Preparations of Staphylococus aureus strains Cowan 1 and Wood 46 and of lipopolysaccharide (LPS) ... more Preparations of Staphylococus aureus strains Cowan 1 and Wood 46 and of lipopolysaccharide (LPS) were found to act as polyclonal B‐cell‐activating substances for human splenic and blood lymphocytes. All three substances induced polyclonal antibody secretion in blood and spleen cell cultures, as tested against fluorescein isothiocyanate‐coupled sheep erythrocytes by a modification of the local hemolysis‐in‐gel assay. Antibodies were of IgM class, as shown by inhibition of plaque formation by anti‐IgM but not by anti‐IgG or anti‐IgA antisera. All these substances also consistently induced the formation of intracellular immunoglobulin and Increased DNA synthesis in stimulated spleen cells. In blood lymphocytes Staph. aureus Cowan 1 induced a consistent increase in DNA synthesis, whereas Staph. aureus Wood and LPS often gave low or no increase in DNA synthesis. Peak antibody formation was observed on day 3 in spleen cells and on day 6 in blood lymphocyte cultures. Stimulation into high‐...
Scandinavian journal of urology and nephrology. Supplementum, 1981
Commencing 1978, we reduced the initial dose of prednisolone to 40 mg/day against a former 120-20... more Commencing 1978, we reduced the initial dose of prednisolone to 40 mg/day against a former 120-200 mg/day for cadaver kidney recipients aged 60 years and above. The patient and graft survivals at 1 year which earlier had been 59 and 47% is 69 and 46% after the change (NS). From August 1980, we reduced the initial prednisolone dose to 30 mg/day for all recipients of cadaver kidneys. From the same time, all patients were given 5 units of leukocyte poor blood prior to the transplantation, and in addition, RATG (Stanford) was given during 2 weeks immediately following the transplantation. Preceding the reduction the patient and graft survivals at 6 months were 91 and 62% while they were 88 and 88% after the reduction (NS). The intravenous dose of methylprednisolone, which is used for the treatment of acute rejection, was reduced twice in this period, first from 6 to 3 g, and then to 1.75 g total dose. The proportion of rejections, successfully treated, had remained unchanged. Our prelim...
The Norrbottnian type of Gaucher disease is a well defined nosological entity with a characterist... more The Norrbottnian type of Gaucher disease is a well defined nosological entity with a characteristic course and clinical manifestations. The disease is caused by a deficiency of the enzyme glucosylceramidase (cerebroside-beta-glucosidase). Studies of genomic DNA and cDNA encoding the enzyme show a single base substitution in exon 10 in the Norrbottnian patients. The enzymic lesion causes an accumulation of glucosylceramide and glucosylsphingosine in cells of the monocyte-macrophage system, particularly in spleen, liver and bone marrow. Early splenectomy results in severe symptoms from skeleton and CNS, owing to accelerated storage of glucosylceramide in these organs. Bone marrow transplantation had a life-saving effect and seems to be the method of choice for beneficial enzyme replacement therapy.
Imniunoglobulin seeretion as evidenced by plaque-forming eells (PFC) in an indireet haemolysis-in... more Imniunoglobulin seeretion as evidenced by plaque-forming eells (PFC) in an indireet haemolysis-in-gel assay, and DNA synfhesis were indueed In human blood lymphocytes by the following preparations ol cytomegalovirus (CMV): Nucleoeapsidc Nc-CMV antigen, ttiembriine M-CMV Lintigen, crude C-CMV preparations and CMV-lncubated adherent cells. Pciik stimulaiions occurred around day fi in cullure. Ne-CMV and M-CMV only stimulated PFC and DNA synthesis in lymphoeytes froin CMV seropositive individuals. C-CMV also stimulated lymphocytes from C'MV seronegative individuals bul gave betler responses in lymphocyies Irom CMV seropositive individuals. CMV-incubatcd adherent cells oecLisionally stimulated lytuphoeytes from CMV seronegative individuals but always in CMV seropusitive blood donors. Ne-. M-, and C-CMV gave high numbers of PFC in B eells enriched by sheep erythrocyte sedimentation and in co-cultures of enrtehed T and B cells. Almost no PFC were induced in enriched T cells. DNA synthesis indueed by all the three antigenie CMV preparations increased after removal ol' adhereni eells. Strong DNA synthesis was indueed in enriched T cells compared to almost itone in enriched B eells. It is concluded that some pure CMV preparations act as antigens and more crude preparations induce polyclonal activation. Different CMV preparations may be used to diagnose CMV, to study immune reactivity against CMV and as a model for CMV infections in vitro.
