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Associations between pretherapeutic body mass index, outcome, and cytogenetic abnormalities in pediatric acute myeloid leukemia.

To, 19/09/2019 - 23:43
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Associations between pretherapeutic body mass index, outcome, and cytogenetic abnormalities in pediatric acute myeloid leukemia.

Cancer Med. 2019 Sep 18;:

Authors: Løhmann DJA, Asdahl PH, Abrahamsson J, Ha SY, Jónsson ÓG, Kaspers GJL, Koskenvuo M, Lausen B, De Moerloose B, Palle J, Zeller B, Sung L, Hasle H

Abstract
BACKGROUND: Associations between body mass index (BMI), outcome, and leukemia-related factors in children with acute myeloid leukemia (AML) remain unclear. We investigated associations between pretherapeutic BMI, cytogenetic abnormalities, and outcome in a large multinational cohort of children with AML.
METHODS: We included patients, age 2-17 years, diagnosed with de novo AML from the five Nordic countries (2004-2016), Hong Kong (2007-2016), the Netherlands and Belgium (2010-2016), and Canada and USA (1995-2012). BMI standard deviations score for age and sex was calculated and categorized according to the World Health Organization. Cumulative incidence functions, Kaplan-Meier estimator, Cox regression, and logistic regression were used to investigate associations.
RESULTS: In total, 867 patients were included. The median age was 10 years (range 2-17 years). At diagnosis, 32 (4%) were underweight, 632 (73%) were healthy weight, 127 (15%) were overweight, and 76 (9%) were obese. There was no difference in relapse risk, treatment-related mortality or overall mortality across BMI groups. The frequency of t(8;21) and inv(16) increased with increasing BMI. For obese patients, the sex, age, and country adjusted odds ratio of having t(8;21) or inv(16) were 1.9 (95% confidence interval (CI) 1.1-3.4) and 2.8 (95% CI 1.3-5.8), respectively, compared to healthy weight patients.
CONCLUSIONS: This study did not confirm previous reports of associations between overweight and increased treatment-related or overall mortality in children. Obesity was associated with a higher frequency of t(8;21) and inv(16). AML cytogenetics appear to differ by BMI status.

PMID: 31532076 [PubMed - as supplied by publisher]

Increased ALK activity induces a poorly differentiated thyroid carcinoma in mice.

To, 19/09/2019 - 23:43
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Increased ALK activity induces a poorly differentiated thyroid carcinoma in mice.

Thyroid. 2019 Sep 16;:

Authors: Kohler H, Latteyer S, Hoenes S, Theurer S, Liao XH, Christoph S, Zwanziger D, Schulte JH, Kero J, Undeutsch H, Refetoff S, Schmid KW, Fuehrer D, Moeller LC

Abstract
BACKGROUND: Radioiodine refractory dedifferentiated thyroid cancer is a major clinical challenge. Anaplastic lymphoma kinase (ALK) mutations with increased ALK activity, especially fusion genes, have been suggested to promote thyroid carcinogenesis, leading to development of poorly differentiated and anaplastic thyroid cancer (PDTC and ATC). To determine the oncogenic potential of increased ALK activity in thyroid carcinogenesis in vivo, we studied mice with thyrocyte-specific expression of a constitutively active ALK mutant.
METHODS: Mice carrying a Cre-activated allele of a constitutively active ALK mutant (F1174L) were crossed with mice expressing tamoxifen-inducible Cre recombinase (CreER<sup>T2</sup>) under control of the thyroglobulin promoter to achieve thyrocyte-specific expression of the ALK mutant (ALK<sup>F1174L</sup> mice). Survival, thyroid hormone serum concentration and tumor development were recorded. Thyroids and lungs were studied histologically. To maintain euthyroidism despite dedifferentiation of the thyroid, a cohort was substituted with L-thyroxine via drinking water.
RESULTS: ALK<sup>F1174L</sup> mice developed massively enlarged thyroids, which showed an early loss of normal follicular architecture 12 weeks after tamoxifen injection. A significant decrease in thyroglobulin and Nkx-2.1 expression as well as impaired thyroid hormone synthesis confirmed dedifferentiation. Histologically, the mice developed a carcinoma resembling human PDTC with a predominantly trabecular/solid growth pattern and an increased mitotic rate. The tumors showed extrathyroidal extension into the surrounding strap muscles and developed lung metastases. Median survival of ALK<sup>F1174L</sup> mice was significantly reduced to 5 months after tamoxifen injection. Reduced thyroglobulin expression and loss of follicular structure led to hypothyroidism with elevated TSH. To test whether TSH stimulation played a role in thyroid carcinogenesis, we kept ALK<sup>F1174L</sup> mice euthyroid by L-thyroxine substitution. These mice developed PDTC with identical histological features compared to hypothyroid mice, demonstrating that PDTC development was due to increased ALK activity and not dependent on TSH stimulation.
CONCLUSION: Expression of a constitutively activated ALK mutant in thyroids of mice leads to development of metastasizing thyroid cancer resembling human PDTC. These results demonstrate in vivo that increased ALK activity is a driver mechanism in thyroid carcinogenesis.

PMID: 31526103 [PubMed - as supplied by publisher]

Equity and diversity in academic medicine: a perspective from the JCI editors.

Ti, 17/09/2019 - 23:42
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Equity and diversity in academic medicine: a perspective from the JCI editors.

