Demonstrating the relationships of length of stay, cost and clinical outcomes in a simulated NICU.

OBJECTIVE: Health-care leaders place significant focus on reducing the average length of stay (ALOS). We examined the relationships among ALOS, cost and clinical outcomes using a neonatal intensive care unit (NICU) simulation model. STUDY DESIGN: A discrete-event NICU simulation model based on the Duke NICU was created. To identify the relationships among ALOS, cost and clinical outcomes, we replaced the standard probability distributions with composite distributions representing the best and worst outcomes published by the National Institutes of Health Neonatal Research Network. RESULT: Both average cost per patient and average cost per ⩽28 week patient were lower in the best NICU ($16,400 vs $19,700 and $56,800 vs $76,700, respectively), while LOS remained higher (27 vs 24 days). CONCLUSION: Our model demonstrates that reducing LOS does not uniformly reduce hospital resource utilization. These results suggest that health-care leaders should not simply rely on initiatives to reduce LOS without clear line-of-sight on clinical outcomes as well.

Treatment of children over the age of one year with unresectable localised neuroblastoma without MYCN amplification: results of the SIOPEN study.

BACKGROUND: In children older than 1 year with localised unresectable neuroblastoma (NB), treatment strategies are heterogeneous according to the national groups. The objective of this phase III non-randomised study was to evaluate the efficacy of conventional chemotherapy followed by surgery. PATIENTS AND METHODS: In the presence of surgical risk factors (SRF), six courses of chemotherapy alternating Carboplatin-Etoposide and Vincristin-Cyclophosphamide-Doxorubicin were given, and surgical resection was attempted after four. Survival analyses were performed using an intention-to-treat approach. The main objective was to achieve a 5-year survival over 80%. RESULTS: Out of 191 registered children, 160 were evaluable. There were 62.5% older than 18 months and 52.5% had unfavourable histology according to International Neuroblastoma Pathology Classification (INPC). Chemotherapy reduced the number of SRFs by one third. Delayed surgery was attempted in 86.3% of patients and was complete or nearly complete in 74%. The 5-year EFS and OS were 76.4% and 87.6% respectively, with significant better results for patients younger than 18 months or with favourable histology. CONCLUSION: This strategy provides encouraging results in children older than 1 year or 12 months with localised unresectable NB without MYCN amplification. However, in children older than 18 months and with unfavourable histology, additional treatment is recommended.

Human milk versus formula after gastroschisis repair: effects on time to full feeds and time to discharge.

OBJECTIVE: To determine if the choice of enteral feeds after gastroschisis repair relates to the time to achieve full feeds and time to discharge. STUDY DESIGN: A retrospective study of infants with gastroschisis from 2000 to 2010 examined demographics, days at closure, days at initiation of feeds, days to full feeds, time to discharge and length of stay. RESULT: Ninety infants were identified, 22 received (human milk) HM exclusively, 15 were fed >50% HM, 16 were fed <50% HM and 26 were fed only cow milk-based formulas. Infants fed exclusively HM had significantly shorter times to full enteral feedings (median 5 days versus 7 days, P=0.03). The time from initiation of feedings to hospital discharge, which accounts for initiation age, significantly favored the exclusively HM-fed infants (median 7 days versus 10 days, P=0.01). CONCLUSION: Exclusive HM feeding after gastroschisis repair decreases time to achieve full enteral feeds and time to discharge.

Selective reduction in trabecular volumetric bone mineral density during treatment for childhood acute lymphoblastic leukemia.

