrative review explores the molecular mechanisms by which neurotropic viruses such as Herpes Simplex Virus, Human Immunodeficiency Virus, Japanese Encephalitis Virus, and Rabies Virus facilitate brain metastasis, focusing on their ability to disrupt blood-brain barrier integrity, modulate immune responses, and create a permissive environment for metastatic cell survival and growth within the central nervous system. Current therapeutic implications and challenges in targeting neurotropic viruses to prevent or treat brain metastasis are discussed, highlighting the need for innovative strategies and multidisciplinary approaches in virology, oncology, and immunology.
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Neoplasias Encefálicas , Neoplasias da Mama , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/virologia , Neoplasias da Mama/terapia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/virologia , Neoplasias Encefálicas/terapia , Feminino , Barreira Hematoencefálica/virologia , Animais , Microambiente Tumoral , Vírus da Raiva/fisiologia , Vírus da Raiva/patogenicidade , Vírus da Raiva/imunologia , Simplexvirus/fisiologiaRESUMO
BACKGROUND: Pancreatoblastoma is a malignant neoplasm of the pancreas, occurring usually in children and rarely in adults. Treatment consists of surgery with a variable combination of adjuvant therapies. Liver metastases are common, whereas brain diffusion is exceptionally rare. OBSERVATIONS: The authors report the case of a 42-year-old man with a 16-year history of metastatic pancreatoblastoma, previously treated with surgery, chemotherapy, and radiotherapy, demonstrating a partial response. He presented with headache and dizziness, and brain magnetic resonance imaging (MRI) showed a cerebellar lesion. A craniotomy was performed with complete tumor removal, and the postoperative course was uneventful. Brain MRI showed gross-total resection of the lesion, and the patient was discharged with an improvement of the preoperative symptoms. Histopathological analysis confirmed the diagnosis of metastasis from pancreatoblastoma. The patient received adjuvant stereotactic radiotherapy and showed further clinical improvement at the last follow-up. LESSONS: Brain metastases from pancreatoblastoma are exceptionally rare and poorly described in the literature. There is no standard therapy for this condition; hence, patients usually undergo treatments similar to those for other central nervous system metastases. All the described patients have had good clinical outcomes yet short-term follow-ups; therefore, further investigations are needed to better understand the best treatments for this condition. https://thejns.org/doi/10.3171/CASE23764.
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BACKGROUND: Glioblastoma and brain metastasis are two types of brain tumors that have a significant impact on the global healthcare system, with high rates of morbidity and mortality. These tumors can be challenging to differentiate from each other, as they often present with similar symptoms and features on medical imaging. The purpose of this study was to investigate whether the neutrophil-to-lymphocyte ratio (NLR) could help distinguish between glioblastoma and brain metastasis. METHODS: This is a retrospective cross-sectional analysis that utilized medical records from six hospitals located in Yogyakarta, Indonesia from the period of 2016 to 2021. The study included patients who were diagnosed with glioblastoma and brain metastasis. Laboratory data was collected upon initial admission, and the diagnosis of glioblastoma and brain metastasis was based on a histopathological examination. RESULTS: This study included a total of 393 subjects, with the glioblastoma group comprising 121 subjects and the brain metastasis group comprising 272 subjects. The group with glioblastoma had a higher NLR (11.12±11.56 vs. 8.75±9.18, P=0.006) than the brain metastasis group. The area under the curve from the receiver operating characteristic analysis was 0.587 (95% confidence Interval: 0.528-0.647, P=0.006). An NLR value greater than 7.14 was found to have 55.4% sensitivity and 62.5% specificity in predicting glioblastoma. CONCLUSIONS: According to this study, the NLR value of patients suffering from glioblastoma was significantly higher when compared to those with brain metastasis. This indicates that there is a higher degree of systemic inflammation in glioblastoma as compared to brain metastasis. Therefore, the NLR value can be a useful diagnostic tool to distinguish between glioblastoma and brain metastasis.
