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1.
Rheumatology (Oxford) ; 61(1): 163-173, 2021 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33744914

RESUMO

OBJECTIVES: Arterial calcification due to deficiency of CD73 (ACDC) is a hereditary autosomal recessive ectopic mineralization syndrome caused by loss-of-function mutations in the ecto-5'-nucleotidase gene. Periarticular calcification has been reported but the clinical characterization of arthritis as well as the microstructure and chemical composition of periarticular calcifications and SF crystals has not been systematically investigated. METHODS: Eight ACDC patients underwent extensive rheumatological and radiological evaluation over a period of 11 years. Periarticular and synovial biopsies were obtained from four patients. Characterization of crystal composition was evaluated by compensated polarized light microscopy, Alizarin Red staining for synovial fluid along with X-ray diffraction and X-ray micro tomosynthesis scanner for periarticular calcification. RESULTS: Arthritis in ACDC patients has a clinical presentation of mixed erosive-degenerative joint changes with a median onset of articular symptoms at 17 years of age and progresses over time to the development of fixed deformities and functional limitations of small peripheral joints with, eventually, larger joint and distinct axial involvement later in life. We have identified calcium pyrophosphate and calcium hydroxyapatite (CHA) crystals in SF specimens and determined that CHA crystals are the principal component of periarticular calcifications. CONCLUSION: This is the largest study in ACDC patients to describe erosive peripheral arthropathy and axial enthesopathic calcifications over a period of 11 years and the first to identify the composition of periarticular calcifications and SF crystals. ACDC should be considered among the genetic causes of early-onset OA, as musculoskeletal disease signs may often precede vascular symptoms.


Assuntos
5'-Nucleotidase/deficiência , Calcinose/diagnóstico por imagem , Artropatias/diagnóstico por imagem , Periartrite/diagnóstico por imagem , Doenças Vasculares/diagnóstico por imagem , 5'-Nucleotidase/genética , Calcinose/genética , Calcinose/patologia , Pré-Escolar , Feminino , Proteínas Ligadas por GPI/genética , Humanos , Artropatias/genética , Artropatias/patologia , Masculino , Pessoa de Meia-Idade , Periartrite/genética , Periartrite/patologia , Radiografia , Doenças Vasculares/genética , Doenças Vasculares/patologia
2.
Lancet Oncol ; 19(2): 207-215, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29361470

RESUMO

BACKGROUND: High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle checkpoint kinase 1 and 2 inhibitor, would be active in BRCA wild-type disease. METHODS: In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma. All patients had a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type status, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status score 0-2, and adequate haematological, renal, hepatic, and bone-marrow function. Patients received intravenous prexasertib 105 mg/m2 administered over 1 h every 14 days in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint of investigator-assessed tumour response, based on RECIST version 1.1, was assessed per protocol (assessable patients who had undergone CT imaging at baseline and attended at least one protocol-specified follow-up) and by intention to treat. The final analysis of this cohort of patients with BRCA wild-type high-grade serous ovarian carcinoma is reported here. This ongoing trial is registered with ClinicalTrials.gov, number NCT02203513, and continues to enrol patients for the BRCA-mutated ovarian cancer cohort. FINDINGS: Between Jan 20, 2015, and Nov 2, 2016, we enrolled 28 women with a median age of 64 years (IQR 58·0-69·5) who had previously received a median of 5·0 (IQR 2·5-5·0) systemic therapies. Most patients (22 [79%]) had platinum-resistant or platinum-refractory disease. All women received at least one dose of prexasertib, but four (14%) of 28 patients were not assessable for RECIST response. Eight (33%, 95% CI 16-55) of 24 patients assessable per protocol had partial responses. In the intention-to-treat population, eight (29%, 95% CI 13-49) of 28 had a partial responses. The most common (in >10% patients) grade 3 or 4 treatment-emergent adverse events were neutropenia in 26 (93%) of 28 patients, reduced white blood cell count in 23 (82%), thrombocytopenia in seven (25%), and anaemia in three (11%). Grade 4 neutropenia was reported in 22 (79%) patients after the first dose of prexasertib and was transient (median duration 6 days [IQR 4-8]) and recovered without growth-factor support in all cases. The treatment-related serious adverse event of grade 3 febrile neutropenia was reported in two (7%) patients. One patient died during the study due to tumour progression. INTERPRETATION: Prexasertib showed clinical activity and was tolerable in patients with BRCA wild-type high-grade serous ovarian carcinoma. This drug warrants further development in this setting, especially for patients with platinum-resistant or platinum-refractory disease. FUNDING: Intramural Research Program of the National Institutes of Health and National Cancer Institute.


