Explore the vast range of titles available.

Patients treated with allogeneic stem cell transplantation (allo-SCT) often develop ocular complications. To investigate the ocular findings in young long-term survivors after allo-SCT without TBI, we examined 96 patients more than 5 years after transplantation. All patients were under 30 years of age at transplantation. The mean follow-up time was 16.8 years (range 6.0–26.1 years). The study was a part of the Norwegian Allo Survivorship Study investigating health impairments in young survivors after allo-SCT. Ophthalmological examination included visual acuity, tear break-up time, corneal fluorescein staining, Schirmer I test, tear film osmolarity, biomicroscopy and dilated ophthalmoscopy. In patients with known systemic chronic GVHD (cGVHD), ocular GVHD (oGVHD) diagnosed by clinical examination was compared with diagnosis using National Institutes of Health (NIH) or International Chronic Ocular Graft-vs-Host-Disease (ICCGVHD) Consensus Group criteria. We diagnosed dry eye disease (DED) in 52 patients (54%), cataract in 3 patients (3%) and retinopathy in 1 patient (1%). Systemic cGVHD was a risk factor for DED (OR 4.40, CI 1.33–14.56, p  = 0.02). Comparison of diagnostic criteria suggests that the more stringent ICCGVHD criteria can better differentiate DED from oGVHD after allo-SCT as compared with the NIH criteria.

[This corrects the article DOI: 10.1371/journal.pone.0273280.].

Neuroblastoma (NBL), one of the main death-causing cancers in children, is known for its remarkable genetic heterogeneity and varied patient outcome spanning from spontaneous regression to widespread disease. Specific copy number variations and single gene rearrangements have been proven to be associated with biological behavior and prognosis; however, there is still an unmet need to enlarge the existing armamentarium of prognostic and therapeutic targets. We performed whole exome sequencing (WES) of samples from 18 primary tumors and six relapse samples originating from 18 NBL patients. Our cohort consists of 16 high-risk, one intermediate, and one very low risk patient. The obtained results confirmed known mutational hotspots in ALK and revealed other non-synonymous variants of NBL-related genes ( TP53 , DMD , ROS , LMO3 , PRUNE2 , ERBB3 , and PHOX2B ) and of genes cardinal for other cancers ( KRAS , PIK3CA , and FLT3 ). Beyond, GOSeq analysis determined genes involved in biological adhesion, neurological cell-cell adhesion, JNK cascade, and immune response of cell surface signaling pathways. We were able to identify novel coding variants present in more than one patient in nine biologically relevant genes for NBL, including TMEM14B , TTN , FLG , RHBG , SHROOM3 , UTRN , HLA-DRB1 , OR6C68 , and XIRP2 . Our results may provide novel information about genes and signaling pathways relevant for the pathogenesis and clinical course in high-risk NBL.

Neuroticism is a basic personality trait concerning negative feelings under stressful conditions. Our purpose was to examine the rate of high neuroticism and factors associated with high neuroticism in long-term (≥ 5 years) survivors of childhood, adolescent, and young adult cancer (CAYACSs). Norwegian CAYACSs aged 0–39 years when diagnosed and treated between 1985 and 2009 for cancer in childhood/adolescence (0–18 years), or as young adults (19–39 years) and alive in 2015 were mailed a questionnaire. Data from 1629 CAYACSs (481 children/adolescents and 1148 young adults) were analyzed. High neuroticism was found in 44% of survivors of childhood/adolescent cancers versus 34% in survivors of young adult cancer (p < 0.001). The rate of high neuroticism in female CAYACSs was 40% and in males 30% (p < 0.001). The corresponding difference between male survivor group was non-significant. In multivariable analysis, young age at survey, more adverse effects, poor self-rated health, female sex, chronic fatigue, and increased depression remained significantly associated with high neuroticism. Cancer treatment, comorbidity, and lifestyle were significant in bivariate analyses. Cancer at earlier age could increase the risk of high neuroticism among adult survivors. Screening for neuroticism could identify CAYACSs at risk for experiencing multiple health concerns and needing special follow-up attention.

Neuroblastoma (NBL), one of the main death-causing cancers in children, is known for its remarkable genetic heterogeneity and varied patient outcome spanning from spontaneous regression to widespread disease. Specific copy number variations and single gene rearrangements have been proven to be associated with biological behavior and prognosis; however, there is still an unmet need to enlarge the existing armamentarium of prognostic and therapeutic targets. We performed whole exome sequencing (WES) of samples from 18 primary tumors and six relapse samples originating from 18 NBL patients. Our cohort consists of 16 high-risk, one intermediate, and one very low risk patient. The obtained results confirmed known mutational hotspots in ALK and revealed other non-synonymous variants of NBL-related genes (TP53, DMD, ROS, LMO3, PRUNE2, ERBB3, and PHOX2B) and of genes cardinal for other cancers (KRAS, PIK3CA, and FLT3). Beyond, GOSeq analysis determined genes involved in biological adhesion, neurological cell-cell adhesion, JNK cascade, and immune response of cell surface signaling pathways. We were able to identify novel coding variants present in more than one patient in nine biologically relevant genes for NBL, including TMEM14B, TTN, FLG, RHBG, SHROOM3, UTRN, HLA-DRB1, OR6C68, and XIRP2. Our results may provide novel information about genes and signaling pathways relevant for the pathogenesis and clinical course in high-risk NBL.

PurposeSurvivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at risk for cardiopulmonary adverse events. Data on long-term effects on cardiorespiratory fitness are limited. To address the gap in knowledge, we aimed to determine peak oxygen uptake (V̇O2peak) and identify associations between cardiorespiratory fitness and clinical characteristics, self-reported physical activity, cardiac, and pulmonary function.MethodsIn a nationwide, single-center cross-sectional study, 90 survivors [aged median (range) 35 (17–54) years, 56% females] were examined, 17 (6–26) years after allo-HSCT. Myeloablative conditioning comprised busulfan/cyclophosphamide or cyclophosphamide only. Methods included pulmonary function tests, echocardiography, and cardiopulmonary exercise test.ResultsChronic graft-versus-host disease (cGVHD) was found in 31% of the subjects, of whom 40% had bronchiolitis obliterans syndrome (BOS). Seventy-one percent of the survivors did not meet WHO recommendations for physical activity and 42% were overweight. Reduced gas diffusion (DLCO) and systolic ventricular dysfunction (LVEF) were found in 44% and 31%, respectively. For the group, mean (95% CI), V̇O2peak was 36.4 (34.7–38.0) mL/min/kg [89 (85–93)% of predicted]. V̇O2peak was low at 43%. Cardiopulmonary factors and deconditioning were equally common limitations for exercise. In a multiple linear regression model, low V̇O2peak was associated with low DLCO, low LVEF, BOS, overweight, and inactivity.ConclusionHalf of the survivors had reduced cardiorespiratory fitness median 17 years after allo-HSCT. Cardiopulmonary factors and deconditioning were equally common limitations to exercise. We encourage long-term cardiopulmonary monitoring of allo-HSCT survivors and targeted advice on modifiable lifestyle factors.

Introduction Long‐term childhood, adolescent, and young adult cancer survivors (CAYACS) are at risk of fatigue and psychological problems. However, their interactions remain largely unexplored. Understanding how they cluster can inform treatment and person‐centered follow‐up care. We aimed to identify and describe profiles of co‐occurring fatigue and psychological symptoms and investigate their associations with health‐related quality of life (HRQOL) in CAYACS. Methods NOR‐CAYACS (The Norwegian Childhood, Adolescents and Young Adult Cancer Survivors study) was a nationwide survey involving adult survivors of any childhood cancer (aged < 19 years at diagnosis) and selected young adult cancers (breast and colorectal cancers, non‐Hodgkin lymphoma, leukemias, and malignant melanomas, aged 19–39 years at diagnosis) identified through the Cancer Registry of Norway. We included 1893 survivors aged ≥ 18 years, ≥ 5 years since diagnosis. We performed latent profile analysis with six continuous outcomes: physical and mental fatigue, depression, anxiety, post‐traumatic stress symptoms, and fear of recurrence. Results We identified an overall “Low” (64%), a “Moderate fatigue/high anxiety” (18%), a “High fatigue/moderate distress” (13%), and an overall “High” (5%) symptom burden profile. The “High” profile exhibited lowest physical‐ and mental‐HRQOL with T‐scores −9.8 (95% confidence interval [95% CI]: −12.5, −7.1) and −25.0 (95% CI: −26.7, −23.3) compared to the “Low” profile. Conclusion We identified four profiles, two characterized by high fatigue and two near normative fatigue levels, each with different psychological symptom burden. Greater symptom burden corresponded to lower HRQOL, with high fatigue profiles showing lower physical HRQOL. These profiles help identify at‐risk individuals and allow for targeting interventions and follow‐up care to survivors' unique constellation of symptoms. Our study identified four unique profiles of fatigue and psychological symptoms in childhood, adolescent, and young adult cancer survivors. Profiles of symptom burden provide insight for the development of multimodal interventions targeting cancer survivors' unique constellation of cancer burden.

