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Salvage use of allogeneic HSCT after reduced intensity conditioning from unrelated donors in multiple myeloma. A study by the Plasma Cell Disorders subcommittee of the EBMT Chronic Malignancies Working Party.

La, 22/04/2017 - 21:03
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Salvage use of allogeneic HSCT after reduced intensity conditioning from unrelated donors in multiple myeloma. A study by the Plasma Cell Disorders subcommittee of the EBMT Chronic Malignancies Working Party.

Haematologica. 2017 Apr 20;:

Authors: Sobh M, Michallet M, Dubois V, Iacobelli S, Koster L, Van Biezen A, Fegueux N, Tabrizi R, Finke J, El-Cheikh J, Schipperus M, Meijer E, von dem Borne P, Petersen E, Russell N, Tholouli E, Passweg J, Garban FR, Maertens J, Chevalier P, Maillard N, Volin L, Francois S, Lioure B, Beguin Y, Gluckman E, Ruggeri A, Garderet L, Kröger N

PMID: 28428268 [PubMed - as supplied by publisher]

Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease.

La, 22/04/2017 - 21:03
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Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease.

Oncotarget. 2017 Feb 28;:

Authors: Tobiasson M, Abdulkadir H, Lennartsson A, Katayama S, Marabita F, De Paepe A, Karimi M, Krjutskov K, Einarsdottir E, Grövdal M, Jansson M, Ben Azenkoud A, Corddedu L, Lehmann S, Ekwall K, Kere J, Hellström-Lindberg E, Ungerstedt J

Abstract
Azacitidine (Aza) is first-line treatment for patients with high-risk myelodysplastic syndromes (MDS), although its precise mechanism of action is unknown. We performed the first study to globally evaluate the epigenetic effects of Aza on MDS bone marrow progenitor cells assessing gene expression (RNA seq), DNA methylation (Illumina 450k) and the histone modifications H3K18ac and H3K9me3 (ChIP seq). Aza induced a general increase in gene expression with 924 significantly upregulated genes but this increase showed no correlation with changes in DNA methylation or H3K18ac, and only a weak association with changes in H3K9me3. Interestingly, we observed activation of transcripts containing 15 endogenous retroviruses (ERVs) confirming previous cell line studies. DNA methylation decreased moderately in 99% of all genes, with a median β-value reduction of 0.018; the most pronounced effects seen in heterochromatin. Aza-induced hypomethylation correlated significantly with change in H3K9me3. The pattern of H3K18ac and H3K9me3 displayed large differences between patients and healthy controls without any consistent pattern induced by Aza. We conclude that the marked induction of gene expression only partly could be explained by epigenetic changes, and propose that activation of ERVs may contribute to the clinical effects of Aza in MDS.

PMID: 28427179 [PubMed - as supplied by publisher]

Quality of life with biweekly docetaxel and capecitabine in advanced gastro-oesophageal cancer.

Pe, 21/04/2017 - 20:56
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Quality of life with biweekly docetaxel and capecitabine in advanced gastro-oesophageal cancer.

Support Care Cancer. 2017 Apr 20;:

Authors: Korkeila EA, Salminen T, Kallio R, Mikkola M, Auvinen P, Pyrhönen S, Ristamäki R

Abstract
PURPOSE: This study aimed to evaluate the feasibility and tolerability of biweekly docetaxel with capecitabine as first-line treatment in advanced gastro-oesophageal cancer.
METHODS: Fifty-three patients at median age of 61 years with advanced gastric cancer were included in this prospective, non-randomized, multicentre phase II trial to receive intravenous docetaxel 50 mg/m(2) on days 1 and 15, and oral capecitabine 1250 mg/m(2) every 12 h, on days 1-7 and 15-21 of each 28-day cycle. QOL was assessed using EORTC QLQ-C30, together with the gastric module (QLQ-STO 22).
RESULTS: Forty-six patients were evaluable for QOL analyses. No deterioration in global health status was found. Social functioning scores improved, and eating difficulties and pain were alleviated during treatment. The most common grade 3 or 4 toxicity was neutropenia (47%), whereas neutropenic fever was uncommon (6%). The clinical benefit rate was 60%, including complete and partial responses as well as stabilized disease. Median overall survival was 8.8 months (95% CI 5.8-11.9 months), and median time to progression was 6.2 months (95% CI 4.9-7.5 months).
CONCLUSIONS: Biweekly docetaxel with capecitabine is a feasible treatment in AGC, delivered on an outpatient basis, with no need for central venous access device. No deterioration of global health status was reported. In addition, pain and eating difficulties were alleviated during study treatment. This trial is registered at ClinicalTrials.gov , number NCT00669370.

PMID: 28424889 [PubMed - as supplied by publisher]

Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2.

Pe, 21/04/2017 - 20:56
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Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2.

J Exp Med. 2017 Apr 19;:

Authors: Moffitt AB, Ondrejka SL, McKinney M, Rempel RE, Goodlad JR, Teh CH, Leppa S, Mannisto S, Kovanen PE, Tse E, Au-Yeung RKH, Kwong YL, Srivastava G, Iqbal J, Yu J, Naresh K, Villa D, Gascoyne RD, Said J, Czader MB, Chadburn A, Richards KL, Rajagopalan D, Davis NS, Smith EC, Palus BC, Tzeng TJ, Healy JA, Lugar PL, Datta J, Love C, Levy S, Dunson DB, Zhuang Y, Hsi ED, Dave SS

Abstract
Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1 We also identified mutations in KRAS, TP53, and TERT Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell-specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.

