A randomized, double-blind, placebo-controlled phase II study to assess the efficacy and safety of mapatumumab with sorafenib in patients with advanced hepatocellular carcinoma.

BACKGROUND: This randomized, double-blind, placebo-controlled, phase II study evaluated the efficacy and safety of mapatumumab (a human agonistic monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 1) in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with advanced HCC (stratified by Barcelona Clinic Liver Cancer stage and Eastern Cooperative Oncology Group performance status) were randomized 1:1 to receive sorafenib (400 mg, twice daily per 21-day cycle) and either placebo (placebo-sorafenib arm) or mapatumumab (30 mg/kg on day 1 per 21-day cycle; mapatumumab-sorafenib arm). The primary end point was time to (radiologic) progression (TTP), assessed by blinded independent central review. Key secondary end points included progression-free survival, overall survival, and objective response. RESULTS: In total, 101 patients were randomized (placebo-sorafenib arm: N = 51; mapatumumab-sorafenib arm: N = 50). There was no significant difference in median TTP between both arms [5.6 versus 4.1 months, respectively; adjusted hazard ratio (one-sided 90% confidence interval) 1.192 (0-1.737)]. No mapatumumab-related benefit was identified when TTP was evaluated in the stratified subgroups. The addition of mapatumumab to sorafenib did not demonstrate improvement in the secondary efficacy end points. The reported frequency of adverse events (AEs) and serious AEs was comparable in both treatment arms. CONCLUSIONS: The addition of mapatumumab to sorafenib did not improve TTP or other efficacy end points, nor did it substantially change the toxicity profile of sorafenib in patients with advanced HCC. Based on these results, further development of the combination of mapatumumab and sorafenib in HCC is not planned.

Fractional anisotropy distributions in 2- to 6-year-old children with autism.

BACKGROUND: Increasing evidence suggests that autism is a disorder of distributed neural networks that may exhibit abnormal developmental trajectories. Characterisation of white matter early in the developmental course of the disorder is critical to understanding these aberrant trajectories. METHODS: A cross-sectional study of 2- to 6-year-old children with autism was conducted using diffusion tensor imaging combined with a novel statistical approach employing fractional anisotropy distributions. Fifty-eight children aged 18-79 months were imaged: 33 were diagnosed with autism, 8 with general developmental delay, and 17 were typically developing. Fractional anisotropy values within global white matter, cortical lobes and the cerebellum were measured and transformed to random F distributions for each subject. Each distribution of values for a region was summarised by estimating δ, the estimated mean and standard deviation of the approximating F for each distribution. RESULTS: The estimated δ parameter, , was significantly decreased in individuals with autism compared to the combined control group. This was true in all cortical lobes, as well as in the cerebellum, but differences were most robust in the temporal lobe. Predicted developmental trajectories of across the age range in the sample showed patterns that partially distinguished the groups. Exploratory analyses suggested that the variability, rather than the central tendency, component of was the driving force behind these results. CONCLUSIONS: While preliminary, our results suggest white matter in young children with autism may be abnormally homogeneous, which may reflect poorly organised or differentiated pathways, particularly in the temporal lobe, which is important for social and emotional cognition.

A HRG-based costing model for estimating pharmacy costs associated with surgical procedures.

OBJECTIVE: The present study addresses pharmacy expenditure within a surgical directorate in a UK hospital. The aim of the study was to develop a health care resource group (HRG)-based costing model that can be used to forecast pharmacy expenditure based on surgical casemix. Such a model will be of benefit as an expenditure projection tool at a time when hospitals are developing accelerated operation programmes in an attempt to decrease hospital waiting times. METHOD: During the period February-April 2000, nursing staff recorded all pharmacy sourced items for each individual operation in the theatres used for general surgery, ENT surgery and gynaecological procedures; each operation was also classified according to its HRG. The associated costs of the items per HRG were identified and the average pharmaceutical cost per HRG calculated and included in the costing model. The model derived costs over the study period were compared with the actual pharmacy expenditure which was obtained from the pharmacy computer system. Finally HRG data for operations carried out in February 2002 were costed using the model for validation purposes. RESULTS: The estimated pharmaceutical cost for surgery items for February-April 2000 was 121,235 UK pounds. This figure was 3.92% over the actual pharmaceutical expenditure as determined from computer records. The February 2002 casemix varied considerably from that of 2000. However, the model estimated pharmaceutical cost of surgery performed in February 2002 (38,054 UK pounds) was again very similar to the computer logged expenditure (1.09% under the actual expenditure for that period) indicating the robustness of the HRG-based costing approach.

Cancer mortality (1956-1985) among male employees of Atomic Energy of Canada Limited with respect to occupational exposure to external low-linear-energy-transfer ionizing radiation.

The mortality experience between 1956 and 1985 of 8977 males employed by Atomic Energy of Canada Limited is reported. A total of 4260 men, 47% of the cohort, were exposed to low doses of external ionizing radiation at low dose rates, with a mean cumulative equivalent dose of 52.1 mSv. For cancers as a whole the excess relative risk, based on 227 deaths, was 0.36% per 10 mSv (90% confidence bounds -0.46, 2.45). This is quite comparable to the corresponding estimate based on the atomic bomb survivors study. There was a positive association between radiation dose and death from leukemia (excluding chronic lymphatic leukemia) P = 0.058. However, this was based on only four deaths and hence cannot sensibly be compared to estimates based on high-dose studies. The present results suggest that, for cancer as a whole, risk estimates based on high-dose studies are unlikely to underestimate risks substantially for low-dose and low-dose-rate exposures.

Imaginal discs can be recovered from cultured embryos mutant for the segment-polarity genes engrailed, naked and patched but not from wingless.

