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INTRODUCTION: Prostate cancer (PCa) ranks second among prevalent cancers in men, necessitating effective screening tools such as multiparametric magnetic resonance imaging (mpMRI) with the prostate imaging reporting and data system (PI-RADS) classification. This study explores the impact of lesion volume on clinically significant prostate cancer (csPCa) detection rates in PI-RADS 3-5 lesions, aiming to contribute insights into the underexplored relationship between lesion size and csPCa detection. MATERIALS AND METHODS: A retrospective analysis was conducted on data from 754 patients undergoing mpMRI-guided transrectal ultrasound (TRUS) prostate biopsy between January 2016 and 2023. Patients with PI-RADS 3, 4, and 5 lesions were included. Lesion size and PI-RADS categories were assessed through mpMRI, followed by MR fusion biopsy. RESULTS: Of the patients, 33.7%, 52.3%, and 14.1% had PI-RADS 3, 4, and 5 lesions, respectively. Lesion sizes correlated significantly with csPCa detection in PI-RADS 4 and 5 categories. For PI-RADS 3 lesions, no significant differences in csPCa rates were observed based on lesion size. However, in PI-RADS 4 and 5 groups, larger lesions showed higher csPCa rates. CONCLUSION: This study suggests that subgroup categorizations based on lesion volume could predict clinically significant PCa with high accuracy, potentially reducing unnecessary biopsies and associated overtreatment. Future research should further explore the relationship between lesion size and csPCa, clarifying discussions regarding the inclusion of systematic biopsies in diagnostic protocols.
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Inhibiting MerTK on macrophages is a promising therapeutic strategy for augmenting anti-tumor immunity. However, blocking MerTK on retinal pigment epithelial cells (RPEs) results in retinal toxicity. Bispecific antibodies (bsAbs) containing an anti-MerTK therapeutic and anti-PD-L1 targeting arm were developed to reduce drug binding to MerTK on RPEs, since PD-L1 is overexpressed on macrophages but not RPEs. In this study, we present a modeling framework using in vitro receptor occupancy (RO) and pharmacokinetics (PK) data to predict efficacy, toxicity, and therapeutic index (TI) of anti-MerTK bsAbs. We first used simulations and in vitro RO data of anti-MerTK monospecific antibody (msAb) to estimate the required MerTK RO for in vivo efficacy and toxicity. Using these estimated RO thresholds, we employed our model to predict the efficacious and toxic doses for anti-MerTK bsAbs with varying affinities for MerTK. Our model predicted the highest TI for the anti-MerTK/PD-L1 bsAb with an attenuated MerTK binding arm, which was consistent with in vivo efficacy and toxicity observations. Subsequently, we used the model, in combination with sensitivity analysis and parameter scans, to suggest an optimal molecular design of anti-MerTK bsAb with the highest predicted TI in humans. Our prediction revealed that this optimized anti-MerTK bsAb should contain a MerTK therapeutic arm with relatively low affinity, along with a high affinity targeting arm that can bind to a low abundance target with slow turnover rate. Overall, these results demonstrated that our modeling framework can guide the rational design of bsAbs.
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Anticorpos Biespecíficos , Humanos , Antígeno B7-H1 , c-Mer Tirosina QuinaseRESUMO
RO7297089, an anti-B-cell maturation antigen (BCMA)/CD16A bispecific tetravalent antibody, is being developed as a multiple myeloma (MM) therapeutic. This study characterized nonclinical pharmacokinetics (PK), pharmacodynamics (PD), soluble BCMA (sBCMA), and soluble CD16 (sCD16) changes following administration of RO7297089 to support clinical trials. Unbound and total RO7297089 concentrations were measured in cynomolgus monkeys. RO7297089 exhibited a bi-phasic systemic concentration-time profile, similar to a typical human immunoglobulin 1 antibody. Target engagement by RO7297089 led to a robust increase (~100-fold) in total systemic sBCMA levels and relatively mild increase (~2-fold) in total sCD16 levels. To describe the relationship of nonclinical PK/PD data, we developed a target-mediated drug disposition (TMDD) model that includes the systemic target engagement of membrane BCMA (mBCMA), sBCMA, membrane CD16 (mCD16), and sCD16. We then used this model to simulate the PK/PD relationship of RO7297089 in MM patients by translating relevant PK parameters and target levels, based on the literature and newly generated data such as baseline sCD16A levels. Our model suggested that the impact of TMDD on RO7297089 exposure may be more significant in MM patients due to significantly higher expression levels of both mBCMA and sBCMA compared to healthy cynomolgus monkeys. Based on model simulations, we propose more frequent dosing of RO7297089 compared to regular monthly frequency in the clinic at the beginning of treatment to ensure sustained target engagement. This study demonstrates a translational research strategy for collecting relevant nonclinical data, establishing a TMDD model, and using simulations from this model to inform clinical dose regimens.
