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Necrosis in solid tumors is commonly associated with poor prognostic but how these lesions expand remains unclear. Studies have found that neutrophils associate with and contribute to necrosis development in glioblastoma by inducing tumor cell ferroptosis through transferring myeloperoxidase-containing granules. However, the mechanism of neutrophilic granule transfer remains elusive. We performed an unbiased small molecule screen and found that statins inhibit neutrophil-induced tumor cell death by blocking the neutrophilic granule transfer. Further, we identified a novel process wherein neutrophils are engulfed by tumor cells before releasing myeloperoxidase-containing contents into tumor cells. This neutrophil engulfment is initiated by integrin-mediated adhesion, and further mediated by LC3-associated phagocytosis (LAP), which can be blocked by inhibiting the Vps34-UVRAG-RUBCN-containing PI3K complex. Myeloperoxidase inhibition or Vps34 depletion resulted in reduced necrosis formation and prolonged mouse survival in an orthotopic glioblastoma mouse model. Thus, our study unveils a critical role for LAP-mediated neutrophil internalization in facilitating the transfer of neutrophilic granules, which in turn triggers tumor cell death and necrosis expansion. Targeting this process holds promise for improving glioblastoma prognosis.
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Ferroptose , Glioblastoma , Neutrófilos , Fagocitose , Glioblastoma/patologia , Glioblastoma/metabolismo , Glioblastoma/imunologia , Glioblastoma/tratamento farmacológico , Animais , Neutrófilos/imunologia , Neutrófilos/metabolismo , Humanos , Camundongos , Ferroptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , NecroseRESUMO
BACKGROUND: Clonal immunoglobulin and T-cell receptor rearrangements serve as tumor-specific markers that have become mainstays of the diagnosis and monitoring of lymphoid malignancy. Next-generation sequencing (NGS) techniques targeting these loci have been successfully applied to lymphoblastic leukemia and multiple myeloma for minimal residual disease detection. However, adoption of NGS for primary diagnosis remains limited. METHODS: We addressed the bioinformatics challenges associated with immune cell sequencing and clone detection by designing a novel web tool, CloneRetriever (CR), which uses machine-learning principles to generate clone classification schemes that are customizable, and can be applied to large datasets. CR has 2 applications-a "validation" mode to derive a clonality classifier, and a "live" mode to screen for clones by applying a validated and/or customized classifier. In this study, CR-generated multiple classifiers using 2 datasets comprising 106 annotated patient samples. A custom classifier was then applied to 36 unannotated samples. RESULTS: The optimal classifier for clonality required clonal dominance ≥4.5× above background, read representation ≥8% of all reads, and technical replicate agreement. Depending on the dataset and analysis step, the optimal algorithm yielded sensitivities of 81%-90%, specificities of 97%-100%, areas under the curve of 91%-94%, positive predictive values of 92-100%, and negative predictive values of 88%-98%. Customization of the algorithms yielded 95%-100% concordance with gold-standard clonality determination, including rescue of indeterminate samples. Application to a set of unknowns showed concordance rates of 83%-96%. CONCLUSIONS: CR is an out-of-the-box ready and user-friendly software designed to identify clonal rearrangements in large NGS datasets for the diagnosis of lymphoid malignancies.
