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1.
Br J Cancer ; 128(9): 1710-1722, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36828871

RESUMO

BACKGROUND: Establishing the existence of health inequalities remains a high research and policy agenda item in the United Kingdom. We describe ethnic and socio-economic differences in paediatric cancer survival, focusing specifically on the extent to which disparities have changed over a 20-year period. METHODS: Cancer registration data for 2674 children (0-14 years) in Yorkshire were analysed. Five-year survival estimates by ethnic group (south Asian/non-south Asian) and Townsend deprivation fifths (I-V) were compared over time (1997-2016) for leukaemia, lymphoma, central nervous system (CNS) and other solid tumours. Hazard ratios (HR: 95% CI) from adjusted Cox models quantified the joint effect of ethnicity and deprivation on mortality risk over time, framed through causal interpretation of the deprivation coefficient. RESULTS: Increasing deprivation was associated with significantly higher risk of death for children with leukaemia (1.11 (1.03-1.20)) and all cancers between 1997 and 2001. While we observed a trend towards reducing differences in survival over time in this group, a contrasting trend was observed for CNS tumours whereby sizeable variation in outcome remained for cases diagnosed until 2012. South Asian children with lymphoma had a 15% reduced chance of surviving at least 5 years compared to non-south Asian, across the study period. DISCUSSION: Even in the United Kingdom, with a universally accessible healthcare system, socio-economic and ethnic disparities in childhood cancer survival exist. Findings should inform where resources should be directed to provide all children with an equitable survival outcome following a cancer diagnosis.


Assuntos
Neoplasias do Sistema Nervoso Central , Leucemia , Criança , Humanos , Etnicidade , Reino Unido/epidemiologia , Fatores Socioeconômicos
2.
Acta Neurochir (Wien) ; 160(4): 793-800, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29188366

RESUMO

INTRODUCTION: The neutrophil-lymphocyte count ratio (NLCR) is an established prognostic marker for renal, lung and colorectal carcinomas and has been suggested to be predictive of histological grade and outcome in adult intracranial tumours. The purpose of this study was to determine whether a correlation of the pre-operative neutrophil count (NC) and NLCR with the final histological grade exists in paediatric intracranial tumours. METHODS: A retrospective analysis was undertaken at a single centre. Patients less than 18 years old at the time of surgery who underwent tumour-related procedures from 2006 to 2015 were included. Patients with recurrent tumours, previous bone marrow transplant and metastases were excluded. Pre-operative full blood counts (FBC), collected before the diagnosis of intracranial pathology and before administration of steroids, were matched with histological diagnosis for each patient. Post-operative FBC was also recorded, together with survival data where applicable. RESULTS: A total of 116 patients (74 male, 42 female; mean age, 8 ± 0.9 years) with a diagnosis of primary intracranial tumours had pre-operative FBC that could be matched to final histological grade. Pre-operative NC and NLCR were higher with increasing grade of tumour: grade 1 (NC 4.29 109/l, NLCR 2.26), grade 2 (NC 4.59 109/l, NLCR 2.38), grade 3 (NC 5.67 109/l, NLCR 2.72) and grade 4 (NC 6.59 109/l, NLCR 3.31). Patients with WHO grade 1 and 2 tumours pooled together had a lower NC (4.37 95% CI ± 0.67 109/l) compared to WHO grade 3 and 4 patients (6.41 95% CI ± 0.99 109/l, p = 0.0013). The NLCR was lower in grade 1 and 2 tumours (2.29 ± 0.59) (compared to grade 3 and 4 tumours; 3.20 ± 0.76) but this did not reach significance (p = 0.069). The subgroup of patients with pilocytic astrocytoma had a significantly lower NC when compared to patients with high-grade tumours (p = 0.005). Medulloblastoma and supratentorial PNET subgroups had significantly higher NC compared to the low-grade group (p = 0.033, p = 0.002). Post-operative NC was significantly higher in the high-grade tumours (p = 0.034), but no difference was observed for NLCR (p = 0.28). CONCLUSIONS: No evidence exists to support the correlation of pre-operative NC or NLCR to histological diagnosis in paediatric intracranial tumours. Our results indicate that a higher pre-operative NC/NLCR correlates with a higher histological grade of tumour. This suggests that immunological mechanisms may be involved in the pathogenesis of paediatric brain tumours, and a further prospective study is required to substantiate and expand these findings.


