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Objective First, to estimate the preventive and the curative effects of postmenopausal hormone therapy (PHT) on menopausal symptoms, and secondly to estimate the sensitivity of a woman to identify the exposure to postmenopausal hormone therapy. Design Randomised and blinded trial Setting Postmenopausal Hormone Therapy Trial in Estonia (EPHT), 1999-2002 Participants 593 women who responded to the relevant questions both at the entry and one-year follow-up questionnaires in the blind sub-trial Intervention HT or placebo at entry in women with or without menopausal symptoms Results The participants were asked in the questionnaires the presence of the menopausal symptoms of sweating, hot flushes and sleeping disorders, and at one-year follow-up to identify the exposure (HT or placebo). The net curative effect of HT (the proportion of disappeared symptoms in symptomatic women in the HT arm (46.4%) minus the same proportion in the placebo arm (25.8%) was 20.6%. The net preventive effect of HT (the proportion of incident symptoms in asymptomatic women in the placebo arm, 44.4%, minus the same proportion in the HT arm, 14.3%) was 30.1%. At one-year follow-up 34.6% of the women in the HT arm made a right guess on their arm. The net sensitivity of guessing the HT (right guess on HT minus wrong guess on placebo) was 15.8%. Conclusions The true HT effect on menopausal symptoms was relatively small. The clinical practice may need to further consider the benefit harm ratio of PHT [ISRCTN35338757].

The clinical value of measuring fractional exhaled nitric oxide (FeNO) in asthma is not clear. We aimed to assess whether FeNO can reliably predict clinical outcomes in asthma treated with inhaled corticosteroids (ICS). We also evaluated whether its predictive role is influenced by different inflammatory phenotypes of asthma.We conducted a systematic review focusing on five clinically relevant questions. Two authors independently screened search results, extracted data and assessed quality of the included studies. Data were synthesised by qualitative methods.12 prospective studies were included, answering partly three of the five questions. In steroid-naïve asthma, a high FeNO level probably predicts good response to ICS. In ICS-treated asthmatics, a low FeNO level probably predicts low risk of exacerbation, and the patient is unlikely to benefit from increasing ICS dose. There were scarce data to conclude whether FeNO predicts exacerbations when ICS treatment is stopped in well-controlled asthma. Only one study reported results separately in different asthma phenotypes.The current evidence on the predictive value of FeNO and its role in the management of asthma is incomplete. Future studies should focus on clinically meaningful questions and probably target only eosinophilic phenotypes where FeNO is best associated with the activity of airway inflammation.

Correction to: Leukemia (2016); 30(5), 1184–1187; doi:10.1038/leu.2015.246 Following the publication of this article the authors noted that the labels in Figures 1b and d have been switched. The correct labels in Figure 1b are; mixed lineage leukemia rearranged (MLL rearranged; dotted line) and unknown (thin solid line).

Background: Studies on adolescents and young adults with acute lymphoblastic leukemia suggest better results when using pediatric protocols for adult patients, while corresponding data for acute my ...

Children with high-risk neuroblastoma (NBL) constitute a heterogenous group, but little attention has been paid to further subdivision of the high-risk group. Although the current therapies including multiple high-dose consolidations have neared their efficacy and tolerability limits, alternative therapies are needed. We wanted to define an ultrahigh-risk group among high-risk NBL patients, to be potential candidates for novel therapies given up-front. Children with high-risk NBL (n=59) treated at a single institution during 1987 to 2010 were evaluated for upfront prognostic factors at diagnosis and response to induction therapy. The overall outcome was not different during 1987 to 1994 versus 1995 to 2010. Therapy consisted of induction chemotherapy, surgery, and high dose-consolidation (single, tandem, or triple) with autologous stem cell rescue, followed by local irradiation and cis-retinoic acid. MYCN amplification and bone metastases were powerful upfront prognostic factors, and a combination of these determined an ultrahigh-risk group with a 5-year event-free survival of 0.125±0.083. The combination of MYCN amplification and bone metastases overruled the intensity of the therapy given and remained the only significant predictor (P

Physical fitness is an essential feature of overall health. Our objective was to compare the physical performance between nontransplanted acute lymphoblastic leukemia (ALL) patients (study patients), healthy controls, and ALL patients after stem cell transplantation (SCT). Forty-five ALL patients (median age, 13.3 y) treated without cranial irradiation were compared with 34 ALL patients (12.0 y) treated with SCT and total body irradiation and 522 age-matched and sex-matched controls. Their physical performance was assessed by 6 muscle tests measuring speed and dynamic endurance, flexibility, acceleration, maximal speed, and speed differentiation. The patients were tested at a minimum of 3 years after treatment. The muscle test results of the study patients did not differ from that of the healthy controls. The study patients had normal body mass indexes (BMI). Only 42% of them exercised at least once a week. Those who exercised >3 times a week and those with a BMI below median had better results. SCT patients had inferior results in 4 out of 6 tests. The physical performance of nontransplanted ALL patients did not differ from that of healthy controls. A higher physical exercise activity and a BMI below median positively correlated with better muscle performance, supporting the importance of encouraging ALL survivors to exercise and avoid obesity.

Background Outcome of high risk neuroblastoma (NBL) remains unsatisfactory in spite of intensive treatment efforts. Consolidation with high-dose (HD) chemotherapy and autologous stem cell transplantation (ASCT) has been intensified with tandem and triple cycles with promising results. Our purpose was to improve the outcome with two or three HD-consolidations. Methods Thirty six children with high risk NBL, diagnosed 1995–2010, had intensive induction and surgery, and were stratified to single, tandem or triple HD-therapy and ASCT, followed by local irradiation and cis-retinoic acid. In inoperable patients surgery was facilitated by preoperative HD-melphalan. Long-term outcome of our old cohort from 1987–1994 was updated. Results Ten year event-free survival (EFS) from diagnosis was 0.44+/−0.10 of the old and 0.43+/−0.085 of the new cohort. EFS from the last ASCT was 0.53 +/−0.12 and 0.48+/−0.091, respectively. Preoperative HD-melphalan rendered 73% of bulky primaries operable in the new cohort. The 5-yr EFS from ASCT was 0.46+/−0.15 for single and 0.73+/−0.15 for tandem ASCT (P = 0.19). All triple ASCT patients, selected by poor/slow response, relapsed or died. Conclusions Thiotepa- and melphalan based HD regimens, with or without total body irradiation (TBI), appeared to give an outcome comparable to major NBL study groups with acceptable toxicity. Tandem HD therapy gave a 5-year EFS of 73%, whereas a third HD consolidation did not offer any additional advantage for ultra high risk patients with slow response. Pediatr Blood Cancer 2012; 59: 1190–1197. © 2012 Wiley Periodicals, Inc.

Acute lymphoblastic leukemia (ALL) diagnosed in the first month of life (congenital ALL) is very rare. Although congenital ALL is often assumed to be fatal, no studies have been published on outcome except for case reports. The present study reports the outcome of 30 patients with congenital ALL treated with the uniform Interfant-99 protocol, a hybrid regimen combining ALL treatment with elements designed for treatment of acute myeloid leukemia. Congenital ALL was characterized by a higher white blood cell count and a strong trend for higher incidence of MLL rearrangements and CD10-negative B-lineage ALL compared with older infants. Induction failure rate was 13% and not significantly different from that in older infants (7%, P = .14), but relapse rate was significantly higher in congenital ALL patients (2-year cumulative incidence [SE] was 60.0 [9.3] vs 34.2 [2.3], P < .001). Two-year event-free survival and survival of congenital ALL patients treated with this protocol was 20% (SE 9.1%). Early death in complete remission and treatment delays resulting from toxicity were not different. The survival of 17% after last follow-up, combined with a toxicity profile comparable with that in older infants, justifies treating congenital ALL with curative intent. This trial was registered at www.clinicaltrials.gov as no. NCT 00015873, and at www.controlled-trials.com as no. ISRCTN24251487.

