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BACKGROUND: Patients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations respond poorly to first-line chemoimmunotherapy, resulting in early relapse and short survival. We investigated the safety and activity of ibrutinib in previously untreated and relapsed or refractory CLL with TP53 aberrations.METHODS: In this investigator-initiated, single-arm phase 2 study, we enrolled eligible adult patients with active CLL with TP53 aberrations at the National Institutes of Health Clinical Center (Bethesda, MD, USA). Patients received 28-day cycles of ibrutinib 420 mg orally once daily until disease progression or the occurrence of limiting toxicities. The primary endpoint was overall response to treatment at 24 weeks in all evaluable patients. This study is registered with ClinicalTrials.gov, number NCT01500733, and is fully enrolled.FINDINGS: Between Dec 22, 2011, and Jan 2, 2014, we enrolled 51 patients; 47 had CLL with deletion 17p13.1 and four carried a TP53 mutation in the absence of deletion 17p13.1. All patients had active disease requiring therapy. 35 enrolled patients had previously untreated CLL and 16 had relapsed or refractory disease. Median follow-up was 24 months (IQR 12.9-27.0). 33 previously untreated patients and 15 patients with relapsed or refractory CLL were evaluable for response at 24 weeks. 32 (97%; 95% CI 86-100) of 33 previously untreated patients achieved an objective response, including partial response in 18 patients (55%) and partial response with lymphocytosis in 14 (42%). One patient had progressive disease at 0.4 months. 12 (80%; 95% CI 52-96) of the 15 patients with relapsed or refractory CLL had an objective response: six (40%) achieved a partial response and six (40%) a partial response with lymphocytosis; the remaining three (20%) patients had stable disease. Grade 3 or worse treatment-related adverse events were neutropenia in 12 (24%) patients (grade 4 in one [2%] patient), anaemia in seven (14%) patients, a

BACKGROUND & AIMS: Iodine fortification is widespread. Systematic monitoring of iodine fortification programs should be carried out to secure an optimal fortification level. Our aim was to investigate the effectiveness of the Danish iodine fortification program by comparing iodine excretion at baseline and at 11-year follow-up, and to study determinants for any change in iodine intake including dietary habits, education, life style factors and health parameters.METHODS: A follow-up study based on the Danish DanThyr cohort examined in 1997-1998 just before iodine fortification was introduced, and reexamined in 2008-2010. In total, 2465 (59.1%) adult participants were reexamined.RESULTS: Median (IQR) iodine concentration in urine had increased by 19 (-25-68) μg/L to 83 (47-133) μg/L. Estimated 24-h iodine excretion had increased by 36 (-21-95) μg/24-h to 134 (93-206), and calculated total iodine intake (diet plus supplements) had increased by 16 (-18-48) μg/day. Iodine excretion had increased significantly in all age and gender groups, but was still below the recommended amount at follow-up. The increase in iodine excretion was positively associated with changes in milk intake, with changes in the use of iodine supplements, and with bread intake at follow-up. Salt intake, education, self-rated health, smoking, alcohol intake and physical activity were not associated with the increase in iodine excretion.CONCLUSIONS: The strategy to combat iodine deficiency in Denmark seems to be working because the fortification led to increased urinary iodine excretion in (almost) all participants. However, the level of iodine fortification of salt is too low.

Fortification with the essential trace element iodine is widespread worldwide. In the present study, results on iodine excretion and intake of iodine-rich foods from a cross-sectional study carried out in 2004-5, 4 to 5 years after the implementation of mandatory iodine fortification, were compared with data in a study carried out in 2008-10. The 2008-10 study was a follow-up of a cross-sectional study carried out before iodine fortification was implemented. Participants in the cross-sectional studies were randomly selected. Both studies were carried out in the cities of Aalborg and Copenhagen in Denmark. The median urinary iodine concentration decreased in women from 97 μg/l (n 2862) to 78 μg/l (n 2041) (P< 0.001). The decrease persisted after adjustment for age, city and education, and if expressed as estimated 24 h iodine excretion. The prevalence of users of iodine containing dietary supplements increased from 29.4 to 37.3 % (P< 0.001). The total fluid intake increased in women (P< 0.001), but the intake of other iodine-rich foods did not change. The median urinary iodine concentration did not change in men (114 μg/l (n 708) and 107 μg/l (n 424), respectively), while the total fluid intake decreased (P= 0.001). Iodine content was measured in milk sampled in 2000-1 and in 2013. The iodine content was lower in 2013 (12 (sd 3) μg/100 g) compared with that in 2000-1 (16 (sd 6) μg/100 g) (P< 0.001). In conclusion, iodine excretion in women has decreased below the recommended level. The reason might probably, at least partly, be a decreased content of iodine in milk.

