Comparison of endpoint data treatment methods for estimation of kinematics and kinetics near impact during the tennis serve.

Tennis stroke mechanics have attracted considerable biomechanical analysis, yet current filtering practice may lead to erroneous reporting of data near the impact of racket and ball. This research had three aims: (1) to identify the best method of estimating the displacement and velocity of the racket at impact during the tennis serve, (2) to demonstrate the effect of different methods on upper limb kinematics and kinetics and (3) to report the effect of increased noise on the most appropriate treatment method. The tennis serves of one tennis player, fit with upper limb and racket retro-reflective markers, were captured with a Vicon motion analysis system recording at 500 Hz. The raw racket tip marker displacement and velocity were used as criterion data to compare three different endpoint treatments and two different filters. The 2nd-order polynomial proved to be the least erroneous extrapolation technique and the quintic spline filter was the most appropriate filter. The previously performed "smoothing through impact" method, using a quintic spline filter, underestimated the racket velocity (9.1%) at the time of impact. The polynomial extrapolation method remained effective when noise was added to the marker trajectories.

A study to determine the minimum volume of blood necessary to be discarded from a central venous catheter before a valid sample is obtained in children with cancer.

BACKGROUND: The objective of this study was to determine the minimum volume of blood that should be discarded from a range of different types of central venous catheter (CVC), such that the subsequent blood sample was not diluted or contaminated by the residual intra-luminal fluid. PROCEDURE: Seventy children aged 1-19 years with central venous access inserted as part of their standard clinical treatment were recruited to this prospective study. Statistical comparison of the extent of variation in biochemical and haematological parameters observed between two blood samples taken following routine 5 ml discard blood volumes, as compared to the extent of variation between samples drawn following a 5 ml discard volume and <5 ml volumes, was carried out. RESULTS: Data indicate that the measurement error in a clinical sample obtained following a 3 ml discard volume is no different to the measurement error obtained when using a standard 5 ml discard volume. Comparable results were obtained from patients with various different types of CVC or portacath access. CONCLUSIONS: The withdrawal of a 3 ml discard volume is sufficient to ensure that the subsequent blood sample is not diluted or contaminated by residual intra-luminal fluid. This may have a significant clinical impact in paediatric oncology, where patients frequently require blood transfusions due to the haematological toxicities associated with chemotherapy. It is hoped that these results will impact on hospital policies concerning specified discard volumes taken from CVCs prior to the withdrawal of blood samples for research purposes and routine clinical analysis.

Limitations in the ability of NB84 to detect metastatic neuroblastoma cells in bone marrow.

BACKGROUND: The accurate assessment of metastases is an essential component of the staging process for children with neuroblastoma. AIMS: To study the sensitivity of the immunohistochemical marker neuroblastoma 84 (NB84) for the detection of bone marrow infiltrates in children with stage 4 neuroblastoma. METHODS: Primary tumour specimens, bone marrow trephine biopsy specimens and lymph node metastases, taken from children with neuroblastoma that had metastasised to bone marrow, were assessed with a panel of commonly used immunohistochemical markers for neuroblastoma. A comparison was drawn between the sensitivity of the marker NB84 for primary tumours and for bone marrow metastases. RESULTS: NB84 immunolabelled all pre-chemotherapy and post-chemotherapy (n = 24) paired primary tumour specimens, as well as each of a further 20, unpaired, pre-chemotherapy primary tumour specimens. It also labelled all (n = 4) lymph node metastases. Immunolabelling of bone marrow trephine biopsy specimens (21/33) was less sensitive. Of 16 primary tumour specimens with a paired bone marrow trephine biopsy specimen, all immunostained positive, whereas only 62.5% of bone marrow biopsy specimens immunostained positive for NB84. The number of bone marrow biopsy specimens immunostaining for NB84 was significantly lower than the number of paired primary tumour specimens (p = 0.041). CONCLUSIONS: NB84 remains a useful marker for the diagnosis of neuroblastoma in primary tumour specimens, but not for neuroblastoma that has metastasised to bone marrow.

Demographic study of leukaemia presenting within the first 3 months of life in the Northern Health Region of England.

AIMS: To determine the incidence and outcome of congenital leukaemia. METHODS: Retrospective population based study of putative leukaemia arising during the first 3 months of life over an 18 year period within the Northern Health Region of England. RESULTS: Nine infants with putative leukaemia were identified. Five had acute leukaemia and four had transient myeloproliferative disorder (TMD). Trisomy 21, either as Down's syndrome or perhaps restricted to proliferating marrow cells, was present in all four infants with TMD. The incidence of congenital acute leukaemia was 8.6/10(6) live births/year, but would be less than half this value if only patients presenting within 4 weeks of birth were counted. Remission was induced in three of the five patients with acute leukaemia. One patient, who presented at birth, remains well five years after diagnosis. All four patients with TMD survive. CONCLUSIONS: Congenital leukaemia is very rare but is not inevitably fatal. Finding trisomy 21 in spontaneously dividing blood or bone marrow cells of an infant with putative acute leukaemia, particularly within 3 months of birth, should encourage a cautious clinical approach and suggests that the diagnosis might be TMD.