J Clin Invest. 2019 Sep 16;:

Authors: Resar LMS, Jaffee EM, Armanios M, Jackson S, Azad NS, Horton MR, Kaplan MJ, Laiho M, Maus MV, Sumner CJ, Wheelan SJ, Wills-Karp M

PMID: 31524636 [PubMed - as supplied by publisher]

Smoking is Associated to DNA Methylation in Atherosclerotic Carotid Lesions.

Ti, 17/09/2019 - 23:42
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Smoking is Associated to DNA Methylation in Atherosclerotic Carotid Lesions.

Circ Genom Precis Med. 2018 09;11(9):e002030

Authors: Siemelink MA, van der Laan SW, Haitjema S, van Koeverden ID, Schaap J, Wesseling M, de Jager SCA, Mokry M, van Iterson M, Dekkers KF, Luijk R, Foroughi Asl H, Michoel T, Björkegren JLM, Aavik E, Ylä-Herttuala S, de Borst GJ, Asselbergs FW, El Azzouzi H, den Ruijter HM, Heijmans BT, Pasterkamp G

Abstract
BACKGROUND: Tobacco smoking is a major risk factor for atherosclerotic disease and has been associated with DNA methylation (DNAm) changes in blood cells. However, whether smoking influences DNAm in the diseased vascular wall is unknown but may prove crucial in understanding the pathophysiology of atherosclerosis. In this study, we associated current tobacco smoking to epigenome-wide DNAm in atherosclerotic plaques from patients undergoing carotid endarterectomy.
METHODS: DNAm at commonly methylated sites (cytosine-guanine nucleotide pairs separated by a phospho-group [CpGs]) was assessed in atherosclerotic plaque samples and peripheral blood samples from 485 carotid endarterectomy patients. We tested the association of current tobacco smoking with DNAm corrected for age and sex. To control for bias and inflation because of cellular heterogeneity, we applied a Bayesian method to estimate an empirical null distribution as implemented by the R package bacon. Replication of the smoking-associated methylated CpGs in atherosclerotic plaques was executed in the second sample of 190 carotid endarterectomy patients, and results were meta-analyzed using a fixed-effects model.
RESULTS: Tobacco smoking was significantly associated to differential DNAm in atherosclerotic lesions of 4 CpGs (false discovery rate <0.05) mapped to 2 different genes ( AHRR, ITPK1) and 17 CpGs mapped to 8 genes and RNAs in blood. The strongest associations were found for CpGs mapped to the gene AHRR, a repressor of the aryl hydrocarbon receptor transcription factor involved in xenobiotic detoxification. One of these methylated CpGs were found to be regulated by local genetic variation.
CONCLUSIONS: The risk factor tobacco smoking associates with DNAm at multiple loci in carotid atherosclerotic lesions. These observations support further investigation of the relationship between risk factors and epigenetic regulation in atherosclerotic disease.

PMID: 30354327 [PubMed - indexed for MEDLINE]

Impact of time since diagnosis and mortality rate on cancer-associated venous thromboembolism: the Scandinavian Thrombosis and Cancer (STAC) cohort.

Ti, 17/09/2019 - 23:42
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Impact of time since diagnosis and mortality rate on cancer-associated venous thromboembolism: the Scandinavian Thrombosis and Cancer (STAC) cohort.

J Thromb Haemost. 2018 07;16(7):1327-1335

Authors: Blix K, Gran OV, Severinsen MT, Cannegieter SC, Jensvoll H, Overvad K, Hammerstrøm J, Tjønneland A, Naess IA, Braekkan SK, Rosendaal FR, Kristensen SR, Hansen JB

Abstract
Essentials Competing risk by death may lead to overestimation of venous thromboembolism (VTE) risk in cancers. We assessed the risk of VTE in cancer with and without accounting for competing risk by death. The risk of VTE was influenced by the mortality rate and the time since cancer diagnosis. Competing risk by death should be taken into account when exploring VTE risk in cancer.
SUMMARY: Background Venous thromboembolism (VTE) is a common complication in cancer, and studies have suggested that aggressive cancers create the highest risk of VTE. However, competing risk by death may result in overestimation of VTE risk in patients with cancers associated with high mortality. Therefore, we estimated the risk of VTE by cancer site, accounting for the differential mortality between cancers. Methods The Scandinavian Thrombosis and Cancer cohort included 144 952 participants followed from 1993-1997 to 2008-2012. Incidence rates, cause-specific hazard ratios (HRs) and subdistribution HRs (SHRs) were assessed for overall cancer and by cancer site according to time intervals since cancer diagnosis. Results During follow-up, 14 272 subjects developed cancer, and 567 had cancer-related VTE. In cause-specific analyses, the VTE risk was highest in the first 6 months after cancer diagnosis (HR 17.5, 95% confidence interval [CI] 15.1-20.3), and declined rapidly thereafter. However, when mortality was taken into account, the risk was similar in the periods 6 months before (SHR 4.8, 95% CI 3.6-6.4) and 6 months after (SHR 4.6, 95% CI 3.9-5.4) cancer diagnosis. The range of the 2-year cumulative VTE incidence rates was substantially narrowed for all cancer sites after competing risk by death was taken into account (from 1-10% to 1-4%). Conclusion VTE risk by cancer site was influenced by the mortality rate and the time since cancer diagnosis. Our findings suggest that the cancer itself is a major contributor to VTE risk, and that competing risk by death should be taken into account when VTE risk in cancer is explored.

