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Papers by per frisk
Journal of Medical Genetics
BackgroundCongenital dyserythropoietic anaemia type I (CDA-I) is a hereditary anaemia caused by b... more BackgroundCongenital dyserythropoietic anaemia type I (CDA-I) is a hereditary anaemia caused by biallelic mutations in the widely expressed genes CDAN1 and C15orf41. Little is understood about either protein and it is unclear in which cellular pathways they participate.MethodsGenetic analysis of a cohort of patients with CDA-I identifies novel pathogenic variants in both known causative genes. We analyse the mutation distribution and the predicted structural positioning of amino acids affected in Codanin-1, the protein encoded by CDAN1. Using western blotting, immunoprecipitation and immunofluorescence, we determine the effect of particular mutations on both proteins and interrogate protein interaction, stability and subcellular localisation.ResultsWe identify six novel CDAN1 mutations and one novel mutation in C15orf41 and uncover evidence of further genetic heterogeneity in CDA-I. Additionally, population genetics suggests that CDA-I is more common than currently predicted. Mutati...
Blood
Introduction:Acute graft-versus-host disease (aGVHD) can develop into a life-threatening complica... more Introduction:Acute graft-versus-host disease (aGVHD) can develop into a life-threatening complication after allogeneic hematopoietic cell transplantation (HSCT). The gastrointestinal (GI) tract is considered to play a key role in the pathophysiology of aGVHD, where the disease-process can start and be one of the target organs.The clinical presentation of acute aGVHD in the lower GI tract includes secretory diarrheas, sometimes bloody stools, abdominal pain with or without paralytic ileus. In the upper GI, symptoms such as nausea, anorexia, vomiting and weight loss are common. First-line therapy for aGVHD includes steroids at doses of 1-2 mg/kg /day. Approximately 50-60 % of the patients with aGI-GVHD fail to respond to steroids and their outcomes are very poor with a long-term mortality between 70-90 %. Bone marrow derived mesenchymal stromal cells (BM-MSCs) were introduced as a novel cell-based therapy by us for aGVHD a few decades ago, but not all patients responded, and many pati...
Blood
Children and adolescents with leukemia are potentially at a high risk of developing vitamin D def... more Children and adolescents with leukemia are potentially at a high risk of developing vitamin D deficiency, due to limited physical activity and sunlight exposure, poor nutrition, chemotherapy, and its complications. The prevalence of vitamin D inadequacy in European pediatric cancer patients has been reported to be high. It is not known how many patients already have vitamin D deficiency at the time of diagnosis and whether vitamin D status at the time of diagnosis influences clinical outcome. We aimed to investigate vitamin D status in children with leukemia at the time of diagnosis and explore possible factors (age, type of leukemia, gender, year and season of sampling) contributing to a low level of 25-hydroxyvitamin D (25-OHD). Furthermore, we aimed to investigate if vitamin D status at the time of diagnosis influences overall survival. We carried out a cross-sectional study including all 295 children (169 boys, 57.3%) aged <18 years who were diagnosed with leukemia in our ins...
Blood
4032 Introduction: T cells expressing tumor-targeting chimeric antigen receptors are showing prom... more 4032 Introduction: T cells expressing tumor-targeting chimeric antigen receptors are showing promise in clinical trials for patients with B cell leukemia and lymphoma. However, increased levels of anti-apoptotic proteins, a common trait among B-cell tumors, may hamper treatment efficacy. ABT-737 is a small molecule inhibitor of anti-apoptotic proteins such as BCL-2, BCL-xL, BCL-w, and MCL-1, which induces apoptosis via the intrinsic apoptosis pathway in contrast to T-cells that utilize the extrinsic pathway controlled by death receptors and their ligands. ABT-737 has been shown to efficiently promote apoptosis in B-cell tumors as exemplified in models of pre-B-ALL. Recently, ABT-737 was shown to synergize with TRAIL to induce apoptosis. This prompted us to investigate if ABT-737 could be combined with T-cell therapy to enhance tumor cell death. Methods: PBMCs from healthy donors and patients with pre-B-ALL was genetically engineered with a second generation chimeric antigen receptor...
