Snap-valve cerebral shunt design for intracranial pressure operation and ultrasound visualization.

Cerebral spinal fluid (CSF) shunts are the main treatment for hydrocephalus. They divert excess CSF from the ventricular system to the abdominal, pleural, or intravascular space where it is absorbed. The shunt valve regulates flow based on intracranial pressure (ICP) to maintain a physiologically stable and safe ICP. Shunt malfunction is difficult to detect, life-threatening and common. The present study demonstrates that snap-though buckling (STB) shells can be transformed into pressure-relief valves that act in the normal physiological range of ICP. Three different shell designs in this preliminary experiment were found to have opening and closing pressures that fall within the physiologically normal range of ICP of 6 to 25 cm H2O. Furthermore, these STB shells demonstrate a valve actuation that is visible by ultrasound and have an implantable form-factor that is similar to currently available shunt valves. The unique characteristics of STB shell valves have potential clinical applications for shunt monitoring using ultrasound imaging and can be fabricated from antibiotic-impregnated materials to mitigate shunt infection. These characteristics make STB valves attractive for future use in cerebral shunt systems.

The implementation of revised guidelines and the performance of a screening programme for congenital hypothyroidism.

OBJECTIVES: To see whether revised screening standards and health-professional training are associated with changes in the performance of a neonatal screening programme for congenital hypothyroidism (CHT). METHODS: Screening data from the regional screening service in Durham and Newcastle, which covers north-east England and North Cumbria. SETTING: We assessed the timing of the different stages of the screening process leading up to the introduction of the revised guidelines between April 2004 and March 2005 (year 1) and afterwards between April 2005 and March 2006 (year 2) in all babies notified as having CHT. We also assessed the interval between sampling and specimen arrival in the laboratory at the beginning and end of year 2 in all babies screened. RESULTS: Twenty-three babies tested positive or borderline in year 1 and 18 babies in year 2. There was reduced variability in the overall time from birth to notification in year 2 versus year 1 (P = 0.001). This reduction was a consequence of a reduced interval between sample collection and arrival in the laboratory (P = 0.047) and for the laboratory to notify the positive test result (P = 0.003). There was a reduction in the mean time from sampling to receipt by the laboratory in the 2997 babies screened in the final month compared with the 2498 babies screened in the first month of year 2 (P = 0.01). CONCLUSION: There was an improvement in neonatal screening programme performance around the time that revised neonatal screening guidelines were introduced. This highlights the importance of ongoing education and training for those involved in screening programmes.

Hypercalcaemia in relapsed medulloblastoma 8 years post-diagnosis; evidence to support PTHrP production by medulloblastoma cells.

BACKGROUND: A 19-year-old male presented with symptomatic hypercalcaemia as the first manifestation of relapsed metastatic medulloblastoma. Management at the time of the initial presentation 8 years earlier was with surgical excision and craniospinal radiotherapy. His biochemistry at the time of relapse and studies of medulloblastoma cell lines provide an insight into the pathogenesis of his hypercalcaemia. METHODS: Parathyroid hormone-related protein (PTHrP) was measured by immunoradiometric assay in blood, and in conditioned and control media from three medulloblastoma cell lines following 72 h growth. RESULTS: The histology at initial presentation (11 years of age) and at the time of relapse (with bone marrow infiltration and widespread bony metastases) demonstrated medulloblastoma. Ionised calcium concentrations at relapse were 2.89 mmol/l and serum PTHrP levels were increased at the same time (2.7 pmol/l; normal range: 0.7-1.8 pmol/l). There was evidence of PTHrP production by one cell line (MHH-MED-8A) while results for both other lines tested were below the limit of detection. CONCLUSIONS: Relapse 8 years after diagnosis is unusual in medulloblastoma and for this relapse to manifest as hypercalcaemia is also very uncommon. Our investigations suggest that the clinical picture was a reflection of PTHrP production by medulloblastoma cells.

The role of the nurse practitioner in psychiatric/mental health nursing: exploring consumer satisfaction.