Feline paraneoplastic syndrome associated with thymoma.

CASE HISTORY: A 6-year-old, spayed, female, domestic short-haired cat presented with severe erythroderma and scaling skin. She showed disturbed gait and mild behavioural changes. CLINICAL FINDINGS: The cat had a generalised, erythematous, scurfy dermatitis with marked, multifocal crusting and skin thickening. The skin was painful and contracted, which appeared to prevent normal freedom of movement. DIAGNOSIS: The cat was suspected to have a paraneoplastic syndrome. A mediastinal mass was located and histologically confirmed as thymoma. The cat was diagnosed with a thymoma- associated cutaneous paraneoplastic syndrome. CLINICAL RELEVANCE: This is a rare condition with few reports in the literature. The skin changes, both grossly and histologically, were considered to be different from those described in cases of paraneoplastic dermatosis associated with pancreatic neoplasia. The clinical presentation was characteristic and more cases may occur in practice than are recognised. In this case, as in previous reports, the tumour was grossly resectable, which could lead to cure of the clinical condition.

Zinc protoporphyrin/haem ratio and plasma ferritin in preterm infants.

OBJECTIVE: To study the utility of the zinc protoporphyrin/haem (ZPP/H) ratio as a measure of iron status in healthy, growing, preterm infants. METHOD: ZPP/H was measured in 109 well, preterm infants from the time of hospital discharge until 1 year of age (637 determinations). RESULTS: ZPP/H was initially high, but steadily declined. This was opposite to what was expected from the known changes in iron stores during the first year of life and the observed changes in plasma ferritin. Subjects with higher ZPP/H ratios tended to have lower ferritins, but changes in ZPP/H in a given subject were poorly reflected by changes in plasma ferritin. Between 6 and 9 months of age, ZPP/H correlated with other measures of iron status, but serum ferritin concentration did not. CONCLUSION: Use of the ZPP/H ratio as a measure of iron status during the first year of life appears to be confounded by the developmental changes in ZPP/H, but in the later half of this period it may be a better measure of iron status than serum ferritin.

Acute lymphoblastic leukaemia of the L3 subtype in adults in the Northern health region of England 1983-99.

AIM: Acute lymphoblastic leukaemia (ALL) with an L3 morphological FAB type is regarded by some as being synonymous with B cell ALL or ALL with a Burkitt-type chromosomal translocation-t(8;14), t(2;8), t(8;22). This paper describes a series from a population based study of 24 patients with L3 ALL presenting over 17 years. METHODS: Clinical data were collected prospectively from all adult patients presenting with acute leukaemia in the Northern region since 1982. Data from all patients diagnosed with FAB type L3 ALL were analysed. RESULTS: Overall, L3 ALL accounts for 8.6% of all adult ALL and it is more common in the elderly than has hitherto been recognised. In addition to classic Burkitt-type translocations (11 of 24 cases), the t(14;18) translocation, which is characteristically found in lower grade lymphomas such as follicular lymphoma, is frequently present (five of 24 cases). CONCLUSION: The presence of L3 ALL is often associated with non-Burkitt-type translocations and the presence of a t(14;18) translocation may indicate that in some cases a clinically non-apparent lymphoproliferative disorder, such as a low grade follicular lymphoma, has transformed to a more aggressive form and, thus, presents as a de novo acute leukaemia.

Loss of nuclear expression of the p33(ING1b) inhibitor of growth protein in childhood acute lymphoblastic leukaemia.

BACKGROUND/AIMS: p33(ING1b) is a tumour suppressor protein involved in growth control and apoptosis. Suppression of p33(ING1b) expression is associated with the loss of cellular growth control and immortalisation, whereas its overexpression causes cell cycle arrest. Moreover, normal p33(ING1b) expression is essential for optimal function of p53. Acute lymphoblastic leukaemia (ALL) is the most common malignancy of childhood, accounting for one third of all childhood malignancies. A variety of cytogenetic abnormalities have been described but there is no single abnormality common to all cases. Deregulation of the TP53 pathway is a common genetic abnormality in human malignancies. However, TP53 mutations are uncommon in ALL. It is possible that alternative mechanisms of regulation of the TP53 apoptosis pathway, such as modulation of p33(ING1b) expression, may be important in ALL. The aim of this study was to assess the expression of p33(ING1b) in childhood ALL. METHODS: One hundred and forty five patients with childhood ALL were investigated in this immunohistochemical study of the expression of p33(ING1b). RESULTS: Loss of nuclear expression of p33(ING1b) was seen in 78% of cases. This was associated with increased cytoplasmic expression of the protein. Kaplan Meier survival analysis demonstrated a trend towards a better prognosis for patients with tumours that had lost nuclear p33(ING1b). CONCLUSION: These results suggest that the loss of nuclear p33(ING1b) expression may be an important molecular event in the pathogenesis of childhood ALL.

