Long-term renal prognosis and risk for hypertension after myeloablative therapies in survivors of childhood high-risk neuroblastoma: A nationwide study.

BACKGROUND: Patients with high-risk neuroblastoma (HR NBL) treated with myeloablative regimens are reported to be at risk for cardiovascular morbidity, and this risk may be increased by impaired renal function. PROCEDURE: Long-term renal function was assessed in a national cohort of 18 (age 22.4 ± 4.9 years) HR NBL survivors by plasma creatinine (P-Cr), urea, and cystatin C (P-Cys C) concentrations, urine albumin/creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR). Ambulatory blood pressure was monitored, and common carotid intima-media thickness (CIMT) and left ventricular mass index (LVMI) were evaluated. RESULTS: No significant difference in P-Cr, P-Cys C, or eGFR was found between the NBL survivors and the age- and sex-matched 20 controls. P-Cys C-based eGFR (eGFRcysc) was significantly lower than the P-Cr-based eGFRcr (97 ± 17 mL/min/1.73 m2 vs 111 ± 19 mL/min/1.73 m2 , P < 0.001) among the NBL survivors. The eGFRcysc was below normal in 28%, and ACR was above normal in 22% of the NBL survivors. Abnormal blood pressure was found in 56% of the survivors, and an additional 17% were normotensive at daytime but had significant nocturnal hypertension. Both ACR and P-Cys C were associated with nighttime diastolic hypertension. CONCLUSIONS: Long-term survivors of childhood HR NBL showed signs of only mild renal dysfunction associated with diastolic hypertension. Elevated ACR and P-Cys C were the most sensitive indicators of glomerular renal dysfunction and hypertension in this patient cohort.

Viral infections and immune reconstitution interaction after pediatric allogenic hematopoietic stem cell transplantation.

Background: Viral infections are a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Although immune suppression plays a central role, the literature shows conflicting results on interplay between post-transplant immune reconstitution (IR) and viral infections. Methods: We prospectively studied viral infections and IR in 30 pediatric patients undergoing allogenic HSCT, with a follow-up time of 24 months. In total, 1337 blood (CMV, EBV, HHV-6, ADV and BKV) and urine (BKV and JCV) virus samples were analyzed. IR including B-cells (CD19+), T cells (CD3+, CD4+, CD8+) and NK-cells were measured. Clinical outcomes included overall survival (OS), non-relapse mortality (NRM), graft-versus-host disease (GVHD) and occurrence of blood culture positive bacterial infections. Results: We found BKV reactivation to be most frequent, 47% of the children had viremia and 77% viruria. The frequencies of CMV, HHV-6 and adeno viremia were 37%, 37% and 6%, respectively. Viremias beyond 3 months post-HSCT were uncommon. Factors such as GVHD, use of steroids, EBV and CMV infections and pre-transplant irradiation affected IR. No specific viral infection or IR related factor was associated to OS or NRM. Conclusions: Viral infections and IR interact in a bi-directional manner. Accordingly, close follow-up of both IR and viral loads is warranted.

Viremic co-infections in children with allogeneic haematopoietic stem cell transplantation are predominated by human polyomaviruses.

BACKGROUND: Viral infections remain the cause of key complications following haematopoietic stem cell transplantation (HSCT). The impact of multiple, concurrent viral reactivations/infections remains to be delineated. METHODS: The clinical correlates of single or multiple viremic infections following HSCT and especially the occurrence of respiratory viruses in the bloodstream were investigated. We retrospectively searched for 23 viruses in a total of 184 sera from 53 paediatric patients. The time-points of interest were pre-HSCT, one, two and three months post-HSCT, and at discharge or death. The viruses were analyzed by quantitative or qualitative PCR. RESULTS: Of the 53 patients, 13 (25%) had viraemias by multiple viruses and 27 (51%) by a single virus. Thirteen patients (25%) had no viruses detected by PCR during the study period. In the children with viremic co-infections, polyomaviruses predominated over herpes viruses. Nearly half the patients, 24/53 (45%) had a polyomavirus in their serum at one or more time-points. At 12/15 time-points and in 11/13 patients with co-infections polyomaviruses were involved, compared with 6/15 time-points and 6/13 patients for cytomegalovirus. Acute graft-versus-host disease (GvHD) and steroid use were significant risk factors for the viraemias caused by more than one virus. CONCLUSIONS: Viral co-detection is a common finding in children undergoing HSCT. With large-scale viral screening also viruses other than CMV could be found as potential pathogens. In this study, BKPyV predominated over CMV as a contributor in viraemias caused by multiple viruses in children receiving HSCT.