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Rearranjo Gênico do Linfócito T , Sequenciamento de Nucleotídeos em Larga Escala , Algoritmos , Rearranjo Gênico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasia Residual/diagnósticoRESUMO
Familial atypical multiple mole melanoma syndrome (FAMMM) is characterised by dysplastic naevi, malignant melanoma and pancreatic cancer. Given that large deletions involving CDKN2A (cyclin-dependent kinase inhibitor 2A) account for only 2% of cases, we describe a family that highlights the co-occurrence of both melanoma and neural system tumours to aid clinical recognition and propose a management strategy. A patient with multiple neurofibromas was referred with a provisional diagnosis of neurofibromatosis type 1 (NF1). Prior molecular testing, though, had failed to identify an NF1 mutation by sequencing and multiplex ligation-dependent probe amplification. His family history was significant for multiple in situ/malignant melanomas at young ages and several different cancers reminiscent of an underlying syndrome. A search of the Familial Cancer Database, FaCD Online, highlighted several families with cutaneous melanoma and nervous system tumours who were subsequently identified to have large deletions spanning CDKN2A Although sequencing of CDKN2A and TP53 failed to identify a mutation, a heterozygous CDKN2A deletion was identified by targeted array comparative genomic hybridisation (CGH). Whole-genome oligonucleotide array CGH and SNP analysis identified an interstitial deletion of at least 1.5 Mb within 9p21.3 and spanning approximately 25 genes. Identification of the underlying molecular abnormality permits predictive testing for at-risk relatives. Given the young cancer diagnoses, a surveillance regimen was developed and a clinical team organised for ongoing management so that genetic testing could be offered to both adults and minor children. Surveillance recommendations addressed cancer risks associated with FAMMM, and other cancers exhibited by this family with a large contiguous gene deletion.
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Triple-negative breast cancer (TNBC) is the most aggressive subtype with high metastasis and mortality rates. Given the lack of actionable targets such as ER and HER2, TNBC still remains an unmet therapeutic challenge. Despite harboring high CDK4/6 expression levels, the efficacy of CDK4/6 inhibition in TNBC has been limited due to the emergence of resistance. The resistance to CDK4/6 inhibition is mainly mediated by RB1 inactivation. Since our aim is to overcome resistance to CDK4/6 inhibition, in this study, we primarily used the cell lines that do not express RB1. Following a screening for activated receptor tyrosine kinases (RTKs) upon CDK4/6 inhibition, we identified the TAM (Tyro3, Axl, and MerTK) RTKs as a crucial therapeutic vulnerability in TNBC. We show that targeting the TAM receptors with a novel inhibitor, sitravatinib, significantly sensitizes TNBC to CDK4/6 inhibitors. Upon prolonged HER2 inhibitor treatment, HER2+ breast cancers suppress HER2 expression, physiologically transforming into TNBC-like cells. We further show that the combined treatment is highly effective against drug-resistant HER2+ breast cancer as well. Following quantitative proteomics and RNA-seq data analysis, we extended our study into the immunophenotyping of TNBC. Given the roles of the TAM receptors in promoting the creation of an immunosuppressive tumor microenvironment (TME), we further demonstrate that the combination of CDK4/6 inhibitor abemaciclib and sitravatinib modifies the immune landscape of TNBC to favor immune checkpoint blockade. Overall, our study offers a novel and highly effective combination therapy against TNBC and potentially treatment-resistant HER2+ breast cancer that can be rapidly moved to the clinic.
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Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors. In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2-14.7) compared with 9 months (95% CI, 4.2-13.8) in the physician-choice group (p = 0.010) as per interim efficacy analysis. The ChemoID assay-guided group has a significantly lower risk of death (hazard ratio [HR] = 0.44; 95% CI, 0.24-0.81; p = 0.008). Results of this study offer a promising way to provide more affordable treatment for patients with rGBM in lower socioeconomic groups in the US and around the world.