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Neoplasias Encefálicas , Glioblastoma , Linfócitos , Neutrófilos , Humanos , Glioblastoma/patologia , Neoplasias Encefálicas/secundário , Masculino , Feminino , Estudos Retrospectivos , Linfócitos/patologia , Estudos Transversais , Pessoa de Meia-Idade , Idoso , Diagnóstico Diferencial , AdultoRESUMO
PURPOSE: This study aimed to systematically assess the quality and performance of computed tomography (CT) radiomics studies in predicting brain metastasis (BM) among patients with lung cancer. METHODS: The PubMed, Embase and Web of Science were searched for studies predicting BM in patients with lung cancer using CT-based radiomics features. Information regarding patients, imaging, and radiomics analysis was extracted from eligible studies. We assessed the quality of included studies using the Radiomics Quality Scoring (RQS) tool and the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). A meta-analysis of studies regarding the prediction of BM in patients with lung cancer was performed. RESULTS: Thirteen studies were identified, with sample sizes ranging from 75 to 602. The mean RQS of the studies was 12 (range 9-16), and the corresponding percentage of the score was 33.55 % (range 25.00-44.44 %). Four studies (30.8 %) were considered as low risk of bias, while the remaining nine studies (69.2 %) were considered to have unclear risks. The meta-analysis included twelve studies. The pooled sensitivity, specificity and Area Under the Curve (AUC) value with 95 % confidence intervals were 0.75 [0.69, 0.80], 0.76 [0.68, 0.82], and 0.81 [0.77-0.84], respectively. CONCLUSION: CT radiomics-based models show promising results as a non-invasive method to predict BM in lung cancer patients. However, multicenter and prospective studies are warranted to enhance the stability and acceptance of radiomics.
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Neoplasias Encefálicas , Neoplasias Pulmonares , Tomografia Computadorizada por Raios X , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Sensibilidade e Especificidade , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , RadiômicaRESUMO
Melanoma represents a critical clinical challenge due to its unfavorable outcomes. This type of skin cancer exhibits unique adaptability to the brain microenvironment, but its underlying molecular mechanisms are poorly understood. Recent findings have suggested that melanoma brain metastases (MBM) may share biological processes similar to those found in various neurodegenerative diseases. To further characterize MBM development, we explore the relationship between the transcriptional profiles of MBM and the neurodegenerative diseases Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We take an in silico approach to unveil a neurodegenerative signature of MBM when compared to melanoma non-brain metastasis (53 dysregulated genes enriched in 11 functional terms, such as associated terms to the extracellular matrix and development) and to non tumor-bearing brain controls (195 dysregulated genes, mostly involved in development and cell differentiation, chromatin remodeling and nucleosome organization, and translation). Two genes, ITGA10 and DNAJC6, emerged as key potential markers being dysregulated in both scenarios. Lastly, we developed an open source, user-friendly web tool (https://bioinfo.cipf.es/metafun-mbm/) that allows interactive exploration of the complete results.
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In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. Employing a human-relevant ex vivo 'chip', AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a significant survival benefit to mice bearing NSCLC intracranial tumors generated using a patient-derived metastatic line. GABA(A) receptor activation stimulates a selective-autophagic response via the multimerization of GABA(A) receptor-associated protein, GABARAP, the stabilization of mitochondrial receptor Nix, and the utilization of ubiquitin-binding protein p62. A high-affinity peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP-Nix multimerization axis that triggers autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity.