Polyomaviruses BK, JC, KI, WU, MC, and TS in children with allogeneic hematopoietic stem cell transplantation.

Timely and reliable detection of viruses is of key importance in early diagnosis of infection(s) following allogeneic HSCT. Among the immunocompetent, infections with BKPyV and JCPyV are mostly subclinical, while post-HSCT, the former may cause HC and the latter PML. The epidemiology and clinical impact of the newly identified KIPyV, WUPyV, MCPyV, and TSPyV in this context remain to be defined. To assess the incidence and clinical impact of BKPyV, JCPyV, KIPyV, WUPyV, MCPyV, and TSPyV infections, we performed longitudinal molecular surveillance for DNAemias of these HPyVs among 53 pediatric HSCT recipients. Surveillance pre-HSCT and for three months post-HSCT revealed BKPyV DNAemia in 20 (38%) patients. Our data demonstrate frequent BKPyV DNAemia among pediatric patients with HSCT and the confinement of clinical symptoms to high copy numbers alone. MCPyV and JCPyV viremias occurred at low and TSPyV viremia at very low prevalences. KIPyV or WUPyV viremias were not demonstrable in this group of immunocompromised patients.

Metronomic therapy can increase quality of life during paediatric palliative cancer care, but careful patient selection is essential.

AIM: Children with refractory or high-risk malignancies frequently suffer from poor quality of life during palliative care. This study explored the effect of metronomic drug administration on survival and quality of life in paediatric patients with various refractory or high-risk tumours. METHODS: We treated 17 patients with a maintenance therapy that consisted of metronomic thalidomide, etoposide and celecoxib. The endpoints of the study were overall and progression-free survival, changes in the Karnofsky-Lansky scores from baseline to the end of the study therapy and radiological responses. RESULTS: The median overall survival after the start of the study therapy was 6.2 months (range 2.0-57.7), and the six-, 12- and 24-month survival rates were 59%, 18% and 18%, respectively. The median progression-free survival was 3.2 months (range 0.3-17.8). The Karnofsky-Lansky scores increased significantly during the study therapy (p = 0.02), with 35% of the patients having a transient improvement in their clinical status. Radiologically, one partial response and two disease stabilisations were encountered. Grade III-V adverse events occurred in 76% of the patients. CONCLUSION: Metronomic therapy may increase the quality of life during palliative care for childhood cancer, but requires careful patient selection to minimise the risk of serious adverse events.

Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome.

Relapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia. Despite improvements in the up-front therapy, survival after relapse is still relatively poor, especially for high-risk relapses. The aims of this study were to assess outcomes following acute lymphoblastic leukemia relapse after common initial Nordic Society of Paediatric Haematology and Oncology protocol treatment; to validate currently used risk stratifications, and identify additional prognostic factors for overall survival. Altogether, 516 of 2735 patients (18.9%) relapsed between 1992 and 2011 and were included in the study. There were no statistically significant differences in outcome between the up-front protocols or between the relapse protocols used, but an improvement over time was observed. The 5-year overall survival for patients relapsing in the period 2002-2011 was 57.5±3.4%, but 44.7±3.2% (P<0.001) if relapse occurred in the period 1992-2001. Factors independently predicting mortality after relapse included short duration of first remission, bone marrow involvement, age ten years or over, unfavorable cytogenetics, and Down syndrome. T-cell immunophenotype was not an independent prognostic factor unless in combination with hyperleukocytosis at diagnosis. The outcome for early combined pre-B relapses was unexpectedly poor (5-year overall survival 38.0±10.6%), which supports the notion that these patients need further risk adjustment. Although survival outcomes have improved over time, the development of novel approaches is urgently needed to increase survival in relapsed childhood acute lymphoblastic leukemia.