PMID: 28424246 [PubMed - as supplied by publisher]

The SCLtTAxBCR-ABL transgenic mouse model closely reflects the differential effects of dasatinib on normal and malignant hematopoiesis in chronic phase-CML patients.

Pe, 21/04/2017 - 20:56
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The SCLtTAxBCR-ABL transgenic mouse model closely reflects the differential effects of dasatinib on normal and malignant hematopoiesis in chronic phase-CML patients.

Oncotarget. 2017 Mar 13;:

Authors: Schubert C, Chatain N, Braunschweig T, Schemionek M, Feldberg K, Hoffmann M, Dufva O, Mustjoki S, Brümmendorf TH, Koschmieder S

Abstract
The second generation tyrosine kinase inhibitor (TKI) dasatinib is a clinically approved drug for chronic myeloid leukemia (CML) as well as Ph+ acute lymphoblastic leukemia. In addition to its antileukemic effects, dasatinib was shown to impact on normal hematopoiesis and cells of the immune system.Due to the fact that the murine in vivo studies so far have not been performed in a chronic-phase CML model under steady-state conditions, our aim was to study the hematopoietic effects of dasatinib (20 mg/kg p.o.) in BCR-ABL expressing SCLtTAxBCR-ABL double transgenic (dtg) mice. Dasatinib robustly antagonized the CML phenotype in vivo in our transgenic mouse model, and this effect included both mature and immature cell populations. However, similar to patients with CML, the fraction of LinnegSca-1+KIT+CD48negCD150+ hematopoietic stem cells was not reduced by dasatinib treatment, suggesting that these cells are not oncogene-addicted. Moreover, we observed differential effects of dasatinib in these animals as compared to wild-type (wt) animals: while granulocytes were significantly reduced in dtg animals, they were increased in wt mice. And Ter119+ erythrocytic and B220+ B cells were increased in dtg mice but decreased in wt mice. Finally, while dasatinib induced a shift from CD49b/NK1.1 positive NK cells from the bone marrow to the spleen in wt animals, there was no change in dtg mice. In conclusion, the present mouse model provides a useful tool to study mechanisms of TKI resistance and dasatinib-associated beneficial effects and adverse events.

PMID: 28423730 [PubMed - as supplied by publisher]

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

Pe, 21/04/2017 - 20:56
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Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites.

Pediatr Blood Cancer. 2017 Apr 19;:

Authors: Toksvang LN, De Pietri S, Nielsen SN, Nersting J, Albertsen BK, Wehner PS, Rosthøj S, Lähteenmäki PM, Nilsson D, Nystad TA, Grell K, Frandsen TL, Schmiegelow K

Abstract
BACKGROUND: Hepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy.
PROCEDURE: In children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs. six-week intervals), as well as alternating high-dose MTX or vincristine/dexamethasone pulses every four weeks.
RESULTS: Among 130 children receiving PEG-asparaginase biweekly, 29 developed SOS (≥2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain ≥2.5%, unexplained thrombocytopenia <75 × 10(9) l(-1) ) at a median of 30 days (interquartile range [IQR]: 17-66) into maintenance (cumulative incidence: 27%). SOS cases fulfilling one, two, or three Ponte di Legno criteria were classified as possible (n = 2), probable (n = 8), or verified (n = 19) SOS, respectively. Twenty-six cases (90%) occurred during PEG-asparaginase treatment, including 21 (81%) within 14 days from the last chemotherapy pulse compared with the subsequent 14 days (P = 0.0025). Cytotoxic 6MP metabolites were significantly higher on PEG-asparaginase compared to after its discontinuation. Time-dependent Cox regression analysis showed increased SOS hazard ratio (HR) for erythrocyte levels of methylated 6MP metabolites (HR: 1.09 per 1,000 nmol/mmol hemoglobin increase, 95% confidence interval: 1.05-1.14). Six-week PEG-asparaginase intervals significantly reduced SOS-specific hazards (P < 0.01).
CONCLUSIONS: PEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.

PMID: 28423235 [PubMed - as supplied by publisher]

Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study.

Pe, 21/04/2017 - 20:56
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Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study.

