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Syötteen kokonainen osoite. 8 tuntia 17 min sitten

Somatic late effects in 5-year survivors of neuroblastoma: A population-based cohort study within the Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study.

8 tuntia 17 min sitten
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Somatic late effects in 5-year survivors of neuroblastoma: A population-based cohort study within the Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study.

Int J Cancer. 2018 Jun 21;:

Authors: Norsker FN, Rechnitzer C, Cederkvist L, Tryggvadottir L, Madanat-Harjuoja LM, Øra I, Thorarinsdottir HK, Vettenranta K, Bautz A, Schrøder H, Hasle H, Winther JF

Abstract
Because of the rarity of neuroblastoma and poor survival until the 1990s, information on late effects in neuroblastoma survivors is sparse. We comprehensively reviewed the long-term risk for somatic disease in neuroblastoma survivors. We identified 721 5-year survivors of neuroblastoma in Nordic population-based cancer registries and identified late effects in national hospital registries covering the period 1977-2012. Detailed treatment information was available for 46% of the survivors. The disease-specific rates of hospitalization of survivors and of 152,231 randomly selected population comparisons were used to calculate standardized hospitalization rate ratios (SHRRs) and absolute excess risks (AERs). During 5,500 person-years of follow-up, 501 5-year survivors had a first hospital contact yielding a SHRR of 2.3 (95% CI 2.1-2.6) and a corresponding AER of 52 (95% CI 44-60) per 1,000 person-years. The highest relative risks were for diseases of blood and blood-forming organs (SHRR 3.8; 95% CI 2.7-5.4), endocrine diseases (3.6 [3.1-4.2]), circulatory system diseases (3.1 [2.5-3.8]), and diseases of the nervous system (3.0 [2.6-3.3]). Approximately 60% of the excess new hospitalizations of survivors were for diseases of the nervous system, urinary system, endocrine system, and bone and soft tissue. The relative risks and AERs were highest for the survivors most intensively treated. Survivors of neuroblastoma have a highly increased long-term risk for somatic late effects in all the main disease groups as compared with background levels. Our results are useful for counseling survivors and should contribute to improving health care planning in post-therapy clinics. This article is protected by copyright. All rights reserved.

PMID: 29926896 [PubMed - as supplied by publisher]

Immune cell contexture in the bone marrow tumor microenvironment impacts therapy response in CML.

8 tuntia 17 min sitten
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Immune cell contexture in the bone marrow tumor microenvironment impacts therapy response in CML.

Leukemia. 2018 Jun 20;:

Authors: Brück O, Blom S, Dufva O, Turkki R, Chheda H, Ribeiro A, Kovanen P, Aittokallio T, Koskenvesa P, Kallioniemi O, Porkka K, Pellinen T, Mustjoki S

Abstract
Increasing evidence suggests that the immune system affects prognosis of chronic myeloid leukemia (CML), but the detailed immunological composition of the leukemia bone marrow (BM) microenvironment is unknown. We aimed to characterize the immune landscape of the CML BM and predict the current treatment goal of tyrosine kinase inhibitor (TKI) therapy, molecular remission 4.0 (MR4.0). Using multiplex immunohistochemistry (mIHC) and automated image analysis, we studied BM tissues of CML patients (n = 56) and controls (n = 14) with a total of 30 immunophenotype markers essential in cancer immunology. CML patients' CD4+ and CD8+ T-cells expressed higher levels of putative exhaustion markers PD1, TIM3, and CTLA4 when compared to control. PD1 expression was higher in BM compared to paired peripheral blood (PB) samples, and decreased during TKI therapy. By combining clinical parameters and immune profiles, low CD4+ T-cell proportion, high proportion of PD1+TIM3-CD8+ T cells, and high PB neutrophil count were most predictive of lower MR4.0 likelihood. Low CD4+ T-cell proportion and high PB neutrophil counts predicted MR4.0 also in a validation cohort (n = 52) analyzed with flow cytometry. In summary, the CML BM is characterized by immune suppression and immune biomarkers predicted MR4.0, thus warranting further testing of immunomodulatory drugs in CML treatment.

PMID: 29925907 [PubMed - as supplied by publisher]

Registration free automatic identification of gold fiducial markers in MRI target delineation images for prostate radiotherapy.

8 tuntia 17 min sitten
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Registration free automatic identification of gold fiducial markers in MRI target delineation images for prostate radiotherapy.

Med Phys. 2017 Nov;44(11):5563-5574

Authors: Gustafsson C, Korhonen J, Persson E, Gunnlaugsson A, Nyholm T, Olsson LE

