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The purpose of the present study was to analyse the importance and prognostic value of renal failure in multiple myeloma patients. The frequency and reversibility of renal failure in 775 multiple myeloma patients diagnosed between 1984-86 and 1990-92 in the Nordic countries were studied. Renal failure, defined as plasma creatinine > 130 micromol/l, was observed in 29% of the cases at the time of diagnosis. During the first year after diagnosis 58% achieved normalisation of p-creatinine, and this was achieved mainly during the first 3 months. Reversibility of renal failure was more frequently observed in patients with moderate renal failure, hypercalcaemia and low Bence-Jones protein excretion. In a multivariate analysis renal failure, high age, stage III disease and hypercalcaemia were independent prognostic factors for survival. Patients who needed dialysis had a poor prognosis, with a median survival of 3.5 months. A 12-months landmark analysis showed that reversibility of renal failure was a more important prognostic factor than response to chemotherapy. It is concluded that renal failure in multiple myeloma is reversible in about half the cases, and reversibility of renal failure improves long-term survival.

The content of stem cells was analysed in bone marrow samples from 75 multiple myeloma patients. In unstimulated bone marrow the percentage of CD34+ cells was significantly reduced in 11 patients previously treated with melphalan-prednisolone (MP)(median= 0.15%) compared to median 0.87% in 31 untreated patients (P=0.0001). The bone marrow cellularity in the two groups did not differ. There was no correlation between the number of courses or total dose of melphalan and content of CD34+ cells in the bone marrow. The clonogenicity as well as the ability to expand the marrow stem cell pool during growth factor treatment were also reduced in MP treated patients compared to untreated patients. Analysis of different subsets of CD34+ cells revealed no influence on the pre B cell compartment in the bone marrow by MP treatment, but the committed stem cells (CD34+CD38+) were reduced more than the uncommitted stem cells (CD34+CD38-) in the MP treated group compared to the untreated patients. Mobilisation to and harvest of total number of CD34+ cells from peripheral blood was also reduced in the MP treated group. There was, however, no difference in the distribution between CD34+CD38+ and CD34+CD38- populations in the leukapheresis products in the untreated and the melphalan-treated group, suggesting selective mobilisation of CD34+CD38+ cells and/or differentiation of CD34+CD38-cells during growth factor stimulation. We conclude that melphalan decreased the number of stem cells in the bone marrow, the ability to expand the stem cell pool and mobilise stem cells to the pheripheral blood.

Recent studies concerning the numbers of circulating clonal B cells in patients with multiple myeloma (MM) have reported conflicting data regarding the exact levels of clonal B cells and the existence of clonal cells in the CD34 compartment. In this report we show that high numbers of clonal cells with a phenotype of late-stage B cells or pre-plasma cells were present in the peripheral blood (PB) of a patient with MM. During treatment the initial high level of PB clonal cells was markedly reduced and remained low (<1%) post transplant, even after disease progression. In addition, we found that the MM clone did not include a B-progenitor population defined by CD34.

Many studies have documented faster engraftment after transplantation with peripheral blood stem cells (PBSC) compared to bone marrow (BM) stem cells. Most comparisons, however, have been between unprimed BM and primed PBSC. We have collected engraftment data on 39 patients from 4 Danish centres and compared G-CSF primed BM with G-CSF primed PBSC in malignant lymphoma and solid tumours. In the lymphoma group 6 BM transplants were compared with 8 PBSC transplants, whereas in the testicular cancer group 16 BM transplants were compared with 9 PBSC transplants. In the lymphoma group, the time to platelet engraftment (platelets >20x10(9)/l unsupported) was median 15 d in PBSC transplants and median 34 d in BM transplants (p=0.003). In the solid tumour patients the difference in time to platelet engraftment was 11 and 18 d in PBSC and BM transplants, respectively (p<0.0001). In an attempt to explain this difference we performed CD34+ subset analysis of BM and PBSC. This analysis revealed a higher content of lineage restricted cells (CD34+CD61+ and CD34+GlyA+) in PBSC compared to BM. In conclusion, G-CSF mobilized PBSC seems to result in faster engraftment than G-CSF primed BM, which could be explained by an increased number of lineage specific progenitors in PBSC compared to BM.

