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S Picton

Publications and source records attributed to S Picton.

At least 19 recordsLinked to original sources
PubMed2001

Body surface area estimation in children using weight alone: application in paediatric oncology.

The majority of chemotherapy regimens and trials specify doses of cytotoxic drugs normalized to body surface area. Estimation of BSA in paediatric patients is particularly problematic, as conventional nomograms require accurate determination of both height and weight. The chemotherapy standards group of the UKCCSG (United Kingdom Children's Cancer Study Group) has evaluated a method for calculation of body surface area (BSA) estimation, based solely on patient weight. In comparison with BSA estimations using 2 commonly used methods, which require both weight and height measurements, deviation in the estimate of BSA was less than 10%. This method may be extended to the dosing of chemotherapeutic agents in infants of body weight less than 10 kg, with appropriate recommendations for dose modification. Until better correlates of drug clearance, such as GFR for carboplatin, are identified BSA is used to standardize doses for most chemotherapeutic agents. The formula presented here provides a more robust and reliable method of calculation of BSA from weight alone. Although this approach has been shown to be equivalent to other currently used methods, care should be taken extending this calculation of BSA to children less than 10 kg, to obese patients and to those with cachexia.

Algorithms↗
PubMed2001

Minimal residual disease at the time of peripheral blood stem cell harvest in patients with advanced neuroblastoma.

BACKGROUND: Despite treatment with high-dose myeloblative chemotherapy and peripheral blood stem cell (PBSC) rescue, a high proportion of children with neuroblastoma relapse and die. Re-infusion of PBSC contaminated with tumour at the time of autologous transplantation may play a significant role in this relapse. In this study the frequency of tumour contamination in PB from children with neuroblastoma has been investigated. PROCEDURE: Minimal residual disease was measured using RT-PCR for tyrosine hydroxylase (TH) mRNA in PBSCs from patients with advanced neuroblastoma. PBSCs from 18 patients in complete clinical remission were studied. RESULTS: Studies in other cancers have suggested minimal contamination of PBSCs with tumour cells; TH mRNA was detected by RT-PCR in 50% (9/18) of PBSC harvests. Seventy-seven percent (7/9) of patients with TH mRNA in PBSC died of disease compared to 44% (4/9) who were TH mRNA-negative. CONCLUSIONS: Therefore, the presence of TH mRNA in PBSCs appeared to be associated with an unfavourable outcome, although this was not statistically significant. In summary, RT-PCR for TH mRNA is a sensitive method for the identification of tumour cells in PBSC harvest. The presence of TH mRNA in PBSC harvest may reflect disease status and be associated with an unfavourable outcome, although long-term clinical outcome studies in a larger patient cohort are required.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

A review of the cytogenetics of 58 pediatric brain tumors.

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.

Astrocytoma↗
PubMed2001

Intolerance to an extensively hydrolysed formula mistaken for postoperative diarrhoea in a child with neuroblastoma.

BACKGROUND: Persistent diarrhoea has recently been reported as a common problem following surgical resection for advanced abdominal neuroblastoma. CASE STUDY: A 10-month-old child, who had previously had no nutritional problems whilst undergoing chemotherapy treatment for a stage IV neuroblastoma, developed severe diarrhoea following tumour resection. He required nutritional support and was commenced on a continuous overnight nasogastric feed of a non-milk protein hydrolysate feed (MCT Pepdite 0-2, S.H.S. International Ltd, UK) His diarrhoea persisted and it was assumed that this was a postoperative problem which in time would regress. Two months later the child was admitted with a rectal prolapse, and a colonoscopy and biopsy suggested allergic protocolitis. The diarrhoea resolved rapidly on stopping the feed. CONCLUSION: Although he was never re-challenged with the non-milk protein hydrolysate, it appears that he had a rare intolerance to an extensively hydrolysed protein formula which was masked by the assumption that his diarrhoea was a postoperative problem.

Abdominal Neoplasms↗
PubMed2000

Ophthalmic complications of childhood medulloblastoma.

