The impact of early viral infections and graft-versus-host disease on immune reconstitution following paediatric stem cell transplantation.

Viral infections and graft-versus-host disease (GVHD) render an impact on both the clinical and immunological recovery following allogeneic hematopoietic stem cell transplantation (HSCT). We studied the recuperation of the immune defence after transplant in the paediatric setting and assessed the impact of early (<100 days post-HSCT) viral [cytomegalovirus (CMV), Ebstein-Barr virus (EBV) and adenovirus] reactivations/infections and GVHD. Fifty-one paediatric recipients of HSCT were enrolled. T cell recovery was evaluated on lymphocyte subpopulations using flow cytometry and functionally by measuring T cell excision circles (TRECs) and through the analysis of T lymphocyte responses to mitogens. B cell recovery was studied by flow cytometry and functionally by ELISPOT. Acute and mild chronic GVHD allowed for a brisk recovery of both cellular and humoral immunity while moderate to severe chronic graft-versus-host disease (cGVHD) associated with a significant, tampering effect on the immunological recovery after transplant. In the former group, the early viral reactivations/infections seemingly linked with a delayed recovery of T lymphocytes and low TRECs values. Moderate to severe cGVHD appears to associate with an impaired immunological recovery after HSCT. Early viral infections linked with prolonged T cell immunodeficiency and thymic dysfunction may be indicative of the presence of subclinical GVHD.

T cell regeneration in pediatric allogeneic stem cell transplantation.

Delayed and/or insufficient T cell recovery post hematopoietic stem cell transplantation (HSCT) leads to an increased risk of morbidity and mortality. We evaluated thymic function and its association with T cell regeneration post HSCT and identified factors involved in the process among pediatric stem cell transplant recipients. T cell regeneration in 66 pediatric patients was prospectively followed by naive T cell phenotyping, measuring of T cell receptor excision circles (TRECs) and expression of Foxp3 by regulatory T cells for the first 18 months post HSCT. TRECs were lower pre-HSCT in children with a malignant than non-malignant primary disease or immunosuppressed controls (P=0.001). Naive T lymphocyte reconstitution and thymic recovery were slow in the recipients of allogeneic stem cell grafts post HSCT. Infections caused by herpesviruses had a prognostic impact on mortality. Children with low TRECs had a high mortality (P=0.05) and low TRECs were also associated with extensive chronic graft-versus-host disease from 6 months onwards. Low amount of Foxp3 pre-HSCT was associated with an increased mortality post HSCT (P=0.03). Our study indicates an association between impaired T cell regeneration and thymic dysfunction and the clinical post transplant complications in pediatric allogeneic stem cell transplantation.

New tools in assessing immune reconstitution after hematopoietic stem cell transplantation.

BACKGROUND AND OBJECTIVES: Immune functions are impaired after allogeneic stem cell transplantation for several months depending on the age of the recipient, initial pathology, degree of HLA and minor histocompatibility antigens mismatches, origin and manipulation of the graft (unmanipulated or T-cell depleted bone marrow transplantation, cord blood) and post-transplantation events (acute or chronic graft-versus-host disease, relapse and infectious complications). MATERIAL AND METHODS, RESULTS AND CONCLUSION: In addition to lymphocyte phenotyping and functional assays, new tools are now available to monitor specific aspects of the immune response in the follow-up of hematopoietic stem cell transplantation: reconstitution of T cell diversity (spectratyping or Immunoscope), thymic function (TREC or "T-cell receptor rearrangement excision DNA circles") and antigen-specific T cell responses (HLA tetramers).

Childhood cancer and later development of the metabolic syndrome.

The improving survival rate of patients with childhood cancer has led to a growing awareness of the long-term effects of malignant disease and its treatment. Various endocrine abnormalities have been reported as frequent long-term adverse effects of cancer treatment in childhood, and among these growth hormone (GH) deficiency is the most common one, especially after cranial irradiation. Besides promoting growth, GH has well-established metabolic effects. Patients with GH deficiency tend to be obese, and obesity per se is also associated with insulin resistance which plays a key role in a cluster of metabolic derangements including glucose intolerance, hypertension, lipid abnormalities and atherosclerotic cardiovascular disease. This condition is known as the metabolic syndrome. Our recent observations indicate that a combination of obesity, glucose intolerance, hyperinsulinaemia and an abnormal lipid profile can be observed in long-term survivors of childhood cancer. Every sixth patient had the triad of obesity, hyperinsulinaemia and low HDL cholesterol, whereas this combination was not seen in any of the controls. The survivors with such a high-risk profile for cardiovascular disease had markedly reduced spontaneous GH secretion, and also additional features of the metabolic syndrome, such as higher systolic blood pressure and higher plasma glucose and serum triglyceride levels. Accordingly, decreased GH secretion, or alternatively some other disturbance in the hypothalamic-pituitary axis, emerging as a consequence of cranial radiation, may expose long-term survivors of childhood cancer to premature evolution of the metabolic syndrome. This can have an important impact on the long-term prognosis in these patients, because the syndrome as such results in an increased risk of cardiovascular morbidity and mortality.

Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome.

Survivors of childhood cancer have been reported to have a severalfold increased risk of death from cardiovascular disease. A cluster of metabolic abnormalities, including obesity, insulin resistance, hyperinsulinemia, glucose intolerance, hypertension, and dyslipidemia, have been designated as forming a metabolic syndrome that is associated with increased cardiovascular mortality. We studied 50 survivors (23 males) of childhood cancer, aged 10.5-31.2 yr, an average of 12.6 yr (range, 7.9-21.3 yr) after their diagnosis and compared them with 50 age- and sex-matched controls for signs of the metabolic syndrome by examining clinical and anthropometric measures, serum lipid profile, and fasting plasma insulin and glucose concentrations. Spontaneous nocturnal GH secretion was also evaluated in the cancer survivors. The patients had increased relative weight (P = 0.03) and body fat mass (P < 0.001), decreased serum high density lipoprotein (HDL) cholesterol (P < 0.001), and a reduced ratio of HDL to total cholesterol (P = 0.01). Fasting plasma glucose and insulin levels were higher (P < 0.001 and P = 0.003, respectively) in the cancer survivors than in the controls. The patients had an increased risk [odds ratio (OR), 4.5; 95% confidence interval (CI), 1.3-15.8; P = 0.01] of obesity (relative weight, > 120%), fasting hyperinsulinemia ( > 111 pmol/L; OR, 3.0; 95% CI, 1.0-8.6; P = 0.04), and reduced HDL cholesterol ( < 1.07 mmol/L; OR, 7.9; 95% CI, 2.2 to 29.6; P < 0.001). A combination of obesity, hyperinsulinemia, and low HDL cholesterol was seen in eight cancer survivors (16%), but in none of the controls (P = 0.01). This high risk group was characterized by reduced spontaneous GH secretion (P = 0.02). Long term survivors of childhood cancer appear to have an increased risk of manifestations of the metabolic syndrome. Decreased GH secretion may contribute to these metabolic abnormalities.

Clinical characteristics and factors affecting growth in long-term survivors of cancer.

We evaluated clinical characteristics and growth in 51 (24 males) long-term survivors of childhood cancer (median follow up 12.7 years). Patients were shorter, had a higher proportion of body fat and higher systolic blood pressure than their controls. The change in relative height during treatment was -0.83 standard deviation score (S.D.S.) in patients with cranial irradiation and -0.32 S.D.S. in patients without cranial irradiation; the figures after treatment were -0.56 and 0.20 S.D.S., respectively. Half (r2 = 0.50) of the variation in growth retardation during therapy could be explained by the cumulative doses of 6-mercaptopurine (6-MP) and vincristine and relative height at diagnosis. Cranial irradiation, increased relative height at diagnosis and young age at diagnosis were significant predictors of growth failure over the total observation period, explaining 43% of the variation. We conclude that long-term survivors of childhood cancer have impaired linear growth, increased body fat mass and elevated systolic blood pressure. Young children who are tall for their age at diagnosis and treated with cranial irradiation have the highest risk of impaired growth after the diagnosis. High doses of 6-MP seem to contribute significantly to growth retardation during therapy.

Decreased isokinetic trunk muscle strength and performance in long-term survivors of childhood malignancies: correlation with hormonal defects.

OBJECTIVE: To evaluate trunk muscle strength and performance in long-term survivors of childhood malignancies relative to age and sex-matched controls, and to relate the muscle strength observations to the therapeutic agents used and possible hormonal disturbances. DESIGN: Age and sex-matched cohort study. SETTING: Referral center in the northern part of Finland. PATIENTS: Forty-six long-term survivors of childhood cancer. Mean age at examination 19.1 years and median off-therapy time 9.4 years. INTERVENTION: Isokinetic dynamometer testing. MAIN OUTCOME MEASURES: Measurements of trunk muscle peak torque (PT) and total work done (TWD) were performed at angle speeds of 50 degrees/sec and 200 degrees/sec. The results were normalized relative to body fat-free weight (FFW). RESULTS: PT in the trunk muscles was lower in the patients at both angle speeds (mean normalized PT = 5.7Nm/kgFFW vs 7.6Nm/kgFFW for controls at 50 degrees/sec), as also was TWD except for extension TWD at the higher angle speed (mean normalized TWD = 59.9J/kgFFW vs 84.6J/kgFFW for controls at 200 degrees/sec). The normalized PT at 50 degrees/sec and TWD at 200 degrees/sec were lower in the males with testicular damage; also, low age at diagnosis correlated positively with muscle strength and performance. There were no differences in normalized PTs or TWDs between cranial radiation and non-radiation cases, or between growth-hormone-deficient and non-deficient cases, and the patients without cranial radiation or with normal growth hormone secretion still had lower normalized PTs and TWDs than the controls. CONCLUSIONS: Survivors of childhood malignancies have decreased maximal trunk muscle strength and performance. The etiology of this effect remains unclear, but young age at diagnosis, as well as serum testosterone levels in male survivors, evidently influence muscle strength and performance.

