Bone marrow transplantation for acute non-lymphoblastic leukemia.

Most results obtained by different study and analytic designs favor that matched allogeneic BMT is superior to chemotherapy in young adults with ANLL in first remission. The place of ABMT is more difficult to assess and requires further study both compared to chemotherapy and allogeneic BMT. Furthermore, the question of purging needs further study in a controlled fashion. For older patients the choice is more difficult. Transplant related mortality increases with age which makes ABMT an attractive alternative to allogenic BMT. However, recent advances in prophylaxis and treatment of transplant related complications such as cytomegalovirus interstitial pneumonia and veno-occlusive disease of the liver might increase long-term survival after allogeneic BMT in older patients. The role of matched unrelated donors in the treatment of ANLL is unresolved but this procedure should probably be reserved for relatively young patients in second complete remission or later.     

Reduced susceptibility to penicillin of viridans group streptococci in the oral cavity of patients with haematological disease

The occurrence of oral penicillin-resistant viridans group streptococci (VGS) was studied in 50 patients with either newly diagnosed acute leukaemia or autologous peripheral stem cell transplants. One patient was excluded because of Staphylococcus aureus growth in the stem cell harvest. VGS were isolated from the oral cavity of 48 of the remaining 49 patients. Of these 48 patients, 12 (25%) yielded VGS resistant (MIC > 2 mg/L) to penicillin. These 12 patients had a higher frequency of septicaemia (p 0.04) and more days of treatment with trimethoprim-sulphamethoxazole (p 0.04) than patients who harboured susceptible or intermediately resistant VGS (MIC 2 mg/L). There were no other statistically significant differences between the two groups. It is important to be aware of the high level of penicillin resistance in oral VGS in patients with haematological disease, and this parameter should be considered when selecting antibiotic therapy for cases of septicaemia caused by VGS in immunocompromised patients.     

Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology

Summary Busulphan levels in plasma were measured in 27 patients during conditioning therapy (1 mg/kg×4 for 4 days) before bone marrow transplantation. The mean minimal concentration found in children aged <5 years (237 ng ml^–1) was lower than that observed in adults or older children (607 and 573 ng ml^–1, respectively). The AUC for the last dose was significantly lower in young children (2,315 h ng ml^–1) than in adults or older children (6,134 and 5,937 h ng ml^–1, respectively). The elimination half-life for the last dose in young children was shorter (2.05 h) than that in either adults (2.59 h) or older children (2.79 h). When the AUC was normalized for body surface area, the difference between young children and the other groups was smaller but remained statistically significant. The total body clearance was significantly higher in young children (7.3 ml min^–1 kg^–1) as compared with both older children and adults (3.02 and 2.7 ml min^–1 kg^–1, respectively). The plasma levels of busulphan showed circadian rhythmicity, especially in young children. The concentration measured during the night in some patients was up to 3-fold that observed during daytime. We conclude that the busulphan dosage for children must be reconsidered and that further studies are urgently needed to develop an optimal therapy.Abbreviations AML acute myeloblastic leukemia - ALL acute lymphatic leukemia - AUL acute undifferentiated leukemia - ABMT autologous bone marrow transplantation - BMT allogeneic bone marrow transplantation This work was supported by grant 2805-B90-01X from the Swedish Cancer Society     

Alpha-interferon maintenance treatment is associated with improved survival after high-dose treatment and autologous stem cell transplantation in patients with multiple myeloma: a retrospective registry study from the European Group for Blood and Marrow Transplantation (EBMT)

The purpose of this study was to evaluate the effect of alpha-IFN maintenance treatment after autologous stem cell transplantation (ASCT) for multiple myeloma in a retrospective registry analysis. 473 patients with multiple myeloma who received IFN maintenance treatment ASCT were compared with 419 patients who did not receive IFN-treatment. Patients who were evaluable for response and in complete or partial remission at 6 months after ASCT were eligible, after excluding patients with graft failure. Cox proportional hazards assumptions were checked and handled by stratification. The prognostic variables unevenly distributed between the two groups were statistically corrected for in the Cox analysis. 391 patients reached complete remission (CR) after ASCT (203 in the IFN group and 188 in the no-IFN group) and 501 were in partial remission (PR, IFN 270, no-IFN 231). Overall survival (OS) and progression-free survival (PFS) were significantly better in the IFN-group (OS, 78 vs 47 months, P = 0.007, and PFS, 29 vs 20 months, P = 0.006, respectively). The difference in OS and PFS was most strongly pronounced in the PR patients. 209 patients have died (IFN, 84; no-IFN, 125). Progressive myeloma was the cause of death in 94% of the IFN-treated patients and in 83% of the no-IFN group (P = NS). Thus, IFN maintenance treatment after ASCT was associated with better OS and PFS. Treatment seemed to be most beneficial in patients who did not achieve CR. The difference in median survival was as long as 2.5 years, and although part of this difference is attributable to differences in other prognostic factors, it might justify possible differences in quality-of-life due to adverse effects of interferon treatment.     