BACKGROUND: To study the ophthalmic complications and sequelae in children surviving medulloblastoma in order to assess the need for therapeutic intervention by the ophthalmologist. PROCEDURE: We identified all children attending the Leeds General Infirmary and St. James' University Hospital for treatment of medulloblastoma in the period January 1990 to March 1997, and the notes of all surviving patients were reviewed. Those patients who had not had an ophthalmic assessment within the last 6 months were recalled for examination. RESULTS: Twenty-four surviving patients underwent full ophthalmic assessment. The follow-up period ranged between 6 months and 7 years (range 3.6 yr): 66% had ocular symptoms at presentation; 25% developed ocular complications following treatment; 50% were left with ocular sequelae; 41% percent required ophthalmic intervention (25% medical/orthoptic intervention; 16% surgical intervention). CONCLUSIONS: Early (preferably preoperative) referral to the ophthalmology department is important in order to ensure appropriate management of diplopia, preservation of binocular single vision, and prevention of amblyopia in younger children.

Abducens Nerve Diseases↗
PubMed2000

Metabolic, cationic and secretory response to D-glucose in depolarized and Ca(2+)-deprived rat islets exposed to diazoxide.

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+.

Animals↗
PubMed2000

Localisation of HHV-8 in AIDS related lymphadenopathy.

BACKGROUND: Many lymph node abnormalities have been described in AIDS. These include opportunistic infections that sometimes result in spindle cell pseudotumours, Kaposi's sarcoma (KS), malignant lymphoma (Hodgkin's and non-Hodgkin's), and florid reactive hyperplasia. Among these, reactive hyperplasia is the most common manifestation of AIDS related lymphadenopathy. AIM: To examine whether human herpesvirus 8 (HHV-8), the aetiological agent of KS, can be localised in AIDS related lymphadenopathy and whether its appearance in such nodes is predictive of Kaposi's sarcoma development. METHODS: A series of human immunodeficiency virus (HIV) positive men (n = 21) with AIDS related lymphadenopathy who at the time of presentation had KS or subsequently developed KS (n = 5) were examined. The prevalence of HHV-8 was assessed in these patients using solution phase polymerase chain reaction (PCR), real time TaqMan quantitative PCR, and in cell amplification techniques (PCR in situ hybridisation (PCR-ISH) and labelled primer driven in cell amplification). RESULTS: Using standard solution phase PCR in a nested format, only two of the 21 patients with AIDS related lymphadenopathy were positive for HHV-8. The lymph node of one of these patients contained KS lesions. Three HHV-8 positive patients were identified using TaqMan PCR (the original two positive patients and one additional patient). All of the positive patients either subsequently developed KS (n = 2) or had KS at the time of diagnosis (n = 1). Two additional patients subsequently developed KS, but were negative for HHV-8 by solution phase PCR and TaqMan PCR. Using PCR-ISH, HHV-8 amplicons were identified in some lymphoid cells (in one patient) and in spindle cells of the KS lesion in another. The positive lymphoid cells were predominantly concentrated in B cell areas of the affected lymph nodes, confirming the B cell tropism exhibited by HHV-8. CONCLUSIONS: The presence of HHV-8 in AIDS related lymphadenopathy is predictive of KS development and probably represents seeding of HHV-8 infected B cells from the peripheral blood. These findings support a role for HHV-8 in the pathobiology of KS.

AIDS-Related Complex↗
PubMed2000

Cellular localisation of HHV-8 in Castleman's disease: is there a link with lymph node vascularity?

AIMS: Human herpesvirus 8 (HHV-8) has been identified in multicentric Castleman's disease and in angioimmunoblastic lymphadenopathies. However, the presence of the virus does not necessarily indicate an aetiological role in these conditions. This study investigates the cell types infected by HHV-8 in Castleman's disease and examines the correlation between HHV-8 and Castleman's disease lymph node angiogenesis. METHODS: Sixteen formalin fixed, paraffin wax embedded samples from patients with Castleman's disease (six multicentric, 10 solitary) were examined for the presence of HHV-8 using the polymerase chain reaction (PCR), non-isotopic in situ hybridisation, PCR in situ hybridisation (PCR-ISH), and real time quantitative TaqMan PCR to HHV-8 open reading frame 26 (ORF-26), and viral (v)-cyclin encoding regions. Vascularity was assessed using CD34, CD31, and factor VIII immunocytochemistry, and lymph nodes were scored as "low" or "high". RESULTS: Five multicentric Castleman's disease and two solitary Castleman's disease biopsies were positive for HHV-8. HHV-8 was identified in approximately 10% of intranodal B lymphocytes, in endothelial cells, and in subcapsular spindle cell proliferations. The copy number of HHV-8 was low at 10-50 copies/1000 cells. The highest copy number was in subcapsular spindle cells. There was no correlation between vascularity score and HHV-8 status. CONCLUSION: The preferential localisation of HHV-8 in subcapsular spindle cell proliferations (where early intranodal Kaposi's sarcoma initiates) and endothelial cells in Castleman's disease might finally explain the link between intranodal Kaposi's sarcoma and Castleman's disease.