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Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Antineoplásicos/uso terapêutico , Resultado do Tratamento , Células-Tronco NeoplásicasRESUMO
PURPOSE: Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan. EXPERIMENTAL DESIGN: Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy. RESULTS: Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice. CONCLUSIONS: This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Animais , Camundongos , Idoso , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Senoterapia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Mutação , Metilação de DNARESUMO
Tumor necrosis is a poor prognostic marker in glioblastoma (GBM) and a variety of other solid cancers. Accumulating evidence supports that necrosis could facilitate tumor progression and resistance to therapeutics. GBM necrosis is typically first detected by magnetic resonance imaging (MRI), after prominent necrosis has already formed. Therefore, radiological appearances of early necrosis formation and the temporal-spatial development of necrosis alongside tumor progression remain poorly understood. This knowledge gap leads to a lack of reliable radiographic diagnostic/prognostic markers in early GBM progression to detect necrosis. Recently, we reported an orthotopic xenograft GBM murine model driven by hyperactivation of the Hippo pathway transcriptional coactivator with PDZ-binding motif (TAZ) which recapitulates the extent of GBM necrosis seen among patients. In this study, we utilized this model to perform a temporal radiographic and histological study of necrosis development. We observed tumor tissue actively undergoing necrosis first appears more brightly enhancing in the early stages of progression in comparison to the rest of the tumor tissue. Later stages of tumor progression lead to loss of enhancement and unenhancing signals in the necrotic central portion of tumors on T1-weighted post-contrast MRI. This central unenhancing portion coincides with the radiographic and clinical definition of necrosis among GBM patients. Moreover, as necrosis evolves, two relatively more contrast-enhancing rims are observed in relationship to the solid enhancing tumor surrounding the central necrosis in the later stages. The outer more prominently enhancing rim at the tumor border probably represents the infiltrating tumor edge, and the inner enhancing rim at the peri-necrotic region may represent locally infiltrating immune cells. The associated inflammation at the peri-necrotic region was further confirmed by immunohistochemical study of the temporal development of tumor necrosis. Neutrophils appear to be the predominant immune cell population in this region as necrosis evolves. This study shows central, brightly enhancing areas associated with inflammation in the tumor microenvironment may represent an early indication of necrosis development in GBM.
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BACKGROUND: Meningioma is the most common extra-axial primary intracranial tumor in adults that rarely metastasizes outside of the central nervous system (CNS). Among recognized sites of metastases, the lung is the most common, but the importance of lung metastases relative to prognosis is unknown. ¹¹¹Indium (¹¹¹In)-octreotide scintigraphy (octreotide scanning) is a valuable imaging modality with which to evaluate intracranial meningiomas and their response to treatment with somatostatin analogues and has the potential to identify extracranial metastatic disease. METHODS: In this retrospective multicenter study, adult patients treated for recurrent meningioma were identified. These patients underwent ¹¹¹In-octreotide positron emission tomography/computed tomography imaging (octreotide scintigraphy) and were found to have positive octreotide uptake in their lungs. RESULTS: Six cases were identified with recurrent meningioma (after surgery, radiotherapy, and at least 1 chemotherapy agent) and pulmonary lesions by octreotide scintigraphy. Biopsy of a pulmonary lesion in 1 patient confirmed the diagnosis of metastatic meningioma. Patients with metastatic pulmonary involvement identified by ¹¹¹In-octreotide scintigraphy in this case series had an overall survival of 6 months, which is less than that reported from previously published series of patients with unknown systemic disease status. CONCLUSIONS: ¹¹¹In-octreotide scintigraphy is useful for assessing both CNS disease and extracranial metastases. The presence of pulmonary metastases appears to negatively affect survival in patients with recurrent meningioma. The usefulness of ¹¹¹In-octreotide scintigraphy should be considered in staging patients with recurrent meningioma who are considered for further treatment. A prospective study to confirm this finding is warranted
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Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/secundário , Neoplasias Meníngeas/patologia , Meningioma/patologia , Recidiva Local de Neoplasia/patologia , Octreotida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Radioisótopos de Índio , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/terapia , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/terapia , Meningioma/diagnóstico por imagem , Meningioma/terapia , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Prognóstico , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent.
