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Permissive hypercapnia for severe acute respiratory distress syndrome in immunocompromised children: A single center experience.

Wed, 06/21/2017 - 21:45

Permissive hypercapnia for severe acute respiratory distress syndrome in immunocompromised children: A single center experience.

PLoS One. 2017;12(6):e0179974

Authors: Fuchs H, Rossmann N, Schmid MB, Hoenig M, Thome U, Mayer B, Klotz D, Hummler HD

Abstract
BACKGROUND: Controlled hypoventilation while accepting hypercapnia has been advocated to reduce ventilator-induced lung injury. The aim of the study was to analyze outcomes of a cohort of immunocompromised children with acute respiratory distress syndrome (ARDS) ventilated with a strategy of stepwise increasing PCO2 targets up to 140 mm Hg.
METHODS: Retrospective analysis of outcomes of a cohort of children with oncologic disease or after stem cell transplantation and severe respiratory failure in comparison with a historical control cohort.
RESULTS: Out of 150 episodes of admission to the PICU 88 children underwent invasive mechanical ventilation for >24h (overall survival 75%). In a subgroup of 38 children with high ventilator requirements the PCO2 target ranges were increased stepwise. Fifteen children survived and were discharged from the PICU. Severe pulmonary hypertension was seen in two patients and no case of cerebral edema was observed. Long term outcome was available in 15 patients and 10 of these patients survived without adverse neurological sequelae. With introduction of this strategy survival of immunocompromised children undergoing mechanical ventilation for >24h increased to 48% compared to 32% prior to introduction (historical cohort).
CONCLUSIONS: A ventilation strategy incorporating very high carbon dioxide levels to allow for low tidal volumes and limited inspiratory pressures is feasible in children. Even severe hypercapnia may be well tolerated. No severe side effects associated with hypercapnia were observed. This strategy could potentially increase survival in immunocompromised children with severe ARDS.

PMID: 28632754 [PubMed - in process]

Exhaled carbon monoxide is correlated with ischemia reperfusion injuries during ex vivo lung perfusion in pigs.

Wed, 06/21/2017 - 21:45

Exhaled carbon monoxide is correlated with ischemia reperfusion injuries during ex vivo lung perfusion in pigs.

J Breath Res. 2017 Jun 20;:

Authors: Maignan M, Gennai S, Debaty G, Romanini D, Schmidt MH, Brenckmann V, Brouta A, Ventrillard I, Briot R

Abstract
Measurement of exhaled carbon monoxide (eCO) might help in the selection of lung grafts during ex vivo lung perfusion since its endogenous production is increased under ischemia reperfusion. The objective of this study was to measure eCO variations depending on the extent of lung ischemia reperfusion injuries. Using a porcine model and a laser spectrometer instrument, eCO was measured during ex vivo lung perfusion. eCO was compared after 30 min (D0) or 24 h (D1) of cold ischemia. The ability of eCO to distinguish lungs deemed suitable for transplantation was evaluated. Six lungs were studied at D0 and compared to six lungs studied at D1. eCO was systematically higher on D1 (1.35 ± 0.26 ppmv vs. 0.95 ± 0.31 ppmv, p = 0.01). The best threshold concentration for eCO to select lungs was 0.86 ppmv (area under the receiver operating characteristic curve: 0.65 [95% confidence interval: 0.34 - 0.97], p=0.40). These results show that eCO varies during EVLP. The interpretation of this variation and the role of eCO as a biomarker of ischemia reperfusion injuries during EVLP should be tested in further clinical studies.

PMID: 28631618 [PubMed - as supplied by publisher]

Transesophageal echocardiography in orthotopic liver transplantation: a comprehensive intraoperative monitoring tool.

Wed, 06/21/2017 - 21:45
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Transesophageal echocardiography in orthotopic liver transplantation: a comprehensive intraoperative monitoring tool.

Crit Ultrasound J. 2017 Dec;9(1):15

Authors: Vetrugno L, Barbariol F, Baccarani U, Forfori F, Volpicelli G, Della Rocca G

Abstract
Intraoperative transesophageal echocardiography is a minimally invasive monitoring tool that can provide real-time visual information on ventricular function and hemodynamic volume status in patients undergoing liver transplantation. The American Association for the Study of Liver Diseases states that transesophageal echocardiography should be used in all liver transplant candidates in order to assess chamber sizes, hypertrophy, systolic and diastolic function, valvular function, and left ventricle outflow tract obstruction. However, intraoperative transesophageal echocardiography can be used to "visualize" other organs too; thanks to its proximity and access to multiple acoustic windows: liver, lung, spleen, and kidney. Although only limited scientific evidence exists promoting this comprehensive use, we describe the feasibility of TEE in the setting of liver transplantation: it is a highly valuable tool, not only as a cardiovascular monitoring, but also as a tool to evaluate lungs and pleural spaces, to assess hepatic vein blood flow and inferior vena cava anastomosis and patency, i.e., in cases of modified surgical techniques. The aim of this case series is to add our own experience of TEE as a comprehensive intraoperative monitoring tool in the field of orthotopic liver transplantation (and major liver resection) to the literature.