Adult↗
PubMed2000

Possible role of diadenosine polyphosphates in glucose-stimulated insulin release: effects of NaF upon metabolic and functional variables in rat isolated islets.

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.

Animals↗
PubMed1999

Effects of high extracellular K(+) concentrations, diazoxide and/or Ca(2+) deprivation upon D-glucose metabolism in pancreatic islets.

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.

Animals↗
PubMed1999

Environmental modulation of the inhibitory action of D-mannoheptulose upon D-glucose metabolism in isolated rat pancreatic islets.

In pancreatic islets prepared from fed rats and incubated at a low concentration (1.7 mM) of D-glucose, D-mannoheptulose (10.0 mM) virtually fails to affect the metabolism of the hexose. Likewise, in islets from starved rats, the relative extent of the inhibitory action of D-mannoheptulose upon D-glucose metabolism is much more marked at high (16.7 mM) than low (1.7 mM) hexose concentration. Nevertheless, despite decreasing the metabolism of D-glucose, starvation augments the sensitivity to D-mannoheptulose in the islets incubated at a low concentration of the hexose, D-galactose, but not D-fructose, also augments the inhibitory action of D-mannoheptulose upon D-glucose metabolism in islets prepared from fed rats and exposed to the low concentration of D-glucose. A comparable situation prevails in islets exposed to 2-ketoisocaproate. Forskolin, however, which decreases D-glucose catabolism in the islets from fed rats exposed to 1.7 mM D-glucose, fails to affect significantly the inhibitory action of D-mannoheptulose on D-glucose metabolism. It is proposed that hexoses transported by the same carrier as D-glucose and non-glucidic nutrient secretagogues somehow increase D-mannoheptulose uptake by the islet cells. The latter two conditions may be operative in islets exposed to a high concentration of D-glucose, this accounting for the exquisite sensitivity to D-mannoheptulose of glucose-stimulated islets.

Animals↗
PubMed1999

Survival from childhood cancer in Yorkshire, U.K.: effect of ethnicity and socio-economic status.

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.

Adolescent↗
PubMed1999

Cyclin D1 expression and HHV8 in Kaposi sarcoma.

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.

Cyclin D1↗
PubMed1999

CD40 upregulation is independent of HHV-8 in the pathogenesis of Kaposi's sarcoma.

AIMS: Human herpesvirus 8 (HHV-8) is now acknowledged as the infective cofactor in the pathogenesis of Kaposi's sarcoma. The mode by which HHV-8 causes Kaposi's sarcoma is unresolved and it is probable that it acts in conjunction with other factors including cytokines, anti-apoptosis proteins, and cell surface receptors. CD40, a cell membrane receptor belonging to the tumour necrosis factor receptor super family, promotes B cell survival and is expressed constitutively on endothelial cells. It is upregulated on cytokine treatment and has been documented recently in Kaposi's sarcoma. Because the HHV-8 genome contains cytokine homologues, this study investigated whether CD40 expression in Kaposi's sarcoma correlated with HHV-8 status, using a unique set of HHV-8 positive and negative specimens. METHODS: Twenty one paraffin wax embedded samples of Kaposi's sarcoma were selected, of which 18 were screened for the presence of HHV-8 using both conventional solution phase and TaqMan polymerase chain reaction (PCR). CD40 immunohistochemistry was assessed using a biotinylated amplification system. Staining was scored semiquantitatively. RESULTS: The results indicated that the expression of CD40 is independent of viral status, being present in both HHV-8 positive and negative specimens. CONCLUSIONS: This suggests that HHV-8 promotes Kaposi's sarcoma cell survival following infection by mechanisms other than those involving CD40.