JAMA Oncol. 2017 Apr 01;3(4):524-548

Authors: Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, Dicker DJ, Chimed-Orchir O, Dandona R, Dandona L, Fleming T, Forouzanfar MH, Hancock J, Hay RJ, Hunter-Merrill R, Huynh C, Hosgood HD, Johnson CO, Jonas JB, Khubchandani J, Kumar GA, Kutz M, Lan Q, Larson HJ, Liang X, Lim SS, Lopez AD, MacIntyre MF, Marczak L, Marquez N, Mokdad AH, Pinho C, Pourmalek F, Salomon JA, Sanabria JR, Sandar L, Sartorius B, Schwartz SM, Shackelford KA, Shibuya K, Stanaway J, Steiner C, Sun J, Takahashi K, Vollset SE, Vos T, Wagner JA, Wang H, Westerman R, Zeeb H, Zoeckler L, Abd-Allah F, Ahmed MB, Alabed S, Alam NK, Aldhahri SF, Alem G, Alemayohu MA, Ali R, Al-Raddadi R, Amare A, Amoako Y, Artaman A, Asayesh H, Atnafu N, Awasthi A, Saleem HB, Barac A, Bedi N, Bensenor I, Berhane A, Bernabé E, Betsu B, Binagwaho A, Boneya D, Campos-Nonato I, Castañeda-Orjuela C, Catalá-López F, Chiang P, Chibueze C, Chitheer A, Choi JY, Cowie B, Damtew S, das Neves J, Dey S, Dharmaratne S, Dhillon P, Ding E, Driscoll T, Ekwueme D, Endries AY, Farvid M, Farzadfar F, Fernandes J, Fischer F, G/Hiwot TT, Gebru A, Gopalani S, Hailu A, Horino M, Horita N, Husseini A, Huybrechts I, Inoue M, Islami F, Jakovljevic M, James S, Javanbakht M, Jee SH, Kasaeian A, Kedir MS, Khader YS, Khang YH, Kim D, Leigh J, Linn S, Lunevicius R, El Razek HMA, Malekzadeh R, Malta DC, Marcenes W, Markos D, Melaku YA, Meles KG, Mendoza W, Mengiste DT, Meretoja TJ, Miller TR, Mohammad KA, Mohammadi A, Mohammed S, Moradi-Lakeh M, Nagel G, Nand D, Le Nguyen Q, Nolte S, Ogbo FA, Oladimeji KE, Oren E, Pa M, Park EK, Pereira DM, Plass D, Qorbani M, Radfar A, Rafay A, Rahman M, Rana SM, Søreide K, Satpathy M, Sawhney M, Sepanlou SG, Shaikh MA, She J, Shiue I, Shore HR, Shrime MG, So S, Soneji S, Stathopoulou V, Stroumpoulis K, Sufiyan MB, Sykes BL, Tabarés-Seisdedos R, Tadese F, Tedla BA, Tessema GA, Thakur JS, Tran BX, Ukwaja KN, Uzochukwu BSC, Vlassov VV, Weiderpass E, Wubshet Terefe M, Yebyo HG, Yimam HH, Yonemoto N, Younis MZ, Yu C, Zaidi Z, Zaki MES, Zenebe ZM, Murray CJL, Naghavi M

Abstract
Importance: Cancer is the second leading cause of death worldwide. Current estimates on the burden of cancer are needed for cancer control planning.
Objective: To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 32 cancers in 195 countries and territories from 1990 to 2015.
Evidence Review: Cancer mortality was estimated using vital registration system data, cancer registry incidence data (transformed to mortality estimates using separately estimated mortality to incidence [MI] ratios), and verbal autopsy data. Cancer incidence was calculated by dividing mortality estimates through the modeled MI ratios. To calculate cancer prevalence, MI ratios were used to model survival. To calculate YLDs, prevalence estimates were multiplied by disability weights. The YLLs were estimated by multiplying age-specific cancer deaths by the reference life expectancy. DALYs were estimated as the sum of YLDs and YLLs. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility. Countries were categorized by SDI quintiles to summarize results.
Findings: In 2015, there were 17.5 million cancer cases worldwide and 8.7 million deaths. Between 2005 and 2015, cancer cases increased by 33%, with population aging contributing 16%, population growth 13%, and changes in age-specific rates contributing 4%. For men, the most common cancer globally was prostate cancer (1.6 million cases). Tracheal, bronchus, and lung cancer was the leading cause of cancer deaths and DALYs in men (1.2 million deaths and 25.9 million DALYs). For women, the most common cancer was breast cancer (2.4 million cases). Breast cancer was also the leading cause of cancer deaths and DALYs for women (523 000 deaths and 15.1 million DALYs). Overall, cancer caused 208.3 million DALYs worldwide in 2015 for both sexes combined. Between 2005 and 2015, age-standardized incidence rates for all cancers combined increased in 174 of 195 countries or territories. Age-standardized death rates (ASDRs) for all cancers combined decreased within that timeframe in 140 of 195 countries or territories. Countries with an increase in the ASDR due to all cancers were largely located on the African continent. Of all cancers, deaths between 2005 and 2015 decreased significantly for Hodgkin lymphoma (-6.1% [95% uncertainty interval (UI), -10.6% to -1.3%]). The number of deaths also decreased for esophageal cancer, stomach cancer, and chronic myeloid leukemia, although these results were not statistically significant.
Conclusion and Relevance: As part of the epidemiological transition, cancer incidence is expected to increase in the future, further straining limited health care resources. Appropriate allocation of resources for cancer prevention, early diagnosis, and curative and palliative care requires detailed knowledge of the local burden of cancer. The GBD 2015 study results demonstrate that progress is possible in the war against cancer. However, the major findings also highlight an unmet need for cancer prevention efforts, including tobacco control, vaccination, and the promotion of physical activity and a healthy diet.

PMID: 27918777 [PubMed - indexed for MEDLINE]

Interferon-gamma-dependent Immunity in Bacillus Calmette-Guérin Vaccine Osteitis Survivors.

Pe, 21/04/2017 - 20:56
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Interferon-gamma-dependent Immunity in Bacillus Calmette-Guérin Vaccine Osteitis Survivors.

Pediatr Infect Dis J. 2016 06;35(6):690-4

Authors: Pöyhönen L, Kröger L, Huhtala H, Mäkinen J, Mertsola J, Martinez-Barricarte R, Casanova JL, Bustamante J, He Q, Korppi M