Journal of Neuro-Oncology
Introduction Pilocytic astrocytoma is the most common brain tumour in childhood but knowledge con... more Introduction Pilocytic astrocytoma is the most common brain tumour in childhood but knowledge concerning its long-term outcome is sparse. The aim of the study was to investigate if children treated for low-grade pilocytic astrocytoma in the posterior fossa had complications affecting physical and psychological health, cognitive functions, learning difficulties and HRQoL. Methods A descriptive single-centre study, where 22 children and young adults out of 27 eligible patients (81%) treated for pilocytic astrocytoma, with a mean follow-up time of 12.4 years (5-19 years) participated (14 adults, two by telephone interviews and eight children). The study included a review of medical records, an interview, neurological investigation, screening tools for psychiatric symptoms (Beck Depression and Anxiety Inventories and Beck Youth Inventory Scales) and HRQoL measures (RAND-36). Results Motor complications were most common, reported in 12 patients and mainly affecting fine-motor skills. Seven patients reported cognitive difficulties affecting performance in school. Educational support was given in the period immediately after treatment but not after primary school. None had elevated levels of psychiatric symptoms and the level of HRQoL as well as their psychosocial and educational situation was in correspondence with Swedish norms. The HRQoL score for vitality (VT) almost reached statistical significance. Conclusions The long-term functional outcome for children treated for low-grade astrocytoma is favourable. However, some patients report neurological complications and learning difficulties, which are unmet in school. Therefore, there is a need to identify those who need more thorough medical and cognitive follow-up programmes including interventions in school.
American Journal of Transplantation
Per Frisk 1 Abbreviations: ALL, acute lymphoblastic leukemia; BMI, body mass index; cGVHD, chroni... more Per Frisk 1 Abbreviations: ALL, acute lymphoblastic leukemia; BMI, body mass index; cGVHD, chronic graft-vs-host disease; DLco, diffusing capacity of the lung for carbon monoxide; E/A, ratio between the E-wave and the A-wave from the flow profile of the mitral valve; FEV 1 , forced expiratory volume in 1 second; FFM, fat-free mass; GH, growth hormone; GH peak , peak value of spontaneous growth hormone secretion; GVHD, graft-vs-host disease; HCT, hematopoietic cell transplantation; LBL, lymphoblastic lymphoma; LV-FS, fractional shortening of the left ventricle; MAPSE, mitral annular plane systolic excursion; TAPSE, tricuspid annular plane systolic excursion; TBI, total body irradiation; TLC, total lung capacity; W peak , peak workload; W peak% , percentage of predicted peak workload.
Pediatric Transplantation
Severe aGvHD is a life-threatening complication after allogeneic HSCT. The GI tract is considered... more Severe aGvHD is a life-threatening complication after allogeneic HSCT. The GI tract is considered to play a key role in aGvHD, where the disease process can start and is one of the major target organs. Here, we present a case of a one-year-old child with a life-threatening GI-aGvHD stage IV, post-HSCT, resistant to steroids and MMF for 4 weeks. He was successfully treated with placenta-derived DSC.
Acta Paediat, 2007
To describe spontaneous cortisol secretion in children after autologous bone marrow transplantati... more To describe spontaneous cortisol secretion in children after autologous bone marrow transplantation (BMT) for acute leukaemia and lymphoma. Spontaneous cortisol secretion was analysed in 39 children before and after BMT. Thirteen patients were conditioned with chemotherapy only (group 1), and 26 patients also with total body irradiation (TBI). In the TBI group, 14 patients had received no additional irradiation (group 2), whereas 12 patients had received cranial irradiation (CRT) previously (group 3). Before BMT, in comparison with group 1, mean morning cortisol was significantly lower in group 2 (252 vs 415 mmol/l, p = 0.004), but not in group 3 (vs 312 mmol/l, p = 0.12). There was no change in group 1 six months after BMT (to 379 nmol/l), whereas morning cortisol increased significantly in group 2 and group 3 (to 386 and 343 nmol/l, respectively; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). The change in mean morning cortisol correlated negatively with pretransplant morning cortisol (r = -0.63, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Neither TBI nor CRT were associated with changes in morning cortisol. Spontaneous cortisol secretion is maintained after BMT irrespective of whether cranial or total body irradiation has been given or not.
Pediatric blood & cancer, 2012
Impairment of pulmonary function after stem cell transplantation (SCT) in childhood has been repo... more Impairment of pulmonary function after stem cell transplantation (SCT) in childhood has been reported before. However, long-term longitudinal studies are scarce. We measured lung volumes and performed dynamic spirometry serially in 18 patients after SCT. At the last investigation, a median of 18.2 years after SCT, the patients were compared with 18 matched controls. The diffusing capacity (DLCO) was only compared cross-sectionally. There was a significant increase in the prevalence of restrictive lung disease (RLD, total lung capacity <80% of that predicted) from 7% (1/14) before SCT to 28% (5/18) 5 years after SCT, and 61% (11/18) a median of 18.2 years after SCT (P = 0.002). In comparison, none of the controls had RLD (61% vs. 0%, P = 0.001). Before SCT, no patient had obstructive lung disease (OLD, forced expiratory volume in 1 sec/vital capacity <70). OLD was found in one of 18 patients (6%) 5 years after SCT but in none of the patients a median of 18.2 years after SCT. Th...