Antigens, Neoplasm↗
PubMed1998

Failure of streptozotocin tetraacetate to undergo extensive hydrolysis and to inhibit D-glucose metabolism and insulinotropic action in rat pancreatic islets.

The esterification of several monosaccharides, such as D-glucose, D-mannoheptulose and 2-deoxy-D-glucose was recently reported to increase their biological efficiency as either nutrient or antimetabolic agent. In the present study, however, the tetraacetate ester of streptozotocin was unexpectedly found to be less potent than unesterified streptozotocin in inhibiting D-glucose metabolism and insulinotropic action in isolated rat pancreatic islets. This coincided with a much lower rate for the hydrolysis of streptozotocin tetraacetate than D-glucose pentaacetate in islet homogenates. These findings document that the esterification of single sugars is not always a successful procedure to enhance their biological potency, for instance because of too low a rate for the intracellular hydrolysis of the ester. To the extent that the activity of the concerned esterase(s) may differ in distinct cell types, as suggested by a prior observation, advantage could be taken of such a situation to target selected esters towards specific, e.g. tumoural cells.

Animals↗
PubMed1998

Epidemiology of childhood brain tumours in Yorkshire, UK, 1974-95: geographical distribution and changing patterns of occurrence.

From a high-quality population-based register of children with cancer, 455 cases diagnosed with central nervous system (CNS) tumours were analysed to examine patterns of occurrence and geographical distribution. There was a significant increase of 1.8% (95% CI 0.5-3.1, P < 0.01) in average annual incidence for all CNS tumours, mainly accounted for by a 3.1% rise (95% CI 0.1-6.1, P < 0.05) in primitive neuroectodermal tumours (PNETs) over the 22-year period 1974-95. These increases were not explained by an increase in the proportion of histologically verified tumours. In the most recent time period (1986-95), astrocytomas occurred more commonly than previously in 0 to 4-year olds. Geographical differences in incidence were evident at a large scale, between counties, for all tumours and astrocytomas, with lower rates in the most urbanized areas. At the level of census district and electoral wards, no association between incidence of CNS tumours and socioeconomic group, person-based population density or ethnicity was observed using Poisson regression modelling. Based on small-scale census geography, the patterns of distribution of CNS tumours do not suggest strong associations with geographical determinants of risk. This study finds a rising incidence of all CNS tumours and particularly primitive neuroectodermal tumours and shows that astrocytomas appear to be occurring at a younger age, most probably because of improved diagnosis with non-invasive technology.

Adolescent↗
PubMed1998

Identification of HHV8 in early Kaposi's sarcoma: implications for Kaposi's sarcoma pathogenesis.

AIMS: Kaposi's sarcoma is a vascular tumour of uncertain pathogenesis possibly caused by an infectious agent, identified in high risk groups. Accumulating solution phase polymerase chain reaction (PCR) and seroepidemiological data suggest that a previously undescribed herpes DNA virus (human herpesvirus 8 (HHV8)) is the causative agent. Using a unique cohort of early Kaposi's sarcoma, the precise cell type infected with HHV8 in such lesions was identified to elucidate further the role of HHV8 in the pathobiology of Kaposi's sarcoma. METHODS: Sixteen cases of early Kaposi's sarcoma (derived from skin and lymph node) were assessed for the presence of HHV8 using both standard solution phase PCR and TaqMan PCR to the KS330 Bam region of HHV8. In situ amplification was also performed on a selected group in an attempt to identify the candidate infected cells. RESULTS: Using both conventional solution phase and TaqMan PCR, 87% of cases were positive. In addition, HHV8 amplicons were localised in situ to endothelial and spindle cell proliferations in early Kaposi's sarcoma. The HHV8 viral load varied from lesion to lesion. CONCLUSIONS: The presence of HHV8 in early lesions supports a role for HHV8 in the pathogenesis of Kaposi's sarcoma. Coupled with recent seroepidemiological studies, these results suggest that HHV8 is the aetiological agent of Kaposi's sarcoma. Its precise interaction with other factors known to be involved in the development of Kaposi's sarcoma, including cytokines and anti-apoptosis genes, requires elucidation.

Adolescent↗