The impact of the familial relationship on vitamin D status has not been investigated previously. The objective of the present cross-sectional study was to assess serum 25-hydroxyvitamin D (25(OH)D) concentration and its determinants in children and adults among families in late summer in Denmark (56°N). Data obtained from 755 apparently healthy children (4-17 years) and adults (18-60 years) recruited as families (n 200) in the VitmaD study were analysed. Blood samples were collected in September-October, and serum 25(OH)D concentration was measured by liquid chromatography-tandem MS. Information on potential determinants was obtained using questionnaires. The geometric mean serum 25(OH)D concentration was 72·1 (interquartile range 61·5-86·7) nmol/l (range 9-162 nmol/l), with 9 % of the subjects having 25(OH)D concentrations < 50 nmol/l. The intra-family correlation was 0·27 in all subjects, 0·24 in the adults and 0·42 in the children. Serum 25(OH)D concentration was negatively associated with BMI (P< 0·001) and positively associated with dietary vitamin D intake (P= 0·008), multivitamin use (P= 0·019), solarium use (P= 0·006), outdoor stay (P= 0·001), sun preference (P= 0·002) and sun vacation (P< 0·001), but was not associated with lifestyle-related factors in the adults when these were assessed together with the other determinants. In conclusion, the majority of children and adults among the families had serum 25(OH)D concentrations >50 nmol/l in late summer in Denmark. Both dietary and sun-related factors were determinants of vitamin D status and the familial component was stronger for the children than for the adults.

BACKGROUND: Vitamin D intakes are lower than dietary recommendations in most populations, and thus, a low vitamin D status is widespread, especially during winter. OBJECTIVE: We investigated the effects of increasing vitamin D intake to the recommended amount by fortification of milk and bread on serum 25-hydroxyvitamin D [25(OH)D] concentrations in families during winter in Denmark. DESIGN: The study was a randomized controlled trial in 782 children and adults (4-60 y old) recruited as 201 families. Families were randomly assigned to vitamin D-fortified or nonfortified milk and bread for 6 mo starting in September. The milk and bread replaced the participants' usual consumptions of products. RESULTS: Median (IQR) vitamin D intakes (habitual diet plus fortified products) were 9.4 μg/d (6.5, 12.3 μg/d) and 2.2 μg/d (1.5, 3.0 μg/d) in fortification and control groups, respectively. Geometric mean (IQR) serum 25(OH)D concentrations decreased from 73.1 nmol/L (61.9, 88.5 nmol/L) to 67.6 nmol/L (56.2, 79.4 nmol/L) in the fortification group and from 71.1 nmol/L (61.2, 85.9 nmol/L) to 41.7 nmol/L (29.5, 58.9 nmol/L) in the control group (both P <0.001). The final 25(OH)D concentration was significantly higher in the fortification group than in the control group (P <0.001). By the end of the study, 50 nmol/L in children and adults in Denmark. This trial was registered at clinicaltrials.gov as NCT01184716.

Mantle cell lymphoma (MCL) is a heterogenic non-Hodgkin lymphoma entity, with a median survival of about 5 years. In 2008 we reported the early based on the median observation time of 4 years results of the Nordic Lymphoma Group MCL2 study of frontline intensive induction immunochemotherapy and autologous stem cell transplantation (ASCT), with more than 60% event-free survival at 5 years, and no subsequent relapses reported. Here we present an update after a median observation time of 6.5 years. The overall results are still excellent, with median overall survival and response duration longer than 10 years, and a median event-free survival of 7.4 years. However, six patients have now progressed later than 5 years after end of treatment. The international MCL Prognostic Index (MIPI) and Ki-67-expression were the only independent prognostic factors. Subdivided by the MIPI-Biological Index (MIPI + Ki-67, MIPI-B), more than 70% of patients with low-intermediate MIPI-B were alive at 10 years, but only 23% of the patients with high MIPI-B. These results, although highly encouraging regarding the majority of the patients, underline the need of a risk-adapted treatment strategy for MCL., Correction in British Journal of Haematology, vol 158, issue 6, 2012, pages 815-816.DOI: 10.1111/bjh.12006