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Mieloma Múltiplo , Animais , Humanos , Imunoterapia , Macaca fascicularis , Mieloma Múltiplo/tratamento farmacológicoRESUMO
High-grade gliomas are the most fatal brain tumors. Grade 4 gliomas are called glioblastoma multiforme (GBM), which are associated with the poorest survival and a 5-year survival rate of less than 4%. Many patients with GBM developed concomitant cognitive dysfunctions and epilepsy. Although the cognitive decline is well defined in glioblastomas, the neurotoxic factors underlying this pathology are not well understood in GBM patients. In this study, we aimed to investigate whether GBM-derived exosomes play a role in neuronal toxicity. For this purpose, exosomes obtained from T98G and U373 GBM cells were applied to primary neuron culture at different concentrations. Subsequently, MTT, LDH, GSH, TAS, and TOS tests were performed. Both GBM-derived exosomes induced a dose-dependent and statistically significant increase of LDH release in cerebellar neurons. MTT assay revealed as both T98G and U373 GBM-derived exosomes induced dose-dependent neurotoxic effects in cerebellar neurons. To the best of our knowledge, this study is the first study demonstrating the toxic potential of GBM-derived exosomes to primary neurons, which may explain the peritumoral edema and cognitive decline in GBM patients.
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Erucic acid, an omega-9 monounsaturated fatty acid present in Brassicaceae plants (rapeseed and mustard oils) is highly consumed by the Chinese population and according to several global survey studies, its highest levels are encountered in the Chinese women's milk. Erucic acid is an activating ligand of the transcription factor PPARδ and an inhibitor of the transcriptional activity of PPARγ, which drive tumorigenesis of glioblastomas and medulloblastomas. In this theoretical review, we propose that erucic acid in diet may associate with the risk of brain tumors. High grade brain tumors including medulloblastomas in children and glioblastomas in adults have devastating consequences for human health and the latter tumors are practically incurable. CONCORD-3 epidemiological study recently published in 2021 revealed a low ratio of medulloblastomas in the pediatric age group and also a low ratio of glioblastomas in adults in the Chinese population. It is certain that such profound differences can not be attributed to a single genetic factor or a single nurture pattern. It is very likely that multiple hereditary, nutritional and environmental factors are responsible for these lower ratios; yet here we propose that erucic acid may be one of the contributing factors. If future epidemiological studies and animal models show antitumor activity of erucic acid regarding brain neoplasias, it can be utilized as a preventive strategy for populations possessing very high risks to develop brain tumors such as those harbouring hereditary syndromes increasing the vulnerability to develop such malignancies.
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Neoplasias Encefálicas , Neoplasias Cerebelares , Glioblastoma , Meduloblastoma , Animais , Feminino , Humanos , Criança , Ácidos Erúcicos , Óleos de Plantas , Dieta , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/prevenção & controle , China/epidemiologiaRESUMO
Glioblastoma multiforme (GBM) is an aggressive brain malignancy and harbors a microenvironment limiting immune cells activity. CAR-T cells are being tested in the treatment of cancers and there exist reports which demonstrate dramatic regression of multicentric GBMs following intrathecal treatment with CAR-T cells. In this article, a triple approach for immune treatment of GBM is proposed. First, GBM tumor specimens for each patient will be saved and cultured to obtain tumor lysates. Then, levamisole will be applied, which possesses immunostimulating, anti-glycolytic, and anti-angiogenic features. Following priming the immune system, GBM patients will be injected with lysates of their own tumor cells plus lysates from a GBM cell line, U251. After 3 months of this treatment, CAR-T cells (transduced with IL13Rα2-CAR) will be applied via intratumoral approach. As such, genetically-modified and native immunocytes may 'meet' in the vicinity of deeply-invading tumor cells and demonstrate greater efficacy via cell-cell interactions. By this, a self-propagating cyclic process - a cancer-immunity cycle - may be initiated to eradicate cancer cells.