There is a substantial body of literature pertaining to the role of the nurse practitioner. Research directed towards consumer satisfaction suggests that the care provided by nurse practitioners is perceived as at least equal to that provided by a medical practitioner. However, there is a paucity of literature examining the nurse practitioner role in the psychiatric/mental health field. An evaluation of a Nurse Practitioner demonstration model has recently been undertaken in the Crisis, Assessment and Treatment Team in Victoria, Australia. This article presents the findings of a qualitative, exploratory study. Individual interviews were conducted with consumers (n = 7) who had received care and treatment provided by the nurse practitioner candidate. Data analysis revealed two main themes: the quality of the service provided, and the unique role of the nurse. The findings supported the available literature in articulating the specific aspects of the nurse practitioner role that are favourably perceived by consumers of services. This study contributes to the limited body of knowledge in the psychiatric/mental health nursing field and specifically emphasizes the importance of the relationship between nurse practitioner and consumer in facilitating the provision of effective care and treatment.

Abnormal cognitive function in treated congenital hypopituitarism.

AIMS: To assess cognitive function in school age children with congenital pituitary hormone deficiency (PHD). METHODS: Ten children with PHD (aged 6.0-15.6 years, mean 11.5 years) and sibling controls (aged 8.7-14.9 years, mean 12.1 years) were assessed using the Wechsler Intelligence Scale for Children (WISC-III UK). RESULTS: The patients' full scale IQ scores were all below average (mean 75, 95% CI 70-80), but were not significantly different to those of sibling controls (mean 82, 95% CI 75-89). There was no difference in verbal IQ between patients and siblings, but performance IQ was significantly reduced (mean 75, 95% CI 68-82 in patients; mean 88, 95% CI 80-96 in sibling controls). The reduced performance IQ reflected a poorer performance in tasks assessing perceptual organisational skills. CONCLUSIONS: Data suggest that children with PHD have an IQ that is below average when compared to the population norm and a reduced performance IQ when compared to sibling controls. This may reflect abnormal brain development or could be linked to the impact of hypoglycaemia or low thyroxine concentrations in early life. This information is of value when counselling parents and planning a child's care and education, although further, more extensive studies of patients and siblings are required.

GH and cortisol response to glucagon administration in short children.

OBJECTIVE: To establish whether there is a link between GH status and glucose response to glucagon and to identify determinants of maximum GH and cortisol concentrations. METHODS: 95 children referred for assessment of short stature, slow growth or suspected hypothalamo-pituitary dysfunction were assigned to normal, organic GH-deficient or non-organic GH-deficient groups on the basis of history, GH response and MRI findings. RESULTS: Baseline glucose and glucose nadir were related to age in normal children, but the glucose response to glucagon was not linked to GH status. Peak GH response was positively related to age in prepubertal children and peak cortisol was inversely related to age. CONCLUSIONS: GH status is not a major determinant of the glucose response to glucagon. There is a relationship between age and the GH/cortisol response in short normal children.

Investigating the limits of filopodial sensing: a brief report using SEM to image the interaction between 10 nm high nano-topography and fibroblast filopodia.

Having the ability to control cell behaviour would be of great advantage in tissue engineering. One method of gaining control over cell adhesion, proliferation, guidance and differentiation is use of topography. Whilst it has be known for some time that cells can be guided by micro-topography, it is only recently becoming clear that cells will respond strongly to nano-scale topography. The fact that cells will take cues from their micro- and nano-environment suggests that the cells are in some way 'spatially aware'. It is likely that cells probe the shape of their surroundings using filopodia, and that this initial filopodia/topography interaction may be critical to down-stream cell reactions to biomaterials, or indeed, the extracellular matrix. One intriguing question is how small a feature can cells sense? In order to investigate the limits of cell sensing, high-resolution scanning electron microscopy has been used to simultaneously view cell filopodia and 10 nm high nano-islands. Fluorescence microscopy has also been used to look at adhesion formation. The results showed distinct filopodial/nano-island interaction and changes in adhesion morphology.

Nonadhesive nanotopography: fibroblast response to poly(n-butyl methacrylate)-poly(styrene) demixed surface features.