During treatment of childhood acute lymphoblastic leukemia (ALL) fracture incidence is increased. Studies using DXA, which measures a composite of both trabecular and cortical BMD, have shown reduced BMD during treatment. We investigated changes in compartmental (cortical and trabecular) volumetric BMD (vBMD) and bone geometry using peripheral quantitative computed tomography. These outcomes were also analysed in relation to adiposity and treatment factors. Thirty nine patients with ALL (64% male, median age 7.2 years (4.1-16.9)) were compared to 34 healthy controls (50% male, median age 9.1 years (4.4-18.7)). DXA-derived age-specific standard deviation scores (SDS) of the lumbar spine (LS) and femoral neck (FN) were reduced in subjects with ALL compared to controls (p ≤ 0.01). This persisted following adjustment for body size using height-specific SDS (LS -0.72 ± 1.02 vs -0.18 ± 0.72, p=0.01; FN -1.53 ± 0.96 vs -0.74 ± 0.74, p=0.001) and bone mineral apparent density (BMAD) SDS (LS -0.76 ± 1.14 vs 0.04 ± 1.08, p=0.01; FN -1.63 ± 1.38 vs -0.16 ± 1.20, p<0.001). Radial and tibial trabecular vBMD was also reduced (196.5 ± 54.9 mg/cm(3) vs 215.2 ± 39.9 mg/cm(3), p=0.03 and 232.8 ± 60.3mg/cm(3) vs 267.5 ± 60.2mg/cm(3), p=0.002, respectively), but cortical vBMD at the radius and tibia was similar in patients and controls. A lowered tibial bone strength index (BSI) was identified in patients with ALL (53.9 ± 23.1mg/mm(4) vs 82.5 ± 27.8 mg/mm(4), p<0.001) suggesting lower fracture threshold from compressive forces. No relationships with measures of adiposity, duration of treatment or cumulative corticosteroid dose were identified. Our findings therefore suggest that reduction in trabecular vBMD during childhood ALL treatment may contribute to the observed increased fracture incidence and bony morbidity in this group.

Increased adiposity and altered adipocyte function in female survivors of childhood acute lymphoblastic leukaemia treated without cranial radiation.

BACKGROUND: Excess adiposity is a complication of childhood acute lymphoblastic leukaemia (ALL) and is commonly attributed to cranial radiation (CRT) administration. Hyperleptinaemia also occurs during ALL treatment, but there are no data on long-term alterations to adipocytokines following treatment without CRT. METHODS: Fifty-four survivors (50% female) and 51 controls (59% female) were recruited. Body composition assessment was by BMI, air displacement plethysmography (BODPOD), bioelectrical impedance analysis (BIA) and skinfold thickness (SFT). Fasting blood samples were analysed for adipocytokines (leptin, adiponectin, resistin, tumour necrosis factor-α, interleukin-6). RESULTS: The BMI standard deviation score (0.71 vs. 0.04, p < 0.05) and fat percentage measured by BIA (29.8% vs. 24.6%, p = 0.01) and SFT (31.7% vs. 28.2%, p = 0.007) were greater in female survivors compared with controls. Adiposity was similar in male survivors and controls. Absolute leptin (17.8 vs. 7.8 ng/ml, p = 0.01) and fat-adjusted leptin concentrations (p < 0.05) were higher in female survivors compared to controls. Female survivors were less insulin sensitive than controls (p = 0.02). These findings were not observed in males. There were no differences in the other adipocytokines between survivors and controls. CONCLUSIONS: Long-term unfavourable alterations to body composition and adipocyte function are observed in female, but not male, survivors of ALL treatment without CRT.

Response to N7 induction chemotherapy in children more than one year of age diagnosed with metastatic neuroblastoma treated in UKCCSG centers.

BACKGROUND: The highest reported metastatic response rate to induction chemotherapy in patients with neuroblastoma has been achieved by Kushner et al. [Kushner et al.: J Clin Oncol 12:2607-2613,1994; Cheung et al.: Med Pediatr Oncol 36: 227-230, 2001; Kushner et al.: J Clin Oncol 22:4888-4892, 2004] using their N6 and subsequently N7 protocols. This N7 induction was adopted by UKCCSG for new patients in 1999. METHODS: Forty-seven children with metastatic neuroblastoma were recruited between 1999 and 2002. They received the N7 intensive chemotherapy protocol, after full staging including evaluation by I123mIBG imaging where possible. RESULTS: Thirty patients with positive mIBG scans were evaluable for response, and complete resolution of metastatic disease was obtained in 16 (53.3%). Fourteen patients without positive mIBG scans were evaluated for response according to bone marrow and bone scan data and 11 (78.6%) cleared metastatic disease. The toxicity of this induction therapy was similar to that seen in previous UK protocols, although 14 patients had Brock grade 3 or 4 ototoxicity. Thirty-three patients proceeded to high-dose therapy with no unanticipated toxicities. For the whole group of 44 evaluable patients, the 3-year event-free survival (EFS) and overall survival (OS) were 38.3 and 46.7%, respectively. CONCLUSIONS: Although feasible in terms of delivery, when used in the UKCCSG centers, this protocol achieved a much lower response rate than in the previously published series in the US [Kushner et al.: J Clin Oncol 12:2607-2613,1994; Cheung et al.: Med Pediatr Oncol 36: 227-230, 2001; Kushner et al.: J Clin Oncol 22:4888-4892, 2004].