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Introduction: Accurate prediction of tumor dynamics following Gamma Knife radiosurgery (GKRS) is critical for optimizing treatment strategies for patients with brain metastases (BMs). Traditional machine learning (ML) algorithms have been widely used for this purpose; however, recent advancements in deep learning, such as autoencoders, offer the potential to enhance predictive accuracy. This study aims to evaluate the efficacy of autoencoders compared to traditional ML models in predicting tumor progression or regression after GKRS. Objectives: The primary objective of this study is to assess whether integrating autoencoder-derived features into traditional ML models can improve their performance in predicting tumor dynamics three months post-GKRS in patients with brain metastases. Methods: This retrospective analysis utilized clinical data from 77 patients treated at the "Prof. Dr. Nicolae Oblu" Emergency Clinic Hospital-Iasi. Twelve variables, including socio-demographic, clinical, treatment, and radiosurgery-related factors, were considered. Tumor progression or regression within three months post-GKRS was the primary outcome, with 71 cases of regression and 6 cases of progression. Traditional ML models, such as Logistic Regression, Support Vector Machine (SVM), K-Nearest Neighbors (KNN), Extra Trees, Random Forest, and XGBoost, were trained and evaluated. The study further explored the impact of incorporating features derived from autoencoders, particularly focusing on the effect of compression in the bottleneck layer on model performance. Results: Traditional ML models achieved accuracy rates ranging from 0.91 (KNN) to 1.00 (Extra Trees). Integrating autoencoder-derived features generally enhanced model performance. Logistic Regression saw an accuracy increase from 0.91 to 0.94, and SVM improved from 0.85 to 0.96. XGBoost maintained consistent performance with an accuracy of 0.94 and an AUC of 0.98, regardless of the feature set used. These results demonstrate that hybrid models combining deep learning and traditional ML techniques can improve predictive accuracy. Conclusion: The study highlights the potential of hybrid models incorporating autoencoder-derived features to enhance the predictive accuracy and robustness of traditional ML models in forecasting tumor dynamics post-GKRS. These advancements could significantly contribute to personalized medicine, enabling more precise and individualized treatment planning based on refined predictive insights, ultimately improving patient outcomes.
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BACKGROUND: Neurocognitive impairments are common in patients with a brain tumour, and may negatively impact on functioning in daily life, particularly on instrumental activities of daily living (IADL). The EORTC IADL-BN32 questionnaire was developed to measure IADL in this patient population. METHODS: In this international validation study, we evaluated the EORTC IADL-BN32 questionnaire on several psychometric properties in a large sample of patients with a primary or metastatic brain tumour. We administered the 32-item questionnaire three times: at 'baseline', after 2 weeks and after 3 months. Procedures were in accordance with EORTC Quality of Life Group module development guidelines. RESULTS: In total, 326 patients participated in the study. A bifactor scale structure showed satisfactory model fit measures, with five multi-item scales and two single items, and an IADL sum score. The internal consistency of the multi-item scales ranged from good to excellent (range Cronbach's α: 0.86-0.97). We found significant differences in scale scores between patients with and without neurocognitive impairments or complaints, supporting the construct validity. Initial cross-cultural validity analyses showed indications of item response biases for certain items. Analyses indicated moderate to good test-retest agreement (intraclass correlation coefficient > 0.70) between baseline and the 2-week follow-up assessment for all but one scale. Deterioration of EORTC IADL-BN32 scale scores were consistent with clinically relevant deterioration on other functional measures with small to large effect sizes, however, subgroup sample sizes were small. CONCLUSION: Overall, the EORTC IADL-BN32 questionnaire exhibited adequate to excellent psychometric properties. Cross-cultural validity and responsiveness should be further explored.
