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1.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33435537

RESUMO

Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood-brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.


Assuntos
Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioma/genética , Transdução de Sinais/genética , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Terapia Combinada , Receptores ErbB/genética , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Glioblastoma/terapia , Glioma/metabolismo , Glioma/patologia , Glioma/terapia , Humanos , Transdução de Sinais/efeitos dos fármacos , Temozolomida/uso terapêutico
2.
Cancer Radiother ; 25(2): 182-190, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33436285

RESUMO

PURPOSE: The efficacy of hypofractionated radiotherapy (HFRT) in glioblastoma (GBM) without age restrictions remains unclear. The aim of this meta-analysis is to access the survival outcomes of HFRT in these patients. METHODS: A comprehensive electronic literature search of PubMed, Web of Science and Cochrane Library was conducted up to June 1, 2020. The main evaluation data were the overall survival (OS) rate at 12 months and 24 months and the progression-free survival (PFS) rate at 6 and 12 months. The secondary evaluation data was the incidence of radionecrosis and adverse events. The study was performed using R "meta" package. RESULTS: Eleven studies met the inclusion criteria, which totally contained 484 participants. The 12-month OS and 24-month OS rate of HFRT in GBM were 71.3% and 34.8%, while the 6-month PFS and 12-month rate were 74.0% and 40.8%. Compared to low-BED (biological equivalent dose) schedules (<78Gy), high-BED schedules may increase survival benefit both in PFS-6 (P=0.003) and PFS-12 (P=0.011), while the difference did not show on OS. Different dose per fraction had no significant effect on both OS and PFS. Incidence of radionecrosis was 14.2%. Although the overall incidence of adverse reactions cannot be quantified, the toxicity of HFRT was acceptable. CONCLUSIONS: Compared with survival data for standard treatment, HFRT seemed to improve overall survival and progression-free survival, while high BED schedules may future increase benefit on PFS. Meanwhile, the toxicity of HFRT was tolerable. Further randomised controlled clinical studies are needed to confirm these findings.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Glioblastoma/terapia , Hipofracionamento da Dose de Radiação , Temozolomida/uso terapêutico , Neoplasias Encefálicas/mortalidade , Quimiorradioterapia/efeitos adversos , Quimioterapia Adjuvante/métodos , Glioblastoma/mortalidade , Humanos , Incidência , Necrose , Intervalo Livre de Progressão , Lesões por Radiação/epidemiologia , Lesões por Radiação/patologia , Taxa de Sobrevida , Fatores de Tempo
3.
Cancer Sci ; 112(3): 1141-1149, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33377228

RESUMO

PIK3CA is the most frequently mutated oncogene in cervical cancer, and somatic mutations in the PIK3CA gene result in increased activity of PI3K. In cervical cancer, the E545K mutation in PIK3CA leads to elevated cell proliferation and reduced apoptosis. In the present study, we designed and synthesized a novel pyrrole-imidazole polyamide-seco-CBI conjugate, P3AE5K, to target the PIK3CA gene bearing the E545K mutation, rendered possible by nuclear access and the unique sequence specificity of pyrrole-imidazole polyamides. P3AE5K interacted with double-stranded DNA of the coding region containing the E545K mutation. When compared with conventional PI3K inhibitors, P3AE5K demonstrated strong cytotoxicity in E545K-positive cervical cancer cells at lower concentrations. PIK3CA mutant cells exposed to P3AE5K exhibited reduced expression levels of PIK3CA mRNA and protein, and subsequent apoptotic cell death. Moreover, P3AE5K significantly decreased the tumor growth in mouse xenograft models derived from PIK3CA mutant cells. Overall, the present data strongly suggest that the alkylating pyrrole-imidazole polyamide P3AE5K should be a promising new drug candidate targeting a constitutively activating mutation of PIK3CA in cervical cancer.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Mutação com Ganho de Função , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Camundongos , Nylons/síntese química , Nylons/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Pirróis/síntese química , Pirróis/farmacologia , Pirróis/uso terapêutico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Medicine (Baltimore) ; 99(51): e23592, 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33371090

