Fatigue in young survivors of extracranial childhood cancer: a Finnish nationwide survey.

PURPOSE/OBJECTIVES: To evaluate self-reports of fatigue by young cancer survivors (aged 11-18 years), to compare young survivors' fatigue scores with the scores of a healthy control group and of the parent proxy evaluation, and to analyze whether demographic or disease-related factors are associated with young survivors' fatigue. DESIGN: Cross-sectional quantitative study. SETTING: An urban hospital in southwestern Finland. SAMPLE: 384 survivors diagnosed with an extracranial malignancy at age 16 or younger, who have survived four or more years postdiagnosis, and who are free of cancer. General matched population controls were randomly selected from the Finnish Population Registry. METHODS: Demographic data and a self-report written fatigue questionnaire. MAIN RESEARCH VARIABLES: Total fatigue (TF), general fatigue (GF), sleep or rest fatigue (SF), and cognitive fatigue. FINDINGS: The control populations reported significantly more issues with TF, GF, and SF than did the survivor population. In survivors, older age, the need for remedial education at school, and a sarcoma diagnosis were associated with increasing fatigue, whereas female gender, better school grades, and greater health-related quality-of-life (HRQOL) scores were associated with lower fatigue. The study variables explained 49%-65% of the variation in fatigue scores. CONCLUSIONS: Although survivors and their matched controls seem to have similar fatigue, subgroups of survivors do experience excessive fatigue, which may have an impact on their HRQOL. IMPLICATIONS FOR NURSING: This study increases the knowledge about fatigue levels of young survivors of extracranial malignancies and identifies the need for instruments specifically designed to assess fatigue in this population. The healthcare team should pay attention to the fatigue level of young survivors, particularly SF.

Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D.

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3'-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies.

Self-reported health-related quality of life of children and adolescent survivors of extracranial childhood malignancies: a Finnish nationwide survey.

PURPOSE: The purpose of this Finnish total cohort survey was to assess and compare the self-reported health-related quality of life (HRQL) in childhood cancer survivors to that of matched controls, to analyse demographic and disease-related factors explaining survivors' HRQL, and to compare the results of two different HRQL instruments, 16D/17D and PedsQL™. METHODS: Questionnaires were mailed to 384 childhood cancer survivors and their randomly selected gender-, age- and living place-matched controls. Eligible survivors (aged 11-18 years) had been treated for extracranial malignancies ≤16 years of age, had survived ≥4 years after the diagnosis, and were currently free of cancer. RESULTS: Of them, 203 (52.9%) survivors and 266 (30.4%) controls replied. Survivors reported higher HRQL than their controls. Diagnostic group, additional non-cancer diagnosis, need of remedial education, and self-rated unhappiness correlated significantly with HRQL. The survivors of Wilms tumor, or neuroblastoma, had lower HRQL scores than the reference group (leukemia). The studied variables explained only 28% of the variation in HRQL scores among survivors. Instrument correlations were moderate (R = 0.40-0.65). CONCLUSIONS: Our findings suggest that the diagnosis of Wilms tumor or neuroblastoma may carry substantial risks for lower HRQL. The available background variables, however, explained less than one-third of the variation in the HRQL scores. Thus, other factors than demographic or cancer-related seem to play a significant role as determinants of HRQL.

Auditory event related potentials as tools to reveal cognitive late effects in childhood cancer patients.

OBJECTIVE: The purpose of this study was to analyze event related potentials mismatch negativity (MMN) and P3a in childhood cancer patients at the time of diagnosis (Study 1) and after treatment (Study 2) to evaluate their clinical usefulness in screening potential treatment-related neurotoxicity. METHODS: The MMN and P3a to phonetic stimuli were examined in 27 childhood cancer patients with age- and sex-matched controls. Neuropsychological tests were also studied. RESULTS: The MMN peak amplitude was attenuated in the patient group at Study 1. Between the studies, poorer enhancement of the MMN peak amplitude correlated with deterioration in the Verbal intelligence quotient (IQ) in leukaemia patients. In addition, prolongation of the MMN peak latency correlated significantly with deterioration in the Full Scale and Performance IQ in the patient group. Deterioration in the Arithmetic subtest and Performance IQ correlated negatively with the age at diagnosis. CONCLUSIONS: The MMN changes between the studies associated with deterioration in the neuropsychological tests indicating that the method could be clinically useful. The performance of the younger patients was more likely to deteriorate during the treatment. SIGNIFICANCE: Changes in the MMN response during cancer treatment seem to be of clinical importance as indicates of the cognitive outcome of childhood cancer patients.