It is becoming clear that cells do not only respond to micrometric scale topography, but may also respond to topography at the nanometric scale. Nano-fabrication methods such as electron beam lithography are, however, expensive and time consuming. Polymer demixing of poly(styrene) and poly(4-bromostyrene) has been found to produce nano-scale islands of reproducible height, and the islands have been previously shown to effect cell events such as adhesion, spreading, proliferation, and differentiation. This study uses demixed poly(styrene) and poly(n-butyl methacrylate) to produce nano-islands with closer packing and narrower widths compared with those previously studied. Observations have been made of morphological and cytoskeletal changes in human fibroblasts interacting with 10- and 50-nm-high islands. The methods used included scanning electron microscopy, fluorescent microscopy, and optical microscopy. The results indicated that the cells do not respond differently to the 10-nm islands compared with planar samples but, in contrast, the 50-nm islands are nonadhesive.

Endothelization and adherence of leucocytes to nanostructured surfaces.

We analyse the leucocyte and endothelial cell response to polybromostyrene-polystyrene (PS/PBrS) and the poly-n-butylmethacrylate-polystyrene (PnBMA/PS) systems, both in flat form or nanostructured surfaces consisting of nanohills with increasing hill height (13-95nm). Experiments were carried out first with blood leucocytes alone, endothelial cells (of three different types) alone, and finally, using blood cells and endothelized nanosurfaces. Blocking monoclonal antibodies specific for CD11, CD29, CD31, CD54, CD166 were used to analyse whether and to what extent adhesion molecules could be involved in the adherence of both blood leucocytes and endothelial cells to different nanosurfaces. Expression of CD29 (beta-1 integrin), CD54 (ICAM-1) and CD166 (ALCAM) on blood leucocytes was dependent on the hill height, being most prominent with 13nm (PS/PBrS) and 45nm hill (PnBMA/PS) nanosurfaces. Adherence of a human microvascular endothelial cell line and umbilical primary endothelial cells was also related to hill height, being most prominent with 13nm hill height. An indirect correlation was observed between the extent of endothelization and the degree of leucocyte adherence. In cases of low to medium extent of endothelization, the adherence of monocytes and granulocytes was mediated by the expression of CD166, CD29 and CD11a (alpha-L integrin), CD29, CD31 (PECAM-1), respectively. Scanning electron microscopy studies showed the predominant emission of pseudopodia at the holes of the surfaces and the focal contacts with the nanosurfaces. Our studies emphasize the relevance of testing functional properties in co-culture experiments in the development and optimization of nanosurfaces for biomedical application.

Fibroblast reaction to island topography: changes in cytoskeleton and morphology with time.

In order to develop next-generation tissue engineering materials, the understanding of cell responses to novel material surfaces needs to be better understood. Topography presents powerful cues for cells, and it is becoming clear that cells will react to nanometric, as well as micrometric, scale surface features. Polymer-demixing of polystyrene and polybromostyrene has been found to produce nanoscale islands of reproducible height, and is very cheap and fast compared to techniques such as electron beam lithography. This study observed temporal changes in cell morphology and actin and tubulin cytoskeleton using scanning electron and fluorescence microscopy. The results show large differences in cell response to 95 nm high islands from 5 min to 3 weeks of culture. The results also show a change in cell response from initial fast organisation of cytoskeleton in reaction to the islands, through to lack of cell spreading and low recruitment of cell numbers on the islands.

In vitro reaction of endothelial cells to polymer demixed nanotopography.

The introduction of topography to material surfaces has been shown to strongly affect cell behaviour, and the effects of micrometric surface morphologies have been extensively characterised. Research is now starting to investigate the reaction of cells to nanometric topography. This study used polymer demixing of polystyrene and poly(4-bromostyrene) producing nanometrically high islands, and observed endothelial cell response to the islands. Three island heights were investigated; these were 13, 35 and 95 nm. The cells were seen to be more spread on the manufactured topographies than that on flat surfaces of similar chemistry. Other morphological differences were also noted by histology, fluorescence and scanning electron microscopy, with many arcuate cells noted on the test surfaces, and cytoskeletal alignment along the arcuate features. Of the nanotopographies, the 13 nm islands were seen to give the largest response, with highly spread cell morphologies containing well-defined cytoskeleton.