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Ferroptose , Glioblastoma/fisiopatologia , Neutrófilos/imunologia , Animais , Linhagem Celular Tumoral , Coenzima A Ligases/genética , Coenzima A Ligases/imunologia , Progressão da Doença , Feminino , Glioblastoma/genética , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Ferro/imunologia , Camundongos , Camundongos Nus , Necrose , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/imunologiaRESUMO
BACKGROUND: The most frequent central nervous system complication of systemic non-Hodgkin's lymphoma (NHL) is lymphomatous meningitis (LM). OBJECTIVE: A clinical series to test the feasibility of combining intra-CSF liposomal ara-C and rituximab for the treatment of recurrent LM. DESIGN: Clinical series of 14 patients with CSF positive lymphomatous meningitis. SETTING: Tertiary-care university medical center. RESULTS: Fourteen patients with recurrent, cytologically positive lymphomatous meningitis were treated. All 14 received liposomal ara-C and rituximab utilizing an Ommaya reservoir. Six patients also received involved-field radiotherapy (brain only two patients; brain and spine two patients; spine only two patients). Best response to treatment included 10 partial responses and four with progressive disease. Estimated median duration of response was 4.0 months (range 1-6 months). Survival ranged from 1.5 to 7 months with an estimated median of 5 months, four patients remain alive and continue to be followed. Cause of death was progressive neurological disease in 7, systemic disease in 1, and combined systemic and neurological disease in 2 patients. CONCLUSIONS: The combination of intra-CSF liposomal ara-C and rituximab administered in this schedule appears to have no additive toxicity and has modest palliative activity in patients with recurrent LM.
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Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Citarabina/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Meningite/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Murinos , Terapia Combinada/métodos , Vias de Administração de Medicamentos , Sistemas de Liberação de Medicamentos , Feminino , Seguimentos , Humanos , Linfoma não Hodgkin/líquido cefalorraquidiano , Linfoma não Hodgkin/complicações , Masculino , Meningite/líquido cefalorraquidiano , Meningite/complicações , Pessoa de Meia-Idade , Fosfolipídeos/uso terapêutico , Rituximab , Análise de SobrevidaRESUMO
To determine the therapeutic efficacy (13-week and 26-week CNS progression-free survival [PFS], response rate, and overall survival) and safety of intraventricular (IVent) topotecan in patients with neoplastic meningitis (NM), we conducted a phase II, open-label, nonrandomized, single-arm trial of IVent topotecan in patients with NM using 400 mug of topotecan IVent twice weekly for 6 weeks, followed by evaluation with imaging, cerebrospinal fluid (CSF), and physical examinations. In the absence of disease progression, patients were then treated with IVent topotecan weekly for 6 weeks, twice monthly for 4 months, and monthly thereafter. Sixty-two patients (23 males and 39 females) were enrolled from April 2001 through March 2006. Median age and KPS at enrollment were 56 (range 5-83) and 80 (range 60-100), respectively. Primary cancers included breast (19), lung (13), CNS (14), and others (16). Forty patients (65%) completed the 6-week induction period, among whom 13 (21%) had CSF clearance of malignant cells. Kaplan-Meier estimates of PFS at 13 and 26 weeks were 30% (95% confidence interval [CI], 20%-45%) and 19% (95% CI, 11%-34%). Overall median survival (50 deaths) was 15 weeks (95% CI, 13-24 weeks). The most common side effect was chemical meningitis in 32% of patients (5% grade 3); 32% experienced no drug side effects. IVent topotecan is well tolerated, but provides no added benefit over other IVent therapies. Because of its modest side effect profile, combining IVent topotecan with other IVent or systemic interventions should be considered.
