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Early discharge and home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban: an international multicentre single-arm clinical trial.

Pe, 24/05/2019 - 23:02
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Early discharge and home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban: an international multicentre single-arm clinical trial.

Eur Heart J. 2019 May 23;:

Authors: Barco S, Schmidtmann I, Ageno W, Bauersachs RM, Becattini C, Bernardi E, Beyer-Westendorf J, Bonacchini L, Brachmann J, Christ M, Czihal M, Duerschmied D, Empen K, Espinola-Klein C, Ficker JH, Fonseca C, Genth-Zotz S, Jiménez D, Harjola VP, Held M, Iogna Prat L, Lange TJ, Manolis A, Meyer A, Mustonen P, Rauch-Kroehnert U, Ruiz-Artacho P, Schellong S, Schwaiblmair M, Stahrenberg R, Westerweel PE, Wild PS, Konstantinides SV, Lankeit M, HoT-PE Investigators

Abstract
AIMS: To investigate the efficacy and safety of early transition from hospital to ambulatory treatment in low-risk acute PE, using the oral factor Xa inhibitor rivaroxaban.
METHODS AND RESULTS: We conducted a prospective multicentre single-arm investigator initiated and academically sponsored management trial in patients with acute low-risk PE (EudraCT Identifier 2013-001657-28). Eligibility criteria included absence of (i) haemodynamic instability, (ii) right ventricular dysfunction or intracardiac thrombi, and (iii) serious comorbidities. Up to two nights of hospital stay were permitted. Rivaroxaban was given at the approved dose for PE for ≥3 months. The primary outcome was symptomatic recurrent venous thromboembolism (VTE) or PE-related death within 3 months of enrolment. An interim analysis was planned after the first 525 patients, with prespecified early termination of the study if the null hypothesis could be rejected at the level of α = 0.004 (<6 primary outcome events). From May 2014 through June 2018, consecutive patients were enrolled in seven countries. Of the 525 patients included in the interim analysis, three (0.6%; one-sided upper 99.6% confidence interval 2.1%) suffered symptomatic non-fatal VTE recurrence, a number sufficiently low to fulfil the condition for early termination of the trial. Major bleeding occurred in 6 (1.2%) of the 519 patients comprising the safety population. There were two cancer-related deaths (0.4%).
CONCLUSION: Early discharge and home treatment with rivaroxaban is effective and safe in carefully selected patients with acute low-risk PE. The results of the present trial support the selection of appropriate patients for ambulatory treatment of PE.

PMID: 31120118 [PubMed - as supplied by publisher]

Second allogeneic stem cell transplantation in patients with acute lymphoblastic leukaemia: a study on behalf of the Acute Leukaemia Working Party of the European Society for Blood and Marrow Transplantation.

To, 23/05/2019 - 23:02
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Second allogeneic stem cell transplantation in patients with acute lymphoblastic leukaemia: a study on behalf of the Acute Leukaemia Working Party of the European Society for Blood and Marrow Transplantation.

Br J Haematol. 2019 May 22;:

Authors: Nagler A, Labopin M, Dholaria B, Finke J, Brecht A, Schanz U, Niittyvuopio R, Neubauer A, Bornhäuser M, Santarone S, Beelen D, Shimoni A, Rösler W, Giebel S, Savani BN, Mohty M

Abstract
Although second allogeneic haematopoietic cell transplantation (allo-HCT2) is a therapeutic option for patients relapsing after first HCT (allo-HCT1), there is limited data on allo-HCT2 in patients with acute lymphoblastic leukaemia (ALL). We retrospectively studied 245 patients receiving allo-HCT2 as a salvage treatment for relapse following allo-HCT1 between the 2000 and 2017. The median age at allo-HCT2 was 34·6 years (range: 18-74). One hundred and one patients (41%) received sibling donor and 144 (59%) unrelated donor allo-HCT2. Acute graft-versus-host disease (GVHD) grade II-IV and III-IV occurred in 33% and 17% of the patients, respectively. The incidence of 2-year total and extensive chronic GVHD was 38% and 19%, respectively. The 2- and 5-year cumulative incidence of non-relapse mortality, relapse incidence, leukaemia-free survival, overall survival and GVHD-free, relapse-free survival (GRFS) were 24% and 26%, 56% and 62%, 20% and 12%, 30% and 14% and 12% & 7%, respectively. In multivariate analysis, factors associated with overall survival were age, time from allo-HCT1 to relapse, conditioning for allo-HCT1, Karnofsky score at allo-HCT2 and donor type for allo-HCT2. In conclusion, outcomes of allo-HCT2 in ALL patients were poor, with only 14% overall survival and 7% GRFS at 5 years with very high relapse incidence.

PMID: 31115916 [PubMed - as supplied by publisher]

Patient-Customized Drug Combination Prediction and Testing for T-cell Prolymphocytic Leukemia Patients.

Ke, 22/05/2019 - 23:02
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Patient-Customized Drug Combination Prediction and Testing for T-cell Prolymphocytic Leukemia Patients.