High-dose Thiotepa as Consolidation Therapy With Autologous Hematopoietic Stem Cell Transplantation for High-risk Ewing Family Tumors: Single-institution Experience.

High-dose therapy (HDTx) with autologous stem cell rescue has been widely applied in very-poor-risk pediatric solid tumors. Promising data have become available with the use of high-dose busulfan, whereas high-dose (HD) thiotepa is less commonly used. We report retrospectively our single-institution experience from 1986 to 2012 of single and tandem HDTx with special emphasis on HD-thiotepa as the backbone of HD regimen in Ewing family tumors, including all 24 patients in the Helsinki University Hospital referral area in population-based fashion (Ewing sarcoma 9, Askin tumor 9, peripheral neuroectodermal tumor 6). The 10-year overall survival for the entire cohort was 0.73±0.01. Thirteen out of the 24 underwent HDTx (10 single, 3 tandem). The HDTx regimen consisted of HD-thiotepa (900 mg/m), VP16, and carboplatin. Additional HD-melphalan and total body irradiation were used in the tandem regimens. There was no toxic mortality. The 5-year event-free survival was 0.73±0.16 for high-risk cases transplanted in 1CR. In the relapse group, 1 out of the 3 survived. Radiotherapy to axial sites was given safely in combination with HD-thiotepa in all 3 patients. Thiotepa-based HDTx approach resulted in an encouraging outcome without toxic mortality for high-risk patients. HD-thiotepa merits further studies in larger controlled series.

Radiotherapy-related arterial intima thickening and plaque formation in childhood cancer survivors detected with very-high resolution ultrasound during young adulthood.

BACKGROUND: The aim of the study was to evaluate arterial morphology and function in a national cohort of long-term survivors of high-risk neuroblastoma (NBL) treated with high-dose chemotherapy and autologous hematopoietic stem cell transplantation with or without total body irradiation (TBI). METHODS AND RESULTS: Common carotid, femoral, brachial, and radial artery morphology were assessed with very-high-resolution vascular ultrasound (25-55 MHz), and carotid artery stiffness and brachial artery flow-mediated dilatation measured with conventional vascular ultrasound in 19 adult or pubertal (age 22.7 ± 4.9 years, range 16-30) NBL survivors transplanted during 1984-1999 at the mean age of 2.5 ± 1.0 years. Results were compared with 20 age- and sex-matched healthy controls. The cardiovascular risk assessment included history, body mass index, fasting plasma lipids, glucose, and 24-h ambulatory blood pressure (BP). The survivors had consistently smaller arterial lumens, increased carotid intima-media thickness (IMT), plaque formation (N = 3), and stiffness, as well as increased radial artery intima thickness (N = 5) compared with the control group. Survivors displayed higher plasma triglyceride and cholesterol levels, and increased heart rate, as well as increased systolic and diastolic BPs. TBI (N = 10) and a low body surface area were independent predictors for decreased arterial lumen size and increased IMT. Three out of five survivors with subclinical intima thickening had arterial plaques. Plaques occurred only among TBI-treated survivors. CONCLUSIONS: Long-term childhood cancer survivors treated with TBI during early childhood display significant signs of premature arterial aging during young adulthood.

Impact of very early CD4(+) /CD8(+) T cell counts on the occurrence of acute graft-versus-host disease and NK cell counts on outcome after pediatric allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Increasing evidence suggests that early and rapid lymphocyte recovery following allogeneic hematopoietic stem cell transplantation (HSCT) is associated with better survival. PROCEDURE: We retrospectively analyzed very early lymphocyte subset counts following transplantation from our 5-year pediatric allogeneic HSCT material to find clinically relevant associations with post transplant outcome, and the major complication of HSCT, acute graft-versus-host disease (aGVHD). We analyzed HSCTs performed due to acute leukemias and lymphomas from matched unrelated donors (MUD, n = 33), unrelated cord blood (UCB, n = 9) and matched sibling donors (MSD, n = 17). RESULTS: Patients with grafts from MUDs and grade II-IV aGVHD) had higher (median 2.1 compared to 0.3, P<0.0001) and earlier (at day +18 post transplant vs. day +25, P = 0.004) first measurable CD4(+) /CD8(+) T cell ratio, compared to patients with no or grade I aGVHD, respectively. At day +32 after HSCT patients with MUDs and significant aGVHD had higher levels of both CD4(+) and CD8(+) T cell subsets. Low (below median 120/µL) versus high natural killer (NK) cell counts at day +32 were associated with 3-year event-free survival of 27.4 +/- 9.0% versus 82.4 +/- 6.4% (P < 0.0001), cumulative transplant-related mortality of 44.7 +/- 12.2% versus 3.0 +/- 3.0% (P < 0.001) and cumulative relapse incidence of 50.4 +/- 12.2% versus 15.0 +/- 6.2% (P = 0.019), respectively. CONCLUSIONS: We conclude that early lymphocyte subset counts following allogeneic HSCT have an association with aGVHD and post transplant outcome.