Abstract
BACKGROUND: Inborn errors of interferon-gamma (IFN-γ)-mediated immunity underlie disseminated disease caused by Mycobacterium bovis Bacillus Calmette-Guérin (BCG) live vaccines. We hypothesized that some patients with osteitis after BCG vaccination may have an impaired IFN-γ immunity. Our aim was to investigate interleukin (IL)-12 and IFN-γ ex vivo production stimulated with BCG and BCG + IFN-γ or BCG + IL-12, respectively, in BCG osteitis survivors.
METHODS: Fresh blood samples were collected from 132 former BCG osteitis Finnish patients now aged 21-49 years, and IL-12 and IFN-γ were measured in cell cultures with and without stimulation with BCG and with BCG + IFN-γ or BCG + IL-12, respectively. As a pilot study, known disease-causing genes controlling IFN-γ immunity (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, IRF8, NEMO and CYBB) were investigated in 20 selected patients by whole exome sequencing.
RESULTS: By the limit of <5th percentile, ex vivo IL-12 concentration and increase in concentration was low in 5 and ex vivo IFN-γ concentration and increase in concentration was low in 6 patients (including 2 samples with both IL-12 and IFN-γ findings). By the limit of <10th percentile, an additional 6 and 4 patients were, respectively, detected (including 2 samples with both findings). With 2 exceptions, low concentrations and low increases in concentrations picked-up the same cases. Mutations in known disease-causing IFN-γ-related genes were not found in any of these patients.
CONCLUSION: These findings call for searching of mutations in new genes governing IFN-γ-dependent immunity to live BCG vaccine.

PMID: 26954602 [PubMed - indexed for MEDLINE]

Effects of thromboprophylactic doses of apixaban and rivaroxaban on coagulation and thrombin generation in association with total hip replacement.

Ke, 19/04/2017 - 08:53
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Effects of thromboprophylactic doses of apixaban and rivaroxaban on coagulation and thrombin generation in association with total hip replacement.

J Thromb Thrombolysis. 2017 May;43(4):562-569

Authors: Helin TA, Virtanen L, Manninen M, Leskinen J, Leppilahti J, Joutsi-Korhonen L, Lassila R

Abstract
Factor Xa inhibitors (FXaI) apixaban and rivaroxaban are used for thromboprophylaxis after major elective orthopaedic surgery. Because few patient sample studies exist, we postoperatively assessed patients undergoing unilateral total hip arthroplasty, including 22 treated with apixaban (2.5 mg BID) and 20 treated with rivaroxaban (10 mg OD). We collected blood samples before and 3 h after drug intake at 4 time points, preoperatively, as well as on day 1, week 1 (day 2-8) and day 28 post-operation. APTT and PT were immediately analysed. Calibrated anti-FXa activity, Russel's Viper Venom Time (RVVT) and thrombin generation (TG; Calibrated Automated Thrombogram(®)) captured the effects of FXaI on coagulation and TG. APTT and PT remained within the reference interval throughout, and did not correlate with FXaI levels (PT R(2) = 0.44, APTT R(2) = 0.07). Mean apixaban concentration at the peak varied by eightfold (19-153 ng/mL), but rivaroxaban only by 1.5-fold (111-183 ng/mL). Rivaroxaban, but not apixaban prolonged RVVT at peak levels. Both FXaIs had a prolonged lag time of TG (p < 0.001). Rivaroxaban decreased ETP peak at all time points and reached a minimum at day 28 (540 nM/min at rivaroxaban 184 ng/mL, p < 0.001), while rivaroxaban trough levels were low and ETP values normal. However, with apixaban, after an initial decrease, ETP did not differ between peak and trough levels until decreasing on day 28 at peak (990 nM/min at apixaban 112 ng/mL, p = 0.005). In conclusion, due to different dosing and pharmacology rivaroxaban and apixaban distinctly inhibited TG under postoperative conditions.

PMID: 28315166 [PubMed - indexed for MEDLINE]

Low interleukin-2 concentration favors generation of early memory T cells over effector phenotypes during chimeric antigen receptor T-cell expansion.

Su, 16/04/2017 - 20:52
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Low interleukin-2 concentration favors generation of early memory T cells over effector phenotypes during chimeric antigen receptor T-cell expansion.

Cytotherapy. 2017 Apr 11;:

Authors: Kaartinen T, Luostarinen A, Maliniemi P, Keto J, Arvas M, Belt H, Koponen J, Loskog A, Mustjoki S, Porkka K, Ylä-Herttuala S, Korhonen M

Abstract
BACKGROUND: Adoptive T-cell therapy offers new options for cancer treatment. Clinical results suggest that T-cell persistence, depending on T-cell memory, improves efficacy. The use of interleukin (IL)-2 for in vitro T-cell expansion is not straightforward because it drives effector T-cell differentiation but does not promote the formation of T-cell memory. We have developed a cost-effective expansion protocol for chimeric antigen receptor (CAR) T cells with an early memory phenotype.
METHODS: Lymphocytes were transduced with third-generation lentiviral vectors and expanded using CD3/CD28 microbeads. The effects of altering the IL-2 supplementation (0-300 IU/mL) and length of expansion (10-20 days) on the phenotype of the T-cell products were analyzed.
RESULTS: High IL-2 levels led to a decrease in overall generation of early memory T cells by both decreasing central memory T cells and augmenting effectors. T memory stem cells (TSCM, CD95(+)CD45RO(-)CD45RA(+)CD27(+)) were present variably during T-cell expansion. However, their presence was not IL-2 dependent but was linked to expansion kinetics. CD19-CAR T cells generated in these conditions displayed in vitro antileukemic activity. In summary, production of CAR T cells without any cytokine supplementation yielded the highest proportion of early memory T cells, provided a 10-fold cell expansion and the cells were functionally potent.
DISCUSSION: The number of early memory T cells in a T-cell preparation can be increased by simply reducing the amount of IL-2 and limiting the length of T-cell expansion, providing cells with potentially higher in vivo performance. These findings are significant for robust and cost-effective T-cell manufacturing.

PMID: 28411126 [PubMed - as supplied by publisher]

Premature Discontinuation of Pediatric Randomized Controlled Trials: A Retrospective Cohort Study.