Polymer-demixed nanotopography: control of fibroblast spreading and proliferation.

Cell response to nanometric scale topography is a growing field. Nanometric topography production has traditionally relied on expensive and time-consuming techniques such as electron beam lithography. This presents disadvantages to the cell biologist in regard to material availability. New research is focusing on less expensive methods of nanotopography production for in vitro cell engineering. One such method is the spontaneous demixing of polymers (in this case polystyrene and polybromostyrene) to produce nanometrically high islands. This article observes fibroblast response to nanometric islands (13, 35, and 95 nm in height) produced by polymer demixing. Changes in cell morphology, cytoskeleton, and proliferation are observed by light, fluorescence, and scanning electron microscopy. Morphological features produced by cells in response to the materials were selected, and cell shape parameters were measured with shape-recognition software. The results showed that island height could either increase or reduce cell spreading and proliferation in relation to control, with 13-nm islands producing cells with the greatest area and 95 nm islands producing cells with the lowest areas. Interaction of filopodia with the islands could been seen to increase as island size was increased.

Attenuation of hypothalamic-pituitary-adrenal axis stress responses in late pregnancy: changes in feedforward and feedback mechanisms.

The hypothalamic-pituitary-adrenal axis is hyporesponsive to stress in late pregnancy, exemplified as reduced adrenocorticotropic hormone (ACTH) and corticosterone responses to restraint, but the mechanisms are unknown. We investigated forward drive and negative feedback upon the hypothalamic-pituitary-adrenal axis in pregnant rats. Corticotropin-releasing hormone (CRH) and vasopressin mRNA expression in the parvocellular paraventricular nucleus and mineralocorticoid and glucocorticoid receptor expression in the paraventricular nucleus and hippocampus were quantified with in situ hybridization. Because it can enhance the corticosterone negative feedback signal, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) bioactivity in these brain regions and anterior pituitary was measured in vitro, and ACTH and corticosterone stress responses were measured after intracerebroventricular glycyrrhetinic acid, an 11beta-HSD inhibitor. Changes in corticosterone feedback on ACTH secretion were examined after pharmacological adrenalectomy by metyrapone and aminoglutethimide. Parvocellular paraventricular nucleus CRH mRNA content was reduced on day 21 and the CRH mRNA : vasopressin mRNA ratio was unaltered, indicating decreased production of both CRH and vasopressin. An increase in glucocorticoid receptor mRNA expression in the dentate gyrus (mineralocorticoid receptor mRNA expression was unaltered) and increased 11beta-HSD1 activity in the paraventricular nucleus and anterior pituitary suggest an increase in slow negative feedback mechanisms in pregnancy, but glycyrrhetinic acid did not modify the stress response. After metyrapone/aminoglutethimide treatment, corticosterone decreased ACTH secretion more slowly in pregnancy, indicating a decrease in rapid feedback sensitivity. Thus, reduced forward drive rather than increased effectiveness of glucocorticoid negative feedback may underlie stress hyporesponsiveness of the hypothalamic-pituitary-adrenal axis in pregnancy.

Early testicular biopsy in males with acute lymphoblastic leukemia: lack of impact on subsequent event-free survival.