Assuntos
Astrocitoma/sangue , Neoplasias Encefálicas/sangue , Neoplasias Cerebelares/sangue , Meduloblastoma/sangue , Recidiva Local de Neoplasia/sangue , Adolescente , Astrocitoma/epidemiologia , Astrocitoma/patologia , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/patologia , Neoplasias Cerebelares/epidemiologia , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Feminino , Humanos , Contagem de Leucócitos , Masculino , Meduloblastoma/epidemiologia , Meduloblastoma/patologia , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia
3.
Br J Cancer ; 112(4): 693-703, 2015 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-25628092

RESUMO

BACKGROUND: Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are highly aggressive brain tumours. Their invasive phenotype contributes to their limited therapeutic response, and novel treatments that block brain tumour invasion are needed. METHODS: Here, we examine the migratory characteristics and treatment effect of small molecule glycogen synthase kinase-3 inhibitors, lithium chloride (LiCl) and the indirubin derivative 6-bromoindirubin-oxime (BIO), previously shown to inhibit the migration of adult glioma cells, on two pHGG cell lines (SF188 and KNS42) and one patient-derived DIPG line (HSJD-DIPG-007) using 2D (transwell membrane, immunofluorescence, live cell imaging) and 3D (migration on nanofibre plates and spheroid invasion in collagen) assays. RESULTS: All lines were migratory, but there were differences in morphology and migration rates. Both LiCl and BIO reduced migration and instigated cytoskeletal rearrangement of stress fibres and focal adhesions when viewed by immunofluorescence. In the presence of drugs, loss of polarity and differences in cellular movement were observed by live cell imaging. CONCLUSIONS: Ours is the first study to demonstrate that it is possible to pharmacologically target migration of paediatric glioma in vitro using LiCl and BIO, and we conclude that these agents and their derivatives warrant further preclinical investigation as potential anti-migratory therapeutics for these devastating tumours.


Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Movimento Celular , Glioma/patologia , Glioma/terapia , Terapia de Alvo Molecular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Criança , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Indóis/farmacologia , Cloreto de Lítio/farmacologia , Invasividade Neoplásica , Oximas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Esferoides Celulares/fisiologia
5.
Cancer Epidemiol ; 71(Pt B): 101777, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32660850

RESUMO

BACKGROUND: Survival of children with cancer in resource-limited regions is very poor compared to better-resourced regions. Retinoblastoma (RB) is a childhood cancer that is commonly reported in many regions of Africa. RB may be safely and effectively treated by non-specialists, which could facilitate more widespread availability of treatment in under-resourced areas. METHODS: A ten-year consecutive series of children with RB treated at Ruharo Eye Centre between December 2009 and November 2019 was prospectively followed up. Chemoreduction followed by surgery is the standard approach to therapy. Costs of therapy and also of travel and food are borne by the program which is unaffordable to most families and necessitates donors. Survival by stage of RB and number of eyes affected was described using Kaplan-Meier plots. Visual acuity was assessed for all children with bilateral disease and the retention of sight during follow-up assessed. RESULTS: Among 665 children with RB, 18.2 % (121 children) presented with metastatic (Stage 4) RB with only two of these children surviving >24 months. Five-year survival was 60.2 % among all children with RB rising to 93.3 % and 87.2 % for children with unilateral and bilateral Stage 1 disease, respectively. Among 184 children with bilateral disease, 130 (70.7 %) retained some level of sight following primary treatment with 91 of those (49.5 % of all bilateral children) retaining vision up to their death or to the end of follow-up. CONCLUSION: Many children in Uganda present with advanced RB and curative treatment is not possible in this setting. Children diagnosed and treated early have good prospects of survival. Retention of sight among many bilaterally affected children is achievable, facilitating access to normal education. Therefore, the strategic priorities for improving survival are changing community perceptions so that children with eye problems are brought without delay, and widening access to modern treatment by using genereal health workers with standard drugs, backed by financial, social and peer support.