The impact of cell dose (number of nucleated donor cells per kilogram recipient weight) on transp... more The impact of cell dose (number of nucleated donor cells per kilogram recipient weight) on transplantation outcome is controversial and may differ for allogeneic and identical twin (syngeneic) bone marrow transplants. We studied the association between cell dose and outcome in 100 unmanipulated identical twin bone marrow transplantations for leukemia, reported to the International Bone Marrow Transplant Registry between 1985 and 1994, using Cox proportional hazards regression for multivariate analyses. Cell doses ranged from 0.3 to 7.4 x 10(8) nucleated cells/kg (median, 3.0 x 10(8)cells/kg). Median follow-up was 75 months. Five-year cumulative incidences of transplant-related mortality with high (more than 3 x 10(8) cells/kg) versus low (less than or equal to 3 x 10(8) cells/kg) cell doses were 2% (95% confidence interval [CI], 0% to 8%) versus 10% (95% CI, 4% to 20%), respectively. Five-year probabilities of leukemia-free survival were 53% (95% CI, 39% to 67%) and 37% (95% CI, 23%...
Long-term survival of 182 leukemic patients after allogeneic bone marrow transplantation (BMT) wa... more Long-term survival of 182 leukemic patients after allogeneic bone marrow transplantation (BMT) was analyzed retrospectively regarding the type of graft-versus-host disease (GvHD) prophylaxis and patient age. Monotherapy with either methotrexate (MTX) (n = 59) or cyclosporin (CSA) (n = 40) was given to 79 patients less than 30 years of age and to 20 older patients. These patients were compared to those receiving a combination of MTX+CSA (n = 55) or T-cell depletion (TCD) (n = 28) (38 patients < or = 30 and 45 > 30 years of age). Patient characteristics were similar in the two pairs of groups. The median follow-up time was between 4.7 and 9.6 years in the different groups. In younger patients, the incidence of grade II-IV acute GvHD was 38% amongst those treated with MTX or CSA and 14% in the MTX+CSA/TCD group (p = 0.008). Forty percent of older patients on monotherapy developed grade II-IV acute GvHD compared to 26% of those over 30 treated with MTX+CSA/TCD (ns). As a consequen...
Significantly decreased levels of all classes Ig were found in saliva and serum of 85 patients be... more Significantly decreased levels of all classes Ig were found in saliva and serum of 85 patients before and up to 5 years after bone marrow transplantation (BMT). Salivary levels of IgG were increased before BMT in patients that died shortly after transplantation (p = 0.04). Significantly higher secretory IgA (sIgA) levels in saliva were noted in patients with malignant disorders than in those with non-malignant diseases, both before (p = 0.007) and after BMT (p = 0.011). Recipients of autologous marrow had higher levels of salivary sIgA before BMT than recipients of allogeneic bone marrow (p = 0.020). With increased BM cell dose at transplantation, lower levels of salivary IgG and albumin were found. Patients with cytomegalovirus infections after transplantation showed increased salivary IgG levels (p = 0.029). Individuals with chronic GVHD had less salivary IgM one year after BMT (median value 3.2 mg/l, p = 0.04) than those without chronic GVHD (median value 42.6 mg/l). All Ig class...
The study comprises 101 cadaveric kidneys transplanted in the last three years (1971-1974). Twent... more The study comprises 101 cadaveric kidneys transplanted in the last three years (1971-1974). Twenty-one retransplantations were included since the graft and patient survival in this group were equivalent to primary transplantations. There were 13 compatible grafts (A and B matches), 29 displaying one incompatible antigen (C match), 35 with two (D match) and 24 with 3 or 4 mismatches (E and G matches). At 9 months, there was a significantly lower graft survival in the E and G match group (33%) compared to the rest (p less than 0.01). For reasons discussed we will, however, for the first time being continue to transplant also the badly matched cadaveric kidneys.
Background and Objective Storage of platelets > 5 days provides improved availability, logistical... more Background and Objective Storage of platelets > 5 days provides improved availability, logistical management and decreased outdating. Promising results on in vitro parameters and on in vivo post-transfusion recovery and survival of autologous platelets in healthy volunteers have earlier been shown. To provide additional verification, randomized patient transfusion studies are needed. Materials and Methods Sixty allogeneic haematopoietic progenitor cell transplant recipients were randomized to receive buffy-coat (BC) platelets stored in platelet additive solution (PAS) for 1-5 days the first time a prophylactic transfusion was needed after transplantation, followed the second time by platelets stored for 6-7 days or vice versa. The corrected count increment (CCI) for 1 and 24 h were calculated. Results CCI 1 h and CCI 24 h were higher for platelets stored 1-5 days as compared to 6-7 days, 10AE4 ± 5AE1 vs. 7AE4 ± 3AE8 (P < 0AE001) and 5AE4 ± 4AE1 vs. 2AE6 ± 2AE6 (P < 0AE001), respectively. Time to next platelet transfusion was significantly longer after a transfusion of platelets stored for 1-5 days as compared to platelets stored for 6-7 days: 2AE2 ± 1AE1 vs. 1AE6 ± 0AE8 days, respectively (P < 0AE005). No differences in bleeding events and no transfusion reaction were recorded. Conclusion The advantage of an extension of platelet storage time beyond day 5 should be balanced against the increased need for platelet transfusions that may occur and the conceivable risk of transfusion failure.