Erythroleukaemia in the north of England: a population based study.

AIMS: To evaluate the incidence and outcome of acute myeloid leukaemia (AML), FAB M6 (erythroleukaemia). METHODS: A demographic study in the Northern Health Region of England between 1983 and 1999. RESULTS: Thirty three cases were diagnosed and registered prospectively. The overall incidence was 0.077 cases/100,000/year. There was a pronounced rise in incidence in patients aged 56 years or more: 6.6 times higher than that in younger patients. Overall survival was poor; median survival was 11 months for those aged less than 56 years, and three months for patients aged 56 years and above (p = 0.045). Acquired karyotypic abnormalities were found in 17 of 27 patients where analysis was attempted. When classified according to the criteria of the Medical Research Council AML trials, karyotype predicted survival, with a median overall survival of 14 months for those with "standard risk" cytogenetic results and two months for "poor risk" results (p = 0.005). CONCLUSION: This study demonstrates a worse survival for patients with erythroleukaemia than that reported in some published trials of selected patients.

How complete and accurate are cancer registrations notified by the National Health Service Central Register for England and Wales?

STUDY OBJECTIVE: To assess the completeness and accuracy of notification of cancers by the National Health Service Central Register (NHSCR) for England and Wales. DESIGN: Comparison of 720 cancer registrations ascertained from NHSCR up to May 1999 with those ascertained for the same cohort from six other sources and a pathology review of the NHSCR cancer registrations. PARTICIPANTS: People born in Cumbria, north west England, 1950-89, and diagnosed with cancer throughout the UK, 1971-1989. MAIN RESULTS: Cancer diagnoses notified by NHSCR differed substantially from those determined by this pathology review for 47 of the 688 notified cases reviewed (7%; 95% CI 5%, 9%). Over one third of these discrepancies were attributable to failures in data capture or coding by the cancer registration system and almost half to changes in diagnosis; 26 of the 47 discrepant cases were reclassified as non-malignant and 21 as malignancies but with a substantially different diagnosis. The 694 confirmed malignancies represented 94% (95%CI 92%, 95%) of the 740 cancers ascertained from all sources. CONCLUSIONS: It is estimated that the cancer registration system missed at least 10% (95%CI 6%, 15%) of all incident cases of malignant disease. Without additional ascertainment from multiple sources and diagnostic review, it would be incautious to use NHSCR cancer registrations as the sole basis of an epidemiological study.

A demographic study of the clinical significance of minimal residual disease in children with acute lymphoblastic leukemia.

BACKGROUND: Minimal residual disease (MRD) detected during remission might predict outcome in children with acute lymphoblastic leukemia. No population-based studies have been carried out. We studied all children with ALL presenting over 5 years within a defined population to determine its clinical importance. PROCEDURE: Patients were investigated for the presence of unique clonal rearrangements of IgH and T-cell receptor genes. Unique patient specific probes were used to detect, by polymerase chain reaction, the presence of clonal markers indicating MRD in mononuclear cells obtained from marrow samples at 1, 3, 5, and 24 months. The effect of MRD on event-free survival was determined. RESULTS: Seventy-seven of 120 children with ALL had informative markers and samples of remission marrow suitable for testing. Presence or absence of MRD did not significantly affect outcome. Gender (P < 0.04) and white cell count (P < 0.04) were independent prognostic factors. Analysis of only those cases with detectable MRD showed that cases with one blast per 100 mononuclear cells, or more, 28 days after starting treatment did worse than those with lower levels (hazard ratio 7.77, P < 0.02). CONCLUSIONS: Mere presence or absence of MRD is probably too crude a measure to be useful and worse than other standard prognostic indicators. A threshold of 10(-2) blasts at 28 days might be discriminatory, but should not be over-interpreted. The number of patients available for this analysis (31) was small, the threshold and sampling points were arbitrary and any effects could be treatment regimen-specific. Large prospective studies are needed.

Topoisomerase II alpha and II beta expression in childhood acute lymphoblastic leukaemia: relation to prognostic factors and clinical outcome.