Mantle cell lymphoma (MCL) is a heterogenic non-Hodgkin lymphoma entity, with a median survival of about 5 years. In 2008 we reported the early - based on the median observation time of 4 years - results of the Nordic Lymphoma Group MCL2 study of frontline intensive induction immunochemotherapy and autologous stem cell transplantation (ASCT), with more than 60% event-free survival at 5 years, and no subsequent relapses reported. Here we present an update after a median observation time of 6·5 years. The overall results are still excellent, with median overall survival and response duration longer than 10 years, and a median event-free survival of 7·4 years. However, six patients have now progressed later than 5 years after end of treatment. The international MCL Prognostic Index (MIPI) and Ki-67-expression were the only independent prognostic factors. Subdivided by the MIPI-Biological Index (MIPI + Ki-67, MIPI-B), more than 70% of patients with low-intermediate MIPI-B were alive at 10 years, but only 23% of the patients with high MIPI-B. These results, although highly encouraging regarding the majority of the patients, underline the need of a risk-adapted treatment strategy for MCL. The study was registered at www.isrctn.org as ISRCTN 87866680.

Purpose Minimal residual disease (MRD) is predictive of clinical progression in mantle-cell lymphoma (MCL). According to the Nordic MCL-2 protocol we prospectively analyzed the efficacy of pre-emptive treatment using rituximab to MCL patients in molecular relapse after autologous stem cell transplantation (ASCT). Patients and Materials MCL patients enrolled onto the study, who had polymerase chain reaction (PCR) detectable molecular markers and underwent ASCT, were followed with serial PCR assessments of MRD in consecutive bone marrow and peripheral blood samples after ASCT. In case of molecular relapse with increasing MRD levels, patients were offered pre-emptive treatment with rituximab 375 mg/m(2) weekly for 4 weeks. Results Of 160 MCL patients enrolled, 145 underwent ASCT, of whom 78 had a molecular marker. Of these, 74 were in complete remission (CR) and four had progressive disease after ASCT. Of the CR patients, 36 underwent a molecular relapse up to 6 years (mean, 18.5 months) after ASCT. Ten patients did not receive pre-emptive treatment mainly due to a simultaneous molecular and clinical relapse, while 26 patients underwent pre-emptive treatment leading to reinduction of molecular remission in 92%. Median molecular and clinical relapse-free survival after pre-emptive treatment were 1.5 and 3.7 years, respectively. Of the 38 patients who remain in molecular remission for now for a median of 3.3 years (range, 0.4 to 6.6 years), 33 are still in clinical CR. Conclusion Molecular relapse may occur many years after ASCT in MCL, and PCR based pre-emptive treatment using rituximab is feasible, reinduce molecular remission, and may prevent clinical relapse.

Udgivelsesdato: 2009-Nov, BACKGROUND: Iodine intake is often measured by a surrogate measure, namely urine iodine excretion as almost all ingested iodine is excreted in the urine. However, the methods for urine collection and the reporting of the results vary. These methods, and their advantages and disadvantages, are considered in this article. SUMMARY: There are two main ways in which urine can be collected for iodine measurement. The first is the collection of urine over a period, usually 24 hours. The second is the collection of a spot urinary sample. Urinary iodine values can be expressed as the content or concentration and reported without modification or as a function of creatinine in the same sample. The 24-hour urine for iodine measurement is often considered as the "reference standard" for giving a precise estimate of the individual iodine excretion and thereby iodine intake. As 24-hour collections are difficult to perform for large number of persons, single spot urinary samples are preferable to the 24-hour urinary collections in population studies. The iodine concentration in urine depends on the intake of both iodine and fluid. This, and the fact that there is a considerable variability in the daily iodine intake, makes the iodine measurement in spot urine samples unreliable for evaluating individuals for iodine deficiency, though they can be used to screen for exposure to large amounts of iodine from sources such as amiodarone and certain radiographic contrast agents. In populations of at least 500 subjects, the median value of spot urinary iodine concentration is a reliable measure of the iodine intake in the population as there is a leveling out of the day-to-day variation in iodine intake and urinary volume. Expressing the urinary iodide concentration as a function of urinary creatinine is useful in correcting for the influence of fluid intake. When doing so, it is recommended to adjust for the age- and sex-specific creatinine excretion in the given population. CONCLUSION: I