Tazobactam-induced haemolytic anaemia, possibly caused by non-immunological adsorption of IgG onto patient's red cells.

A patient with pneumonia was treated with Tazocin (piperacillin/tazobactam). However, the expected haemoglobin (Hb) increment after transfusion was not achieved. Plasma bilirubin and lactate dehydrogenase were raised. The direct antiglobulin test (DAT) was positive (4+) for immunoglobulin G (IgG) only, but no RBC antibodies were demonstrable in the plasma or an eluate from the patient's RBCs. Drug-induced haemolysis was suspected. After discontinuing Tazocin administration, Hb and bilirubin levels returned to expected values. The patient's plasma gave a positive (3+) indirect antiglobulin reaction only with RBCs pretreated with tazobactam. However, random patient plasmas also gave weak (+/- to 1+) reactions, indicating non-immunological adsorption of IgG onto RBCs rather than specific anti-tazobactam antibodies. Subsequently, plasma samples with varying IgG levels (0.8-89.7 g L(-1)) were tested against RBCs pretreated with tazobactam. The amount of plasma IgG non-immunologically adsorbed onto the drug-coated RBCs was found to correlate directly with the plasma IgG level. The patient had a high plasma IgG level (41.6 g L(-1)) which explains why the antiglobulin test was stronger with the patient's plasma than with random plasma samples. Previous reports (Garratty & Arndt, (1998) British Journal of Haematology, 100, 777-783; Arndt & Garratty (2000) Transfusion, 40, 29S) suggested that non-immunological coating of RBCs with IgG may affect RBC survival; our results would support that suggestion. This is the first reported case of haemolytic anaemia associated with tazobactam.

Late relapse and prognosis for neuroblastoma patients surviving 5 years or more: a report from the European Neuroblastoma Study Group "Survey".

BACKGROUND AND PROCEDURE: Most deaths from neuroblastoma occur within 2 years of diagnosis but there have been several anecdotal reports of relapse and death after much longer periods of follow up. In order to investigate and quantify the risk of late events we analysed data for patients registered with the European Neuroblastoma Study Group between 1982 and 1990. Out of a total of 1,277 children registered, 427 were alive with follow-up beyond 5 years from diagnosis (median follow-up of 8.8 years, range 5-14 years). Of these 406 were in remission with no prior recurrence, 16 were in remission having experienced a relapse prior to 5 years, and 5 were alive with progressive disease. RESULTS: For the 406 patients in remission with no prior relapse the 10 year progression free survival (PFS) was 96% (CI 94-98). For those aged over 1 year with stage 4 disease at diagnosis 10 year PFS was 88% (CI 79-96) compared to 98% (CI 97-99) for other patients combined, P< 0.001. In a multivariate analysis of all 422 patients in remission at 5 years, significant risk factors for subsequent relapse were age > 1 yr with stage 4 disease at diagnosis (relative risk 10.5, P < 0.001) and prior relapse (RR 4.2, P= 0.01). CONCLUSIONS: The results of this study emphasise the importance of longterm follow-up of patients and the need for late monitoring of clinical trials in children with neuroblastoma. They also provide a baseline for comparison with future and hopefully more effective treatment programmes.

Effect of fatty acid supplementation on growth and differentiation of human IMR-32 neuroblastoma cells in vitro.