Cancer Res. 2018 05 01;78(9):2407-2418

Authors: He L, Tang J, Andersson EI, Timonen S, Koschmieder S, Wennerberg K, Mustjoki S, Aittokallio T

Abstract
The molecular pathways that drive cancer progression and treatment resistance are highly redundant and variable between individual patients with the same cancer type. To tackle this complex rewiring of pathway cross-talk, personalized combination treatments targeting multiple cancer growth and survival pathways are required. Here we implemented a computational-experimental drug combination prediction and testing (DCPT) platform for efficient in silico prioritization and ex vivo testing in patient-derived samples to identify customized synergistic combinations for individual cancer patients. DCPT used drug-target interaction networks to traverse the massive combinatorial search spaces among 218 compounds (a total of 23,653 pairwise combinations) and identified cancer-selective synergies by using differential single-compound sensitivity profiles between patient cells and healthy controls, hence reducing the likelihood of toxic combination effects. A polypharmacology-based machine learning modeling and network visualization made use of baseline genomic and molecular profiles to guide patient-specific combination testing and clinical translation phases. Using T-cell prolymphocytic leukemia (T-PLL) as a first case study, we show how the DCPT platform successfully predicted distinct synergistic combinations for each of the three T-PLL patients, each presenting with different resistance patterns and synergy mechanisms. In total, 10 of 24 (42%) of selective combination predictions were experimentally confirmed to show synergy in patient-derived samples ex vivo The identified selective synergies among approved drugs, including tacrolimus and temsirolimus combined with BCL-2 inhibitor venetoclax, may offer novel drug repurposing opportunities for treating T-PLL.Significance: An integrated use of functional drug screening combined with genomic and molecular profiling enables patient-customized prediction and testing of drug combination synergies for T-PLL patients. Cancer Res; 78(9); 2407-18. ©2018 AACR.

PMID: 29483097 [PubMed - indexed for MEDLINE]

Late treatment-related mortality versus competing causes of death after allogeneic transplantation for myelodysplastic syndromes and secondary acute myeloid leukemia.

Ti, 21/05/2019 - 23:01
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Late treatment-related mortality versus competing causes of death after allogeneic transplantation for myelodysplastic syndromes and secondary acute myeloid leukemia.

Leukemia. 2019 03;33(3):686-695

Authors: Schetelig J, de Wreede LC, van Gelder M, Koster L, Finke J, Niederwieser D, Beelen D, Mufti GJ, Platzbecker U, Ganser A, Heidenreich S, Maertens J, Socié G, Brecht A, Stelljes M, Kobbe G, Volin L, Nagler A, Vitek A, Luft T, Ljungman P, Yakoub-Agha I, Robin M, Kröger N

Abstract
The causes and rates of late patient-mortality following alloHCT for myelodysplastic syndromes or secondary acute myeloid leukemia were studied, to assess the contribution of relapse-related, treatment-related, and population factors. Data from EBMT on 6434 adults, who received a first alloHCT from January 2000 to December 2012, were retrospectively studied using combined land-marking, relative-survival methods and multi-state modeling techniques. Median age at alloHCT increased from 49 to 58 years, and the number of patients aged ≥65 years at alloHCT increased from 5 to 17%. Overall survival probability was 53% at 2 years and 35% at 10 years post-alloHCT. Survival probability at 5 years from the 2-year landmark was 88% for patients <45-year old and 63% for patients ≥65-year old at alloHCT. Cumulative incidence of nonrelapse mortality (NRM) for patients <45-year old at transplant was 7% rising to 25% for patients aged ≥65. For older patients, 31% of NRM-deaths could be attributed to population mortality. Favorable post-alloHCT long-term survival was seen; however, excess mortality-risk for all age groups was shown compared to the general population. A substantial part of total NRM for older patients was attributable to population mortality, information which aids the balanced explanation of post-HCT risk and helps improve long-term care.

PMID: 30573777 [PubMed - indexed for MEDLINE]

The PanCareSurFup consortium: research and guidelines to improve lives for survivors of childhood cancer.

Ti, 21/05/2019 - 23:01
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The PanCareSurFup consortium: research and guidelines to improve lives for survivors of childhood cancer.

Eur J Cancer. 2018 11;103:238-248

Authors: Byrne J, Alessi D, Allodji RS, Bagnasco F, Bárdi E, Bautz A, Bright CJ, Brown M, Diallo I, Feijen EAML, Fidler MM, Frey E, Garwicz S, Grabow D, Gudmundsdottir T, Hagberg O, Harila-Saari A, Hau EM, Haupt R, Hawkins MM, Jakab Z, Jankovic M, Kaatsch P, Kaiser M, Kremer LCM, Kuehni CE, Kuonen R, Ladenstein R, Lähteenmäki PM, Levitt G, Linge H, LLanas D, Michel G, Morsellino V, Mulder RL, Reulen RC, Ronckers CM, Sacerdote C, Skinner R, Steliarova-Foucher E, van der Pal HJ, de Vathaire F, Vũ Bezin G, Wesenberg F, Wiebe T, Winter DL, Falck Winther J, Witthoff E, Zadravec Zaletel L, Hjorth L

Abstract
BACKGROUND: Second malignant neoplasms and cardiotoxicity are among the most serious and frequent adverse health outcomes experienced by childhood and adolescent cancer survivors (CCSs) and contribute significantly to their increased risk of premature mortality. Owing to differences in health-care systems, language and culture across the continent, Europe has had limited success in establishing multi-country collaborations needed to assemble the numbers of survivors required to clarify the health issues arising after successful cancer treatment. PanCareSurFup (PCSF) is the first pan-European project to evaluate some of the serious long-term health risks faced by survivors. This article sets out the overall rationale, methods and preliminary results of PCSF.
METHODS: The PCSF consortium pooled data from 13 cancer registries and hospitals in 12 European countries to evaluate subsequent primary malignancies, cardiac disease and late mortality in survivors diagnosed between ages 0 and 20 years. In addition, PCSF integrated radiation dosimetry to sites of second malignancies and to the heart, developed evidence-based guidelines for long-term care and for transition services, and disseminated results to survivors and the public.
RESULTS: We identified 115,596 individuals diagnosed with cancer, of whom 83,333 were 5-year survivors and diagnosed from 1940 to 2011. This single data set forms the basis for cohort analyses of subsequent malignancies, cardiac disease and late mortality and case-control studies of subsequent malignancies and cardiac disease in 5-year survivors.
CONCLUSIONS: PCSF delivered specific estimates of risk and comprehensive guidelines to help survivors and care-givers. The expected benefit is to provide every European CCS with improved access to care and better long-term health.