We investigated the number and seriousness of moon-car accidents in our region (a moon-car is a toy-vehicle, see Fig. 1). The study was retrospective combined with a telephone-interview. Forty-seven patients were seen in the emergency room after a moon-car accident in the period 1/1 1990-31/12 95. There were 12 fractures, including five fractures of the tibial shaft and one supracondylar humeral fracture which was operated. There were 17 wounds, 14 of which were sutured. Seventeen patients had distorsions/contusions, three cases of head contusions (observed for concussion) and two with teeth damages. We found that the number of moon-car accidents is increasing (13 patients the last year), and that the accidents are not only minor. New rules in day care centres should be able to especially limit the number of more serious accidents.

We have previously reported a more than 50% risk of insufficient harvests (< 2 x 10(6) CD34+ cells/kg) following a fixed timing of leukapheresis in an unselected patient population collected for autologous stem cell transplantation. The failures were easily identified as patients who had < 20,000/ml CD34+ blood cells at the time of harvest. Consequently, in an attempt to optimize the timing strategy, we decided to perform daily analysis of the blood levels and perform leukapheresis within 24 h after the blood cell count exceeded 20,000 CD34+/ml. The results of this prospective study showed (a) that leukapheresis collections that were initiated based on the CD34+ blood level resulted in a success rate of 85% following 1-3 day harvests, (b) that high-level mobilizers with > 80,000 CD34+ cells/ml can be harvested successfully by only one procedure, and (c) that low-level mobilizers with < 40,000 CD34+ cells/ml still have a high risk of inadequate harvests. In summary, the optimized timing strategy is effective, but there is still room for improvement. First, new potent priming procedures for low-level and bad mobilizers are required, and second, algorithms to reduce the leukapheresis volume and time for high-level mobilizers should be established.

To day it is possible to predict the probability of fast engraftment based on a very simple flow cytometry standard analysis of CD34+ cells as documented by the 28 laboratories within the NSCL-G. However, the risk for delayed platelet engraftment still needs to be predicted in clinical practice for patients receiving less than 10 x 10(6) CD34+ cells/kg. Here we present data from our center supporting that identification by double staining of uncommitted (CD34+/CD38-) and lineage specific (CD34+/CD61+) progenitors may allow us to predict patients at high risk for prolonged platelet recovery. Following high dose therapy more than 30% of patients with haematological malignancies do suffer from disease recurrence within the first 3-6 months following high dose therapy. Today there are strong indications that such patients may have been transplanted with an autograft contaminated with a high number of potentially malignant B cells. Here we present a novel methodology for quantitation of blood circulating tumor cells by combining flow cytometry, cell sorting, limiting dilution and single cell RT-PCR. Such methodology has documented mobilization of clonal B cells following priming of the peripheral blood stem cell harvest and it can be used to identify minor populations and predict the efficacy of patient specific purging strategy. Consequently, quality assessment of autografts may include techniques which can predict fast three lineage engraftment as well as the risk for prolonged platelet recovery and can identify the group of patients/autografts with a strong contamination of potential tumor cells with a risk of early relapse. The future supportive cell therapy may depend upon improvements of such technologies and strategies including the selective administration of lineage specific growth factors e.g., trombopoietin as well as patient specific controlled purging strategies.

The determination of CD34-expressing cells by multiparameter flow cytometry is now widely used to estimate the reconstitution potential of cells harvested by cytapheresis for peripheral blood stem cell and progenitor cell transplantation. There is a correlation between the number of CD34-expressing cells collected and committed progenitor cells (CFU-GM and BFU-E) capable of forming colonies in vitro, but there is considerable variation in the proportion of CD34-expressing cells capable of clonogenic growth. The data in this study of 782 cytapheresis samples indicates that there is a negative correlation between the clonogenicity of the CD34-expressing cells and the absolute number or the proportion of CD34-expressing cells within the harvest. In 116 samples the proportion of CD34-expressing cells co-expressing the CD45-RA-antigen (a subset of CD34-expressing cells which includes virtually all clonogenic cells in terms of CFU-GM) was determined, but this did not help to identify the clonogenicity of a given sample. These findings may have clinical relevance, particularly when mobilization is judged to be relatively poor or when a good harvest is to be divided for multiple high-dose procedures.