La, 15/04/2017 - 20:51
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Premature Discontinuation of Pediatric Randomized Controlled Trials: A Retrospective Cohort Study.

J Pediatr. 2017 Mar 03;:

Authors: Schandelmaier S, Tomonaga Y, Bassler D, Meerpohl JJ, von Elm E, You JJ, Bluemle A, Lamontagne F, Saccilotto R, Amstutz A, Bengough T, Stegert M, Olu KK, Tikkinen KAO, Neumann I, Carrasco-Labra A, Faulhaber M, Mulla SM, Mertz D, Akl EA, Sun X, Busse JW, Ferreira-González I, Nordmann A, Gloy V, Raatz H, Moja L, Rosenthal R, Ebrahim S, Vandvik PO, Johnston BC, Walter MA, Burnand B, Schwenkglenks M, Hemkens LG, Guyatt G, Bucher HC, Kasenda B, Briel M

Abstract
OBJECTIVES: To determine the proportion of pediatric randomized controlled trials (RCTs) that are prematurely discontinued, examine the reasons for discontinuation, and compare the risk for recruitment failure in pediatric and adult RCTs.
STUDY DESIGN: A retrospective cohort study of RCTs approved by 1 of 6 Research Ethics Committees (RECs) in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics, trial discontinuation, and reasons for discontinuation from protocols, corresponding publications, REC files, and a survey of trialists.
RESULTS: We included 894 RCTs, of which 86 enrolled children and 808 enrolled adults. Forty percent of the pediatric RCTs and 29% of the adult RCTs were discontinued. Slow recruitment accounted for 56% of pediatric RCT discontinuations and 43% of adult RCT discontinuations. Multivariable logistic regression analyses suggested that pediatric RCT was not an independent risk factor for recruitment failure after adjustment for other potential risk factors (aOR, 1.22; 95% CI, 0.57-2.63). Independent risk factors were acute care setting (aOR, 4.00; 95% CI, 1.72-9.31), nonindustry sponsorship (aOR, 4.45; 95% CI, 2.59-7.65), and smaller planned sample size (aOR, 1.05; 95% CI 1.01-1.09, in decrements of 100 participants).
CONCLUSION: Forty percent of pediatric RCTs were discontinued prematurely, owing predominately to slow recruitment. Enrollment of children was not an independent risk factor for recruitment failure.

PMID: 28410086 [PubMed - as supplied by publisher]

Monitoring once-weekly recombinant factor IX prophylaxis in hemophilia B with thrombin generation assay and factor IX activity.

Pe, 14/04/2017 - 20:49
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Monitoring once-weekly recombinant factor IX prophylaxis in hemophilia B with thrombin generation assay and factor IX activity.

Int J Lab Hematol. 2017 Apr 13;:

Authors: Nummi V, Jouppila A, Lassila R

Abstract
INTRODUCTION: Prophylaxis is the recommended treatment mode for severe hemophilia B. However, no single treatment regimen fits for all patients. Once-weekly prophylaxis with high-dose recombinant factor IX (rFIX) is efficacious, nevertheless, laboratory outcomes following 72 h after administration are lacking.
METHODS: In a prospective open-label noncomparative study, 10 severe/moderate (FIX ≤2 IU/dL) adult patients received rFIX dose (60-100 IU/kg) after >72 h washout on two occasions, separated by 7 days. We measured one-stage and chromogenic FIX, ROTEM, and thrombin generation (TG) assay in plasma after washout, 30 min after infusion, and at days 3, 4, and 7.
RESULTS: Median FIX clotting/chromogenic activity increased from 1.5/2.0 to 87/62 IU/dL following rFIX administration, chromogenic assay resulting in 30% lower recovery. Correspondingly TG was severely reduced at baseline and improved at recovery (peak thrombin 6.0 to 54 nm). Standard ROTEM failed to detect FIX deficiency. Both FIX activity and TG remained increased from days 3 to 7, with median trough levels of FIX clotting/chromogenic 3.0/3.0 IU/dL (≥1 IU/dL in all severe patients) and peak thrombin 9.1 nm measured on day 7. FIX and TG assays were equally consistent between weeks 1 and 2.
CONCLUSIONS: Once-weekly rFIX prophylaxis results in favorable laboratory outcome.

PMID: 28406575 [PubMed - as supplied by publisher]

Factor XIII deficiency enhances thrombin generation due to impaired fibrin polymerization - An effect corrected by Factor XIII replacement.

Pe, 14/04/2017 - 20:49
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Factor XIII deficiency enhances thrombin generation due to impaired fibrin polymerization - An effect corrected by Factor XIII replacement.