PMID: 30286417 [PubMed - indexed for MEDLINE]

Effect of Wilms tumor histology on response to neoadjuvant chemotherapy.

Ti, 21/05/2019 - 23:01
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Effect of Wilms tumor histology on response to neoadjuvant chemotherapy.

J Pediatr Surg. 2019 Apr;54(4):771-774

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

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

PMID: 29887169 [PubMed - indexed for MEDLINE]

Associations between neutrophil recovery time, infections and relapse in pediatric acute myeloid leukemia.

Ti, 21/05/2019 - 23:01
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Associations between neutrophil recovery time, infections and relapse in pediatric acute myeloid leukemia.

Pediatr Blood Cancer. 2018 09;65(9):e27231

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

Abstract
BACKGROUND: Children with acute myeloid leukemia (AML) treated similarly show different toxicity and leukemic responses. We investigated associations between neutrophil recovery time after the first induction course, infection and relapse in children treated according to NOPHO-AML 2004 and DB AML-01.
PROCEDURE: Newly diagnosed patients with AML with bone marrow blast <5% between day 15 after the start of the treatment and the start of second induction course, and in complete remission after the second induction course were included (n = 279). Neutrophil recovery time was defined as the time from the start of the course to the last day with absolute neutrophil count <0.5 × 109 /l. Linear and Cox regressions were used to investigate associations.
RESULTS: Neutrophil recovery time after the first induction course was positively associated with neutrophil recovery time after the remaining courses, and longer neutrophil recovery time (≥25 days) was associated with increased risk of grade 3-4 infections (hazard ratio 1.4, 95% confidence interval [CI], 1.1-1.8). Longer neutrophil recovery time after the first induction (>30 days) was associated with the increased risk of relapse (5-year cumulative incidence: 48% vs. 42%, hazard ratio 1.7, 95% CI, 1.1-2.6) for cases not treated with hematopoietic stem cell transplantation in first complete remission.
CONCLUSION: Longer neutrophil recovery time after the first induction course was associated with grade 3-4 infections and relapse. If confirmed, this knowledge could be incorporated into risk stratification strategies in pediatric AML.

PMID: 29781563 [PubMed - indexed for MEDLINE]

The Cdh5-CreERT2 transgene causes conditional Shb gene deletion in hematopoietic cells with consequences for immune cell responses to tumors.

Su, 19/05/2019 - 23:01
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The Cdh5-CreERT2 transgene causes conditional Shb gene deletion in hematopoietic cells with consequences for immune cell responses to tumors.

Sci Rep. 2019 May 17;9(1):7548

Authors: He Q, Li X, Singh K, Luo Z, Meija-Cordova M, Jamalpour M, Lindahl B, Kriz V, Vuolteenaho R, Ulvmar M, Welsh M

Abstract
The tamoxifen-responsive conditional Cdh5-CreERT2 is commonly used for endothelial cell specific conditional deletion of loxP-flanked gene sequences. To address the role of endothelial cell Shb gene for B16F10 melanoma immune responses, tamoxifen-injected Cdh5-CreERT2/WT and Cdh5-CreERT2/Shbflox/flox mice received subcutaneous tumor cell injections. We observed a decrease of tumor myeloid cell Shb mRNA in the tamoxifen treated Cdh5-CreERT2/Shbflox/flox mice, which was not present when the mice had undergone a preceding bone marrow transplantation using wild type bone marrow. Differences in CD4+/FoxP3+ Tregs were similarly abolished by a preceding bone marrow transplantation. In ROSA26-mTmG mice, Cdh5-CreERT2 caused detectable floxing in certain bone marrow populations and in spleen cells. Floxing in bone marrow could be detected two months after tamoxifen treatment. In the spleen, however, floxing was undetectable two months after tamoxifen treatment, suggesting that Cdh5-CreERT2 is operating in a non-renewable population of hematopoietic cells in this organ. These data suggest that conditional gene deletion in hematopoietic cells is a potential confounder in experiments attempting to assess the role of endothelial specific effects. A cautious approach to achieve an endothelial-specific phenotype would be to adopt a strategy that includes a preceding bone marrow transplantation.

PMID: 31101877 [PubMed - in process]

Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy.

Su, 19/05/2019 - 23:01
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Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy.

