Platelet donor selection for HLA-immunised patients; the impact of donor-specific HLA antibody levels.

BACKGROUND: Approximately 20% of patients with a recurrently poor platelet transfusion increment show human leukocyte antigen (HLA) alloantibodies. The aim of this study was to analyse the impact of mean fluorescence intensity (MFI) levels of donor-specific HLA antibodies and the feasibility of the HLAMatchmaker algorithm in donor selection. STUDY DESIGN AND METHODS: A total of 270 HLA-typed platelet transfusion responses of 40 patients were included in the study. The patients' immunisation status was determined with Luminex-based methods, and HLA alloantibody strengths were defined as the MFI. For the Matchmaker eplet matching, the HLA-ABC Eplet Matching Version 2.1 was used. RESULTS: In 62% of the 270 transfusions, HLA antibodies against the transfused platelets were present, with a median cumulative MFI level of 2026 (range: 299-29 203). In multivariate analysis, a cumulative MFI level higher than 1000 emerged as an independent risk factor for a poor platelet transfusion increment, along with infection and the age of the product. CONCLUSION: The HLAMatchmaker algorithm alone is not a sufficient tool for donor selection. Donor selection based primarily on the levels of donor-specific HLA antibodies is a preferable practice.

Effect of obesity on the response to insulin therapy in noninsulin-dependent diabetes mellitus.

An initial improvement in glycemic control is often followed by gradual deterioration of glycemia during insulin treatment of patients with noninsulin-dependent diabetes mellitus (NIDDM). We examined the causes of such worsening in a 12-month follow-up analysis of 100 insulin-treated NIDDM patients in the Finnish Multicenter Insulin Therapy Study who were treated with either combination therapy with insulin or insulin alone. In the entire study group, glycemic control averaged 9.7 +/- 0.2% at 0 months and 8.0 +/- 0.1%, 8.0 +/- 0.1%, 8.2 +/- 0.1%, and 8.5 +/- 0.2% at 3, 6, 9, and 12 months (P < 0.001 for each time point vs. 0 months). Glycemic control at 12 months was significantly worse than that at 3 (P < 0.001), 6 (P < 0.001), and 9 months (P < 0.02). Baseline body mass index was the most significant predictor of deterioration in glycemic control. During 1 yr, hemoglobin A1c decreased almost 3-fold more (by 1.7 +/- 0.2%; P < 0.001 vs. 0 months) in patients whose baseline weight was below the mean baseline body mass index of 28.1 kg/m2 (nonobese patients) than in those whose weight exceeded 28.1 kg/m2 (obese patients; 0.5 +/- 0.2%; P = NS vs. 0 months; P < 0.01 vs. obese patients). Glycemic control improved similarly over 1 yr in the nonobese subjects and deteriorated similarly in the obese patients regardless of their treatment regimen. Insulin doses, per body weight, were similar in the nonobese and obese patients. The nonobese patients consistently gained less weight during 12 months of combination therapy with insulin (3.5 +/- 0.6 kg at 12 months) than during insulin therapy alone (5.1 +/- 0.6 kg; P < 0.05). The treatment regimen did not influence weight gain in the obese group, who gained 4.4 +/- 1.0 kg during combination therapy with insulin and 4.5 +/- 1.1 kg during insulin therapy alone. We reached the following conclusions: 1) after an initial good response, glycemic control deteriorates more in obese than in nonobese patients with NIDDM; 2) in obese patients, weight gain per se cannot explain the poor glycemic response to combination or insulin therapy, but it may induce a disproportionately large increase in insulin requirements because of greater insulin resistance in the obese than in the nonobese; 3) in nonobese patients, glycemic control improves equally during 1 yr with combination therapy with insulin and insulin alone, but combination therapy with insulin is associated with less weight gain than treatment with insulin alone; 4) weight gain appears harmful, as it is associated with increases in blood pressure and low density lipoprotein cholesterol.

Hypothalamic-pituitary axis remains intact after interferon-alpha treatment in hematologic diseases.