Objective: This study examined whether experience of cancer in childhood leaves a hypersensitivity to various somatic symptoms. Further, are self-reported somatic symptoms explained by medical late-effects or a worry of recurrence of the cancer? Methods: Of the total of 44 female survivors of leukaemia, 42 were compared with 69 age-matched healthy controls. We used a questionnaire to study self reported somatic symptoms and a face-to-face interview to explore worries about recurrence of the illness. Health status and medical late effects were evaluated by a paediatric haematologist. Results: In contrast to our assumptions, young survivors of leukaemia reported fewer somatic symptoms than healthy age-matched comparison subjects (p < 0.001). Late physical sequelae were uncommon except in the survivors of allogeneic bone marrow transplantation. Of the survivors, 52% were afraid of recurrence of the illness. The presence of physical or visible impairment and worry of recurrence were unrelated to frequency of somatic symptoms. Conclusions: The results suggest that experience of childhood leukaemia and its treatment does not result in increased somatic concerns or hypochondriacal tendencies.

Summary Background Acute lymphoblastic leukaemia in infants younger than 1 year is rare, and infants with the disease have worse outcomes than do older children. We initiated an international study to investigate the effects of a new hybrid treatment protocol with elements designed to treat both acute lymphoblastic leukaemia and acute myeloid leukaemia, and to identify any prognostic factors for outcome in infants. We also did a randomised trial to establish the value of a late intensification course. Methods Patients aged 0–12 months were enrolled by 17 study groups in 22 countries between 1999 and 2005. Eligible patients were stratified for risk according to their peripheral blood response to a 7-day prednisone prophase, and then given a hybrid regimen based on the standard protocol for acute lymphoblastic leukaemia, with some elements designed for treatment of acute myeloid leukaemia. Before the maintenance phase, a subset of patients in complete remission were randomly assigned to receive either standard treatment or a more intensive chemotherapy course with high-dose cytarabine and methotrexate. The primary outcomes were event-free survival (EFS) for the initial cohort of patients and disease-free survival (DFS) for the patients randomly assigned to a treatment group. Data were analysed on an intention-to-treat basis. This trial was registered with ClinicalTrials.gov, number NCT 00015873, and at controlled-trials.com, number ISRCTN24251487. Findings In the 482 enrolled patients who underwent hybrid treatment, 260 (58%) were in complete remission at a median follow-up of 38 (range 1–78) months, and EFS at 4 years was 47·0% (SE 2·6, 95% CI 41·9–52·1). Of 445 patients in complete remission after 5 weeks of induction treatment, 191 were randomised: 95 patients to receive a late intensification course, and 96 to a control group. At a median follow-up of 42 (range 1–73) months, 60 patients in the treatment group and 57 controls were disease-free. DFS at 4 years did not differ between the two groups (60·9% [SE 5·2] for treatment group vs 57·0% [5·5] for controls; p=0·81). During the intensification phase, of 71 patients randomly assigned to the treatment group, and for whom toxicity data were available, 35 (49%) had infections, 21 (30%) patients had mucositis, 22 (31%) patients had toxic effects on the liver, and 2 (3%) had neurotoxicity. All types of rearrangements in the (mixed lineage leukaemia) MLL gene, very high white blood cell count, age of younger than 6 months, and a poor response to the prednisone prophase were independently associated with inferior outcomes. Interpretation Patients treated with our hybrid protocol, and especially those who responded poorly to prednisone, had higher EFS than most reported outcomes for treatment of infant ALL. Delayed intensification of chemotherapy did not benefit patients.

BACKGROUND This cross-sectional study evaluated the overall bone health and the prevalence of vertebral complications after stem cell transplantation (SCT) in prepubertal children and adolescents. METHODS A total of 44 children and adolescents (median age, 10 years) were evaluated at a median of 3.8 years after SCT for areal bone mineral density (aBMD) with dual-energy X-ray absoptiometry and for vertebral fractures with instant vertebral assessment. Pretransplant and posttransplant medications and nutritional parameters were recorded, and plasma levels of vitamin D, calcium, phosphate, and parathormone were measured. RESULTS Of the 44 patients, 16 (36%) had a BMD Z-score of

Studies on adolescents and young adults with acute lymphoblastic leukemia suggest better results when using pediatric protocols for adult patients, while corresponding data for acute myeloid leukemia (AML) are limited.We investigated disease characteristics and outcome for de novo AML patients 10-30 years old treated in pediatric or adult departments. We included 166 patients 10-18 years of age with AML treated according to the pediatric NOPHO-protocols (1993-2009) compared with 253 patients aged 15-30 years treated in hematology departments (1996-2009) in the Nordic countries.The incidence of AML was 4.9/million/year for the age group 10-14 years, 6.5 for 15-18 years, and 6.9 for 19-30 years. Acute promyelocytic leukemia (APL) was more frequent in adults and in females of all ages. Pediatric patients with APL had similar overall survival as pediatric patients without APL. Overall survival at 5 years was 60% (52-68%) for pediatric patients compared to 65% (58-70%) for adult patients. Cytogenetics and presenting white blood cell count were the only independent prognostic factors for overall survival. Age was not an independent prognostic factor.No difference was found in outcome for AML patients age 10-30 years treated according to pediatric as compared to adult protocols.

Objective This study was undertaken to compare utilization of health services and health care costs in a randomized hormone therapy trial. Study design A total of 1823 healthy postmenopausal women aged 50 to 64 years at the time of sampling were allocated to combined continuous hormone therapy or placebo or no treatment. The analysis was based on routinely collected electronic data in the Estonian Health Insurance Fund database during a follow-up period from 2 to 5 years. Results In the nonblind subtrial, the number of all health care visits was 10% higher and the number of visits to family practitioners 16% higher per person-year in the hormone therapy arm. Per person-year, the number of vaginal sonograms was 14% and the number of electrocardiograms 19% higher in the nonblind hormone therapy arm. Outpatient health care costs and drug expenses were higher in the nonblind hormone therapy arm. In the blind subtrial, the number of gynecologic operations, vaginal sonograms and total health care costs was higher in the hormone therapy arm. Conclusion Hormone therapy caused additional expenses on health care.

Slightly, but significantly, reduced bone mineral density (BMD) has been detected as a late effect after stem cell transplantation (SCT) performed in childhood. The aim of the study was to evaluate the risk factors of reduced BMD after SCT in childhood. We evaluated areal BMD of 16 young adults (six males, 10 females), aged 21 yr (range 15-34) by dual-energy X-ray absorptiometry at the lumbar spine, at the femoral neck, in the total hip, and in the total body. Bone turnover rate was evaluated by markers of bone formation and resorption. Six of the 16 patients had reduced BMD with a Z-score of < or = -1 at least at one measurement site. Factors associated with reduced BMD were prepubertal status at transplant (p = 0.03), delayed pubertal growth (p = 0.03), pubertal onset gonadal hormone insufficiency (p = 0.02), and female sex (p = 0.02). Surprisingly, height in SDs and lumbar spine BMD correlated negatively (p = 0.008) in those with reduced bone mass, indicating that low areal density could not be due the small size of the vertebrae. Bone turnover markers were similar for those with normal and reduced BMD. In conclusion, 38% of the SCT long-term survivors had reduced areal BMD. Prepubertal status at transplant with pubertal onset gonadal hormone insufficiency and female sex predisposed to reduced bone mass after SCT performed in childhood.