The time of stem cell harvest and the mobilization regimen may play important roles in terms of achieving adequate numbers of stem cells by leukapheresis. To optimize the timing of leukapheresis, we have determined simultaneously the number of CD34+ cells in the peripheral blood as well as in the leukapheresis product of 214 apheresis procedures performed in 66 unselected patients with malignant hematologic diseases and solid tumors. A significant correlation between the number of CD34+ cells in peripheral blood and the leukapheresis product (R = 0.8) was found. The presence of more than 20 x 10(3)/ml blood CD34+ cells gave a sufficient yield (> or = 1.0 x 10(6) CD34+ cells/kg) in 81% of the cases. In an attempt to compare two priming regimens, we performed leukapheresis twice in 12 patients with stable disease. In the first sequence, stem cells were mobilized with rhG-CSF (10 micrograms/kg/day) alone and, in the second sequence, with cyclophosphamide (4 g/m2) plus rhG-CSF. A significantly higher yield of CD34+ cells and a better correlation between CD34+ cells in the peripheral blood and the leukapheresis product were found after priming with high-dose cyclophosphamide plus rhG-CSF, compared with priming with rhG-CSF alone. In a multivariate analysis, three factors were found to correlate with the yield of CD34+ cells, namely prior chemotherapy, bone marrow function, and the mobilization regimen. The use of cyclophosphamide priming improves CD34+ mobilization, and the introduction of blood CD34+ level optimizes the timing for harvest of stem cells, which should be performed early during treatment of malignancies.

High dose chemotherapy supported by haematopoietic stem cells is increasingly used for a variety of malignancies. Peripheral blood stem cells (PBSC) are replacing bone marrow stem cells in autologous transplantations. In this paper we report our experiences with transplantations using PBSC with respect to haematopoietic recovery. Forty-nine patients with breast cancer and different malignant haematological diseases receiving autologous transplantations with three different sources of haematopoietic stem cells were compared for engraftment parameters. Between 1989 and 1992, 27 patients were transplanted with autologous bone marrow stem cells alone (group 1) followed by 11 patients transplanted with bone marrow stem cells and PBSC (group 2) and subsequently 11 patients transplanted with PBSC alone (group 3). The median times to achieve granulocyte level > 0.5 x 10(9)/l posttransplant were 22 days for group 1, 10 days for group 2 and 13 days for group 3. The median times to achieve platelet level > 20 x 10(9)/l unsupported posttransplant were 30 days for group 1, 16 days for group 2 and 15 days for group 3. In conclusion, haematopoietic recovery was faster in patients receiving PBSC than in a control group of 27 patients receiving bone marrow stem cells alone.

It has been known for decades that blood neutrophilia occurs after the administration of etiocholanolone, adrenocortical steroids, and endotoxins. Neutrophil leukocytosis in general may be due to several mechanisms such as increased stimulation of the myelopoiesis, increased release from the marrow, a shift from the marginated to the circulating pool (demargination), prolongation in the peripheral half-life, and decreased migration of neutrophils from the blood to the tissue. However, the principal cause of the neutrocytosis for each of the above mentioned agents is increased release of neutrophils from the bone marrow reserves. Since a sufficient reserve capacity is a prerequisite for optimal defenses against infections, the marrow response has been used to estimate the dose of chemotherapy expected to be tolerated without life-threatening neutropenia. However, none of the above "test substances" have gained widespread use due to adverse reactions or undesirable effects on neutrophil function. Recent progress in biotechnology has developed recombinant human (rh) hematopoietic growth factors ready for clinical use. Marrow myelopoiesis is stimulated by granulocyte colony-stimulating factor (rhG-CSF) and granulocyte-macrophage CSF (rhGM-CSF). The immediate effect, however, is mobilization of mature neutrophil granulocytes to the blood. Bone marrow cellularity seems to influence the neutrophil number mobilized during 24 hours by one subcutaneous injection of either rhG-CSF or rhGM-CSF. A recent pilot study has suggested such a "24 hour stimulation test" to predict severe neutropenia following cyclic chemotherapy. This concept is illustrated by two case reports. The "stimulation test" suggests that we may devise strategies to define patient subsets which may benefit from prophylactic growth factor administration during cyclic chemotherapy.