Assuntos
Recursos em Saúde/provisão & distribuição , Neoplasias da Retina/mortalidade , Neoplasias da Retina/terapia , Retinoblastoma/mortalidade , Retinoblastoma/terapia , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estadiamento de Neoplasias , Estudos Prospectivos , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Análise de Sobrevida , Tempo para o Tratamento , Resultado do Tratamento , Uganda/epidemiologia
6.
Br J Cancer ; 103(9): 1448-52, 2010 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-20842119

RESUMO

BACKGROUND: Few studies have examined epidemiological differences between ethnic groups for children and young adults with cancer. METHODS: Subjects aged 0-29 years, diagnosed between 1990 and 2005 in the former Yorkshire Regional Health Authority, were included in the analysis. Ethnicity (south Asian or not) was assigned using name analysis program and Hospital Episode Statistics data. Differences in incidence (per 1,000,000 person-years) rates and trends were analysed using joinpoint and Poisson regression analysis. RESULTS: Overall cancer incidence was similar for south Asians (12.1, 95% CI: 10.7-13.5; n=275) and non-south Asians (12.6, 95% CI: 12.2-13.1; n=3259). Annual incidence rates increased significantly by 1.9% per year on average (95% CI: 1.2-2.6%), especially for south Asians (7.0%; 95% CI: 4.2-9.9%). CONCLUSION: If present trends continue, the higher rate of increase seen among south Asians aged 0-29 years in Yorkshire will result in three times higher cancer incidence than non-south Asians by 2020.


Assuntos
Neoplasias/etnologia , Neoplasias/epidemiologia , Adolescente , Adulto , Ásia , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Reino Unido
7.
Eur J Cancer ; 61: 36-43, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27151553

RESUMO

BACKGROUND: Medulloblastoma and primitive neuroectodermal tumours (PNET) are the most common central nervous system (CNS) embryonal tumours diagnosed in childhood. Survival outcomes are worse for children diagnosed with CNS PNET compared to medulloblastoma. Less is known about survival outcomes in teenagers and young adults (TYA). METHODS: Data were extracted from two population-based cancer registries of children and young people (0-24 years) in the north of England for all diagnoses of medulloblastoma and CNS PNET between 1990 and 2013. Incidence and survival trends were analysed using Poisson and Cox regression. RESULTS: Between 1990 and 2013, 197 medulloblastomas and 58 CNS PNET were diagnosed, age-standardised incidence rates of 3.8 and 1.5 per million, respectively. Medulloblastoma incidence decreased over time while there was no significant change in trend for CNS PNET. The overall 5-year survival rate was 54%. The risk of death was 2.4 times higher (95% confidence interval [CI] 1.6, 3.7) for patients with CNS PNET compared to medulloblastoma, after adjustment for patient characteristics. There was a 39% reduction (95% CI 0.43, 0.87) in the risk of death for patients diagnosed between 2000 and 2013 compared to 1990-1999. Risk of death did not differ for TYA (15-24 years) compared to children aged 5-9 years. CONCLUSIONS: Medulloblastoma incidence decreased over time and differences in survival between medulloblastoma and PNET emerged within the first-year post diagnosis leading to poorer outcomes for children and young adults diagnosed with PNET; however, a significant improvement in survival over time was observed.


Assuntos
Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Lactente , Masculino , Taxa de Sobrevida , Adulto Jovem
8.
Biochim Biophys Acta ; 1451(2-3): 255-62, 1999 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-10556580

RESUMO

A rise in D-glucose concentration may augment insulin release independently of changes in K(+) conductance or Ca(2+) influx in pancreatic islet cells, the insulinotropic action of the hexose remaining dependent on an increased generation of high-energy phosphates. In the present study, therefore, it was investigated to which extent the procedures currently used to assess the modalities of the secretory response to D-glucose independent of its effect on ATP-sensitive K(+) channels and Ca(2+) inflow may themselves affect the catabolism of the hexose in isolated rat pancreatic islets. A rise in the extracellular K(+) concentration from 5 to 30 or 60 mM failed to significantly affect the metabolism of D-glucose. At 90 mM K(+), however, the maximal velocity of the glycolytic flux was decreased and the apparent K(m) for D-glucose lowered, without an obvious alteration of the preferential stimulation of oxidative mitochondrial events in response to a rise in D-glucose concentration. Such a preferential stimulation was abolished, however, either by diazoxide at a low, but not high, K(+) concentration or by Ca(2+) deprivation, in the absence or presence of diazoxide, at a high K(+) concentration. It is speculated that these metabolic changes may be attributable, in part at least, to an altered activity of key cytosolic (e.g. pyruvate kinase) and mitochondrial (e.g. FAD-linked glycerophosphate dehydrogenase) enzymes.