RESUMO

RATIONALE: Non-small cell lung cancer (NSCLC) patients with brain metastases (BMs) have been found as subjects of poor prognosis. Whole-brain radiotherapy (WBRT), surgery, and stereotactic radiosurgery, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), or some combinations are the most commonly employed strategies for the treatment of treatments BMs. However, some patients are resistant to all these treatments. PATIENT CONCERNS: We present an NSCLC patient with progression of BMs after treatment with WBRT and EGFR-TKIs. The patient was diagnosed with multiple metastases on July 9, 2014, and treated with docetaxel plus cisplatin chemotherapy followed with gefitinib as the maintenance therapy. The patient showed recurrence of BMs after 8-months of chemotherapy. WBRT with 30 Gy was administrated in 10 fractions. Tumor progression of the brain was diagnosed with an magnetic resonance imaging scan after 2-months of WBRT. DIAGNOSES: The patient was diagnosed as pulmonary adenocarcinoma with diffuse metastases in both lungs and multiple metastases in bone and brain. Progression of BMs was confirmed through magnetic resonance imaging. INTERVENTIONS: This patient was administered temozolomide (150 mg/m2/d for 5 days every 28-day cycle). As a whole, 6 cycles were performed after the progression of BMs from August 2015. OUTCOMES: The patient got complete brain remission and lived without discomfort. The intracranial lesion did not progress until the progression of the lung lesion and led to death on February 20, 2019. The intracranial progression-free survival was 42 months, whereas the overall survival was 55 months. LESSONS: For patients with NSCLC and BMs, temozolomide can be used as a treatment option, especially in patients with EGFR-TKIs resistance or without driver mutations.


Assuntos
Adenocarcinoma de Pulmão/patologia , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias Pulmonares/patologia , Temozolomida/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Intervalo Livre de Progressão
5.
N Z Med J ; 133(1523): 41-54, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33032302

RESUMO

AIM: The aim of this study was to determine the prevalence of dental developmental disturbances in long-term survivors of childhood malignancies in New Zealand children. This study reports associations with potential risk factors to inform oncologists and dentists of the likelihood of dental abnormalities. METHODS: The study population was children aged 14-16 years old who were diagnosed with cancer prior to 10 years of age. A total of 156 children were eligible, of which 59 participated in this study. The indices used in this study were Holtta's Defect Index (HDI), and Oral Health Impact Profile-14 (OHIP-14). RESULTS: The prevalence of agenesis was 15.3%, microdontia 6.8% and root abnormalities 32.2%. Cyclophosphamide equivalent doses above 8,000mg/m2, stem cell therapy (SCT), and head and neck radiation therapy (HNRT) were associated with a higher mean number of teeth missing due to agenesis. SCT and HNRT were associated with a higher total HDI. A binary logistic regression was carried out to determine the odds of agenesis and found that HNRT was the main contributing factor (OR=7.7, p-value=0.04). The linear regression model found that dactinomycin and agenesis correlated with the largest mean OHIP-14. CONCLUSION: This study found that childhood cancer survivors in New Zealand had a high prevalence of developmental dental abnormalities and it identified potential risk factors related to their cancer treatment. Inequitable access to oral rehabilitation for this patient group argues for a mechanism for consistent improved access to publicly funded dental care across district health boards in New Zealand.


Assuntos
Anodontia , Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias , Adolescente , Anodontia/complicações , Anodontia/epidemiologia , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Estudos Transversais , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Masculino , Neoplasias/complicações , Neoplasias/epidemiologia , Neoplasias/terapia , Nova Zelândia , Prevalência , Radioterapia/efeitos adversos , Transplante de Células-Tronco/efeitos adversos
6.
Lancet Haematol ; 7(11): e827-e837, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33091356

RESUMO

Waldenström macroglobulinaemia is an indolent B-cell lymphoma with clearly defined criteria for diagnosis, initiation of therapy, and response, which was established by consensus panels at previous International Workshops for Waldenström Macroglobulinaemia (IWWM). The treatment options for Waldenström macroglobulinaemia continued to be researched after the publication of the eighth IWWM consensus recommendations in 2016, and at the tenth IWWM in New York, USA (October, 2018) an international consensus panel was formed to update treatment recommendations. Participants were selected as members of the consensus panel based on their expertise on Waldenström macroglobulinaemia. The initial live discussion took place during the tenth IWWM meeting and two separate teleconferences were held in June, 2019, and January, 2020, to refine recommendations. No external or financial support was received for the elaboration of these recommendations. According to these updated consensus recommendations, alkylating drugs (bendamustine, cyclophosphamide) and proteasome inhibitors (bortezomib, carfilzomib, ixazomib), both in combination with rituximab, as well as BTK inhibitors (ibrutinib), alone or in combination with rituximab, are preferred first-line therapy options for symptomatic patients with Waldenström macroglobulinaemia. In previously treated patients with Waldenström macroglobulinaemia who had an initial durable response, reuse of a previous regimen or another primary therapy regimen are acceptable options. Novel BTK inhibitors (acalabrutinib, zanubrutinib, tirabrutinib) and the BCL2 antagonist venetoclax appear safe and active, and represent emerging options for the treatment of Waldenström macroglobulinaemia. The choice of therapy should be guided by the patient's clinical profile, genomic features, and drug availability.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Consenso , Humanos , Guias de Prática Clínica como Assunto , Inibidores de Proteassoma/uso terapêutico
8.
Medicine (Baltimore) ; 99(39): e22299, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991435