Läkartidningen, Jan 27, 2002
Bone marrow transplantation (BMT) is an established treatment of hematological malignancies in ch... more Bone marrow transplantation (BMT) is an established treatment of hematological malignancies in children. With a rapidly increasing number of long-term survivors, more attention is focused on late sequelae to this therapy. Several cataractogenic factors are involved in BMT, such as ionizing irradiation, corticosteroid treatment, and chemotherapeutic agents. Lens opacity is therefore a potential late side-effect of BMT. The incidence and degree of cataract in 29 children who had undergone autologous or syngeneic BMT were recorded. Median follow-up was eight years (4-10 years). 21 children had received total body irradiation prior to BMT; they all developed cataract of the posterior subcapsular type after three years (median). Six children needed surgical repair in the form of intraocular lens implantation after extracapsular cataract extraction.
Pediatric Transplantation, 2012
We measured risk factors for CVD in 18 patients at a median of 18.2 yr after SCT and in sex and a... more We measured risk factors for CVD in 18 patients at a median of 18.2 yr after SCT and in sex and age-matched controls. Three patients (17%), but none of the controls, met the criteria for the MetS (p = 0.25). In the patients, we found higher levels of triglycerides (0.94 vs. 0.62 mm, p = 0.019), total cholesterol (5.1 vs. 4.0 mm, p = 0.017), LDL (3.4 vs. 2.6 mm, p = 0.019), apolipoprotein B (1.04 vs. 0.74 g/L, p = 0.004), apolipoprotein B/A1 ratio (0.7 vs. 0.5, p = 0.026), and lower levels of adiponectin (4.9 vs. 7.5 mg/L, p = 0.008) than in the controls. The patients had a lower GHmax (9 vs. 20.7 mU/L, p = 0.002). GHmax was significantly correlated inversely with triglycerides (r = -0.64, p = 0.008), total cholesterol (r = -0.61, p = 0.011), apolipoprotein B (r = -0.60, p = 0.014), and apolipoprotein B/A1 ratio (r = -0.66, p = 0.005). We recorded a significantly thicker carotid intima layer among the patients than among matched controls (0.15 vs. 0.13 mm, p = 0.034). The level of adiponectin correlated inversely with carotid intima thickness (r = -0.55, p = 0.023). After SCT in childhood, long-term survivors may be at risk of developing premature CVD.
Pediatric Transplantation, 2007
Pediatric Nephrology, 2010
We evaluated renal function at a median follow-up of 18 (range 10.3-22.1) years after total body ... more We evaluated renal function at a median follow-up of 18 (range 10.3-22.1) years after total body irradiation in 18 patients treated with stem-cell transplantation (SCT) (autologous SCT in 15 and allogeneic SCT in three) for hematologic malignancies and compared them with 18 healthy controls. No patient had chronic graft-versus-host disease. We found no difference in glomerular filtration rate estimated from cystatin C (105 vs 111 ml/min/1.73 m(2), p = 0.28). Patients had higher albumin excretion (0.8 vs 0.4 mg/mmol, p = 0.001), but no patient had overt albuminuria (&amp;amp;amp;amp;amp;amp;amp;gt;200 mg/L). Patients had higher diastolic blood pressure (74 vs 67 mmHg, p = 0.003). Two patients (11%) had hypertension. Patients had lower tubular reabsorption of phosphate (0.78 vs 0.91 mmol/L, p = 0.014) and higher excretion of alpha-1-microglobulin (AMG/urine creatinine, 0.4 vs 0.25 mg/mmol, p = 0.038), which correlated with time after SCT (r = 0.6, p = 0.01). We found no difference in fractional excretion (FE) of other electrolytes, amino acid excretion, or urine osmolality. We conclude that renal function was relatively well preserved at a median follow-up of 18 years after childhood SCT. The higher albumin excretion in our patients is of concern, as is the association between excretion of AMG and time after SCT, suggesting that both glomerular and tubular function may deteriorate further.