Abstract
PURPOSE: The superior soft tissue contrast of magnetic resonance imaging (MRI) compared to computed tomography (CT) has urged the integration of MRI and elimination of CT in radiotherapy treatment (RT) for prostate. An intraprostatic gold fiducial marker (GFM) appears hyperintense on CT. On T2-weighted (T2w) MRI target delineation images, the GFM appear as a small signal void similar to calcifications and post biopsy fibrosis. It can therefore be difficult to identify the markers without CT. Detectability of GFMs can be improved using additional MR images, which are manually registered to target delineation images. This task requires manual labor, and is associated with interoperator differences and image registration errors. The aim of this work was to develop and evaluate an automatic method for identification of GFMs directly in the target delineation images without the need for image registration.
METHODS: T2w images, intended for target delineation, and multiecho gradient echo (MEGRE) images intended for GFM identification, were acquired for prostate cancer patients. Signal voids in the target delineation images were identified as GFM candidates. The GFM appeared as round, symmetric, signal void with increasing area for increasing echo time in the MEGRE images. These image features were exploited for automatic identification of GFMs in a MATLAB model using a patient training dataset (n = 20). The model was validated on an independent patient dataset (n = 40). The distances between the identified GFM in the target delineation images and the GFM in CT images were measured. A human observatory study was conducted to validate the use of MEGRE images.
RESULTS: The sensitivity, specificity, and accuracy of the automatic method and the observatory study was 84%, 74%, 81% and 98%, 94%, 97%, respectively. The mean absolute difference in the GFM distances for the automatic method and observatory study was 1.28 ± 1.25 mm and 1.14 ± 1.06 mm, respectively.
CONCLUSIONS: Multiecho gradient echo images were shown to be a feasible and reliable way to perform GFM identification. For clinical practice, visual inspection of the results from the automatic method is needed at the current stage.

PMID: 28803447 [PubMed - indexed for MEDLINE]

Decreased spermatogonial quantity in prepubertal boys with leukaemia treated with alkylating agents.

8 tuntia 17 min sitten
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Decreased spermatogonial quantity in prepubertal boys with leukaemia treated with alkylating agents.

Leukemia. 2017 06;31(6):1460-1463

Authors: Poganitsch-Korhonen M, Masliukaite I, Nurmio M, Lähteenmäki P, van Wely M, van Pelt AMM, Jahnukainen K, Stukenborg JB

PMID: 28270690 [PubMed - indexed for MEDLINE]

Low STAT3 expression sensitizes to toxic effects of β-adrenergic receptor stimulation in peripartum cardiomyopathy.

8 tuntia 17 min sitten
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Low STAT3 expression sensitizes to toxic effects of β-adrenergic receptor stimulation in peripartum cardiomyopathy.

Eur Heart J. 2017 02 01;38(5):349-361

Authors: Stapel B, Kohlhaas M, Ricke-Hoch M, Haghikia A, Erschow S, Knuuti J, Silvola JM, Roivainen A, Saraste A, Nickel AG, Saar JA, Sieve I, Pietzsch S, Müller M, Bogeski I, Kappl R, Jauhiainen M, Thackeray JT, Scherr M, Bengel FM, Hagl C, Tudorache I, Bauersachs J, Maack C, Hilfiker-Kleiner D

Abstract
Aims: The benefit of the β1-adrenergic receptor (β1-AR) agonist dobutamine for treatment of acute heart failure in peripartum cardiomyopathy (PPCM) is controversial. Cardiac STAT3 expression is reduced in PPCM patients. Mice carrying a cardiomyocyte-restricted deletion of STAT3 (CKO) develop PPCM. We hypothesized that STAT3-dependent signalling networks may influence the response to β-AR agonist treatment in PPCM patients and analysed this hypothesis in CKO mice.
Methods and Results: Follow-up analyses in 27 patients with severe PPCM (left ventricular ejection fraction ≤25%) revealed that 19 of 20 patients not obtaining dobutamine improved cardiac function. All seven patients obtaining dobutamine received heart transplantation (n = 4) or left ventricular assist devices (n = 3). They displayed diminished myocardial triglyceride, pyruvate, and lactate content compared with non-failing controls. The β-AR agonist isoproterenol (Iso) induced heart failure with high mortality in postpartum female, in non-pregnant female and in male CKO, but not in wild-type mice. Iso induced heart failure and high mortality in CKO mice by impairing fatty acid and glucose uptake, thereby generating a metabolic deficit. The latter was governed by disturbed STAT3-dependent signalling networks, microRNA-199a-5p, microRNA-7a-5p, insulin/glucose transporter-4, and neuregulin/ErbB signalling. The resulting cardiac energy depletion and oxidative stress promoted dysfunction and cardiomyocyte loss inducing irreversible heart failure, which could be attenuated by the β1-AR blocker metoprolol or glucose-uptake-promoting drugs perhexiline and etomoxir.
Conclusions: Iso impairs glucose uptake, induces energy depletion, oxidative stress, dysfunction, and death in STAT3-deficient cardiomyocytes mainly via β1-AR stimulation. These cellular alterations may underlie the dobutamine-induced irreversible heart failure progression in PPCM patients who frequently display reduced cardiac STAT3 expression.