PMID: 29691978 [PubMed - indexed for MEDLINE]

Distinct factors determine the kinetics of disease relapse in adults transplanted for acute myeloid leukaemia.

Ti, 17/09/2019 - 23:42
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Distinct factors determine the kinetics of disease relapse in adults transplanted for acute myeloid leukaemia.

J Intern Med. 2018 04;283(4):371-379

Authors: Craddock C, Versluis J, Labopin M, Socie G, Huynh A, Deconinck E, Volin L, Milpied N, Bourhis JH, Rambaldi A, Chevallier P, Blaise D, Manz M, Vellenga E, Vekemans MC, Maertens J, Passweg J, Vyas P, Schmid C, Löwenberg B, Ossenkoppele G, Mohty M, Cornelissen JJ, Nagler A, Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and HOVON-SAKK

Abstract
BACKGROUND: Disease recurrence remains the major cause of death in adults with acute myeloid leukaemia (AML) treated using either intensive chemotherapy (IC) or allogenic stem cell transplantation (allo-SCT).
AIMS: The timely delivery of maintenance drug or cellular therapies represent emerging strategies with the potential to reduce relapse after both treatment modalities, but whilst the determinants of overall relapse risk have been extensively characterized the factors determining the timing of disease recurrence have not been characterized.
MATERIALS AND METHODS: We have therefore examined, using a series of sequential landmark analyses, relapse kinetics in a cohort of 2028 patients who received an allo-SCT for AML in CR1 and separately 570 patients treated with IC alone.
RESULTS: In the first 3 months after allo-SCT, the factors associated with an increased risk of relapse included the presence of the FLT3-ITD (P < 0.001), patient age (P = 0.012), time interval from CR1 to transplant (P < 0.001) and donor type (P = 0.03). Relapse from 3 to 6 months was associated with a higher white cell count at diagnosis (P = 0.001), adverse-risk cytogenetics (P < 0.001), presence of FLT3-ITD mutation (P < 0.001) and time interval to achieve first complete remission (P = 0.013). Later relapse was associated with adverse cytogenetics, mutated NPM1, absence of chronic graft-versus-host disease (GVHD) and the use of in vivo T-cell depletion. In patients treated with IC alone, the factors associated with relapse in the first 3 months were adverse-risk cytogenetics (P < 0.001) and FLT3-ITD status (P = 0.001). The factors predicting later relapse were the time interval from diagnosis to CR1 (P = 0.22) and time interval from CR1 to IC (P = 0.012).
DISCUSSION AND CONCLUSION: Taken together, these data provide novel insights into the biology of disease recurrence after both allo-SCT and IC and have the potential to inform the design of novel maintenance strategies in both clinical settings.

PMID: 29214689 [PubMed - indexed for MEDLINE]

Diagnostics and treatment of diffuse intrinsic pontine glioma: where do we stand?

Ma, 16/09/2019 - 23:43
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Diagnostics and treatment of diffuse intrinsic pontine glioma: where do we stand?

J Neurooncol. 2019 Sep 14;:

Authors: El-Khouly FE, Veldhuijzen van Zanten SEM, Santa-Maria Lopez V, Hendrikse NH, Kaspers GJL, Loizos G, Sumerauer D, Nysom K, Pruunsild K, Pentikainen V, Thorarinsdottir HK, Rutkauskiene G, Calvagna V, Drogosiewicz M, Dragomir M, Deak L, Kitanovski L, von Bueren AO, Kebudi R, Slavc I, Jacobs S, Jadrijevic-Cvrlje F, Entz-Werle N, Grill J, Kattamis A, Hauser P, Pears J, Biassoni V, Massimino M, Lopez Aguilar E, Torsvik IK, Joao Gil-da-Costa M, Kumirova E, Cruz-Martinez O, Holm S, Bailey S, Hayden T, Thomale UW, Janssens GOR, Kramm CM, van Vuurden DG

Abstract
INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines.
METHODS: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively.
RESULTS: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials.
CONCLUSION: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

PMID: 31522324 [PubMed - as supplied by publisher]

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks.

Pe, 13/09/2019 - 23:41
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EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks.

Hepatology. 2019 Sep 12;:

Authors: Gouya L, Ventura P, Balwani M, Bissell DM, Rees DC, Stölzel U, Phillips JD, Kauppinen R, Langendonk JG, Desnick RJ, Deybach JC, Bonkovsky HL, Parker C, Naik H, Badminton M, Stein PE, Minder E, Windyga J, Bruha R, Cappellini MD, Sardh E, Harper P, Sandberg S, Aarsand AK, Andersen J, Alegre F, Ivanova A, Talbi N, Chan A, Querbes W, Ko J, Penz C, Liu S, Lin T, Simon A, Anderson KE

Abstract
Acute hepatic porphyria comprises a group of rare, genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months prior to the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a healthcare facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased healthcare utilization. Conclusions: Patients experienced attacks often requiring treatment in a healthcare facility and/or with hemin, as well as chronic symptoms that adversely influence day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. This article is protected by copyright. All rights reserved.

PMID: 31512765 [PubMed - as supplied by publisher]

Anti-tumor activity of cediranib, a pan-vascular endothelial growth factor receptor inhibitor, in pancreatic ductal adenocarcinoma cells.