Pediatric Blood & Cancer, 2013
Chronic health conditions are known to be both abundant and severe after pediatric hematopoietic ... more Chronic health conditions are known to be both abundant and severe after pediatric hematopoietic stem cell transplantation (SCT). The present objective was to investigate the impact of disease and treatment on individual QoL and health-related quality of life (HRQoL) in long-term survivors of childhood lymphoblastic malignancy treated with conventional therapy versus SCT. Survivors of lymphoblastic malignancy treated with (n = 18) or without (n = 52) SCT were recruited a median follow-up time of 18 and 14 years, respectively. The indication for SCT was relapsed disease in 17 of 18 cases. Autologous stem cells were used in 15 cases. Total body irradiation (TBI) was included in the conditioning regimen for all SCT patients. A cross-sectional study was conducted using two validated instruments: SEIQoL-DW (individual QoL) and SF-36 (HRQoL). Content analysis was used to analyze SEIQoL-DW and an overall QoL index score was calculated. Two multiple linear regression analyses were performed to detect factors influencing outcomes. Poorer ratings of overall QoL and more negative consequences related to physical dysfunctions were shown in the SCT group. The findings indicate that being unemployed or on sick leave are associated with a decline in HRQoL and individual QoL rather than SCT, cranial radiation therapy, present age, or sex. In this small sample of long-term survivors of SCT, QoL seems reasonably good and similar to that of those having received conventional therapy. However, managing an employment must be acknowledged as an important part of life that has a great impact on QoL.
Medical and Pediatric Oncology, 2001
Ifosfamide is successfully employed in the treatment of bone and soft tissue sarcomas in children... more Ifosfamide is successfully employed in the treatment of bone and soft tissue sarcomas in children and young adults. Used at high doses (HDI) the drug may cause severe multiorgan toxicity. Peripheral neuropathy is a less well-known side effect that may limit its use. We describe a 16-year-old girl with a Ewing sarcoma who was given post-operative treatment with HDI (15 mg/m(2) infused over 5 days). After the second course she experienced paresthesias in both feet. After the third course she developed signs of severe toxicity in the CNS, kidneys, heart, and severe pain in her feet. Neurologic and neurophysiologic investigations, including neurographic studies of motor and sensory nerves, EMG, and thermotest, were performed in the acute phase and after 6 and 21 months, respectively. Renal and cardiac function was also assessed. She developed generalized weakness of the arms and legs and an extremely painful hyperesthesia of the soles. The symptoms improved gradually during follow-up but remained to some extent even after more than 2 years. Serial neurophysiologic investigations indicated classical signs of axonal neuropathy, which tended to improve during follow-up. After 18 months the glomerular filtration rate and the effective renal plasma flow were 30 and 12% of normal, respectively, while other organ functions had returned to baseline. Symptoms of peripheral neuropathy after HDI may herald severe multiorgan toxicity, if continued. Early administration of anesthetics through the intrathecal route should be considered in case of ifosfamide-induced painful peripheral neuropathy.
Immunology, 2011
Cytotoxic CD4 + T cells have been found in patients with chronic lymphocytic leukaemia (CLL) and ... more Cytotoxic CD4 + T cells have been found in patients with chronic lymphocytic leukaemia (CLL) and seem to be involved in the regulation of malignant B cells. The CD4 + T regulatory cells (Tregs) can regulate various immune cells, including B cells, by inducing their apoptosis. Hence, different subgroups of CD4 + T cells may be involved in the regulation of malignant B cells. In this study, the cytotoxic phenotype and function of various CD4 + T-cell subgroups were investigated in patients with B-cell malignancies. Peripheral blood was collected from patients with CLL, various B-cell lymphomas, healthy adult donors, children with precursor B-cell acute lymphoblastic leukaemia (pre-B ALL) and from healthy children. CD4 + T cells (CD3 + CD4 + FoxP3)), Tregs (CD3 + CD4 + CD127 low FoxP3 +) and CD127 high FoxP3 + T cells (CD3 + CD4 + CD127 high FoxP3 +) were analysed for their expression of the cytolytic markers CD107a and Fas ligand. Patients with CLL had increased CD107a expression on all tested T-cell subgroups compared with healthy donors. Similar results were found in patients with B-cell lymphomas whereas the CD107a expression in children with pre-B ALL was no different from that in healthy controls. Fas ligand expression was similar between patient cells and cells of healthy donors. CD4 + T cells and Tregs from patients with CLL and healthy donors were subsequently purified and cultured in vitro with autologous B cells. Both subgroups lysed B cells and killing was confirmed by granzyme ELISAs. In conclusion, cytotoxic populations of CD4 + T cells, including Tregs, are present in patients with B-cell malignancy and may be an important factor in immune-related disease control.
