Treatment of intermediate risk rhabdomyosarcoma and undifferentiated sarcoma with alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide

Over 50% of patients with newly diagnosed rhabdomyosarcoma (RMS) are in the 'intermediate risk' group with a 3-year progression-free survival of approximately 65%. This group consists of stage 1, group III, non-orbit tumours; stage 2, group II and III; and all stage 3 patients utilising the Intergroup Rhabdomyosarcoma Study (IRS) staging system. The role of doxorubicin in the treatment of RMS has been controversial. Ifosfamide, both alone and in combination with etoposide, has significant activity in patients with RMS. The aim of this pilot study was to examine the efficacy and toxicity of a chemotherapy regimen of alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide for intermediate risk RMS. 30 patients with intermediate risk RMS or undifferentiated sarcoma (US) were treated with alternating cycles of vincristine/doxorubicin/cyclophosphamide (VDC) and etoposide/ifosfamide (EI) at planned intervals of 3 weeks. Local treatment of the tumour in most cases was performed after four cycles of chemotherapy, followed by an additional 10 cycles of chemotherapy. At a median follow-up of 37.5 months, the Kaplan-Meier estimate of 3-year event-free survival was 85% (95% confidence interval 72-99%). The overall survival at 3 years was 91% (95% confidence interval 80-100%). No patient died from toxicity. The most common toxicity was febrile neutropenia in 35% of VDC and 26% of EI cycles. No nephrotoxicity or cardiac toxicity was seen. No patient progressed prior to week 12 local therapy. Alternating cycles of VDC and EI are an effective treatment for patients with intermediate risk RMS and US. Toxicity is tolerable. Delaying local treatment until week 12 does not compromise outcome.     

Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia

PURPOSE: To determine, in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) on interferon alfa (IFNalpha), whether combining pretreatment characteristics and early response profiles would distinguish patients with differential benefits that would allow better decisions on subsequent therapy. PATIENTS AND METHODS: A total of 274 patients treated from 1982 through 1990 with IFNalpha regimens were analyzed. A second group of 137 patients treated with IFNalpha and low-dose cytarabine (ara-C) between 1990 and 1994 was later used to confirm the guidelines derived from the original study group analysis. Patients' pretreatment factors and response to IFNalpha therapy at 3, 6, and 12 months were analyzed in relation to subsequent achievement of major cytogenetic response. After univariate analysis of prognostic factors, a multivariate analysis selected, at 6 months, independent pretreatment factors that added to the response status in predicting subsequent outcome. The results were then applied at the 3- and 12-month periods and confirmed in the subsequent population. RESULTS: Response to IFNalpha therapy at 3, 6, and 12 months was a significant predictor of later major cytogenetic response. The presence of splenomegaly > or = 5 cm below the costal margin (BCM) or thrombocytosis > or = 700 x 10(9)/L pretreatment added significant independent prediction to response. At 6 months, patients with a partial hematologic response (PHR) or resistant disease had a less than 10% chance of achieving a later major cytogenetic response, as were those in complete hematologic response (CHR) and who had pretreatment splenomegaly and thrombocytosis. Applying the model at 3 months showed that only patients with < or = PHR and pretreatment splenomegaly or thrombocytosis at 3 months had such a low major cytogenetic response rate. Finally, at 12 months, patients with CHR still had a 15% to 25% chance of having a major cytogenetic response later if they did not have pretreatment splenomegaly and thrombocytosis. CONCLUSION: This analysis allows better selection of patients with Ph-positive CML on IFNalpha therapy for continuation of IFNalpha versus changing therapy early in the course of CML. For treatment programs that choose to change patients to other investigational therapies (eg, intensive chemotherapy and/or autologous stem-cell transplantation [SCT]), baseline outcome expectations are provided for patients continued on IFNalpha therapy, against which the results of new approaches can be compared.     

Differences in receptor binding of LDL subfractions

Differences in low density lipoprotein (LDL) receptor-binding affinity among LDL particles of different size were examined in competitive binding assays in human skin fibroblasts and LDL (d = 1.020 to 1.050 g/mL) from subjects with a predominance of large (> or = 272 A), medium (259 to 271 A), and small (< or = 257 A) LDL. Among 57 normolipidemic subjects with LDL cholesterol (-C) levels < 160 mg/dL, binding affinity was reduced by 16% in those with predominantly large LDL and by 14% in those with small LDL compared with most subjects who had a predominance of medium-size LDL and in all LDL size subgroups in 66 subjects with LDL-C > or = 160 mg/dL. Differences in LDL receptor-binding affinity were further investigated by using LDL density subfractions (I, d = 1.026 to 1.032 g/mL; II, d = 1.032 to 1.038 g/mL; and III, d = 1.038 to 1.050 g/mL) from three subjects with predominantly large (pattern A) and small (pattern B) LDL particles. The binding affinity (Kd) of LDL-II was similar for patterns A and B (9.2 +/- 1.4 and 9.4 +/- 0.7, respectively) and 30% lower in LDL-III from both groups (P < .05). The binding affinity of LDL-I in pattern A (12.6 +/- 1.5 micrograms/mg) was lower (P < .05) than that in LDL-II and LDL-I from pattern B (8.0 +/- 2.4 micrograms/mg). After incubation with a monoclonal antibody that specifically blocked the LDL receptor-binding domain of apoE, LDL-I from two pattern B subjects showed substantially lower binding affinity (Kd = 20.0 and 19.2 micrograms/mg) than in pattern A (Kd = 13.2 and 14.2 micrograms/mg), a result consistent with our finding of a higher apoE content in pattern B LDL-I (P < .001). Thus, factors associated with variations in particle size and apoE content in LDL subclasses in normolipidemic subjects contribute to the differences in LDL receptor binding that may result in differing metabolic behavior in vivo.     