Pe, 13/09/2019 - 23:41
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Anti-tumor activity of cediranib, a pan-vascular endothelial growth factor receptor inhibitor, in pancreatic ductal adenocarcinoma cells.

Cell Oncol (Dordr). 2019 Sep 06;:

Authors: Momeny M, Alishahi Z, Eyvani H, Esmaeili F, Zaghal A, Ghaffari P, Tavakkoly-Bazzaz J, Alimoghaddam K, Ghavamzadeh A, Ghaffari SH

Abstract
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal subtype of pancreatic cancer, with a 5-year survival rate of < 3%. Early tumor dissemination, late diagnosis and insensitivity to conventional treatment are the major reasons for its high mortality rate. Members of the vascular endothelial growth factor (VEGF) family are overexpressed in PDAC and play important roles in its malignant progression, suggesting that VEGF-targeted therapies may interrupt the proliferation and motility of PDAC cells. Here, we evaluated the anti-tumor activity of cediranib, a pan-VEGF receptor inhibitor, on PDAC cells.
METHODS: Anti-proliferative effects of cediranib were determined using cell proliferation and crystal violet staining assays. Annexin V/PI staining, radiation therapy, and cell migration and invasion assays were carried out to examine the effects of cediranib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of cediranib.
RESULTS: We found that cediranib decreased PDAC cell proliferation and clonogenic survival and induced apoptotic cell death through inhibition of the anti-apoptotic proteins cIAP1, XIAP, MCL-1 and survivin. Combination with cediranib synergistically increased the sensitivity of PDAC cells to chemotherapeutic agents such as gemcitabine and paclitaxel, and potentiated the effects of radiation therapy on PDAC cell growth inhibition and apoptosis induction. Furthermore, we found that treatment with cediranib impaired PDAC cell migration and invasion via expression reduction of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, N-cadherin and Snail.
CONCLUSIONS: Our data indicate that cediranib may exhibit anti-tumor activity in PDAC cells and provide a rationale for further investigation of the potential of VEGF receptor-targeted therapies for the treatment of PDAC.

PMID: 31512195 [PubMed - as supplied by publisher]

Loss of prostatic acid phosphatase and α-synuclein cause motor circuit degeneration without altering cerebellar patterning.

To, 12/09/2019 - 23:41
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Loss of prostatic acid phosphatase and α-synuclein cause motor circuit degeneration without altering cerebellar patterning.

PLoS One. 2019;14(9):e0222234

Authors: Rahimi-Balaei M, Buchok M, Vihko P, Parkinson FE, Marzban H

Abstract
Prostatic acid phosphatase (PAP), which is secreted by prostate, increases in some diseases such as prostate cancer. PAP is also present in the central nervous system. In this study we reveal that α-synuclein (Snca) gene is co-deleted/mutated in PAP null mouse. It is indicated that mice deficient in transmembrane PAP display neurological alterations. By using immunohistochemistry, cerebellar cortical neurons and zone and stripes pattern were studied in Pap-/- ;Snca-/- mouse cerebellum. We show that the Pap-/- ;Snca-/- cerebellar cortex development appears to be normal. Compartmentation genes expression such as zebrin II, HSP25, and P75NTR show the zone and stripe phenotype characteristic of the normal cerebellum. These data indicate that although aggregation of PAP and SNCA causes severe neurodegenerative diseases, PAP -/- with absence of the Snca does not appear to interrupt the cerebellar architecture development and zone and stripe pattern formation. These findings question the physiological and pathological role of SNCA and PAP during cerebellar development or suggest existence of the possible compensatory mechanisms in the absence of these genes.

PMID: 31509576 [PubMed - in process]

Risk of cardiovascular disease among Nordic childhood cancer survivors with diabetes mellitus: A report from adult life after childhood cancer in Scandinavia.

To, 12/09/2019 - 23:41
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Risk of cardiovascular disease among Nordic childhood cancer survivors with diabetes mellitus: A report from adult life after childhood cancer in Scandinavia.

Cancer. 2018 11 15;124(22):4393-4400

Authors: Winther JF, Bhatia S, Cederkvist L, Gudmundsdottir T, Madanat-Harjuoja L, Tryggvadottir L, Wesenberg F, Hasle H, Sällfors Holmqvist A, ALiCCS Study Group

Abstract
BACKGROUND: Childhood cancer survivors have an increased risk of cardiovascular disease (CVD) and diabetes mellitus. Because diabetes is a potentially modifiable risk factor for CVD in the general population, it is important to understand how diabetes affects the risk of CVD among childhood cancer survivors.
METHODS: This study examined the risk of CVD among survivors with diabetes and 142,742 population comparison subjects. From the national cancer registries of the 5 Nordic countries, 29,324 one-year survivors of cancer diagnosed before the age of 20 years between 1968 and 2008 were identified. Study subjects were linked to the national hospital registers. The cumulative incidence of CVD was determined with competing risk methods. A Cox proportional hazards model was used to estimate the effects of diabetes and cancer on the hazard of CVD. The interaction between diabetes and cancer was analyzed.
RESULTS: Diabetes was diagnosed in 324 of the 29,324 one-year survivors, and CVD was diagnosed in 2108. The hazard of diabetes was 1.7 times higher among survivors than comparison subjects (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.5-1.9), whereas the HR of CVD was 3.6 (95% CI, 3.3-3.8) 1 to 15 years after the cancer diagnosis and 1.9 (95% CI, 1.8-2.0) after more than 15 years. Individuals with diabetes had a 2.4 times higher hazard of CVD (95% CI, 2.1-2.8) among both survivors and comparison subjects in comparison with individuals without diabetes.
CONCLUSIONS: Childhood cancer survivors with diabetes have a markedly increased risk of CVD in comparison with survivors without diabetes. However, diabetes does not increase the risk of CVD more in survivors than the general population.