Blood. 2019 May 17;:

Authors: Zucca E, Rondeau S, Vanazzi A, Østenstad B, Mey UJM, Rauch D, Wahlin BE, Hitz F, Hernberg M, Johansson AS, de Nully Brown P, Hagberg H, Ferreri AJM, Lohri A, Novak U, Zander T, Bersvendsen H, Bargetzi M, Mingrone W, Krasniqi F, Dirnhofer S, Hayoz S, Hawle H, Berardi Vilei S, Ghielmini M, Kimby E

Abstract
The SAKK 35/10 phase-2 trial (NCT01307605), developed by the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG), compared the activity of rituximab versus rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m2 IV on day 1, weeks 1-4, repeated week 12-15 in responding patients) or to rituximab (same schedule) in combination with lenalidomide (15 mg PO daily for 18 weeks). Primary endpoint was complete response (CR/CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk FLIPI in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%, 95% CI: 26-48% vs. 25%, 95% CI: 16-36%) and confirmed by an independent response review of only CT scans (61%, 95% CI: 49-72% vs. 36%, 95% CI: 26-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates, longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (≥ 90%). Toxicity grade ≥3 was more common in the combination arm (56% vs. 22% of pts), mainly represented by neutropenia (23% vs. 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with higher but expected and manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored.

PMID: 31101627 [PubMed - as supplied by publisher]

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.

Pe, 17/05/2019 - 23:00
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Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.

Nat Commun. 2019 04 15;10(1):1741

Authors: Ferreira MA, Gamazon ER, Al-Ejeh F, Aittomäki K, Andrulis IL, Anton-Culver H, Arason A, Arndt V, Aronson KJ, Arun BK, Asseryanis E, Azzollini J, Balmaña J, Barnes DR, Barrowdale D, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Białkowska K, Blomqvist C, Bogdanova NV, Bojesen SE, Bolla MK, Borg A, Brauch H, Brenner H, Broeks A, Burwinkel B, Caldés T, Caligo MA, Campa D, Campbell I, Canzian F, Carter J, Carter BD, Castelao JE, Chang-Claude J, Chanock SJ, Christiansen H, Chung WK, Claes KBM, Clarke CL, EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, de la Hoya M, Dennis J, Devilee P, Diez O, Dörk T, Dunning AM, Dwek M, Eccles DM, Ejlertsen B, Ellberg C, Engel C, Eriksson M, Fasching PA, Fletcher O, Flyger H, Friedman E, Frost D, Gabrielson M, Gago-Dominguez M, Ganz PA, Gapstur SM, Garber J, García-Closas M, García-Sáenz JA, Gaudet MM, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Gronwald J, Guénel P, Haiman CA, Hall P, Hamann U, He W, Heyworth J, Hogervorst FBL, Hollestelle A, Hoover RN, Hopper JL, Hulick PJ, Humphreys K, Imyanitov EN, ABCTB Investigators, HEBON Investigators, BCFR Investigators, Isaacs C, Jakimovska M, Jakubowska A, James PA, Janavicius R, Jankowitz RC, John EM, Johnson N, Joseph V, Karlan BY, Khusnutdinova E, Kiiski JI, Ko YD, Jones ME, Konstantopoulou I, Kristensen VN, Laitman Y, Lambrechts D, Lazaro C, Leslie G, Lester J, Lesueur F, Lindström S, Long J, Loud JT, Lubiński J, Makalic E, Mannermaa A, Manoochehri M, Margolin S, Maurer T, Mavroudis D, McGuffog L, Meindl A, Menon U, Michailidou K, Miller A, Montagna M, Moreno F, Moserle L, Mulligan AM, Nathanson KL, Neuhausen SL, Nevanlinna H, Nevelsteen I, Nielsen FC, Nikitina-Zake L, Nussbaum RL, Offit K, Olah E, Olopade OI, Olsson H, Osorio A, Papp J, Park-Simon TW, Parsons MT, Pedersen IS, Peixoto A, Peterlongo P, Pharoah PDP, Plaseska-Karanfilska D, Poppe B, Presneau N, Radice P, Rantala J, Rennert G, Risch HA, Saloustros E, Sanden K, Sawyer EJ, Schmidt MK, Schmutzler RK, Sharma P, Shu XO, Simard J, Singer CF, Soucy P, Southey MC, Spinelli JJ, Spurdle AB, Stone J, Swerdlow AJ, Tapper WJ, Taylor JA, Teixeira MR, Terry MB, Teulé A, Thomassen M, Thöne K, Thull DL, Tischkowitz M, Toland AE, Torres D, Truong T, Tung N, Vachon CM, van Asperen CJ, van den Ouweland AMW, van Rensburg EJ, Vega A, Viel A, Wang Q, Wappenschmidt B, Weitzel JN, Wendt C, Winqvist R, Yang XR, Yannoukakos D, Ziogas A, Kraft P, Antoniou AC, Zheng W, Easton DF, Milne RL, Beesley J, Chenevix-Trench G

Abstract
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

PMID: 30988301 [PubMed - indexed for MEDLINE]

A case report and follow-up of the first live birth after heterotopic transplantation of cryopreserved ovarian tissue in Eastern Europe.

To, 16/05/2019 - 22:59
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A case report and follow-up of the first live birth after heterotopic transplantation of cryopreserved ovarian tissue in Eastern Europe.