The effect of metronidazole on busulfan pharmacokinetics in patients undergoing hematopoietic stem cell transplantation

Busulfan (Bu) is an important component of some myeloablative regimens prior to stem cell transplantation (SCT). Over the last few years it has been shown that other drugs administered concomitantly can influence Bu pharmacokinetics. In the present study, we compared Bu concentrations (trough levels) in three groups of patients. Group A (n=5) received metronidazole as graft-versus-host disease prophylaxis during Bu treatment. Group B (n=9) received Bu only for 2 days followed by 2 days of Bu and metronidazole. Group C (n=10) was a control group that received Bu without metronidazole. The mean Bu levels for Group A receiving metronidazole during conditioning was significantly (P<0.001) higher (948+/-280 ng/ml), compared to those observed in the control group (507+/-75 ng/ml). In Group B, the administration of metronidazole resulted in a significant (P<0.001) increase in Bu levels (807+/-90 ng/ml) during the last 2 days, compared to 452+/-68 ng/ml during the first 2 days. In Group A, one patient died with multiorgan failure, three experienced veno-occlusive disease (VOD) and one developed hemorrhagic cystitis. Elevated liver transaminases (AST, ALT) and bilirubin were detected in all Group A patients. In Group B, six patients had elevated liver function tests but no VOD was observed. We conclude that metronidazole should not be administered simultaneously with Bu to avoid the high plasma levels of Bu, which may lead to severe toxicity and/or treatment related mortality.     

Epidemiology of adult ankle fractures in Sweden between 1987 and 2004: a population-based study of 91,410 Swedish inpatients

Background and purpose

Previous national epidemiological data on the characteristics and trends of patients with ankle fractures have been limited. We therefore analyzed data on Swedish inpatients with ankle fractures in this nationwide population study, based on data from 1987 through 2004.

Patients and methods

Data on all inpatients aged 15 years and older with ankle fracture were extracted from the Swedish National Patient Register for the period 1987–2004.

Results

We identified 91,410 hospital admissions with ankle fracture, corresponding to an annual incidence rate of 71 per 10⁵ person-years. During the study period, the number of hospital admissions increased by 0.2% annually, mainly from increase in fracture incidence in the elderly women. Mean age at admission was 45 (SD 19) years for men and 58 (18) for women. The major mechanism of injury was falling at the same level (64%).

Interpretation

This nationwide study of inpatients with ankle fractures showed an increase in fracture incidence, particularly in elderly women.Ankle fractures are among the most common fractures treated in orthopaedic surgery today. They are also a significant source of morbidity in both the young and the elderly (Donaldson et al. 1990, Jones et al. 1994, van Staa et al. 2001). Previous epidemiological studies have shown trends of increasing incidence over time, mainly in elderly women (Bengnér et al. 1986, Daly et al. 1987, Baron et al. 1996, Kannus et al. 1996, Court-Brown et al. 1998, van Staa et al. 2001, Kannus et al. 2002). However, most of these studies have included limited numbers of patients, and mostly originated from single hospitals or limited areas.Basic epidemiological data such as incidence, fracture type, age and sex distribution, mechanisms of injury, and surgical procedures can provide estimates when discussing disease burden and in the planning and provision of healthcare.The purpose of this study was to perform an epidemiological analysis of all adult ankle fractures requiring hospital admission in Sweden from 1997 through 2004, including incidence, causes of fracture, surgical procedures, patient characteristics, and trends over time.     