Assuntos
Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Pirazinas/uso terapêutico , Pirazóis/uso terapêutico , Adulto , Idoso , Proteína BRCA1/efeitos dos fármacos , Proteína BRCA1/genética , Proteína BRCA2/efeitos dos fármacos , Proteína BRCA2/genética , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Medição de Risco , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Adulto Jovem
3.
Neurosciences (Riyadh) ; 17(2): 151-5, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22465890

RESUMO

OBJECTIVE: To investigate the safety, tolerability, and short-term efficacy of treatment with erythropoietin in patients with optic neuritis as a first demyelination event. METHODS: We conducted this randomized double-blind pilot study in the Shiraz University of Medical Sciences, Shiraz, Iran, from March 2007 to January 2009. The participants were patients aged 18-45 years with optic neuritis and at least 3 hyperintense lesions on T2-weighted and FLAIR MRI, but no clinically definite multiple sclerosis (MS). They were randomized into 2 groups. The case group (5 patients) received intravenous methyl prednisolone (1000 mg/24 hours) and intravenous erythropoietin (20,000 unit/24 hours) for 5 consecutive days, and the control group (5 patients) received intravenous methyl prednisolone at the same dose as the case group, and a placebo. The groups were followed for one year and compared for adherence to protocol, adverse drug effects, mean duration of conversion to clinically definite MS, and MRI changes. RESULTS: All patients tolerated the protocol. One patient who received erythropoietin developed cerebral venous sinus thrombosis and anti-cardiolipin antibody positivity. One patient in the control group, but no patients in the case group, fulfilled the McDonald criteria for MS during the follow-up period, but none of the participants in either group developed clinically definite MS according to the Poser criteria. CONCLUSION: Erythropoietin may be effective, but should be used with caution.


Assuntos
Doenças Desmielinizantes/tratamento farmacológico , Eritropoetina/administração & dosagem , Esclerose Múltipla/tratamento farmacológico , Neurite Óptica/tratamento farmacológico , Doença Aguda , Adolescente , Adulto , Doenças Desmielinizantes/patologia , Quimioterapia Combinada , Eritropoetina/efeitos adversos , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Neurite Óptica/patologia , Projetos Piloto , Prednisolona/administração & dosagem , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
4.
Clin Cancer Res ; 26(16): 4268-4279, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32398324

RESUMO

PURPOSE: Preclinical studies suggest PARP inhibition (PARPi) induces immunostimulatory micromilieu in ovarian cancer thus complementing activity of immune checkpoint blockade. We conducted a phase II trial of PARPi olaparib and anti-PD-L1 durvalumab and collected paired fresh core biopsies and blood samples to test this hypothesis. PATIENTS AND METHODS: In a single-center, proof-of-concept phase II study, we enrolled women aged ≥18 with recurrent ovarian cancer. All patients were immune checkpoint inhibitor-naïve and had measurable disease per RECISTv1.1, ECOG performance status 0-2, and adequate organ and marrow function. Patients received olaparib 300 mg twice daily and durvalumab 1,500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoint was overall response rate (ORR). Secondary objectives were safety and progression-free survival (PFS). Translational objectives included biomarker evaluation for relationships with clinical response and immunomodulatory effects by treatment. RESULTS: Thirty-five patients with ovarian cancer [median, four prior therapies (IQR, 2-5.5), predominantly platinum-resistant (86%), BRCA wild-type (77%)] received at least one full cycle of treatment. ORR was 14% [5/35; 95% confidence interval (CI), 4.8%-30.3%]. Disease control rate (PR+SD) was 71% (25/35; 95% CI, 53.7%-85.4%). Treatment enhanced IFNγ and CXCL9/CXCL10 expression, systemic IFNγ/TNFα production, and tumor-infiltrating lymphocytes, indicating an immunostimulatory environment. Increased IFNγ production was associated with improved PFS [HR, 0.37 (95% CI, 0.16-0.87), P = 0.023], while elevated VEGFR3 levels were associated with worse PFS (HR, 3.22 (95% CI, 1.23-8.40), P = 0.017]. CONCLUSIONS: The PARPi and anti-PD-L1 combination showed modest clinical activity in recurrent ovarian cancer. Our correlative study results suggest immunomodulatory effects by olaparib/durvalumab in patients and indicate that VEGF/VEGFR pathway blockade would be necessary for improved efficacy of the combination.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antígeno B7-H1/genética , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Poli(ADP-Ribose) Polimerases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Quimiocina CXCL10/genética , Quimiocina CXCL9/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/efeitos adversos , Interferon gama/genética , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Fator A de Crescimento do Endotélio Vascular/genética
5.
J Neurosurg Sci ; 61(3): 277-282, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25665526