BACKGROUND: The occurrence of invasive fungal infection (IFIs) in a pediatric hematology/oncology unit after renovation of the ventilation system, and initiating routine azole antifungal prophylaxis was monitored. In addition, the value of serial screening for Aspergillus galactomannan (GM) for diagnosing invasive aspergillosis was assessed. PROCEDURE: A total of 98 consecutive high-risk pediatric patients were prospectively surveyed for signs of IFI and weekly monitored for serum GM. The data was not made available to treating physicians. RESULTS: Only 2 patients had proven and 27 possible IFI based on the European Organization for Research and Treatment of Cancer/Mycoses Study Group definitions. The incidence of proven IFI was 1/31 (3.2%) in the allogeneic stem cell transplant (SCT) (Aspergillus spp), 0/26 in the autologous SCT, and 1/60 (1.6%) in the induction therapy group (C. krusei). GM was detected at least in one tested sample in 12/98 patients (12.2%), in five patients in two or more sequential samples. In the latter group, IFI was proven in one patient and could not be excluded in the others. Four of the five patients belonged to the 31 allogeneic and one to the 26 autologous SCT patients. In patients with only one positive GM test none developed signs of IFI and only one received empirical amphotericin B. CONCLUSIONS: With the currently used preventative and prophylactic measures, IFI is uncommon in children with high-risk for infection. Regular screening for GM could be useful among allogeneic SCT patients and two positive samples should prompt further investigative procedures and pre-emptive antifungal therapy.

Objective : To investigate treatment adherence and factors related to non-adherence in the Estonian postmenopausal hormone therapy (EPHT) trial. Methods : A total of 1823 postmenopausal women aged 50–64 years were recruited into the EPHT trial from 1999 to 2001. They were randomised into the blind group receiving continuous orally administered postmenopausal hormone therapy (PHT) or a placebo and to a non-blind group receiving open-label PHT or no drugs. A woman was classified as non-adherent, if she had stopped treatment for at least 6-month period in treatment arms or used PHT for at least 6-month period in the control group. Adherence was calculated by the Kaplan–Meier method, and factors affecting adherence were studied with Cox proportional hazard modelling. Results : The rate of adherent women declined approximately 50% during the first year in all treatment arms. Less than 10% of the control group women started taking prescribed PHT. Older women, with lower education, with only one birth, never used oral contraceptives (OC), with lower physical activity or who were dissatisfied with the information received from the trial staff, were more likely to discontinue. In treatment arms, the two most often cited reasons for non-adherence were side-effects and woman's loss of interest in participation. Control group women started PHT due to the menopausal symptoms or on doctor's recommendation. Conclusions : The adherence was similar to that found for PHT use in everyday life. Higher adherence was related to younger age, higher education, previous OC use, physical activity and satisfaction with received information.

Udgivelsesdato: 2005-Mar To determine the epidemiology and outcome of children with Down syndrome (DS) diagnosed with acute leukaemia in the Nordic countries, data registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) population-based leukaemia registry were analysed. Of 3494 children with acute leukaemia diagnosed between July 1984 and December 2001, 136 patients (3.9%) with DS were identified. 2.1% of the children with acute lymphoid leukaemia (ALL) and 14.0% of the children with acute myeloid leukaemia (AML) had DS. In ALL, DS patients had similar age and sex distribution and no major differences in blood counts compared with non-DS children. None of the DS patients had T cell leukaemia. Outcome was inferior to that of non-DS children and treatment results did not improve over time. In AML, DS patients showed a significant female predominance and all but one were

We examined the recovery of circulating monocytoid (Lin- CD11+ HLA-DR+) and plasmacytoid (Lin- CD123+ HLA-DR+) precursor (pre) dendritic cell (DC) subsets after allogeneic stem cell transplantation (SCT) in 39 children, using age-matched healthy children as controls. The frequencies of DCs in peripheral blood samples were determined by flow cytometry. The initial recovery of DC occurred simultaneously with myeloid engraftment. However, with time, DC subset values declined, being very low 40-50 days after SCT. Low monocytoid and plasmacytoid DC values were associated significantly with the development of severe acute graft-versus-host disease (aGVHD) (P=0.042 and 0.017, respectively). Plasmacytoid DC values were lower than in the age-matched controls for the entire follow-up period (range 102-2569 days), although, with time, values approached normal levels. Normal monocytoid DC numbers were observed within 300-400 days post SCT. The severity of chronic GVHD did not correlate with quantitative recovery of DC. We conclude that in pediatric SCT, initial recovery of DC production is concurrent with that of myelopoiesis, yet with time, DC subset values decline and low counts are associated with severe aGVHD. Monocytoid DC numbers approach normal levels within a year of SCT, but plasmacytoid DC counts recover very slowly.

Background Human herpesvirus-6 (HHV-6) and -7 (HHV-7) may reactivate with immunosuppression and cause symptoms varying from subclinical to severe organ manifestations. The presence of HHV-6 and -7 and their possible association with clinical problems among pediatric recipients of stem cell grafts was studied in a single institution setting between November 1999 and December 2001. Procedure A total of 60 patients, mean age 8.5 years, were transplanted: 2/3 received allogeneic grafts and 1/3 autologous stem cell rescue. The presence of HHV-6 and -7 was studied in blood by polymerase chain reaction (PCR) (HHV-6) and antigenemia (HHV-6 and -7). Results Both HHV-6 and -7 were frequently present in the blood of stem cell graft recipients. No significant difference in the incidence of HHV-6 or -7 reactivations between the allogeneic and autologous patients nor recipients of sibling or unrelated donor (URD) grafts was observed. HHV-6 antigenemia was associated with fever, rash, and delayed engraftment. Among symptomatic patients two cases of encephalitis were encountered with both having HHV-6 detectable in their cerebrospinal fluid (CSF) by PCR. Conclusions HHV-6 and -7 seem to be common in blood both pre- and post-transplant among pediatric recipients of stem cell grafts. Prolonged reactivations appear to correlate with clinical symptoms such as fever, rash, and bone marrow suppression in the post-stem cell transplant setting (SCT), but severe complications are rare. Transient reactivations appear to be of very limited clinical significance. © 2005 Wiley-Liss, Inc.

Purpose To compare the effect of blind design (active drug and placebo) and nonblind design (active drug and no treatment) on recruitment. Setting A primary prevention trial with postmenopausal hormone therapy in Estonia. Methods Women who were eligible and willing to participate on the basis of the questionnaire survey were randomized into blind and nonblind groups. Recruitment rates are based on record keeping, and reasons for participating were requested in the first-year follow-up. Results The recruitment was 30% higher in the nonblind group: of the 4,295 women invited, 37% (95% confidence interval CI = 35–39%) in the blind group and 48% (95% CI = 46–49%) in the nonblind group were recruited. In both groups, once randomized, most of the losses were women who did not attend the first clinical examination: 49% (blind; 95% CI = 47–51%) and 40% (nonblind; 95% CI = 38–42%). The rest were found ineligible or lost their interest during clinical examinations. The reasons for joining the trial were relatively similar in the two groups. Conclusions Blinding decreased women's interest in joining a long-term preventive trial. Women's reasons for joining the trial were not influenced by blinding.