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Antineoplásicos/administração & dosagem , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/secundário , Topotecan/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Injeções Espinhais , Masculino , Neoplasias Meníngeas/mortalidade , Pessoa de Meia-Idade , Prognóstico , Topotecan/efeitos adversosRESUMO
PURPOSE OF REVIEW: Despite remarkable advances in the treatment of non-Hodgkin's lymphoma of all histologic subtypes, nervous system involvement remains a dire complication associated with a rapid decline in quality of life, few good treatment options, and a short overall survival. In fact, these advances in treatment may be fueling an increase in the frequency of nervous system relapse. A better understanding of the epidemiology, diagnostic techniques, and options for prophylaxis of the central nervous system may be one of the best strategies for improving the outcome in patients with non-Hodgkin's lymphoma. RECENT FINDINGS: Central nervous system relapse in patients with non-Hodgkin's lymphoma is, typically, an early event, occurs in the setting of well described histologic, demographic, and clinical risk factors, and is characterized primarily by the involvement of the cerebrospinal fluid. Cerebrospinal fluid prophylaxis in high-risk patients appears to be effective in reducing the frequency of this complication. SUMMARY: More aggressive attention to diagnosis, focused on cytologic and flow cytometric evaluation of the cerebrospinal fluid in high-risk patients, will identify more patients with early and potentially more treatable central nervous system lymphoma. Cerebrospinal fluid prophylaxis appears to reduce the frequency of this complication in high-risk populations, but controversy remains regarding the most important high-risk characteristics and the optimum prophylactic interventions.
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Antibióticos Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/prevenção & controle , Linfoma não Hodgkin/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/secundário , Humanos , Linfoma não Hodgkin/patologiaRESUMO
BACKGROUND: Numerous studies have examined the impact of initiating an external ventricular drain (EVD) placement and handling protocol on the infection rate dating back to the early 2000s. METHODS: We report a quantitative systematic review of the published literature, described our own protocol (including a mandatory checklist), and present our single institution experience. Search terms "external ventricular drain protocol" or "external ventricular drain placement protocol" or "preventing infections in external ventricular drains" or "external ventricular drain infections" were entered into standard search engines in a systematic fashion. Articles were reviewed and graded independently for class of evidence. There were 10 relevant class IV articles and no discrepancies among article ratings (i.e., κ = 1). The published evidence was reviewed and evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria. RESULTS: Our meta-analysis revealed a statistically significant drop in rates of EVD infection after initiation of the protocol, although the overall quality of the body of evidence according to the GRADE criteria was "very poor". Preimplementation and postimplementation infection rates were collected and analyzed in combination with the results from our literature review. The EVD infection rate in our institution was 12% in the 8 months before protocol initiation (January 2015 to August 2015), and dropped to 0% in the 7 months after initiation. CONCLUSIONS: Although the quality of the literature supporting EVD placement protocols is poor, all published studies show a consistent and substantial benefit, and this effect was recapitulated in our own meta-analysis-based prospective EVD protocol experience.
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Cateteres de Demora/tendências , Infecção Hospitalar/prevenção & controle , Drenagem/tendências , Contaminação de Equipamentos/prevenção & controle , Ventriculostomia/tendências , Cateteres de Demora/efeitos adversos , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/etiologia , Drenagem/efeitos adversos , Humanos , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ventriculostomia/efeitos adversosRESUMO
The positive results of recent clinical trials examining endovascular treatment of acute stroke were the culmination of nearly two decades of studies of endovascular stroke treatment. We systematically reviewed this body of work, evaluated the strength of evidence, and performed a meta-analysis to define the clinical impact of these investigations. Terms were entered into search engines in a systematic fashion. Articles were reviewed independently by study authors, graded for level of evidence, and combined in a meta-analysis. The overall body of evidence was evaluated using GRADE criteria. Our search yielded 948 articles. Twenty-five met predefined inclusion criteria. We identified 12 grade I, 1 grade II, 5 grade III, and 7 grade IV studies (κ=0.86). Meta-analysis for independence at 90days showed a benefit of endovascular treatment (grade I studies OR 1.58 [1.20-2.07]). When limiting the analysis to studies using stent retriever, the OR increased to 2.44 (1.77-3.36). The number needed to treat (NNT) was 8. Endovascular treatment was not associated with increased symptomatic intracranial hemorrhage, and forgoing endovascular treatment was associated with death at 90 days. The quality of evidence according to GRADE criteria was "moderate." In summary, we found impressive evidence for a benefit of endovascular treatment of acute stroke, particularly when using stent retriever devices. Our meta-analysis is unique in that it includes all studies related to this topic and defines the clinical impact of the data, providing NNT. We show that thrombectomy is among the most effective stroke treatments currently available.