Bone health and risk factors of cardiovascular disease--a cross-sectional study in healthy young adults.

OBJECTIVE: Both osteoporosis and cardiovascular disease (CVD) are diseases that comprise a growing medical and economic burden in ageing populations. They share many risk factors, including ageing, low physical activity, and possibly overweight. We aimed to study associations between individual risk factors for CVD and bone mineral density (BMD) and turnover markers (BTMs) in apparently healthy cohort. DESIGN: A cross-sectional assessment of 155 healthy 32-year-old adults (74 males) was performed for skeletal status, CVD risk factors and lifestyle factors. METHODS: We analysed serum osteocalcin, procollagen I aminoterminal propeptide (P1NP), collagen I carboxy-terminal telopeptide (ICTP) and urine collagen I aminoterminal telopeptide (U-NTX), as well as serum insulin, plasma glucose, triglyceride and HDL-cholesterol levels. BMD, fat and lean mass were assessed using DXA scanning. Associations were tested with partial correlations in crude and adjusted models. Bone status was compared between men with or without metabolic syndrome (defined according to the NCEP-ATPIII criteria) with multivariate analysis. RESULTS: Osteocalcin and P1NP correlated inversely with insulin (R = -0.243, P = 0.003 and R = -0.187, P = 0.021) and glucose (R = -0.213, P = 0.009 and R = -0.190, P = 0.019), but after controlling for fat mass and lifestyle factors, the associations attenuated with insulin (R = -0.162, P = 0.053 and R = -0.093, P = 0.266) and with glucose (R = -0.099, P = 0.240 and R = -0.133, P = 0.110), respectively. Whole body BMD associated inversely only with triglycerides in fully adjusted model. In men with metabolic syndrome, whole body BMD, osteocalcin and P1NP were lower compared to healthy men, but these findings disappeared in fully adjusted model. CONCLUSIONS: In young adults, inverse associations between BTM/BMD and risk factors of CVD appeared in crude models, but after adjusting for fat mass, no association continued to be present. In addition to fat mass, lifestyle factors, especially physical activity, modified the associations between CVD and bone characteristics. Prospective studies are needed to specify the role of mediators and lifestyle factors in the prevention of CVD and osteoporosis.

Assessment of renal function during high-dose methotrexate treatment in children with acute lymphoblastic leukemia.

BACKGROUND: High-dose methotrexate (HD-MTX) is potentially nephrotoxic. The feasibility of novel biomarkers to indicate renal injury due to HD-MTX infusion was studied in children with acute lymphoblastic leukemia (ALL). PROCEDURE: Markers for glomerular and tubular injury were evaluated prospectively after HD-MTX infusion in 20 children with ALL. Plasma creatinine, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) were measured 24-48 hr before MTX-infusion and 24, 36, 48, and 72 hr after starting the HD-MTX treatment, and thereafter daily until the MTX concentration was below 0.1 µmol/L. Urine NGAL, ß2 -microglobulin, and creatinine concentrations as well as dipstick and urinalysis were performed at the same time points. RESULTS: In children with ALL, HD-MTX treatment at 5 g/m(2) over 24 hr was well tolerated and none of the patients developed significant glomerular or tubular dysfunction. The mean plasma cystatin C level increased significantly (P < 0.001) from 0.83 mg/L at baseline to 0.94 mg/L at 36 hr after starting the HD-MTX treatment. The cystatin C concentration remained within reference range in all but two patients (10%). There was no significant change in plasma creatinine level during or after HD-MTX treatment, the values being normal in all patients. Plasma and urea NGAL did not increase during or after the HD-MTX treatment. CONCLUSIONS: Our results suggest that plasma cystatin C concentration alone is a sensitive marker to monitor renal function during and after HD-MTX infusion in pediatric ALL patients. Plasma or urine NGAL do not provide any further advantage in the follow-up of these patients.