The objective of this study was to investigate B-lymphocyte reconstitution in patients undergoing... more The objective of this study was to investigate B-lymphocyte reconstitution in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) after myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) regimens. B-lymphocyte reconstitution was studied by monitoring the CDR3 repertoire with spectratyping. We demonstrate a delay in the recovery of the B-lymphocyte repertoire, measured by variation in size distribution of the immunoglobulin H CDR3 in patients conditioned with RIC compared to MAC. We found no general explanation for this finding, but when clinical data for each patient were studied in detail, we could identify a cause for the oligoclonality of the B-lymphocyte repertoire after HSCT with RIC for each of the patients. Older patients and donors, low cell dose at transplantation, relapse, graft-versus-host disease (GVHD) and its treatment as well as cytomegalovirus infection and its treatment are all possible causes for the restriction of the B-lymphocyte repertoire observed in this study. Taken together, reconstitution of the B-lymphocyte repertoire after HSCT is a process dependent on multiple factors and differs between patients. The conditioning regimen may be of importance, but data from this study suggest that individual factors and the various complications occurring after HSCT are more likely to determine the development of the B-lymphocyte repertoire.
The evaluation of different stem cell transplantation (SCT) regimens is hampered by a bias in the... more The evaluation of different stem cell transplantation (SCT) regimens is hampered by a bias in the literature ± there is a clear trend towards reporting only those protocols that turn out better than average. In order not to repeat each other's mistakes, it is equally valuable for us to learn what doesn't work. Therefore, it is to the advantage of the transplantation community to pay heed to reports like the one presented by Vettenranta and co-workers in this issue of Pediatric Transplantation, where a conditioning regimen containing high-dose melphalan and total body irradiation (TBI) is deemed too toxic for general use. Their conclusion also brings into the open the discussion about the bene®t vs. the adverse effects of dose escalation. What if less is actually more? Perhaps we should move in the other direction, i.e. reduce the conditioning to levels where we can be sure to achieve engraftment of allogeneic stem cells but without excessive side-effects. It is common knowledge that the young patient tolerates chemotherapy better than an adult does. In the allogeneic stem cell transplantation (alloSCT) setting, this is evident from the fact that the transplantation-related mortality (TRM) is lower in children than in adults (1, 2). Based on this fact, several experimental high-dose chemotherapy regimens have been developed for poor-prognosis pediatric solid tumors, such as Ewing's sarcoma, medulloblastoma, osteogenic sarcoma, and neuroblastoma (3±5). The drawback is that these mega-dose protocols are highly toxic and require autologous stem cell salvage therapy. High-dose chemotherapy has increased long-term survival to some degree, but to the cost of acute and late sideeffects. The bene®ts may therefore be reduced by an increased regimen-related mortality. Similarly, in the treatment of pediatric hematological malignancies, mainly acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML), we have seen substantial dose escalation over the past few decades in order to achieve reduced relapse frequencies and higher survival rates. So far, this has been successful and we now have a growing population of long-term leukemia survivors. However, we also see a great deal more of late side-effects such as endocrine hypofunction, poor growth, pubertal dysfunction, and infertility (6). It seems as though dose escalation in ALL treatment has come to a halt and the focus today lies ± at least in part ± on trying to predict in which patients it will be possible to safely reduce chemotherapy. Perhaps the mega-dose strategy serves its purpose in the autologous transplant setting. But is it relevant also for allo-SCT? Most SCT conditioning protocols contain a combination of two modalities: total body irradiation (TBI) and one or more cytostatic agents, often cyclophosphamide, etoposide, or melphalan (7). Although TBI doses in excess of 10±12 Gy are associated with lower relapse frequencies, TRM is increased. This leaves the total event-free survival (EFS) unchanged, but with a higher rate of late effects. For instance, two randomized studies from Seattle, one on patients with AML and the other on patients with chronic myelogenous leukemia (CML), showed a lower relapse rate with 15.75 Gy than with 12 Gy (8, 9). However, the higher TBI dose was associated with greater toxicity and a higher TRM than the lower TBI dose and therefore the EFS was the same in the two groups. Cranial irradiation is not an option in the young child (younger than 2±3 yr of age), Pediatr Transplantation 2000: 4: 247±251
In vivo protein synthesis decreases in mononuclear cells following a combined stress hormone infu... more In vivo protein synthesis decreases in mononuclear cells following a combined stress hormone infusion given to healthy volunteers as a human trauma model. Here, the purpose was to further investigate this finding and to measure in vivo protein synthesis in isolated T lymphocytes. Furthermore, the effects of stress hormones on the lymphocyte subpopulations and mononuclear cells, characterized by flow cytometry and phytohemagglutinin (PHA)-induced and unstimulated proliferative responses in vitro, were elucidated. Healthy volunteers (n = 16) were randomized into 2 groups to receive either a stress hormone or a saline infusion for 6 hours. In vivo protein synthesis was studied before and after the treatment by measuring the incorporation of stable isotopically-labeled phenylalanine into lymphocyte and mononuclear cell proteins. Protein synthesis decreased after stress hormone infusion in both cell populations: in T lymphocytes from 13.0% +/- 0.7%/d (mean +/- SD) to 8.6% +/- 2.1%/d (P &amp;amp;lt;.01) and in mononuclear cells from 13.3% +/- 1.2%/d to 6.3 +/- 2.0%/d (P &amp;amp;lt;.001). No change in proliferative responsiveness in vitro was observed. The stress hormone infusion produced a decrease in the percentage of T helper CD3/CD4 from 41% to 18% (P &amp;amp;lt;.001), T cytotoxic CD3/CD8 from 27% to 15% (P &amp;amp;lt;.001), as well as total T CD3 cells from 69% to 35% (P &amp;amp;lt;.001). There was an increase in the percentage of natural killer (NK) cells CD16/CD56 from 17% to 55% (P &amp;amp;lt;.001). Determination of phenotypes expressed on activated T lymphocytes showed that CD3/HLA-DR was unchanged and CD3/CD25 decreased from 14% to 7% (P &amp;amp;lt;.01) in the stress hormone group. The study showed that the decrease of in vivo protein synthesis was 34% in T lymphocytes as compared with 53% in mononuclear cells, when determined immediately after a 6-hour stress hormone infusion. This change was associated with a pronounced decrease in all lymphocyte subpopulations, except for the NK cells, which increased substantially.
