Impact of CR before and after allogeneic and autologous transplantation in multiple myeloma: results from the EBMT NMAM2000 prospective trial.

Previous studies have shown that obtaining complete hematologic remission (CR) in multiple myeloma is an important predictor of PFS and OS. This applies both to autologous and allogeneic transplantation. However, the importance of CR obtained before vs after second transplant or following allogeneic vs autologous transplantation is not clear. We investigated the role of CR analyzing data from the EBMT-NMAM2000 interventional prospective study comparing tandem autologous/reduced intensity conditioning allogeneic transplantation (auto/RICallo) to autologous transplantation-single or double (auto/auto). Allocation to treatment was performed according to availability of a matched sibling donor. Cox regression and multi-state models were applied. The long-term probability of survival in CR was superior in auto/RICallo, both comparing groups according to treatment allocated at start (28.8 vs 11.4% at 60 months, P=0.0004) and according to actual administration of second transplant (25.6 vs 9.6% at 60 months, P=0.008). CR achieved before the second transplant was predictive for PFS (hazard ratio (HR)=0.44, P= 0.003) and OS (HR 0.51, P=0.047) irrespective of the type of second transplant. CR achieved after auto/RICallo was more beneficial for PFS (HR=0.53, P=0.027) than CR after auto/auto (HR=0.81, P=0.390), indicating a better durability of CR obtained after an allotransplant procedure.

Role of chromosomal abnormalities in chronic lymphocytic leukemia.

Chromosomal aberrations occur in both B-CLL and T-CLL. The polyclonal B-cell mitogens, in particular Epstein-Barr virus and lipopolysaccharide from E. coli, have been used successfully to reveal chromosomal abnormalities in 40-60% of patients with B-CLL, while T-cell mitogens have shown chromosomal aberrations in T-CLL. The most common clonal chromosomal aberration in B-CLL is an extra chromosome 12, alone or together with other abnormalities. Other common aberrations are 14q+, structural aberrations on 6, 11, 12 and 13. Proto-oncogenes are frequently located close to breakpoints. The proto-oncogene c-K-ras is located on chromosome 12 and an abnormal transcript has recently been implicated in a subset of B-CLL-patients. An extra chromosome 12 as well as multiple chromosomal abnormalities in B-CLL appear to predict a less favourable prognosis. T-CLL is in most patients characterized by an inv(14), an extra 8q and structural abnormalities in chromosome 7. The genes for the specific T-cell receptor as well as the immunoglobulin heavy chain are located on these chromosomes. Chromosomal aberrations appear to have pathogenetic importance in both B-CLL and T-CLL.

Del(3)(p13) in B-prolymphocytic leukemia--a new nonrandom chromosomal aberration possibly related to the c-ras oncogene.

Cytogenetic analysis was performed on the leukemic cells from two patients with B-prolymphocytic leukemia. Both patients had del(3)(p13) chromosomal abnormality, as well as other clonal aberrations. Del(3p) was previously reported in one case of B-cell prolymphocytic leukemia, and is known to be a specific aberration in small-cell carcinoma of the lung. In B-cell prolymphocytic leukemia, as in other B-lymphocytic leukemias/lymphomas, the karyotype often involves chromosomes #3, #6, #11, and #12. All of these chromosomes are suggested sites for the c-ras oncogene family.

Safety and efficacy of a high cumulative dose of salbutamol inhaled via Turbuhaler or via a pressurized metered-dose inhaler in patients with asthma.

An open, crossover and randomized study was carried out to compare the safety and efficacy of salbutamol inhaled using the dry-powder inhaler Turbuhaler, and using a pressurized metered-dose inhaler (pMDI). Twelve patients with moderate to severe asthma, aged 47-68 years, were included in the study. On two separate days, patients received a total dose of 1600 micrograms of salbutamol administered in a cumulative dose fashion: 100, 100, 200, 400 and 800 micrograms at 3-min intervals. Salbutamol inhaled via Turbuhaler caused a larger decrease in serum potassium concentration than did salbutamol inhaled via pMDI. The estimated relative dose potency of the hypokalaemic effect of salbutamol Turbuhaler vs salbutamol pMDI was 2.0 with a 95% confidence interval of 1.3-3.6. Turbuhaler caused a small (but statistically significantly greater than with pMDI) increase in heart rate, QTc interval and tremor. Blood pressure was unaffected by the treatments. No adverse events of clinical relevance were reported. The estimated relative dose potency of the bronchodilating effect (FEV1) of salbutamol Turbuhaler vs salbutamol pMDI was 3.0 with a 95% confidence interval of 1.8-5.8. In conclusion, salbutamol inhaled via Turbuhaler was more potent and seemed to have a better therapeutic ratio than salbutamol inhaled via pMDI. Both treatments were equally well tolerated.