BMC Womens Health. 2019 May 14;19(1):65

Authors: Tammiste T, Kask K, Padrik P, Idla K, Rosenstein K, Jatsenko T, Veerus P, Salumets A

Abstract
BACKGROUND: Ovarian insufficiency is a major concern for long-term cancer survivors. Although semen freezing is well established to preserve male fertility, the possibilities to secure post-cancer female fertility are mostly limited to oocyte or embryo freezing. These methods require time-consuming ovarian stimulation with or without in vitro fertilization (IVF) that evidently delays cancer therapy. Ovarian tissue cryopreservation and subsequent thawed tissue autotransplantation are considered the most promising alternative strategy for restoring the fertility of oncology patients, which has not yet received the full clinical acceptance. Therefore, all successful cases are needed to prove its reliability and safety.
CASE PRESENTATION: Here we report a single case in Estonia, where a 28-year-old woman with malignant breast neoplasm had ovarian cortex cryopreserved before commencing gonadotoxic chemo- and radiotherapy. Two years after cancer therapy, the patient underwent heterotopic ovarian tissue transplantation into the lateral pelvic wall. The folliculogenesis was stimulated in the transplanted tissue by exogenous follicle-stimulating hormone and oocytes were collected under ultrasound guidance for IVF and embryo transfer. The healthy boy was born after full-term gestation in 2014, first in Eastern Europe.
CONCLUSION: Despite many countries have reported the first implementation of the ovarian tissue freezing and transplantation protocols, the data is still limited on the effectiveness of heterotopic ovarian transplant techniques. Thus, all case reports of heterotopic ovarian tissue transplantation and long-term follow-ups to describe the children's health are valuable source of clinical experience.

PMID: 31088441 [PubMed - in process]

Enhanced nutrient supply and intestinal microbiota development in very low birth weight infants.

To, 16/05/2019 - 22:59
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Enhanced nutrient supply and intestinal microbiota development in very low birth weight infants.

Pediatr Res. 2019 May 14;:

Authors: Blakstad EW, Korpela K, Lee S, Nakstad B, Moltu SJ, Strømmen K, Rønnestad AE, Brække K, Iversen PO, de Vos WM, Drevon CA

Abstract
BACKGROUND: Promoting a healthy intestinal microbiota may have positive effects on short- and long-term outcomes in very low birth weight (VLBW; BW < 1500 g) infants. Nutrient supply influences the intestinal microbiota.
METHODS: Fifty VLBW infants were randomized to an intervention group receiving enhanced nutrient supply or a control group. Fecal samples from 45 infants collected between birth and discharge were analyzed using 16S ribosomal RNA (rRNA) amplicon sequencing.
RESULTS: There was considerable individual variation in microbiota development. Microbial richness decreased towards discharge in the controls compared to the intervention group. In the intervention group, there was a greater increase in diversity among moderately/very preterm (MVP, gestational age ≥ 28 weeks) infants and a steeper decrease in relative Staphylococcus abundance in extremely preterm (EP, gestational age < 28 weeks) infants as compared to controls. Relative Bifidobacterium abundance tended to increase more in MVP controls compared to the intervention group. Abundance of pathogens was not increased in the intervention group. Higher relative Bifidobacterium abundance was associated with improved weight gain.
CONCLUSION: Nutrition may affect richness, diversity, and microbiota composition. There was no increase in relative abundance of pathogens among infants receiving enhanced nutrient supply. Favorable microbiota development was associated with improved weight gain.

PMID: 31086354 [PubMed - as supplied by publisher]

A New Model to Predict Benign Histology in Residual Retroperitoneal Masses After Chemotherapy in Nonseminoma.

To, 16/05/2019 - 22:59
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A New Model to Predict Benign Histology in Residual Retroperitoneal Masses After Chemotherapy in Nonseminoma.

Eur Urol Focus. 2018 12;4(6):995-1001

Authors: Leão R, Nayan M, Punjani N, Jewett MAS, Fadaak K, Garisto J, Lewin J, Atenafu EG, Sweet J, Anson-Cartwright L, Boström P, Chung P, Warde P, Bedard PL, Bagrodia A, Freifeld Y, Power N, Winquist E, Hamilton RJ

Abstract
BACKGROUND: Postchemotherapy retroperitoneal lymph node dissection (pcRPLND) is indicated in testicular cancer patients with normalised or plateaued serum tumour markers and residual retroperitoneal lesions >1cm. Challenges remain in predicting postchemotherapy residual mass (pcRM) histology, which may lead to unnecessary surgery.
OBJECTIVE: To develop an accurate model to predict pcRM histology in patients with nonseminomatous germ cell tumours (NSGCTs).
DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of 335 patients undergoing pcRPLND for metastatic NSGCTs to develop a model to predict benign histology in retroperitoneal pcRM. Our model was compared with others and externally validated.
INTERVENTION: Chemotherapy and pcRPLND.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable logistic regression to evaluate the presence of benign histology, and fractional polynomials to allow for a nonlinear association between continuous variables and the outcome. The final Princess Margaret model (PMM) was selected based on the number of variables used, reliability, and discriminative capacity to predict benign pcRM.
RESULTS AND LIMITATIONS: PMM included the presence of teratoma in the orchiectomy, prechemotherapy α-fetoprotein, prechemotherapy mass size, and change in mass size during chemotherapy. Model specificity was 99.3%. Compared with Vergouwe et al's model, PMM had significantly better accuracy (C statistic 0.843 vs 0.783). PMM appropriately identified a larger number of patients for whom pcRPLND can safely be avoided (13.9% vs 0%). Validated in external cohorts, the model retained high discrimination (C statistic 0.88 and 0.80). Larger and prospective studies are needed to further validate this model.
CONCLUSIONS: Our clinical model, externally validated, showed improved discriminative ability in predicting pcRM histology when compared with other models. The higher accuracy and reduced number of variables make this a novel and appealing model to use for patient counselling and treatment strategies.
PATIENT SUMMARY: Princess Margaret model accurately predicted postchemotherapy benign histology. These results might have clinical impact by avoiding unnecessary retroperitoneal lymph node dissection and consequently changing the paradigm of advanced testicular cancer treatment.