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Levamisol , Linfócitos T , Humanos , Levamisol/farmacologia , Levamisol/uso terapêuticoRESUMO
Many investigations exist regarding the effect of the DNA repair enzyme MGMT (O 6 -methylguanine- DNA-methyltransferase)-encoding gene methylation on the antineoplasticity of temozolomide in glioblastoma patients. However, there exist surprisingly lesser studies regarding the associations between MGMT enzyme biochemistry with glial carcinogenesis. MGMT involves in risk of malignancies associated with ionizing radiation, smoking, exposure to polycyclic aromatic hydrocarbons, chlorinated solvents, vinylchloride and hairdyes. All these factors are also proposed to link with gliomagenesis, yet MGMT interactions with these carcinogens in gliomagenesis are not studied yet. In future, MGMT sequencing may be employed in vulnerable populations working in industries associated with exposure to these carcinogens to develop preventive strategies. Given that MGMT is involved in DNA repair, a polymorphism may simultaneously modify the risk of gliomas while enhancing temozolomide cytotoxicity in both marrow and tumor cells.
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Neoplasias Encefálicas , Hidrocarbonetos Policíclicos Aromáticos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/prevenção & controle , Carcinogênese/genética , Carcinógenos , DNA , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Dacarbazina , Humanos , O(6)-Metilguanina-DNA Metiltransferase/genética , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Solventes , Temozolomida , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND: Glioblastoma multiforme (GBM) is a brain malignancy with worst survival. Low dose progesterone stimulates GBM growth, while progesterone receptor (PR)-antagonist mifepristone was shown to reduce growth and to enhance temozolomide sensitivity in GBM cells. Mifepristone is not available in all countries due to ethical reasons and may cause adrenal insufficiency and pelvic infections. Ulipristal is also a PR-antagonist used in treatment of uterine leiomyomas with higher biosafety. Ulipristal is demonstrated to suppress growth of breast cancer, yet it is not tested as yet whether it can also block growth and sensitize to temozolomide in glioblastoma as it was previously shown with mifepristone. Our first aim was to detect whether ulipristal exerts antiproliferative and chemotherapy-sensitizing effects in glioblastoma. Hydroxyurea inhibits DNA replication via blocking ribonucleotide reductase (RR) and it was demonstrated to increase temozolomide antineoplasticity in GBM. Progesterone receptor-activation in the uterus enhances RR transcription. Hence, we have hypothesized that PR-inactivation with ulipristal would further enhance hydroxyurea antineoplasticity by shutting down DNA synthesis mechanisms through further suppression of RR. Lastly, there exists no study as yet whether ulipristal, hydroxyurea and temozolomide could exert ternary antineoplastic efficacy, which was our last aim to define. METHODS: To reveal interactions between ulipristal, hydroxyurea and temozolomide, we treated human U251 GBM cell line with these agents alone and in combination and measured cell proliferation, total antioxidant capacity (TAC) and total oxidant status (TOS) in conditioned medium and cellular cytokine gene expressions. RESULTS: All agents significantly reduced cell proliferation significantly, yet the most significant decrease of GBM cells occured with the triple drug combination at the 96th hour. All agents significantly decreased TAC and increased TOS in culture media, which was mostly relevant for the triple combination at the 96th hour. All these 3 agents tend to reduce the expression of immunosuppressive and/or GBM-growth stimulating cytokines TGFß, IL-10 and IL-17 while increasing the expression of GBM-growth suppressing cytokine IL-23. CONCLUSIONS: Repurposal of these agents in treatment of GBM would be a plausible approach if future studies prove their efficacy.