Background B cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common paediatric cancer. BCP-ALL blasts typically retain wild type p53, and are therefore assumed to rely on indirect measures to suppress transformation-induced p53 activity. We have recently demonstrated that the second messenger cyclic adenosine monophosphate (cAMP) through activation of protein kinase A (PKA) has the ability to inhibit DNA damage-induced p53 accumulation and thereby promote survival of the leukaemic blasts. Development of BCP-ALL in the bone marrow (BM) is supported by resident BM-derived mesenchymal stromal cells (MSCs). MSCs are known to produce prostaglandin E 2 (PGE 2 ) which upon binding to its receptors is able to elicit a cAMP response in target cells. We hypothesized that PGE 2 produced by stromal cells in the BM microenvironment could stimulate cAMP production and PKA activation in BCP-ALL cells, thereby suppressing p53 accumulation and promoting survival of the malignant cells. Methods Primary BCP-ALL cells isolated from BM aspirates at diagnosis were cocultivated with BM-derived MSCs, and effects on DNA damage-induced p53 accumulation and cell death were monitored by SDS-PAGE/immunoblotting and flow cytometry-based methods, respectively. Effects of intervention of signalling along the PGE 2 -cAMP-PKA axis were assessed by inhibition of PGE 2 production or PKA activity. Statistical significance was tested by Wilcoxon signed-rank test or paired samples t test. Results We demonstrate that BM-derived MSCs produce PGE 2 and protect primary BCP-ALL cells from p53 accumulation and apoptotic cell death. The MSC-mediated protection of DNA damage-mediated cell death is reversible upon inhibition of PGE 2 synthesis or PKA activity. Furthermore our results indicate differences in the sensitivity to variations in p53 levels between common cytogenetic subgroups of BCP-ALL. Conclusions Our findings support our hypothesis that BM-derived PGE 2 , through activation of cAMP-PKA signalling in BCP-ALL blasts, can inhibit the tumour suppressive activity of wild type p53, thereby promoting leukaemogenesis and protecting against therapy-induced leukaemic cell death. These novel findings identify the PGE 2 -cAMP-PKA signalling pathway as a possible target for pharmacological intervention with potential relevance for treatment of BCP-ALL.

Purpose Factors associated with the long-term dental effects after chemotherapy for childhood malignancies have not been well described. The primary aims of this study were as follows: (1) to assess whether age at diagnosis and treatment-related factors are associated with dental defects in survivors of childhood acute lymphoblastic leukemia (ALL) and (2) to assess the survivors’ annual expenses for dental treatment compared to reference data. Methods This cross-sectional study enrolled 111 Norwegian survivors of ALL diagnosed before the age of 16. All of the subjects completed a questionnaire and underwent medical and oral examinations. Dental defects were registered according to the individual defect index, with 0 = no defects and 140 = anodontia, and the caries experience was registered according to the decayed-missing-filled teeth index (DMFT). Age-matched reference data were drawn from a national general population survey ( n  = 555). Results The mean age at examination was 29.1 years (SD 7.2), and mean follow-up period was 22.9 years (SD 7.3). In a regression model, diagnoses occurring at ≤5 years of age ( B  = −9.6, p  < 0.001) and a cumulative dose of anthracyclines >120 mg/m 2 ( B  = 11.5, p  < 0.001) were strongly associated with more severe dental defects. Survivors treated after the age of 5 had experienced more caries than those treated at a younger age [DMFT 9.6 (SD 6.1) vs. 6.0 (SD 4.6), respectively; p  = 0.001]. High annual expenses for dental treatment were reported by a larger percentage of the reference population compared to the survivor group (18 vs. 9 %, respectively; p  = 0.02). Conclusions The age at diagnosis and the dose of anthracyclines appear to be strongly associated with the severity of dental defects, although few survivors reported high annual expenses for dental treatment. The increased risk of dental defects during adulthood should be communicated to ALL survivors.

Measuring left ventricular (LV) global longitudinal strain (GLS) is recommended in screening of long-term cancer survivors for cardiotoxicity. However, there are limited data on GLS in this setting, in particular in survivors with apparently normal LV function without risk factors of impaired GLS. In the present study, we measured GLS in 191 adult survivors of childhood lymphoma or acute lymphoblastic leukemia, with normal LV ejection fraction and fractional shortening (FS) and without known hypertension, diabetes mellitus, myocardial infarction, or stroke. We compared GLS in the survivors with 180 controls. Mean GLS was −19.0 ± 2.2% in the survivor group and −21.4 ± 2.0% in the controls (p <0.001). Impaired GLS, defined as mean – 1.96 SDs in the control group, occurred in 53 of 191 survivors (28%). We included survivors with impaired LV ejection fraction and/or FS or traditional risk factors (n = 231 in all) in multiple regression analyses to explore associations with previous cancer treatment. Survivors treated with mediastinal radiotherapy had an odds ratio of impaired GLS of 5.2 (95% confidence interval 2.2 to 12) compared with other survivors. Survivors treated with cumulative anthracycline doses >300 mg/m2 had an odds ratio of 4.8 (95% confidence interval 1.7 to 14) of impaired GLS. In conclusion, this study demonstrates a high proportion of LV dysfunction assessed by GLS in apparently healthy adult survivors of childhood cancer. Impaired GLS was associated with previous exposure to mediastinal radiotherapy and high doses of anthracyclines. The prognostic role of measuring GLS in this specific patient population should be examined in prospective studies.