PMID: 29428550 [PubMed - indexed for MEDLINE]

Accuracy and usability of the eGVHD app in assessing the severity of graft-versus-host disease at the 2017 EBMT annual congress.

To, 16/05/2019 - 22:59
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Accuracy and usability of the eGVHD app in assessing the severity of graft-versus-host disease at the 2017 EBMT annual congress.

Bone Marrow Transplant. 2018 04;53(4):490-494

Authors: Schoemans HM, Goris K, Van Durm R, Vanbrabant K, De Geest S, Maertens J, Wolff D, Greinix H, Ruutu T, Pavletic SZ, Im A, Lee SJ, Basak GW, Duarte RF, Dobbels F, Complications and Quality of Life Working Party of the EBMT

PMID: 29330389 [PubMed - indexed for MEDLINE]

Intravenous but not intrathecal central nervous system-directed chemotherapy improves survival in patients with testicular diffuse large B-cell lymphoma.

Ke, 15/05/2019 - 22:59
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Intravenous but not intrathecal central nervous system-directed chemotherapy improves survival in patients with testicular diffuse large B-cell lymphoma.

Eur J Cancer. 2019 May 10;115:27-36

Authors: Mannisto S, Vähämurto P, Pollari M, Clausen MR, Jyrkkiö S, Kellokumpu-Lehtinen PL, Kovanen P, Karjalainen-Lindsberg ML, d'Amore F, Leppä S

Abstract
BACKGROUND: Testicular lymphoma is a rare malignancy affecting mainly elderly men, the majority representing diffuse large B-cell lymphoma (DLBCL). Its relapse rate is higher than that of nodal DLBCL, often affecting the central nervous system (CNS) with dismal prognosis.
PATIENTS AND METHODS: We searched for patients with testicular DLBCL (T-DLBCL) involvement from the pathology databases of Southern Finland University Hospitals and the Danish Lymphoma Registry. Clinical information was collected, and outcomes between treatment modalities were evaluated. Progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OS) were assessed using Kaplan-Meier and Cox proportional hazards methods.
RESULTS: We identified 235 patients; of whom, 192 were treated with curative anthracycline-based chemotherapy. Full survival data were available for 189 patients. In univariate analysis, intravenous CNS-directed chemotherapy, and irradiation or orchiectomy of the contralateral testis translated into favourable PFS, DSS and OS, particularly among the elderly patients (each p ≤ 0.023). Intrathecal chemotherapy had no impact outcome. In multivariate analyses, the advantage of intravenous CNS-directed chemotherapy (hazard ration [HR] for OS, 0.419; 95% confidence interval [CI], 0.256-0.686; p = 0.001) and prophylactic treatment of contralateral testis (HR for OS, 0.514; 95% CI, 0.338-0.782; p = 0.002) was maintained. Rituximab improved survival only among high-risk patients (International Prognostic Index≥3, p = 0.019). The cumulative risk of CNS progression was 8.4% and did not differ between treatment modalities.
CONCLUSION: The results support the use of CNS-directed chemotherapy and prophylactic treatment of the contralateral testis in patients with T-DLBCL involvement. Survival benefit appears resulting from better control of systemic disease rather than prevention of CNS progression.

PMID: 31082690 [PubMed - as supplied by publisher]

Gonadal function after Busulfan compared to Treosulfan in children and adolescents undergoing allogeneic hematopoietic stem cell transplantation. On Behalf of the Pediatric and Transplant Complications Working Parties of EBMT.

Ke, 15/05/2019 - 22:59
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Gonadal function after Busulfan compared to Treosulfan in children and adolescents undergoing allogeneic hematopoietic stem cell transplantation. On Behalf of the Pediatric and Transplant Complications Working Parties of EBMT.

Biol Blood Marrow Transplant. 2019 May 10;:

Authors: Faraci M, Diesch T, Labopin M, Dalissier A, Lankester A, Gennery A, Sundin M, Uckan-Cetinkaya D, Bierings M, Peters AMJ, Garwer M, Schulz A, Michel G, Giorgiani G, Gruhn B, Locatelli F, Giardino S, Uyttebroeck A, Rialland F, Itäla-Remes M, Dreger P, Shaw PJ, Bordon V, Schlegel PG, Mellgren K, Moraleda JM, Patrick K, Schneider P, Jubert C, Lawitschka A, Salooja N, Basak GW, Corbaciuoglu S, Duarte R, Bader P

Abstract
INTRODUCTION: Gonadal impairment is an important late effect having a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after Busulfan (Bu) or Treosulfan (Treo) conditioning regimens in pre and post-pubertal children.
MATERIAL AND METHODS: This is a retrospective, multicenter study including children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemo-radiotherapy before the transplant.
RESULTS: We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range 5-18); 89 patients were males and 48 were females. Eighty-nine patients were pre-pubertal at transplant, while 48 were post-pubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of females treated with Treo in pre-pubertal stage reached spontaneous puberty compared to those treated with Bu (p=0.02). Spontaneous menarche was more frequent after Treo than after Bu (p< 0.001). Post-pubertal males and females treated with Treo had significantly lower luteinizing hormone (LH) levels (p=0.03 and p=0.04, respectively) compared to the Bu group.
CONCLUSIONS: Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population.

PMID: 31082473 [PubMed - as supplied by publisher]

Hearing Status in Survivors of Childhood Acute Myeloid Leukemia Treated With Chemotherapy Only: A NOPHO-AML Study.

Ke, 15/05/2019 - 22:59
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Hearing Status in Survivors of Childhood Acute Myeloid Leukemia Treated With Chemotherapy Only: A NOPHO-AML Study.