JOY: protein sequence-structure representation and analysis

MOTIVATION: JOY is a program to annotate protein sequence alignments with three-dimensional (3D) structural features. It was developed to display 3D structural information in a sequence alignment and to help understand the conservation of amino acids in their specific local environments. RESULTS:: The JOY representation now constitutes an essential part of the two databases of protein structure alignments: HOMSTRAD (http://www-cryst.bioc.cam.ac.uk/homstrad ) and CAMPASS (http://www-cryst.bioc.cam.ac. uk/campass). It has also been successfully used for identifying distant evolutionary relationships. AVAILABILITY: The program can be obtained via anonymous ftp from torsa.bioc.cam.ac.uk from the directory /pub/joy/. The address for the JOY server is http://www-cryst.bioc.cam.ac.uk/cgi-bin/joy.cgi. CONTACT: kenji@cryst.bioc.cam.ac.uk     

Isolation and partial characterization of a prothrombin-activating enzyme from the venom of the Australian rough-scaled snake (Tropidechis carinatus)

A prothrombin activator from the venom of Tropidechis carinatus has been isolated by means of gel filtration and benzamidine-based affinity chromatography, a novel use of the latter technique. Two bands possessing prothrombinase activity were obtained from the affinity chromatography procedure and designated A1 and A2. The bulk of the enzyme activity was recovered in peak A2 which represented 27-31% of the starting activity and a 14-16-fold purification. The venom contained, in total, around 5% by weight of the two isoforms of the prothrombin activator. The two fractions were electrophoretically similar on polyacrylamide electrophoresis, migrating with a mol. wt of 64,500 under native conditions and as a single band of 41,500 under reducing conditions. The prothrombinase was dependent on factor Va, phospholipid and calcium ions for its activity and is, thus, a member of the type II class of prothrombinases requiring such co-factors. The enzyme did not possess any phospholipase activity nor did it cleave the substrates N-alpha-benzoyl-L-arginine-p-nitroanilide (BAPNA), N-benzoyl-L-tyrosine ethyl ester (BTEE), azocollagen or azocasein, indicating a lack of amidolytic, esterolytic and broad-spectrum protease activity.     

Limb and abdominal injuries: principles of treatment

In the period reviewed, the Royal Victoria Hospital received over 7000 casualties, representing approximately half of the civil disturbance injuries for the province. Primary resuscitation did not differ from that of road traffic accidents, but the surgical management did. Extensive débridement was essential, followed by delayed primary suture some days later. Two hundred and nine penetrating abdominal wounds were reviewed, and the necessity of exploring the abdomen in all such injuries is emphasized.     

Pulmonary effects of chronic exposure to airborne cadmium

In haemoglobinometry grave errors are still being made even though an internationally accepted standardized method is available for the determination of the haemoglobin content of blood. Up to the present only haemiglobincyanide reference solutions have been available on a wide scale to check the measuring stage of the standardized haemiglobincyanide method. These reference solutions are shown to remain stable, under proper storage conditions, for more than 10 years. Concentrated haemoglobin solutions have become available recently, offering the possibility to control the dilution and conversion steps of the haemiglobincyanide method. Such a solution is shown to remain stable, under proper storage conditions, for at least a year. Using both haemiglobincyanide reference solutions and concentrated haemoglobin solutions, as well as having the possibility of checking the cyanide content of the reagent used, an acceptable intra-laboratory control program may now be set up.     

Changes in CNS responsiveness during hibernation

The ability of the midbrain reticular formation (MRF) to produce thermogenic responses and to trigger arousal from hibernation was tested during successive quarters of individual hibernation bouts. Golden-mantled ground squirrels (Citellus lateralis) were implanted with bilateral cannula guides into the MRF. Single, bilateral, 1-mul injections of acetylcholine (ACh) at concentrations of 50, 100, or 200 mug/mul were delivered in each quarter of the same bout or in selected quarters of different bouts. The results show that the magnitude of thermogenic responses evoked by ACh stimulation of the MRF was depressed during the early portion of the bout and increased as time in the bout elapsed. Furthermore, the magnitude of responses evoked during hibernation was depressed in comparison to those evoked during euthermia, indicating the influence of inhibition on the responsiveness of the CNS during hibernation. We suggest that during hibernation, a progressive change in responsiveness of the CNS, perhpas focused in the MRF, controls the duration of each hibernation bout.