Polyunsaturated fatty acids play a critical role in the structure and function of the developing nervous system. It has been proposed that fatty acids may effect a variety of biologic processes through the activation of the peroxisome proliferator activated receptors (PPARs)-ligand activated transcription factors. In this report, we demonstrate that fatty acids can inhibit the proliferation of the human neuronal cell line IMR-32. The fatty acids linoleate, alpha-linoleate, arachidonate, docosahexaenoate, and oleate all inhibited [(3)H]thymidine incorporation of IMR-32 cells after 72 h. Fatty acid supplementation also led to the morphologic differentiation of the IMR-32 cells. Linoleate and arachidonate, fatty acids of the n-6 series, induced the most extensive differentiation. Furthermore, the addition of fatty acids to IMR-32 cells led to PPAR activation, suggesting that PPAR activation may be an important event in fatty acid modulation of IMR-32 cell growth. In support of this hypothesis, clofibric acid, a specific ligand of PPARalpha, also inhibited IMR-32 cell proliferation and strongly induced PPAR activation. Together these results suggest that fatty acids may play an important role in the development of neuronal precursor cells and that activation of the PPARs may be one pathway by which fatty acids modulate the growth and differentiation of neuronal precursor cells.

A randomized trial of 13-Cis retinoic acid in children with advanced neuroblastoma after high-dose therapy.

One hundred and seventy-five children with Stage 3 or 4 neuroblastoma who had obtained a good response to conventional therapy were randomly allocated to 13-Cis retinoic acid at a dose of 0.75 mg/kg/day or placebo for up to 4 years. Toxicity was mild but no advantage in event-free survival was shown for the children receiving retinoic acid.

Clinical prognostic factors in 1277 patients with neuroblastoma: results of The European Neuroblastoma Study Group 'Survey' 1982-1992.

In 1982 the European Neuroblastoma Study Group (ENSG) established a prospective registry for patients with newly diagnosed neuroblastoma ('The ENSG Survey'). Clinical information was collected primarily to: (a) establish an ENSG database; and (b) investigate prognostic factors in neuroblastoma. This paper summarises the results of the survey. By 1992, 1277 patients with a median age of 26 months (range: 0-289 months), gender ratio of 1.19 M:F had been registered from 30 centres. The median follow-up of survivors is 9.7 years (range: 1-14 years). Overall 5-year survival (S) is 45% (95% CI 42-48%), and event-free survival (EFS) is 43% (95% CI 40-45%). For both survival and EFS the key established prognostic factors, stage and age, are highly significant (P<0.001). In particular, patients under 1 year of age at diagnosis, whatever the disease stage, had a more favourable prognosis than older patients; stage 2 (EFS 93% (95% (CI 85-97) versus 76% (95% CI 67-86), P=0.02), stage 3 (EFS 91% (95% CI 82-96) versus 52% (95% CI 44-60), P<0.001) and stage 4 (EFS 59% (95% CI 48-69) versus 16% (95% CI 13-19), P<0.001). Multivariate analysis established that the anatomical location of the primary tumour (i.e. abdominal versus other sites) and primary tumour volume also conferred a statistically significant difference. In stage 4 disease the 20% of patients without demonstrable bone marrow involvement had a more favourable prognosis than those with infiltrated marrow (EFS 36% (95% CI 13-19) versus 16% (95% CI 29-45), P<0.001). Urine catecholamine metabolite levels (raised versus normal), histology (ganglioneuroblastoma versus neuroblastoma) and gender had no significant effect on outcome after stage and age were accounted for. 5-year survival following first relapse is only 5.6% (95% CI 2.8-8.4). This ENSG Survey provides secure data for future comparisons with new prognostic factors and treatment programmes.

Comparative genomic hybridization and histological variation in primitive neuroectodermal tumours.

The objective of this study was to test the hypothesis that chromosomal imbalances in central nervous system primitive neuroectodermal tumours (PNETs) reflect site and histology. We used comparative genomic hybridization to study 37 cases of PNET, of which four were cerebral and 31 were medulloblastomas classified histologically as classic (n = 17) or nodular/desmoplastic (n = 14). Tumour immunophenotype was characterized with antibodies to neuroglial, mesenchymal and epithelial markers. Chromosomal imbalances were detected in 28 medulloblastomas (90%), and significant associations between tumour variants and genetic abnormalities were demonstrated. Aberrations suggesting isochromosome 17q were present in eight (26%) medulloblastomas, of which seven were classic variants. None of these cases, or a further six with gain of 17q, showed immunoreactivity for glial fibrillary acidic protein. Loss on 9q was found in six cases (19%), five of them nodular/desmoplastic. Loss of 22 occurred in four (13%), all classic medulloblastomas in young patients with a poor outcome and immunoreactivity for more than one epithelial or mesenchymal marker. Different patterns of imbalance were found in the cerebral PNETs. There were no abnormalities of chromosome 17, but all three cases with imbalance showed losses of 3p12.3-p14.