Cancer related factors do not explain the quality of life scores for childhood cancer survivors analysed with two different generic HRQL instruments.

THE AIMS: The aims of this Finnish total cohort survey were to compare the health related quality of life (HRQL) of childhood cancer survivors with for age, gender and place of residence matched controls, to analyse whether the disease-related factors do explain the survivors scores, and to evaluate the similarity of HRQL scores gained with two different generic instruments. METHODS: Questionnaires (SF-36 version 2 and the 15D) were mailed to 468 survivors and their controls. RESULTS: A total of 271 survivors and 329 controls replied. The survivors rated with both instruments their HRQL in most areas as high or higher than their controls. Mobility score was, however, significantly lower for survivors than controls. Females rated their HRQL lower than respective males. Self-rated happiness had the highest effect in explaining the variation of 15D and mental component summary (MCS) scores. Survivors treated for osteosarcoma or with stem cell transplantation (SCT) rated their physical HRQL significantly lower than the others. SCT treatment indicated significantly lower MCS scores than the reference treatment. Correlation between the physical component summary (PCS) scores and 15D total scores was low (R=0.20-0.28). MCS and 15D total scores correlated (R=0.48-0.60) better with each other, but the gained correlation coefficients still differed significantly from each other (p=0.04) and showed better correlation in the controls. CONCLUSIONS: Our findings suggest, that the diagnosis of osteosarcoma, and SCT treatment are substantial risks for adverse HRQL. However, disease related factors did not remarkably explain the variation of HRQL scores gained with generic HRQL instruments. Our findings suggest, that the diagnosis of osteosarcoma, and SCT treatment are substantial risks for adverse HRQL. More evaluation is needed in order to decide whether any of the available generic instruments are feasible for studying HRQL for this special population.

Evaluation of the effects of different transfusion trigger levels during the treatment of childhood acute lymphoblastic leukemia.

Differences in the triggering levels for red blood cell (RBC) and platelet (PLT) transfusions were analyzed in association to the amount and total costs of transfusions and the number of febrile episodes during childhood acute lymphoblastic leukemia (ALL) treatment. Transfusions are given with hemoglobin (Hb) < or =90 to 100 g/L and PLT count < or =20 to 30 x 10(9)/L in Tampere, and with Hb < or =80 g/L and PLT count < or =10 x 10(9)/L in Turku. Median pretransfusion PLT count was 48 x 10(9)/L in Tampere, and 16 x 10(9)/L in Turku. The number and costs of PLT transfusions were 35% higher in Tampere. Median Hb before transfusion was 95 g/L in Tampere, and 77 g/L in Turku. The costs of RBC transfusions were 29% lower in Turku as child units (90 mL) were preferred. The number of RBC transfusions was associated with the treatment protocol (P=0.001), and PLT transfusions with the treatment protocol (P<0.001) and the treatment center (P=0.04). The number of febrile episodes was associated with the treatment protocol (P=0.03), and age at diagnosis (P=0.07). Lower trigger levels did not cause more delays or complications in treatment. Clinical trials are, however, necessary to determine optimal criteria for supportive blood transfusions in childhood cancer patients.

Effect of childhood acute lymphoblastic leukemia therapy on spermatogonia populations and future fertility.