Remodelling after distal forearm fractures in children. II. The final orientation of the distal and proximal epiphyseal plates of the radius.

In 39 children the steric orientation of both the distal and the proximal epiphyseal plates of the radius was evaluated 4 months to 10 years after distal forearm fractures that had healed with residual angulation. A residual fracture angulation was found to induce a change in orientation of both the distal and proximal epiphyseal plates. The final result of the reorientation was a normalization of the inclination of the plates in relation to the long axis of the bone. The proximal epiphyseal plate attained practically a normal orientation. The distal epephyseal plate tended towards overcorrection. In two of the four cases with a primary angulation exceeding 20 degrees considerable normalization occurred, but a "normal" state was not reached. This indicates an upper limit for angulations permitting normalization of the orientation of the distal epiphyseal plate of the radius.

Remodelling after distal forearm fractures in children. I. The effect of residual angulation on the spatial orientation of the epiphyseal plates.

The effect of residual fracture angulation on the distal radial and ulnar epiphyseal plates was studied in children aged 1 to 15 years. Thirty-eight fractures located in the distal fifth of the forearm bones were observed for 1 to 25 months after the fractures had healed. The forearms were examined radiographically on two to five occasions and the inclinations of the epiphyseal plates in relation to the long axis of the proximal fragments were measured. The results showed that an abnormal inclination of the epiphyseal plate after healing of a distal forearm fracture induced an alteration of growth in the epiphyseal plate. The redistribution of growth tended to correct the abnormal inclination. The rate of correction followed an exponential course. The age of the child at the time of the fracture and the distance from the fracture to the epiphyseal plate did not influence the capacity for correction.

Remodelling after distal forearm fractures in children. III. Correction of residual angulation in fractures of the radius.

The outcome of residual angulation of the radius after 38 distal forearm fractures in children was investigated. The period of observation ranged from 4 months to 10 years and 8 months. The correction of a residual angulation after a fracture was shown to be governed by three factors. 1. An increase in the time between healing of the fracture and completed growth at the epiphyseal plates resulted in a more complete correction. 2. A larger adaxial dislocation of the epiphyseal plate at the time of healing of the fracture, reflecting a larger primary fracture angulation and a greater distance from the fracture to the epiphyseal plate, resulted in a less complete correction. 3. A more complete correction or overcorrection of the distal epiphyseal plate increased the correction of the angulation of the fracture. These findings strongly indicate that the process of correction of a residual angulation after a healed fracture can be explained in terms of the combined effects of the direction and amount of longitudinal growth at the epiphyseal plate. A trigonometrical equation based on this theory predicted the residual angulations of the fractures, at follow-up, with an error of less than 1 degree.

Chromosomal aberrations in progressive and indolent chronic B-lymphocytic leukaemia. A longitudinal study.

Chromosome analyses of B-cell mitogen-activated cells from 95 patients with chronic B-lymphocytic leukaemia revealed clonal chromosomal aberrations in 50 patients (53%), of which 24 had an extra chromosome 12 with or without other aberrations. Patients with clonal aberrations, especially those with +12, had poorer survival than other patients. Longitudinal studies, with a mean of 3.5 samplings during a median interval of 3.5 years, were performed in 41 patients, of which 24 (59%) had progressive disease. Twenty-nine of the patients in the longitudinal study (71%), 16 with and 13 without clonal aberrations, retained their karyotype unaltered. In 6 patients a clonal aberration was found only once. Six patients showed minor changes of the karyotype. The karyotype seems to be established at diagnosis, and marks the disease of the individual CLL-patient.

Consistency of chromosomal aberrations in chronic B-lymphocytic leukemia. A longitudinal cytogenetic study of 41 patients.