PURPOSE: Children with acute lymphoblastic leukemia (ALL) who had bulky disease (lymphomatous features) at diagnosis had the highest rate of testicular relapse (20%) of any ALL subgroup on previous Children's Cancer Group (CCG) studies in the late 1980s. To limit curative, but sterilizing, testicular irradiation to those with testicular disease, testicular biopsies were performed to detect occult testicular disease within the first 6 months of treatment. Testicular irradiation then was provided to those with occult disease to increase disease-free survival. Identification of those with occult disease was believed to be a factor that would influence ultimate survival in such patients in that era. PATIENTS AND METHODS: One hundred ninety-nine patients had bilateral testicular wedge biopsies performed during the first maintenance therapy phase of the four different chemotherapy regimens. Patients with positive biopsy results were treated with testicular irradiation and continued on therapy. RESULTS: Eleven of 199 biopsy results (5.5%) were judged positive. Patients with positive biopsy results given testicular radiation had a 45% subsequent adverse event rate, compared with 36% for those with a negative biopsy results (P = 0.4). The survival rates for the two groups were similar. The low rate of positive biopsy specimens resulted in discontinuation of the procedure before closure of the study. CONCLUSION: Positive testicular biopsy results early in remission identified patients at a slightly higher risk of subsequent adverse events but did not influence survival. However, because negative biopsy results (94.5%) did not alter the prescribed treatment, the small number of positive biopsy results did not warrant undertaking the procedure in most male patients with ALL, and this procedure was abandoned.

Sex-steroid induction of endogenous opioid inhibition on oxytocin secretory responses to stress.

In pregnancy, endogenous opioids inhibit enhanced basal and stressor-stimulated oxytocin neurone activity and secretion. By contrast, stress responses of the hypothalamo-pituitary-adrenal (HPA) axis are reduced in pregnancy. We investigated whether the high levels of oestradiol and progesterone of pregnancy could induce these changes. Silastic capsules containing oestradiol or progesterone (or control capsules) were implanted s.c. in virgin female rats for 16 or 17 days, with or without progesterone removal on day 15 to mimic the progesterone withdrawal seen at the end of pregnancy. Plasma concentrations of oxytocin, adrenocorticotrophic hormone (ACTH) and corticosterone were measured in jugular vein blood samples from conscious rats. Under basal conditions, naloxone (5 mg/kg) increased oxytocin secretion in all groups, but had no greater effect in sex-steroid treated rats, and did not induce Fos expression in the supraoptic nucleus. Forced swimming, a stressor, increased oxytocin secretion at 5 min in vehicle-injected controls, and this response was slightly attenuated in the sex-steroid treated groups. Pretreatment with naloxone greatly enhanced the response in the sex-steroid treated rats, and was less effective in the controls. In rats treated with oestradiol alone, naloxone prolonged the response. Thus, the combined sex-steroid treatment enhanced the responsiveness of oxytocin neurones to the stressor, while simultaneously restraining oxytocin secretion via endogenous opioid inhibition. In the same rats, ACTH and corticosterone secretion was also stimulated by the stressor, but the hypothalamo-pituitary-adrenal (HPA) axis response was not attenuated in sex-steroid treated rats. Naloxone weakly reduced the HPA axis response in controls and was ineffective in the sex-steroid treated rats. We conclude that oestradiol and progesterone may be responsible for inducing the opioid restraint and enhanced oxytocin neurone responsiveness in pregnancy.

Treatment outcome and prognostic factors for infants with acute lymphoblastic leukemia treated on two consecutive trials of the Children's Cancer Group.

PURPOSE: Infants represent a very poor risk group for acute lymphoblastic leukemia (ALL). We report treatment outcome for such patients treated with intensive therapy on consecutive Children's Cancer Group (CCG) protocols. PATIENTS AND METHODS: Between 1984 and 1993, infants with newly diagnosed ALL were enrolled onto CCG-107 (n = 99) and CCG-1883 (n = 135) protocols. Postconsolidation therapy was more intensive on CCG-1883. On both studies, prophylactic treatment of the CNS included both high-dose systemic chemotherapy and intrathecal therapy, in contrast to whole-brain radiotherapy, which was used in earlier studies. RESULTS: Most patients (>95%) achieved remission with induction therapy. The most frequent event was a marrow relapse (46 patients on CCG-107 and 66 patients on CCG- 1883). Four-year event-free survival was 33% (SE = 4.7%) on CCG-107 and 39% (SE = 4.2%) on CCG- 1883. Both studies represent an improvement compared with a 22% (SE = 5.1%) event-free survival for historical controls. Four-year cumulative probabilities of any marrow relapse or an isolated CNS relapse were, respectively, 49% (SE = 5%) and 9% (SE = 3%) on CCG-107 and 50% (SE = 5%) and 3% (SE = 2%) on CCG-1883, compared with 63% (SE = 6%) and 5% (SE = 3%) for the historical controls. Independent adverse prognostic factors were age less than 3 months, WBC count of more than 50,000/microL, CD10 negativity, slow response to induction therapy, and presence of the translocation t(4;11). CONCLUSION: Outcome for infants on CCG-107 and CCG- 1883 improved, compared with historical controls. Marrow relapse remains the primary mode of failure. Isolated CNS relapse rates are low, indicating that intrathecal chemotherapy combined with very-high-dose systemic therapy provides adequate protection of the CNS. The overall unsatisfactory outcome observed for the infant ALL population warrants the future use of novel alternative therapies.