Assuntos
Cálcio/deficiência , Diazóxido/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Potássio/farmacologia , Animais , Radioisótopos de Carbono , Relação Dose-Resposta a Droga , Feminino , Glucose/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Potenciais da Membrana , Ratos , Ratos Wistar , Trítio
9.
Cell Calcium ; 27(4): 213-22, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10858667

RESUMO

D-glucose stimulates insulin release from islets exposed to both diazoxide, to activate ATP-responsive K+ channels, and a high concentration of K+, to cause depolarization of the B-cell plasma membrane. Under these conditions, the insulinotropic action of D-glucose is claimed to occur despite unaltered cytosolic Ca2+ concentration, but no information is so far available on the changes in Ca2+ fluxes possibly caused by the hexose. In the present experiments, we investigated the effect of D-glucose upon 45Ca efflux from islets exposed to both diazoxide and high K+ concentrations. In the presence of diazoxide and at normal extracellular Ca2+ concentration, D-glucose (16.7 mmol/l) inhibited insulin release at 5 mmol/l K+, but stimulated insulin release of 90 mmol/l K+. In both cases, the hexose inhibited 45Ca outflow. In the presence of diazoxide, but absence of Ca2+, D-glucose (8.3 to 25.0 mmol/l) first caused a rapid decrease in insulin output followed by a progressive increase in secretory rate. This phenomenon was observed both at 5 mmol/l or higher concentrations (30, 60 and 90 mmol/l) of extracellular K+. It coincided with a monophasic decrease in 45Ca efflux and either a transient (at 5 mmol/l K+) or sustained (at 90 mmol/l K+) decrease in overall cytosolic Ca2+ concentration. The decrease in 45Ca efflux could be due to inhibition of Na(+)-Ca2+ countertransport with resulting localized Ca2+ accumulation in the cell web of insulin-producing cells. A comparable process may be involved in the secretory response to D-glucose in islets exposed to diazoxide and a high concentration of K+ in the presence of extracellular Ca2+.


Assuntos
Cálcio/metabolismo , Diazóxido/farmacologia , Glucose/farmacologia , Ilhotas Pancreáticas/metabolismo , Animais , Polaridade Celular/efeitos dos fármacos , Células Cultivadas , Citosol/efeitos dos fármacos , Citosol/metabolismo , Relação Dose-Resposta a Droga , Matriz Extracelular/metabolismo , Glucose/metabolismo , Glibureto/farmacologia , Hexoses/farmacologia , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Potássio/metabolismo , Potássio/farmacologia , Ratos
10.
Eur J Cancer ; 35(13): 1816-23, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10673997

RESUMO

The effect of ethnicity and socio-economic status on the survival of a population-based cohort of 1979 children diagnosed with cancer between 1974 and 1995 was investigated. Ethnicity was assigned by computer algorithms and visual inspection as south Asian (or not) for each child, based on their full name. Socio-economic status was measured using the Carstairs index, based on census areas of case residence at diagnosis. 15 children (0.8%) were lost to follow-up. Log-rank tests showed survival from all cancers did not differ between south Asians and other children and no increased risk was observed for south Asians in any diagnostic category, although numbers were small. Increasing levels of deprivation were associated with significant trends of poorer survival from all cancers, leukaemias and brain tumours. Risk of death was typically higher for children from the most deprived areas although differences were not statistically significant after accounting for other factors including ethnicity. Taking all children with malignant disease together, neither ethnicity nor socio-economic status appear to influence survival after taking other factors into consideration.


