Normal tissue complication probability models in plan evaluation of children with brain tumors referred to proton therapy.

Background: Children with brain tumors undergoing radiotherapy are at particular risk of radiation-induced morbidity and are therefore routinely considered for proton therapy (PT) to reduce the dose to healthy tissues. The aim of this study was to apply pediatric constraints and normal tissue complication probability (NTCP) models when evaluating the differences between PT and contemporary photon-based radiotherapy, volumetric modulated arc therapy (VMAT). Methods: Forty patients (aged 1-17 years) referred from Norwegian institutions to cranial PT abroad during 2014-2016 were selected for VMAT re-planning using the original CT sets and target volumes. The VMAT and delivered PT plans were compared by dose/volume metrics and NTCP models related to growth hormone deficiency, auditory toxicity, visual impairment, xerostomia, neurocognitive outcome and secondary brain and parotid gland cancers. Results: The supratentorial brain, temporal lobes, hippocampi, hypothalamus, pituitary glands, cochleas, salivary glands, optic nerves and chiasm received lower mean doses from PT. Reductions in population median NTCP were significant for auditory toxicity (VMAT: 3.8%; PT: 0.3%), neurocognitive outcome (VMAT: 3.0 IQ points decline at 5 years post RT; PT: 2.5 IQ points), xerostomia (VMAT: 2.0%; PT: 0.6%), excess absolute risk of secondary cancer of the brain (VMAT: 9.2%; PT: 6.7%) and salivary glands (VMAT: 2.8%; PT:0.5%). Across all patients, 23/38 PT plans had better or comparable estimated risks for all endpoints (within ±10% of the risk relative to VMAT), whereas for 1/38 patients all estimates were better or comparable with VMAT. Conclusions: PT reduced the volumes of normal tissues exposed to radiation, particularly low-to-intermediate dose levels, and this was reflected in lower NTCP. Of the included endpoints, substantial reductions in population medians were seen from the delivered PT plans for auditory complications, xerostomia, and risk of secondary cancers of the brain and salivary glands.

Novel GTF2I-PDGFRB and IKZF1-TYW1 fusions in pediatric leukemia with normal karyotype.

BACKGROUND: Many cases of acute lymphoblastic leukemia (ALL) carry visible acquired chromosomal changes of pathogenetic, diagnostic, and prognostic importance. Nevertheless, from one-fourth to half of newly diagnosed ALL patients have no visible chromosomal changes detectable by G-banding analysis at diagnosis. The introduction of powerful molecular methodologies has shown that many karyotypically normal ALLs carry clinically important submicroscopic aberrations. CASE PRESENTATION: We used fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), RNA sequencing, reverse transcription (RT) and genomic polymerase chain reaction (PCR), as well as Sanger sequencing to investigate a case of pediatric ALL with a normal karyotype. FISH with a commercial PDGFRB breakapart probe showed loss of the distal part of the probe suggesting a breakpoint within the PDGFRB locus. aCGH revealed submicroscopic deletions in chromosome bands 5q32q35.3 (about 30 Mb long, starting within PDGFRB and finishing in the CANX locus), 7q34 (within TCRB), 9p13 (PAX5), 10q26.13 (DMBT1), 14q11.2 (TRAC), and 14q32.33 (within the IGH locus). RNA sequencing detected an in-frame GTF2I-PDGFRB and an out-of-frame IKZF1-TYW1 fusion transcript. Both fusion transcripts were verified by RT-PCR together with Sanger sequencing and interphase FISH. The GTF2I-PDGFRB fusion was also verified by genomic PCR and FISH. The corresponding GTF2I-PDGFRB fusion protein would consist of almost the entire GTF2I and that part of PDGFRB which harbors the catalytic domain of the tyrosine kinase. It would therefore seem to lead to abnormal tyrosine kinase activity in a manner similar to what has been seen for other PDGFRB fusion proteins. CONCLUSIONS: The examined pediatric leukemia is a Ph-like ALL which carries novel GTF2I-PDGFRB and IKZF1-TYW1 fusion genes together with additional submicroscopic deletions. Because hematologic neoplasms with PDGFRB-fusion genes can be treated with tyrosine kinase inhibitors, the detection of such novel fusions may be clinically important. Since the GTF2I-PDGFRB could be detected only after molecular studies of the leukemic cells, further investigations of ALL-cases, perhaps especially but not exclusively with a normal karyotype, are needed in order to determine the frequency of GTF2I-PDGFRB in leukemia, and also to find out which clinical impact the fusion may have.

Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites.