Thromb Res. 2017 Jan;149:56-61

Authors: Pitkänen HH, Jouppila A, Lemponen M, Ilmakunnas M, Ahonen J, Lassila R

Abstract
INTRODUCTION: Factor XIII (FXIII) cross-links fibrin, completing blood coagulation. Congenital FXIII deficiency is managed with plasma-derived FXIII (pdFXIII) or recombinant FXIII (rFXIII) concentrates.
AIM: As the mechanisms protecting patients with low FXIII levels (<5IU/dL) from spontaneous bleeds remain unknown we assessed the interplay between thrombin generation (TG), fibrin formation and clot kinetics before and after FXIII administration in three patients with FXIII deficiency.
METHODS: Patients received initially rFXIII (35IU/kg, A-subunit) following with pdFXIII at 1250IU or 2500IU (12-30IU/kg) monthly. TG (CAT), thromboelastometry (ROTEM), prothrombin fragments F1+2, fibrinogen and FXIII activity (FXIII:C) were measured at baseline and one-hour recovery.
RESULTS: FXIII was at the target level of 20±6IU/dL at the 4-week trough. rFXIII corrected FXIII to 98±15 and high-dose pdFXIII to a level of 90±6, whereas low-dose/half dose pdFXIII reached 45±4IU/dL. Although fibrinogen (Clauss Method) was normal, coagulation in FIBTEM was impaired, which FXIII administration tended to correct. CAT implied 1.6- to 1.9-fold enhanced TG, which FXIII administration normalized. Inhibition of fibrin polymerization by Gly-Pro-Arg-Pro peptide mimicked FXIII deficiency in CAT by enhancing TG both in control and FXIII recovery plasma. Antithrombin, α2-macroblobulin-thrombin complex and prothrombin were normal, whereas F1+2 were elevated compatible with in vivo TG.
DISCUSSION: FXIII deficiency impairs fibrinogen function and fibrin formation simultaneously enhancing TG on the poorly polymerizing fibrin strands, when fibrin's antithrombin I -like function is absent. Our study suggests an inverse link between low FXIII levels and enhanced TG modifying structure-function relationship of fibrin to support hemostasis.

PMID: 27902939 [PubMed - indexed for MEDLINE]

Use of point-of-care testing and early assessment model reduces length of stay for ambulatory patients in an emergency department.

Ke, 12/04/2017 - 20:49
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Use of point-of-care testing and early assessment model reduces length of stay for ambulatory patients in an emergency department.

Scand J Trauma Resusc Emerg Med. 2016 Oct 18;24(1):125

Authors: Kankaanpää M, Raitakari M, Muukkonen L, Gustafsson S, Heitto M, Palomäki A, Suojanen K, Harjola VP

Abstract
BACKGROUND: To assess whether the use of point-of-care testing (POCT) and early assessment team (EAT) model shortens emergency department (ED) length of stay (LOS).
METHODS: This prospective, observational study with comparison between three study periods was performed in three phases in a metropolitan ED with 57,000 annual visits. Data were collected from adult ambulatory patients who were discharged home. Phase 1 served as a control (n = 1559 in one month). In phase 2, a comprehensive POCT panel including complete blood count, sodium, potassium, glucose, C-reactive protein, creatinine, alkaline phosphatase, alanine aminotransferase, bilirubin, amylase, and D-dimer was launched (n = 1442 in one month). In phase 3 (n = 3356 in subsequent two months), POCT approach continued. In addition, the working process was changed by establishing an EAT consisting of an emergency medicine resident and a nurse. The team operated from 12 noon to 10 p.m. was. The primary outcome was LOS (hh:mm) in the ED. Waiting times for patients requiring laboratory testing were analysed also, including time from admission to laboratory blood sampling (A2S interval), time from blood sampling to results ready (S2R interval) and time from results to discharge (R2D interval).
RESULTS: Median LOS of patients requiring laboratory tests in phase 1 was 3:51 (95 % confidence interval 03:38-04:04). During phase 2, introduction of POCT reduced median LOS by 29 min to 03:22 (03:12-03:31, p = 0.000). In phase 3, the EAT model reduced median LOS further by 17 min to 03:05 (02:59-03:12, p = 0.033). Altogether, the process was expedited by 46 min compared with the phase 1. Surprisingly, A2S interval was unaffected by the interventions among all patients needing laboratory testing. In comparison to phase 1, shortening of S2R interval was observed in phase 2 and 3, and that of R2D interval in all patients with laboratory assessments in phase 3.
DISCUSSION: The present study included adult ambulatory patients and is the first one to examine the impact of comprehensive POC test panel, first alone and then with additional process change. As a result, LOS was reduced significantly for patients needing laboratory tests. Considerable shortening in LOS came from introduction of POCT, and EAT process decreased the LOS further. We used a comprehensive POC test panel in order to maximise the patient population benefiting from the positive impacts of POC on laboratory turnaround time and length of stay. In EAT, diverse setups exist, and these differences affect the interpretation of results. The process changes in phase 3 were done by rearranging work shifts and no extra resources were added. Regarding to staffing the process improvement was thus cost neutral.
CONCLUSIONS: The advantage of POCT alone compared with central laboratory seemed to lie in shorter waiting times for results and earlier discharge home. Moreover, POCT and EAT model shorten LOS additively compared with conventional processes. However, a longer time is seemingly needed to adopt a new working process in the ED, and to establish its full benefit.

PMID: 27756354 [PubMed - indexed for MEDLINE]

More chronic GvHD and non-relapse mortality after peripheral blood stem cell compared with bone marrow in hematopoietic transplantation for paediatric acute lymphoblastic leukemia: a retrospective study on behalf of the EBMT Paediatric Diseases Working...

Ti, 11/04/2017 - 20:48
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More chronic GvHD and non-relapse mortality after peripheral blood stem cell compared with bone marrow in hematopoietic transplantation for paediatric acute lymphoblastic leukemia: a retrospective study on behalf of the EBMT Paediatric Diseases Working Party.

Bone Marrow Transplant. 2017 Apr 10;:

Authors: Simonin M, Dalissier A, Labopin M, Willasch A, Zecca M, Mouhab A, Chybicka A, Balduzzi A, Volin L, Peters C, Bader P, Dalle JH

PMID: 28394370 [PubMed - as supplied by publisher]

Outcome of Hematopoietic Cell Transplantation for DNA-Double Strand Breakage Repair Disorders.

Ti, 11/04/2017 - 20:48
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Outcome of Hematopoietic Cell Transplantation for DNA-Double Strand Breakage Repair Disorders.