PMID: 30307617 [PubMed - indexed for MEDLINE]

HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development.

To, 12/09/2019 - 23:41
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HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development.

Cancer Discov. 2018 05;8(5):616-631

Authors: de Bock CE, Demeyer S, Degryse S, Verbeke D, Sweron B, Gielen O, Vandepoel R, Vicente C, Vanden Bempt M, Dagklis A, Geerdens E, Bornschein S, Gijsbers R, Soulier J, Meijerink JP, Heinäniemi M, Teppo S, Bouvy-Liivrand M, Lohi O, Radaelli E, Cools J

Abstract
Leukemia is caused by the accumulation of multiple genomic lesions in hematopoietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression, two events identified as significantly co-occurring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors, with a significant decrease in disease latency compared with JAK3 or HOXA9 alone. Integrated RNA sequencing, chromatin immunoprecipitation sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) revealed that STAT5 and HOXA9 have co-occupancy across the genome, resulting in enhanced STAT5 transcriptional activity and ectopic activation of FOS/JUN (AP1). Our data suggest that oncogenic transcription factors such as HOXA9 provide a fertile ground for specific signaling pathways to thrive, explaining why JAK/STAT pathway mutations accumulate in HOXA9-expressing cells.Significance: The mechanism of oncogene cooperation in cancer development remains poorly characterized. In this study, we model the cooperation between activated JAK/STAT signaling and ectopic HOXA9 expression during T-cell leukemia development. We identify a direct cooperation between STAT5 and HOXA9 at the transcriptional level and identify PIM1 kinase as a possible drug target in mutant JAK/STAT/HOXA9-positive leukemia cases. Cancer Discov; 8(5); 616-31. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 517.

PMID: 29496663 [PubMed - indexed for MEDLINE]

Relapse and survival after transplantation for complex karyotype acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and the University of Texas MD Anderson Cancer Center.

To, 12/09/2019 - 23:41
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Relapse and survival after transplantation for complex karyotype acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and the University of Texas MD Anderson Cancer Center.

Cancer. 2018 05 15;124(10):2134-2141

Authors: Ciurea SO, Labopin M, Socie G, Volin L, Passweg J, Chevallier P, Beelen D, Milpied N, Blaise D, Cornelissen JJ, Fegueux N, Polge E, Kongtim P, Rondon G, Esteve J, Mohty M, Savani BN, Champlin RE, Nagler A

Abstract
BACKGROUND: Despite recent advances in allogeneic hematopoietic stem cell transplantation (AHSCT), the outcome of patients who have acute myeloid leukemia (AML) with a complex karyotype (CK) remains poor. The objective of this study was to identify prognostic factors associated with post-transplantation survival in a large cohort of patients with CK AML.
METHODS: In total, data on 1342 consecutively patients who underwent transplantation for CK (≥3 chromosomal abnormalities) AML were provided by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and from the University of Texas MD Anderson Cancer Center database were included in the analysis. The median patient age was 52 years. The donors were human leukocyte antigen-matched related donors (N = 749), matched unrelated donors (N = 513), and mismatched unrelated donors (N = 80).
RESULTS: Relapse was the main cause of treatment failure. Overall, 51% of patients relapsed, 17.6% died of treatment-related mortality, and 31.3% survived leukemia-free. In multivariate analysis, the factors associated with an increased risk of relapse were age (>40 years; hazard ratio [HR], 1.1 per 10 years; P = .02), secondary AML (HR, 1.35; P = .01), active disease at transplantation (HR, 1.98; P < .001), and deletion/monosomy 5 (HR, 1.5; P < .001); whereas age (HR, 1.15 per 10 years; P < .001), secondary AML (HR, 1.36; P = .001), active disease at transplantation (HR, 1.99; P < .001), deletion/monosomy 5 (HR, 1.24; P = .008), and deletion/monosomy 7 (HR, 1.44; P < .001) predicted for leukemia-free survival.
CONCLUSIONS: Disease relapse remains the most common cause of treatment failure for patients with CK AML after transplantation. Novel approaches to decrease the relapse rate and improve survival are needed in these patients. Cancer 2018;124:2134-41. © 2018 American Cancer Society.

PMID: 29469961 [PubMed - indexed for MEDLINE]

What is the outcome in patients with acute leukaemia who survive severe acute graft-versus-host disease?

To, 12/09/2019 - 23:41
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What is the outcome in patients with acute leukaemia who survive severe acute graft-versus-host disease?