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The T cell-dependent bispecific (TDB) antibody, anti-CD79b/CD3, targets CD79b and CD3 cell-surface receptors expressed on B cells and T cells, respectively. Since the anti-CD79b arm of this TDB binds only to human CD79b, a surrogate TDB that binds to cynomolgus monkey CD79b (cyCD79b) was used for preclinical characterization. To evaluate the impact of CD3 binding affinity on the TDB pharmacokinetics (PK), we utilized non-tumor-targeting bispecific anti-gD/CD3 antibodies composed of a low/high CD3 affinity arm along with a monospecific anti-gD arm as controls in monkeys and mice. An integrated PKPD model was developed to characterize PK and pharmacodynamics (PD). This study revealed the impact of CD3 binding affinity on anti-cyCD79b/CD3 PK. The surrogate anti-cyCD79b/CD3 TDB was highly effective in killing CD79b-expressing B cells and exhibited nonlinear PK in monkeys, consistent with target-mediated clearance. A dose-dependent decrease in B cell counts in peripheral blood was observed, as expected. Modeling indicated that anti-cyCD79b/CD3 TDB's rapid and target-mediated clearance may be attributed to faster internalization of CD79b, in addition to enhanced CD3 binding. The model yielded unbiased and precise curve fits. These findings highlight the complex interaction between TDBs and their targets and may be applicable to the development of other biotherapeutics.
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Meperidine (pethidine) is a µ-opioid receptor (MOR) agonist widely used in the treatment of cancer pain. While MOR agonists in experimental models have demonstrated both pro- and antitumorigenic properties, meperidine has unique features which may be predominantly anticancer in nature. Meperidine both inhibits NMDA (N-methyl-D-Aspartate) receptors, which are involved in the progression of glioblastoma, and blocks NADH:Ubiquinone Oxidoreductase, which may hinder mitochondrial respiration. In the developing embryonic neural tissue, meperidine reduces cell proliferation around the neural tube and lowers the expression of the B RE (brain and reproductive organ-expressed). This is notable given that the B RE gene is implicated in cancer chemoresistance and gliomagenesis. Further, meperidine inhibits P-glycoprotein, which is involved in cancer multidrug resistance and the degradation of the sphingolipid backbone, ceramide. By enhancing the pro-autophagic and pro-apoptotic ceramide levels in cancer cells, meperidine stimulates cell death and reverses multidrug resistance. Tamoxifen, a safe medication employed in the treatment of breast cancer, directly blocks P-glycoprotein and boosts levels of ceramide both via inhibition of glycosylceramide synthase and ceramidase. Further, tamoxifen blocks NMDA-neurotoxicity and therefore it may act synergistically with meperidine in reducing glioblastoma progression associated with NMDA-activation. Finally, tamoxifen blocks glycolysis which may enhance the mitochondrial-blocking activity of meperidine to shut down energy metabolism of glioblastoma cells. Because of these properties, we believe that the combination of meperidine and tamoxifen merits study in cell culture and animal models to investigate a potential synergistic relationship in the treatment of glioblastoma.
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Glioblastoma , Tamoxifeno , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose , Ceramidas/metabolismo , Ceramidas/farmacologia , Ceramidas/uso terapêutico , Glioblastoma/tratamento farmacológico , Humanos , Meperidina/farmacologia , Redes e Vias Metabólicas , N-Metilaspartato/metabolismo , Tamoxifeno/metabolismo , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêuticoRESUMO
Cancer is one of the main causes of human mortality and brain tumors, including invasive pituitary adenomas, medulloblastomas and glioblastomas are common brain malignancies with poor prognosis. Therefore, the development of innovative management strategies for refractory cancers and brain tumors is important. In states of mitochondrial dysfunction - commonly encountered in malignant cells - cells mostly shift to anaerobic glycolysis by increasing the expression of LDHA (Lactate Dehydrogenase-A) gene. Oxamate, an isosteric form of pyruvate, blocks LDHA activity by competing with pyruvate. By blocking LDHA, it inhibits protumorigenic cascades and also induces ROS (reactive oxygen species)-induced mitochondrial apoptosis of cancer cells. In preclinical studies, oxamate blocked the growth of invasive pituitary adenomas, medulloblastomas and glioblastomas. Oxamate also increases temozolomide and radiotherapy sensitivity of glioblastomas. Oxamate is highly polar, which may preclude its clinical utilization due to low penetrance through cell membranes. However, this obstacle could be overcome with nanoliposomes. Moreover, different oxamate analogs were developed which inhibit LDHC4, an enzyme also involved in cancer progression and germ cell physiology. Lastly, phenformin, an antidiabetic agent, exerts anticancer effects via complex I inhibition in the mitochondria and leading the overproduction of ROS. Oxamate combination with phenformin reduces the lactic acidosis-causing side effect of phenformin while inducing synergistic anticancer efficacy. In sum, oxamate as a single agent and more efficiently with phenformin has high potential to slow the progression of aggressive cancers with special emphasis to brain tumors.