PMID: 28201733 [PubMed - indexed for MEDLINE]

Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

Ke, 20/06/2018 - 21:06
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

J Natl Cancer Inst. 2018 Jun 16;:

Authors: Schmit SL, Edlund CK, Schumacher FR, Gong J, Harrison TA, Huyghe JR, Qu C, Melas M, Van Den Berg DJ, Wang H, Tring S, Plummer SJ, Albanes D, Alonso MH, Amos CI, Anton K, Aragaki AK, Arndt V, Barry EL, Berndt SI, Bezieau S, Bien S, Bloomer A, Boehm J, Boutron-Ruault MC, Brenner H, Brezina S, Buchanan DD, Butterbach K, Caan BJ, Campbell PT, Carlson CS, Castelao JE, Chan AT, Chang-Claude J, Chanock SJ, Cheng I, Cheng YW, Chin LS, Church JM, Church T, Coetzee GA, Cotterchio M, Cruz Correa M, Curtis KR, Duggan D, Easton DF, English D, Feskens EJM, Fischer R, FitzGerald LM, Fortini BK, Fritsche LG, Fuchs CS, Gago-Dominguez M, Gala M, Gallinger SJ, Gauderman WJ, Giles GG, Giovannucci EL, Gogarten SM, Gonzalez-Villalpando C, Gonzalez-Villalpando EM, Grady WM, Greenson JK, Gsur A, Gunter M, Haiman CA, Hampe J, Harlid S, Harju JF, Hayes RB, Hofer P, Hoffmeister M, Hopper JL, Huang SC, Huerta JM, Hudson TJ, Hunter DJ, Idos GE, Iwasaki M, Jackson RD, Jacobs EJ, Jee SH, Jenkins MA, Jia WH, Jiao S, Joshi AD, Kolonel LN, Kono S, Kooperberg C, Krogh V, Kuehn T, Küry S, LaCroix A, Laurie CA, Lejbkowicz F, Lemire M, Lenz HJ, Levine D, Li CI, Li L, Lieb W, Lin Y, Lindor NM, Liu YR, Loupakis F, Lu Y, Luh F, Ma J, Mancao C, Manion FJ, Markowitz SD, Martin V, Matsuda K, Matsuo K, McDonnell KJ, McNeil CE, Milne R, Molina AJ, Mukherjee B, Murphy N, Newcomb PA, Offit K, Omichessan H, Palli D, Cotoré JPP, Pérez-Mayoral J, Pharoah PD, Potter JD, Qu C, Raskin L, Rennert G, Rennert HS, Riggs BM, Schafmayer C, Schoen RE, Sellers TA, Seminara D, Severi G, Shi W, Shibata D, Shu XO, Siegel EM, Slattery ML, Southey M, Stadler ZK, Stern MC, Stintzing S, Taverna D, Thibodeau SN, Thomas DC, Trichopoulou A, Tsugane S, Ulrich CM, van Duijnhoven FJB, van Guelpan B, Vijai J, Virtamo J, Weinstein SJ, White E, Win AK, Wolk A, Woods M, Wu AH, Wu K, Xiang YB, Yen Y, Zanke BW, Zeng YX, Zhang B, Zubair N, Kweon SS, Figueiredo JC, Zheng W, Marchand LL, Lindblom A, Moreno V, Peters U, Casey G, Hsu L, Conti DV, Gruber SB

Abstract
Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.
Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.
Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.
Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

PMID: 29917119 [PubMed - as supplied by publisher]

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.

Ke, 20/06/2018 - 21:06
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A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.

Nat Genet. 2018 Jun 18;:

Authors: Wu L, Shi W, Long J, Guo X, Michailidou K, Beesley J, Bolla MK, Shu XO, Lu Y, Cai Q, Al-Ejeh F, Rozali E, Wang Q, Dennis J, Li B, Zeng C, Feng H, Gusev A, Barfield RT, Andrulis IL, Anton-Culver H, Arndt V, Aronson KJ, Auer PL, Barrdahl M, Baynes C, Beckmann MW, Benitez J, Bermisheva M, Blomqvist C, Bogdanova NV, Bojesen SE, Brauch H, Brenner H, Brinton L, Broberg P, Brucker SY, Burwinkel B, Caldés T, Canzian F, Carter BD, Castelao JE, Chang-Claude J, Chen X, Cheng TD, Christiansen H, Clarke CL, NBCS Collaborators, Collée M, Cornelissen S, Couch FJ, Cox D, Cox A, Cross SS, Cunningham JM, Czene K, Daly MB, Devilee P, Doheny KF, Dörk T, Dos-Santos-Silva I, Dumont M, Dwek M, Eccles DM, Eilber U, Eliassen AH, Engel C, Eriksson M, Fachal L, Fasching PA, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Fritschi L, Gabrielson M, Gago-Dominguez M, Gapstur SM, García-Closas M, Gaudet MM, Ghoussaini M, Giles GG, Goldberg MS, Goldgar DE, González-Neira A, Guénel P, Hahnen E, Haiman CA, Håkansson N, Hall P, Hallberg E, Hamann U, Harrington P, Hein A, Hicks B, Hillemanns P, Hollestelle A, Hoover RN, Hopper JL, Huang G, Humphreys K, Hunter DJ, Jakubowska A, Janni W, John EM, Johnson N, Jones K, Jones ME, Jung A, Kaaks R, Kerin MJ, Khusnutdinova E, Kosma VM, Kristensen VN, Lambrechts D, Le Marchand L, Li J, Lindström S, Lissowska J, Lo WY, Loibl S, Lubinski J, Luccarini C, Lux MP, MacInnis RJ, Maishman T, Kostovska IM, Mannermaa A, Manson JE, Margolin S, Mavroudis D, Meijers-Heijboer H, Meindl A, Menon U, Meyer J, Mulligan AM, Neuhausen SL, Nevanlinna H, Neven P, Nielsen SF, Nordestgaard BG, Olopade OI, Olson JE, Olsson H, Peterlongo P, Peto J, Plaseska-Karanfilska D, Prentice R, Presneau N, Pylkäs K, Rack B, Radice P, Rahman N, Rennert G, Rennert HS, Rhenius V, Romero A, Romm J, Rudolph A, Saloustros E, Sandler DP, Sawyer EJ, Schmidt MK, Schmutzler RK, Schneeweiss A, Scott RJ, Scott CG, Seal S, Shah M, Shrubsole MJ, Smeets A, Southey MC, Spinelli JJ, Stone J, Surowy H, Swerdlow AJ, Tamimi RM, Tapper W, Taylor JA, Terry MB, Tessier DC, Thomas A, Thöne K, Tollenaar RAEM, Torres D, Truong T, Untch M, Vachon C, Van Den Berg D, Vincent D, Waisfisz Q, Weinberg CR, Wendt C, Whittemore AS, Wildiers H, Willett WC, Winqvist R, Wolk A, Xia L, Yang XR, Ziogas A, Ziv E, kConFab/AOCS Investigators, Dunning AM, Pharoah PDP, Simard J, Milne RL, Edwards SL, Kraft P, Easton DF, Chenevix-Trench G, Zheng W