This study describes the occurrence of renal failure among 1353 newly diagnosed cases of multiple myeloma. Renal function was evaluated by serum creatinine concentration in 1353 cases, 31% of whom had renal failure at the time of diagnosis. In 1206 cases an estimation of creatinine clearance was made. When renal failure was defined by using creatinine clearance estimation, 49% had renal failure at the time of diagnosis. Renal failure was present in 24% of patients with an M component of IgG-, 31% of IgA- and 100% of IgD-type. 52% of patients with light chain disease had renal failure. The frequency of renal failure was similar in lambda- and kappa-light chain disease. Patients with a high excretion of Bence Jones protein in the urine (> 10 g/24 h) had renal failure significantly more often than patients with lower excretion. Renal failure was related to advanced disease; 41% of patients with stage III (Durie-Salmon) disease had renal failure. Renal failure was found in 45% of patients with hypercalcaemia. When estimated creatinine clearance was used as a predictor of renal function, the same trends were found as mentioned above. In addition, the proportion of patients with renal failure was found to increase with advancing age.

In adults and children suffering from urge, urge incontinence, frequent voidings, and nocturia, urodynamic examination often confirms the diagnosis of detrusor instability. We assessed the outcome of biofeedback therapy in 15 children aged 6-12 years and 7 adults aged 20-52 years, all with cystometrically proven detrusor instability. The detrusor pressure was visually conveyed to the patient during repeated bladder fillings. The patient was instructed to interrupt detrusor pressure increments by tensing the pelvic floor musculature. None of the children were found completely cured; however, 9 showed a marked decrease in either the number of the extent of symptoms. Two children showed moderate improvement, while 4 remained unaffected by the treatment. One adult was completely cured, 2 improved moderately, and 4 showed no improvement. None of these patients were converted to stable cystometry. Upon termination of the BF treatment a follow-up study was conducted for patients exhibiting pronounced or moderate improvement. The beneficial effect was maintained except in one case.

Renal failure is a frequent complication in multiple myeloma and it is present in about 50% of patients with newly-diagnosed multiple myeloma. Renal failure at the time of diagnosis has earlier been associated with a bad prognosis, but a better prognostic factor is the response to chemotherapy. In general, it is important to distinguish between 1) renal insufficiency at the time of diagnosis, 2) acute renal insufficiency and 3) chronic renal insufficiency developing during the course of the disease. The patients in the first two groups are treated with intensive therapy which is long-lasting (median four to six weeks). The improved function of the kidney is correlated to an improved survival. Patients developing chronic renal insufficiency late in the course of the disease should receive palliative therapy. The most important factors that provoke acute renal insufficiency are dehydration, hypercalcaemia and/or infection, but renal insufficiency is also provoked by the use of nephrotoxic drugs, hyperuricaemia and/or hyperviscosity. Chronic renal insufficiency is provoked by deposits of light chains, infiltration by plasma cells or deposits of amyloid. The treatment consists of elimination of the provoking factors and start of chemotherapy.

Aminoglycosides are among the most active antimicrobial agents against Gram-negative infections, but they also share the potential for oto- and nephrotoxicity. Animal studies have shown that dosing aminoglycosides once daily is more efficient and less nephrotoxic than the conventional multiple daily dosing regimens. Pharmacokinetic and microbiological data support this finding. Clinical trials confirm that once-daily dosing is more efficient and less toxic than multiple daily dosing. The two most important risk factors for nephrotoxicity seem to be the duration of aminoglycoside treatment and high trough levels of aminoglycoside. Netilmicin and amikacin are the drugs most often used in clinical trials of once-daily dosing regimens. Recommendations for once-daily dosing of netilmicin are given.

Neurologically normal children with recurrent urinary tract infections (UTIs), night- and daytime wetting, and urge and painful voiding may have staccato voiding due to pelvic floor contractions. The immediate effect of non-invasive urodynamic biofeedback (BF) therapy was assessed using a historical follow-up study in 31 children aged 5-15 years suffering from urodynamically proven overactive urethra during voiding. A long-term follow-up study was performed to investigate whether improvement was maintained. Twenty-four children (77.5%) benefited from the treatment. Of these 16 (51.5%) were cured, while 8 (26%) had a pronounced reduction in their symptoms. Although the flow was normalized in 17 (55%) and nearly normalized in 7 (22.5%), there was no significant correlation between subjective and objective criteria of improvement. Similarly, no relationship was found between the initial urodynamic characteristics and the treatment outcome. During a mean follow-up time of 4 years (range: 1-7.5 years) two of the initially cured patients relapsed. They were recurred with a refresher course. Three had had a single or a few episodes of cystitis in the course of several years. Of the patients with pronounced reduction in their symptoms, three relapsed. A refresher course was attempted in two patients; one was successful. It can thus be concluded that BF is an effective way of treating this disturbance and the beneficial effect is to a wide degree maintained.