Background. Potential problems with breast implants have been widely discussed, but few data exist on the childbearing and offspring of women with implants. The purpose of this study was to investigate the occurrence and conditions of pregnancies of women who have had cosmetic breast implantation (exposed women), and the health of their newborns. Methods. Women who had breast implants for cosmetic reasons in the period 1967-1999 ( n = 2236) were identified from hospital surgical records. The births of the exposed women were identified through record linkage to the Population Register. The perinatal health of the infants was studied by the data in the Medical Birth Register in 1987-1999. For each birth to an exposed woman, 20 control mothers who gave birth in the same year were chosen randomly from the Medical Birth Register. Differences in mothers' background characteristics were adjusted by logistic regression. Results. The women had received their first cosmetic breast implants at young ages (mean 31 ye...

BACKGROUND The objective of the current study was to examine the occurrence of tooth agenesis and microdontia in pediatric stem cell transplantation (SCT) recipients. METHODS The impact of total body irradiation (TBI) and age at SCT on agenesis and microdontia of permanent teeth was examined in 55 patients from panoramic radiographs. Assessment A1 (for tooth agenesis and microdontia) excluded the third molars, and assessment A2 (for tooth agenesis) included the third molars. Patients were grouped according to TBI status (the TBI group vs. the non-TBI group) and age at SCT (patients age ≤ 3.0 years [Group Y], patients ages 3.1–5.0 years [Group M], and patients age ≥ 5.1 years [Group O]). RESULTS From 1 to 12 teeth were missing in 77%, 40%, and 0% of patients (assessment A1) in Groups Y, M, and O, respectively (Group Y vs. Group M, P = 0.055; Group Y vs. Group O, P < 0.001; and Group M vs. Group O, P = 0.002), increasing to 83%, 78%, and 43%, respectively, when the third molars were included (assessment A2; P values were not significant). Correspondingly, 75%, 60%, and 13%, respectively, of patients had 1–12 microdontic teeth (assessment A1: Group Y vs. Group M, P = 0.306; Group Y vs. Group O, P < 0.001; and Group M vs. Group O, P = 0.003). Recipient age at the time of SCT was found to have a negative correlation with the number of missing teeth (P = 0.001) and microdontic teeth (P = 0.005). TBI appeared to have little effect on the prevalence of tooth agenesis (assessment A1: TBI group, 32%; non-TBI group, 29%; assessment A2: TBI group, 72%; non-TBI group, 46%; P values were not significant) or on the prevalence of microdontia (assessment A1: TBI, 41%; non-TBI, 50%; P value was not significant). A tendency toward an increased number of affected teeth was noticed in the group of patients who received TBI. CONCLUSIONS Depending on their age at SCT, 50–100% of pediatric SCT recipients will later present with agenesis and/or microdontia of permanent teeth that may jeopardize occlusal development. Young age (≤ 5.0 years) at SCT was found to be a stronger risk factor than TBI, although TBI caused additive impairment. Cancer, 2005. © 2004 American Cancer Society.

Objective: To compare Estonian and Finnish gynaecologists’ and general practitioners’ (GP) opinions on and prescribing practices in hormone treatment (HT) during and after menopause. Methods: Data was collected using similar postal questionnaires. In 2000 in Estonia, a random sample included 212 gynaecologists and 288 GPs (68% responded); and in 1989 in Finland, 100 male and 100 female gynaecologists, 100 general practitioner specialists and 100 non-specialists (73% responded). Gynaecologists and GPs were compared to each other within the countries, and the two countries were compared within the specialities. Results: Gynaecologists’ opinions of benefits were positive and similar in Estonia and Finland, and more positive than those of GPs. Gynaecologists and GPs in both countries had similar opinions about harms. Gynaecologists were in favour of longer HT than GPs, and longer treatment was recommended in Finland than in Estonia. In both countries a large proportion of physicians (48% of gynaecologists in Estonia and 65% in Finland) stated that they would routinely prescribe HT to all women at menopause without contraindication, regardless of symptoms, and some (31% of gynaecologists in Estonia and 19% in Finland) favoured routine prescribing to all postmenopausal women. Conclusions: Estonian physicians’ positive attitudes suggest increased use of HT. Comparisons of the two countries and specialities suggest that physicians’ positive opinions may long predate increased use.

Treatment of acute leukemia relapse following an allogeneic transplantation is a challenge. We reinduced three pediatric patients with acute myeloid leukemia (AML) relapsing after a marrow transplantation from a sibling donor into remission with chemotherapy and used donor lymphocyte infusions (DLIs) as consolidation. In two of the cases, the allogeneic recognition was enhanced through the use of interferon in the absence of clinical graft vs. host disease (GVHD). Subsequently, all the three developed (acute grade III-IV or chronic extensive) GVHD and remain in remission with a good quality of life 19, 15 and 14 months post-relapse. We consider an active approach in the treatment of pediatric AML relapsing post-transplant justified.

Mortality patterns among women with cosmetic breast implants have not been well characterized. We examined cause-specific mortality among women who underwent cosmetic breast implantation at major public hospitals and private clinics in Finland from 1970 through 2000. Causes of death through 2001 were identified through the national mortality register. Expected numbers of deaths were calculated on the basis of mortality rates in the general female population, and standardized mortality ratios (SMR), i.e. ratios of observed to expected deaths, and 95% confidence intervals (CI) were calculated. Among the 2166 women with cosmetic breast implants, we observed 31 deaths versus 32.1 expected. Overall disease mortality was below expectation, mainly due to low mortality from diseases of the circulatory system (SMR, 0.28; 95% CI, 0.03-1.02). Mortality from cancer was close to expectation. There was a statistically significant excess of suicide, based on 10 deaths, which was most pronounced during the first 5 years of follow-up (SMR, 4.26; 95% CI, 1.56-9.26). In conclusion, although based on small numbers, women with cosmetic breast implants did not experience higher mortality overall than women in the general population. The high suicide risk supports other studies and warrants further detailed investigation.

Summary. Three consecutive protocols for childhood acute myeloid leukaemia (AML) have been used in the Nordic countries since 1984: the Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML84 was of moderate intensity, NOPHO-AML88 of high intensity with upfront loading and aggressive consolidation. NOPHO-AML93 utilized the same treatment blocks as NOPHO-AML88, but after the first block those children with a hypoplastic non-leukaemic bone marrow were allowed to recover from aplasia. Poor responders received intensified induction therapy. Between January 1993 and December 2000, 219 children without Down's syndrome were entered on NOPHO-AML93. Compared with NOPHO-AML88, the event-free survival (EFS) at 7 years increased from 41% to 49% (P = 0·06) and 7-year overall survival increased from 47% to 64% (P

Aim: To evaluate ovarian function after modern intensive multi-agent chemotherapy for osteosarcoma given during childhood or adolescence. Methods: After discontinuation of treatment, 10 female osteosarcoma survivors were followed up for 1.5–14 (median 4.6) years. Their age at diagnosis was a median of 12.9 (range 6–15) years and at the last follow up 18.6 (range 16–22). The main follow up included recording of their pubertal and menstrual status and of sex hormone determinations. Results: Prior to diagnosis, 5/10 had had their menarche, and one had it while on therapy. At discontinuation of chemotherapy, ovarian function had severely deteriorated; none of the girls experienced regular menstrual cycles. However, during follow up, significant restoration of ovarian function was evident. At the last follow up, 9/10 patients were menstruating spontaneously. During follow up, four patients, three of whom had received high doses of alkylating agents, presented with clear hypergonadotrophism with high FSH levels (14.4–132 IU/l). Three of these four patients initiated menstruation after their gonadotrophin levels normalised. Conclusions: The modern multi-agent chemotherapy applied for osteosarcoma impairs ovarian function. Normalisation of ovarian function is common, even in cases with severe hypergonadotrophic hypogonadism, but may only occur after several years off chemotherapy. Regular assessment of ovarian function and cautious use of hormone replacement therapy are important in patients with chemotherapy induced gonadal damage.

