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1.
J Am Pharm Assoc (2003) ; 64(1): 9-26.e6, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37844733

RESUMO

BACKGROUND: The U.S. Food and Drug Administration (FDA) revised the labels of sodium-glucose transporter 2 (SGLT2) inhibitors in December 2015 to inform users regarding the risk of diabetic ketoacidosis (DKA). As more drugs of this class are approved and their indications are expanded, this serious adverse effect has been increasingly reported. OBJECTIVE: This review evaluated observational studies to inform the prevalence of SGLT2-inhibitor-associated DKA compared with other antihyperglycemic agents. METHODS: A systematic review was conducted in PubMed and EMBASE until 19 July 2022 (PROSPERO: CRD42022385425). We included published retrospective cohort active comparator/new user (ACNU) and prevalent new user studies assessing SGLT2-inhibitor-associated DKA prevalence in adult patients with type 2 diabetes mellitus (T2DM) against active comparators. We excluded studies which lacked 1:1 propensity score matching. The JBI Checklist for Cohort Studies guided the risk-of-bias assessments. Meta-analysis was conducted based on the inverse variance method in R software. RESULTS: Sixteen studies with a sample of 2,956,100 nonunique patients met the inclusion criteria. Most studies were conducted in North America (n = 9) and adopted the ACNU design (n = 15). Meta-analysis of 14 studies identified 33% higher DKA risk associated with SGLT2 inhibitors (HR = 1.33, 95% CI: 1.14-1.55, P < 0.01). Meta-regression analysis identified the study location (P = 0.02), analysis principle (P < 0.001), exclusion of chronic comorbidities (P = 0.007), and canagliflozin (P = 0.04) as significant moderator variables. CONCLUSIONS: Despite limitations related to heterogeneity, generalizability, and misclassification, the results of this study show that SGLT2 inhibitors increase the prevalence of DKA among adult T2DM patients in the real world. The findings supplement evidence from randomized controlled trials (RCTs) and call for continued vigilance.


Assuntos
Diabetes Mellitus Tipo 2 , Cetoacidose Diabética , Inibidores do Transportador 2 de Sódio-Glicose , Adulto , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Cetoacidose Diabética/induzido quimicamente , Cetoacidose Diabética/epidemiologia , Cetoacidose Diabética/complicações , Prevalência , Transportador 2 de Glucose-Sódio , Nimustina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos
2.
Tohoku J Exp Med ; 261(3): 187-194, 2023 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-37635063

RESUMO

Convection-enhanced delivery (CED) delivers agents directly into tumors and the surrounding parenchyma. Although a promising concept, clinical applications are often hampered by insufficient treatment efficacy. Toward developing an effective CED-based strategy for delivering drugs with proven clinical efficacy, we performed a basic characterization study to explore the locally delivered characteristics of the water soluble nitrosourea nimustine hydrochloride (ACNU). First, ACNU distribution after CED in rodent brain was studied using mass spectrometry imaging. Clearance of 14C-labeled ACNU after CED in striatum was also studied. ACNU was robustly distributed in rodent brain similar to the distribution of the hydrophilic dye Evans blue after CED, and locally delivered ACNU was observed for over 24 h at the delivery site. Subsequently, to investigate the potential of ACNU to induce an immunostimulative microenvironment, Fas and transforming growth factor-ß1 (TGF-ß1) was assessed in vitro. We found that ACNU significantly inhibited TGF-ß1 secretion and reduced Fas expression. Further, after CED of ACNU in 9L-derived intracranial tumors, the infiltration of CD4/CD8 lymphocytes in tumors was evaluated by immunofluorescence.CED of ACNU in xenografted intracranial tumors induced tumor infiltration of CD4/CD8 lymphocytes. ACNU has a robust distribution in rodent brain by CED, and delayed clearance of the drug was observed at the local infusion site. Further, local delivery of ACNU affects the tumor microenvironment and induces immune cell migration in tumor. These characteristics make ACNU a promising agent for CED.