Late cranial MRI after cranial irradiation in survivors of childhood cancer.

We carried out MRI on 43 survivors of childhood cancer after different treatment protocols with or without cranial radiotherapy. They were free of disease, therapy having been discontinued 2-20 years earlier. Treatment had been for various malignancies, excluding brain tumours; 27 had received cranial irradiation for acute lymphoblastic leukaemia (ALL) or lymphoma. Two asymptomatic young women treated for ALL had falx meningiomas. White matter changes, low intensity foci (representing calcification or old haemorrhage) and heterogeneous intensity focic old haemorrhages) were seen only in patients who had undergone radiotherapy. Because of the possibility of benign, potentially curable brain tumours occurring after cranial irradiation, it may be wise to carry out occasional cranial imaging in the follow-up of these patients. No routine imaging follow-up is needed after chemotherapy alone.

Pituitary size assessed with magnetic resonance imaging as a measure of growth hormone secretion in long term survivors of childhood cancer.

We investigated 37 long term survivors of childhood cancer to study the relationship among growth, GH secretion, and pituitary size. The median follow-up time after diagnosis was 13.2 yr. The pituitary gland was visualized with magnetic resonance imaging. Radiated patients (n = 25) had a reduced relative height and showed a greater reduction in relative height after diagnosis than nonradiated patients (n = 12). The patients had lower spontaneous nocturnal GH secretion than controls due to a reduced peak amplitude. Spontaneous GH secretion was lower in radiated patients than in nonradiated subjects. The patients had lower plasma insulin-like growth factor-I (IGF-I) and serum IGF-binding protein-3 (IGFBP-3) concentrations than the controls. Radiated subjects had decreased IGF-I and IGFBP-3 concentrations compared to nonradiated subjects. Half of the patients (20 of 37) evaluated with magnetic resonance imaging had a reduced pituitary size (pituitary height, < -2 SD score). Radiated subjects had smaller pituitary glands than nonradiated ones. Seventeen of 20 patients (85%) with reduced pituitary size had decreased nocturnal GH release. There was a positive correlation between nocturnal GH secretion, plasma IGF-I, and serum IGFBP-3 levels, on the one hand, and pituitary height, on the other. These results indicate that cranial radiation may result in tissue damage, leading to decreased pituitary size, reduced spontaneous GH secretion, and impaired linear growth. The finding of reduced IGF-I levels in both radiated and nonradiated patients combined with decreased IGFBP-3 concentrations in radiated patients, indicates that cytotoxic chemotherapy may induce hepatic damage resulting in decreased IGF-I synthesis.

Decreased pituitary gland height after radiation treatment to the hypothalamic-pituitary axis evaluated by MR.

PURPOSE: To evaluate treatment-related changes in pituitary gland morphology after childhood cancer and to compare these findings with growth data. METHODS: Forty-three survivors of childhood cancer were evaluated by cranial MR imaging. Twenty-nine of the patients had received radiation therapy to the hypothalamic-pituitary axis with doses of 10 to 46 Gy. The height of the pituitary gland was measured from midline sagittal images and compared with age- and sex-matched controls. Pituitary gland heights were compared with body height standard deviation scores in patients. RESULTS: The patients who had received radiation therapy to the hypothalamic-pituitary axis had significantly smaller pituitary glands than patients in the nonirradiated group or their age- and sex-matched controls (mean, 3.5 mm versus 5.9 and 5.8 mm, respectively). They were also significantly shorter than patients in the nonirradiated group. CONCLUSION: Radiation therapy to the hypothalamic-pituitary area may lead to poor growth of the pituitary gland and short stature.

Hemolysis. Which laboratory investigations and when?

The Scandinavian Society for Clinical Chemistry and NORDKEM have had a number of joint efforts to facilitate the optimal performance and use of clinical laboratory investigations. A new committee (DOOKK or Diagnosis and Organ Oriented Committee for Clinical Chemistry) was established (in 1984) in order to improve collaboration between clinicians and laboratory physicians. In particular, the approach has been to work out recommendations for different clinical working hypotheses concerning restricted diagnoses or organ-specific problems. The aim of our project ("Hemolysis") was to create a rational scheme for the use of clinical chemical and hematological laboratory investigations in suspected or known cases of hemolysis.