In acute myeloblastic leukemia (AML) the follow-up of minimal residual disease (MRD) has focused on specific chromosomal aberrations (e.g. t(15;17), t(8;21), inv16/t(16;16)) mostly employing reverse transcriptase-PCR. High or increasing levels of MRD are associated with an increased risk of relapse but low levels may persist in patients with prolonged or even durable remission. In adult patients with AML the increased risk of relapse has also been demonstrated using flow cytometry and fluorescence in situ hybridization (FISH). We evaluated the presence of MRD among pediatric patients with AML during and after the cessation of therapy. We were able to establish a clonal marker for the follow-up in 80% of our cases; 11 of the 15 with a clonal marker had detectable MRD at some point during follow-up while 4/15 relapsed 12-14 months after diagnosis. In two there was hematological relapse preceded by an increase in their FISH-detectable number of clonal cells. In 7 of the 11 remaining in CR1 there were small (1%) numbers of clonal cells detectable at one or more time-points. Out of the group of 15 pediatric patients with AML, 12 are currently alive in CCR with a median follow-up of 44 months (range 7-63 months). Our data establish the role of metaphase-FISH in the follow-up of AML in children and emphasize the importance of an increasing level of MRD in predicting a relapse. Yet, low and stable levels of marrow MRD a ppear compatible with CCR.

The use of high-dose melphalan (L-phenyalalanine mustard or L-PAM) has been shown to be associated with both hematological and non-hematological toxicity. It has been employed in the conditioning for allogeneic stem cell transplants from related donors but experience on its use in the unrelated setting has not been reported. As an attempt to elucidate the role of high-dose L-PAM (210 mg/m2) and total body irradiation (TBI) as a preparative regimen for allogeneic marrow transplantation from matched unrelated donors, they were employed in an institutional pilot series of seven pediatric patients. When compared with recipients of unrelated marrow grafts conditioned using other regimens, those treated with high-dose L-PAM experienced a markedly more severe acute graft-vs.-host disease (GvHD). The overall incidence of grade III-IV acute GvHD was higher (86% vs. 14%) among those treated with L-PAM. As judged by gastrointestinal (GI) symptoms, clinically significant (stages +2 to +4) gut GvHD was strikingly more prevalent among those treated with L-PAM (86% vs. 9%, p < 0.005). Toxic mortality prior to day + 100 was 29% in the L-PAM group and 9% in the non-L-PAM group of patients. With a mean follow-up of 21 months no increase in the incidence of chronic GvHD has been encountered among those conditioned with L-PAM. We conclude that the use of preparative L-PAM for allogeneic transplants from unrelated donors is associated with considerable procedure-related toxicity. We strongly suggest its use in this setting to be viewed with caution.

Invasive fungal infections (IFI) with substantial mortality constitute an increasing problem among BMT patients. From 1986 to 1996 148 children underwent BMT, and are included in a retrospective analysis of the incidence, risk factors and outcome of IFI. By histopathology or culture-proven IFI (Candida, 10; Aspergillus, 8) was documented in 12/73 (16%) allogeneic and in 6/75 (8%) autologous BMT patients. Of these 18 patients, 15 subsequently died, and in 12 (66%) IFI was regarded as the main cause of death. In addition to the patients with documented IFI, 48 had suspected and 82 no fungal infection. Invasive candidal infections were more frequent in patients with semiquantitatively estimated abundant candidal colonization as compared with those with no colonization (18% vs 3%, P = 0.015). In the allogeneic group, 50% of those with severe (grades III-IV) aGVHD had IFI as opposed to 8% of those with no or mild aGVHD (P < 0.001). Regarding cGVHD, 57% of those with extensive cGVHD vs 5% of those with absent or limited cGVHD had IFI (P < 0.001). The dose of steroids was associated with IFI: 77% of those who received high-dose steroids (methylprednisolone 0.25-1 g/day for 5 days) vs 5% of those with conventional-dose (prednisone 2 mg/kg/day) had IFI (P < 0.001). Particularly for BMT patients at risk, new, quicker and better diagnostic tests and more effective anti-fungal agents, both for prophylaxis and treatment, are needed.

Summary Background This follow-up study aimed to assess the frequency of late effects on glucose and lipid metabolism after bone-marrow transplantation in childhood. Methods 23 long-term survivors (median age 20 years) were studied 3–18 years after bone-marrow transplantation and compared with 23 healthy controls matched for age and sex and with 13 patients in remission from leukaemia. Findings 12 (52%) of the 23 bone-marrow transplantation patients had insulin resistance, including impaired glucose tolerance in six and type 2 diabetes in four. The core signs of the metabolic syndrome (hyperinsulinaemia and hypertriglyceridaemia combined), were found in nine (39%) of the bone-marrow transplantation patients compared with one (8%) of the 13 leukaemia patients and none of the healthy controls (p=0·0015). The frequency of insulin resistance increased with the time since bone-marrow transplantation. Abdominal obesity, but not overweight, was common among the patients with insulin resistance. Interpretation Long-term survivors of bone-marrow transplantation are at substantial risk of insulin resistance, impaired glucose tolerance, and type 2 diabetes even at normal weight and young age. They also develop typical signs of the metabolic syndrome. We advocate measurement of serum lipids, fasting blood glucose, and serum insulin for the follow-up of all patients who undergo transplants in childhood, to be continued regularly and possibly life-long.

Seventy pediatric patients with cancer treated at the Hospital for Children and Adolescents, University of Helsinki, Finland, died while in terminal care and 30 children of therapy-related complications during active anticancer therapy in the period 1987-92. The purpose of this study was to compare these groups and characterize the main problems of the families during the mourning process. The method of evaluation was a structured interview of every parent separately. Parents of 60/70 children after terminal care, and parents of 26/30 children who died during active anticancer therapy, were interviewed. Unexpectedly, differences were minimal between families who lost a child after terminal care and those whose child died during active anticancer therapy. Parents reported physical and/or mental problems with similar frequency (39% and 34%); average self-reported recovery times were similar (14 and 16 mo); return to work was similar in both groups, 70% returning doing so within 1 mo. However, pronounced differences were observed between the mothers and the fathers; the mothers requiring longer recovery times and returning to work later. Of the siblings, 18% in the terminal care group had problems compared with 32% in the active therapy group. These included fear, behavioral problems, problems with friends and school-related problems. In conclusion, when a child with cancer dies, the ability of the respective families to cope does not seem to differ whether the child dies after terminal care or during active anticancer therapy. The inevitable loss of the child is the major event. Most parents and siblings have the potential and ability to recover normally after the death of a child, although they will never be completely the same.