RESUMO

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a condition characterized by a hyperinflammatory state and persistent macrophage activation, resulting in reactive phagocytosis of the hematopoietic elements. In children, it is usually a hereditary disorder, while in adults it is usually acquired secondary to viral infections, collagenoses, or tumors. Although accounting for 10% of hematologic malignancies, HLH is rarely associated with multiple myeloma (MM) and other plasmacytic dyscrasias. PATIENT CONCERNS: A 64-year-old Brazilian man seeked medical care with a 3-month history of intermittent fever, weight loss, night sweats, and progressive anemic symptoms. DIAGNOSIS: Total blood count showed severe bicytopenia (normocytic-normochromic anemia and thrombocytopenia), biochemical exams showed elevation of creatinine, as well as monoclonal peak in serum protein electrophoresis, high IgA dosage, and serum immunofixation with IgA kappa paraprotein. Bone marrow biopsy showed 30% of monoclonal and phenotypically anomalous plasmocytes, confirming the diagnosis of MM. Diagnosis of HLH was established by the presence of clinical and laboratory criteria: fever, splenomegaly, cytopenias, hypofibrinogenemia, hyperferritinemia, elevation of triglycerides, and several figures of erythrophagocytosis in bone marrow aspirate. INTERVENTIONS: The patient experienced pulse therapy with methylprednisolone for hemophagocytic lymphohistiocytosis, followed by initial therapy for multiple myeloma with cyclophosphamide and dexamethasone. OUTCOMES: Once the diagnosis of MM and secondary hemophagocytic syndrome was established, the patient had a rapid clinical deterioration despite the established therapeutic measures, evolving with cardiovascular failure, acute liver failure, acute disseminated intravascular coagulation, worsening renal dysfunction requiring dialysis support, respiratory dysfunction, and lowering of consciousness, characterizing rapid multiple organ dysfunction, ultimately leading to the death of the patient. INNOVATION: Here, we aimed to describe the sixth reported case of HLH associated with MM, according to cases cataloged in the PubMed database, and the first case evaluated by 18-fluordeoxyglucose positron emission tomography (18-FDG-PETCT). CONCLUSION: Our case report seeks to provide support for a better clinical and laboratory characterization of this rare paraneoplastic entity associated with MM, and aims to call the attention of hematologists and intensivists to this condition that falls within the scope of the differential diagnosis of rapid onset multiple organ failure in patients with plasmacytic neoplasms.


Assuntos
Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/etiologia , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Anemia/sangue , Anemia/etiologia , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/uso terapêutico , Medula Óssea/patologia , Brasil/epidemiologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Quimioterapia Combinada , Evolução Fatal , Febre/diagnóstico , Febre/etiologia , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/diagnóstico , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Insuficiência de Múltiplos Órgãos/complicações , Paraproteinemias/sangue , Plasmócitos/patologia , Esplenomegalia/diagnóstico , Esplenomegalia/etiologia , Trombocitopenia/sangue , Trombocitopenia/etiologia , Perda de Peso
9.
Clinics (Sao Paulo) ; 75: e1553, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32935821