IgA deficiency developed in a 2-year-old boy with aplastic anaemia who received a bone-marrow gra... more IgA deficiency developed in a 2-year-old boy with aplastic anaemia who received a bone-marrow graft from his HLA-identical, 6-year-old, IgA-deficient sister. Southern blot analysis revealed the presence of alpha-genes in both children, thus suggesting a defect of lymphocyte stem-cell differentiation as a cause of IgA deficiency. Tissue typing showed homozygosity of HLA A1, B8, DR3, the haplotype associated with IgA deficiency in healthy people. Despite normal serum levels of IgG subclasses in both donor and recipient, both children showed a relative lack of specific IgG2 anticarbohydrate antibodies. This suggests that their IgA deficiency is part of a more fundamental aberration of immunoglobulin class and subclass distribution.
ABSTRACT Ellis and colleagues reported on a bone marrow transplant (BMT) recipient who developed ... more ABSTRACT Ellis and colleagues reported on a bone marrow transplant (BMT) recipient who developed tremor and was somewhat withdrawn but well oriented during treatment with liposomal amphotericin B (AmBisome) 4 mg/kg/day for Aspergillus pneumonia [1]. After discontinuation of cyclosporin, the symptoms disappeared. Since severe tremor and myoclonus had not previously been observed in their BMT unit, it was suggested that AmBisome for instance might have interfered with the metabolism/red-cell-binding of cyclosporin. As pointed out by Ellis and co-workers, mild tremor is a common complication in transplant recipients treated with cyclosporin. In BMT patients treated with cyclosporin, tremor has been reported in between 23% and 100% of the patients in different reports [2]. Central nervous system (CNS) toxicity, although rare, has been noted in BMT recipients. This and other neurological disturbances may be aggravated by cyclosporin-induced hypomagnesemia [3]. In our experience with 187 transplant recipients, 89 bone marrow transplant recipients and 98 organ transplant recipients, AmBisome was given for 197 episodes. In 34 cases AmBisome was given for verified invasive fungal infection, in 80 cases due to suspected invasive fungal infections and in 83 cases it was given as prophylaxis. Among the 89 BMT recipients treated with AmBisome for 92 episodes, all had concomitant cyclosporin medication. Confusion, thought to be associated with prophylactic AmBisome treatment (1 mg/kg/day), was seen in a 53-year-old woman with myeloma. A 46-year-old man with acute myeloid leukemia was treated with AmBisome, 2.3 mg/kg/day, due to suspected invasive Candida infection. He developed seizures 3 days prior to death by multiorgan failure and Staphylococcus septicemia. Tremor probably due to cyclosporin treatment was seen in two patients. No other neurological side-effects were noted during AmBisome treatment. In our material of 102 BMT recipients treated with cyclosporin but not with AmBisome, two developed CNS neurotoxicity [4]. One was a 7-year-old boy suffering from acute lymphoblastic leukemia, who had an epileptic attack with seizures, uncontrolled urination, deviation of the eyes and cortical blindness while having high cyclosporin blood levels (&gt;1000 ng/ml). In addition, a 37-year-old woman with chronic myeloid leukemia had grand mal seizures shortly after BMT. Among the 98 organ transplant recipients, 64 liver, 20 renal and 14 recipients of combined organs were treated with AmBisome for a total of 105 episodes. Side-effects probably not due to AmBisome treatment included confusion in two liver transplant recipients and peripheral neuropathy in one. Tremor was seen in four patients. In a previous analysis of organ transplant recipients at our unit who were not treated with AmBisome, CNS toxicity caused by cyclosporin was noted in one of 449 renal transplant recipients and in 9 of 29 liver transplant recipients (35%)
Preparations of Staphylococus aureus strains Cowan 1 and Wood 46 and of lipopolysaccharide (LPS) ... more Preparations of Staphylococus aureus strains Cowan 1 and Wood 46 and of lipopolysaccharide (LPS) were found to act as polyclonal B‐cell‐activating substances for human splenic and blood lymphocytes. All three substances induced polyclonal antibody secretion in blood and spleen cell cultures, as tested against fluorescein isothiocyanate‐coupled sheep erythrocytes by a modification of the local hemolysis‐in‐gel assay. Antibodies were of IgM class, as shown by inhibition of plaque formation by anti‐IgM but not by anti‐IgG or anti‐IgA antisera. All these substances also consistently induced the formation of intracellular immunoglobulin and Increased DNA synthesis in stimulated spleen cells. In blood lymphocytes Staph. aureus Cowan 1 induced a consistent increase in DNA synthesis, whereas Staph. aureus Wood and LPS often gave low or no increase in DNA synthesis. Peak antibody formation was observed on day 3 in spleen cells and on day 6 in blood lymphocyte cultures. Stimulation into high‐...