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Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Procedimentos Endovasculares , Humanos , Trombectomia/estatística & dados numéricos , Terapia Trombolítica/métodos , Terapia Trombolítica/estatística & dados numéricos , Resultado do TratamentoRESUMO
Cadmium selenide (CdSe) based quantum dots modified with polyethylene glycol and chemically linked to interleukin-13 (IL13) were prepared with the aim of identifying the high affinity receptor (IL13Rα2) which is expressed in glioma stem cells and exosomes secreted by these cancer stem cells. IL13 conjugated quantum dots (IL13QD) were thoroughly characterized for their physicochemical properties including particle size and surface morphology. Furthermore, the specific binding of the IL13QD to glioma cells and to glioma stem cells (GSC) was verified using a competitive binding study. The exosomes were isolated from the GSC conditioned medium and the expression of IL13Rα2 in the GSC and exosomes was verified. The binding property of IL13QD to the tumor associated exosomes was initially confirmed by transmission electron microscopy. The force of attraction between the quantum dots and U251 glioma cells and the exosomes was investigated by atomic force microscopy, which indicated a higher force of binding interaction between the IL13QD and IL13Rα2 expressing glioma cells and exosomes secreted by glioma stem cells. Flow cytometry of the IL13QD and exosomes from the culture media and cerebrospinal fluid (CSF) of patients with glioma tumors indicated a distinctly populated complex pattern different from that of non-targeted quantum dots and bovine serum albumin (BSA) conjugated quantum dots confirming specific binding potential of the IL13QD to the tumor associated exosomes. The results of this study demonstrate that IL13QD can serve as an ex vivo marker for glioma stem cells and exosomes that can inform diagnosis and prognosis of patients harboring malignant disease. STATEMENT OF SIGNIFICANCE: Functionalized quantum dots are flexible semiconductor nanomaterials which have an immense application in biomedical research. In particular, when they are functionalized with biomolecules like proteins or antibodies, they have the specialized ability to detect the expression of receptors and antigens in cells and tissues. In this study we designed a cytokine (interleukin-13) functionalized quantum dot to detect a cancer associated receptor expressed in cancer stem cells and the extracellular vesicles (exosomes) secreted by the cancer cells themselves. The binding pattern of these cytokine modified quantum dots to the cancer stem cells and exosomes alters the physical properties of the complex in the fixed and suspended form. This altered binding pattern can be monitored by a variety of techniques, including transmission electron microscopy, atomic force microscopy and flow cytometry, and subsequent characterization of this quantum dot binding profile provides useful data that can be utilized as a fingerprint to detect cancer disease progression. This type of functionalized quantum dot fingerprint is especially useful for invasive cancers including brain and other metastatic cancers and may allow for earlier detection of disease progression or recurrence, thus saving the lives of patients suffering from this devastating disease.