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Neoplasias Encefálicas/patologia , L-Lactato Desidrogenase/antagonistas & inibidores , Ácido Oxâmico/farmacologia , Animais , Linhagem Celular Tumoral , Glicólise/fisiologia , Humanos , L-Lactato Desidrogenase/metabolismo , Mitocôndrias/metabolismo , Neoplasias/patologia , Fenformin/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Temozolomida/farmacologiaRESUMO
This study is focused on the preparation and characterization of erucic acid (EA) and phytosphingosine (PS) containing cationic nanoemulsions (NEs) for plasmid DNA (pDNA) delivery. Repurposing of cationic agents guided us to PS, previously used for enhanced interaction with negatively charged surfaces. It was reported that EA might act anti-tumoral on C6 glioma, melanoma, neuroblastoma, and glioblastoma. However, there is only one study about mixed oleic acid-EA liposomes. This gap attracted our interest in the possible synergistic effects of PS and EA on MDA-MB-231 and MCF-7 breast cancer cells. Three cationic NEs (NE 1, NE 2, and NE 3) were prepared and characterized in terms of droplet size (DS), polydispersity index (PDI), and zeta potential (ZP) before and after complexation with pDNA, long-term stability, SDS release, cytotoxicity, and transfection studies. The cationic NEs had DSs of <200 nm, PDIs <0.3, and ZPs > +30 mV. Long-term stability studies revealed that NE 2 and NE 3 were stable. NE 1-pDNA had appropriate particle properties. NE 2 reduced the viability of MDA-MB-231 cells to 11% and of MCF-7 cells to 13% and resulted in the highest number of transfected cells. To sum up, NE 2 containing PS and EA is appropriate for delivering pDNA.
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Neoplasias da Mama , Cátions , Sobrevivência Celular , DNA , Ácidos Erúcicos , Feminino , Humanos , Tamanho da Partícula , Plasmídeos/genética , Esfingosina/análogos & derivados , TransfecçãoRESUMO
BACKGROUND: Dysfunction of the gastrointestinal tract (GIT) is one of the most common non-motor symptom of Parkinson's Disease (PD). Pathological processes causing PD were suggested to initiate in the enteric nervous system (ENS) and proceed to the central nervous system (CNS). There are studies showing that low-carbohydrate ketogenic diets can improve motor symptoms of PD. Caprylic acid (C8) is the principal fatty acid component of the medium-chain triglycerides in the ketogenic diets. In this study, we aimed to evaluate the effects of caprylic acid, in neurotoxin exposed zebrafish focusing on the relationship between intestinal and brain oxidative stress and inflammation. METHODS: Adult zebrafish were exposed to rotenone (5 µg/L) (R group) and caprylic acid (20 and 60 mg/mL) (L + HDCA and R + HDCA groups) for 30 days. At the end of 30 days locomotor activities were determined. Levels of lipid peroxidation (LPO), nitric oxide, glutathione and superoxide dismutase and glutathione S-transferase activities were determined by spectrophotometric methods and gene expressions of tnfâº, il1, il6, il21, ifnÉ£ and bdnf were evaluated by RT-PCR in the brain and intestinal tissues of zebrafish. RESULTS: Caprylic acid ameliorated LPO, NO, SOD and the expressions of tnfâº, il1, il6, il21, ifnÉ£ and bdnf in brain and intestines. Locomotor activities were only ameliorated in high dose R + HDCA group. CONCLUSIONS: Caprylic acid ameliorated the neurotoxin-induced oxidative stress and inflammation both in the brain and intestines and enhanced locomotor activity in zebrafish.