Serial chromosome analyses with a mean of 3.7 samplings during a mean interval of 4.2 years (range, 1.5 to 8.6 years) were performed on B-cell mitogen-activated chronic B-lymphocytic leukemia (CLL) cells from 41 patients. Twenty-four of these patients (59%) had progressive disease. Clonal chromosomal aberrations were found in 28 patients; 12 had an extra chromosome 12. Thirty patients (73%), 17 with and 13 without clonal aberrations, retained their karyotype throughout the study, although six lost minor subclones. In five patients (12%), a clonal aberration was found only once. Six patients (15%) showed changes of the karyotype. One treated patient with multiple aberrations acquired another monosomy. Another patient with multiple aberrations and prolymphocytic transformation gained a marker chromosome. One treated patient with an initially normal karyotype acquired two independent clonal aberrations. Three patients lost one subclone but retained another clone that increased in frequency. In two cases, clonal changes were associated with clinical changes. The chromosomal aberrations are mostly established already at diagnosis and mark the disease of the CLL patient. Cytogenetic analysis at any time is representative and useful in the prognosis prediction.

Translocation between chromosome 7 and chromosome 22, t(7;22)(p22;q12), in a patient with chronic myelocytic leukemia.

A 46-year-old man with chronic myelocytic leukemia had a new variant translocation between chromosome 22 and chromosome 7 in bone marrow cells. No involvement of chromosome 9 was seen. The patient entered blastic transformation within half a year, by which time he had acquired an isochromosome 17 in addition to the variant translocation.

A new translocation involving three chromosomes in chronic myelocytic leukemia, 46,XY,t(9;11;22).

Bone-marrow metaphases in a 63-year-old male with newly discovered chronic myelocytic leukemia (CML) showed a complex translocation involving chromosomes 9, 11, and 22. About half of the short arm of chromosome 11 was translocated to the terminal part of the long arm of chromosome 9, and the missing fragment on chromosome 22 was translocated to the short arm of the abnormal chromosome 9. The clinical features were typical of CML, and the patient is in good physical condition 10 months after diagnosis on a regimen of busulfan.

Ph chromosome and B-cell malignancy-associated chromosomal aberrations in non-leukaemic immunoblastic B-cell lymphoma.

A 62-year-old female with a microK phenotypic immunoblastic B-cell lymphoma with bone marrow involvement but without leukaemia is reported. Bone marrow cells, cytogenetically studied at diagnosis, showed a Philadelphia chromosome due to a (9p;22q) translocation, deleted chromosomes 3 and 6, a 14q+ marker, and two extra chromosomes 18. The Ph chromosome is previously only once reported in a well-characterized B-cell lymphoma, whereas the latter aberrations are common findings in B-cell malignancies.

Sensitive mRNA detection using unfixed tissue: combined radioactive and non-radioactive in situ hybridization histochemistry.

In the present study some experimental parameters for in situ hybridization histochemistry (ISHH) have been analysed using 35S-labelled and alkaline phosphatase-conjugated probes, in order to develop a reproducible double-labelling procedure. We have compared the total exclusion of tissue fixation with tissue sections fixed by immersion in formalin. In addition, the effect of dithiothreitol was assessed both when combining radiolabelled and non-radioactive probes on a single tissue section and when the probes were used separately. Hybridization of unfixed tissue resulted in stronger specific labelling and lower background both for radiolabelled and alkaline phosphatase-conjugated probes. No loss in tissue preservation was seen at the light microscopic level after hybridization of unfixed tissue. High concentrations (200 mM) of dithiothreitol strongly suppressed background when using 35S-labelled probes, whereas in the non-radioactive procedure, alkaline phosphatase labelling could only be achieved with very low dithiothreitol concentrations (less than 1 mM). This incompatibility led to a protocol using unfixed tissue sections and a sequential hybridization procedure, with the radiolabelled probe and high concentrations of dithiothreitol in the first step and the alkaline phosphatase-conjugated probe without dithiothreitol in the second step.

Concentration of angiotensin-converting enzyme in tears of patients with sarcoidosis.

The concentration of angiotensin-converting enzyme (ACE) was studied in 39 patients with sarcoidosis, 6 of whom had active uveitis, 7 patients with non-sarcoid uveitis and 36 healthy controls. ACE concentration in tears was also compared with total protein concentration in tears in order to exclude the effect of varying dilution of tears at sampling. Mean tear ACE concentration and ACE/protein ratio were higher in patients with sarcoidosis than in controls. There were no significant differences in tear ACE concentration or ACE/protein ratio between sarcoidosis patients with uveitis and those with no eye involvement. Tear ACE concentration and ACE/protein ratio did not correlate significantly with serum ACE concentration. It is concluded that the mean concentration of tear ACE and ACE/protein ratio are elevated in sarcoidosis, but that this elevation is independent of any eye involvement.