Coinfusion of mobilized hematopoietic stem cells from an HLA-mismatched third-party donor with umbilical cord blood graft to support engraftment.

We evaluated the role of mismatched third-party hematopoietic stem cells (TPC) in shortening the neutropenia after umbilical cord blood transplantation (UCBT). A TPC graft was given to 7/37 children with UCBT to support engraftment due to anticipated increased risk of nonengraftment (N=6) or active infection (N=1). TPC grafts were collected with apheresis from haploidentical family members. The median UCB and CD34 cell counts were 5.10 (range, 4.13 to 9.98)×10/kg and 5.98 (range, 4.40 to 14.00)×10/kg, respectively. The median time to neutrophil engraftment was shorter in the patients with TPC (12 d; range, 9 to 24 d) than those without (23 d; range, 12 to 44 d) (P=0.010). TPC chimerism was lost in median at 28 (range, 24 to 103) days posttransplant. TPC grafts from mothers engrafted similarly as the grafts from other family members. UCB graft cell count and the use of methotrexate posttransplant strongly contributed to engraftment. TPC may form a valuable transient bridging graft over the neutropenia after UCBT in patients with anticipated high-risk of nonengraftment or toxicity due to pretransplant infections.

Adult testicular volume predicts spermatogenetic recovery after allogeneic HSCT in childhood and adolescence.

BACKGROUND: Testicular dysfunction and infertility are of major concern in long-term survivors after allogeneic hematopoietic stem cell transplantation (HSCT). This study assesses predictive factors for very long-term testicular recovery after allogeneic HSCT in childhood and adolescence. PROCEDURE: Testicular volume, sperm production and long-term need of testosterone substitution were evaluated among 106 male survivors transplanted at Huddinge and Helsinki University Hospitals from 1978 through 2000, at a mean age of 8 ± 4.6 years (range 1-17). A mean ± SD of 13 ± 4.8 years (range 4-28) had elapsed since their HSCT and the mean age of the participants was 22 ± 6.0 years (range 12-42). An adult testicular volume was recorded in 74 patients at a mean age of 19 ± 3.3 years (range 14-36). RESULTS: Recipients conditioned with busulfan-based regimens or regimens containing only cyclophosphamide had significantly larger adult testicular volumes (mean volume 18 ml and 16 ml vs. 9 ml, P < 0.00001, respectively) and lower serum levels of FSH (mean 9 IU and 5 IU vs. 19 IU, P < 0.01 and 0.001, respectively) compared to those conditioned with total body irradiation (TBI). Multivariate analysis demonstrated that a non-leukemia diagnosis (P < 0.01) and adult testicular volume ≥ 15 ml (P < 0.03) positively impacted spermatogenetic recovery. CONCLUSIONS: A larger adult testicular volume, normal serum levels of FSH and spermatozoa detected in a majority of seminal fluids after busulfan-based or cyclophosphamide conditionings suggest very long-term recovery of spermatogenesis after chemotherapy-based regimens. A simple measurement of adult testicular volume may help predict spermatogenetic potential among pediatric HSCT survivors.

Radiation therapy and concurrent topotecan followed by maintenance triple anti-angiogenic therapy with thalidomide, etoposide, and celecoxib for pediatric diffuse intrinsic pontine glioma.