RESUMO

OBJECTIVES: To assess the patterns of failure and prognostic factors in Brazilian patients with glioblastoma multiforme (GBM) treated with radiotherapy (RT) and concurrent and adjuvant temozolomide (TMZ). METHODS: Patients with diagnosed GBM post-resection received postoperative RT. TMZ was administered concurrently at 75 mg/m2/day for 28 consecutive days and adjuvant therapy at 150-200 mg/m2/day for 5 days every 28 days. Radiographic failure was defined as any new T1-enhancing lesion or biopsy-confirmed progressive enhancement inside of the radiation field. When possible, patients with recurrence were salvaged with metronomic TMZ, either in combination with a local treatment or alone (surgery or re-irradiation). Several prognostic factors were evaluated for overall survival (OS). Univariate and multivariate analyses were performed to identify significant factors. A p-value <0.05 was considered significant. RESULTS: This study included 50 patients. The median follow-up time was 21 months. The median RT dose was 60 Gy and all patients received concomitant TMZ. During follow-up, 41 (83.6%) failures were observed, including 34 (83%) in-field, 4 (9.7%) marginal, and 3 (7.3%) distant failures. Metronomic TMZ was used as salvage treatment in 22 (44%) cases and in combination with local treatment in 12 (24%) cases. The median OS and progression-free survival times for the entire cohort were 17 and 9 months, respectively. In univariate analysis, the following factors were significant for better OS: maximal surgical resection (p=0.03), Karnofsky Performance Score (KPS)>70 at diagnosis (p=0.01), metronomic TMZ treatment (p=0.038), recursive partitioning analysis class III (p=0.03), and time to failure >9 months (p=0.0001). In multivariate analysis, the following factors remained significant for better OS: metronomic TMZ (p=0.01) and time to failure >9 months (p=0.0001). CONCLUSION: The median OS of Brazilian patients with GBM treated with RT and TMZ was satisfactory. Although TMZ therapy has become the standard of care for patients with newly diagnosed GBM, the recurrence rate is extremely high. Metronomic TMZ as salvage treatment improved survival in these patients.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Glioblastoma/terapia , Recidiva Local de Neoplasia/epidemiologia , Temozolomida/uso terapêutico , Neoplasias Encefálicas/patologia , Brasil/epidemiologia , Quimioterapia Adjuvante , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Estudos Retrospectivos , Sobrevida , Resultado do Tratamento
10.
Ann Hematol ; 99(10): 2367-2375, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32816079

RESUMO

This study aimed to define the maximum tolerated dose (MTD) of temozolomide (TMZ) concurrent with radiotherapy (RT) after high-dose methotrexate (HD-MTX) for newly diagnosed primary central nervous system lymphoma (PCNSL). Adult patients with PCNSL were treated according to a response-adapted strategy. HD-MTX (3.5 g/m2) was followed by concomitant RT and escalating TMZ (50-60-75 mg/m2/day, 5 days/week). The total radiation dose was modulated according to the patient's response to HD-MTX. All patients received 30 Gy to the whole brain plus leptomeninges to C2, including the third posterior of the orbital cavity (clinical target volume 2; CTV2), plus 6, 10, or 16 Gy to the primary site, including the residual mass (CTV1), if a complete response (CR), partial response (PR)/stable disease (SD), or progressive disease (PD) was observed, respectively. Acute toxicities were graded according to the RTOG-EORTC criteria. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicity or grade 3-4 hepatic toxicity, although 75 mg/m2/day was the maximum dose regardless of DLT. Neurocognitive function was evaluated using the Mini-Mental State Examination. Three patients were enrolled at each TMZ dose level (total = 9 patients). Twelve lesions were treated. Six patients received 2 cycles of HD-MTX, while 3 received only 1 cycle because of hepatic or renal toxicity. All patients completed chemoradiotherapy without interruptions. No DLT events were recorded. TMZ appears to be tolerable at a dose of 75 mg/m2/day when administered concomitantly with radiotherapy and after HD-MTX.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Irradiação Craniana , Linfoma não Hodgkin/terapia , Temozolomida/uso terapêutico , Adolescente , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Quimioterapia Adjuvante , Transtornos Cognitivos/induzido quimicamente , Quimioterapia de Consolidação , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Masculino , Dose Máxima Tolerável , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Neoplasia Residual , Intervalo Livre de Progressão , Estudos Prospectivos , Temozolomida/efeitos adversos , Adulto Jovem
11.
Science ; 369(6506): 936-942, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820119

RESUMO

Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2Kb-restricted CD8+ T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.