CONTEXT: Isolation of spermatogonial stem cells before potentially sterilizing cancer therapy, followed by transplantation of these cells into the testis after such treatment, may be an effective approach to prevent infertility among prepubertal boys suffering from acute lymphoblastic leukemia (ALL). A key clinical consideration in this context is the timing of biopsy, if collection of spermatogonia could be delayed from diagnosis to the later phase of leukemia treatment, better patient selection could be offered. OBJECTIVE: The objective of the study was to examine the routine testicular biopsy material collected to detect testicular leukemia to evaluate if treatment for leukemia affects numbers and maturation of the spermatogonia during the prepubertal period. DESIGN AND PARTICIPANTS: The study involved 28 testicular biopsies from 23 prepubertal boys treated for ALL. OUTCOME MEASURE: Samples were stained immunohistochemically to evaluate the expression of the spermatogonial markers MAGE 4A, OCT4, CD9, and AP2gamma, and of the Sertoli cell marker WT-1. To relate these findings to gonadal function after sexual maturation, the surviving patients were evaluated as adults. RESULTS: Several MAGE 4A-, CD9-, or OCT4-positive spermatogonia were detected in testicular biopsies after standard risk therapy without cyclophosphamide, whereas their numbers were significantly reduced in six patients receiving high-risk ALL therapy involving cyclophosphamide. No significant alteration in spermatogonial numbers was associated with testicular leukemia. All patients not treated with cyclophosphamide recovered normal testicular function, with normal sperm quality and endocrine function. CONCLUSION: Treatment for childhood leukemia without high-dose cyclophosphamide seldom depletes the spermatogonial stem cell pool totally.

Absence of polysialylated NCAM is an unfavorable prognostic phenotype for advanced stage neuroblastoma.

BACKGROUND: The expression of a neural crest stem cell marker, polysialic acid (polySia), and its main carrier, neural cell adhesion molecule (NCAM), have been detected in some malignant tumors with high metastatic activity and unfavorable prognosis, but the diagnostic and prognostic value of polySia-NCAM in neuroblastoma is unclear. METHODS: A tumor tissue microarray (TMA) of 36 paraffin-embedded neuroblastoma samples was utilized to detect polySia-NCAM expression with a polySia-binding fluorescent fusion protein, and polySia-NCAM expression was compared with clinical stage, age, MYCN amplification status, histology (INPC), and proliferation index (PI). RESULTS: PolySia-NCAM-positive neuroblastoma patients had more often metastases at diagnosis, and polySia-NCAM expression associated with advanced disease (P = 0.047). Most interestingly, absence of polySia-NCAM-expressing tumor cells in TMA samples, however, was a strong unfavorable prognostic factor for overall survival in advanced disease (P = 0.0004), especially when MYCN was not amplified. PolySia-NCAM-expressing bone marrow metastases were easily detected in smears, aspirates and biopsies. CONCLUSION: PolySia-NCAM appears to be a new clinically significant molecular marker in neuroblastoma, hopefully with additional value in neuroblastoma risk stratification.

Respiratory viral infections in children with leukemia.

BACKGROUND: Respiratory viruses occur frequently in the community and are a common cause of fever in children. Data on respiratory viral infections in children with cancer are limited. METHODS: A long-term, prospective, multicenter study was carried out in Finland searching for respiratory viruses in febrile children with leukemia. For this purpose, 138 febrile episodes in 51 children with leukemia were analyzed. Twelve types of respiratory viruses were searched for by viral culture, antigen detection, and polymerase chain reaction tests. RESULTS: Evidence of a respiratory viral infection was found in 61 of 138 febrile episodes (44%), accounting for an incidence of 0.8 (range, 0-2.4) per person year at risk during the treatment of leukemia. The most common viruses detected were rhinovirus (22%), respiratory syncytial virus (11%), human bocavirus (5%), and influenza A virus (4%). Dual viral infections were detected in 12 cases (9%). Half of the children had respiratory symptoms with cough being the most common symptom. Two children developed pneumonia. The mean duration of fever was 2.6 (SD 1.7) days in children with respiratory viral infection and 2.1 (SD 1.3) days in children without evidence of viral infection (P = 0.44). CONCLUSIONS: Respiratory viruses are found commonly during febrile episodes in children with leukemia. The detection of viruses permits the use of available antiviral agents, may explain a poor response to antimicrobial agents, and minimizes the proportion of febrile episodes without possible etiologic agents in children with leukemia.