BACKGROUND: Despite major treatment attempts, the prognosis for pediatric diffuse intrinsic pontine gliomas (DIPGs) remains dismal. Gliomas are highly vascularized tumors, suggesting that the prevention of vessel formation by anti-angiogenic treatment might be effective. PROCEDURE: Forty-one pediatric patients with DIPG were treated according to the Angiocomb protocol, starting with radiotherapy combined with topotecan and followed by anti-angiogenic triple medication consisting of thalidomide, etoposide, and celecoxib. Overall survival, radiological response, quality of life, requirement of corticosteroids, and adverse effects were monitored. Eight patients treated with only radiotherapy were used as controls. RESULTS: For study patients, the 12 and 24 months overall survival was 61% and 17%, respectively. The median overall survival was 12 months (range 4-60 months). Four radiological complete responses were seen, of which two were transient. Radiologically, 56% of the tumors reduced in size and 78% in signal intensity. Study patients were able to visit school or daycare and walk for a significantly longer time compared to controls (Log Rank 0.036 and 0.008, respectively). Adverse effects were generally minor. CONCLUSIONS: The Angiocomb protocol created a noticeable share of long-term survivors and was well tolerated, suggesting that anti-angiogenic therapy for patients with DIPG should be studied more in the future.

Breast-fed infants and their later cardiovascular health: a prospective study from birth to age 32 years.

The aim of the present study was to evaluate the impact of infant breast-feeding on cardiovascular risk in young adults. This unique study group involved 158 subjects (eighty-two females) originally collected prospectively at birth in 1975 and followed up to the age of 32 years. Frequent visits during the first year guaranteed the knowledge of the precise duration of breast-feeding. All infants received at least some breast milk. Participants were assessed for both individual cardiovascular risk factors (blood pressure, plasma lipids, homeostatic model assessment of insulin resistance and waist circumference) and the general clinical risk of cardiovascular events by calculating the Framingham risk score (FRS) and the metabolic syndrome criteria score (NCEP-ATPIII; National Cholesterol Education Program's Adult Treatment Panel III). Data on lifestyle factors were carefully collected. Linear regression analyses revealed that the effect of the duration of breast-feeding was not relevant (0·02 decrease in the FRS per one additional breast-feeding month; 95 % CI - 0·19, 0·09). Similarly, the effect of breast-feeding was minor on all of the individual cardiovascular risk factors. We used sex, physical activity, dietary fat and vitamin C, smoking and alcohol consumption as covariates. Again, logistic regression analyses detected no significant impact of the duration of breast-feeding on the risk of the metabolic syndrome according to the NCEP-ATPIII (OR 0·95, 95 % CI 0·8, 1·1). The strongest independent predictor for later CVD risk was male sex. In conclusion, in this prospectively followed cohort of young adults born at term and at weight appropriate for gestational age, the duration of breast-feeding did not have an impact on the accumulation of cardiovascular risk factors.

Antithrombin deficiency after prolonged asparaginase treatment in children with acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) have several risk factors for deep venous thromboses (DVTs) such as central venous catheters and asparaginase (ASP), related antithrombin (AT) deficiency. After introduction of a new standard and intermediate-risk ALL treatment protocol with prolonged continuous ASP treatment, two symptomatic DVTs in 10 patients were observed at the Children's Hospital, Helsinki, Finland. To prevent further thrombotic complications yet ensuring continuous exposure to ASP, an AT substitution strategy was adopted in Helsinki. The same ALL treatment protocol is used without AT substitution in the other Nordic countries. In this retrospective study, we describe the effect of prolonged ASP treatment on AT and fibrinogen levels in children without AT substitution in Stockholm, Sweden (n = 39) and the AT substitution in children with AT activity below 0.55 kIU/l in Helsinki (n = 36, intervention group). The intervention group is compared with children treated similarly earlier in Helsinki without AT substitution (n = 10). The median lowest AT activity during the ASP treatment without AT substitution was 0.55 kIU/l. Fibrinogen level of 1.0 g/l or less was found in 14% of all routine samples during the ASP treatment. In the intervention group, 23 (64%) received AT concentrate. Two (20%) children had symptomatic DVT before initiation of the AT substitution and two (6%) thereafter. We conclude that most children are exposed to low AT activity during ASP treatment predisposing to thrombosis. The effect of prophylactic AT substitution remains unclear.

Ultrahigh-risk group within the high-risk neuroblastoma category.