Journal of Medical Genetics
BackgroundCongenital dyserythropoietic anaemia type I (CDA-I) is a hereditary anaemia caused by b... more BackgroundCongenital dyserythropoietic anaemia type I (CDA-I) is a hereditary anaemia caused by biallelic mutations in the widely expressed genes CDAN1 and C15orf41. Little is understood about either protein and it is unclear in which cellular pathways they participate.MethodsGenetic analysis of a cohort of patients with CDA-I identifies novel pathogenic variants in both known causative genes. We analyse the mutation distribution and the predicted structural positioning of amino acids affected in Codanin-1, the protein encoded by CDAN1. Using western blotting, immunoprecipitation and immunofluorescence, we determine the effect of particular mutations on both proteins and interrogate protein interaction, stability and subcellular localisation.ResultsWe identify six novel CDAN1 mutations and one novel mutation in C15orf41 and uncover evidence of further genetic heterogeneity in CDA-I. Additionally, population genetics suggests that CDA-I is more common than currently predicted. Mutati...
Blood
Introduction:Acute graft-versus-host disease (aGVHD) can develop into a life-threatening complica... more Introduction:Acute graft-versus-host disease (aGVHD) can develop into a life-threatening complication after allogeneic hematopoietic cell transplantation (HSCT). The gastrointestinal (GI) tract is considered to play a key role in the pathophysiology of aGVHD, where the disease-process can start and be one of the target organs.The clinical presentation of acute aGVHD in the lower GI tract includes secretory diarrheas, sometimes bloody stools, abdominal pain with or without paralytic ileus. In the upper GI, symptoms such as nausea, anorexia, vomiting and weight loss are common. First-line therapy for aGVHD includes steroids at doses of 1-2 mg/kg /day. Approximately 50-60 % of the patients with aGI-GVHD fail to respond to steroids and their outcomes are very poor with a long-term mortality between 70-90 %. Bone marrow derived mesenchymal stromal cells (BM-MSCs) were introduced as a novel cell-based therapy by us for aGVHD a few decades ago, but not all patients responded, and many pati...
Blood
Children and adolescents with leukemia are potentially at a high risk of developing vitamin D def... more Children and adolescents with leukemia are potentially at a high risk of developing vitamin D deficiency, due to limited physical activity and sunlight exposure, poor nutrition, chemotherapy, and its complications. The prevalence of vitamin D inadequacy in European pediatric cancer patients has been reported to be high. It is not known how many patients already have vitamin D deficiency at the time of diagnosis and whether vitamin D status at the time of diagnosis influences clinical outcome. We aimed to investigate vitamin D status in children with leukemia at the time of diagnosis and explore possible factors (age, type of leukemia, gender, year and season of sampling) contributing to a low level of 25-hydroxyvitamin D (25-OHD). Furthermore, we aimed to investigate if vitamin D status at the time of diagnosis influences overall survival. We carried out a cross-sectional study including all 295 children (169 boys, 57.3%) aged <18 years who were diagnosed with leukemia in our ins...
Blood
4032 Introduction: T cells expressing tumor-targeting chimeric antigen receptors are showing prom... more 4032 Introduction: T cells expressing tumor-targeting chimeric antigen receptors are showing promise in clinical trials for patients with B cell leukemia and lymphoma. However, increased levels of anti-apoptotic proteins, a common trait among B-cell tumors, may hamper treatment efficacy. ABT-737 is a small molecule inhibitor of anti-apoptotic proteins such as BCL-2, BCL-xL, BCL-w, and MCL-1, which induces apoptosis via the intrinsic apoptosis pathway in contrast to T-cells that utilize the extrinsic pathway controlled by death receptors and their ligands. ABT-737 has been shown to efficiently promote apoptosis in B-cell tumors as exemplified in models of pre-B-ALL. Recently, ABT-737 was shown to synergize with TRAIL to induce apoptosis. This prompted us to investigate if ABT-737 could be combined with T-cell therapy to enhance tumor cell death. Methods: PBMCs from healthy donors and patients with pre-B-ALL was genetically engineered with a second generation chimeric antigen receptor...