Hematological parameters in preterm infants from birth to 16 weeks of age with reference to iron balance.

BACKGROUND: The objective of this study was to describe the natural kinetics of serum soluble transferrin receptor (S-TfR), ferritin and reticulocyte indices in preterm neonates, and to find out whether these analytes relate to hematocrit (Hct) level in determining the need for red cell (RBC) transfusions. METHODS: During a 2-year period, 100 preterm neonates were recruited in a tertiary level neonatal intensive care unit. Inclusion criteria were gestational age < or =34 weeks or birth weight <2000 g. Biochemical markers of iron deficiency and hematological indices were serially analyzed from birth. This report focuses on the first 16 weeks after birth. RESULTS: The trends of the studied analytes were presented with reference ranges. RBC transfusions did not have a significant effect on reticulocyte hemoglobin content (CHr) or reticulocyte count. Reticulocytes were lowest after the first week and S-TfR at 9 weeks of age. CHr and fraction of immature reticulocytes were highest at birth and decreased thereafter. CHr and reticulocyte count were significantly different in two groups determined by Hct level (Hct < or > or =0.30). This difference was not observed in S-TfR or ferritin concentrations. CONCLUSIONS: In addition to reflecting the activity of erythropoiesis, S-TfR seems to reflect iron balance in preterm neonates. By using CHr and reticulocyte, it is possible to obtain more information about iron balance in relation to erythropoiesis, and it might be useful to combine this information with Hct before making a decision about a transfusion.

Acute lymphoblastic leukemia in adolescents and young adults in Finland.

BACKGROUND: Interest has recently been paid to adolescents and young adults with acute lymphoblastic leukemia, particularly because all reports so far published indicate that these patients have a better outcome when treated with pediatric rather than adult therapeutic protocols. There are different biological subtypes of acute lymphoblastic leukemia with distinct features and prognoses; the distribution of these subtypes is not well known among adolescents. We, therefore, studied acute lymphoblastic leukemia in adolescents and young adults aged 10 to 25 years in Finland. DESIGN AND METHODS: This population-based study included 225 consecutive patients aged 10-25 years diagnosed with acute lymphoblastic leukemia during 1990-2004. One hundred and twenty-eight patients (10-16 years) were treated with pediatric Nordic (NOPHO) protocols, and 97 patients (17-25 years) with Finnish Leukemia Group National protocols. We characterized the biological subtypes, clinical features and outcome of these patients. RESULTS: For the whole cohort, the remission rate was 96%, 5-year event-free survival 62% and overall survival 72%. The 5-year event-free survival was 67% for the pediatric treatment group and 60% for the adult treatment group (p=n.s.). Patients with inferior outcome were those with a white blood cell count >or= 100 x 10(9)/L, the Philadelphia chromosome and MLL. Good prognostic features were TEL-AML1, hyperdiploidy, and pediatric intermediate risk stratification. CONCLUSIONS: Unlike all previous studies, we found that the outcome of adolescents and young adults with acute lymphoblastic leukemia treated with pediatric or adult therapeutic protocols was comparable. The success of the adult acute lymphoblastic leukemia therapy emphasizes the benefit of central referral of patients to academic centers and adherence to research protocols.

Long-term follow-up of renal function after high-dose methotrexate treatment in children.

BACKGROUND: High-dose methotrexate (HD-MTX) is commonly used in treatment of pediatric leukemias and lymphomas. Transient deterioration in renal function is frequently noted during HD-MTX treatment, but possible long-term changes are less well known. In this study we aimed to study long-term renal prognosis after HD-MTX treatment, and to find possible underlying risk factors for reduced renal function. PROCEDURE: Medical records of pediatric cancer patients treated with HD-MTX were reviewed retrospectively after follow-up of 1-10 years. Renal function before and after chemotherapy was investigated in a total of 28 patients. Assessment of glomerular and tubular function was prospectively evaluated in each case. Glomerular function was evaluated by either (51)Cr-EDTA or (99m)Tc-DTPA clearance methods, and by urinary albumin excretion. Tubular function was assessed by measuring blood electrolyte levels and urinary alpha(1)- or beta(2)-microglobulin. RESULTS: A decrease in glomerular filtration rate (GFR) was statistically significant as follow-up time increased (P = 0.02). Age at the time of diagnosis and exposure to potentially nephrotoxic antibiotics during cancer treatment had no influence on GFR. However, albuminuria was observed more often in patients treated with amphotericin B or gentamycin (P = 0.04). No changes in tubular function were observed. CONCLUSIONS: Our results show that HD-MTX treatment significantly decreases GFR and may cause albuminuria in pediatric cancer patients several years after treatment. Long-term renal follow-up of these patients is therefore important.