Udgivelsesdato: 2009-Sep, OBJECTIVE: The iodine status of a population is traditionally evaluated by either urinary iodine (UI) excretion or by some measure of thyroid volume and the prevalence of goitre. In this prospective study of a mandatory iodization programme, we aimed to evaluate serum thyroglobulin (Tg) as a marker of iodine status in the population. METHODS: Two identical cross-sectional studies were performed before (1997-1998, n=4649) and after (2004-2005, n=3570) the initiation of the Danish iodization programme in two areas with mild and moderate iodine deficiency. Serum Tg was measured from blood samples. Thyroid volume was measured by ultrasonography. RESULTS: Before iodization, the median serum Tg was considerably higher in moderate than in mild iodine deficiency. Iodization led to a lower serum Tg in all examined age groups. The marked pre-iodization difference in Tg level between the regions was eliminated. The prevalence of Tg above the suggested reference limit (40 microg/l) decreased from 11.3 to 3.7% (P<0.0001). Using bootstrapping, we demonstrated a higher efficacy of Tg than of thyroid volume to show a difference between pre- and post-iodization values. CONCLUSION: We found serum Tg to be a suitable marker of iodine nutrition status in the population. The results may suggest that the Danish iodization programme has led to a sufficient iodine intake, even if the median UI excretion is still marginally low according to WHO criteria.

The Danish Fitness and Nutrition Council has examined the scientific literature to evaluate the performance and health-related aspects of consuming dietary supplements in the context of physical activity. Certain nutritional supplements such as creatine and caffeine have documented ergogenic effects in specific situations. However, for the moderately physically active adult and healthy individual, who already consumes an energy- and nutrient balanced diet, consuming any currently legal dietary supplement does not seem to confer additional benefits on performance or health.

The aim was to study the occurrence of in-transit nodes at a preoperative lymphoscintigraphy for patients with primary melanoma, and to reveal their potential role in prognosis. From 1984 to 1996, 911 patients, hospitalized for wide excision of a clinically localized primary cutaneous head-neck or truncal melanoma, had a static lymphoscintigraphy on the day before surgery as part of a prospective protocol. Lymph nodes were in no case removed at the time of scintigraphy. Recurrence and survival patterns were compared for patients with in-transit nodes with the remaining patients with only regional nodes. Follow-up time was a minimum of 10 years. In-transit nodes were visualized by lymphoscintigraphy in 6% of the patients, 18% of whom had a later recurrence in this region. The melanomas in the in-transit node group were slightly thicker, and ulceration was slightly more frequent (neither significant). The in-transit node group had significantly more lymph node basins visualized at scintigraphy compared with the remaining group of patients with only regional nodes. The risk of recurrence and/or death from melanoma was significantly worse (P

BACKGROUND: Knowledge of the structure of gene expression is essential for mammalian transcriptomics research. We analyzed a collection of more than one million porcine expressed sequence tags (ESTs), of which two-thirds were generated in the Sino-Danish Pig Genome Project and one-third are from public databases. The Sino-Danish ESTs were generated from one normalized and 97 non-normalized cDNA libraries representing 35 different tissues and three developmental stages. RESULTS: Using the Distiller package, the ESTs were assembled to roughly 48,000 contigs and 73,000 singletons, of which approximately 25% have a high confidence match to UniProt. Approximately 6,000 new porcine gene clusters were identified. Expression analysis based on the non-normalized libraries resulted in the following findings. The distribution of cluster sizes is scaling invariant. Brain and testes are among the tissues with the greatest number of different expressed genes, whereas tissues with more specialized function, such as developing liver, have fewer expressed genes. There are at least 65 high confidence housekeeping gene candidates and 876 cDNA library-specific gene candidates. We identified differential expression of genes between different tissues, in particular brain/spinal cord, and found patterns of correlation between genes that share expression in pairs of libraries. Finally, there was remarkable agreement in expression between specialized tissues according to Gene Ontology categories. CONCLUSION: This EST collection, the largest to date in pig, represents an essential resource for annotation, comparative genomics, assembly of the pig genome sequence, and further porcine transcription studies.