Drosophila embryos homozygous for strong mutations in each of the segment-polarity genes wingless (wg), engrailed (en), naked (nkd) and patched (ptc) form a larval cuticle in which there is a deletion in every segment. The mutant embryos normally fail to hatch but by in vivo culture we were able to show which could produce adult structures. Cultured wg⁻ embryos did not produce any adult structures. Cultured en⁻ embryos produced eye-antennal derivatives and rarely produced partial thoracic structures. nkd⁻ and ptc⁻ embryos produced eye-antennal and thoracic derivatives. The nkd⁻ and ptc⁻ thoracic imaginal discs developed with an abnormal morphology and abnormal pattern of en-expression. Our findings are consistent with the idea that the thoracic imaginal discs derive from two adjacent groups of cells that express wg and en respectively in the embryo.

Ready for battle.

As a newly elected member of the English National Board, I would like to thank my fellow nurses, friends and colleagues who voted for me.

Chromosomal continuity in the abdominal region of the bithorax complex of Drosophila is not essential for its contribution to metameric identity.

We have examined the developmental consequences for larval and imaginal segmental cuticular structure of a chromosomal translocation involving a breakpoint in the abdominal region of the bithorax complex (BX-C). This complex makes an essential contribution to the development of metameric differences in part of the thorax and in all abdominal segments. The breakpoint is proximal to the most distal (iab-7) homeobox, and results in the translocation to the Y chromosome of the Ultrabithorax (Ubx) and abdominal-A (abd-A) domains. The genotype deficient for the distal part of the complex shows normal function for Ubx and abd-A but has a phenotype typical for severe Abd-B mutations. Conversely, the distal fragment retains a segment identity function which must represent a contribution from Abd-B in parasegments 13 and 14; the latter metamere is wild type, indicating that it does not require the contribution of Ubx or abd-A. We also constructed a genotype comprising the proximal fragment of this translocation together with an overlapping distal fragment of the BX-C derived from Df(3R)Ubx109. It therefore contained all sequences of the BX-C though in the abdominal region the abd-A and Abd-B domains were not adjacent to each other in the chromosome. This genotype was phenotypically normal and demonstrates that DNA sequences in the abd-A and Abd-B regions do not require cis-arrangement for their activity.

Renal cell carcinoma in the first two decades of life.

Renal cell carcinoma occurs rarely in the first two decades of life. This paper reviews the clinical and radiographic features of 17 such patients (10F: 7M, mean age = 12 years) seen in a 24 year period. The almost equal sex incidence contrasts with the male preponderance in adults. All patients presented with symptoms and signs referable to the primary lesion. In comparison to Wilms' tumor, renal cell carcinoma in childhood and adolescence usually presents with a smaller abdominal mass which is frequently not palpable or visible on plain abdominal radiographs. Ultrasound and CT showed non-specific solid intrarenal masses. This rare tumor of childhood should be included in the differential diagnosis of intrarenal mass lesions, particularly in older children with hematuria and renal calcification on plain radiographs. One child in this series had tuberous sclerosis. The prognosis depends on the stage of disease at presentation.

Hodgkin's disease in children: treatment results with MOPP and low-dose, extended-field irradiation.

Combined therapy with MOPP and extended-field irradiation for all children with Hodgkin's disease (except those with favorable clinical stage [CS] 1) was effective in disease control. Overall 5-year survival and relapse-free survival rates were 92% and 82%, respectively. Only one of 27 CS 2 and 3 patients has relapsed (median followup, 4.3 years). Two patients in complete remission died of viral infection. The cost-benefit ratio for such treatment remains to be determined. Morbidity was decreased by the omission of staging laparotomy with splenectomy and by reduction in radiation dose and to a lesser extent volume, but it was increased by the addition of MOPP. In such combined treatment, the smallest number of cycles of MOPP, the lowest radiation dose, and the smallest radiation volume that may be used without loss of treatment effectiveness remain to be determined.

Echocardiography in adriamycin cardiotoxicity.

Twenty-six patients receiving adriamycin for osteogenic sarcoma had serial echocardiographic assessments of their left ventricular function. A statistically significant deterioration of function was noted throughout the course. Ventricular function tended to normalize in the period following cessation of adriamycin. The velocity of circumferential fibre shortening (Vcf) and ejection fraction (EF) were the best parameters. Sudden declines in these values resulted in us withholding therapy until the parameters again improved. Fatal congestive heart failure was seen in only one patient. Echocardiography thus provides the clinician with a valuable tool enabling one to improve the therapeutic usefulness of adriamycin by removing much of the uncertainty over the development of cardiotoxicity.

Long-term control of central nervous system leukaemia.

Seventy-four children with acute lymphoblastic leukaemia had one or more episodes of central nervous system (CNS) leukaemia. 5 children had CNS involvement at diagnosis; 4 survived for less than one year. In 35 children who had not had a previous bone marrow relapse on treatment and who received combination chemotherapy, the median duration of haematological remission from the time of first CNS relapse was almost 3 years. 5 children received full dose (2400 rads) craniospinal irradiation after their first CNS relapse; 4 have remained in CNS and haematological remission for 2 1/2 years or more. 18 children who had a CNS relapse after irradiation received 4-weekly intrathecal methotrexate; in 8 children this was given via an intraventricular reservoir. The median duration of CNS remission in children receiving intrathecal methotrexate was 2 years. Systemic and intrathecal treatment was stopped in 7 children after 2 1/2 years in continuous remission and in 2 children after 2 years. 4 of these 9 children remain in remission at intervals from 41 to 69 weeks off treatment but one is severely retarded. These results show that CNS disease is compatible with prolonged survival, but illustrate the difficulties of eradicating established CNS leukaemia.