J Intern Med. 2018 02;283(2):166-177

Authors: Ringdén O, Labopin M, Sadeghi B, Mailhol A, Beelen D, Fløisand Y, Ghavamzadeh A, Finke J, Ehninger G, Volin L, Socié G, Kröger N, Stuhler G, Ganser A, Schmid C, Giebel S, Mohty M, Nagler A

Abstract
BACKGROUND: Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic haematopoietic stem cell transplantation (HSCT). With new promising therapies, survival may improve for severe aGVHD.
OBJECTIVES: We wanted to analyze the long-term outcome in patients who survive severe aGVHD.
METHODS: This study was a landmark analysis of 23 567 patients with acute Leukaemia who survived for more than 6 months after HSCT, 2002-2014. Patients alive after severe aGVHD (n = 1738) were compared to controls.
RESULTS: Patients with severe aGVHD had higher non-relapse mortality (NRM) and higher rate of extensive chronic GVHD (cGVHD) than the controls (P < 10-5 ). The probability of relapse was significantly lower in the severe aGVHD group, but Leukaemia-free survival (LFS) and overall survival were significantly lower than for the controls (P < 10-5 ). Five-year LFS in patients with severe aGVHD was 49%, as opposed to 61% in controls with no or mild GVHD and 59% in patients with moderate GVHD.
CONCLUSIONS: HSCT patients who survive severe aGVHD have higher risk of developing extensive cGVHD, a higher NRM, a lower relapse probability, and lower LFS than other HSCT patients. This study is a platform for outcome analysis in patients treated with novel therapies for acute GVHD.

PMID: 29027756 [PubMed - indexed for MEDLINE]

Personalized laboratory medicine: a patient-centered future approach.

Ti, 10/09/2019 - 23:41
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Personalized laboratory medicine: a patient-centered future approach.

Clin Chem Lab Med. 2018 11 27;56(12):1981-1991

Authors: Prodan Žitnik I, Černe D, Mancini I, Simi L, Pazzagli M, Di Resta C, Podgornik H, Repič Lampret B, Trebušak Podkrajšek K, Sipeky C, van Schaik R, Brandslund I, Vermeersch P, Schwab M, Marc J, behalf of EFLM/ESPT working group of Personalised Laboratory Medicine on

Abstract
In contrast to population-based medical decision making, which emphasizes the use of evidence-based treatment strategies for groups of patients, personalized medicine is based on optimizing treatment at the level of the individual patient. The creation of molecular profiles of individual patients was made possible by the advent of "omics" technologies, based on high throughput instrumental techniques in combination with biostatistics tools and artificial intelligence. The goal of personalized laboratory medicine is to use advanced technologies in the process of preventive, curative or palliative patient management. Personalized medicine does not rely on changes in concentration of a single molecular marker to make a therapeutic decision, but rather on changes of a profile of markers characterizing an individual patient's status, taking into account not only the expected response to treatment of the disease but also the expected response of the patient. Such medical approach promises a more effective diagnostics with more effective and safer treatment, as well as faster recovery and restoration of health and improved cost effectiveness. The laboratory medicine profession is aware of its key role in personalized medicine, but to empower the laboratories, at least an enhancement in cooperation between disciplines within laboratory medicine will be necessary.

PMID: 29990304 [PubMed - indexed for MEDLINE]

Safety and efficacy of AMG 714 in patients with type 2 refractory coeliac disease: a phase 2a, randomised, double-blind, placebo-controlled, parallel-group study.

Ma, 09/09/2019 - 23:40
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Safety and efficacy of AMG 714 in patients with type 2 refractory coeliac disease: a phase 2a, randomised, double-blind, placebo-controlled, parallel-group study.

Lancet Gastroenterol Hepatol. 2019 Sep 04;:

Authors: Cellier C, Bouma G, van Gils T, Khater S, Malamut G, Crespo L, Collin P, Green PHR, Crowe SE, Tsuji W, Butz E, Cerf-Bensussan N, Macintyre E, Parnes JR, Leon F, Hermine O, Mulder CJ, RCD-II Study Group Investigators