Many endocrinologic disturbances have been reported during and after interferon-alpha (IFN-alpha) treatment. These disturbances have often been caused by autoantibodies. The aim of this prospective study was to evaluate whether IFN-alpha causes hormonal changes and if it is necessary to search for such disturbances routinely. Ten patients with hematologic malignancies were examined before and after 4 months of IFN-alpha treatment. Pituitary function was tested by hypothalamic releasing hormones (thyrotropin-releasing hormone, TRH, growth hormone-releasing hormone, GHRH, gonadotropin-releasing hormone, GnRH). The adrenal glands were tested with the adrenocorticotropin (ACTH) test. The human chorionic gonadotropin (hCG) test was performed on the men (n = 4). The IFN treatment was well tolerated, and no long-term hormonal side effects were found. The testosterone/sex hormone binding globulin (SHBG) index tended to improve. There were no significant differences between the hormone responses before and after IFN-alpha treatment. We conclude that the hypothalamic-pituitary axis remains intact after IFN-alpha treatment. There is no need to follow patients endocrinologically if the patients are not predisposed by autoantibodies.

Long-term effects of allogeneic bone marrow transplantation (BMT) on pituitary, gonad, thyroid and adrenal function in adults.

To evaluate the late-effects of allogeneic bone marrow transplantation (BMT) on endocrine function 20 adults (10 females, 10 males) with hematological malignancies were studied after a mean of 3.2 years (range 1.0-10.0) following BMT. The mean age of patients at the time of BMT was 39 years. Dynamic tests of the hypothalamic-pituitary axis included growth hormone releasing hormone (GHRH), gonadotropin releasing hormone (GnRH) and thyrotropin releasing hormone (TRH) stimulations with measurements of serum growth hormone (GH), follicle stimulating hormone (FSH), luteinizing hormone (LH), thyrotropin (TSH) and prolactin (PRL) responses. Adrenal function was assessed with the adrenocorticotropin (ACTH) test. Five patients (25%) had a subnormal GH response to GHRH stimulation, but all had a normal serum insulin-like growth factor I (IGF-I) value. There was an inverse nonlinear relationship between the body mass index (BMI; kg/m2) and GH response but no relation between the GH response and total body irradiation (TBI), intrathecal treatment or occurrence of graft-versus-host disease. In females, serum FSH and LH basal levels and responses to GnRH, in spite of oestrogen substitution therapy in 9/10 patients, indicated ovarian failure and early menopause. Most responses to GnRH were delayed. All males had elevated serum basal FSH levels indicating damage in seminiferous tubulus and infertility. Serum basal LH was elevated only in four males but testosterone values were all within normal limits. However, the mean free androgen index (FAI) was in the low normal range, and two subjects had abnormally low FAI. Serum free thyroxine (fT4) levels were normal in all but one, but an exaggerated TSH response to TRH occurred in seven patients (35%). Four of them had received TBI and one total nodal irradiation suggesting radiation-induced damage to the thyroid gland. In 19 of the 20 patients, adrenal function judged with ACTH test was normal. We conclude that functional impairments of the hypothalamus-pituitary-gonad/thyroid axis are common while disturbances in GH, adrenal and prolactin occur less often in patients after intensive treatment and BMT. Typically, the target organ is more commonly affected than the hypothalamus-pituitary axis. In spite of normal serum testosterone and LH values, serum FAI may reveal androgen deficiency.

Bone mineral density after allogeneic bone marrow transplantation.

Bone turnover markers and bone mineral density (BMD) were studied in 25 adult patients (14 females, 11 males) who had undergone allogeneic bone marrow transplantation (BMT). The interval from BMT to the first examination was at least 1 year (mean 3, range 1-10). Mean age of the patients at the time of first evaluation was 42 (range 19-54) years. Blood samples and urine collections for evaluation of biochemical factors reflecting skeletal turnover were performed together with the first BMD measurement. BMD was measured from the lumbar vertebrae (L2 to L4) with computed tomography and results were expressed as Z-scores. At the time of the first measurement five patients (20%) had Z-scores <-2.5 s.d. and 12 patients (48%) between -1 and -2.5 s.d. In 12 patients BMD assessments were repeated and it seemed that reduction in BMD had mostly occurred during and shortly after BMT and remained the same during follow-up. The cross-linked carboxyterminal telopeptide of type I collagen (ICTP) correlated negatively with BMD (r = -0.45, P = 0.045) as did bone-specific alkaline phosphatase (BAP; r = -0.64, P = 0.002). No correlation between BMD and time interval from diagnosis to BMT, conditioning regimen, corticosteroid use or hospital stay during transplantation was found. In conclusion, bone disease is common after BMT. Our findings demonstrate an increased collagen and bone turnover and a high risk of osteoporosis. BMD measurements must be repeated regularly and collagen markers such as ICTP and BAP can be beneficial in estimating the activity of bone disease.