Superior sagittal sinus thrombosis complicating maintenance treatment for acute lymphoblastic leukemia.

A girl with acute lymphoblastic leukemia in remission had two seizures during the maintenance phase of her treatment. Magnetic resonance imaging with angiography identified a superior sagittal sinus thrombosis as the likely explanation for her symptoms. Possible causes are considered, and previous reports of the neurotoxicity of agents used in the treatment of leukemia are reviewed.

Dysgerminoma in mother and daughter: use of lactate dehydrogenase as a tumor marker in the child.

A 7-year-old girl presented with an extragonadal dysgerminoma arising from the pelvis. Her mother had been treated for a histologically identical pituitary tumor 3 years previously. The child's serum lactate dehydrogenase (LDH) level was markedly elevated at presentation and fell as the tumor responded to treatment. The potential use of LDH as a marker for gonadal dysgerminoma is well documented, but raised LDH in association with primary extragonadal dysgerminoma has not been described previously. In addition, this is the first report of extragonadal dysgerminoma occurring in female relatives.

Therapy of human T-cell acute lymphoblastic leukaemia in severe combined immunodeficient mice with two different anti-CD7-saporin immunotoxins containing hindered or non-hindered disulphide cross-linkers.

A SCID mouse model of human T-ALL has been used to determine the in vivo therapeutic efficacy of two anti-CD7-saporin immunotoxins constructed with either a hindered (HB2-SMPT-Sap) or non-hindered (HB2-SPDP-Sap) disulphide bond between antibody and saporin. Groups of 10 SCID mice were injected intravenously (i.v.) with 2 x 10(6) human T-ALL HSB-2 cells followed seven days later by i.v. injection with either a single dose or with 3 doses of HB2-SPDP-Sap or HB2-SMPT-Sap given on alternate days. Control groups received equivalent sham injections of PBS or molar equivalent amounts of unconjugated HB2 antibody+saporin. Animals receiving a single dose of HB2-SMPT-Sap showed better survival than animals receiving a single dose of HB2-SPDP-Sap but the difference was not shown to be significant by log-rank analysis. When given as a triple dose both immunotoxins performed similarly. Comparison of single-dose with triple-dose IT therapy revealed that the therapeutic effect of a triple dose of HB2-SPDP-Sap was significantly better than that of single dose, but this was not the case with HB2-SMPT-Sap. Pharmacokinetic studies of HB2-SPDP-Sap and HB2-SMPT-Sap in normal and HSB-2 leukaemia bearing SCID mice failed to reveal any difference in clearance rates for these two IT's. We conclude from these studies that there is no therapeutic advantage to be gained from constructing the HB2-Sap IT with a hindered disulphide bond in this particular model of human T-ALL.

Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events.