Abstract
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

PMID: 29915430 [PubMed - as supplied by publisher]

Anxiety and pain during bone marrow aspiration and biopsy.

Ke, 20/06/2018 - 21:06
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Anxiety and pain during bone marrow aspiration and biopsy.

Scand J Pain. 2017 Dec 29;3(2):92-96

Authors: Kuivalainen AM, Pitkäniemi J, Widenius T, Elonen E, Rosenberg P

Abstract
Background Previously we found that pre-procedural nervousness and tension (translated into English as "anxiety"), assessed on a non-validated five-point scale, correlated with pain intensity of the various stages of bone marrow aspiration and biopsy (BMAB). The fewer the previous BMAB procedures the stronger the pain from a repeated procedure. The primary purpose of the present observational study is to evaluate the state of anxiety just before BMAB and to find out whether it affects the pain experiences during the various stages of the BMAB procedure. We also examined whether first-timers differ from patients with previous BMAB experience in the degree of anxiety and intensity of BMAB procedural pain. Methods A total of 166 adult outpatients undergoing the BMAB from the Helsinki University Hospital were enrolled, 48 of them being first-timers. The level of anxiety was measured with State-Trait Anxiety Inventory (STAI) and the pain experiences associated with the various stages of the procedure were evaluated on the NRS-scale (Numeral Rating Scale 0-10) and using the Finnish pain vocabulary. BMAB was planned to be performed under lidocaine infiltration anaesthesia but, on request, patients were allowed to receive premedication with diazepam orally or alfentanil i.m. If, in spite of supplemental local anaesthetic the patient still felt pain from the sampling needle tip, i.m. alfentanil was administered. Results There was a clear association between anxiety and pain during all stages of the procedure, except during biopsy. The NRS scores varied from 0 to 10 in all the various stages of BMAB. The first-timers did not differ from the more experienced patients with regard to pain experiences; only the pain felt during the local anaesthetic infiltration was milder (P = 0.007) in first-timers than in the others. Procedural pain in those who were given analgesic or sedative premedication was similar (P < 0.05) to that in the non-premedicated patients. The words characterizing the pain of the various stages belonged to a major extent (76-90%) to the sensory class of words. Conclusion Pre-procedural anxiety had a major impact on the pain ratings. The first-timers and patients with previous experience of BMAB had a similar degree of pre-procedural anxiety, as well as of the intensity of procedural pain, except that infiltration of local anaesthetic was less painful in the first-timers. Implications Identification of anxious (fearful) patients prior to BMAB, and premedicating them individually may improve satisfaction in both patient and caregiver.

PMID: 29913774 [PubMed - in process]

Warmed and buffered lidocaine for pain relief during bone marrow aspiration and biopsy. A randomized and controlled trial.

Ke, 20/06/2018 - 21:06
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Warmed and buffered lidocaine for pain relief during bone marrow aspiration and biopsy. A randomized and controlled trial.