Assuntos
Antineoplásicos , Neoplasias Encefálicas , Ratos , Animais , Nimustina/uso terapêutico , Fator de Crescimento Transformador beta1 , Ratos Endogâmicos F344 , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Encefálicas/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Microambiente Tumoral
3.
Technol Health Care ; 31(2): 635-645, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36314174

RESUMO

BACKGROUND: Glioblastoma is the most common and most aggressive type of primary brain tumor. OBJECTIVE: The aim of this study was to investigate the efficacy and safety of intranasal granulocyte-macrophage colony stimulating factor (GM-CSF) administration combined with chemoradiotherapy in patients with glioblastoma who underwent surgery. METHODS: Ninety-two patients were randomly divided into two groups: a control group (n= 46), who received radiotherapy with adjuvant local delivery of nimustine hydrochloride (ACNU) and systemic administration of temozolomide, and an intervention group (n= 46), who received intranasal GM-CSF prior to each cycle of adjuvant chemotherapy in addition to the treatment of the control group. Karnofsky performance status (KPS) scores, progression-free survival (PFS), overall survival (OS), and adverse effects were calculated and compared between the two groups. RESULTS: Compared with the control group, the intervention group had longer PFS (7.8 vs. 6.9 months, P= 0.016) and OS (19.2 vs. 17.1 months, P= 0.045, without adjustment for interim analyses). The KPS scores were also higher in the intervention group than in the control group after 6 months (84.35 ± 8.86 vs. 80.65 ± 7.72; t= 4.552, P= 0.036). Furthermore, the patients in the intervention group had lower incidence of neutropenia and thrombocytopenia (8.7% vs. 29.5%, P= 0.012; 8.7% vs. 18.2%, P= 0.186). Other adverse events were similar in both groups, and most adverse events were grade I/II and resolved spontaneously. CONCLUSION: Intranasal GM-CSF enhances the efficacy of the local ACNU administration combined with oral temozolomide chemotherapy. The survival and performance status were significantly improved in patients with glioblastoma after surgery. Additionally, the GM-CSF therapy was able to reduce the occurrence of chemotherapy-related neutropenia and thrombocytopenia.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neutropenia , Trombocitopenia , Humanos , Temozolomida/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Nimustina/uso terapêutico , Fator Estimulador de Colônias de Macrófagos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Neutropenia/tratamento farmacológico , Trombocitopenia/tratamento farmacológico , Granulócitos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia
4.
Cells ; 11(8)2022 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-35455970

RESUMO

The increase in follicular atresia and the decrease in the fecundity of laying hens occur with the aging process. Therefore, the key measure for maintaining high laying performance is to alleviate follicular atresia in the aging poultry. Follicle-stimulating hormone (FSH), as an important pituitary hormone to promote follicle development and maturation, plays an important role in preventing reproductive aging in diverse animals. In this study, the physiological state of the prehierarchical small white follicles (SWFs) and atretic SWFs (ASWFs) were compared, followed by an exploration of the possible capacity of FSH to delay ASWFs' progression in the hens. The results showed that the DNA damage within follicles increased with aging, along with Golgi complex disintegration, cell cycle arrest, increased apoptosis and autophagy in the ASWFs. Subsequently, the ACNU-induced follicular atresia model was established to evaluate the enhancing capacity of FSH on increasing cell proliferation and attenuating apoptosis in ASWFs. FSH inhibited DNA damage and promoted DNA repair by regulating the CHK2/p53 pathway. Furthermore, FSH inhibited CHK2/p53, thus, suppressing the disintegration of the Golgi complex, cell cycle arrest, and increased autophagy in the atretic follicles. Moreover, these effects from FSH treatment in ACNU-induced granulosa cells were similar to the treatment by a DNA repair agent AV-153. These results indicate that FSH protects aging-resulted DNA damage in granulosa cells by inhibiting CHK2/p53 in chicken prehierarchical follicles.


Assuntos
Hormônio Foliculoestimulante , Atresia Folicular , Animais , Galinhas/metabolismo , Dano ao DNA , Feminino , Hormônio Foliculoestimulante/farmacologia , Células da Granulosa/metabolismo , Nimustina/metabolismo , Nimustina/farmacologia , Proteína Supressora de Tumor p53/metabolismo
5.
Vet Med Sci ; 8(1): 3-8, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599792

RESUMO

BACKGROUND: Nimustine, similar to lomustine, is an alkylating agent from the nitrosourea family. There have been some reports regarding lomustine treatment for tumour-bearing cats. However, information regarding nimustine treatment for tumour-bearing cats is limited. OBJECTIVES: To retrospectively evaluate adverse events and clinical outcomes in tumour-bearing cats receiving nimustine. METHODS: Information regarding diagnosis, treatment condition, adverse events, and clinical outcomes was collected in tumour-bearing cats receiving nimustine through reviews of medical records. RESULTS: Nine cats with lymphoma were treated with nimustine in the primary therapy (n = 2) and in the rescue therapy (n = 7). Median starting dose of nimustine was 25 mg/m2 (range: 20-30 mg/m2 ) with dosing interval of three weeks and 1-11 administrations. Adverse events were mild gastrointestinal toxicity (grade 1) including diarrhoea (n = 2) and vomiting (n = 2) and mild myelosuppression (grade 1 or 2) including thrombocytopenia (n = 3) and neutropenia (n = 1). No severe adverse events were observed. Progression-free survival durations among cats receiving nimustine in the primary therapy and in the rescue therapy were 274-688 days (median: 481 days) and 9-671 days (median: 102 days), respectively. Overall survival durations among cats receiving nimustine in the primary therapy and in the rescue therapy were 275-745 days (median: 510 days) and 14-671 days (median: 109 days), respectively. CONCLUSIONS: Nimustine was well tolerated and showed clinical outcomes similar to lomustine in cats with lymphoma. These findings suggest that nimustine might be an alternative to lomustine in the treatment of feline lymphoma.