Assuntos
Neoplasias/mortalidade , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Inglaterra/epidemiologia , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Neoplasias/economia , Neoplasias/etnologia , Sistema de Registros , Fatores de Risco , Fatores Socioeconômicos , Taxa de Sobrevida , Sobreviventes
11.
Bone Marrow Transplant ; 13(5): 559-62, 1994 May.
Artigo em Inglês | MEDLINE | ID: mdl-8054908

RESUMO

Bone marrow transplantation (BMT) was carried out on 38 patients with thalassaemia major over a period of 9 years; 30 were Asian. In all cases, the donor was an HLA-identical relative. The mean age at transplant was 6.4 years (range 0.5-20 years). Conditioning was busulphan and cyclophosphamide (CY). Cyclosporin (CsA) (n = 30), CsA + methotrexate (n = 6) or CsA + T cell depletion (n = 2) were used for prophylaxis against graft-versus-host disease (GVHD). Thirty-four patients successfully engrafted. Two patients required a second transplant and two achieved mixed chimerism, eventually rejecting their grafts. Nine patients (23.6) developed acute GVHD grade III-IV. Eleven patients (28.9) developed chronic GVHD. There were 11 deaths, 7 within the first 100 days post-BMT. Twenty-seven patients are alive from 156 to 3213 days post-BMT. The actuarial survival at 9 years post-BMT was 70%. The mortality is higher than in previously reported series; possible reasons for this are discussed.


Assuntos
Transplante de Medula Óssea , Talassemia/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Lactente , Masculino , Talassemia/mortalidade
12.
J Clin Pathol ; 52(8): 569-73, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10645225

RESUMO

BACKGROUND: Human herpesvirus 8 (HHV8) appears to be the agent responsible for Kaposi sarcoma. The mechanism remains undetermined but may involve cell cycle regulating genes including D type cyclins which are pivotal in cell cycle progression. Recent HHV8 genetic analysis has revealed the presence of a v-cyclin which is homologous to D type cyclins. AIMS: First, to assess whether there is an independent relation between endogenous cyclin D1 expression in Kaposi sarcoma and HHV8 status; second to determine whether v-cyclin mRNA expression varies with Kaposi sarcoma stage. METHODS: Cyclin D1 immunohistochemistry was performed on 17 paraffin embedded Kaposi sarcoma samples from 16 patients. HHV8 status was assessed in 15 of these using nested polymerase chain reaction (PCR) to ORF 26 and the newly described technique of TaqMan PCR. An additional 10 fresh Kaposi sarcoma samples (early and nodular) were examined for HHV8 v-cyclin RNA. RESULTS: One case, which did not contain amplifiable HHV8, showed strong cyclin D1 staining. The remaining cases were negative or weakly staining; v-cyclin transcript load was higher in early Kaposi sarcoma. CONCLUSIONS: While endogenous cyclin D1 expression is independent of HHV8 status, v-cyclin transcription is higher in early lesions, supporting the "viral hit" hypothesis.


Assuntos
Ciclina D1/metabolismo , Herpesvirus Humano 8/isolamento & purificação , Proteínas de Neoplasias/metabolismo , Sarcoma de Kaposi/virologia , Feminino , Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Masculino , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Viral/genética , Sarcoma de Kaposi/metabolismo , Proteínas Virais/metabolismo
13.
Cancer Genet Cytogenet ; 131(1): 1-12, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11734311

RESUMO

We describe the cytogenetic results of 58 pediatric central nervous system (CNS) tumors of variable histology, investigated between 1992 and 2000. Successful cytogenetics were obtained for 53 patients, with clonal chromosome abnormalities demonstrated in 25. Notable findings included (1) 2p abnormality in four primitive neuroectodermal tumors (PNET); (2) 1p loss in four low-grade gliomas and two PNET; (3) telomeric associations in one pilocytic astrocytoma; (4) chromosome 7 gain in four astrocytomas and two PNET; (5) 17p loss in four PNET; (6) double minutes in one PNET and three glioblastomas; and (7) chromosome 10 loss in four PNET. Higher grade tumors demonstrated greater karyotype complexity. Low-grade tumors showed either minimal simple chromosome changes or a normal karyotype. Chromosome abnormalities were more frequent in supratentorial tumors than their infratentorial counterparts. Our results add weight to the limited existing body of cytogenetic documentation for pediatric CNS tumors and provide further evidence that 2p loss is a consistent region of chromosome involvement in PNET. We advocate further studies of CNS tumors, in particular, to evaluate the importance of 2p changes and to compare cytogenetic results for supratentorial tumors and their infratentorial counterparts.