Scand J Pain. 2017 Dec 29;5(1):43-47

Authors: Kuivalainen AM, Ebeling F, Rosenberg P

Abstract
Background and purpose Local infiltration anaesthesia is frequently painful due to low pH of the used anaesthetics, such as lidocaine. Usually pH of the solution is near 4.0, which causes tissue irritation and excitation of the pain mediating nerve endings. Warming and buffering the local anaesthetic solution have been shown to reduce the patient's experience of pain and unpleasantness during infiltration. Buffering reduces the dissociation of the local anaesthetic molecule and may enhance the anaesthetic's entrance into nerve cells. In this randomized placebo-controlled trial warmed and buffered lidocaine with adrenaline was compared to room temperature unbuffered lidocaine with adrenaline infiltrated before bone marrow aspiration and/or biopsy (BMAB). The aim was to find out to what extent warming and buffering would diminish pain during infiltration and whether this would be reflected in less pain also during subsequent steps of the BMAB procedure. Methods One hundred patients scheduled to undergo BMAB were interviewed regarding subjective experiences from previous medical procedures, current chronic and temporary medications, and their present state of anxiety before the BMAB procedure. They received local anaesthetic infiltration of lidocaine prior to BMAB. The solution used was either warmed lidocaine 20 mg/ml with adrenaline buffered with sodium bicarbonate 75 mg/ml (warmed and buffered group, 50 patients, pH approximately 7.3, 32°C) or unbuffered lidocaine 20 mg/ml with adrenaline mixed with NaCl 0.9% solution (control group, 50 patients, pH approximately 3.7, room temperature). The lidocaine concentration was similar in both groups. The bone marrow sampling needle was inserted 2 min after local anaesthetic infiltration. The grade of preprocedural anxiety, and pain sensations during the BMAB, both rated on NRS (numeral rating scale, 0-10) were compared between the groups. Results In comparison with the use of an unbuffered solution at room temperature warmed and buffered lidocaine with adrenaline caused less pain during infiltration (median NRS 4.0 vs. 2.0, P < 0.002) but it did not make performing the other phases of BMAB any less painful. As expected, painful experiences from previous medical, other than BMAB, or dental procedures and anxiety were associated with local anaesthetic infiltration pain during BMAB. Patients' own pain or anxiolytic medication did not lessen pain during BMAB. Conclusions By warming and buffering the lidocaine solution containing adrenaline it is possible to make the pain during infiltration less intense. Unfortunately, such benefit was not detected during the following steps of BMAB, initiated 2 min later. Preprocedural anxiety made procedural pain more intense including that of the local anaesthetic infiltration. Implications Warming and buffering the local anaesthetic prior to its administration is an effective and simple way of diminishing pain during infiltration. This benefit seems to be underutilized in the BMAB procedure. However, warming and buffering are not sufficient enough to diminish pain during bone marrow sampling and thus additional pain alleviating methods should be used, particularly in patients showing preprocedural anxiety.

PMID: 29913658 [PubMed - in process]

Nitrous oxide analgesia for bone marrow aspiration and biopsy - A randomized, controlled and patient blinded study.

Ti, 19/06/2018 - 21:06

Nitrous oxide analgesia for bone marrow aspiration and biopsy - A randomized, controlled and patient blinded study.

Scand J Pain. 2017 Dec 29;7(1):28-34

Authors: Kuivalainen AM, Ebeling F, Poikonen E, Rosenberg PH

Abstract
Background and aims Bone marrow aspiration and/or biopsy (BMAB), performed under local anaesthesia in adults, is a common and often painful procedure. Anxiety is known to intensify pain during the procedure. Nitrous oxide (N2O), known for its sedative and analgesic benefit in various short medical procedures and labour pain, could be advantageous also for pain relief during bone marrow examination. N2O acts rapidly and is eliminated in a couple of minutes once the inhalation is stopped, and occasional side effects (e.g. dizziness and nausea) are mild. The aim of this study was to compare the analgesic effects of inhaled 50% mixture of nitrous oxide and oxygen to 50% oxygen during bone marrow examination. Methods In this randomized, controlled, patient and observer blinded study patients received either 50% mixture of nitrous oxide and oxygen or 50% mixture of oxygen in air during bone marrow examination, in addition to local analgesia. Both patient groups comprised 35 adult patients. Pre-procedural anxiety and procedural pain were rated on the Numeral Rating Scale (NRS 0‒10). Cognitive function was measured before and 30 min after the procedure. Possible side effects were recorded. A telephone interview was performed 24 h later. Results There were no statistically significant differences in pain scores of the procedural steps (median NRS ranging 3.0‒4.0) between the study groups. High pain scores of 8‒10 comprised 0% vs. 8.6% of the scores during infiltration, 2.9% vs. 5.7% during puncture, 11.4% vs. 14.3% during aspiration and 2.9% vs. 2.9% during biopsy in N2O and 50% O2 groups, respectively (NS). Pre-procedural anxiety (median NRS 3.5 in both groups), measured in the outpatient clinic just prior to procedure, correlated with pain intensity during bone marrow aspiration (P = 0.045). There were no significant differences between side effects. During the BMAB four patients (3 in N2O group, 1 in 50% O2 group) reported dizziness and one patient in the N2O group reported nausea. Gas inhalation did not affect the cognitive function of the participants. In both groups the majority (>80%) of the patients was satisfied with the inhalation technique. During the 24 h interview, most of the participants were pain free and they did not report any serious adverse effects. Conclusions In spite of similar moderate to strong procedural pain in both groups and no benefit of N2O, most patients were satisfied with the inhalational techniques. We assume that the bedside presence of an anaesthesiologist and the distraction caused by the inhalational arrangements introduced positive context-sensitive therapeutic effect independent of the gas used. Pre-procedural anxiety predicted pain associated with bone marrow aspiration. Implications Inhaled 50% nitrous oxide was not an effective analgesic during bone marrow examination in our unselected outpatient population. Further studies should concentrate on its use with patients predicted to be at increased risk of suffering intense pain during the procedure, such as very anxious patients or those who have a painful history of previous bone marrow examinations.

PMID: 29911602 [PubMed - in process]

Environmental impact of switching from the synthetic glucocorticoid prednisolone to the natural alkaloid berberine.

Pe, 15/06/2018 - 21:04
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Environmental impact of switching from the synthetic glucocorticoid prednisolone to the natural alkaloid berberine.