Scandinavian journal of urology and nephrology. Supplementum, 1981
Commencing 1978, we reduced the initial dose of prednisolone to 40 mg/day against a former 120-20... more Commencing 1978, we reduced the initial dose of prednisolone to 40 mg/day against a former 120-200 mg/day for cadaver kidney recipients aged 60 years and above. The patient and graft survivals at 1 year which earlier had been 59 and 47% is 69 and 46% after the change (NS). From August 1980, we reduced the initial prednisolone dose to 30 mg/day for all recipients of cadaver kidneys. From the same time, all patients were given 5 units of leukocyte poor blood prior to the transplantation, and in addition, RATG (Stanford) was given during 2 weeks immediately following the transplantation. Preceding the reduction the patient and graft survivals at 6 months were 91 and 62% while they were 88 and 88% after the reduction (NS). The intravenous dose of methylprednisolone, which is used for the treatment of acute rejection, was reduced twice in this period, first from 6 to 3 g, and then to 1.75 g total dose. The proportion of rejections, successfully treated, had remained unchanged. Our prelim...
The Norrbottnian type of Gaucher disease is a well defined nosological entity with a characterist... more The Norrbottnian type of Gaucher disease is a well defined nosological entity with a characteristic course and clinical manifestations. The disease is caused by a deficiency of the enzyme glucosylceramidase (cerebroside-beta-glucosidase). Studies of genomic DNA and cDNA encoding the enzyme show a single base substitution in exon 10 in the Norrbottnian patients. The enzymic lesion causes an accumulation of glucosylceramide and glucosylsphingosine in cells of the monocyte-macrophage system, particularly in spleen, liver and bone marrow. Early splenectomy results in severe symptoms from skeleton and CNS, owing to accelerated storage of glucosylceramide in these organs. Bone marrow transplantation had a life-saving effect and seems to be the method of choice for beneficial enzyme replacement therapy.
Imniunoglobulin seeretion as evidenced by plaque-forming eells (PFC) in an indireet haemolysis-in... more Imniunoglobulin seeretion as evidenced by plaque-forming eells (PFC) in an indireet haemolysis-in-gel assay, and DNA synfhesis were indueed In human blood lymphocytes by the following preparations ol cytomegalovirus (CMV): Nucleoeapsidc Nc-CMV antigen, ttiembriine M-CMV Lintigen, crude C-CMV preparations and CMV-lncubated adherent cells. Pciik stimulaiions occurred around day fi in cullure. Ne-CMV and M-CMV only stimulated PFC and DNA synthesis in lymphoeytes froin CMV seropositive individuals. C-CMV also stimulated lymphocytes from C'MV seronegative individuals bul gave betler responses in lymphocyies Irom CMV seropositive individuals. CMV-incubatcd adherent cells oecLisionally stimulated lytuphoeytes from CMV seronegative individuals but always in CMV seropusitive blood donors. Ne-. M-, and C-CMV gave high numbers of PFC in B eells enriched by sheep erythrocyte sedimentation and in co-cultures of enrtehed T and B cells. Almost no PFC were induced in enriched T cells. DNA synthesis indueed by all the three antigenie CMV preparations increased after removal ol' adhereni eells. Strong DNA synthesis was indueed in enriched T cells compared to almost itone in enriched B eells. It is concluded that some pure CMV preparations act as antigens and more crude preparations induce polyclonal activation. Different CMV preparations may be used to diagnose CMV, to study immune reactivity against CMV and as a model for CMV infections in vitro.