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Eixo Encéfalo-Intestino/fisiologia , Caprilatos/farmacologia , Animais , Encéfalo/metabolismo , Eixo Encéfalo-Intestino/efeitos dos fármacos , Caprilatos/metabolismo , Modelos Animais de Doenças , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Glutationa/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/metabolismo , Rotenona/efeitos adversos , Superóxido Dismutase/metabolismo , Peixe-Zebra , Proteínas de Peixe-ZebraRESUMO
Despite most of the prolactinomas can be treated with endocrine therapy and/or surgery, a significant percentage of these tumors can be resistant to endocrine treatments and/or recur with prominent invasion into the surrounding anatomical structures. Hence, clinical, pathological, and molecular definitions of aggressive prolactinomas are important to guide for classical and novel treatment modalities. In this review, we aimed to define molecular endocrinological features of dopamine agonist-resistant and aggressive prolactinomas for designing future multimodality treatments. Besides surgery, temozolomide chemotherapy and radiotherapy, peptide receptor radionuclide therapy, estrogen pathway modulators, progesterone antagonists or agonists, mTOR/akt inhibitors, pasireotide, gefitinib/lapatinib, everolimus, and metformin are tested in preclinical models, anecdotal cases, and in small case series. Moreover, chorionic gonadotropin, gonadotropin releasing hormone, TGFß and PRDM2 may seem like possible future targets for managing aggressive prolactinomas. Lastly, we discussed our management of a unique prolactinoma case by asking which tumors' proliferative index (Ki67) increased from 5-6% to 26% in two subsequent surgeries performed in a 2-year period, exerted massive invasive growth, and secreted huge levels of prolactin leading up to levels of 1 605 671 ng/dl in blood.
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Agonistas de Dopamina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Prolactinoma/terapia , Terapia Combinada , Humanos , Prognóstico , Prolactinoma/metabolismo , Prolactinoma/patologiaRESUMO
INTRODUCTION: Astroblastoma, MN1-altered (old name: high-grade neuroepithelial tumor/HGNET with MN1 alteration) is a recently described central nervous system tumor mostly affecting pediatric patients and profoundly young girls. Differential pathological diagnoses of these tumors include ependymoma, pleomorphic xanthoastrocytoma, embryonal tumor with multilayered rosettes, meningioma, and even glioblastoma. As the treatment approaches to these tumors differ, it is essential to increase the awareness about these tumors in the neurosurgical community. CLINICAL PRESENTATION: A 7-year-old female patient admitted with a 7-day history of headache, nausea, and vomiting. A contrasted MRI scan revealed a left parietal 4 × 4 × 5 cm mass with central necrosis and peripheral contrast enhancement. The tumor's histopathological findings were suggestive of a metastatic carcinoma with unknown primary, yet further genetic analysis revealed MN1 alteration. Peculiarly, the tumor pathomorphological features were not compatible with astroblastomas and exerted features strongly indicating a metastatic cancer; however, systemic PET and whole-body MRI failed to detect a primary malignancy. OUTCOME AND CONCLUSIONS: Eighteen months after gross-total tumor resection, an in-field and out-field multifocal recurrence developed which required a second surgery and subsequent chemo-radiotherapy. The patient is doing well for 1 year after the second treatment regimen at the time of this report. Despite the final cIMPACT6 classification in 2020 advised to define all MN1 altered brain tumors as astroblastomas, there exist prognostic differences in MN1-altered tumors with and without morphological features of astroblastoma. Rare morphological variants of MN1-altered tumors shall be recognized for their future prognostic and clinical classification. HGNET with MN1 alteration seems still be a more proper definition of such malignancies as an umbrella term.
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Neoplasias Encefálicas , Carcinoma , Neoplasias Neuroepiteliomatosas , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Criança , Feminino , Humanos , Recidiva Local de Neoplasia , Neoplasias Neuroepiteliomatosas/diagnóstico por imagem , Neoplasias Neuroepiteliomatosas/genética , Transativadores , Proteínas Supressoras de TumorRESUMO
AIM: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a rare entity with a diffuse, infiltrative pattern, awaiting to be included in the WHO CNS tumor classification; it occurs in pediatric and young patients with seizures and harbors mutually exclusive BRAFV600E or FGFR mutations. Nonetheless, the presence of these mutations may not be obligatory for diagnosis. The conventional histology of these tumors resembles that of oligodendrogliomas. We aimed to discuss a PLNTY case in a young woman presenting with seizures due to a parietal brain tumor and to provide an analysis of the literature. Histopathologically the tumor was consistent of oligodendroglioma-like neoplastic cells showing almost diffuse CD34 and olig-2 staining, retained ATRX expression, p53-negativity, and a low Ki67 index with no necrosis or microvascular proliferation. MATERIALS AND METHODS: 1p/19q statuswas analyzed with FISH; IDH1 and IDH2 mutations were analyzed with minisequence analysis. Translocations, mutations, and expression analyses were studied for 18, 19, and 21 genes via targeted new-generation deep RNA sequencing, respectively. RESULTS: The tumor did not carry 1p/19q codeletion, was IDH wild-type, and had radiological features compatible with the diagnosis of PLNTY. The tumor did not show BRAF or FGFR alterations but had an EGFR c.2342A>G (p.Asn781Ser) mutation which was likely a non-driver mutation due to its low allele frequency of 4%. CONCLUSION: PLNTYs are rare brain tumors, and their accurate diagnosis is important to avoid improper management. Their prognosis shall be stratified according to their mutations.