BACKGROUND/AIMS: Many regimens used in the treatment of childhood acute lymphoblastic leukaemia (ALL) include Daunorubicin or Etoposide, which act as topoisomerase poisons. It has been suggested that there may be a relation between topoisomerase expression and response to topoisomerase poisons, based mainly on results from in vitro studies. Therefore, the aim of this study was to investigate this relation in a clinical setting and determine whether topoisomerase II alpha and II beta might be of predictive value in ALL. METHODS: Cellular expression of topoisomerases II alpha and II beta was assessed in 177 cases of ALL by immunohistochemistry using monoclonal antibodies to the two enzymes. The percentages of cell nuclei showing positive staining for topoisomerase II alpha and II beta expression were assessed. RESULTS: Taking the series as a whole, a clear separation of survival curves was seen with the established prognostic markers white blood cell (WBC) count, CD10 status, and sex. However, topoisomerase II alpha and II beta expression showed no relation to survival. No association was found between the topoisomerases and the prognostic markers CD10 and WBC count; however, topoisomerase II alpha expression was found to be related to sex, with expression being lower in girls (p = 0.002). CONCLUSIONS: These results suggest that the response to topoisomerase poisons cannot be predicted by the assessment of topoisomerase II alpha and II beta expression as defined by immunohistochemistry.

Chemotherapy and marrow transplantation for congenital leukaemia.

The optimum approach to congenital leukaemia is unclear. Results of treatment are generally discouraging and palliation is offered to many. The successful treatment of an infant with congenital leukaemia is reported.

Anti-E in pregnancy.

Since the introduction of anti-Rhesus (Rh) D prophylaxis for RhD-negative women, other Rh and non-Rh red cell alloantibodies have become relatively more important and are now responsible for the greater proportion of haemolytic disease of the newborn. Anti-C and anti-E are the most commonly implicated non-D Rh antibodies in the pathogenesis of haemolytic disease of the newborn'. In 1977 Pepperell et al. reported the outcome of 44 women with anti-E. This is the only published series that investigates the implications of anti-E during pregnancy. The present report presents a retrospective study of the outcome of 122 pregnancies in which anti-E was the sole alloantibody detected.

A comparison of molecular and enzyme-based assays for the detection of thiopurine methyltransferase mutations.

S-Methylation by thiopurine methyltransferase (TPMT) is an important route of metabolism for the thiopurine drugs. About one in 300 individuals are homozygous for a TPMT mutation associated with very low enzyme activity and severe myelosuppression if treated with standard doses of drug. To validate the use of molecular genetic techniques for the detection of TPMT deficiency, we have determined red blood cell TPMT activity in 240 adult blood donors and 55 normal children. Genotype was determined by restriction fragment length analysis of polymerase chain reaction products in a cohort of 79 of the blood donors and five cases of azathioprine-induced myelosupression, and this confirmed a close relationship between genotype and phenotype. In 17 of the 24 cases in which mutations were found, DNA was also available from remission bone marrow. In one of these cases, DNA from the remission marrow sample indicated the presence of a non-mutated allele that had not been seen in the blast DNA sample obtained at presentation. These results indicate that polymerase chain reaction-based assays give reliable and robust results for the detection of TPMT deficiency, but that caution should be exercised in relying exclusively on DNA obtained from lymphoblasts in childhood leukaemia.

Population-based study of the pattern of molecular markers of minimal residual disease in childhood and adult acute lymphoblastic leukemia: an assessment of the practical difficulty of representative sampling for trial purposes. Northern Region Haematology Group.

BACKGROUND: The prevalence, in unselected patients with acute lymphoblastic leukaemia (ALL), of clonal rearrangements suitable for minimal residual disease (MRD) studies has not been formally investigated. PROCEDURE: This was a prospective, demographic study of the frequency of molecular markers of MRD in all patients with ALL presenting over 5 years within the Northern Health Region of England (population 3.1 million). Presentation marrow samples were examined to detect informative markers. RESULTS: One hundred twenty-four children (age <15 years) developed non-Burkitt ALL. No material was available for study in 21. Eighty-six had clonal gene rearrangements (BCR/ABL, immunoglobulin heavy chain (IGH) and/or T cell receptor (TCR) gene rearrangements). All entered remission; 84 (68% of the original cohort) survived to become eligible for MRD studies. One hundred sixteen adults developed ALL, of whom 48 were not studied due to insufficient cellular material in the bone marrow aspirate or to logistical problems in central referral of samples from other hospitals. Material from elderly adults (age >55 years) was less likely to be sent for analysis, 36% vs. 59% (P = 0.024). Thirty-eight had BCR/ABL and/or IGH/TCR gene rearrangements. Thirty-one (27% of the original cohort) entered remission and became eligible for MRD studies. Informative gene rearrangements were more common in children than adults (83% vs. 63%, P < 0.003). CONCLUSIONS: The results reveal substantial potential, unintentional, selection bias. Large-scale multicentre studies of MRD in children may well produce clinically relevant and representative data. Those who mount similar studies in adults should not assume they will be similarly representative or as successful in accrual of material.