BACKGROUND: Hepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy. PROCEDURE: In children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs. six-week intervals), as well as alternating high-dose MTX or vincristine/dexamethasone pulses every four weeks. RESULTS: Among 130 children receiving PEG-asparaginase biweekly, 29 developed SOS (≥2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain ≥2.5%, unexplained thrombocytopenia <75 × 109 l-1 ) at a median of 30 days (interquartile range [IQR]: 17-66) into maintenance (cumulative incidence: 27%). SOS cases fulfilling one, two, or three Ponte di Legno criteria were classified as possible (n = 2), probable (n = 8), or verified (n = 19) SOS, respectively. Twenty-six cases (90%) occurred during PEG-asparaginase treatment, including 21 (81%) within 14 days from the last chemotherapy pulse compared with the subsequent 14 days (P = 0.0025). Cytotoxic 6MP metabolites were significantly higher on PEG-asparaginase compared to after its discontinuation. Time-dependent Cox regression analysis showed increased SOS hazard ratio (HR) for erythrocyte levels of methylated 6MP metabolites (HR: 1.09 per 1,000 nmol/mmol hemoglobin increase, 95% confidence interval: 1.05-1.14). Six-week PEG-asparaginase intervals significantly reduced SOS-specific hazards (P < 0.01). CONCLUSIONS: PEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.

The effect of coffee consumption on serum total cholesterol in the Sami and Norwegian populations.

OBJECTIVE: To assess coffee consumption in the Sami and Norwegian populations and to investigate the impact of unfiltered boiled coffee consumption on serum cholesterol concentrations. DESIGN: A cross-sectional study. Information was collected by self-administrated questionnaires and total serum cholesterol was analysed. Participants were divided into three ethnic groups: Sami I (Sami used as home language in the last three generations), Sami II (at least one Sami identity marker) and Norwegian. SETTING: In an area with Sami, Kven/Finnish and Norwegian populations, the SAMINOR study, 2003-2004. SUBJECTS: A total of 5647 men and 6347 women aged 36-79 years. RESULTS: More than 90 % of the study populations were coffee drinkers. Only 22 % were unfiltered coffee consumers. Sami I had the highest proportion of participants who consumed nine or more cups of unfiltered coffee per day, although the number of participants was limited. Total coffee consumption was associated with increased total cholesterol for men (P < 0·01) and women (P < 0·0001). For those who drank only unfiltered coffee, a significant association was found only in Norwegian men, adjusted for physical activity in leisure time, BMI and smoking habits (P < 0·001). From the lowest (less than five cups) to the highest (nine or more cups) unfiltered coffee consumption category, the mean total cholesterol levels increased by 0·29 mmol/l in Norwegian men. CONCLUSIONS: Unfiltered coffee consumption was lower in the present study compared to previous reports. In general, total coffee consumption was positively associated with total cholesterol levels. However, for unfiltered coffee consumption, an association was found only in Norwegian men.

Ethnic differences in the prevalence of general and central obesity among the Sami and Norwegian populations: the SAMINOR study.

AIMS: To estimate the prevalence of general (body mass index) and central (waist circumference and waist/hip ratio) obesity in an area with a mixed Sami and Norwegian population. METHODS: A cross-sectional population-based study carried out in 2003- 2004, the SAMINOR study. The attendance rate was 60.6%. A total of 7,301 men and 7,841 women, aged 36-79, were included in the analyses. Height, weight, waist and hip circumference were measured, body mass index (BMI) calculated and information concerning lifestyle was collected by questionnaire. RESULTS: The prevalence of general obesity (BMI > or = 30 kg/m(2)) in participants who had Sami as their home language for three generations (Sami I) and Norwegian participants was 38.7% and 24.3% for women respectively; and for men 26.9% and 23.4% respectively. More than 40% of the women had central obesity (waist circumference > or = 88 cm), and the highest prevalence was found in Sami I women (45%). The highest prevalence of central obesity (waist circumference > or = 102 cm) was found in Norwegian men (24.2%). The ethnic differences persisted after adjustment for age, education, physical activity in leisure time, and smoking habits. CONCLUSIONS: The prevalence of obesity was high in this population and central obesity was most pronounced in women, particularly in Sami women. Sami men were less obese than Norwegian men. Further studies are necessary to examine a possible explanation for these findings, especially to elaborate on the impact of diet.

Population based study of health and living conditions in areas with both Sámi and Norwegian populations--the SAMINOR study.

OBJECTIVES: The overall aim of the SAMINOR project was to study health and diseases in relation to living conditions among the Sámi population and to compare these with the Norwegian population in the same area. This article provides an overview of the background of the study and a description of the methods employed for the data collection. We give sample characteristics and elaborate on different definitions of ethnicity. STUDY DESIGN: Cross-sectional, population-based study, including questionnaires, a clinical examination and analyses of blood samples. METHODS: All individuals 30 or 36 to 79 years of age who were living in defined municipalities or specified local areas with a known Sámi population were invited to a cardiovascular screening program. The data were collected during 2003-2004. The questionnaires focused on living conditions, health, Sámi traditions and ethnicity. The eligible population consisted of 27,987 individuals and 16,865 (60.6%) participated by answering at least one questionnaire. Analyses were restricted to the 36 to 79 year-old age group which had 16,538 participants. The screening program comprised a blood sample, measurements of blood pressure, height, weight, and waist and hip ratio. Different definitions of Sámi ethnicity were explored. RESULTS: Of the sample, 35.6% reported Sámi background, and 13.2% reported that they, their parents and their grandparents had Sámi as their domestic language. This stringent definition of Sámi produced clearer differences between Sámi and Norwegians, as shown for some measures of socioeconomic status. CONCLUSIONS: The findings that are related to more strict definitions of Sámi ethnicity have important implications for the interpretation of earlier works and for future studies.