Assuntos
Doenças do Gato , Linfoma , Animais , Doenças do Gato/induzido quimicamente , Doenças do Gato/tratamento farmacológico , Gatos , Lomustina/efeitos adversos , Linfoma/tratamento farmacológico , Linfoma/veterinária , Nimustina/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
6.
Cancer Sci ; 112(11): 4736-4747, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34536314

RESUMO

Glioblastomas (GBM) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ-resistant GBM (TMZ-R-GBM). Lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents against GBM before TMZ, have occasionally been used for the salvage therapy of TMZ-R-GBM; however, their efficacy has not yet been thoroughly examined. Therefore, we investigated the antitumor effects of CCNU and ACNU against TMZ-R-GBM. As a model of TMZ-R-GBM, TMZ resistant clones of human GBM cell lines (U87, U251MG, and U343MG) were established (TMZ-R-cells) by the culture of each GBM cells under continuous TMZ treatment, and the antitumor effects of TMZ, CCNU, or ACNU against these cells were analyzed in vitro and in vivo. As a result, although growth arrest and apoptosis were triggered in all TMZ-R-cells after the administration of each drug, the antitumor effects of TMZ against TMZ-R-cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ-R-cells as well as parental cells. It was also demonstrated that TMZ resistance of TMZ-R-cells was regulated at the initiation of DNA damage response. Furthermore, survival in mice was significantly prolonged by systemic treatment with CCNU or ACNU but not TMZ after implantation of TMZ-R-cells. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against TMZ-R-GBM.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Lomustina/uso terapêutico , Nimustina/uso terapêutico , Temozolomida/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/metabolismo , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Glioblastoma/metabolismo , Histonas/metabolismo , Humanos , Injeções Intraperitoneais , Lomustina/administração & dosagem , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/tratamento farmacológico , Nimustina/administração & dosagem , Terapia de Salvação/métodos , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Vet Med Sci ; 7(6): 2103-2107, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34405564

RESUMO

A 7-year-old spayed female Scottish Fold cat presented with a 4-week history of anorexia, weight loss and vomiting. Abdominal ultrasonography revealed a jejunal mass and a slightly enlarged jejunal lymph node. A fine-needle aspiration of the mass revealed many round cells with multiple small intracytoplasmic magenta granules. The mass was diagnosed as a large granular lymphocyte (LGL) lymphoma based on cytology. The LGL lymphoma was completely resected via open surgery. The histologic and cytologic evaluations showed no neoplastic findings in the jejunal lymph node, liver, spleen, kidney or bone marrow. The LGL lymphoma was localized to the jejunum. Postoperatively, the cat received chemotherapy with nimustine, L-asparaginase and prednisolone. The cat is currently receiving nimustine every 6 weeks, without adverse events, and treatment has been administrated a total of 18 times up until day 552. The cat is in a good condition, and the LGL lymphoma has not recurred. Nimustine should be considered one of the effective chemotherapeutic agents in the treatment of feline LGL lymphoma cases in the future.


Assuntos
Antineoplásicos , Doenças do Gato , Linfoma , Animais , Doenças do Gato/tratamento farmacológico , Doenças do Gato/cirurgia , Gatos , Feminino , Linfócitos/patologia , Linfoma/patologia , Linfoma/veterinária , Recidiva Local de Neoplasia/veterinária , Nimustina
8.
J Am Anim Hosp Assoc ; 56(3): 146, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32182105

RESUMO

The objective of this retrospective study was to report treatment outcomes in dogs with histiocytic sarcoma (HS) that were treated with nimustine (ACNU). This study evaluated data from 11 dogs including 5 with macroscopic tumors that were treated in the primary setting and 6 that underwent aggressive local therapy while being treated in the adjuvant setting. The median ACNU starting dose was 25 mg/m2 (range, 20-30 mg/m2; 3- to 5-wk intervals, 1-8 administrations). The median overall survival in the primary and adjuvant settings was 120 days (median progression-free survival [PFS], 63 days) and 400 days (median PFS, 212 days), respectively. Neutropenia was observed in eight cases (grade 1, n = 1; grade 2, n = 2; grade 3, n = 2; grade 4, n = 3) with nadir neutrophil count at 1 wk after ACNU administration. Mild gastrointestinal toxicity (grade 1-2) was observed in three cases. ACNU was well tolerated and showed a similar outcome to that seen for lomustine, which is a drug commonly used to treat canine HS, in terms of overall survival and PFS in the current study population. Further investigations will need to be undertaken to definitively determine if ACNU is an appropriate alternative to lomustine for the treatment of HS.