Assuntos
Antígenos de Neoplasias/imunologia , Bacteriófagos/imunologia , Streptococcus faecium ATCC 9790/virologia , Microbioma Gastrointestinal/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Proteínas da Cauda Viral/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Reações Cruzadas , Ciclofosfamida/uso terapêutico , Epitopos/imunologia , Fezes/virologia , Antígenos H-2/imunologia , Humanos , Camundongos , Neoplasias/dietoterapia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Proteínas da Cauda Viral/uso terapêutico
12.
Medicine (Baltimore) ; 99(28): e21147, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664146

RESUMO

High-grade gliomas (HGGs) are a rapidly progressive and highly recurrent group of primary brain tumors. Despite aggressive surgical resection with chemoradiotherapy, prognoses remained poor. Valproic acid (VPA), a histone deacetylase inhibitor has shown the potential to inhibit glioma cell growth in vitro through several diverse mechanisms. However clinical studies regarding the effect of VPA on HGGs are limited. This study aimed to investigate whether using VPA in patients with HGGs under temozolomide (TMZ) would lead to a better overall survival (OS).We used the Taiwan National Health Insurance Research database to conduct this population-based cohort study. A total of 2379 patients with HGGs under TMZ treatment were included and were further classified into VPA (n = 1212, VPA ≥ 84 defined daily dose [DDD]) and non-VPA (n = 1167, VPA < 84 DDD) groups. Each patient was followed from 1998 to 2013 or until death. A Cox proportional hazard regression was performed to evaluate the effect of VPA and OS.The VPA group had a longer mean OS time compared with the non-VPA group (OS: 50.3 ±â€Š41.0 vs 42.0 ±â€Š37.2 months, P < .001). In patients between 18 and 40 years old, the difference is most significant (OS: 70.5 ±â€Š48.7 vs 55.1 ±â€Š46.0, P = .001). The adjusted hazard ratio is 0.81 (95% confidence interval, 0.72-0.91) for the VPA group relative to the non-VPA group.VPA at over 84 DDD improved OS in HGGs TMZ treatment.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Estadiamento de Neoplasias , Vigilância da População/métodos , Temozolomida/uso terapêutico , Ácido Valproico/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Inibidores Enzimáticos/uso terapêutico , Feminino , Seguimentos , Glioma/diagnóstico , Glioma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Taiwan/epidemiologia , Adulto Jovem
13.
PLoS One ; 15(7): e0235016, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32609726

RESUMO

OBJECTIVE: Intravitreal melphalan injections are commonly used in the treatment for intraocular retinoblastoma. This study compares retinal toxicity and ocular survival between two formulations, with and without propylene glycol (Alkeran vs. Evomela, respectively). METHODS: A retrospective cohort study of retinoblastoma patients who received intravitreal injections of Alkeran and Evomela at 30 µg from September 2012 to January 2019 at a single tertiary care center were enrolled. Retinal toxicity was measured using electroretinogram (ERG) and compared using a multivariate analysis of 338 injections in 101 eyes of 96 patients. Ocular survival of 163 eyes in 150 patients was compared across formulations using Cox proportional hazards model. Eyes were censored at the time a patient received a dose other than 30 µg. RESULTS: Overall, ERG decline (mean, 95% CI) for each injection was -5.58 µV (-7.17, -3.99). No significant differences in ERG decrement were found between Alkeran (with alcohol) -5.52uV (-6.99, -4.05). and Evomela (without alcohol) -5.65uV (-8.31 to -2.98) formulations (p = 0.93). Ocular survival at 24 months was 93.6% (95% CI 86.2, 97.1) with alcohol and 91.7% (95% CI 53.9, 98.8) without alcohol. The hazard ratio (HR) for without vs with alcohol was 0.50 (95% CI 0.06 to 4.07); no significant difference in ocular survival was found between formulations (p = 0.52). CONCLUSIONS AND RELEVANCE: No differences were found in retinal toxicity and ocular survival between 30 µg intravitreal injections of Alkeran or Evomela for intraocular retinoblastoma. Given the increased stability of Evomela, intravitreal treatment could be expanded to centers without the ability to supply Alkeran due to its shorter safety window; however, Alkeran is less expensive. For those with existing infrastructure, Alkeran is a comparable, cost-effective alternative.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Melfalan/uso terapêutico , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Adolescente , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Criança , Pré-Escolar , Humanos , Lactente , Injeções Intravítreas , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Retina/efeitos dos fármacos , Resultado do Tratamento
14.
Medicine (Baltimore) ; 99(24): e20223, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541449