The role of endogenous opioids in neurohypophysial and hypothalamo-pituitary-adrenal axis hormone secretory responses to stress in pregnant rats.

Endogenous opioid regulation of neurohypophysial and hypothalamo-pituitary-adrenal (HPA) axis hormone secretion in response to forced swimming (90 s in deep water at 19 degrees C) was investigated in virgin and 21-day-pregnant rats. There was no difference in basal plasma oxytocin concentrations between pregnant and virgin rats, but the opioid antagonist, naloxone, increased basal oxytocin secretion in the pregnant rats. Forced swimming increased oxytocin secretion similarly in pregnant and virgin rats, and this response was enhanced by naloxone. In pregnant rats naloxone had a greater effect (by 3.1-fold) than in virgins, showing stronger endogenous opioid restraint of an enhanced oxytocin secretory response to stress in pregnancy. Vasopressin secretion was not increased with forced swimming in virgin or pregnant rats, and naloxone had no effect. ACTH and corticosterone secretion in response to forced swimming was attenuated in pregnant rats compared to virgin rats, measured at 5 min. Naloxone had no effect on basal plasma ACTH or corticosterone concentration, but it reduced ACTH secretion in virgin rats 5 min after forced swimming; in pregnant rats naloxone had no such effect. Naloxone removed the pregnancy-related attenuation in corticosterone secretion measured at 5 min after forced swimming. Fifteen minutes after forced swimming, plasma corticosterone concentrations were not different between groups. In the late-pregnant rats, the increases in plasma ACTH and corticosterone induced by forced swimming were significantly prolonged compared to virgins. The results show that endogenous opioid inhibition emerges in pregnancy to restrict the responses of oxytocin neurones to a stressor. In contrast, the endogenous opioid enhancement of mechanisms regulating HPA axis secretory responses in virgin rats is not evident during pregnancy.

Attenuated neuroendocrine responses to emotional and physical stressors in pregnant rats involve adenohypophysial changes.

1. The responsiveness of the rat hypothalamo-pituitary-adrenal (HPA) axis and hypothalamo-neurohypophysial system (HNS) to emotional (elevated plus-maze) and physical (forced swimming) stressors and to administration of synthetic corticotrophin-releasing hormone (CRH) was investigated during pregnancy and lactation. In addition to pregnancy-related adaptations at the adenohypophysial level, behavioural responses accompanying the neuroendocrine changes were studied. 2. Whereas basal (a.m.) plasma corticosterone, but not corticotrophin (adrenocorticotrophic hormone; ACTH), levels were increased on the last day (i.e. on day 22) of pregnancy, the stress-induced rise in both plasma hormone concentrations was increasingly attenuated with the progression of pregnancy beginning on day 15 and reaching a minimum on day 21 compared with virgin control rats. A similar attenuation of responses to both emotional and physical stressors was found in lactating rats. 3. Although the basal plasma oxytocin concentration was elevated in late pregnancy, the stress-induced rise in oxytocin secretion was slightly lower in day 21 pregnant rats. In contrast to vasopressin, oxytocin secretion was increased by forced swimming in virgin and early pregnant rats indicating a differential stress response of these neurohypophysial hormones. 4. The blunted HPA response to stressful stimuli is partly due to alterations at the level of corticotrophs in the adenohypophysis, as ACTH secretion in response to CRH in vivo (40 ng kg-1, i.v.) was reduced with the progression of pregnancy and during lactation. In vitro measurement of cAMP levels in pituitary segments demonstrated reduced basal levels of cAMP and a lower increase after CRH stimulation (10 nM, 10 min) in day 21 pregnant compared with virgin rats, further indicating reduced corticotroph responsiveness to CRH in pregnancy. 5. The reduced pituitary response to CRH in late pregnancy is likely to be a consequence of a reduction in CRH receptor binding as revealed by receptor autoradiography. [125I] CRH binding in the anterior pituitary was significantly reduced in day 11, 17 and 22 pregnant rats compared with virgin controls. 6. Anxiety-related behaviour of the animals as revealed by the time on and entries into the open arms of the elevated plus-maze was different between virgin and pregnant rats with decreased number of entries indicating increased anxiety with the progression of pregnancy (except on pregnancy day 18). The emotional behaviour, however, was not correlated with the neuroendocrine responses. 7. The results indicate that the reduced response of the HPA axis to stressors described previously during lactation is already manifested around day 15 of pregnancy in the rat and involves physiological adaptations at the adenohypophysial level. However, alterations in stressor perception at higher brain levels with the progression of pregnancy may also be involved.