The impact of cell dose (number of nucleated donor cells per kilogram recipient weight) on transp... more The impact of cell dose (number of nucleated donor cells per kilogram recipient weight) on transplantation outcome is controversial and may differ for allogeneic and identical twin (syngeneic) bone marrow transplants. We studied the association between cell dose and outcome in 100 unmanipulated identical twin bone marrow transplantations for leukemia, reported to the International Bone Marrow Transplant Registry between 1985 and 1994, using Cox proportional hazards regression for multivariate analyses. Cell doses ranged from 0.3 to 7.4 x 10(8) nucleated cells/kg (median, 3.0 x 10(8)cells/kg). Median follow-up was 75 months. Five-year cumulative incidences of transplant-related mortality with high (more than 3 x 10(8) cells/kg) versus low (less than or equal to 3 x 10(8) cells/kg) cell doses were 2% (95% confidence interval [CI], 0% to 8%) versus 10% (95% CI, 4% to 20%), respectively. Five-year probabilities of leukemia-free survival were 53% (95% CI, 39% to 67%) and 37% (95% CI, 23%...
Long-term survival of 182 leukemic patients after allogeneic bone marrow transplantation (BMT) wa... more Long-term survival of 182 leukemic patients after allogeneic bone marrow transplantation (BMT) was analyzed retrospectively regarding the type of graft-versus-host disease (GvHD) prophylaxis and patient age. Monotherapy with either methotrexate (MTX) (n = 59) or cyclosporin (CSA) (n = 40) was given to 79 patients less than 30 years of age and to 20 older patients. These patients were compared to those receiving a combination of MTX+CSA (n = 55) or T-cell depletion (TCD) (n = 28) (38 patients < or = 30 and 45 > 30 years of age). Patient characteristics were similar in the two pairs of groups. The median follow-up time was between 4.7 and 9.6 years in the different groups. In younger patients, the incidence of grade II-IV acute GvHD was 38% amongst those treated with MTX or CSA and 14% in the MTX+CSA/TCD group (p = 0.008). Forty percent of older patients on monotherapy developed grade II-IV acute GvHD compared to 26% of those over 30 treated with MTX+CSA/TCD (ns). As a consequen...
Significantly decreased levels of all classes Ig were found in saliva and serum of 85 patients be... more Significantly decreased levels of all classes Ig were found in saliva and serum of 85 patients before and up to 5 years after bone marrow transplantation (BMT). Salivary levels of IgG were increased before BMT in patients that died shortly after transplantation (p = 0.04). Significantly higher secretory IgA (sIgA) levels in saliva were noted in patients with malignant disorders than in those with non-malignant diseases, both before (p = 0.007) and after BMT (p = 0.011). Recipients of autologous marrow had higher levels of salivary sIgA before BMT than recipients of allogeneic bone marrow (p = 0.020). With increased BM cell dose at transplantation, lower levels of salivary IgG and albumin were found. Patients with cytomegalovirus infections after transplantation showed increased salivary IgG levels (p = 0.029). Individuals with chronic GVHD had less salivary IgM one year after BMT (median value 3.2 mg/l, p = 0.04) than those without chronic GVHD (median value 42.6 mg/l). All Ig class...
The study comprises 101 cadaveric kidneys transplanted in the last three years (1971-1974). Twent... more The study comprises 101 cadaveric kidneys transplanted in the last three years (1971-1974). Twenty-one retransplantations were included since the graft and patient survival in this group were equivalent to primary transplantations. There were 13 compatible grafts (A and B matches), 29 displaying one incompatible antigen (C match), 35 with two (D match) and 24 with 3 or 4 mismatches (E and G matches). At 9 months, there was a significantly lower graft survival in the E and G match group (33%) compared to the rest (p less than 0.01). For reasons discussed we will, however, for the first time being continue to transplant also the badly matched cadaveric kidneys.
Background and Objective Storage of platelets > 5 days provides improved availability, logistical... more Background and Objective Storage of platelets > 5 days provides improved availability, logistical management and decreased outdating. Promising results on in vitro parameters and on in vivo post-transfusion recovery and survival of autologous platelets in healthy volunteers have earlier been shown. To provide additional verification, randomized patient transfusion studies are needed. Materials and Methods Sixty allogeneic haematopoietic progenitor cell transplant recipients were randomized to receive buffy-coat (BC) platelets stored in platelet additive solution (PAS) for 1-5 days the first time a prophylactic transfusion was needed after transplantation, followed the second time by platelets stored for 6-7 days or vice versa. The corrected count increment (CCI) for 1 and 24 h were calculated. Results CCI 1 h and CCI 24 h were higher for platelets stored 1-5 days as compared to 6-7 days, 10AE4 ± 5AE1 vs. 7AE4 ± 3AE8 (P < 0AE001) and 5AE4 ± 4AE1 vs. 2AE6 ± 2AE6 (P < 0AE001), respectively. Time to next platelet transfusion was significantly longer after a transfusion of platelets stored for 1-5 days as compared to platelets stored for 6-7 days: 2AE2 ± 1AE1 vs. 1AE6 ± 0AE8 days, respectively (P < 0AE005). No differences in bleeding events and no transfusion reaction were recorded. Conclusion The advantage of an extension of platelet storage time beyond day 5 should be balanced against the increased need for platelet transfusions that may occur and the conceivable risk of transfusion failure.