PLoS One. 2018;13(6):e0199095

Authors: Allijn IE, Oldenkamp R, Storm G, Ragas AMJ, Schiffelers RM

Abstract
Low amounts of human pharmaceuticals in the aquatic environment can affect bacteria, animals and ultimately humans. Here, the environmental consequences of a shift in prescription behavior from prednisolone to berberine was modeled using an environmental decision support system based on four consecutive steps: emission, fate, exposure and effect. This model estimates the relative aquatic and human health impacts of alternative pharmaceutical prescriptions throughout Europe. Since a Defined Daily Dose (DDD) of berberine has yet to be formulated, the environmental impacts of berberine and prednisolone were compared under the assumption of equal DDDs. Subsequently, the relative impact ratio indicates the extent to which the actual DDD of berberine might be higher to still be environmentally preferable over prednisolone. In fact, berberine can be administered at a six times higher dose throughout Europe before its impact on the aquatic environment exceeds that of one prescription of prednisolone. On average, the results for impacts on human health are similar, with the median impact ratio ranging between 5.87 and 22.8 depending on the level of drinking water purification. However, for some regions in Spain, Austria, Baltic States and Finland, berberine can only be considered an environmentally better alternative if it is administered at a lower dose than prednisolone. We conclude that for most regions in Europe it is, up until a certain dose of berberine, beneficial for the aquatic environment and therefore human health to prefer prescription of berberine over prednisolone.

PMID: 29902284 [PubMed - in process]

Dissection of progenitor compartments resolves developmental trajectories in B-lymphopoiesis.

Pe, 15/06/2018 - 21:04
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Dissection of progenitor compartments resolves developmental trajectories in B-lymphopoiesis.

J Exp Med. 2018 Jun 13;:

Authors: Jensen CT, Åhsberg J, Sommarin MNE, Strid T, Somasundaram R, Okuyama K, Ungerbäck J, Kupari J, Airaksinen MS, Lang S, Bryder D, Soneji S, Karlsson G, Sigvardsson M

Abstract
To understand the developmental trajectories in early lymphocyte differentiation, we identified differentially expressed surface markers on lineage-negative lymphoid progenitors (LPs). Single-cell polymerase chain reaction experiments allowed us to link surface marker expression to that of lineage-associated transcription factors (TFs) and identify GFRA2 and BST1 as markers of early B cells. Functional analyses in vitro and in vivo as well as single-cell gene expression analyses supported that surface expression of these proteins defined distinct subpopulations that include cells from both the classical common LPs (CLPs) and Fraction A compartments. The formation of the GFRA2-expressing stages of development depended on the TF EBF1, critical both for the activation of stage-specific target genes and modulation of the epigenetic landscape. Our data show that consecutive expression of Ly6D, GFRA2, and BST1 defines a developmental trajectory linking the CLP to the CD19+ progenitor compartment.

PMID: 29899037 [PubMed - as supplied by publisher]

Genomic landscape characterization of large granular lymphocyte leukemia with a systems genetics approach.

Pe, 15/06/2018 - 21:04
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Genomic landscape characterization of large granular lymphocyte leukemia with a systems genetics approach.

Leukemia. 2017 05;31(5):1243-1246

Authors: Coppe A, Andersson EI, Binatti A, Gasparini VR, Bortoluzzi S, Clemente M, Herling M, Maciejewski J, Mustjoki S, Bortoluzzi S

PMID: 28167832 [PubMed - indexed for MEDLINE]

HIF1-alpha Regulates Acinar Cell Function and Response to Injury in Mouse Pancreas.

To, 14/06/2018 - 21:04
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HIF1-alpha Regulates Acinar Cell Function and Response to Injury in Mouse Pancreas.

Gastroenterology. 2018 05;154(6):1630-1634.e3

Authors: Park MJ, Iyer S, Xue X, Bragazzi Cunha J, Gu S, Moons D, Pipe SW, Williams JA, Simeone DM, Shah YM, Omary MB

Abstract
We investigated whether intrapancreatic coagulation, with deposition of the fibrinogen-γ dimer (Fib-γD) and hypoxia, affect the severity of acute pancreatitis (AP) in mice. Pancreata of mice with AP induced by administration of cerulein or by L-arginine, or from patients with pancreatitis, had increased deposition of Fib-γD compared with control pancreata. Heparin administration protected mice from cerulein-induced AP and prevented Fib-γD formation. Cerulein administration resulted in activation and stabilization of hypoxia-inducible factor-1α (HIF1α) in pancreata of oxygen-dependent degradation domain-luciferase HIF1α reporter mice. Cerulein also led to induction of genes regulated by HIF1α, including Vegfa and Ero1a, before evidence of Fib-γD deposition or histologic features of AP. Expression of tissue factor, which is regulated by vascular endothelial growth factor, also increased following cerulein administration. Mice with acinar cell-specific disruption of Hif1a (Hif1aAc-/-) developed spontaneous endoplasmic reticulum stress and less severe AP, but did not accumulate Fib-γD following administration of cerulein. Feeding mice increased pancreatic expression of HIF1α, indicating a physiologic role in the exocrine pancreas. Therefore, HIF1α has bifunctional roles, in exocrine pancreas homeostasis and progression of AP that is promoted by intrapancreatic coagulation.