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OBJECTIVE: To clarify a rational surgical priority, clinical characteristics were compared between brain metastases (BM) from renal cell carcinoma (RCC) and other cancers. METHODS: We reviewed 425 consecutive patients with BM who underwent treatments including surgery between January 2014 and December 2022. Primary cancers included lung (n = 220), breast (n = 46), digestive (n = 65), RCC (n = 25), and others (n = 69). Tumor volume (T), edema volume (E), and edema volume/tumor volume ratio (E/T ratio) were compared between RCC and other primary cancers. Cutoff T values for identifying both symptomatic tumors and tumors suitable for surgery were determined by receiver operating characteristic curves. Factors including E/T ratio, age, Karnofsky Performance Scale score, and tumor characteristics were statistically analyzed. RESULTS: Cutoff values of T and E to determine surgical suitability were 4.973 cm3 (sensitivity, 0.848; specificity, 0.74) and 23.088 cm3 (sensitivity, 0.894; specificity, 0.623), respectively. E/T ratio was significantly higher for RCC than for other cancers (P < 0.01). These results remained consistent after propensity score matching. RCC tended to show a significantly lower frequency of posterior fossa tumor (16%, P < 0.01) and higher rates of single lesions (72%, P = 0.03) and intratumoral hemorrhage (24%, P = 0.02). Subgroup analysis limited to surgical cases showed that E was consistent across tumors, T tended to be smaller, and E/T ratio was significantly higher in RCC. CONCLUSIONS: Generally, symptomatic BM were indicated for surgery. BM from RCC were characteristically single, low-volume lesions with expanding edema and intratumoral hemorrhage, causing symptoms. These results suggest that surgery should be a high priority for BM from RCC.
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BACKGROUND AND AIM: Stereotactic radiotherapy (SRT) is an established treatment for melanoma brain metastases (MBM). Recent evidence suggests that perilesional edema volume (PEV) might compromise the delivery and efficacy of radiotherapy to treat BM. This study investigated the association between SRT efficacy and PEV extent in MBM. MATERIALS AND METHODS: This retrospective study reviewed medical records from January 2020 to September 2023. Patients with up to 5 measurable MBMs, intracranial disease per RANO/iRANO criteria, and on low-dose corticosteroids were included. MRI scans assessed baseline neuroimaging, with PEV analyzed using 3D Slicer. SRT plans were based on MRI-CT fusion, delivering 18-32.5 Gy in 1-5 fractions. Outcomes included intracranial objective response rate (iORR) and survival measures (L-iPFS and OS). Statistical analysis involved decision tree analysis and multivariable logistic regression, adjusting for clinical and treatment variables. RESULTS: Seventy-two patients with 101 MBM were analyzed, with a mean age of 68.83 years. The iORR was 61.4%, with Complete Response (CR) in 21.8% and Partial Response (PR) in 39.6% of the treated lesions. PEV correlated with KPS, BRAF status, and treatment response. Decision tree analysis identified a PEV cutoff at 0.5 cc, with lower PEVs predicting better responses (AUC = 0.82 sensitivity: 86.7%, specificity:74.4%,). Patients with PEV ≥ 0.5 cc had lower response rates (iORR 44.7% vs. 63.8%, p < 0.001). Median OS was 9.4 months, with L-iPFS of 27 months. PEV significantly impacted survival outcomes. CONCLUSIONS: A more extensive PEV was associated with a less favorable outcome to SRT in MBM.
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BACKGROUND: The aim of this study was to determine the relationship between serum uric acid level at diagnosis and asymptomatic brain metastasis in patients with extensive-stage small cell lung cancer. METHODS: A total of 69 patients with extensive-stage small cell lung cancer without symptomatic brain metastases, whose serum uric acid level was measured at the time of diagnosis, were included in this retrospective cross-sectional study. The patients were divided into two groups as those with and without asymptomatic brain metastases. The Mann-Whitney U test was used for comparison between groups, and Spearman's correlation test was used for correlation analysis. The cut-off level of serum uric acid level was analyzed, and sensitivity, specificity, and accuracy rates were determined for brain metastasis. Independent factors affecting asymptomatic brain metastasis were determined by multivariate Cox regression analysis. RESULTS: The median serum uric acid level of all patients was 6.9 mg/dL. Twenty-two percent of patients had asymptomatic brain metastases, and serum uric acid levels were significantly higher in these patients (P = 0.0014). The cut-off value for serum uric acid level was calculated as 6.2 mg/dL. The sensitivity, specificity, and accuracy of this value for brain metastasis were 84%, 76%, and 78%, respectively. High serum uric acid level was an independent risk factor for asymptomatic brain metastasis (OR 3.446 95% CI 1.337-5.480; P = 0.005). CONCLUSION: In conclusion, a serum uric acid level of 6.2 mg/dL and above at the time of diagnosis may predict asymptomatic brain metastasis in patients.