Opinions on childhood cancer care and degree of agreement between patient/mother and mother/father pairs.

During the past decades in Finland and internationally, numerous improvements have been made to relieve the inconveniencies faced by patients and their parents during childhood cancer treatment. The aim of this study was to find out which issues are rated differently by patients and proxies and also by mothers and fathers. The results may, in the future, guide us in planning the assessments aimed to be used near the time of treatment. In a cross-sectional setting, queries were performed from 3 to 48 months after diagnosis, and a questionnaire with visual analog scales was used. The issues in relation to disease, treatment, and social network were assessed. There were 99 families responding, which was 67% of all eligible families. An analysis of observer agreement of categorical assessments was performed between mother and father in 61 families, and between mother and school-aged patient in 34 families. Changes in appearance, influence of isolation, missing school, and treatment-related procedures such as venous punctures were rated more unpleasant/worrisome by school-aged patients than parents. Thus, these issues cannot be assessed reliably by proxies. Child's social relations, acute side effects of treatment, and perceived support and also adequacy of information from hospital team were quite reliably assessed by proxies. The influences of pain and procedures under anesthesia were, however, overestimated by the proxies. The concerns about acute symptoms, possibilities of recovery, and especially late effects did not seem to be an issue affecting the patients' well-being. However, these items did significantly bother the minds of the parents, especially mothers, and may thus have an indirect influence on the patients' life as well. The minor differences between the ratings of fathers and mothers could mainly be explained by mothers' major role as caregivers and fathers' role as breadwinners of the family. However, as fathers may be less involved in hospital-related issues, they also may miss some information and support provided by the hospital team.

Comparison of glomerular function tests in children with cancer.

Evaluation of renal function should be performed as part of the follow-up during and after chemotherapy in pediatric cancer patients. The aim of this study was to compare an isotope clearance method [isotope glomerular filtration rate (iGFR)] with alternative methods to determine GFR in such patients. Isotope GFR [(99m)Tc-labeled diethylene triaminopentoacetic acid (DTPA) or (51)Cr-labeled ethylenediaminetetra-acetate (EDTA)] was measured in 36 children (112 studies) and compared with simultaneously measured creatinine clearance (CrCl), serum creatinine (SCr), and cystatin C (CysC) concentrations, as well as the results of Schwartz, Counahan-Barratt, and Cockroft-Gault formulae, using general linear mixed models. Our results showed a significant association between iGFR and CysC concentrations (p < 0.001). No linear relationship was observed between CrCl and iGFR (p = 0.7). As expected, the results of height-based formulae (Counahan-Barratt and Schwartz) had significantly (p = 0.004) better correlation to iGFR than the results of a formula based on weight (Cockroft-Gault) (p = 0.19). Despite significant linear correlation, intraclass correlation coefficients showed poor agreement. Tests of similarity between iGFR estimates showed differences between average values of GFR. Therefore, determination of iGFR remains the method of choice in estimation of GFR in cancer patients. In our study population, assay of serum CysC was the most reliable alternative method to measure glomerular function.

Wilms tumour gene 1 overexpression in bone marrow as a marker for minimal residual disease in acute myeloid leukaemia.