Journal of Neuro-Oncology
Introduction Pilocytic astrocytoma is the most common brain tumour in childhood but knowledge con... more Introduction Pilocytic astrocytoma is the most common brain tumour in childhood but knowledge concerning its long-term outcome is sparse. The aim of the study was to investigate if children treated for low-grade pilocytic astrocytoma in the posterior fossa had complications affecting physical and psychological health, cognitive functions, learning difficulties and HRQoL. Methods A descriptive single-centre study, where 22 children and young adults out of 27 eligible patients (81%) treated for pilocytic astrocytoma, with a mean follow-up time of 12.4 years (5-19 years) participated (14 adults, two by telephone interviews and eight children). The study included a review of medical records, an interview, neurological investigation, screening tools for psychiatric symptoms (Beck Depression and Anxiety Inventories and Beck Youth Inventory Scales) and HRQoL measures (RAND-36). Results Motor complications were most common, reported in 12 patients and mainly affecting fine-motor skills. Seven patients reported cognitive difficulties affecting performance in school. Educational support was given in the period immediately after treatment but not after primary school. None had elevated levels of psychiatric symptoms and the level of HRQoL as well as their psychosocial and educational situation was in correspondence with Swedish norms. The HRQoL score for vitality (VT) almost reached statistical significance. Conclusions The long-term functional outcome for children treated for low-grade astrocytoma is favourable. However, some patients report neurological complications and learning difficulties, which are unmet in school. Therefore, there is a need to identify those who need more thorough medical and cognitive follow-up programmes including interventions in school.
American Journal of Transplantation
Per Frisk 1 Abbreviations: ALL, acute lymphoblastic leukemia; BMI, body mass index; cGVHD, chroni... more Per Frisk 1 Abbreviations: ALL, acute lymphoblastic leukemia; BMI, body mass index; cGVHD, chronic graft-vs-host disease; DLco, diffusing capacity of the lung for carbon monoxide; E/A, ratio between the E-wave and the A-wave from the flow profile of the mitral valve; FEV 1 , forced expiratory volume in 1 second; FFM, fat-free mass; GH, growth hormone; GH peak , peak value of spontaneous growth hormone secretion; GVHD, graft-vs-host disease; HCT, hematopoietic cell transplantation; LBL, lymphoblastic lymphoma; LV-FS, fractional shortening of the left ventricle; MAPSE, mitral annular plane systolic excursion; TAPSE, tricuspid annular plane systolic excursion; TBI, total body irradiation; TLC, total lung capacity; W peak , peak workload; W peak% , percentage of predicted peak workload.
Pediatric Transplantation
Severe aGvHD is a life-threatening complication after allogeneic HSCT. The GI tract is considered... more Severe aGvHD is a life-threatening complication after allogeneic HSCT. The GI tract is considered to play a key role in aGvHD, where the disease process can start and is one of the major target organs. Here, we present a case of a one-year-old child with a life-threatening GI-aGvHD stage IV, post-HSCT, resistant to steroids and MMF for 4 weeks. He was successfully treated with placenta-derived DSC.
Acta Paediat, 2007
To describe spontaneous cortisol secretion in children after autologous bone marrow transplantati... more To describe spontaneous cortisol secretion in children after autologous bone marrow transplantation (BMT) for acute leukaemia and lymphoma. Spontaneous cortisol secretion was analysed in 39 children before and after BMT. Thirteen patients were conditioned with chemotherapy only (group 1), and 26 patients also with total body irradiation (TBI). In the TBI group, 14 patients had received no additional irradiation (group 2), whereas 12 patients had received cranial irradiation (CRT) previously (group 3). Before BMT, in comparison with group 1, mean morning cortisol was significantly lower in group 2 (252 vs 415 mmol/l, p = 0.004), but not in group 3 (vs 312 mmol/l, p = 0.12). There was no change in group 1 six months after BMT (to 379 nmol/l), whereas morning cortisol increased significantly in group 2 and group 3 (to 386 and 343 nmol/l, respectively; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). The change in mean morning cortisol correlated negatively with pretransplant morning cortisol (r = -0.63, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Neither TBI nor CRT were associated with changes in morning cortisol. Spontaneous cortisol secretion is maintained after BMT irrespective of whether cranial or total body irradiation has been given or not.
Pediatric blood & cancer, 2012
Impairment of pulmonary function after stem cell transplantation (SCT) in childhood has been repo... more Impairment of pulmonary function after stem cell transplantation (SCT) in childhood has been reported before. However, long-term longitudinal studies are scarce. We measured lung volumes and performed dynamic spirometry serially in 18 patients after SCT. At the last investigation, a median of 18.2 years after SCT, the patients were compared with 18 matched controls. The diffusing capacity (DLCO) was only compared cross-sectionally. There was a significant increase in the prevalence of restrictive lung disease (RLD, total lung capacity <80% of that predicted) from 7% (1/14) before SCT to 28% (5/18) 5 years after SCT, and 61% (11/18) a median of 18.2 years after SCT (P = 0.002). In comparison, none of the controls had RLD (61% vs. 0%, P = 0.001). Before SCT, no patient had obstructive lung disease (OLD, forced expiratory volume in 1 sec/vital capacity <70). OLD was found in one of 18 patients (6%) 5 years after SCT but in none of the patients a median of 18.2 years after SCT. Th...
