Results of the randomized phase IIB ARCTIC trial of low-dose rituximab in previously untreated CLL.

ARCTIC was a multicenter, randomized-controlled, open, phase IIB non-inferiority trial in previously untreated chronic lymphocytic leukemia (CLL). Conventional frontline therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). The trial hypothesized that including mitoxantrone with low-dose rituximab (FCM-miniR) would be non-inferior to FCR. A total of 200 patients were recruited to assess the primary end point of complete remission (CR) rates according to IWCLL criteria. Secondary end points were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity, safety and cost-effectiveness. The trial closed following a pre-planned interim analysis. At final analysis, CR rates were 76 FCR vs 55% FCM-miniR (adjusted odds ratio: 0.37; 95% confidence interval: 0.19-0.73). MRD-negativity rates were 54 FCR vs 44% FCM-miniR. More participants experienced serious adverse reactions with FCM-miniR (49%) compared to FCR (41%). There are no significant differences between the treatment groups for PFS and OS. FCM-miniR is not expected to be cost-effective over a lifetime horizon. In summary, FCM-miniR is less well tolerated than FCR with an inferior response and MRD-negativity rate and increased toxicity, and will not be taken forward into a confirmatory trial. The trial demonstrated that oral FCR yields high response rates compared to historical series with intravenous chemotherapy.

Inhaled nitrous oxide (Entonox) as a short acting sedative during bone marrow examination.

Bone marrow aspiration and biopsy is a procedure of central importance in the diagnosis of haematological disease and is one that can be safely performed in the outpatient clinic using only local anaesthesia. We evaluated the role of inhaled nitrous oxide (Entonox) as an adjuvant to local anaesthesia (LA) in patients requiring bone examination. We prospectively studied the role of Entonox in patients attending our outpatient department who required bone marrow examination. All patients received LA with injected 2% lignocaine but patients were then assigned to either LA alone or LA plus inhaled Entonox. Following the procedure patients were given a questionnaire and asked to score the discomfort associated with the procedure. Twenty-eight of 85 patients (33%) who received LA alone scored their pain as 3 (severe) compared with seven of 51 patients (14%) who received LA plus Entonox, P = 0.013. No adverse events were associated with Entonox use. Forty-three of the 51 patients who received Entonox stated that they would prefer to use this method of anaesthesia again. We conclude that inhaled Entonox is a useful adjuvant to local anaesthesia for patients undergoing bone marrow examination.

Diagnosis, biology and treatment of hairy-cell leukaemia.

Hairy-cell leukaemia (HCL) is usually readily diagnosed by seeing typical hairy cells (HCs) in the blood film. The diagnosis is then confirmed by tartrate-resistant acid phosphatase staining, marker analysis, and bone marrow examination. HCs are clonal mature memory B cells with specific features of activation. This HC activation is responsible for many of the pathological features of the disease, including its distinctive bone marrow fibrosis, splenic red pulp invasion, and pseudo-sinus formation. Chlorodeoxyadenasine is the treatment of first choice. Deoxycoformycin and rituximab are useful for the treatment of relapsed/refractory disease. The nature of the primary oncogenic event(s) remains unknown and is the major unresolved issue in HCL.

The diagnosis and treatment of hairy-cell leukaemia.

The diagnosis of HCL is usually straightforward and is based on the identification of typical HCs in the blood and bone marrow. The suspected diagnosis is confirmed by a combination of TRAP cytochemistry, a distinctive immunophenotype and characteristic BM trephine appearances. Nucleoside treatment is highly effective in inducing prolonged remissions; relapsing patients can usually be successfully retreated with nucleoside. Monoclonal antibody therapy is a promising novel approach to the treatment of resistant disease.

Use of the intermittent pneumatic compression device in venous ulcer disease.

The intermittent pneumatic compression device is a relatively new treatment for patients with venous ulcers. With the advent of this therapy being used by the patient in the home setting, the nurse is the primary point of contact for patient questions, concerns, and patient education. Nurses need to know the optimal compression pressure, inflation time, and sequencing time cycles to advise patients in the proper use of this therapy and how to screen patients for its safe use. The major contraindication for this therapy is the presence of deep venous thrombi. A review of the literature is presented, concluding with a recommended scientific basis for optimal compression pressure, inflation time, and sequencing time cycle pattern for the intermittent pneumatic sequential compression device in the venous ulcer patient population. Patient education strategies and topics are discussed.

Comparison of P2 purinergic receptors of aortic endothelial cells with those of adrenal medulla: evidence for heterogeneity of receptor subtype and of inositol phosphate response.

Vascular endothelial cells from different parts of the circulation are known to show different functional responses, presumably corresponding to physiological roles. Previous studies have shown that ATP acts on P2 purinergic receptors of endothelial cells of major blood vessels, stimulating the formation of inositol phosphates. Here we have compared the action of ATP and congeners acting on endothelial cells of bovine thoracic aorta with cells derived from the microvasculature of bovine adrenal medulla. With measurement of total inositol phosphates, cells from the aorta showed a rank order of agonist potency of 2-methylthio-ATP greater than adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S) greater than ADP greater than ATP greater than beta, gamma-imido-ATP greater than beta, gamma-methylene-ATP, consistent with action at receptors of the P2Y subtype. However, with adrenal cells the rank order of potency was ATP gamma S greater than ATP greater than beta, gamma-imido-ATP greater than ADP greater than beta, gamma-methylene-ATP = 2-methylthio-ATP. This profile is not consistent with either P2X or P2Y receptors. When the nature of this inositol phosphate response was analyzed with anion exchange chromatography, it was found that the aortic cells showed an inositol trisphosphate stimulation that peaked within a few seconds and rapidly declined, whereas the response of the adrenal medulla cells continued to rise through 5 min. Analysis of isomers of inositol phosphates revealed a different pattern of metabolism between the two cell types, which may account for the different time course of response. With adrenal cells, ATP at low micromolar concentrations caused a dose-dependent increase in levels of cyclic AMP and had a greater than additive effect on cyclic AMP levels when combined with submaximal stimulation by prostaglandin E2. These results suggest the presence of a P2Y receptor on aortic endothelial cells, with an 'atypical' purinocepter, i.e., neither P2X nor P2Y, on adrenal cells. Furthermore, they show that activation of P2 receptors on the two cell types has different functional consequences.