OBJECTIVES: Wilms tumour gene 1 (WT1) is overexpressed in leucocytes of most acute myeloid leukaemia (AML) patients. However, the clinical relevance of WT1 gene expression as minimal residual disease (MRD) marker in AML has been questioned. METHODS: We determined the expression of WT1 gene in bone marrow (BM) mononuclear cells of 100 AML patients at diagnosis and compared it with other MRD markers during follow up in 16 patients using quantitative reverse transcription-polymerase chain reaction. RESULTS: The median WT1 gene expression was 9.7% of K562 cell line WT1 expression (lower quartile 1.5%, upper quartile 29.9%, n = 100) at diagnosis and, 0.053% (lower quartile 0.022%, upper quartile 0.125%, n = 87) in molecular or immunophenotypic remission. Median WT1 expression in control BM was 0.029% (lower quartile 0.013%, upper quartile 0.061%, n = 22). The upper 99% percentile of remission samples was 0.3%, which was regarded as the cut-off of increased WT1 gene expression in AML and was exceeded in 87% of all AML patients at diagnosis. WT1 and the other MRD markers showed only minor differences in profiles during follow-up. WT1 expression at diagnosis with median value 9.7% as the cut-off level or as a continuous variable had no prognostic significance for 2-yr survival. CONCLUSIONS: The sensitivity of WT1 as a MRD marker was low due to the relatively high background WT1 gene expression in BM cells at remission and in subjects without haematological malignancies. Therefore, WT1 gene expression analysis would be beneficial only in those patients who do not have a more specific and sensitive MRD marker.

Hypothyroidism among pediatric cancer patients: a nationwide, registry-based study.

The aim of the study was to determine the incidence and prevalence of hypothyroidism (HT) among childhood cancer survivors by means of register linkage. Patients extracted from the Finnish Cancer Registry data base (5,180 patients with cancer diagnosis at the age of 0-15 years, and born after 1970) were linked with thyroxin reimbursement data (Drug Reimbursement Register) and with thyroxin purchase data (prescription database) maintained by the Social Insurance Institution. At the end of follow-up, the prevalence of HT (10,509/100,000) was found to exceed that in the general population (240/100,000) for those aged <35 years. Diagnostic group (p < 0.0001) and gender (p < 0.0025) had significant effect on the risk of developing HT. Males were less prone to the development of HT. Cumulative incidence rate of HT was highest in patients with thyroid cancer (TC), Hodgkin lymphoma, central nervous system (CNS) tumors and neuroblastoma. Except in patients with TC (4.5 months) and CNS tumors (19 months), the median time for the appearance of HT was quite long, varying between 2 and 4.5 years. We consider our results valuable in providing new data for the planning of thyroid function follow-up in different diagnostic groups of childhood cancer survivors.

Human bocavirus in children with acute lymphoblastic leukemia.

A new human parvovirus, human bocavirus, has recently been identified in respiratory secretions, feces and serum. It is associated with lower and most likely also upper respiratory tract infections. Most commonly reported symptoms are cough, rhinorrhea, expiratory wheezing and fever, and the virus is preferentially detected in young children. We report three children with acute lymphoblastic leukemia who had acute febrile episodes with concomitant detection of human bocavirus in their respiratory secretions. One of them had five consecutive febrile episodes during 6 months, all associated with the presence of human bocavirus at varying viral loads, suggesting prolonged shedding or reactivation of the virus.

Mixed bacterial-viral infections in septic children with leukemia.

BACKGROUND: Febrile infections in children with leukemia are common. The occurrence of possible mixed bacterial-viral infections is unknown. METHODS: We searched for viruses in leukemic children with blood culture-positive bacterial infections. The prospective multicenter survey included 156 febrile episodes in 51 children with acute leukemia. The mean follow-up time was 1.5 years per patient (27,743 patient-days at risk). Sixteen viruses were searched for from nasal swab and stool samples using virus culture, virus antigen detection, and polymerase chain reaction tests. RESULTS: Bacterial blood cultures were positive in 19 (11%) febrile episodes among 17 children. In half of the septic episodes (11 of 19), a virus was also found. Rhinovirus and respiratory syncytial virus were the most common viruses detected. CONCLUSIONS: Our findings suggest that invasive bacterial infections are commonly associated with viral infections in children with leukemia.