The objective of this study was to investigate B-lymphocyte reconstitution in patients undergoing... more The objective of this study was to investigate B-lymphocyte reconstitution in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) after myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) regimens. B-lymphocyte reconstitution was studied by monitoring the CDR3 repertoire with spectratyping. We demonstrate a delay in the recovery of the B-lymphocyte repertoire, measured by variation in size distribution of the immunoglobulin H CDR3 in patients conditioned with RIC compared to MAC. We found no general explanation for this finding, but when clinical data for each patient were studied in detail, we could identify a cause for the oligoclonality of the B-lymphocyte repertoire after HSCT with RIC for each of the patients. Older patients and donors, low cell dose at transplantation, relapse, graft-versus-host disease (GVHD) and its treatment as well as cytomegalovirus infection and its treatment are all possible causes for the restriction of the B-lymphocyte repertoire observed in this study. Taken together, reconstitution of the B-lymphocyte repertoire after HSCT is a process dependent on multiple factors and differs between patients. The conditioning regimen may be of importance, but data from this study suggest that individual factors and the various complications occurring after HSCT are more likely to determine the development of the B-lymphocyte repertoire.
The evaluation of different stem cell transplantation (SCT) regimens is hampered by a bias in the... more The evaluation of different stem cell transplantation (SCT) regimens is hampered by a bias in the literature ± there is a clear trend towards reporting only those protocols that turn out better than average. In order not to repeat each other's mistakes, it is equally valuable for us to learn what doesn't work. Therefore, it is to the advantage of the transplantation community to pay heed to reports like the one presented by Vettenranta and co-workers in this issue of Pediatric Transplantation, where a conditioning regimen containing high-dose melphalan and total body irradiation (TBI) is deemed too toxic for general use. Their conclusion also brings into the open the discussion about the bene®t vs. the adverse effects of dose escalation. What if less is actually more? Perhaps we should move in the other direction, i.e. reduce the conditioning to levels where we can be sure to achieve engraftment of allogeneic stem cells but without excessive side-effects. It is common knowledge that the young patient tolerates chemotherapy better than an adult does. In the allogeneic stem cell transplantation (alloSCT) setting, this is evident from the fact that the transplantation-related mortality (TRM) is lower in children than in adults (1, 2). Based on this fact, several experimental high-dose chemotherapy regimens have been developed for poor-prognosis pediatric solid tumors, such as Ewing's sarcoma, medulloblastoma, osteogenic sarcoma, and neuroblastoma (3±5). The drawback is that these mega-dose protocols are highly toxic and require autologous stem cell salvage therapy. High-dose chemotherapy has increased long-term survival to some degree, but to the cost of acute and late sideeffects. The bene®ts may therefore be reduced by an increased regimen-related mortality. Similarly, in the treatment of pediatric hematological malignancies, mainly acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML), we have seen substantial dose escalation over the past few decades in order to achieve reduced relapse frequencies and higher survival rates. So far, this has been successful and we now have a growing population of long-term leukemia survivors. However, we also see a great deal more of late side-effects such as endocrine hypofunction, poor growth, pubertal dysfunction, and infertility (6). It seems as though dose escalation in ALL treatment has come to a halt and the focus today lies ± at least in part ± on trying to predict in which patients it will be possible to safely reduce chemotherapy. Perhaps the mega-dose strategy serves its purpose in the autologous transplant setting. But is it relevant also for allo-SCT? Most SCT conditioning protocols contain a combination of two modalities: total body irradiation (TBI) and one or more cytostatic agents, often cyclophosphamide, etoposide, or melphalan (7). Although TBI doses in excess of 10±12 Gy are associated with lower relapse frequencies, TRM is increased. This leaves the total event-free survival (EFS) unchanged, but with a higher rate of late effects. For instance, two randomized studies from Seattle, one on patients with AML and the other on patients with chronic myelogenous leukemia (CML), showed a lower relapse rate with 15.75 Gy than with 12 Gy (8, 9). However, the higher TBI dose was associated with greater toxicity and a higher TRM than the lower TBI dose and therefore the EFS was the same in the two groups. Cranial irradiation is not an option in the young child (younger than 2±3 yr of age), Pediatr Transplantation 2000: 4: 247±251
In vivo protein synthesis decreases in mononuclear cells following a combined stress hormone infu... more In vivo protein synthesis decreases in mononuclear cells following a combined stress hormone infusion given to healthy volunteers as a human trauma model. Here, the purpose was to further investigate this finding and to measure in vivo protein synthesis in isolated T lymphocytes. Furthermore, the effects of stress hormones on the lymphocyte subpopulations and mononuclear cells, characterized by flow cytometry and phytohemagglutinin (PHA)-induced and unstimulated proliferative responses in vitro, were elucidated. Healthy volunteers (n = 16) were randomized into 2 groups to receive either a stress hormone or a saline infusion for 6 hours. In vivo protein synthesis was studied before and after the treatment by measuring the incorporation of stable isotopically-labeled phenylalanine into lymphocyte and mononuclear cell proteins. Protein synthesis decreased after stress hormone infusion in both cell populations: in T lymphocytes from 13.0% +/- 0.7%/d (mean +/- SD) to 8.6% +/- 2.1%/d (P &amp;amp;lt;.01) and in mononuclear cells from 13.3% +/- 1.2%/d to 6.3 +/- 2.0%/d (P &amp;amp;lt;.001). No change in proliferative responsiveness in vitro was observed. The stress hormone infusion produced a decrease in the percentage of T helper CD3/CD4 from 41% to 18% (P &amp;amp;lt;.001), T cytotoxic CD3/CD8 from 27% to 15% (P &amp;amp;lt;.001), as well as total T CD3 cells from 69% to 35% (P &amp;amp;lt;.001). There was an increase in the percentage of natural killer (NK) cells CD16/CD56 from 17% to 55% (P &amp;amp;lt;.001). Determination of phenotypes expressed on activated T lymphocytes showed that CD3/HLA-DR was unchanged and CD3/CD25 decreased from 14% to 7% (P &amp;amp;lt;.01) in the stress hormone group. The study showed that the decrease of in vivo protein synthesis was 34% in T lymphocytes as compared with 53% in mononuclear cells, when determined immediately after a 6-hour stress hormone infusion. This change was associated with a pronounced decrease in all lymphocyte subpopulations, except for the NK cells, which increased substantially.