Comparison of the vasodilator responses of isolated human and rat middle meningeal arteries to migraine related compounds

Background

Migraine attacks occur spontaneously in those who suffer from the condition, but migraine-like attacks can also be induced artificially by a number of substances. Previously published evidence makes the meninges a likely source of migraine related pain. This article investigates the effect of several vasodilators on meningeal arteries in order to find a connection between the effect of a substance on a meningeal vessel and its ability to artificially induce migraine.

Methods

A myograph setup was used to test the vasodilator properties of the substances acetylcholine (ACh), sodium nitroprusside (SNP), sildenafil, prostaglandin E₂ (PGE₂), pituitary adenylate cyclase activating peptide-38 (PACAP-38), calcitonin gene-related peptide (CGRP) and NaCl buffer on meningeal arteries from human and rat. An unpaired t-test was used to statistically compare the mean E_max(%) at the highest concentration of each substance to the E_max(%) of NaCl buffer.

Results

In the human experiments, all substances except PACAP-38 had an E_max (%) higher than the NaCl buffer, but the difference was only significant for SNP and CGRP. For the human samples, clinically tested antimigraine compounds (sumatriptan, telcagepant) were applied to the isolated arteries, and both induced a significant decrease of the effect of exogenously administrated CGRP. In experiments on rat middle meningeal arteries, pre-contracted with PGF_2α, similar tendencies were seen. When the pre-contraction was switched to K⁺ in a separate series of experiments, CGRP and sildenafil significantly relaxed the arteries.

Conclusions

Still no definite answer can be given as to why pain is experienced during an attack of migraine. No clear correlation was found between the efficacy of a substance as a meningeal artery vasodilator in human and the ability to artificially induce migraine or the mechanism of action. Vasodilatation could be an essential trigger, but only in conjunction with other unknown factors. The vasculature of the meninges likely contributes to the propagation of the migrainal cascade of symptoms, but more research is needed before any conclusions can be drawn about the nature of this contribution.     

The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity

Busulphan and cyclophosphamide (Bu/CP) are widely used in preparative regimens for bone marrow transplantation. Many studies have shown a wide variation in busulphan pharmacokinetics. Moreover, higher rates of liver toxicity were reported in Bu/CP protocols than in a total body irradiation (TBI)-containing regimen. In the present paper we investigated the effect of the time interval between the last dose of busulphan and the first dose of cyclophosphamide on the pharmacokinetics of CP and its cytotoxic metabolite 4-hydroperoxycyclophosphamide (4-OHCP). Thirty-six patients undergoing bone marrow transplantation (BMT) were included in the study. We also investigated the occurrence of veno-occlusive disease, mucositis and graft-versus-host disease. Ten patients conditioned with CP followed by TBI served as a control group (TBI). Twenty-six patients were conditioned with Bu/CP. The patients received Bu (1 mg/kg x 4 for 4 days), followed by CP (60 mg/kg for 2 days) administered as a 1-h infusion. Patients received their CP therapy either 7-15 h (group A, n = 12) or 24-50 h (group B, n = 14) after the last dose of Bu. None of the patients were given phenytoin or any other drug known to enhance CP metabolism. The administration of CP less than 24 h after the last dose of Bu resulted in: (1) a significantly (P = 0.003) lower clearance for cyclophosphamide was observed in group A (0.036 l/h/kg) compared to 0.055 and 0.055 l/h/kg, in the B and TBI groups, respectively; (2) significantly (P = 0.002) longer elimination half-life in group A (10.93 h) than in groups B and TBI (6.87 and 7.52 h, respectively); (3) significantly (P < 0.001) lower exposure to the cytotoxic metabolite (4-OHCP), expressed as the ratio AUC4-OHCP/AUCCP, in group A (0.0053) than that obtained in group B (0.013) and group TBI (0.012); (4) the patients in group A had a significantly (P < 0.05) higher incidence of VOD (seven of 12) than the other groups, B and TBI (2/14 and 1/10, respectively); and (5) mucositis was significantly higher in group A patients (8/12), being seen in only one patient in group B and none in the TBI group. The present study has shown that the interval between busulphan and cyclophosphamide administration can negatively affect the pharmacokinetics of cyclophosphamide and its cytotoxic metabolite. We conclude that the timing of CP administration must be considered in order to improve drug efficacy and reduce conditioning-related toxicity.