The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries.

Between 1982 and 2009 a total of 92 patients with myelofibrosis (MF) in chronic phase underwent allo-SCT in nine Nordic transplant centers. Myeloablative conditioning (MAC) was given to 40 patients, and reduced intensity conditioning (RIC) was used in 52 patients. The mean age in the two groups at transplantation was 46±12 and 55±8 years, respectively (P<0.001). When adjustment for age differences was made, the survival of the patients treated with RIC was significantly better (P=0.003). Among the RIC patients, the survival was significantly (P=0.003) better for the patients with age <60 years (a 10-year survival close to 80%) than for the older patients. The type of stem cell donor did not significantly affect the survival. No significant difference was found in TRM at 100 days between the MAC- and the RIC-treated patients. The probability of survival at 5 years was 49% for the MAC-treated patients and 59% in the RIC group (P=0.125). Patients treated with RIC experienced significantly less aGVHD compared with patients treated with MAC (P<0.001). The OS at 5 years was 70, 59 and 41% for patients with Lille score 0, 1 and 2, respectively (P=0.038, when age adjustment was made). Twenty-one percent of the patients in the RIC group were given donor lymphocyte infusion because of incomplete donor chimerism, compared with none of the MAC-treated patients (P<0.002). Nine percent of the patients needed a second transplant because of graft failure, progressive disease or transformation to AML, with no significant difference between the groups. Our conclusions are (1) allo-SCT performed with RIC gives a better survival compared with MAC. (2) age over 60 years is strongly related to a worse outcome and (3) patients with higher Lille score had a shorter survival.

Autologous blood cell transplantation in multiple myeloma: impact of CD34+ cell selection with long follow-up.

Positive CD34(+) selection to purge blood cell harvests is one way to attempt to reduce the high relapse risk after high-dose chemotherapy (HDT) supported by autologous blood cell transplantation (ABCT) in patients with multiple myeloma (MM). Until recently, however, the impact of CD34(+) selection, if any, on long-term clinical outcome in MM has remained obscure. We have analyzed engraftment kinetics, response to HDT, progression-free survival (PFS), and overall survival (OS) for 64 consecutive MM patients who have been treated with up-front HDT plus ABCT at our institution between 1993 and 1998. Nonrandomized comparisons were made between transplants with unselected (39 patients) and CD34(+)-selected (25 patients) grafts. The engraftment kinetics, need of blood product support, discharge time from hospital, and response to HDT were similar for both unselected and selected transplants. The median PFS was also similar (26 and 30 months, respectively) for the both groups. With a median follow-up time for the survivors of 67.5 months, the median OS (78 and 75 months, respectively) did not differ between transplants with unselected and selected grafts. In conclusion, this nonrandomized study suggests that positive CD34(+) selection has no beneficial impact on long-term outcome of patients with MM.

Interferon-alpha treatment decreases serum cross-linked C-terminal telopeptide of type I collagen in haematological diseases.