Assuntos
Antineoplásicos/uso terapêutico , Doenças do Cão/tratamento farmacológico , Sarcoma Histiocítico/veterinária , Nimustina/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Cães , Feminino , Sarcoma Histiocítico/tratamento farmacológico , Sarcoma Histiocítico/mortalidade , Masculino , Neutropenia/induzido quimicamente , Neutropenia/veterinária , Nimustina/efeitos adversos , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
9.
Oper Neurosurg (Hagerstown) ; 18(4): 451-459, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31414134

RESUMO

BACKGROUND: Spinal cord high-grade glioma has poor prognosis. Especially, no treatment protocols have been established for recurrent cases. OBJECTIVE: To apply a novel treatment method, convection-enhanced delivery (CED), for recurrent high-grade glioma. CED can deliver chemotherapeutic agents directly into the intramedullary lesion and possibly lead to remarkable regression of enlarging tumors that are, otherwise, difficult to control. METHODS: Two patients developed high-grade glioma in the thoracic spinal cord. Partial resection and chemotherapy and radiotherapy induced remission of the disease. However, following the initial treatment, recurrence was noted in the spinal cord at 6 and 12 mo, respectively. No effective treatment was available for these recurrent lesions. Therefore, the authors decided to use CED to infuse nimustine hydrochloride (ACNU) directly into the spinal cord. During the procedure, the infusion cannula was inserted into the spinal cord lesion under intraoperative computed tomography scan. RESULTS: After ACNU CED, successive magnetic resonance imaging confirmed remarkable shrinkages of the tumors in both cases. However, the patient's preinfusion symptoms, including bilateral lower extremity weakness, did not change after the treatment. Importantly, overall survivals of the 2 patients were as long as 67 and 33 mo. CONCLUSION: The authors report the first 2 cases of recurrent spinal cord high-grade glioma. ACNU CED dramatically regressed enhanced mass lesions and provided local tumor controls in the spinal cord.


Assuntos
Convecção , Glioma , Sistemas de Liberação de Medicamentos , Glioma/diagnóstico por imagem , Glioma/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/tratamento farmacológico , Nimustina/uso terapêutico , Medula Espinal
10.
Neurol Med Chir (Tokyo) ; 60(1): 37-44, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31748440

RESUMO

After introduction of levetiracetam (LEV), treatment of seizures in patients with malignant brain tumors has prominently improved. On the other hand, we still experience some cases with LEV-uncontrollable epilepsy. Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoaxazolepropionate acid receptor antagonist that has recently been approved for treating focal epilepsy as a secondary drug of choice. Available literature reporting PER medication in patients with gliomas is still sparse. Here, we report our initial experience with glioma patients and report efficacy of adding low dose 2-4 mg PER to LEV in patients whose seizure were uncontrollable with LEV monotherapy. Clinical outcome data of 18 consecutive patients were reviewed. This included nine males and nine females aged 24-76 years (median, 48.5 years), treated for glioma between June 2009 to December 2018. We added PER to patients with LEV-uncontrollable epilepsy. Adverse effects, irritability occurred in two patients, but continuous administration was possible in all cases. Though epileptic seizures occurred in four cases receiving 2 mg PER, 17 cases achieved seizure freedom by dose increments; final dose, 2-4 mg PER added to LEV 500-3000 mg. Our study revealed anti-epileptic efficacy of low dose PER 2-4 mg as first add-on therapy to LEV in glioma patients who have failed or intolerable to LEV monotherapy. Low dose PER added on to LEV may have favorable efficacy with tolerable adverse effects in glioma patients with LEV-uncontrollable epilepsy.