IgA deficiency developed in a 2-year-old boy with aplastic anaemia who received a bone-marrow gra... more IgA deficiency developed in a 2-year-old boy with aplastic anaemia who received a bone-marrow graft from his HLA-identical, 6-year-old, IgA-deficient sister. Southern blot analysis revealed the presence of alpha-genes in both children, thus suggesting a defect of lymphocyte stem-cell differentiation as a cause of IgA deficiency. Tissue typing showed homozygosity of HLA A1, B8, DR3, the haplotype associated with IgA deficiency in healthy people. Despite normal serum levels of IgG subclasses in both donor and recipient, both children showed a relative lack of specific IgG2 anticarbohydrate antibodies. This suggests that their IgA deficiency is part of a more fundamental aberration of immunoglobulin class and subclass distribution.
ABSTRACT Ellis and colleagues reported on a bone marrow transplant (BMT) recipient who developed ... more ABSTRACT Ellis and colleagues reported on a bone marrow transplant (BMT) recipient who developed tremor and was somewhat withdrawn but well oriented during treatment with liposomal amphotericin B (AmBisome) 4 mg/kg/day for Aspergillus pneumonia [1]. After discontinuation of cyclosporin, the symptoms disappeared. Since severe tremor and myoclonus had not previously been observed in their BMT unit, it was suggested that AmBisome for instance might have interfered with the metabolism/red-cell-binding of cyclosporin. As pointed out by Ellis and co-workers, mild tremor is a common complication in transplant recipients treated with cyclosporin. In BMT patients treated with cyclosporin, tremor has been reported in between 23% and 100% of the patients in different reports [2]. Central nervous system (CNS) toxicity, although rare, has been noted in BMT recipients. This and other neurological disturbances may be aggravated by cyclosporin-induced hypomagnesemia [3]. In our experience with 187 transplant recipients, 89 bone marrow transplant recipients and 98 organ transplant recipients, AmBisome was given for 197 episodes. In 34 cases AmBisome was given for verified invasive fungal infection, in 80 cases due to suspected invasive fungal infections and in 83 cases it was given as prophylaxis. Among the 89 BMT recipients treated with AmBisome for 92 episodes, all had concomitant cyclosporin medication. Confusion, thought to be associated with prophylactic AmBisome treatment (1 mg/kg/day), was seen in a 53-year-old woman with myeloma. A 46-year-old man with acute myeloid leukemia was treated with AmBisome, 2.3 mg/kg/day, due to suspected invasive Candida infection. He developed seizures 3 days prior to death by multiorgan failure and Staphylococcus septicemia. Tremor probably due to cyclosporin treatment was seen in two patients. No other neurological side-effects were noted during AmBisome treatment. In our material of 102 BMT recipients treated with cyclosporin but not with AmBisome, two developed CNS neurotoxicity [4]. One was a 7-year-old boy suffering from acute lymphoblastic leukemia, who had an epileptic attack with seizures, uncontrolled urination, deviation of the eyes and cortical blindness while having high cyclosporin blood levels (&gt;1000 ng/ml). In addition, a 37-year-old woman with chronic myeloid leukemia had grand mal seizures shortly after BMT. Among the 98 organ transplant recipients, 64 liver, 20 renal and 14 recipients of combined organs were treated with AmBisome for a total of 105 episodes. Side-effects probably not due to AmBisome treatment included confusion in two liver transplant recipients and peripheral neuropathy in one. Tremor was seen in four patients. In a previous analysis of organ transplant recipients at our unit who were not treated with AmBisome, CNS toxicity caused by cyclosporin was noted in one of 449 renal transplant recipients and in 9 of 29 liver transplant recipients (35%)
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