Our purpose was to increase the dose intensity of chemotherapy and reduce the days with neutropenic fever in childhood high-risk (HR) acute lymphoblastic leukemia (ALL) by systematic use of granulocyte-macrophage colony-stimulating factor (GM-CSF).All children with HR-ALL in Finland during 1990-1996 were included. Two open-label study groups were formed: 1) 34 children diagnosed between January, 1992, and December, 1996, received seven or nine courses (depending on cranial RT or no cranial RT) of GM-CSF at 5 microg/kg s.c. daily until an absolute neutrophil count (ANC) of 1,000 x 10(6)/liter at scheduled places in the protocol and 2) 80 control children, those diagnosed between January, 1990, and December, 1991, plus all with significant coexpression of myeloid markers, did not receive GM-CSF.Dose intensity increased in patients who received regular GM-CSF support. The intensive phase of therapy, including induction, consolidation courses, and delayed intensification, was 33 days shorter (P0.001) in children with seven courses and 26 days shorter (P0.01) in those with nine courses of GM-CSF compared to controls. The number of infections during the whole ALL therapy was reduced by use of GM-CSF in children aged5 years (P0.001), but not in those aged5 years. The mean total duration of intravenous antibiotics per child was 39 days in the GM-CSF group and 48 days in the control group (P0. 001). Systematic use of GM-CSF was cost-effective.Systematic use of GM-CSF improved dose intensity by shortening the intensive treatment period by about 4 weeks. Use of GM-CSF reduced the days for inpatient antibiotics by about 1 week per child, which translates into reduced costs.

Impaired growth after TBI prior to BMT has been a constant finding in children with leukemia. The growth of poor-risk neuroblastoma (NBL) survivors treated with myeloablative preparative regimens and ABMT at the Hospital for Children and Adolescents, University of Helsinki, since 1982 is reported. Two separate groups were analyzed: (1) The TBI- patients (n = 15) were conditioned with high-dose chemotherapy only. They had been treated at the age of 1.0-6.3 (mean 3.0) years and the post-ABMT follow-up time was 1.5-14.5 (mean 7.7) years. (2) The TBI+ patients (n = 16) had received TBI in addition to high-dose chemotherapy. They had been treated at the age of 1.3-4. 8 (mean 3.0) years, and the post-ABMT follow-up time was 1.5-8.0 (mean 4.7) years. The height standard deviation score (SDS) was similar for the two groups at the time of diagnosis, -0.3 +/- 1.2 (mean +/- s.d.), and at the time of ABMT, -0.7 +/- 1.1. After transplantation, the height SDS continued to decrease in the TBI+ group, the mean being -2.0 SDS at 5 years after ABMT. In the TBI-group, the mean height SDS remained within -0.7 to -0.9 to the 10 years of follow-up. Five patients received growth hormone (GH) therapy starting 2-6 years after ABMT. They all had low GH secretion in provocative tests. All showed some response to GH therapy. The mean height SDS increased 0.4 SDS during the 3 years following the start of GH therapy, while in the untreated patients a decrease of 0. 8 SDS during the corresponding time (P = 0.009) was observed. We conclude that NBL patients grow poorly following ABMT when TBI is included in the conditioning regimen, but close to normally when treated without TBI. The need for GH therapy should be evaluated early to avoid an unnecessary decrease in final height.

The use of volunteer, unrelated donors has substantially increased the number of potential donors for pediatric marrow transplantation during the past few years. We describe our single institution experience of short-term toxicity after pediatric marrow transplantation using sibling or unrelated donors. Fully matched (A, B and DR loci) donors were employed in 94% of the cases in both groups. Conditioning of similar intensity and uniform supportive care were employed in the two groups. Both primary non-engraftment and secondary graft failure were more common among recipients of unmanipulated URD grafts. Clinically significant (grades III-IV) acute GVHD and toxic mortality during the immediate post-transplant period were also higher in this group of patients. Pediatric marrow transplantation using volunteer, unrelated donors appears to be associated with an increased incidence of procedure-related toxic complications.

Background The purpose of this study was to find out whether autopsy of children with cancer should be recommended after terminal care, or whether in those circumstances it could be abandoned. Patients and Methods One hundred pediatric patients with cancer treated at the Children's Hospital, University of Helsinki, Finland, died during 1987–92. Seventy children died while in organized terminal care. The underlying diagnoses were brain tumors (21), other solid tumors (24), and leukemias (25). The method was a retrospective analysis of patients' records and autopsy reports, in addition to a structured interview of the two parents separately. Results Autopsy was performed in 40 (57%) of these 70 cases. It was more often performed on children dying in hospital (69%) than in those dying at home (39%). The autopsy rate also varied with the underlying disease: 68% of patients with leukemia, 50% of those with solid tumors, and 52% of those with brain tumors were autopsied. Autopsy afforded totally new medical information in 20% of cases, and important additional information in 55%. Nothing unexpected was found in 25%. Almost all the parents (94%) who agreed to autopsy felt that it was appropriate. Of both mothers and fathers, 50% felt that knowing the findings at autopsy was helpful for them, and all the parents except one mother thought that the autopsy of their child would at least be helpful to other patients. Conclusions Autopsy often provides important and even unexpected information in those dying after terminal care. The majority of our parents felt that autopsy was an acceptable and appropriate practice. We recommend that autopsies should be performed, with the parents' consent, even after terminal care. Med. Pediatr. Oncol. 30:284–289, 1998. © 1998 Wiley-Liss, Inc.

This study was designed to assess the sexuality of young women surviving acute leukaemia in childhood or early adolescence. Thirty of 31 survivors were compared with 50 healthy age matched controls. Three methods were used: a self report questionnaire, a face to face interview conducted by a psychiatrist, and a projective psychological test. The age at initiation of dating and sexual activity, the frequency of sexual intercourse, and opinions on sexual behaviour were similar in the two groups. With regard to inner sexuality, however, the survivors differed significantly from the healthy controls. Their images of sexuality were more restrictive, and their attitudes, especially those concerning sexual pleasure, were more negative than those of the controls. Sexual identity among the survivors was less often feminine and more often infantile as compared with the controls. The findings obtained with the three methods of assessment were concordant.

Purpose In pediatric relapsed acute myeloid leukemia (AML), optimal reinduction therapy is unknown. Studies suggest that liposomal daunorubicin (DNX; DaunoXome; Galen, Craigavon, United Kingdom) is effective and less cardiotoxic, which is important in this setting. These considerations led to a randomized phase III study by the International Berlin-Frankfurt-Münster Study Group. Patients and Methods Patients with relapsed or primary refractory non–French-American-British type M3 AML who were younger than 21 years of age were eligible. Patients were randomly assigned to fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) or to FLAG plus DNX in the first reinduction course. The primary end point was status of the bone marrow (BM) sampled shortly before the second course of chemotherapy (the day 28 BM). Data are presented according to intention-to-treat for all 394 randomly assigned patients (median follow-up, 4.0 years). Results The complete remission (CR) rate was 64%, and the 4-year probability of survival (pOS) was 38% (SE, 3%). The day 28 BM status (available in 359 patients) was good (≤ 20% leukemic blasts) in 80% of patients randomly assigned to FLAG/DNX and 70% for patients randomly assigned to FLAG (P = .04). Concerning secondary end points, the CR rate was 69% with FLAG/DNX and 59% with FLAG (P = .07), but overall survival was similar. However, core-binding factor (CBF) AML treated with FLAG/DNX resulted in pOS of 82% versus 58% with FLAG (P = .04). Grade 3 to 4 toxicity was essentially similar in both groups. Conclusion DNX added to FLAG improves early treatment response in pediatric relapsed AML. Overall long-term survival was similar, but CBF-AML showed an improved survival with FLAG/DNX. International collaboration proved feasible and resulted in the best outcome for pediatric relapsed AML reported thus far.