Assuntos
Anticonvulsivantes/uso terapêutico , Neoplasias Encefálicas/complicações , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Glioma/complicações , Levetiracetam/uso terapêutico , Piridonas/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Terapia Combinada , Resistência a Medicamentos , Epilepsia Resistente a Medicamentos/etiologia , Feminino , Seguimentos , Glioma/diagnóstico por imagem , Glioma/terapia , Humanos , Levetiracetam/farmacologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Procedimentos Neurocirúrgicos , Nimustina/administração & dosagem , Nitrilas , Piridonas/farmacologia , Radioterapia Adjuvante , Receptores de AMPA/antagonistas & inibidores , Estudos Retrospectivos , Temozolomida/administração & dosagem , Adulto Jovem
11.
World Neurosurg ; 126: 624-630, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30599247

RESUMO

BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) is categorized as grade II, other astrocytic tumors per the 2016 World Health Organization classification. Despite being a relatively benign type of tumor, PXA often has an aggressive clinical course. The more malignant form of PXA is now known as anaplastic pleomorphic xanthoastrocytoma (A-PXA) and is categorized as a grade III tumor. Clinical and genetic factors associated with malignant transformation remain unclear. In particular, typical genetic expression patterns in PXA and A-PXA remain unidentified. CASE DESCRIPTION: We present a case of recurrent PXA in which malignant transformation followed a promoter mutation in TERT. In this case, genetic chronologic changes accompanying malignant transformation of PXA were thoroughly examined. The promoter mutation was detected in the second operative specimen after stereotactic radiosurgery (SRS) at the first tumor recurrence. Subsequently, a malignant transformation to the A-PXA occurred at the time of the second recurrence, and the tumor repeatedly recurred afterward. CONCLUSIONS: TERT promotor mutations may contribute to the malignant transformation of PXA; the mechanism of this mutation is unknown, but it may have been caused by SRS. Therefore, improvident use of radiation should be avoided to prevent the malignant transformation of PXA.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Transformação Celular Neoplásica/genética , Mutação , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas/genética , Telomerase/genética , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Astrocitoma/tratamento farmacológico , Astrocitoma/patologia , Astrocitoma/cirurgia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Terapia Combinada , Inibidor de Quinase Dependente de Ciclina p15/genética , Procedimentos Cirúrgicos de Citorredução , Análise Mutacional de DNA , DNA de Neoplasias/genética , Feminino , Deleção de Genes , Genes p16 , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Nimustina/uso terapêutico , Fotoquimioterapia , Porfirinas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Radiocirurgia , Reoperação , Lobo Temporal/patologia
12.
Neurology ; 90(19): e1673-e1681, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29643079

RESUMO

OBJECTIVE: We investigated whether cognitive performance between ages 43 and 69 years was associated with timing of menopause, controlling for hormone replacement therapy, childhood cognitive ability, and sociobehavioral factors. METHODS: We used data from 1,315 women participating in the Medical Research Council National Survey of Health and Development (a British birth cohort study) with known age at period cessation and up to 4 assessments of verbal memory (word-learning task) and processing speed (letter-cancellation task) at ages 43, 53, 60-64, and 69. We fitted multilevel models with linear and quadratic age terms, stratified by natural or surgical menopause, and adjusted for hormone replacement therapy, body mass index, smoking, occupational class, education, and childhood cognitive ability. RESULTS: Verbal memory increased with later age at natural menopause (0.17 words per year, 95% confidence interval [CI]: 0.07-0.27, p = 0.001); an association remained, albeit attenuated, after full adjustment (0.09, 95% CI: 0.02-0.17, p = 0.013). Verbal memory also increased with later age at surgical menopause (0.16, 95% CI: 0.06-0.27, p = 0.002), but this association was fully attenuated after adjustment. Search speed was not associated with age at menopause. CONCLUSION: Our findings suggest lifelong hormonal processes, not just short-term fluctuations during the menopause transition, may be associated with verbal memory, consistent with evidence from a variety of neurobiological studies; mechanisms are likely to involve estrogen receptor ß function. Further follow-up is required to assess fully the clinical significance of these associations.


Assuntos
Envelhecimento , Cognição/fisiologia , Menopausa , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Bleomicina , Estudos de Coortes , Ciclofosfamida , Citarabina , Doxorrubicina , Feminino , Humanos , Memória/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Nimustina , Fatores Socioeconômicos , Reino Unido/epidemiologia , Aprendizagem Verbal/fisiologia
13.
J Cancer Res Ther ; 14(1): 78-83, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29516964