Trisomy 8 in the chronic phase of Philadelphia negative chronic myelocytic leukaemia.

An unusual case of Philadelphia negative chronic myelocytic leukaemia and an extra chromosome 8 in all bone marrow cells is described. The abnormality was present at diagnosis of the disease and throughout the chronic phase which lasted for somewhat less than 2 years. The patient died soon after the blastic transformation with no other chromosomal abnormalities.

Theophylline pharmacokinetics in children, comparing sustained release spheres (Theo-Dur sprinkle) with elixir.

A new sustained release theophylline preparation (Theo-Dur Sprinkle, TDS) was given b.i.d. and a theophylline elixir t.i.d. to eight children with bronchial asthma, 4-10 years of age, in an open study with a randomized cross over design. The serum concentration curves of theophylline were compared. The individual theophylline dose was close to 20 mg/kg body weight per day. On day 3 of each regimen, blood samples were taken 11 times over 24 h. There were great differences between morning concentrations of theophylline, with a range from 0.9-10.7 mg/l in children given elixir, while corresponding values for children given TDS were 4.1-19.3 mg/l. Fluctuation during a dosing interval was 276% for elixir but only 54% in the case of TDS. The morning theophylline levels on two consecutive days did not differ significantly when the children were treated with TDS. The bioavailability of theophylline from TDS was 94% (range 54%-121%). Parents preferred TDS in seven of the eight cases. TDS showed satisfactory sustained release properties but the study confirmed the need for individually tailored dosage of theophylline based on monitoring of symptoms and serum concentrations.

Nonrandom chromosomal aberrations in chronic lymphocytic leukemia revealed by polyclonal B-cell-mitogen stimulation.

Peripheral blood lymphocytes from 11 patients with chronic lymphocytic leukemia were stimulated by Epstein-Barr virus (EBV), lipopolysaccharide from Escherichia (LPS), and phytohemagglutinin (PHA). Chromosome analysis with the Q-banding technique after 5 days incubation revealed an extra chromosome 12 in 5 of the patients and a translocation between chromosome 11 and chromosome 14 in 1. Two patients had a deletion of chromosome 6, and only 3 patients had a normal karyotype. In most patients, the abnormalities were found in the majority of metaphases after stimulation with EBV, LPS, or both mitogens, while PHA revealed a normal karyotype, with the exception of a total of 4 metaphases in 3 patients. An extra chromosome 12 appears to be specifically associated with chronic lymphocytic leukemia. The frequency of chromosomal abnormalities in this disease appears to be much higher than has previously been thought.

Isochromosome 17 in a patient with a myeloproliferative disorders terminating in eosinophilic leukemia.

A patient is described, who for more than two years had a myeloproliferative disorder which terminated in eosinophilic leukemia. Chromosome analysis revealed an isochromosome 17 in all metaphases of bone marrow cells. This abnormality has now been found in two out of six patients with eosinophilic leukemia investigated by banding techniques, and may therefore have etiologic importance. Chromosome analysis in the hypereosinophilic syndrome has practical value for differentiating malignant and non-malignant disease.

Extra chromosome 12 and prognosis in chronic lymphocytic leukaemia.

Peripheral blood lymphocytes from 22 consecutive patients with chronic lymphocytic leukaemia were stimulated with the polyclonal B-cell mitogens lipopolysaccharide from E. coli (LPS) and Epstein-Barr virus (EBV). Stimulation was successful for chromosome analysis in 14 patients. Eleven patients had chromosomal aberrations and 7 of these had an extra chromosome 12. In 2 patients an extra chromosome 12 was the only abnormality, while additional aberrations were found in 5 patients. 3 patients had complex aberrations involving deletion of chromosome 6. 1 of these patients also had a translocation between chromosomes 12 and 14. 1 patient had a translocation between chromosomes 11 and 14. In 3 patients no aberrations were detected. The time elapsing between diagnosis and appearance of clinical symptoms which were indications for treatment was significantly shorter in patients with an extra chromosome 12 than in these without this abnormality. Thus, it appears that an extra chromosome 12 is associated with a more rapid course of the disease, and may therefore be of importance for the predition of prognosis.