The aim of this study was to evaluate whether an insufficient flow of information from the primary to the secondary sector was the cause of unnecessary duplications of investigations. From practitioners of 202 patients admitted to a medical department information about paraclinical examinations during the previous year was obtained. In all 111 general practitioners participated. An average of 3.0 blood analyses and 0.9 other investigations were carried out on each patient. 44% of the patients were not investigated at all. An average of 1.9 blood analyses and 0.2 other investigations on each patient were repeated. 22% of the repetitions in both cases were due to insufficient communication between the practitioner and the hospital. These figures seem low and insufficient communication between the primary and the secondary sector appears to be a minor problem.

Fifty-six patients were investigated by repetitive cystometry in the supine or sitting position. The incidence of detrusor hyperreflexia and the circumstances under which it was found did not differ from previous studies. The cystometry data concerning volumes showed a remarkable degree of variability. Values for first sensation and maximal capacity could vary more than 500%. An increment from the first cystometry to the fourth was consistently found. The increments were most pronounced when cystometry with fast filling followed cystometry with medium filling regardless of the patient's position. The major factor in the changes is considered to be the patient's adaptation to the investigational situation. This finding might have major significance in the evaluation of drug studies where repeated cystometries with different time intervals are used.

Recent studies have shown the occurrence of rhythmic urethral pressure variations (UPV) in the normal female urethra in the awake state. The nature of these variations still needs further elucidation. In this study we investigated the changes in urethral pressure (UP) and in UPV as they occur in healthy females awake and asleep. UPV, intravesical-(IVP) and rectal pressure (RP), together with anal electromyography (EMG) and electroencephalography (EEG) were measured in 10 healthy fertile female volunteers. The registration was done in the awake state, during falling asleep and during sleep. During falling asleep the average urethral pressure as well as the UPV amplitude and frequencies decreased and remained at a lower stable level during sleep. Urethral pressure and its variations seemed to be interrelated since the UPV frequency and amplitude decreased when the average UP decreased. From this study it appears that urethral pressure is influenced by extrinsic factors such as the waking, resting and sleeping states. Although some extrinsic modulation of urethral pressure variations occurs, their persistance in sleep suggests their local nature.

Immunohistological methods using monoclonal antibodies have proved to be valuable in the differentiation between cells of various origins. We have previously shown most leucocyte differentiation antigens to be very resistant to post-mortem disintegration (Pallesen & Knudsen 1985). In the present study we have examined the preservation of several non-haematopoietic antigens in tissue samples of human skin, kidney, liver, pancreas, lung, thyroid gland, uterine tissue, female breast and brain from 30 autopsies performed at specific intervals after death. Frozen tissue sections were stained using monoclonal antibodies and an immunoperoxidase method. A total of 17 monoclonal antibodies against various intermediate filament proteins, epithelial antigens, various hormones and factor VIII related antigen were tested. We found surprisingly good preservation and staining of tissue antigens--even 3 d after death--in all organs except pancreas. It is concluded that many tissue antigens are fairly resistant to post-mortem disintegration and that immunohistology may be applied to diagnostic problems in human autopsy material.

The development of monoclonal antibodies and of techniques for demonstrating antigens in situ in frozen tissue sections has been responsible for remarkable progress in diagnostic histopathology. We explored the potential of these techniques when applied to post mortem tissues that were frozen at various intervals after death and stained by monoclonal antibodies using immunoperoxidase technique. The monoclonal antibodies were selected according to their reactivity with essential markers of the lymphatic system and also to their availability. Lymph nodes and splenic tissue from 30 autopsy cases were stained in addition to thymic tissue from eight deceased infants. The antigens proved to be surprisingly well preserved. Staining could be precisely evaluated with UCHT1, OKT6 and anti-Leu-7 antibodies at least 72 h after death; staining with DAKO-pan-B, DAKO-LC and anti-Leu-3a was also very reliable. Antigens expressed by T-suppressor lymphocytes and dendritic reticulum cells were less well preserved. The T8-antigen of suppressor lymphocytes was usually demonstrable in the lymph nodes but less frequently in the splenic tissues. It is concluded that most leucocyte antigens are very resistant to post mortem disintegration, and that they can be reliably interpreted by immunohistological staining using monoclonal antibodies. We therefore recommend this in autopsy specimens in cases where in-vivo examination was not feasible.