RESUMO

BACKGROUND: Glioblastoma (GBM) is one of the worst cancers with bad prognosis despite systemic chemotherapy and radiotherapy after surgery. METHODS: In this study, 71 patients with GBM were enrolled and randomly assigned to two groups: Receiving radiotherapy with concomitant and adjuvant temozolomide (TMZ) (TMZ, standard therapy) after surgery, or receiving radiotherapy with concomitant and adjuvant local delivery of nimustine (ACNU) rendezvousing with oral TMZ (rendezvous therapy). In the follow-up of all patients and the progression-free survival (PFS), overall survival (OS), Karnofsky performance score (KPS) and toxicities were recorded. RESULTS: For the whole cohort, the median OS was 18.0 months, and the median PFS was 7.8 months. A significantly longer OS was observed in patients received rendezvous therapy than those who receiving standard therapy (18.5 months vs. 16.0 months; P = 0.014), as well as PFS (8.8 months vs. 7.0 months; P = 0.008). The KPS ≥70 rates were 81.8%, 40.9%, 20.5% in 1, 2, and 3 years for the rendezvous therapy group, significantly superior to standard therapy group. The most common toxicities were tolerable gastrointestinal reaction, liver dysfunction, and hematological toxicities, which were relieved with symptomatic treatment. Grade 3 or 4 toxicity was documented in 8 (18.3%) patients in rendezvous therapy group, while it was observed in 6 (22.2%) patients in standard therapy group during whole treatment process. CONCLUSIONS: Compared to standard therapy, the antitumor effects of rendezvous therapy were more effective in GBM patients without increasing the toxicities.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia , Terapia Combinada , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Feminino , Seguimentos , Glioblastoma/diagnóstico , Glioblastoma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Nimustina/administração & dosagem , Modelos de Riscos Proporcionais , Qualidade de Vida , Radioterapia/efeitos adversos , Radioterapia/métodos , Temozolomida , Tomografia Computadorizada por Raios X , Resultado do Tratamento
14.
Exp Dermatol ; 27(1): 64-70, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28833504

RESUMO

Together with regulatory T cells (Tregs), tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment. Although cytotoxic antimelanoma drugs such as dacarbazine (DTIC), nimustine hydrochloride (ACNU) and vincristine (VCR) have been used for the treatment of malignant melanoma as adjuvant therapy in Japan, the detailed mechanisms of their immunomodulatory effects are not fully understood. As the majority of TAMs are alternatively activated M2 macrophages that favour tumor development, the aim of this study was to elucidate the immunomodulatory effects of these reagents on human monocyte-derived M2 macrophages. First, mRNA expressions and protein production of immune checkpoint molecules, PD-L1 and chemokines by CD163+ CD206+ M2 macrophages derived from peripheral blood mononuclear cells were investigated to determine the immunomodulatory effects of DTIC, ACNU, and VCR. DTIC and VCR significantly decreased PD-L1 mRNA expression, which was confirmed by flow cytometry. Moreover, the mRNA expression and production of CCL22 were significantly decreased by DTIC, which suggested that DTIC might suppress the recruitment of Tregs in the tumor site. Furthermore, the decreased expression of PD-L1 and production of CCL22 were validated in vivo, using the B16F10 mouse melanoma model, leading to abrogation of the suppressive function of T-cell proliferation. The present report suggests one of the possible antimelanoma mechanisms of DAV combination chemotherapy for melanoma patients.


Assuntos
Antineoplásicos/farmacologia , Macrófagos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno B7-H1/metabolismo , Dacarbazina/farmacologia , Feminino , Japão , Lectinas Tipo C/metabolismo , Leucócitos Mononucleares/metabolismo , Macrófagos/metabolismo , Receptor de Manose , Lectinas de Ligação a Manose/metabolismo , Melanoma Experimental , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Nimustina/farmacologia , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Vincristina/farmacologia
15.
JCO Clin Cancer Inform ; 2: 1-21, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30652567

RESUMO

PURPOSE: A major adverse effect arising from nimustine hydrochloride (ACNU) therapy for brain tumors is myelosuppression. Because its timing and severity vary among individual patients, the ACNU dose level has been adjusted in an empiric manner at individual medical facilities. To our knowledge, ours is the first study to develop a machine-learning approach to estimate myelosuppression through analysis of patient factors before treatment and attempts to clarify the relationship between myelosuppression and hematopoietic stem cells from daily clinical data. Adverse effect prediction will allow ACNU dose adjustment for patients predicted to have decreases in blood cell counts and will enable focused follow-up of patients undergoing chemoradiotherapy. PATIENTS AND METHODS: Patients were newly pathologically diagnosed with WHO grade 2 or 3 tumors and were treated with ACNU-based chemoradiotherapy. For detailed analysis of the timing and intensity of adverse effects in patients, we developed a data-weighted support vector machine (SVM) based on adverse event criteria (nadir-weighted SVM [NwSVM]). To evaluate the estimation accuracy of blood cell count dynamics, the determination coefficient ( r2) between real and estimated data was calculated by three regression methods: polynomial, SVM, and NwSVM. RESULTS: Only the NwSVM-based regression enabled estimation of the dynamics of all blood cell types with high accuracy (mean r2 = 0.81). The mean timing of nadir arrival estimated using this regression was 35 days for platelets, 41 days for RBCs, 52 days for lymphocytes, 57 days for WBCs, and 62 days for neutrophils. CONCLUSION: The NwSVM can be used to predict myelosuppression and clearly depicts nadir timing differences between platelets and other blood cells.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Leucopenia/diagnóstico , Aprendizado de Máquina , Modelos Estatísticos , Mielopoese/efeitos dos fármacos , Nimustina/efeitos adversos , Adulto , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Neoplasias Encefálicas/patologia , Feminino , Seguimentos , Humanos , Leucopenia/induzido quimicamente , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
16.
Medicine (Baltimore) ; 96(41): e8218, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29019889