Interferon-alpha (IFN-alpha) is used in the treatment of many haematological diseases and it is known that IFN-alpha may affect bone turnover. The effect of IFN-alpha on bone metabolism was studied in 10 haematological patients. The mean duration of the treatment was 4 (range: 2.8-7.2) months. Besides the usual markers of bone metabolism, levels of the cross-linked C-terminal telopeptide of type I collagen (ICTP), the N-terminal propeptide of type I procollagen (PINP) and the bone-specific alkaline phosphatase were measured. The bone mineral density was measured by computed tomography. During IFN-alpha treatment, serum ICTP decreased from a mean of 5.4 (range: 1.8-12.4) to 3.6 (range: 1.4-8.8) microg/l (P = 0.017). All other variables reflecting bone metabolism remained unaltered during IFN-alpha treatment. The bone mineral density remained unchanged. It was concluded that the observed decrease in ICTP may be an indicator of a beneficial therapeutic effect of IFN-alpha on bone turnover, resulting in decreased bone resorption. However, it is possible that elevated pretreatment ICTP values reflected disease of the bone marrow.

The hypothalamus-pituitary-gonad axis and testicular function in male patients after treatment for haematological malignancies.

OBJECTIVE: The effect of aggressive chemotherapy on the hypothalamus-pituitary-gonad axis and on testicular function was assessed in nine male patients who had received chemotherapy only (CT, group I) and in 10 males after allogeneic bone marrow transplantation (BMT, group II). The mean time from CT or BMT to the assessment was 3.7 (range, 1.0-11.7) years. DESIGN: The responses of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were assessed by the gonadotropin-releasing hormone (GnRH) test and, in addition, serum basal values for testosterone and sex hormone binding globulin (SHBG) were measured and the free androgen index (FAI) was calculated. In 13/19 patients the human chorionic gonadotropin (hCG) test was performed. RESULTS: In group I, only one patient had an abnormal basal FSH value, but all (100%) had pathologically poor responses to the GnRH test. In contrast, all baseline FSH values were raised in group II (mean, 18; range, 11-30 U L-1), indicating toxic injury to the seminiferous tubules. Also in group II the responses to GnRH weer low throughout the test (90%) and there were no clear peak values. In group II, the basal FSH and its maximum response to GnRH were significantly more affected than in group I (P < 0.001). The difference may be due to the effect of the conditioning regimen. Serum basal LH was raised in three of the patients in group I and they also had abnormal releasing test responses. In group II, baseline LH was abnormal in four patients, but the responses to GnRH were normal. However, the maximum responses to the releasing test was significantly more affected in group II (P = 0.024). Serum testosterone levels were normal in all test subjects in both study groups. However, in two patients in both groups, the serum free androgen index was below the low reference limit, and an impaired response of serum testosterone to hCG stimulation was common (60%). CONCLUSIONS: A toxic injury in the testis is common in haematological patients, especially after high-dose chemoradiotherapy. Serum basal testosterone usually remains normal, but even then subnormal serum free androgen index, impaired testosterone response to hCG injection and abnormal response in LH may indicate a deficient androgen status. It may well be that testosterone replacement therapy should be considered in these cases.

Protein C substitution in sepsis-associated purpura fulminans.

OBJECTIVE: To assess the effect of protein C (PC) substitution on imminent peripheral necroses and overall outcome in patients with sepsis-associated purpura fulminans. DESIGN: Case series. SETTING: Intensive care units of two university hospitals. PATIENTS: A total of 12 patients with purpura fulminans, disseminated intravascular coagulation and imminent peripheral necroses in association with sepsis caused by Neisseria meningitidis (n = 5), Streptococcus pneumoniae (n = 2), Capnocytophaga canimorsus (n = 2), and Staphylococcus aureus (n = 1). In two patients, no pathogens were identified. INTERVENTIONS: Intravenous administration of PC concentrate (100 IU/kg every 6 hrs). In addition, antithrombin III substitution, antimicrobial therapy, hemodynamic support, and mechanical ventilation in all patients and hemodiafiltration in 10 patients. MAIN RESULTS: After the onset of PC, progressive peripheral ischemia was reversed irrespective of the etiology of infection. Laboratory variables reflecting disseminated intravascular coagulation improved rapidly, although the recovery of the platelet count was retarded in the patients who subsequently died. No drug-related adverse events were noted. Amputations were necessary in two patients, and necrotic tips of fingers and toes were macerated in a third. The hospital mortality was 42%. Of the five lethal cases, two were caused by S. pneumoniae, one by N. meningitidis, one by C. canimorsus, and one by an unknown pathogen. CONCLUSIONS: This article provides encouraging results on the use of PC substitution in meningococcal purpura and presents new data on the administration of this drug to patients with septic purpura caused by other bacterial species. By clinical judgment, PC limited the extent of tissue necrosis. The small number of patients does not allow for any conclusions on the potential effect of PC on mortality. A controlled and randomized study with a larger number of patients is needed before any recommendations can be given on the use of PC in sepsis-related purpura fulminans and shock.

Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus.

BACKGROUND: Insulin is widely used to improve metabolic control in patients with non-insulin-dependent diabetes mellitus (NIDDM), but there is no consensus about the optimal regimen of insulin treatment. METHODS: We treated 153 patients with NIDDM for three months with five regimens: (1) oral hypoglycemic drug therapy plus NPH insulin given at 7 a.m. (the morning-NPH group), (2) oral hypoglycemic drug therapy plus NPH insulin given at 9 p.m. (the evening-NPH group), (3) NPH and regular insulin (ratio, 70 units to 30 units) given before breakfast and dinner (the two-insulin-injection group), (4) NPH insulin at 9 p.m. and regular insulin before meals (the multiple-insulin-injection group), and (5) continued oral hypoglycemic drug therapy (the control group). RESULTS: The mean (+/- SE) value for glycosylated hemoglobin decreased similarly in all four insulin-treatment groups (1.7 +/- 0.3, 1.9 +/- 0.2, 1.8 +/- 0.3, and 1.6 +/- 0.3 percent, respectively). The decrease was significantly greater in these four groups than in the control group (0.5 +/- 0.2 percent; P < 0.001 vs. all insulin-treated groups). Weight gain was significantly less (1.2 +/- 0.5 kg) in the evening-NPH group than in the other insulin-treatment groups (2.2 +/- 0.5 kg in the morning-NPH group, 1.8 +/- 0.5 kg in the two-insulin-injection group, and 2.9 +/- 0.5 kg in the multiple-injection group; P < 0.05). In addition, the increment in the mean diurnal serum free insulin concentration was 50 to 65 percent smaller in the evening-NPH group than in the other insulin-treatment groups. Subjective well-being improved significantly more in the insulin-treatment groups than in the control group (P < 0.001). CONCLUSIONS: In patients with NIDDM who are receiving oral hypoglycemic drug therapy, the addition of NPH insulin in the evening improves glycemic control in a manner similar to combination therapy with NPH insulin in the morning, a two-insulin-injection regimen, or a multiple-insulin-injection regimen, but induces less weight gain and hyperinsulinemia. The data thus suggest that patients with NIDDM do not benefit from multiple insulin injections and that nocturnal insulin administration appears preferable to daytime administration.

Daily measurements of blood CD34+ cells after stem cell mobilization predict stem cell yield and posttransplant hematopoietic recovery.

The value of daily monitoring of the blood CD34+ cell concentration as a guide to the optimal timing of stem cell harvests was studied in 60 patients who underwent 66 stem cell mobilizations and 189 leukaphereses. There was a highly significant correlation between the blood CD34+ count and the CD34+ cell content in the apheresis product of the same day (r = 0.904, p < 0.01). Thus, the target yield of 4 x 10(6) CD34+ cells/kg can be harvested in one or two leukaphereses when the blood CD34+ cell count exceeds 50 x 10(6)/L. However, an insufficient harvest is to be expected when the blood CD34+ cell count is below 20 x 10(6)/L. The data from 35 autologous blood cell transplantations with a minimum CD34+ cell yield of 1.5 x 10(6)/kg showed that the recovery of blood neutrophil counts to 1.0 x 10(9)/L occurred in all patients within 9-14 days, but the time to recovery of the platelet counts to 20 x 10(9)/L may exceed 14 days, especially if the CD34+ cell content is below 4 x 10(6)/kg. Daily monitoring of blood CD34+ cell counts is a rapid and reliable means to guide the timing of stem cell collections. The count predicts well the CD34+ cell content of the harvests, the number of leukaphereses needed, and the speed of hematopoietic recovery.