PURPOSE To evaluate the following prospectively in poor-risk neuroblastoma (NBL) patients: (1) the feasibility and efficacy of in vivo purging of bone marrow; and (2) the outcome after autologous bone marrow transplantation (ABMT) when immunologically tumor-free, unpurged autografts were used. PATIENTS AND METHODS Twenty-three children with poor-risk NBL were evaluated during induction chemotherapy by repeat bone marrow examinations, including aspirate, biopsy, and an immunofluorescence method using the anti-GD2 monoclonal antibody 3A7. Nineteen patients completed the program with surgery with or without local irradiation followed by ABMT. RESULTS Autologous bone marrow grafts, both immunologically and cytologically clean, were obtained and used in 19 of 23 children. The overall 4-year disease-free survival of the 19 grafted children was 53%, with a toxic death rate of 16% and a posttransplant relapse rate of 37%. According to the in vivo purging efficacy of the 18 children with initial marrow disease, the following three groups were formed: patients with (1) perfect in vivo purging (n = 5); (2) eventually successful in vivo purging (n = 8); and (3) unsuccesful in vivo purging (n = 5). The 4-year DFS was 100%, 67%, and 0%, respectively (P < 0.001). The five patients with unsuccessful in vivo purging failed because of resistant/progressive bulky disease. CONCLUSION In patients with poor-risk NBL, in vivo purging of bone marrow by conventional chemotherapy is feasible, can be monitored, and the purging efficacy during the first 3 months after diagnosis is a strong prognostic factor reflecting tumor responsiveness to therapy. Autografting with immunologically clean, unpurged marrows gives a DFS well comparable to previous studies using ex vivo purging.

Purpose : Four children with an osteomyelitic process in the jaw bones while on cytotoxic chemotherapy were treated by radical surgery and antimicrobial chemotherapy. Patients and Methods : Symptoms (local swelling and pain in the jaw, necrotic gingivitis, and spontaneous loss of teeth) appeared 3 weeks, 4 weeks, and 8 months after diagnosis of leukemia, and 8 days posttransplant in a patient with severe aplastic anemia. Three had the process in the mandible and one in the maxilla. Specific diagnoses of Aspergillus flavus, Saccharomyces cerevisiae, and Actinomyces species were obtained histologically from surgical samples. Treatment was radical surgery to remove all infected and necrotic tissue : removal of a substantial part of the mandible and loss of seven to eight permanent teeth in those with mandibular lesions. Actinomycosis was treated with penicillin for 2 years. The patients with fungal lesions received amphotericin B for 2, 5, and 6 months, with adjuvant itraconazole, fluconazole, or 5-fluorocytosine for 9-12 months. Anticancer chemotherapy was continued. Results : All the bony lesions healed. The patient with acute myeloid leukemia died in relapse 1 year postdiagnosis ; her aspergillus osteomyelitis had been inactive for 8 months. The other three patients are alive and well 1.9, 2.1, and 1.9 years after termination of antimicrobial therapy. Conclusions : We emphasize the necessity of specific diagnosis from appropriate surgical samples and conclude that in patients undergoing chemotherapy bony lesions caused by opportunistic microorganisms may be curable with aggressive surgery and prolonged medication.

Serologic responses to hepatitis B vaccine were investigated in 197 pediatric cancer patients. The patients, ages 1 to 21 years, comprised 66 with solid tumors, 101 with hematologic malignancies and 30 with various benign conditions. Of them 51 were receiving cytotoxic chemotherapy and 114 had not received chemotherapy for 0.2 to 11 years. Three doses of plasma-derived hepatitis B vaccine (20 micrograms) were given at 0, 1 and 6 months; and antibody concentrations to hepatitis B surface antigen were determined at 3, 6 and 8 months. The geometric mean antibody concentration after 3 vaccine doses was 1076 mIU/ml in cancer patients receiving chemotherapy and 18,833 mIU/ml in cancer patients not receiving chemotherapy. The protective titer of antibody (or = 10 mIU/ml) was reached after 3 doses of vaccine by 67% of patients receiving chemotherapy and by 97% of those not receiving chemotherapy. The patients being treated for solid tumors had weaker responses than those being treated for hematologic malignancies: after 3 vaccine doses no response was observed in 6 of 11 patients with solid tumors compared with 3 of 25 of patients with hematologic malignancies. Children receiving anticancer chemotherapy have essentially weaker responses to hepatitis B vaccine than children not receiving chemotherapy or those with benign conditions. This reflects the profound immunosuppression during chemotherapy. The effect of more intensive immunization schedules should be investigated.

Neutropenia is the major factor predisposing to sepsis in cancer patients, and its duration is important for survival. We administered leukocyte transfusions (LT) to 10 children suffering from documented life-threatening infections during profound, prolonged neutropenia. Nine had acute leukemia, and one had aplastic anemia; three were bone marrow transplant recipients. These 10 were the only patients in our unit who received LT during the past 7 years. The median leukocyte dose was 0.6 x 10(9)/kg in total. Instead of leukapheresis products, we used pooled buffy coats from random donors, with a high relative content of lymphocytes and especially T lymphocytes. The leukocyte concentrates were irradiated with 15 Gy. In all 10 patients, we observed prompt and sustained myeloid marrow recovery following LT. Such an effect of LT has never been described before. We hypothesize that in the internal milieu of these aplastic patients the transfused leukocytes were stimulated to secrete cytokines, the result being a cascade-like phenomenon and stimulation and proliferation of the patient's own bone marrow cells. The bone marrow-stimulating effect of LT merits further study.

Outcome of high risk neuroblastoma (NBL) remains unsatisfactory in spite of intensive treatment efforts. Consolidation with high-dose (HD) chemotherapy and autologous stem cell transplantation (ASCT) has been intensified with tandem and triple cycles with promising results. Our purpose was to improve the outcome with two or three HD-consolidations.Thirty six children with high risk NBL, diagnosed 1995-2010, had intensive induction and surgery, and were stratified to single, tandem or triple HD-therapy and ASCT, followed by local irradiation and cis-retinoic acid. In inoperable patients surgery was facilitated by preoperative HD-melphalan. Long-term outcome of our old cohort from 1987-1994 was updated.Ten year event-free survival (EFS) from diagnosis was 0.44+/-0.10 of the old and 0.43+/-0.085 of the new cohort. EFS from the last ASCT was 0.53 +/-0.12 and 0.48+/-0.091, respectively. Preoperative HD-melphalan rendered 73% of bulky primaries operable in the new cohort. The 5-yr EFS from ASCT was 0.46+/-0.15 for single and 0.73+/-0.15 for tandem ASCT (P = 0.19). All triple ASCT patients, selected by poor/slow response, relapsed or died.Thiotepa- and melphalan based HD regimens, with or without total body irradiation (TBI), appeared to give an outcome comparable to major NBL study groups with acceptable toxicity. Tandem HD therapy gave a 5-year EFS of 73%, whereas a third HD consolidation did not offer any additional advantage for ultra high risk patients with slow response. Pediatr Blood Cancer 2012; 59: 1190-1197. © 2012 Wiley Periodicals, Inc.