Treatment of patients with acute lymphoblastic leukemia with bulky extramedullary disease and T-cell phenotype or other poor prognostic features: randomized controlled trial from the Children's Cancer Group.

BACKGROUND: Children with acute lymphoblastic leukemia with multiple poor prognostic factors and who have a lymphomatous mass at diagnosis, whether of T- or non-T-immunophenotype, are at increased risk of short term remission and extramedullary recurrence, and are in need of better therapies. METHODS: Six hundred and ninety-four eligible patients ranging in age from 1-20 years were entered on the study. Sixty-five percent of the patients had T-cell immunophenotype. Of these, 678 were randomized to one of four regimens: Regimen A: Berlin-Frankfurt-Munster (BFM) 76/79; Regimen B: LSA2-L2 with cranial irradiation; Regimen C: LSA2-L2 without cranial irradiation; and Regimen D: the New York (NY) regimen. RESULTS: Complete remission was induced in 97% of patients. The overall event free survival (EFS) +/- the standard deviation was 60 +/- 4% 6 years after diagnosis, in contrast to 36 +/- 6% in a comparable historic group. The EFS of the 371 T-cell patients was 62 +/- 7%. EFS was best on the NY (67 +/- 7%) and the BFM (67 +/- 6%) arms. These were significantly better than the EFS on the 2 LSA-L2 regimens, with an EFS of 53 +/- 8% (Regimen B) and 42 +/- 11% (Regimen C) (P = 0.03 and 0.0003 for NY vs. Regimen B and NY vs. Regimen C; P = 0.01 and 0.0001 for BFM vs. Regimen B and BFM vs. Regimen C). Regimen C had a 3-fold greater central nervous system (CNS) recurrence rate than the identical chemotherapy Regimen B (16 +/- 5% vs. 6 +/- 4%; P = 0.02), although the difference in overall EFS did not reach the required level for significance. Testicular recurrence varied from 2-8% in comparison with 20% in the historic group. EFS was not influenced by age, gender, CNS disease at diagnosis, morphology, or immunophenotype. In addition to treatment regimen and early response rate, initial leukocyte count, hemoglobin level, liver, spleen, and lymph node enlargement, and the presence of a mediastinal mass had univariate prognostic influence on EFS. In multivariate analysis, only the kinetics of response, leukocyte count (unfavorably, P < 0.0001), and mediastinal mass status (favorably, P = 0.01) were prognostic. CONCLUSIONS: The adverse prognostic implications of lymphomatous ALL can be minimized by the NY and BFM regimens. Cranial irradiation resulted in better CNS disease control when added to the LSA2-L2 regimen, but did not improve the overall disease free survival. With improved systemic chemotherapy, there was no excess of lymph node, testicular, or other local recurrence without prophylactic irradiation to sites of initial bulk disease or to the testes.