J Allergy Clin Immunol. 2017 Apr 06;:

Authors: Slack J, Albert MH, Balashov D, Belohradsky BH, Bertaina A, Bleesing J, Booth C, Büchner J, Buckley RH, Ouachée-Chardin M, Deripapa E, Drabko K, Eapen M, Feuchtinger T, Finocchi A, Gaspar HB, Ghosh S, Gillio A, Gonzalez-Granado LI, Grunebaum E, Güngör T, Heilmann C, Helminen M, Higuchi K, Imai K, Kalwak K, Kanazawa N, Karasu G, Kucuk ZY, Laberko A, Lange A, Mahlaoui N, Meisel R, Moshous D, Muramatsu H, Parikh S, Pasic S, Schmid I, Schuetz C, Schulz A, Schultz KR, Shaw PJ, Slatter MA, Sykora KW, Tamura S, Taskinen M, Wawer A, Wolska-Kus Nierz B, Cowan MJ, Fischer A, Gennery AR, Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation, European Society for Immunodeficiencies, Stem Cell Transplant for Immunodeficiencies in Europe (SCETIDE), the Center for International Blood and Marrow Transplant Research,, Primary Immunodeficiency Treatment Consortium

Abstract
BACKGROUND: Rare DNA breakage-repair disorders predispose to infection and lympho-reticular malignancies. Hematopoietic cell transplantation (HCT) is curative but co-administered chemo- or radio-therapy is damaging due to systemic radio-sensitivity. We collected HCT outcome data for Nijmegen Breakage syndrome (NBS), DNA ligase IV deficiency (LIG4), Cernunnos-XLF deficiency and ataxia-telangiectasia.
METHODS: Data from 38 centres worldwide, including indication, donor, conditioning regimen, graft-versus-host disease (GvHD) and outcome were analyzed. Conditioning was classified as myeloablative (MAC) if it contained radiotherapy or alkylators and reduced intensity (RIC) if no alkylators and/or fludarabine ≤150 mg/m(2) and cyclophosphamide ≤ 40 mg/kg were used.
RESULTS: 55 new, 14 updated and 18 previously published patients were analyzed. Median age at HCT was 48 (range 1.5 - 552) months. 29 were transplanted for infection, 21 malignancy, 13 bone marrow failure, 13 pre-emptively, 5 had multiple indications, and 6 had no information. 22 received MAC, 59 RIC, 4 were infused;- information unavailable for 2. 73/77 patients with LIG4, Cernunnos-XLF deficiency or NBS received conditioning. Survival was 53/77 (69%), worse for MAC than RIC (p=0.006). Most deaths occurred early post-transplant suggesting poor tolerance of conditioning. Survival in ataxia-telangiectasia patients was 25%. 41/83 patients experienced aGvHD (49%): less in RIC compared to MAC, 26/56 (46%) vs 12/21 (57%) (p=0.45). Median follow-up was 35 (range 2-168) months. No secondary malignancies were reported during 15 years follow-up. Growth and developmental delay remained post-HCT; immune-mediated complications resolved.
CONCLUSION: RIC-HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for ataxia-telangiectasia is not recommended.

PMID: 28392333 [PubMed - as supplied by publisher]

Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility.

La, 08/04/2017 - 20:33
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Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility.

Sci Rep. 2017 Apr 06;7(1):681

Authors: Mantere T, Tervasmäki A, Nurmi A, Rapakko K, Kauppila S, Tang J, Schleutker J, Kallioniemi A, Hartikainen JM, Mannermaa A, Nieminen P, Hanhisalo R, Lehto S, Suvanto M, Grip M, Jukkola-Vuorinen A, Tengström M, Auvinen P, Kvist A, Borg Å, Blomqvist C, Aittomäki K, Greenberg RA, Winqvist R, Nevanlinna H, Pylkäs K

Abstract
Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish breast cancer cases (n = 578-1565) and controls (n = 337-1228). Mutations showing potential cancer association were analyzed in additional Finnish cohorts. c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p = 0.018) and likely represents a Northern Finnish founder mutation. A deleterious c.2715 + 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640_644del5) in RNF168, causative for recessive RIDDLE syndrome, had high prevalence in majority of the analyzed cohorts, but did not associate with breast cancer. In conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warranting further investigations in other populations. Furthermore, high frequency of RNF168 c.640_644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms.

PMID: 28386063 [PubMed - in process]

Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

La, 08/04/2017 - 20:33
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Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

Nature. 2017 01 05;541(7635):81-86

Authors: Wahl S, Drong A, Lehne B, Loh M, Scott WR, Kunze S, Tsai PC, Ried JS, Zhang W, Yang Y, Tan S, Fiorito G, Franke L, Guarrera S, Kasela S, Kriebel J, Richmond RC, Adamo M, Afzal U, Ala-Korpela M, Albetti B, Ammerpohl O, Apperley JF, Beekman M, Bertazzi PA, Black SL, Blancher C, Bonder MJ, Brosch M, Carstensen-Kirberg M, de Craen AJ, de Lusignan S, Dehghan A, Elkalaawy M, Fischer K, Franco OH, Gaunt TR, Hampe J, Hashemi M, Isaacs A, Jenkinson A, Jha S, Kato N, Krogh V, Laffan M, Meisinger C, Meitinger T, Mok ZY, Motta V, Ng HK, Nikolakopoulou Z, Nteliopoulos G, Panico S, Pervjakova N, Prokisch H, Rathmann W, Roden M, Rota F, Rozario MA, Sandling JK, Schafmayer C, Schramm K, Siebert R, Slagboom PE, Soininen P, Stolk L, Strauch K, Tai ES, Tarantini L, Thorand B, Tigchelaar EF, Tumino R, Uitterlinden AG, van Duijn C, van Meurs JB, Vineis P, Wickremasinghe AR, Wijmenga C, Yang TP, Yuan W, Zhernakova A, Batterham RL, Smith GD, Deloukas P, Heijmans BT, Herder C, Hofman A, Lindgren CM, Milani L, van der Harst P, Peters A, Illig T, Relton CL, Waldenberger M, Järvelin MR, Bollati V, Soong R, Spector TD, Scott J, McCarthy MI, Elliott P, Bell JT, Matullo G, Gieger C, Kooner JS, Grallert H, Chambers JC