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Neoplasias Encefálicas/patologia , Neoplasias Neuroepiteliomatosas/patologia , Neoplasias Encefálicas/complicações , Feminino , Humanos , Neoplasias Neuroepiteliomatosas/complicações , Lobo Parietal/patologia , Convulsões/etiologiaRESUMO
In this review study, we focus on potential benefits of the transcription factor PPARδ and its ligand erucic acid (EA) in management of neuroectodermal tumors and Parkinson's Disease. PPARδ is a nuclear receptor and transcription factor that induces myelination, promotes oligodendroglial and neuronal differentiation, and possess anti-neuroinflammatory properties. While both pro-tumorigenic and anti-tumorigenic effects have been described for PPARδ, we propose that PPARδ may perform a predominantly anticancer role in tumors originating from the neuroectoderm. PPARδ ligand-activation via oleic acid and GW501516, or overexpression of PPARδ, elicits profound antitumor actions in neuroblastoma and melanoma. In glioblastomas, there is evidence indicating a differentiation failure of O2A (oligodendroglial-astrocytic biprogenitor) cells and it has been shown that EA reduced DNA synthesis in C6 rat glioblastoma spheroid cultures in clinically achievable concentrations. EA is a ω9 fatty acid which is being used in the treatment of adrenoleukodystrophy. EA is widely consumed in Asian countries via ingestion of cruciferous vegetables including mustard and rapeseed oil. EA also exerts antioxidant and anti-inflammatory activities. Recent studies of Parkinson's Disease (PD) have implicated demyelination, white matter pathology, oligodendroglial injury, and neural inflammation in the underlying pathophysiology. In the rotenone PD model in rats, PPARδ ligand GW501516 saves dopaminergic neurons during injury induced by chemical toxins and improves behavioral functioning in PD via alleviation of endoplasmic reticulum stress. PPARδ agonists also reduce the NLRP3 inflammasome-associated neural inflammation in the MPTP PD model in mice. Herein, we propose that PPARδ and its ligand EA highly deserve to be studied in animal models of neuroblastoma, glioblastoma, and PD.
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Glioblastoma , Neuroblastoma , PPAR delta , Doença de Parkinson , Animais , Modelos Animais de Doenças , Ácidos Erúcicos , Humanos , Ligantes , Camundongos , Bainha de Mielina , RatosRESUMO
"Benign" metastatic leiomyomas (BML) are indolently growing metastatic tumors which mostly associate with uterine leiomyomas in women in reproductive ages. The reason to define these lesions as "benign" despite metastasis is their pathological features with low mitotic counts, lack of or minimal nuclear atypia, pseudocyst formation, and coagulative necrosis unlike leiomyosarcomas. Despite lack of pathological malignant features, they may cause significant morbidity and even mortality. Here, we describe a BML case with metastases to vertebrae and skull bones. Vertebral and skull metastases of BMLs were very rarely reported. In treatment of these tumors, hysterectomy and GnRH modifier treatments are widely employed. GnRH agonists act by desensitization and downregulation of the GnRH receptors, while GnRH antagonists act via the canonical competitive blockage. These treatments reduce FSH and LH levels, thereby reducing the systemic levels of sex steroids which stimulate leiomyoma growth. However, leiomyomas inherently harbor aromatase activity and synthesize their own estrogen; hence, treatment with systemic estrogen antagonists may provide better tumor control. Another important factor in BML pathogenesis is progesterone, and both progesterone receptor antagonists and high-dose progesterone receptor agonists may reduce BML growth. Following surgical treatment of the calvarial mass and radiotherapy of the vertebral metastatic foci, our BML case was successfully managed with hysterectomy and anastrozole treatment. Higher awareness of BML cases and their molecular endocrinological features in the neurosurgical community may pave to develop better strategies for treatment of these tumors causing high morbidity.