Abstract
BACKGROUND: Refractory coeliac disease type 2 is a rare subtype of coeliac disease with high mortality rates; interleukin 15 (IL-15) is strongly implicated in its pathophysiology. This trial aimed to investigate the effects of AMG 714, an anti-IL-15 monoclonal antibody, on the activity and symptoms of refractory coeliac disease type 2.
METHODS: This was a randomised, double-blind, placebo-controlled, phase 2a study of adults with a confirmed diagnosis of refractory coeliac disease type 2. Patients were randomly assigned at a 2:1 ratio to receive seven intravenous doses over 10 weeks of AMG 714 (8 mg/kg) or matching placebo. Biopsy samples were obtained at baseline and week 12 for cellular analysis and histology. The change in the proportion of aberrant intraepithelial lymphocytes from baseline to week 12 with respect to all intraepithelial lymphocytes was the primary endpoint and was quantified using flow cytometry. Secondary endpoints were the change in aberrant intraepithelial lymphocytes with respect to intestinal epithelial cells; intestinal histological scores (villous height-to-crypt depth ratio; VHCD); intraepithelial lymphocyte counts; Marsh score; and patient-reported symptom measures, including the Bristol stool form scale (BSFS) and gastrointestinal symptom rating scale (GSRS). Main analyses were done in the per-protocol population of patients who received their assigned treatment, provided evaluable biopsy samples, and did not have major protocol deviations; only patients with non-atypical disease were included in the analyses of aberrant intraepithelial lymphocytes, including the primary analysis. Safety was assessed in all patients who received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02633020) and EudraCT (2015-004063-36).
FINDINGS: From April 13, 2016, to Jan 19, 2017, 28 patients were enrolled and randomly assigned to AMG 714 (n=19) and placebo (n=9). Six patients were not included in the primary analysis because of protocol deviation (one in the AMG 714 group), insufficient biopsy samples (one in the AMG 714 group), and atypical intraepithelial lymphocytes (three in the AMG 714 group and one in the placebo group). At 12 weeks, the least square mean difference between AMG 714 and placebo in the relative change from baseline in aberrant intraepithelial lymphocyte percentage was -4·85% (90% CI -30·26 to 20·56; p=0·75). The difference between the AMG 714 and placebo groups in aberrant intraepithelial lymphocytes with respect to epithelial cells at 12 weeks was -38·22% (90% CI -95·73 to 19·29; nominal p=0·18); the difference in change in Marsh score from baseline was 0·09% (95% CI -1·60-1·90; nominal p=0·92); the difference in VHCD ratio was 10·67% (95% CI -38·97 to 60·31; nominal p=0·66); and the difference in change in total intraepithelial lymphocyte count was -12·73% (95% CI -77·57-52·12); nominal p=0·69). Regarding symptoms, the proportion of patients with diarrhoea per the BSFS score decreased from ten (53%) of 19 at baseline to seven (37%) of 19 at week 12 in the AMG 714 group and increased from two (22%) of nine at baseline to four (44%) of nine at week 12 in the placebo group (nominal p=0·0008); and the difference between the groups in change in GSRS score was -0·14 (SE 0·19; nominal p=0·48). Eight (89%) patients in the placebo group and 17 (89%) in the AMG 714 group had treatment-emergent adverse events, including one (11%) patient in the placebo group and five (26%) in the AMG 714 group who had serious adverse events. The most common adverse event in the AMG 714 group was nasopharyngitis (eight [42%] patients vs one [11%] in the placebo group).
INTERPRETATION: In patients with refractory coeliac disease type 2 who were treated with AMG 714 or placebo for 10 weeks, there was no difference between the groups in terms of the primary endpoint of aberrant intraepithelial lymphocyte reduction from baseline. Effects on symptoms and other endpoints suggest that further research of AMG 714 may be warranted in patients with refractory coeliac disease type 2.
FUNDING: Celimmune and Amgen.

PMID: 31494097 [PubMed - as supplied by publisher]

Dasatinib and navitoclax act synergistically to target NUP98-NSD1+/FLT3-ITD+ acute myeloid leukemia.

La, 07/09/2019 - 23:40
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Dasatinib and navitoclax act synergistically to target NUP98-NSD1+/FLT3-ITD+ acute myeloid leukemia.

Leukemia. 2019 06;33(6):1360-1372

Authors: Kivioja JL, Thanasopoulou A, Kumar A, Kontro M, Yadav B, Majumder MM, Javarappa KK, Eldfors S, Schwaller J, Porkka K, Heckman CA

Abstract
Acute myeloid leukemia (AML) with co-occurring NUP98-NSD1 and FLT3-ITD is associated with unfavorable prognosis and represents a particularly challenging treatment group. To identify novel effective therapies for this AML subtype, we screened patient cells and engineered cell models with over 300 compounds. We found that mouse hematopoietic progenitors co-expressing NUP98-NSD1 and FLT3-ITD had significantly increased sensitivity to FLT3 and MEK-inhibitors compared to cells expressing either aberration alone (P < 0.001). The cells expressing NUP98-NSD1 alone had significantly increased sensitivity to BCL2-inhibitors (P = 0.029). Furthermore, NUP98-NSD1+/FLT3-ITD+ patient cells were also very sensitive to BCL2-inhibitor navitoclax, although the highest select sensitivity was found to SRC/ABL-inhibitor dasatinib (mean IC50 = 2.2 nM). Topoisomerase inhibitor mitoxantrone was the least effective drug against NUP98-NSD1+/FLT3-ITD+ AML cells. Of the 25 significant hits, four remained significant also compared to NUP98-NSD1-/FLT3-ITD+ AML patients. We found that SRC/ABL-inhibitor dasatinib is highly synergistic with BCL2-inhibitor navitoclax in NUP98-NSD1+/FLT3-ITD+ cells. Gene expression analysis supported the potential relevance of dasatinib and navitoclax by revealing significantly higher expression of BCL2A1, FGR, and LCK in NUP98-NSD1+/FLT3-ITD+ patients compared to healthy CD34+ cells. Our data suggest that dasatinib-navitoclax combination may offer a clinically relevant treatment strategy for AML with NUP98-NSD1 and concomitant FLT3-ITD.

PMID: 30568173 [PubMed - indexed for MEDLINE]

Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia.

La, 07/09/2019 - 23:40
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Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia.