Assuntos
Neoplasias Encefálicas/genética , Aberrações Cromossômicas , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Criança , Cromossomos Humanos Par 2/genética , Feminino , Predisposição Genética para Doença , Humanos , Cariotipagem , Masculino , Metáfase/genética
14.
Diabetes Metab ; 28(6 Pt 2): 3S70-7; discussion 3S108-12, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12688636

RESUMO

Effects of cytotoxic agents and hydrogen peroxide were examined using pancreatic BRIN-BD11 cells and the parental insulinoma RINm5F cell line. Cell viability was determined using the MTT colorimetric assay and the TUNEL assay was used to assess apoptosis and acridine orange assay was used to determine levels of apoptosis versus necrosis. RT-PCR studies were employed to investigate the effects of the toxins on the expression of antioxidative enzymes, superoxide dismutase (SOD), glutathionine peroxidase (GPX) and catalase (CAT). Streptozotocin, hydrogen peroxide, alloxan and ninhydrin exerted time- and concentration-dependent toxic effects on BRIN-BD11 and RINm5F cells. RT-PCR showed that 90 minutes exposure of BRIN-BD11 cells or RINm5F cells to 5 mM ninhydrin down regulates SOD, GPX and CAT antioxidative enzymes. Glutathionine peroxidase gene expression was also down regulated in both types of cell by hydrogen peroxide. There were no significant differences in antioxidant gene expression after exposure to the other toxins under the conditions employed. TUNEL assay revealed that streptozotocin (8 mM) and hydrogen peroxide (125 microM) had no significant effect on the number of cells undergoing apoptosis. However after exposure to ninhydrin (5 mM) almost 100% of the non-viable BRIN-BD11 cells and around 50% of the RINm5F cells were dying by apoptosis. With the BRIN-BD11 cells there was around a 30% increase in the number of apoptotic cells compared with 50% in the RINm5F cells after exposure to alloxan (16 mM). The results indicate multiple effects of cytotoxic agents on functional integrity and antioxidant enzyme gene expression in clonal beta-cells.


Assuntos
Aloxano/toxicidade , Citotoxinas/farmacologia , Insulina/genética , Insulina/metabolismo , Ilhotas Pancreáticas/citologia , Estreptozocina/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Peróxido de Hidrogênio/toxicidade , Secreção de Insulina , Insulinoma , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/enzimologia , Cinética , Ninidrina/farmacologia , Neoplasias Pancreáticas , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
15.
Int J Mol Med ; 5(5): 493-503, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10762652

RESUMO

Diadenosine polyphosphates, such as diadenosine triphosphate (A2P3) and diadenosine tetraphosphate (A2P4), were recently proposed to participate in the stimulus-secretion coupling for nutrient-stimulated insulin release. Since NaF, an inhibitor of inorganic pyrophosphatase, was reported to lower A2P3 and A2P4 content in glucose-stimulated pancreatic islets, its effects upon metabolic, cationic, biosynthetic and secretory variables in rat pancreatic islets were investigated in the present study. Up to a concentration close to 0.1 mM, NaF failed to affect most of these variables, except for a decrease in 45Ca net uptake. Much higher concentrations of NaF (e.g. 5.0 mM) were required to cause inhibition of the metabolic, ionic, biosynthetic and secretory responses of the islets to nutrient secretagogues. Yet, even at this high concentration, NaF failed to lower the islet content in tritiated A2P3 and A2P4 in islets prelabelled with [2,8-3H]adenosine and failed to prevent the glucose-induced increase in such a content. It is concluded, therefore, that NaF may not represent a suitable tool to assess the participation of diadenosine polyphosphates in the process of nutrient-induced insulin secretion.