RESUMO

RATIONALE: Small cell lung cancer (SCLC) characterized by high degree of malignancy and rapid tumor progression. Intracranial metastases often appear at the time of the initial diagnosis or treatment. Besides of radiotherapy, chemotherapy is supposed to have limited effect. PATIENT CONCERNS: A 66-year-old male had blurred vision and unsteady step with moderate headache, nausea, vomit. DIAGNOSES: The patient was diagnosed with SCLC with intracranial metastases. INTERVENTIONS: High dose of nimustine (ACNU) (300 mg/m) add to the regimen containing carboplatin and irinotecan. OUTCOMES: Although the patient suffered severe myelosuppression, the intracranial lesion almost disappeared and maintained half a year. LESSONS: ACNU at a dose of 200 mg/m might be tolerable in combination with other chemotherapeutic drugs for the treatment of SCLC with intracranial metastases besides radiotherapy.


Assuntos
Neoplasias Encefálicas , Neoplasias Pulmonares/patologia , Nimustina , Carcinoma de Pequenas Células do Pulmão/patologia , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos Antineoplásicos , Encéfalo/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Relação Dose-Resposta a Droga , Humanos , Masculino , Estadiamento de Neoplasias , Exame Neurológico/métodos , Nimustina/administração & dosagem , Nimustina/efeitos adversos , Resultado do Tratamento , Transtornos da Visão/diagnóstico , Transtornos da Visão/etiologia
17.
Clin Cancer Res ; 23(22): 7020-7033, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28821557

RESUMO

Purpose: We aimed to characterize and target drug-tolerant BRCA1-deficient tumor cells that cause residual disease and subsequent tumor relapse.Experimental Design: We studied responses to various mono- and bifunctional alkylating agents in a genetically engineered mouse model for BRCA1/p53-mutant breast cancer. Because of the large intragenic deletion of the Brca1 gene, no restoration of BRCA1 function is possible, and therefore, no BRCA1-dependent acquired resistance occurs. To characterize the cell-cycle stage from which Brca1-/-;p53-/- mammary tumors arise after cisplatin treatment, we introduced the fluorescent ubiquitination-based cell-cycle indicator (FUCCI) construct into the tumor cells.Results: Despite repeated sensitivity to the MTD of platinum drugs, the Brca1-mutated mammary tumors are not eradicated, not even by a frequent dosing schedule. We show that relapse comes from single-nucleated cells delaying entry into the S-phase. Such slowly cycling cells, which are present within the drug-naïve tumors, are enriched in tumor remnants. Using the FUCCI construct, we identified nonfluorescent G0-like cells as the population most tolerant to platinum drugs. Intriguingly, these cells are more sensitive to the DNA-crosslinking agent nimustine, resulting in an increased number of multinucleated cells that lack clonogenicity. This is consistent with our in vivo finding that the nimustine MTD, among several alkylating agents, is the most effective in eradicating Brca1-mutated mouse mammary tumors.Conclusions: Our data show that targeting G0-like cells is crucial for the eradication of BRCA1/p53-deficient tumor cells. This can be achieved with selected alkylating agents such as nimustine. Clin Cancer Res; 23(22); 7020-33. ©2017 AACR.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Genes BRCA1 , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/genética , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Cisplatino/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Genes p53 , Humanos , Camundongos , Camundongos Knockout , Nimustina/farmacologia
18.
Acta Neurochir (Wien) ; 159(5): 939-946, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28247160