Leukemia. 2019 06;33(6):1324-1336

Authors: Modvig S, Madsen HO, Siitonen SM, Rosthøj S, Tierens A, Juvonen V, Osnes LTN, Vålerhaugen H, Hultdin M, Thörn I, Matuzeviciene R, Stoskus M, Marincevic M, Fogelstrand L, Lilleorg A, Toft N, Jónsson OG, Pruunsild K, Vaitkeviciene G, Vettenranta K, Lund B, Abrahamsson J, Schmiegelow K, Marquart HV

Abstract
Minimal residual disease (MRD) measured by PCR of clonal IgH/TCR rearrangements predicts relapse in T-cell acute lymphoblastic leukemia (T-ALL) and serves as risk stratification tool. Since 10% of patients have no suitable PCR-marker, we evaluated flowcytometry (FCM)-based MRD for risk stratification. We included 274 T-ALL patients treated in the NOPHO-ALL2008 protocol. MRD was measured by six-color FCM and real-time quantitative PCR. Day 29 PCR-MRD (cut-off 10-3) was used for risk stratification. At diagnosis, 93% had an FCM-marker for MRD monitoring, 84% a PCR-marker, and 99.3% (272/274) had a marker when combining the two. Adjusted for age and WBC, the hazard ratio for relapse was 3.55 (95% CI 1.4-9.0, p = 0.008) for day 29 FCM-MRD ≥ 10-3 and 5.6 (95% CI 2.0-16, p = 0.001) for PCR-MRD ≥ 10-3 compared with MRD < 10-3. Patients stratified to intermediate-risk therapy on day 29 with MRD 10-4-<10-3 had a 5-year event-free survival similar to intermediate-risk patients with MRD < 10-4 or undetectable, regardless of method for monitoring. Patients with day 15 FCM-MRD < 10-4 had a cumulative incidence of relapse of 2.3% (95% CI 0-6.8, n = 59). Thus, FCM-MRD allows early identification of patients eligible for reduced intensity therapy, but this needs further studies. In conclusion, FCM-MRD provides reliable risk prediction for T-ALL and can be used for stratification when no PCR-marker is available.

PMID: 30552401 [PubMed - indexed for MEDLINE]

Refined graft-versus-host disease/relapse-free survival in transplant from HLA-identical related or unrelated donors in acute myeloid leukemia.

To, 05/09/2019 - 23:40
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Refined graft-versus-host disease/relapse-free survival in transplant from HLA-identical related or unrelated donors in acute myeloid leukemia.

Bone Marrow Transplant. 2018 10;53(10):1295-1303

Authors: Battipaglia G, Ruggeri A, Labopin M, Volin L, Blaise D, Socié G, Tabrizi R, Cornelissen JJ, Ghavamzadeh A, Huynh A, Wu D, Yakoub-Agha I, Maertens J, Chevallier P, Mohty M, Nagler A

Abstract
Refined graft-versus-host disease (GVHD)/relapse-free survival (GRFS) considers main outcomes of allogeneic stem cell transplant (HSCT), estimating long-term survival without significant morbidity as a surrogate of HSCT success. We compared GRFS in 5059 adults with acute myeloid leukemia (AML), undergoing HSCT in first complete remission from 2000 to 2015 either from a matched sibling (MSD, n = 3731) or unrelated donor (MUD, n = 1328). Median age was 49 (range: 18-76) years. Median follow-up was 32 and 60 months in MSD and MUD, respectively (p < 0.01). Compared to MSD, at 4 years, MUD recipients had lower GRFS, with higher NRM, grade III-IV acute GVHD, and extensive chronic GVHD (HR: 1.42, p < 0.01). We also performed a risk factor analyses, showing unfavorable cytogenetics (HR: 1.42, p < 0.01) and peripheral blood as stem cell source (HR: 1.22, p < 0.01) associated to lower GRFS, while this was higher with in vivo T-cell depletion (TCD, HR: 0.73, p < 0.01) and shorter time from diagnosis to HSCT (HR 0.96, p < 0.01). Different factors, modifiable or not, such as donor type, stem cell source, disease biology, and in vivo TCD, impact on GRFS and this may guide in the future transplant choices to improve morbidity and long-term quality of life.

PMID: 29662244 [PubMed - indexed for MEDLINE]

NET-CAGE characterizes the dynamics and topology of human transcribed cis-regulatory elements.

Ke, 04/09/2019 - 23:39
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NET-CAGE characterizes the dynamics and topology of human transcribed cis-regulatory elements.

Nat Genet. 2019 Sep;51(9):1369-1379

Authors: Hirabayashi S, Bhagat S, Matsuki Y, Takegami Y, Uehata T, Kanemaru A, Itoh M, Shirakawa K, Takaori-Kondo A, Takeuchi O, Carninci P, Katayama S, Hayashizaki Y, Kere J, Kawaji H, Murakawa Y

Abstract
Promoters and enhancers are key cis-regulatory elements, but how they operate to generate cell type-specific transcriptomes is not fully understood. We developed a simple and robust method, native elongating transcript-cap analysis of gene expression (NET-CAGE), to sensitively detect 5' ends of nascent RNAs in diverse cells and tissues, including unstable transcripts such as enhancer-derived RNAs. We studied RNA synthesis and degradation at the transcription start site level, characterizing the impact of differential promoter usage on transcript stability. We quantified transcription from cis-regulatory elements without the influence of RNA turnover, and show that enhancer-promoter pairs are generally activated simultaneously on stimulation. By integrating NET-CAGE data with chromatin interaction maps, we show that cis-regulatory elements are topologically connected according to their cell type specificity. We identified new enhancers with high sensitivity, and delineated primary locations of transcription within super-enhancers. Our NET-CAGE dataset derived from human and mouse cells expands the FANTOM5 atlas of transcribed enhancers, with broad applicability to biomedical research.

PMID: 31477927 [PubMed - in process]