Assuntos
Fosfatos de Dinucleosídeos/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Fluoreto de Sódio/farmacologia , Animais , Cálcio/farmacocinética , Radioisótopos de Cálcio/farmacocinética , Feminino , Glucose/metabolismo , Técnicas In Vitro , Pirofosfatase Inorgânica , Peptídeos/metabolismo , Perfusão , Pirofosfatases/antagonistas & inibidores , Ratos , Ratos Wistar
16.
Eur J Clin Nutr ; 57(1): 31-6, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12548294

RESUMO

OBJECTIVE: The purpose of this study was to determine the most appropriate dose of oral glutamine to use in a further clinical study in paediatric oncology patients. DESIGN: This was a phase I, pharmokinetic study. SETTING: The study was carried out at The Yorkshire Regional Centre for Paediatric Oncology and Haematology, St James's University Hospital, Leeds, UK. SUBJECTS: Thirteen patients undergoing treatment for paediatric malignancy participated in this study. All 13 completed the study. INTERVENTIONS: The most appropriate dose was determined by patient acceptability and by plasma glutamine and ammonia levels measured at timed intervals after ingestion of a single glutamine dose. RESULTS: Doses of 0.35, 0.5 and 0.65 g/kg were well tolerated with no untoward plasma glutamine and ammonia levels. One patient was recruited to a higher dose of 0.75 g/kg, but the plasma glutamine and ammonia levels peaked at 2601 and 155 micro mol/l, respectively. The ammonia level was greater than the acceptable upper limit. It was difficult to disperse the glutamine adequately at this dose, resulting in the suspension being found to be unpalatable and therefore no further patients were recruited at this dose. CONCLUSION: It was concluded that 0.65 g/kg is a safe dose of glutamine to use in a clinical study in paediatric oncology patients.


Assuntos
Amônia/sangue , Glutamina/sangue , Glutamina/farmacocinética , Neoplasias/tratamento farmacológico , Administração Oral , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Área Sob a Curva , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Glutamina/administração & dosagem , Humanos , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Infusões Parenterais , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Intubação Gastrointestinal , Masculino , Dose Máxima Tolerável , Taxa de Depuração Metabólica , Segurança
17.
J Infect ; 26(2): 181-4, 1993 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8473764

RESUMO

A 5-month-old girl given an allogeneic bone marrow transplant for Hurler's syndrome succumbed to fatal pneumonia 5 weeks after the transplant. Adenovirus type 2 was isolated from her urine before she died. Immunoperoxidase and electron microscopical studies of liver and lungs post mortem confirmed a disseminated adenovirus infection. The serological findings and the patient's young age suggested that the infection was a primary one. The importance of considering exogenous sources of adenovirus infection in bone marrow transplant recipients is discussed.


Assuntos
Infecções por Adenovirus Humanos/etiologia , Transplante de Medula Óssea/efeitos adversos , Mucopolissacaridose I/terapia , Infecções por Adenovirus Humanos/diagnóstico , Feminino , Humanos , Hospedeiro Imunocomprometido , Lactente
18.
J Pediatr Surg ; 34(6): 1025-8, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10392928

RESUMO

BACKGROUND: Osteogenic sarcoma rarely occurs in soft tissues and generally affects individuals beyond the second decade of life. METHODS: The authors report a rare case of an extra osseous osteogenic sarcoma arising in the retroperitoneum of an adolescent, review the literature, and outline the diagnostic and therapeutic dilemmas. The role of adjuvant chemotherapy, using drugs used in managing bony osteosarcomas, is discussed. CONCLUSIONS: Retroperitoneal sarcomas may simulate ovarian teratomas. Careful consideration of the differential diagnosis of large cystic abdominal masses in adolescent females when size precludes adequate assessment of tumor mobility and imaging fails to demonstrate the ovaries is essential if these rare tumors are to be managed effectively.