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Compostos de Cádmio , Rastreamento de Células/métodos , Micropartículas Derivadas de Células , Glioma , Interleucina-13 , Células-Tronco Neoplásicas , Pontos Quânticos/química , Compostos de Selênio , Compostos de Cádmio/química , Compostos de Cádmio/farmacologia , Linhagem Celular Tumoral , Micropartículas Derivadas de Células/metabolismo , Micropartículas Derivadas de Células/patologia , Glioma/líquido cefalorraquidiano , Glioma/diagnóstico , Glioma/metabolismo , Glioma/patologia , Humanos , Interleucina-13/química , Interleucina-13/farmacologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Compostos de Selênio/química , Compostos de Selênio/farmacologiaRESUMO
PURPOSE: The efficacy and safety of intrathecal topotecan were assessed in patients with neoplastic meningitis (NM) by retrospective chart review. SUMMARY: Fourteen patients (median age, 57 years) with NM were treated with the standard of care (i.e., regional or systemic chemotherapy or irradiation or both) plus intrathecal topotecan between January 2004 and September 2005. Three patients developed NM in the setting of systemic cancer; 11 patients had primary central nervous system (CNS) malignancies. All patients received 0.4 mg of topotecan intrathecally two times per week. The efficacy of intrathecal topotecan was assessed on the basis of the number of doses to cerebrospinal fluid (CSF) cytologic clearing--defined as the disappearance of malignant cells from a previously positive CSF cytology. Safety was evaluated by chart documentation of adverse events that might have been associated with topotecan given intrathecally. Of the 11 patients with primary CNS tumors, 6 patients achieved CSF clearing after the first dose of intrathecal topotecan, 2 patients after the second dose, and 1 patient after the fifth dose. For the 3 patients with secondary CSF tumors, 1 patient achieved CSF clearing after the third dose and 2 patients did not reach the primary endpoint. Overall, 6 of the 14 patients achieved CSF clearing after the first dose of intrathecal topotecan; in 10 of the 14 patients, CSF clearing of malignant cells was observed at some point during treatment. Toxicity was modest. The most common adverse effect reported was fatigue. CONCLUSION: Intrathecal topotecan appeared to be effective and safe in adult patients with NM.
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Antineoplásicos/uso terapêutico , Injeções Espinhais , Neoplasias Meníngeas/tratamento farmacológico , Topotecan/uso terapêutico , Antineoplásicos/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Auditoria Médica , Pessoa de Meia-Idade , Estudos Retrospectivos , Topotecan/administração & dosagem , Resultado do TratamentoRESUMO
PURPOSE: Motexafin gadolinium is a redox mediator that selectively targets tumor cells, is detectable by magnetic resonance imaging (MRI), and enhances the effect of radiation therapy. This lead-in phase to a randomized trial served to evaluate radiologic, neurocognitive, and neurologic progression end points and to evaluate the safety and radiologic response of motexafin gadolinium administered concurrently with 30 Gy in 10-fraction whole-brain radiation therapy for the treatment of brain metastases. PATIENTS AND METHODS: Motexafin gadolinium (5.0 mg/kg/d for 10 days) was administered before each radiation treatment in this prospective international trial. Patients were evaluated by MRI, neurologic examinations, and neurocognitive tests. Prospective criteria and centralized review procedures were established for radiologic, neurocognitive, and neurologic progression end points. RESULTS: Twenty-five patients with brain metastases from lung (52%) and breast (24%) cancer, recursive partitioning analysis class 2 (96%), and an average of 11 brain metastases were enrolled. Neurocognitive function was highly impaired at presentation. Motexafin gadolinium was well tolerated. Freedom from neurologic progression was 77% at 1 year. Median survival was 5.0 months. In 29% of patients, the cause of death was brain metastasis progression. The radiologic response rate was 68%. Motexafin gadolinium's tumor selectivity was established with MRI. CONCLUSION: (1) Centralized neurologic progression scoring that incorporated neurocognitive tests was implemented successfully. (2) Motexafin gadolinium was well tolerated. (3) Local control, measured by radiologic response rate, neurologic progression, and death caused by progression of brain metastasis, seemed to be improved compared with historical results. A randomized phase III trial using these methods for evaluation of efficacy has just been completed.