Background: The transmembrane presenilin (PSEN) protein, PSEN1 and PSEN2, have been proposed to be the catalytic components of the ¿-secretase protein complex, which is an intramembranous multimeric protease involved in development, cell regulatory processes, and neurodegeneration in Alzheimer's disease. Here we describe the sequencing, chromosomal mapping, and polymorphism analysis of PSEN1 and PSEN2 in the domestic pig (Sus scrofa domesticus). Conclusion: The data provide evidence for structural and functional conservation of PSENs in mammalian lineages, and may suggest that the high sequence similarity and colocatalization of PSEN1 and PSEN2 in brain tissue reflect a certain degree of fucntional redundancy. The data show that pigs may provide a new animal model for detailed analysis of the developmental functions of the PSENs.

Udgivelsesdato: JUL 1, Motivation: Single nucleotide polymorphisms (SNPs) analysis is an important means to study genetic variation. A fast and cost-efficient approach to identify large numbers of novel candidates is the SNP mining of large scale sequencing projects. The increasing availability of sequence trace data in public repositories makes it feasible to evaluate SNP predictions on the DNA chromatogram level. MAVIANT, a platform-independent Multipurpose Alignment VIewing and Annotation Tool, provides DNA chromatogram and alignment views and facilitates evaluation of predictions. In addition, it supports direct manual annotation, which is immediately accessible and can be easily shared with external collaborators. Results: Large-scale SNP mining of polymorphisms bases on porcine EST sequences yielded more than 7900 candidate SNPs in coding regions (cSNPs), which were annotated relative to the human genome. Non-synonymous SNPs were analyzed for their potential effect on the protein structure/function using the PolyPhen and SIFT prediction programs. Predicted SNPs and annotations are stored in a web-based database. Using MAVIANT SNPs can visually be verified based on the DNA sequencing traces. A subset of candicate SNPs was selected for experimental validation by resequencing and genotyping. This study provides a web-based DNA chromatogram and contig browser that facilitates the evaluation and selection of candidate SNPs, which can be applied as genetic markers for genome wide genetic studies. Availability: The stand-alone version of MAVIANT program for local use is freely available under GPL license terms at christian.bendixen@agrsci.dk Supplementary information: Supplementary data are available at Bioinformatics online.

The gene responsible for neurofibromatosis type 1 (NF1), one of the more common inherited human disorders, was identified recently, and segments of it were cloned. Two translocation breakpoints that interrupt the NF1 gene in NF1 patients flank a 60-kb segment of DNA that contains the EVI2A locus (previously reported as the EVI2 locus), the human homolog of a mouse gene, Evi-2A, implicated in retrovirus-induced murine myeloid tumors. EVI2A lies within an intron of the NF1 gene and is transcribed from telomere toward centromere, opposite to the direction of transcription of the NF1 gene. Here we describe a second locus, EVI2B, also located between the two NF1 translocation breakpoints. Full-length cDNAs from the EVI2B locus detect a 2.1-kb transcript in bone marrow, peripheral blood mononuclear cells, and fibroblasts. Sequencing studies predict an EVI2B protein of 448 amino acids that is proline-rich and contains an N-terminal signal peptide, an extracellular domain with four potential glycosylation sites, a single hydrophobic transmembrane domain, and a cytoplasmic hydrophilic domain. At the level of genomic DNA the EVI2B locus lies within the same intron of the NF1 gene as EVI2A and contains a 57-bp 5' exon that is noncoding, an 8-kb intron, and a 2078-bp 3' exon that includes the entire open reading frame. EVI2B is transcribed in the same direction as EVI2A; its 5' exon lies only 4 kb downstream from the 3' exon of the EVI2A locus. In the mouse the 5' exon of the homologous gene, Evi-2B, lies approximately 2.8 kb from the 3' end of Evi-2A, in the midst of a cluster of viral integration sites identified in retrovirus-induced myeloid tumors; thus, Evi-2B may function as an oncogene in these tumors.