PMID: 29409830 [PubMed - indexed for MEDLINE]

Endothelin A receptor blocker and calcimimetic in the adenine rat model of chronic renal insufficiency.

To, 14/06/2018 - 21:04
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Endothelin A receptor blocker and calcimimetic in the adenine rat model of chronic renal insufficiency.

BMC Nephrol. 2017 Oct 27;18(1):323

Authors: Törmänen S, Pörsti I, Lakkisto P, Tikkanen I, Niemelä O, Paavonen T, Mustonen J, Eräranta A

Abstract
BACKGROUND: We studied whether endothelin receptor antagonist and calcimimetic treatments influence renal damage and kidney renin-angiotensin (RA) components in adenine-induced chronic renal insufficiency (CRI).
METHODS: Male Wistar rats (n = 80) were divided into 5 groups for 12 weeks: control (n = 12), 0.3% adenine (Ade; n = 20), Ade + 50 mg/kg/day sitaxentan (n = 16), Ade + 20 mg/kg/day cinacalcet (n = 16), and Ade + sitaxentan + cinacalcet (n = 16). Blood pressure (BP) was measured using tail-cuff, kidney histology was examined, and RA components measured using RT-qPCR.
RESULTS: Adenine caused tubulointerstitial damage with severe CRI, anemia, hyperphosphatemia, 1.8-fold increase in urinary calcium excretion, and 3.5-fold and 18-fold increases in plasma creatinine and PTH, respectively. Sitaxentan alleviated tubular atrophy, while sitaxentan + cinacalcet combination reduced interstitial inflammation, tubular dilatation and atrophy in adenine-rats. Adenine diet did not influence kidney angiotensin converting enzyme (ACE) and AT4 receptor mRNA, but reduced mRNA of renin, AT1a, AT2, (pro)renin receptor and Mas to 40-60%, and suppressed ACE2 to 6% of that in controls. Sitaxentan reduced BP by 8 mmHg, creatinine, urea, and phosphate concentrations by 16-24%, and PTH by 42%. Cinacalcet did not influence BP or creatinine, but reduced PTH by 84%, and increased hemoglobin by 28% in adenine-rats. The treatments further reduced renin mRNA by 40%, while combined treatment normalized plasma PTH, urinary calcium, and increased ACE2 mRNA 2.5-fold versus the Ade group (p < 0.001).
CONCLUSIONS: In adenine-induced interstitial nephritis, sitaxentan improved renal function and tubular atrophy. Sitaxentan and cinacalcet reduced kidney renin mRNA by 40%, while their combination alleviated tubulointerstitial damage and urinary calcium loss, and increased kidney tissue ACE2 mRNA.

PMID: 29078759 [PubMed - indexed for MEDLINE]

Therapeutic use of transferrin to modulate anemia and conditions of iron toxicity.

Ke, 13/06/2018 - 21:03
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Therapeutic use of transferrin to modulate anemia and conditions of iron toxicity.

Blood Rev. 2017 Nov;31(6):400-405

Authors: Boshuizen M, van der Ploeg K, von Bonsdorff L, Biemond BJ, Zeerleder SS, van Bruggen R, Juffermans NP

Abstract
As the main iron transporter, transferrin delivers iron to target tissues like the bone marrow for erythropoiesis. Also, by binding free iron, transferrin prevents formation of reactive oxygen species. Transferrin deficiency due to congenital hypotransferrinemia is characterized by anemia as well as oxidative stress related to toxic free iron. Transferrin supplementation may be beneficial in two ways. First, transferrin can correct anemia by modulating the amount of iron that is available for erythropoiesis. This is obvious for patients that suffer from hypotransferrinemia, but may also have beneficial effects for β-thalassemia patients. Second, under conditions of iron overload, transferrin reduces oxidative stress by binding free iron in the circulation and in tissues. Hereby, transferrin protects the host against the reactive oxygen species that can be formed as a consequence of free iron. This beneficial effect is shown in hematological patients undergoing chemotherapy and stem cell transplantation. Transferrin may also be beneficial in lung injury, ischemia-reperfusion injury and hypomyelination. This review summarizes the preclinical and clinical data on the efficacy of exogenous transferrin administration to modulate certain forms of anemia and to prevent the toxic effects of free iron. Thereby, we show that transferrin has promising therapeutic potential in a wide variety of conditions.

PMID: 28755795 [PubMed - indexed for MEDLINE]

Effect of Wilms tumor histology on response to neoadjuvant chemotherapy.

Ti, 12/06/2018 - 21:02

Effect of Wilms tumor histology on response to neoadjuvant chemotherapy.