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Leiomioma/diagnóstico por imagem , Progesterona/antagonistas & inibidores , Neoplasias Cranianas/terapia , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias Uterinas/diagnóstico por imagem , Adulto , Feminino , Antagonistas de Hormônios/farmacologia , Antagonistas de Hormônios/uso terapêutico , Humanos , Leiomioma/sangue , Leiomioma/terapia , Progesterona/sangue , Neoplasias Cranianas/sangue , Neoplasias Cranianas/diagnóstico por imagem , Neoplasias Cranianas/secundário , Neoplasias da Coluna Vertebral/sangue , Neoplasias da Coluna Vertebral/secundário , Neoplasias da Coluna Vertebral/terapia , Neoplasias Uterinas/sangue , Neoplasias Uterinas/terapiaRESUMO
Epidemiological studies reported in 2016 and 2019 demonstrated that breast cancer patients under tamoxifen treatment had significantly reduced risks of meningioma development. Tamoxifen treatment duration longer than 1500 days or with cumulative dosage higher than 26 320 mg have especially lowered risk of meningioma. Clinical long-term anticancer efficacy of tamoxifen shall associate with simultaneous suppression of estrogen receptor and downregulation of certain growth factor pathways, which may associate with - but not limited to - protein kinase-C (PKC) signaling. In this study, we will put the evidence together and indicate that tamoxifen may be effective in meningioma treatment in some patients who do not express estrogen receptor but expresses PKC, yet much higher doses of tamoxifen will be needed to treat meningiomas than those applied to treat breast cancer. We underline the fact that immunohistochemical analysis of both estrogen receptor and PKC (especially α, δ, λ and ι isoenzymes) may guide in patient stratification for selective benefitting from tamoxifen in management of meningiomas. Lastly, it would also be logical to test individual responses of meningiomas to tamoxifen in primary monolayer and spheroid cultures before starting treatment in each patient as the differential distribution of PCK isoenzymes may cause also untoward effects.
Assuntos
Neoplasias da Mama , Neoplasias Meníngeas , Meningioma , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/prevenção & controle , Feminino , Humanos , Isoenzimas/uso terapêutico , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/epidemiologia , Neoplasias Meníngeas/prevenção & controle , Meningioma/tratamento farmacológico , Meningioma/epidemiologia , Meningioma/prevenção & controle , Receptores de Estrogênio/metabolismo , Tamoxifeno/uso terapêuticoRESUMO
BACKGROUND: Dural thickening is observed in lymphoma, dural carcinomatosis, meningioma, tuberculosis, and autoimmune diseases. We encountered a patient with dural thickening and complaints of neck and back pain, numbness and loss of strength in the hands. The patient also suffered from polychondritis and had previously received steroid and methotrexate treatment for this indication. The patients' serum was also positive for ANA, yet she did not have any other findings suggesting lupus. Our radiological and pathological analysis revealed IHSP (IgG4-related hypertrophic sclerosing pachymeningitis). In this review study, we provided a detailed literature survey to increase the awareness about IHSP in the neurosurgical community. METHODS: MRI (magnetic resonance imaging)-based radiological analyses revealed a posterior extramedullary spinal mass extending from C2 to T2-T3 level. The dural mass was surgically excised and a broad panel of immunohistochemical markers including S100, EMA, CD246/ALK-1, CD45, CD20, CD79a, CD138, CD68, CD1a and CD34 was studied. Immunoglobulin heavy chain/kappa chain gene rearrangement analysis was performed which ruled out a lymphoproliferative disorder. RESULTS: MRI and pathological findings suggested IHSP. As the disease relapsed with a new anterior extramedullary multilobulated lesion extending from C5 to T1 level, the patient is now closely monitored for further medical and surgical treatment. CONCLUSIONS: IHSP is a relatively novel entity of hypertrophic pachymeningitis and should be included in the differential diagnosis of dural thickening. The fibrosis accompanying IHSP may not respond to medical treatment, which includes steroids and immunosuppressive agents. Additionally, neurological deficits, seizures, spinal decompression, hydrocephalus, or brainstem compression necessitate early surgical intervention. A continued vigilance is also necessary as the disease may relapse long-term following surgical treatment.