In a double blind study of 58 episodes of fever and profound neutropenia, children with cancer received either recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or placebo, combined with identical antimicrobial therapy, i.e. imipenem, on admission. The criteria for discontinuation of therapy were identical. A difference was demonstrated both in the number of hospital days, totaling 252 days in the rhGM-CSF group and 354 in the placebo group, days receiving antibiotics (220 vs. 322), and in the resolution of neutropenia (4.5 days vs. 6.0 days; P0.05). The number of episodes requiring antimicrobial therapy for longer than 10 days was 5 of 28 (12%) in the rhGM-CSF group as opposed to 15 of 30 (50%) in the placebo group (P = 0.01). rhGM-CSF was well-tolerated. We conclude that rhGM-CSF was efficacious in accelerating myeloid recovery and reducing the length of hospitalization in febrile neutropenia.

Background. With the improving cure rate in childhood malignancies, increasing interest has been focused on long-term survivors. To evaluate late sequelae of childhood leukemia, the muscle strength of 43 young female survivors was investigated and compared with that of 69 healthy age-matched women. The patients had been off therapy for 1 to 19 years. Methods. The anthropometric characteristics measured were height and weight, and body mass index was calculated. The maximal isometric strengths for elbow flexion, knee extension, and hand grip were measured on a special dynamometer chair. Dynamic muscular endurance was measured by pushup and situp tests. Results. The mean height of the patients was 6.5 cm shorter (P < 0.001) and their mean weight 4.8 kg lighter (P = 0.011) than that of the reference subjects. Muscle strength was in most tests poorer in the patients than in the reference subjects. The differences were statistically significant in elbow flexion and knee extension, and in both muscular endurance tests. There was an association between the maximal isometric strengths and the anthropometric characteristics. Even when allowance was made for the smaller size of the patients, however, they still had less muscle strength than the reference subjects. Of the various treatment modalities, radiation therapy to the cranial area and chemotherapy with L-aspara-ginase were independently associated with the lower muscle strength values. Conclusions. The muscle strength of female patients may be subnormal for many years after therapy for childhood leukemia. To compensate for these deficiencies, the possible benefits of prophylactic and individually planned exercise should be studied. Cancer 1993; 72:276–81.

We evaluated 91 episodes of fever in 46 profoundly neutropenic children with cancer, in a search for any symptom, sign or laboratory test that would serve to identify patients with septicemia and differentiate them from those in no immediate need of prompt antimicrobial therapy. Seventeen episodes (19%) were bacteremias, 59 (64%) were suspected septic infections, 9 (10%) were focal bacterial infections and 6 (7%) proved not to be bacterial infections. We were unable to detect any parameter, either on admission or after two days of antimicrobial therapy (except for blood culture findings), that would be helpful in differentiating bacteremia from an episode not of bacterial origin. We focused on serum levels of C reactive protein and found them unreliable on an individual level. Prompt institution of antimicrobial therapy at the occurrence of fever results in low mortality, but does not allow assignment of cases to different categories.

Abstract 2700 Objective: Infant acute lymphoblastic leukemia (ALL) is characterized by distinct biological and clinical features. In this study, we aimed at detailed evaluation of infant ALL immunophenotype based on the large cohort of patients treated homogeneously on INTERFANT'99 protocol. Patients and Methods: We were able to obtain sufficient flow cytometry based immunophenotypic data from 286 (130 boys and 156 girls) of 483 infant ALL cases treated on INTERFANT'99 protocols. The distribution of patient and leukemia characteristics as well as clinical outcome were very similar to the entire study cohort (Pieters et al, Lancet 2007; 370: 240–250). The positivity for a certain antigen was defined at the cut-off value of >20% of cells expressing this antigen. In B-cell precursor ALL (BCP-ALL), evaluated antigens included CD10, CD20, CD34, myeloid markers (CD13, CD33, CD15 and/or CD65) and NG2 antigen assessed with 7.1 antibody. The strength of association between characteristics (patient's age and gender, initial white blood count [WBC], CNS involvement, presence of MLL gene rearrangements, prednisone response [PR]) and antigen expression was analyzed with Fisher exact test adjusted for multiple comparisons. Univariate analysis of outcome by immunophenotype was based on event free survival (EFS) and compared by log-rank test. Multivariate analysis was performed using Cox model in MLL-rearranged cases. P values < 0.05 were considered to be significant. Results: Altogether, 272 cases of infant BCP-ALL and 14 of infant T-ALL were analyzed. Most BCP-ALL cases were CD10 negative (66%), CD20 negative (88%), CD34 positive (60%), and NG2 positive (58%). Co-expression of myeloid antigens was less frequent and concerned CD13 in 8%, CD33 in 17%, CD15 in 31%, and CD65 in 28%. CD10 negativity and NG2 expression were significantly more frequent in younger infants, patients with initial high leukocytosis and with MLL rearrangements. CD34 expression was observed more frequently in younger infants, while CD20 positivity was significantly associated with lower initial leukocytosis and absence of MLL rearrangement. For myeloid antigen expression, the only significant association was more frequent CNS involvement in infants with CD13+ and/or CD33+ BCP-ALL. Analysis of outcome showed significantly better prognosis for CD10 positivity (4-year EFS of 56.3 as compared to 37.2 for CD10 negative BCP-ALL), absence of NG2 expression (4-year EFS of 63.9 as compared to 34.9 for NG2 positive BCP-ALL) and CD33 negativity (4-year EFS of 47.6 as compared to 27.7 for CD33 positive BCP-ALL). There was also a trend towards better outcome in CD20 positive infant BCP-ALL. While CD10 negativity and NG2 positivity were associated with well-known high-risk features, prognostic significance of CD33 expression is somewhat more difficult to explain. Of note, CD10 negativity was not associated to a worst outcome in MLL-rearranged patients. Moreover, in this subset, multivariate analysis showed that none of the markers analyzed had independent prognostic significance, after adjustment for sex, age at diagnosis, WBC and PR. In rare infant T-ALL cases, we observed equal distribution to different immunophenotypic subgroups as defined by EGIL classification. Conclusion: Infant BCP-ALL has distinct immunophenotypic features. However, immunophenotype has no independent prognostic relevance when MLL, age, WBC, PR and other factors are included. Disclosures: No relevant conflicts of interest to declare.

We present a set of tests for physical performance used for annual prospective follow-up after a pediatric transplant. Of the 103 eligible patients transplanted at a mean age of 8.8 years, 94 were included. The results were divided into early, performed 1 (n=46) or 2 (n=12) years post transplant, and late tests (n=66), performed 4-16 (mean 6) years post transplant. A total of 30 patients had tests both at early and late time points (paired tests). The control subjects included 522 healthy age- and gender-matched schoolchildren. Using their test results, the s.d. score (SDS) was calculated for each patient and for each test individually. Both in the early and late tests, patients had the mean SDS for each test significantly lower (P

Interferon gamma receptor deficiency is a rare autosomal recessive inherited disorder, with poor prognosis due to early-onset, recurrent, and disseminated mycobacterial infections. Hematopoietic stem cell transplantation (HSCT), the only curative treatment, is particularly difficult in these patients owing to a high rate of graft rejection. We report the first successful hematopoietic stem cell transplantation with an unrelated donor, performed in a schoolgirl with severe interferon gamma receptor 1deficiency caused by a novel mutation.