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<0.019) in a multiple step-wise forward Cox regression analysis. We conclude that high-risk NBL patients can be categorized into prognostic subgroups based on MYCN status and bone metastases. MYCN amplification and bone metastases combined determined an ultrahigh-risk group of patients being suitable candidates for novel alternative therapies.

Time-related arterial changes after allogeneic hematopoietic stem cell transplantation in children.

BACKGROUND: Metabolic syndrome is a frequent late effect in young adults after hematopoietic stem cell transplantation (HSCT) performed in childhood. METHODS: To further study the signs of cardiovascular changes in HSCT patients, we performed noninvasive vascular ultrasonic measurements of arterial stiffness and endothelial function in 25 children (median age: 11.2 y) and in 22 healthy matched controls. RESULTS: The distensibility of the common carotid artery (CCA) was significantly lower in the patients than in the controls (mean = 0.48, SD = 0.19 vs. mean = 0.64 mm Hg(-1) × 10(-2), SD = 0.28; P = 0.024). The distensibility decreased with time passed after HSCT (P = 0.009). The compliance of the CCA was decreased (mean = 0.10, SD = 0.04 vs. mean = 0.13 mm(2) × mm Hg(-1), SD = 0.05; P = 0.041), and the incremental elastic modulus (E inc) was higher in the patients than in the controls (mean = 2.05, SD = 0.7 vs. mean = 1.6 mm × 10(3), SD = 0.6; P = 0.019). E inc was associated with time passed after HSCT (P = 0.036). The size of the brachial artery and flow-mediated dilation did not differ between the groups. CONCLUSION: Early mechanical changes of the arterial wall were found at young age after HSCT. Ultrasonography may offer a noninvasive method to find early alterations of the vascular bed and to optimize prevention of atherosclerosis in HSCT patients.

Targeted resequencing of 9p in acute lymphoblastic leukemia yields concordant results with array CGH and reveals novel genomic alterations.

Genetic alterations of the short arm of chromosome 9 are frequent in acute lymphoblastic leukemia. We performed targeted sequencing of 9p region in 35 adolescent and adult acute lymphoblastic leukemia patients and sought to investigate the sensitivity of detecting copy number alterations in comparison with array comparative genomic hybridization (aCGH), and besides, to detect novel genetic anomalies. We found a high concordance of copy number variations (CNVs) as detected by next generation sequencing (NGS) and aCGH. By both methodologies, the recurrent deletion at CDKN2A/B locus was identified, whereas NGS revealed additional, small regions of CNVs, seen more frequently in adult patients, while aCGH was better at detecting larger CNVs. Also, by NGS, we detected novel structural variations, novel SNVs and small insertion/deletion variants. Our results show that NGS, in addition to detecting mutations and other genetic aberrations, can be used to study CNVs.

BK polyomavirus-associated hemorrhagic cystitis among pediatric allogeneic bone marrow transplant recipients: treatment response and evidence for nosocomial transmission.

BACKGROUND: BK polyomavirus-associated hemorrhagic cystitis (BK-PyVHC) is a significant complication of allogenic hematopoietic stem cell transplantation (HSCT), but risk factors and treatment are currently unresolved. BK-PyVHC typically presents with clinical cystitis, macrohematuria, and increasing urine and blood BKV loads. OBJECTIVES: Characterization of children undergoing allogeneic HSCT with BK-PyVHC and their clinical and antibody response to cidofovir treatment. STUDY DESIGN: By prospective screening of urine and plasma in 50 pediatric allogenic HSCT performed between 2008 and 2010, we identified 6 (12%) children with BK-PyVHC. Cidofovir was administered intravenously to 5 patients and intravesically to 4 patients (3 double treatments). RESULTS: Decreasing BKV viremia of>2log(10)copies/mL and clinical resolution was seen in 4 patients over 5-12 weeks. Responses occurred only in patients mounting BKV-specific IgM and IgG responses. Epidemic curve plots, BKV genotyping and contact tracing provided evidence of transmission between 2 BKV-seronegative patients, but ruled out transmission among the remaining four patients CONCLUSIONS: The data suggest that BK-PyVHC may be the result of nosocomial transmission in children with low/undetectable BKV antibodies and raises urgent questions about appropriate infection control measures and the role of cidofovir.