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Irradiação Craniana , Metaloporfirinas/uso terapêutico , Adulto , Idoso , Cognição/efeitos dos fármacos , Intervalo Livre de Doença , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estudos Prospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Many meningiomas are identified by imaging and followed, with an assumption that they are WHO Grade I tumors. The purpose of our investigation is to find clinical or imaging predictors of WHO Grade II/III tumors to distinguish them from Grade I meningiomas. METHODS: Patients with a pathologic diagnosis of meningioma from 2002-2009 were included if they had pre-operative MRI studies and pathology for review. A Neuro-Pathologist reviewed and classified all tumors by WHO 2007. All Brain MRI imaging was reviewed by a Neuro-radiologist. Pathology and Radiology reviews were blinded from each other and clinical course. Recursive partitioning was used to create predictive models for identifying meningioma grades. RESULTS: Factors significantly correlating with a diagnosis of WHO Grade II-III tumors in univariate analysis: prior CVA (p = 0.005), CABG (p = 0.010), paresis (p = 0.008), vascularity index = 4/4: (p = 0.009), convexity vs other (p = 0.014), metabolic syndrome (p = 0.025), non-skull base (p = 0.041) and non-postmenopausal female (p = 0.045). Recursive partitioning analysis identified four categories: 1. prior CVA, 2. vascular index (vi) = 4 (no CVA), 3. premenopausal or male, vi < 4, no CVA. 4. Postmenopausal, vi < 4, no CVA with corresponding rates of 73, 54, 35 and 10% of being Grade II-III meningiomas. CONCLUSIONS: Meningioma patients with prior CVA and those grade 4/4 vascularity are the most likely to have WHO Grade II-III tumors while post-menopausal women without these features are the most likely to have Grade I meningiomas. Further study of the associations of clinical and imaging factors with grade and clinical behavior are needed to better predict behavior of these tumors without biopsy.
Assuntos
Imageamento por Ressonância Magnética , Neoplasias Meníngeas/patologia , Meningioma/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biópsia , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Neoplasias Meníngeas/etiologia , Meningioma/etiologia , Pessoa de Meia-Idade , Gradação de Tumores , Pós-Menopausa , Valor Preditivo dos Testes , Sistema de Registros , Medição de Risco , Fatores de Risco , Fatores Sexuais , Adulto JovemRESUMO
Injury to the central and peripheral nervous systems is an increasingly frequent consequence of standard radiation treatment protocols for tumors involving or adjacent to nervous system structures. Characteristic temporal, clinical, radiographic, and laboratory features distinguish a number of specific radiation injury syndromes, but meticulous and repeated evaluations over time are often required to establish a diagnosis. These syndromes vary with regard to prognosis and therapeutic options, and competing diagnoses with very different natural histories and therapies often mask or mimic the signs and symptoms of radiation-related nervous system injury. The ability to efficiently negotiate this complicated differential diagnostic landscape allows for early diagnosis of tumor recurrence or an alternative etiology, prompt institution of appropriate therapy, avoidance of unnecessary diagnostic studies, and confident prognostication for patients and families. Even after the diagnosis of a radiation-related complication is made, continued vigilance for additional sites or manifestations of radiation injury is mandatory. Meanwhile, further research into treatment, prevention, and the causes of individual susceptibility to radiation injury are essential.
Assuntos
Encefalopatias/etiologia , Lesões por Radiação/etiologia , Radioterapia/efeitos adversos , Biópsia , Encefalopatias/patologia , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Lesões por Radiação/patologiaRESUMO
Brain lesions identified following the diagnosis and eradication of primary cancers are often ambiguous in origin, existing as a solitary metastasis or an independent primary brain tumor. The brain is a relatively common site of metastasis with breast cancer, although determining whether metastases have originated from the breast or brain is often not possible without invasive biopsies. In the current case report, a patient presented with a brain lesion identified by radiography and was without systemic disease. The patient had previously exhibited a complete response to chemotherapy and surgery for a poorly differentiated invasive ductal carcinoma. The origin of the brain lesion could not be determined by magnetic resonance imaging, giving rise to a diagnostic dilemma with diverging treatment options. We previously reported a method to isolate and enumerate tumor cells of epithelial origin in the cerebrospinal fluid (CSF). CSF tumor cell analysis of the patient revealed massive CSF tumor cell burden of epithelial origin, indicating that the brain lesion was likely of breast origin. The current case report highlights the use of CSF tumor cell detection as a differential diagnostic tool, in addition to its previously demonstrated use as a marker of disease burden and therapeutic response.