RESUMO

BACKGROUND: Convection-enhanced delivery (CED) is a technique allowing local infusion of therapeutic agents into the central nervous system, circumventing the blood-brain or spinal cord barrier. OBJECTIVE: To evaluate the utility of nimustine hydrochloride (ACNU) CED in controlling tumor progression in an experimental spinal cord glioma model. METHODS: Toxicity studies were performed in 42 rats following the administration of 4 µl of ACNU CED into the mid-thoracic spinal cord at concentrations ranging from 0.1 to 10 mg/ml. Behavioral analyses and histological evaluations were performed to assess ACNU toxicity in the spinal cord. A survival study was performed in 32 rats following the implantation of 9 L cells into the T8 spinal cord. Seven days after the implantation, rats were assigned to four groups: ACNU CED (0.25 mg/ml; n = 8); ACNU intravenous (i.v.) (0.4 mg; n = 8); saline CED (n = 8); saline i.v. (n = 8). Hind limb movements were evaluated daily in all rats for 21 days. Tumor sizes were measured histologically. RESULTS: The maximum tolerated ACNU concentration was 0.25 mg/ml. Preservation of hind limb motor function and tumor growth suppression was observed in the ACNU CED (0.25 mg/ml) and ACNU i.v. groups. Antitumor effects were more prominent in the ACNU CED group especially in behavioral analyses (P < 0.05; log-rank test). CONCLUSIONS: ACNU CED had efficacy in controlling tumor growth and preserving neurological function in an experimental spinal cord tumor model. ACNU CED can be a viable treatment option for spinal cord high-grade glioma.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Glioma/tratamento farmacológico , Nimustina/administração & dosagem , Neoplasias da Medula Espinal/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Convecção , Masculino , Nimustina/uso terapêutico , Ratos , Ratos Endogâmicos F344
19.
J Pathol ; 241(4): 511-521, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27943283

RESUMO

Women with heterozygous germline mutations in the BRCA1 tumour suppressor gene are strongly predisposed to developing early-onset breast cancer through loss of the remaining wild-type BRCA1 allele and inactivation of TP53. Although tumour prevention strategies in BRCA1-mutation carriers are still limited to prophylactic surgery, several therapeutic strategies have been developed to target the DNA repair defects (also known as 'BRCAness') of BRCA1-deficient tumours. In particular, DNA-damaging agents such as platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors show strong activity against BRCA1-mutated tumours. However, it is unclear whether drugs that target BRCAness can also be used to prevent tumour formation in BRCA1-mutation carriers, especially as loss of wild-type BRCA1 may not be the first event in BRCA1-associated tumourigenesis. We performed prophylactic treatments in a genetically engineered mouse model in which de novo development of BRCA1-deficient mammary tumours is induced by stochastic loss of BRCA1 and p53. We found that prophylactic window therapy with nimustine, cisplatin or olaparib reduced the amount and size of mammary gland lesions, and significantly increased the median tumour latency. Similar results were obtained with intermittent prophylactic treatment with olaparib. Importantly, prophylactic window therapy with nimustine and cisplatin resulted in an increased fraction of BRCA1-proficient mammary tumours, suggesting selective survival and malignant transformation of BRCA1-proficient lesions upon prophylactic treatment with DNA-damaging agents. Prophylactic therapy with olaparib significantly prolonged mammary tumour-free survival without any significant increase in the fraction of BRCA1-proficient tumours, warranting the evaluation of this PARP inhibitor in prophylactic trials in BRCA1-mutation carriers. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteínas Supressoras de Tumor/genética , Animais , Antineoplásicos/uso terapêutico , Proteína BRCA1 , Cisplatino/farmacologia , Reparo do DNA , Modelos Animais de Doenças , Feminino , Mutação em Linhagem Germinativa , Humanos , Neoplasias Mamárias Animais/patologia , Neoplasias Mamárias Animais/prevenção & controle , Camundongos , Nimustina/farmacologia , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Supressoras de Tumor/metabolismo
20.
Artigo em Inglês | MEDLINE | ID: mdl-27599192

RESUMO

A new method to evaluate the anticancer activity at the molecular level has been developed. In our assay, the interaction between alkylating anticancer drugs-Fe3O4/CA with DNA has been investigated for the Resonance Light Scattering (RLS) signal enhancement. Water-based nano-Fe3O4, as a probe, has the ability of good solubility, biodegradability and low bulk resistivity etc. The experimental results show that, the activity order of three kinds of drugs is Nimustine (ACNU)>Semustine (Me-CCNU)>Chlormethine (HN2), which is satisfied with the results of the cell apoptosis experiment and the IC50 by MTT method. This assay is simple, sensitive and high efficient. And the theoretical basics for the development of new anticancer drugs as well as the assessments of their efficacy to cure breast and hepatic cancer have been provided.


Assuntos
Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacologia , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Nanopartículas Metálicas/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ácido Cítrico/química , DNA/química , DNA/metabolismo , Portadores de Fármacos/farmacologia , Feminino , Compostos Férricos/química , Humanos , Concentração Inibidora 50 , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Células MCF-7 , Nimustina/farmacologia , Semustina/farmacologia , Espectrofotometria Infravermelho , Viscosidade
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