Assuntos
Neoplasias Encefálicas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Ácido Úrico , Humanos , Ácido Úrico/sangue , Masculino , Feminino , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/diagnóstico , Pessoa de Meia-Idade , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/secundário , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Idoso , Estudos Retrospectivos , Estudos Transversais , Adulto , Biomarcadores Tumorais/sangue , Prognóstico , Sensibilidade e Especificidade , Estadiamento de NeoplasiasRESUMO
PURPOSE: Breast cancer brain metastasis (BCBM) is a deadly clinical problem, and the exact underlying mechanisms remain elusive. Junctional adhesion molecule (JAM), a tight junction protein, is a key negative regulator of cancer cell invasion and metastasis. METHODS: Junction adhesion molecule 3 (JAM3) expression in breast cancer was analyzed using bioinformatics methods and confirmed by PCR, western blotting, and immunofluorescence (IF) in cell lines. The effects of exogenous expression of JAM3 using lentiviral vectors on invasion, adhesion, and apoptosis were verified using transwell assays and flow cytometry. Differentially expressed genes (DEGs) were detected by RNA sequencing and verified by qâPCR and Western blotting. The effect of JAM3 silencing using siRNA was assessed by an adhesion assay. KaplanâMeier analysis was applied to calculate the impact of JAM3 expression and classic clinicopathologic characteristics on survival. RESULTS: Bioinformatics analysis revealed that JAM3 expression was reduced in BCBM. Exogenous expression of JAM3 minimizes the ability of breast cancer cells to invade and adhere and promotes their apoptosis. Silencing JAM3 results in morphology changes and the recovery of invasion and adhesion to ECMs, and the TGF-ß/Smad signaling pathway may be involved. JAM3 predicts less metastasis and good survival in patients with BCBM. Statistical analysis of BCBM samples detected by immunohistochemistry (IHC) and the associated clinicopathological characteristics revealed that low levels of JAM3 expression and high levels of TNF-ß1 are linked to the clinical progression of both primary and metastatic breast tumors. Kaplan-Meier analysis revealed that a high expression level of JAM3 was associated with longer survival. CONCLUSION: JAM3 can serve as a key negative regulator of breast cancer cell invasion, apoptosis, and brain metastasis, possibly through the TGF/Smad signaling pathway. JAM3 is anticipated to be a promising biomarker for the diagnosis and prognosis of breast cancer.
RESUMO
Purpose: Lung cancer is a devastating disease, with brain metastasis being one of the most common distant metastases of lung adenocarcinoma. This study aimed to investigate the prognostic characteristics of individuals with brain metastases originating from invasive lung adenocarcinoma of distinct pathological subtypes, providing a reference for the management of these patients. Methods: Clinical data from 156 patients with lung adenocarcinoma-derived brain metastases were collected, including age, sex, smoking status, Karnofsky Performance Status scores, pathological subtype, lymph node metastasis, tumor site, treatment mode, T stage, and N stage. Patients were classified into two groups (highly differentiated and poorly differentiated) based on their pathological subtypes. Propensity score matching was used to control for confounding factors. The prognostic value of pathological subtypes was assessed using Kaplan-Meier analysis and Cox proportional hazards regression modeling. Results: Kaplan-Meier analysis indicated that patients in the moderately to highly differentiated group had better prognoses. Multivariate analysis revealed that being in the poorly differentiated group was a risk factor for poorer prognosis. Thoracic tumor radiation therapy, chemotherapy, and surgery positively influenced the time interval between lung cancer diagnosis and brain metastasis. Conclusions: The pathological subtypes of lung adenocarcinoma-derived brain metastases are associated with patient prognosis. Patients in the poorly differentiated group have worse prognoses compared to those in the moderately to highly differentiated group. Therefore, patients in the poorly differentiated group may require more frequent follow-ups and aggressive treatment.