J Pediatr Surg. 2018 May 19;:

Authors: Taskinen S, Leskinen O, Lohi J, Koskenvuo M, Taskinen M

Abstract
PURPOSE: To evaluate the association between Wilms tumor histology at diagnosis and the change in Wilms' tumor volume during preoperative chemotherapy.
METHODS: We included all the 52 patients operated for Wilms tumor at 1988-2015, who had both pathology samples and either CT or MRI-images before and after preoperative chemotherapy, available for reevaluation.
RESULTS: The median tumor volume was 586 ml (IQR 323-903) at diagnosis. The median change in tumor volume was -68% (IQR -85 to -40, p < 0.001) and the proportion of tumor necrosis 85% (IQR 24-97), after preoperative chemotherapy. There was a correlation between blastemal cell content in prechemotherapy cutting needle biopsy (CNB) sample and the reduction in tumor volume (Rho = -0.452, p = 0.002). High stromal and epithelial cell contents in CNB samples were associated with the lesser change in tumor volume (Rho = 0.279, p  =0.053 and Rho = 0.300, p = 0.038 respectively). Reduction of tumor volume and the proportion of tumor necrosis after chemotherapy were associated (Rho = -0.502, p < 0.001). The actual viable tumor volume decreased in median by 97% (IQR 65-100), and the decrease could be seen in all cellular components. In three patients, the tumor volume increased more than 10% during the preoperative chemotherapy. Two of them had anaplastic tumor in the nephrectomy specimen.
CONCLUSION: Wilms tumor total and viable tumor volumes were reduced by 68% and 97% with preoperative chemotherapy, respectively. High proportion of blastemal cells in CNB was associated with greatest decrease in Wilms tumor volume. Increase in tumor volume during preoperative chemotherapy may indicate anaplastic tumor and prolonging of preoperative therapy should be avoided.
TYPE OF STUDY: Retrospective review.
LEVEL OF EVIDENCE: Level III.

PMID: 29887169 [PubMed - as supplied by publisher]

SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub.

Pe, 08/06/2018 - 21:00
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SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub.

Nat Commun. 2018 Jun 06;9(1):2192

Authors: Piazza R, Magistroni V, Redaelli S, Mauri M, Massimino L, Sessa A, Peronaci M, Lalowski M, Soliymani R, Mezzatesta C, Pirola A, Banfi F, Rubio A, Rea D, Stagno F, Usala E, Martino B, Campiotti L, Merli M, Passamonti F, Onida F, Morotti A, Pavesi F, Bregni M, Broccoli V, Baumann M, Gambacorti-Passerini C

Abstract
SETBP1 variants occur as somatic mutations in several hematological malignancies such as atypical chronic myeloid leukemia and as de novo germline mutations in the Schinzel-Giedion syndrome. Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex. Deletion of two AT-hooks abrogates the binding of SETBP1 to gDNA and impairs target gene upregulation. Genes controlled by SETBP1 such as MECOM are significantly upregulated in leukemias containing SETBP1 mutations. Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis. In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration. In summary, this work unveils a SETBP1 function that directly affects gene transcription and clarifies the mechanism operating in myeloid malignancies and in the Schinzel-Giedion syndrome caused by SETBP1 mutations.

PMID: 29875417 [PubMed - in process]

EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment.

To, 07/06/2018 - 21:00
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EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment.

Bone Marrow Transplant. 2018 Jun 05;:

Authors: Schoemans HM, Lee SJ, Ferrara JL, Wolff D, Levine JE, Schultz KR, Shaw BE, Flowers ME, Ruutu T, Greinix H, Holler E, Basak G, Duarte RF, Pavletic SZ, EBMT (European Society for Blood and Marrow Transplantation) Transplant Complications Working Party and the “EBMT−NIH (National Institutes of Health)−CIBMTR (Center for International Blood and Marrow Transplant Research) GvHD Task Force”

PMID: 29872128 [PubMed - as supplied by publisher]

Preoperative Biomarker Panel, Including Fibrinogen and FVIII, Improves Diagnostic Accuracy for Pancreatic Ductal Adenocarcinoma.

To, 07/06/2018 - 09:00
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Preoperative Biomarker Panel, Including Fibrinogen and FVIII, Improves Diagnostic Accuracy for Pancreatic Ductal Adenocarcinoma.

Clin Appl Thromb Hemost. 2018 Jan 01;:1076029618779133

Authors: Mattila N, Seppänen H, Mustonen H, Przybyla B, Haglund C, Lassila R

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer often diagnosed late. Earlier detection is urgently needed. Pancreatic ductal adenocarcinoma is known to associate with increased coagulation activity. We studied whether preoperative coagulation biomarkers are useful in distinguishing PDAC from a benign tumor, intraductal papillary mucinous neoplasm (IPMN) in this observational study. We analyzed standard clinical and coagulation variables in patients operated during 2010 and 2015 at Helsinki University Hospital. Pancreatic ductal adenocarcinoma with preoperative coagulation variables available and no neoadjuvant treatment or other active cancer was observed in 80 patients (stage I-III in 67 and IV in 13) and IPMN in 18 patients. Fibrinogen, factor VIII (FVIII), carbohydrate antigen (CA) 19-9, albumin, alkaline phosphatase, and conjugated bilirubin were higher in both stages I to III and IV PDAC compared to IPMN ( P < .05). Factor VIII was highest in stage IV ( P < .05). Combining these variables in a panel increased sensitivity and specificity for PDAC. In receiver operating characteristic analysis, the area under the curve (95% confidence interval) was 0.95 (0.90-1.00) for the panel, compared to 0.80 (0.71-0.88) for CA 19-9 alone ( P < .01). In conclusion, PDAC was associated with increased fibrinogen and FVIII. Combining these coagulation biomarkers with CA 19-9, albumin, and alkaline phosphatase improves diagnostic accuracy.

PMID: 29865859 [PubMed - as supplied by publisher]