Läkartidningen, Jan 27, 2002
Bone marrow transplantation (BMT) is an established treatment of hematological malignancies in ch... more Bone marrow transplantation (BMT) is an established treatment of hematological malignancies in children. With a rapidly increasing number of long-term survivors, more attention is focused on late sequelae to this therapy. Several cataractogenic factors are involved in BMT, such as ionizing irradiation, corticosteroid treatment, and chemotherapeutic agents. Lens opacity is therefore a potential late side-effect of BMT. The incidence and degree of cataract in 29 children who had undergone autologous or syngeneic BMT were recorded. Median follow-up was eight years (4-10 years). 21 children had received total body irradiation prior to BMT; they all developed cataract of the posterior subcapsular type after three years (median). Six children needed surgical repair in the form of intraocular lens implantation after extracapsular cataract extraction.
Pediatric Transplantation, 2012
We measured risk factors for CVD in 18 patients at a median of 18.2 yr after SCT and in sex and a... more We measured risk factors for CVD in 18 patients at a median of 18.2 yr after SCT and in sex and age-matched controls. Three patients (17%), but none of the controls, met the criteria for the MetS (p = 0.25). In the patients, we found higher levels of triglycerides (0.94 vs. 0.62 mm, p = 0.019), total cholesterol (5.1 vs. 4.0 mm, p = 0.017), LDL (3.4 vs. 2.6 mm, p = 0.019), apolipoprotein B (1.04 vs. 0.74 g/L, p = 0.004), apolipoprotein B/A1 ratio (0.7 vs. 0.5, p = 0.026), and lower levels of adiponectin (4.9 vs. 7.5 mg/L, p = 0.008) than in the controls. The patients had a lower GHmax (9 vs. 20.7 mU/L, p = 0.002). GHmax was significantly correlated inversely with triglycerides (r = -0.64, p = 0.008), total cholesterol (r = -0.61, p = 0.011), apolipoprotein B (r = -0.60, p = 0.014), and apolipoprotein B/A1 ratio (r = -0.66, p = 0.005). We recorded a significantly thicker carotid intima layer among the patients than among matched controls (0.15 vs. 0.13 mm, p = 0.034). The level of adiponectin correlated inversely with carotid intima thickness (r = -0.55, p = 0.023). After SCT in childhood, long-term survivors may be at risk of developing premature CVD.
Pediatric Transplantation, 2007
Pediatric Nephrology, 2010
We evaluated renal function at a median follow-up of 18 (range 10.3-22.1) years after total body ... more We evaluated renal function at a median follow-up of 18 (range 10.3-22.1) years after total body irradiation in 18 patients treated with stem-cell transplantation (SCT) (autologous SCT in 15 and allogeneic SCT in three) for hematologic malignancies and compared them with 18 healthy controls. No patient had chronic graft-versus-host disease. We found no difference in glomerular filtration rate estimated from cystatin C (105 vs 111 ml/min/1.73 m(2), p = 0.28). Patients had higher albumin excretion (0.8 vs 0.4 mg/mmol, p = 0.001), but no patient had overt albuminuria (&amp;amp;amp;amp;amp;amp;amp;gt;200 mg/L). Patients had higher diastolic blood pressure (74 vs 67 mmHg, p = 0.003). Two patients (11%) had hypertension. Patients had lower tubular reabsorption of phosphate (0.78 vs 0.91 mmol/L, p = 0.014) and higher excretion of alpha-1-microglobulin (AMG/urine creatinine, 0.4 vs 0.25 mg/mmol, p = 0.038), which correlated with time after SCT (r = 0.6, p = 0.01). We found no difference in fractional excretion (FE) of other electrolytes, amino acid excretion, or urine osmolality. We conclude that renal function was relatively well preserved at a median follow-up of 18 years after childhood SCT. The higher albumin excretion in our patients is of concern, as is the association between excretion of AMG and time after SCT, suggesting that both glomerular and tubular function may deteriorate further.