Assuntos
Neoplasias Abdominais/diagnóstico , Osteossarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias Abdominais/diagnóstico por imagem , Neoplasias Abdominais/patologia , Neoplasias Abdominais/cirurgia , Criança , Feminino , Humanos , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/patologia , Osteossarcoma/cirurgia , Radiografia , Neoplasias de Tecidos Moles/diagnóstico por imagem , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/cirurgia
19.
Clin Oncol (R Coll Radiol) ; 25(3): 205-14, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23178199

RESUMO

AIM: There is a paucity of work documenting the influence of patterns of care on survival for teenagers and young adults with primary central nervous system tumours. Therefore, the aim of this study was to undertake a detailed assessment examining any changes in the patterns of care over time and how these related to survival outcomes for 16-24 year olds diagnosed with a primary central nervous system tumour between 1990 and 2009. MATERIALS AND METHODS: We used high-quality data from one population-based cancer registry in Yorkshire, UK to describe primary central nervous system tumours in teenagers and young adults (16-24 years) diagnosed between 1990 and 2009. The Birch classification scheme was used to identify differences by tumour subgroup. Incidence, patterns of care and survival trends were described using Poisson and Cox regression. RESULTS: There were 163 cases comprising 98 astrocytomas, 17 'other gliomas', 14 ependymomas, 11 medulloblastomas and 23 'other intracranial and intraspinal neoplasms' yielding an overall incidence of 18.1 million person-years. Care varied significantly over time and by principal treatment centre (Leeds 77%, Hull 23%), co-ordinating specialty (neurosurgery 53%, clinical oncology 22%, paediatrics 17%, other adult services 8%) and treatment received. Cox regression showed no significant difference in survival by age, gender, treatment centre, level of deprivation, year of diagnosis or co-ordinating specialty, but a significant difference by tumour grade and diagnostic group. Survival improved for all diagnostic groups except astrocytoma, although only the medulloblastoma group showed a significant change over time. CONCLUSION: The lack of any significant improvement in survival over time in most diagnostic groups warrants further investigation and provides justification for a more collaborative regional approach to the care of central nervous system tumours, perhaps through the development of regional guidelines for this unique population. More detailed analysis of relapse patterns and prediagnostic symptoms would also be informative for this cohort.


Assuntos
Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/terapia , Adolescente , Fatores Etários , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Humanos , Incidência , Masculino , Padrões de Prática Médica , Análise de Sobrevida , Reino Unido/epidemiologia , Adulto Jovem
20.
Eur J Cancer ; 49(18): 3856-62, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24011536

RESUMO

Diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis with no chemotherapy regimen so far resulting in any significant improvement over standard radiotherapy. In this trial, a prolonged regimen (21/28d) of temozolomide was studied with the aim of overcoming O(6)-methylguanine methyltransferase (MGMT) mediated resistance. Forty-three patients with a defined clinico-radiological diagnosis of DIPG received radiotherapy and concomitant temozolomide (75 mg/m(2)) after which up to 12 courses of 21d of adjuvant temozolomide (75-100mg/m(2)) were given 4 weekly. The trial used a 2-stage design and passed interim analysis. At diagnosis median age was 8 years (2-20 years), 81% had cranial nerve abnormalities, 76% ataxia and 57% long tract signs. Median Karnofsky/Lansky score was 80 (10-100). Patients received a median of three courses of adjuvant temozolomide, five received all 12 courses and seven did not start adjuvant treatment. Three patients were withdrawn from study treatment due to haematological toxicity and 10 had a dose reduction. No other significant toxicity related to temozolomide was noted. Overall survival (OS) (95% confidence interval (CI)) was 56% (40%, 69%) at 9 months, 35% (21%, 49%) at 1 year and 17% (7%, 30%) at 2 years. Median survival was 9.5 months (range 7.5-11.4 months). There were five 2-year survivors with a median age of 13.6 years at diagnosis. This trial demonstrated no survival benefit of the addition of dose dense temozolomide, to standard radiotherapy in children with classical DIPG. However, a subgroup of adolescent DIPG patients did have a prolonged survival, which needs further exploration.


Assuntos
Neoplasias do Tronco Encefálico/terapia , Dacarbazina/análogos & derivados , Glioma/terapia , Adolescente , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias do Tronco Encefálico/patologia , Quimiorradioterapia , Quimioterapia Adjuvante , Criança , Pré-Escolar , Dacarbazina/uso terapêutico , Esquema de Medicação , Feminino , Glioma/patologia , Humanos , Avaliação de Estado de Karnofsky , Masculino , Qualidade de Vida , Indução de Remissão , Análise de Sobrevida , Temozolomida , Fatores de Tempo , Resultado do Tratamento , Reino Unido , Adulto Jovem
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