PURPOSE: The purpose of this study was to better define the toxicity of low dose (less than or equal to 15 mg/d prednisone or equivalent) long-term (greater than 1 year) corticosteroids in the treatment of rheumatoid arthritis (RA). PATIENTS AND METHODS: We examined an historical cohort of 112 RA patients on low dose (6.1 +/- 3.1 mg/d, mean +/- SD) long-term (6.2 +/- 4.6 years) prednisone (CS) and compared them to 112 matched RA patients not using prednisone (CO). CS were matched one-to-one with CO for sex (75% women), age (+/- 5 yrs), race (98% white), and duration of disease (+/- 5 yrs). Subjects were determined by review of unselected medical records from three distinct rheumatology practice settings. For CS, charts were abstracted from the date of prednisone start for predefined adverse events (AEs). RESULTS: Ninety-two (92) AEs were noted in CS versus 31 in CO and included: fracture (CS:21 versus CO:8), serious infections (CS:14 versus CO:4), gastrointestinal (GI) bleed or ulcer (CS:11 versus CO:4), and cataracts (CS:17 versus CO:5). At time of first AE, CS prednisone average dose was 7.0 +/- 2.6 mg with a duration of 4.9 +/- 3.9 years. Stepwise multiple logistic regression analysis was used to create a model which included all clinically relevant variables and all parameters significantly different at the cohort inception. Prednisone average dose of greater than 10 to less than or equal to 15 mg/d correlated most strongly with the development of an AE (Odds Ratio (OR) = 32.3, 95% Confidence Interval (CI) 4.6, 220). Average prednisone 5 to 10 mg (OR = 4.5, 95% CI 2.1, 9.6), RA nodules (OR = 3.9, 95% CI 1.9, 8.0), and bony erosions (OR = 2.4, 95% CI 1.2, 4.7) also entered the final model. Kaplan Meier survival curves for the development of the first AE showed a dose-response relationship between prednisone and AE occurrence, independent of rheumatoid nodules. Subset analyses utilized a nested case control design for the development of three serious AEs: fractures, serious infections, and GI events. These analyses revealed possible relationships between prednisone use and the development of each specific AE (prednisone use OR: fracture 3.9, 95% CI 0.8, 18.1; infection 8.0, 95% CI 1.0, 64.0; and GI event 3.3, 95% CI 0.9, 12.1). CONCLUSIONS: Although disease severity is an important confounding factor, low dose long-term prednisone use equal to or greater than 5 mg/d is correlated with the development of specific adverse events in a dose-dependent fashion.

Effectiveness of HB2 (anti-CD7)--saporin immunotoxin in an in vivo model of human T-cell leukaemia developed in severe combined immunodeficient mice.

The transplantation of the human T-cell acute lymphoblastic leukaemia (T-ALL) cell line HSB-2 into severe combined immunodeficient (SCID) mice was found to produce a disseminated pattern of leukaemia similar to that seen in man. The intravenous injection of 10(7) HSB-2 cells was associated with a universally fatal leukaemia. Histopathological examination of animals revealed the spread of leukaemia initially from bone marrow to involve all major organs including the meninges. An immunotoxin (HB2-Sap) was constructed by conjugating the anti-CD7 MAb HB2 to the ribosome-inactivating protein saporin. An in vitro protein synthesis inhibition assay revealed specific delivery of HB2-Sap immunotoxin (IT) to CD7+ HSB-2 target cells with an IC50 of 4.5 pM. When SCID mice were injected with 10(6) HSB-2 cells and then treated 8 days later with a single intravenous dose of 10 micrograms of immunotoxin there was a significant therapeutic effect evidenced by the numbers of animals surviving in the therapy group compared with untreated controls (chi 2 = 5.348, P = 0.021). These results demonstrate the useful application of human leukaemia xenografts in SCID mice and the potential therapeutic effect of an anti-CD7 immunotoxin in human T-ALL.

Immunotoxin studies in a model of human T-cell acute lymphoblastic leukemia developed in severe combined immune-deficient mice.

The transplantation of the human T-cell acute lymphoblastic leukemia (T-ALL) cell line HSB-2 into severe combined immune-deficient (SCID) mice was found to produce a disseminated pattern of leukemia similar to that seen in humans. The iv injection of 10(7) HSB-2 cells was associated with a universally fatal leukemia. Histopathological examination of animals revealed the spread of leukemia initially from bone marrow to involve all major organs including the meninges. An immunotoxin (HB2-Sap) was constructed by conjugating the anti-CD7 monoclonal antibody (MAb) HB2 to the ribosome inactivating protein (RIP) saporin. An in vitro protein synthesis inhibition assay revealed specific delivery of HB2-Sap immunotoxin (IT) to CD7+ HSB-2 target cells with an IC50 of 4.5 pM. In an in vivo study, the IT was shown to significantly prolong the survival of SCID mice injected with HSB-2 cells compared to untreated control animals. This therapeutic effect was seen both with a single injection of 10 micrograms of IT given 7 d after the injection of HSB-2 cells, and was even more effective when IT was administered as three daily injections of 10 micrograms on d 7, 8, and 9. These results demonstrate the useful application of human leukemia xenografts in SCID mice and the potential therapeutic effect of an anti-CD7 IT in human T-ALL.