RESUMO

BACKGROUND: Epilepsy surgery has been proved to be feasible and cost-effective in developing countries. In the current paper, we discussed the outcome of patients with mesial temporal lobe epilepsy (MTLE) and medically-refractory seizures who had surgery at our center in Shiraz, Iran. METHODS: Patients aged 18 years and older with refractory MTLE and mesial temporal sclerosis operated at Namazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran from May 2009 through December 2011 were enrolled. Presurgical evaluation included clinical history, neurological examination, 2-hour video-EEG recording, and 1.5-T MRI. All patients were submitted to standard temporal lobectomy at the side determined by MRI and video-EEG. RESULTS: Twenty-two patients (12 women and 10 men) underwent surgery between May 2009 and December 2011. All patients were followed postoperatively for at least 12 months (mean=24.8±7.7 months; minimum=12 months; maximum=36 months). At the last follow-up visit, 18 patients (81.8%) had a good outcome (15 patients [68.2%] had Engel class 1 and three others had Engel class 2). The total cost of presurgical evaluation and epilepsy surgery at our center was less than $500. CONCLUSIONS: Resources are limited for the vast majority of medically-refractory patients with epilepsy who live in the developing countries. However, it is feasible to select good surgical candidates for anterior temporal lobectomy relying on the clinical history and examination, MRI and interictal EEG. Broader application of epilepsy surgery should be encouraged in countries with limited financial resources.


Assuntos
Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia do Lobo Temporal/cirurgia , Procedimentos Neurocirúrgicos/métodos , Avaliação de Resultados em Cuidados de Saúde , Adolescente , Adulto , Países em Desenvolvimento/economia , Epilepsia do Lobo Temporal/economia , Feminino , Seguimentos , Humanos , Irã (Geográfico) , Masculino , Procedimentos Neurocirúrgicos/economia , Esclerose Tuberosa/economia , Esclerose Tuberosa/cirurgia , Adulto Jovem
6.
Urol Oncol ; 35(7): 473-491, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28506596

RESUMO

Medical imaging of the 3 most common genitourinary (GU) cancers-prostate adenocarcinoma, renal cell carcinoma, and urothelial carcinoma of the bladder-has evolved significantly during the last decades. The most commonly used imaging modalities for the diagnosis, staging, and follow-up of GU cancers are computed tomography, magnetic resonance imaging (MRI), and positron emission tomography (PET). Multiplanar multidetector computed tomography and multiparametric MRI with diffusion-weighted imaging are the main imaging modalities for renal cell carcinoma and urothelial carcinoma, and although multiparametric MRI is rapidly becoming the main imaging tool in the evaluation of prostate adenocarcinoma, biopsy is still required for diagnosis. Functional and molecular imaging using 18-fluorodeoxyglucose-PET and sodium fluoride-PET are essential for the diagnosis, and especially follow-up, of metastatic GU tumors. This review provides an overview of the latest advances in the imaging of these 3 major GU cancers.


Assuntos
Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Neoplasias Urogenitais/diagnóstico por imagem , Neoplasias Urogenitais/diagnóstico , Feminino , Humanos , Masculino , Neoplasias Urogenitais/terapia
7.
Spine (Phila Pa 1976) ; 41(21): 1661-1667, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27798555

RESUMO

STUDY DESIGN: A case-control study of the Trp2/3 alleles of COL9A2/3 genes and their correlation with occurrence of Lumbar disc disease (DDD) as phenotyped by magnetic resonance imaging. OBJECTIVE: To establish a better understanding of relationship between presence of said alleles and occurrence of DDD in South-Western Iranian population. SUMMARY OF BACKGROUND DATA: A number of genetic predisposing factors have been identified in elevating the risk of developing DDD. Specifically, the Trp2 and Trp3 alleles of COL9A2 and COL9A3 genes have been suggested as DDD risk variants. METHODS: A total of 108 patients (mean age = 41±11.8 yrs, range = 20-66 yrs) with 57 controls (mean age = 35±10.0 yrs, range = 20-58 yrs) participated in the study. The frequency of G/A polymorphism in COL9A2 gene on location 326 on chromosome 1 and G/A/C/ or T polymorphism in 103 location of COL9A3 gene on chromosome 20 was assessed using a PCR short-primer technique. Outcome measure was defined as presence of DDD on MRI. Odds ratios (OR) and 95% confidence intervals (CI) were used to assess the likelihood of DDD given occurrence of Trp2(3). RESULTS: Each allele was present in both patients and controls. The Trp2 allele was positive in 28.5% of individuals (31.5% of patients; 22.8% of controls), OR 1.55 (0.71-3.56). The Trp3 allele, the frequency was 23.6% in all patients (26.9% patients; 17.5% controls), OR 1.72 (0.73-4.33). We observed a 5.8-fold increase in the odds of DDD in males when the Trp3 allele was present, OR 5.83 (1.09-9.98), P = 0.0273. CONCLUSION: Both Trp2 and Trp3 alleles occurred more frequently compared with other studied ethnicities. The sampled Iranian population exhibited a similar Trp2 frequency to a Southern Chinese population, and Trp3 occurrence to Finnish and Greek population. We found that male patient were much more likely to develop DDD when Trp 3 was present. LEVEL OF EVIDENCE: N/A.


Assuntos
Colágeno Tipo IX/genética , Predisposição Genética para Doença , Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/genética , Vértebras Lombares/diagnóstico por imagem , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Povo Asiático , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Disco Intervertebral/diagnóstico por imagem , Irã (Geográfico) , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores Sexuais , População Branca , Adulto Jovem
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