J Pediatr Hematol Oncol. 2019 01;41(1):e12-e17

Authors: Skou AS, Olsen SØ, Nielsen LH, Glosli H, Jahnukainen K, Jarfelt M, Jónmundsson GK, Malmros J, Nysom K, Hasle H, Nordic Society of Pediatric Hematology and Oncology (NOPHO)

Abstract
BACKGROUND: As more children survive acute myeloid leukemia (AML) it is increasingly important to assess possible late effects of the intensive treatment. Hearing loss has only sporadically been reported in survivors of childhood AML. We assessed hearing status in survivors of childhood AML treated with chemotherapy alone according to 3 consecutive NOPHO-AML trials.
PROCEDURE: A population-based cohort of children treated according to the NOPHO-AML-84, NOPHO-AML-88, and NOPHO-AML-93 trials included 137 eligible survivors among whom 101 (74%) completed a questionnaire and 99 (72%) had otologic and audiologic examination performed including otoscopy (72%), pure tone audiometry (70%), and tympanometry (60%). Eighty-four of 93 (90%) eligible sibling controls completed a similar questionnaire.
RESULTS: At a median of 11 years (range, 4 to 25) after diagnosis, hearing disorders were rare in survivors of childhood AML and in sibling controls, with no significant differences. None had severe or profound hearing loss diagnosed at audiometry. Audiometry detected a subclinical hearing loss ranging from slight to moderate in 19% of the survivors, 5% had low-frequency hearing loss, and 17% had high-frequency hearing loss.
CONCLUSIONS: The frequency of hearing disorders was low, and hearing thresholds in survivors of childhood AML were similar to background populations of comparable age.

PMID: 30550508 [PubMed - indexed for MEDLINE]

The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.

Ti, 14/05/2019 - 22:59
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The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.

Hum Mutat. 2018 05;39(5):729-741

Authors: Colombo M, Lòpez-Perolio I, Meeks HD, Caleca L, Parsons MT, Li H, De Vecchi G, Tudini E, Foglia C, Mondini P, Manoukian S, Behar R, Garcia EBG, Meindl A, Montagna M, Niederacher D, Schmidt AY, Varesco L, Wappenschmidt B, Bolla MK, Dennis J, Michailidou K, Wang Q, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Beckmann MW, Beeghly-Fadel A, Benitez J, Boeckx B, Bogdanova NV, Bojesen SE, Bonanni B, Brauch H, Brenner H, Burwinkel B, Chang-Claude J, Conroy DM, Couch FJ, Cox A, Cross SS, Czene K, Devilee P, Dörk T, Eriksson M, Fasching PA, Figueroa J, Fletcher O, Flyger H, Gabrielson M, García-Closas M, Giles GG, González-Neira A, Guénel P, Haiman CA, Hall P, Hamann U, Hartman M, Hauke J, Hollestelle A, Hopper JL, Jakubowska A, Jung A, Kosma VM, Lambrechts D, Le Marchand L, Lindblom A, Lubinski J, Mannermaa A, Margolin S, Miao H, Milne RL, Neuhausen SL, Nevanlinna H, Olson JE, Peterlongo P, Peto J, Pylkäs K, Sawyer EJ, Schmidt MK, Schmutzler RK, Schneeweiss A, Schoemaker MJ, See MH, Southey MC, Swerdlow A, Teo SH, Toland AE, Tomlinson I, Truong T, van Asperen CJ, van den Ouweland AMW, van der Kolk LE, Winqvist R, Yannoukakos D, Zheng W, kConFab/AOCS Investigators, Dunning AM, Easton DF, Henderson A, Hogervorst FBL, Izatt L, Offitt K, Side LE, van Rensburg EJ, Embrace S, Hebon S, McGuffog L, Antoniou AC, Chenevix-Trench G, Spurdle AB, Goldgar DE, Hoya M, Radice P

Abstract
Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.

PMID: 29460995 [PubMed - indexed for MEDLINE]

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

Ti, 14/05/2019 - 22:59
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Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