Abstract
Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10(-7), range P = 9.2 × 10(-8) to 6.0 × 10(-46); n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10(-6), range P = 5.5 × 10(-6) to 6.1 × 10(-35), n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10(-54)). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.

PMID: 28002404 [PubMed - indexed for MEDLINE]

Discovery of novel heart rate-associated loci using the Exome Chip.

To, 06/04/2017 - 20:31
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Discovery of novel heart rate-associated loci using the Exome Chip.

Hum Mol Genet. 2017 Apr 03;:

Authors: van den Berg ME, Warren HR, Cabrera CP, Verweij N, Mifsud B, Haessler J, Bihlmeyer NA, Fu YP, Weiss S, Lin HJ, Grarup N, Li-Gao R, Pistis G, Shah N, Brody JA, Müller-Nurasyid M, Lin H, Mei H, Smith AV, Lyytikäinen LP, Hall LM, van Setten J, Trompet S, Prins BP, Isaacs A, Radmanesh F, Marten J, Entwistle A, Kors JA, Silva CT, Alonso A, Bis JC, de Boer R, de Haan HG, de Mutsert R, Dedoussis G, Dominiczak AF, Doney AS, Ellinor PT, Eppinga RN, Felix SB, Guo X, Hagemeijer Y, Hansen T, Harris TB, Heckbert SR, Huang PL, Hwang SJ, Kähönen M, Kanters JK, Kolcic I, Launer LJ, Li M, Yao J, Linneberg A, Liu S, Macfarlane PW, Mangino M, Morris AD, Mulas A, Murray AD, Nelson CP, Orrú M, Padmanabhan S, Peters A, Porteous DJ, Poulter N, Psaty BM, Qi L, Raitakari OT, Rivadeneira F, Roselli C, Rudan I, Sattar N, Sever P, Sinner MF, Soliman EZ, Spector TD, Stanton AV, Stirrups KE, Taylor KD, Tobin MD, Uitterlinden A, Vaartjes I, Hoes AW, van der Meer P, Völker U, Waldenberger M, Xie Z, Zoledziewska M, Tinker A, Polasek O, Rosand J, Jamshidi Y, van Duijn CM, Zeggini E, Wouter Jukema J, Asselbergs FW, Samani NJ, Lehtimäki T, Gudnason V, Wilson J, Lubitz SA, Kääb S, Sotoodehnia N, Caulfield MJ, Palmer CN, Sanna S, Mook-Kanamori DO, Deloukas P, Pedersen O, Rotter JI, Dörr M, O'Donnell CJ, Hayward C, Arking DE, Kooperberg C, van der Harst P, Eijgelsheim M, Stricker BH, Munroe PB

Abstract
Background Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation.Aim To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104,452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134,251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.Results We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2, SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long range regulatory chromatin interactions in heart tissue (SCD, SLF2, MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Conclusion Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

PMID: 28379579 [PubMed - as supplied by publisher]

Venous thromboembolism after surgical treatment of non-spinal skeletal metastases - An underdiagnosed complication.

Ke, 05/04/2017 - 20:30
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Venous thromboembolism after surgical treatment of non-spinal skeletal metastases - An underdiagnosed complication.

Thromb Res. 2016 May;141:124-8

Authors: Ratasvuori M, Lassila R, Laitinen M

Abstract
INTRODUCTION AND AIM: Venous thromboembolism (VTE) is a severe complication associated both with major orthopaedic surgery and cancer. However, survival and postoperative complications of skeletal metastases despite their thrombogenic potential, have received little attention in both the clinical management and research setting. This single-centre observational cohort study aimed to evaluate the incidence and impact of VTE in association with cancer surgery targeted to the management of fractures secondary to skeletal metastases.
METHODS: Data were collected retrospectively from the medical database. We included consecutive 306 patients operated for 343 non-spinal skeletal metastases during a 15-year period (1999-2014). The incidence of VTE and its risk factors were assessed using binary logistic regression analysis. Kaplan-Meier and Cox regression analyses were used to evaluate variables affecting survival.
RESULTS: The rate of symptomatic VTE was 10% (30/306) during the 3-month postoperative period, while 79% received thromboprophylaxis. Fatal pulmonary embolism (PE) rate was high, 3.3% (10/306) after surgery. Intraoperative oxygen saturation drop, pulmonary metastases and intramedullary nailing were independent risk factors for VTE. Indicators of decreased survival were lung cancer, intramedullary nailing, multiple skeletal and pulmonary metastases, anaemia, leukocytosis, and PE.
CONCLUSION: Relationship between fractures secondary to skeletal metastases and VTE needs further clinical attention. Whether the survival of patients with fractures secondary to skeletal metastases can be improved by targeted thromboprophylactic means should be studied further.

PMID: 27017349 [PubMed - indexed for MEDLINE]