Pediatric Blood & Cancer, 2013
Chronic health conditions are known to be both abundant and severe after pediatric hematopoietic ... more Chronic health conditions are known to be both abundant and severe after pediatric hematopoietic stem cell transplantation (SCT). The present objective was to investigate the impact of disease and treatment on individual QoL and health-related quality of life (HRQoL) in long-term survivors of childhood lymphoblastic malignancy treated with conventional therapy versus SCT. Survivors of lymphoblastic malignancy treated with (n = 18) or without (n = 52) SCT were recruited a median follow-up time of 18 and 14 years, respectively. The indication for SCT was relapsed disease in 17 of 18 cases. Autologous stem cells were used in 15 cases. Total body irradiation (TBI) was included in the conditioning regimen for all SCT patients. A cross-sectional study was conducted using two validated instruments: SEIQoL-DW (individual QoL) and SF-36 (HRQoL). Content analysis was used to analyze SEIQoL-DW and an overall QoL index score was calculated. Two multiple linear regression analyses were performed to detect factors influencing outcomes. Poorer ratings of overall QoL and more negative consequences related to physical dysfunctions were shown in the SCT group. The findings indicate that being unemployed or on sick leave are associated with a decline in HRQoL and individual QoL rather than SCT, cranial radiation therapy, present age, or sex. In this small sample of long-term survivors of SCT, QoL seems reasonably good and similar to that of those having received conventional therapy. However, managing an employment must be acknowledged as an important part of life that has a great impact on QoL.
Medical and Pediatric Oncology, 2001
Ifosfamide is successfully employed in the treatment of bone and soft tissue sarcomas in children... more Ifosfamide is successfully employed in the treatment of bone and soft tissue sarcomas in children and young adults. Used at high doses (HDI) the drug may cause severe multiorgan toxicity. Peripheral neuropathy is a less well-known side effect that may limit its use. We describe a 16-year-old girl with a Ewing sarcoma who was given post-operative treatment with HDI (15 mg/m(2) infused over 5 days). After the second course she experienced paresthesias in both feet. After the third course she developed signs of severe toxicity in the CNS, kidneys, heart, and severe pain in her feet. Neurologic and neurophysiologic investigations, including neurographic studies of motor and sensory nerves, EMG, and thermotest, were performed in the acute phase and after 6 and 21 months, respectively. Renal and cardiac function was also assessed. She developed generalized weakness of the arms and legs and an extremely painful hyperesthesia of the soles. The symptoms improved gradually during follow-up but remained to some extent even after more than 2 years. Serial neurophysiologic investigations indicated classical signs of axonal neuropathy, which tended to improve during follow-up. After 18 months the glomerular filtration rate and the effective renal plasma flow were 30 and 12% of normal, respectively, while other organ functions had returned to baseline. Symptoms of peripheral neuropathy after HDI may herald severe multiorgan toxicity, if continued. Early administration of anesthetics through the intrathecal route should be considered in case of ifosfamide-induced painful peripheral neuropathy.
Immunology, 2011
Cytotoxic CD4 + T cells have been found in patients with chronic lymphocytic leukaemia (CLL) and ... more Cytotoxic CD4 + T cells have been found in patients with chronic lymphocytic leukaemia (CLL) and seem to be involved in the regulation of malignant B cells. The CD4 + T regulatory cells (Tregs) can regulate various immune cells, including B cells, by inducing their apoptosis. Hence, different subgroups of CD4 + T cells may be involved in the regulation of malignant B cells. In this study, the cytotoxic phenotype and function of various CD4 + T-cell subgroups were investigated in patients with B-cell malignancies. Peripheral blood was collected from patients with CLL, various B-cell lymphomas, healthy adult donors, children with precursor B-cell acute lymphoblastic leukaemia (pre-B ALL) and from healthy children. CD4 + T cells (CD3 + CD4 + FoxP3)), Tregs (CD3 + CD4 + CD127 low FoxP3 +) and CD127 high FoxP3 + T cells (CD3 + CD4 + CD127 high FoxP3 +) were analysed for their expression of the cytolytic markers CD107a and Fas ligand. Patients with CLL had increased CD107a expression on all tested T-cell subgroups compared with healthy donors. Similar results were found in patients with B-cell lymphomas whereas the CD107a expression in children with pre-B ALL was no different from that in healthy controls. Fas ligand expression was similar between patient cells and cells of healthy donors. CD4 + T cells and Tregs from patients with CLL and healthy donors were subsequently purified and cultured in vitro with autologous B cells. Both subgroups lysed B cells and killing was confirmed by granzyme ELISAs. In conclusion, cytotoxic populations of CD4 + T cells, including Tregs, are present in patients with B-cell malignancy and may be an important factor in immune-related disease control.