RESUMO

INTRODUCTION: At present, there is no uniform consensus on the treatment of brain metastases from esophageal cancer. The studies on the treatment of brain metastases from esophageal cancer by radiotherapy combined with temozolomide (TMZ) are even rarer. PATIENT CONCERNS: A 69-year-old woman was admitted to our hospital for brain metastases from esophageal cancer after thoracic irradiation. DIAGNOSES: Magnetic resonance imaging of the head showed a round, heterogeneous metastatic tumor in the left parietal lobe. Brain magnetic resonance imaging showed edema around brain metastasesInterventions: After radiotherapy plus TMZ in this patient's head, the brain metastatic tumor was significantly decreased. OUTCOMES: At the end of radiotherapy, and 1 and 2 months after the end of radiotherapy, the metastatic tumor continued to shrink, and no obvious side effects were observed. LESSONS: This study suggests that radiotherapy plus TMZ might be a feasible option for brain metastases from esophageal cancer.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Esofágicas/patologia , Temozolomida/uso terapêutico , Administração Oral , Assistência ao Convalescente , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Terapia Combinada/métodos , Neoplasias Esofágicas/radioterapia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Metástase Neoplásica/patologia , Radioterapia/métodos , Temozolomida/administração & dosagem , Resultado do Tratamento
16.
PLoS One ; 15(5): e0232249, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32357178

RESUMO

AIM: To report our first three-and-a-half years' experience with intra-arterial chemotherapy (IAC) in managing retinoblastoma (RB). METHODS: Single institution, retrospective, interventional case series of 14 retinoblastoma patients managed with IAC from December 2014 to June 2018. Demographics were described. Outcomes measures were tumor response, treatment complications and globe salvage. RESULTS: Subjects' mean age at the first administration of IAC was 31.4 months. 57.1% of the eyes were Group D and E retinoblastoma, while 79% were bilateral disease. 93% of the eyes were as secondary treatment. Of 32 IAC cannulations performed, 23 (71.8%) were successful and received chemotherapy drug melphalan. Each eye received a mean of 1.8 (range 1-4) IAC injections. 53% of the eyes showed regression post treatment. After a mean follow up period of 19 months, globe salvage rate was 38%. Most of the adverse effects experienced were localized and transient. CONCLUSION: IAC has provided an added recourse in the armamentarium of retinoblastoma treatment in our center. IAC treatment is a viable alternative in the treatment of retinoblastoma to salvage globe, for eyes that would conventionally require enucleation especially in bilateral disease.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Melfalan/uso terapêutico , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Antineoplásicos Alquilantes/administração & dosagem , Pré-Escolar , Feminino , Humanos , Lactente , Infusões Intra-Arteriais , Malásia , Masculino , Melfalan/administração & dosagem , Estudos Retrospectivos , Terapia de Salvação , Resultado do Tratamento
17.
BMC Neurol ; 20(1): 178, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393192

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is one of the most aggressive malignant brain tumors. Intracranial GBM metastases to the spine are rarely detected clinically. Secondary gliosarcomas after treatment of primary GBM are rarely described. CASE PRESENTATION: Herein, we report the case of a 53-year-old woman who presented to our emergency room with progressive headache and weakness on the left side. Plain computed tomography and contrast magnetic resonance imaging of the brain revealed an approximately 6.8 cm × 4.5 cm right temporoparietooccipital intraaxial cystic tumor with surrounding diffuse perifocal edema that caused midline shift toward the left. Emergency craniotomy was performed to remove the tumor, and pathological examination revealed GBM. The patient received proton beam therapy, Gliadel implantation, and oral temozolomide chemotherapy as well as targeted therapy with bevacizumab. Approximately 15 months after diagnosis, she underwent surgical resection of the right temporal recurrent tumor and was newly diagnosed as having a metastatic spinal tumor. Pathologically, the right temporal and metastatic spinal tumors were gliosarcoma and GBM, respectively. CONCLUSIONS: Concurrent spinal metastasis and gliosarcomatous transformation, which are two types of GBM complications, are rare. To our knowledge, this is the first report of a case of recurrent GBM with gliosarcoma after proton bean therapy.


Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/patologia , Glioblastoma/secundário , Gliossarcoma/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias da Coluna Vertebral/secundário , Antineoplásicos Alquilantes/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Craniotomia , Evolução Fatal , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/terapia , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/terapia , Terapia com Prótons , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/cirurgia , Temozolomida/uso terapêutico , Tomografia Computadorizada por Raios X
18.
Jpn J Clin Oncol ; 50(8): 948-952, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32463097

RESUMO

The prognosis of patients with relapsed osteosarcoma is extremely poor and the optimal treatment remains to be identified. Here, we retrospectively analysed the clinical outcomes of nine patients with relapsed osteosarcoma treated with temozolomide/etoposide. Of the two patients who received temozolomide/etoposide as palliative therapy for unresectable tumours, one remained alive with stable disease for >4 years. The remaining seven patients received temozolomide/etoposide as adjuvant therapy following resection of relapsed metastatic disease; of these, one was free from disease for 41 months. Potentially beneficial effects were observed in two of three O6-methylguanine-DNA methyltransferase protein-negative patients, whereas all five O6-methylguanine-DNA methyltransferase-positive patients experienced subsequent relapse. None of the patients experienced severe adverse effects requiring hospitalization. Temozolomide/etoposide is a feasible candidate as salvage therapy for relapsed osteosarcoma. Further studies are needed to verify the utility of O6-methylguanine-DNA methyltransferase protein expression as a biomarker for predicting the response to this treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Etoposídeo/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Temozolomida/uso terapêutico , Adolescente , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Criança , Feminino , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Adulto Jovem
19.
Nature ; 580(7804): 517-523, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32322066

RESUMO

A high tumour mutational burden (hypermutation) is observed in some gliomas1-5; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Mutação , Animais , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/imunologia , Reparo de Erro de Pareamento de DNA/genética , Frequência do Gene , Genoma Humano/efeitos dos fármacos , Genoma Humano/genética , Glioma/imunologia , Humanos , Masculino , Camundongos , Repetições de Microssatélites/efeitos dos fármacos , Repetições de Microssatélites/genética , Mutagênese/efeitos dos fármacos , Mutação/efeitos dos fármacos , Fenótipo , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Análise de Sequência de DNA , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Medicine (Baltimore) ; 99(16): e19804, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32311997

RESUMO

BACKGROUND AND OBJECTIVES: Rituximab (RTX) is considered to be a promising drug for curing membranous nephropathy. However, the efficacy and safety of RTX in treating membranous nephropathy remain uncertain. This meta-analysis aimed to investigate the efficacy and safety of RTX in patients with membranous nephropathy. METHODS: A literature search was performed using Pubmed, Embase, OVID, and Cochrane Library and randomized controlled trials (RCTs) case-controls and cohort studies published till 30 July 2019 were assessed. The studies assessing the efficacy and safety of RTX in patients with membranous nephropathy were included. RESULTS: Eight relevant trials involving 542 patients were included in the meta-analysis. It was found that RTX did not significantly improve serum albumin levels and e-GFR when compared with the control group (including cyclosporine and cyclophosphamide, chlorambucil, prednisone, non-immunosuppressive anti-proteinuria treatment), serum albumin levels (OR = 0.31, 95%CI-0.12-0.74, P = .15), e-GFR (OR = -1.49, 95%CI-17.14-14.17, P = .85). However, RTX did reduce the serum creatinine (OR = -0.01, 95%CI-0.36-0.34, P = .95) and urinary protein (OR = -2.39, 95%CI -7.30 -2.53, P = .34) levels. Also, in comparison to the control group, RTX did improve the total remission rate (OR = 1.63, 95%CI 0.48-5.54, P = .43), achieve a higher rate of complete remission (OR = 2.54, 95%CI 1.65-3.90, P < .01) and also reduced the amount of M-type phospholipase A2 receptor-Antibody depletion in patients (OR = 5.59, 95%CI 1.81-17.2, P = .003). RTX-related adverse events were mostly mild (most infusion-related reactions) in nature and serious adverse events were rare. CONCLUSION: RTX proved to be efficient, well-tolerated and a safe drug in the treatment of membranous nephropathy. Most patients reach complete remission during the follow-up period, and relapse is rare. RTX may turn out to be promising in membranous nephropathy patients.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Glomerulonefrite Membranosa/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Estudos de Casos e Controles , Clorambucila/uso terapêutico , Ciclofosfamida/uso terapêutico , Ciclosporina/uso terapêutico , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Glomerulonefrite Membranosa/fisiopatologia , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Proteinúria/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores da Fosfolipase A2/efeitos dos fármacos , Receptores da Fosfolipase A2/imunologia , Indução de Remissão , Rituximab/efeitos adversos , Segurança , Albumina Sérica/efeitos dos fármacos , Resultado do Tratamento
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