Hum Mutat. 2018 05;39(5):593-620

Authors: Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH, Thomassen M, Weitzel JN, Chan TL, Couch FJ, Goldgar DE, Kruse TA, Palmero EI, Park SK, Torres D, van Rensburg EJ, McGuffog L, Parsons MT, Leslie G, Aalfs CM, Abugattas J, Adlard J, Agata S, Aittomäki K, Andrews L, Andrulis IL, Arason A, Arnold N, Arun BK, Asseryanis E, Auerbach L, Azzollini J, Balmaña J, Barile M, Barkardottir RB, Barrowdale D, Benitez J, Berger A, Berger R, Blanco AM, Blazer KR, Blok MJ, Bonadona V, Bonanni B, Bradbury AR, Brewer C, Buecher B, Buys SS, Caldes T, Caliebe A, Caligo MA, Campbell I, Caputo SM, Chiquette J, Chung WK, Claes KBM, Collée JM, Cook J, Davidson R, de la Hoya M, De Leeneer K, de Pauw A, Delnatte C, Diez O, Ding YC, Ditsch N, Domchek SM, Dorfling CM, Velazquez C, Dworniczak B, Eason J, Easton DF, Eeles R, Ehrencrona H, Ejlertsen B, EMBRACE, Engel C, Engert S, Evans DG, Faivre L, Feliubadaló L, Ferrer SF, Foretova L, Fowler J, Frost D, Galvão HCR, Ganz PA, Garber J, Gauthier-Villars M, Gehrig A, GEMO Study Collaborators, Gerdes AM, Gesta P, Giannini G, Giraud S, Glendon G, Godwin AK, Greene MH, Gronwald J, Gutierrez-Barrera A, Hahnen E, Hauke J, HEBON, Henderson A, Hentschel J, Hogervorst FBL, Honisch E, Imyanitov EN, Isaacs C, Izatt L, Izquierdo A, Jakubowska A, James P, Janavicius R, Jensen UB, John EM, Vijai J, Kaczmarek K, Karlan BY, Kast K, Investigators K, Kim SW, Konstantopoulou I, Korach J, Laitman Y, Lasa A, Lasset C, Lázaro C, Lee A, Lee MH, Lester J, Lesueur F, Liljegren A, Lindor NM, Longy M, Loud JT, Lu KH, Lubinski J, Machackova E, Manoukian S, Mari V, Martínez-Bouzas C, Matrai Z, Mebirouk N, Meijers-Heijboer HEJ, Meindl A, Mensenkamp AR, Mickys U, Miller A, Montagna M, Moysich KB, Mulligan AM, Musinsky J, Neuhausen SL, Nevanlinna H, Ngeow J, Nguyen HP, Niederacher D, Nielsen HR, Nielsen FC, Nussbaum RL, Offit K, Öfverholm A, Ong KR, Osorio A, Papi L, Papp J, Pasini B, Pedersen IS, Peixoto A, Peruga N, Peterlongo P, Pohl E, Pradhan N, Prajzendanc K, Prieur F, Pujol P, Radice P, Ramus SJ, Rantala J, Rashid MU, Rhiem K, Robson M, Rodriguez GC, Rogers MT, Rudaitis V, Schmidt AY, Schmutzler RK, Senter L, Shah PD, Sharma P, Side LE, Simard J, Singer CF, Skytte AB, Slavin TP, Snape K, Sobol H, Southey M, Steele L, Steinemann D, Sukiennicki G, Sutter C, Szabo CI, Tan YY, Teixeira MR, Terry MB, Teulé A, Thomas A, Thull DL, Tischkowitz M, Tognazzo S, Toland AE, Topka S, Trainer AH, Tung N, van Asperen CJ, van der Hout AH, van der Kolk LE, van der Luijt RB, Van Heetvelde M, Varesco L, Varon-Mateeva R, Vega A, Villarreal-Garza C, von Wachenfeldt A, Walker L, Wang-Gohrke S, Wappenschmidt B, Weber BHF, Yannoukakos D, Yoon SY, Zanzottera C, Zidan J, Zorn KK, Hutten Selkirk CG, Hulick PJ, Chenevix-Trench G, Spurdle AB, Antoniou AC, Nathanson KL

Abstract
The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

PMID: 29446198 [PubMed - indexed for MEDLINE]

A nearly fatal primary Epstein-Barr virus infection associated with low NK-cell counts in a patient receiving azathioprine: a case report and review of literature.

Su, 12/05/2019 - 22:59
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A nearly fatal primary Epstein-Barr virus infection associated with low NK-cell counts in a patient receiving azathioprine: a case report and review of literature.

BMC Infect Dis. 2019 May 10;19(1):404

Authors: Honkila M, Niinimäki R, Taskinen M, Kuismin O, Kettunen K, Saarela J, Turunen S, Renko M, Tapiainen T

Abstract
BACKGROUND: Symptomatic primary Epstein-Barr virus infection is a usually self-limiting illness in adolescents. We present a case of an adolescent who had been receiving azathioprine for inflammatory bowel disease for four years and developed a life-threatening primary Epstein-Barr virus infection successfully treated with rituximab.
CASE PRESENTATION: An 11-year-old girl presented with chronic, bloody diarrhea. Endoscopic biopsies confirmed a diagnosis of chronic ulcerative colitis with features of Crohn's disease. Azathioprine was initiated after one year due to active colitis. She responded well and remission was achieved. At the age of 16 years she developed a life-threatening Epstein-Barr virus infection including severe multiple organ failure and was critically ill for 4 weeks in the intensive care unit. Natural killer cells were virtually absent in the lymphocyte subset analysis. Azathioprine was stopped on admission. She was initially treated with corticosteroids, acyclovir and intravenous immunoglobulin. Approximately 30 days after admission, she developed signs of severe hepatitis and pneumonitis and received weekly rituximab infusions for 8 weeks. Primary immunodeficiency was excluded by whole exome sequencing in two independent laboratories. Persistent viremia stopped when the natural killer cell count started to rise, approximately 90 days after the cessation of azathioprine.
CONCLUSIONS: We found 17 comparable cases in the literature. None of the previous cases reported in the literature, who had been treated with azathioprine and developed either a severe or a fatal Epstein-Barr virus infection, underwent full genetic and prospective immunological workup to rule out known primary immunodeficiencies. Recently, azathioprine has been shown to cause rather specific immunosuppression, resulting in natural killer cell depletion. Our case demonstrates that slow recovery from azathioprine-induced natural killer cell depletion, 3 months after the stopping of azathioprine, coincided with the clearance of viremia and clinical recovery. Finally, our choice of treating the patient with rituximab, as previously used for patients with a severe immunosuppression and Epstein-Barr virus viremia, appeared to be successful in this case. We suggest testing for Epstein-Barr virus serology before starting azathioprine and measuring natural killer cell counts during the treatment to identify patients at risk of developing an unusually severe primary Epstein-Barr virus infection.

PMID: 31077135 [PubMed - in process]