PMID: 28631103 [PubMed - in process]

Chemotherapy in combination with cytokine-induced killer cell transfusion: An effective therapeutic option for patients with extensive stage small cell lung cancer.

Wed, 06/21/2017 - 21:45
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Chemotherapy in combination with cytokine-induced killer cell transfusion: An effective therapeutic option for patients with extensive stage small cell lung cancer.

Int Immunopharmacol. 2017 May;46:170-177

Authors: Huang J, Kan Q, Lan, Zhao X, Zhang Z, Yang S, Li H, Wang L, Xu L, Cheng Z, Zhang Y

Abstract
BACKGROUND AND AIMS: In the past decade of clinical studies, the combination of chemotherapy with cytokine induced killer (CIK) cell transfusion has confirmed a promised efficacy in several types of cancer. CIK cells are a mixture of T lymphocytes, generated from peripheral blood mononuclear cells induced by multiple cytokines. This study was aimed to evaluate the clinical efficacy of chemotherapy combined with CIK- cell therapy in patients with extensive stage small cell lung cancer (ES SCLC).
PATIENTS AND METHODS: Forty four patients with ES SCLC were enrolled in this study. All the patients received treatment from Oct 2010 to Sep 2013 in the First Affiliated Hospital of Zhengzhou University. Included patients were equally divided into 2 groups according to the treatment strategies. Patients in the combined treatment group received chemotherapy combined with CIK-cell transfusion and patients in the control group received chemotherapy alone. The short-term effects, overall survival (OS), progress free survival (PFS) and therapy-related adverse events were analyzed retrospectively.
RESULTS: Short-term efficacy evaluation indicated that the total response rates in the combined treatment group and control group were 40.9% (9/22) and 9.1% (2/22), respectively. There was a significant difference between the two groups (p=0.0339). Furthermore, the PFS of the combined treatment group was significantly longer than that of the control group (8 vs. 4months, P=0.005). No severe side effect was observed after transfusion of CIK cells.
CONCLUSION: These results indicated that chemotherapy combined with CIK-cell immunotherapy might provide a safe and effective treatment for patients with ES SCLC.

PMID: 28292730 [PubMed - indexed for MEDLINE]

Idiopathic pulmonary haemosiderosis in paediatric patients: how to make an early diagnosis.

Wed, 06/21/2017 - 21:45
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Idiopathic pulmonary haemosiderosis in paediatric patients: how to make an early diagnosis.

Ital J Pediatr. 2016 Sep 20;42(1):86

Authors: Castellazzi L, Patria MF, Frati G, Esposito AA, Esposito S

Abstract
BACKGROUND: Idiopathic pulmonary haemosiderosis (IPH) is a rare but potentially lethal condition in paediatric patients. This condition is considered an immune-mediated disorder, but its pathogenesis is still unknown. Idiopathic pulmonary haemosiderosis is characterized by the classical triad of haemoptysis, iron-deficiency anaemia, and diffuse parenchymal consolidation on chest radiology. Unfortunately, this triad of signs is not frequent in children at the onset of this disease, resulting in a delay in diagnosis and a negative outcome.
CASE PRESENTATION: This case report describes a 4-year-old girl who was admitted for an acute episode of lower respiratory tract infection associated with severe dyspnoea, polypnoea, and severe anaemia (haemoglobin levels, 5.9 g/dL). She had a history of previous similar episodes, with anaemia treated unsuccessfully with iron supplementation and managed through repeated blood transfusions in the acute phase. She did not experience haemoptysis. A computed tomography (CT) scan of the thorax showed ground-glass opacity suggestive of pulmonary haemorrhage. After other causes of intra-alveolar haemorrhage were excluded, IPH was confirmed by the presence of siderophages in bronchoalveolar lavage. Immunosuppressive corticosteroid treatment was immediately started with a good clinical response.
CONCLUSION: This case highlights the fact that IPH should be suspected in children with recurrent lower respiratory tract infections who have a history of iron-deficiency anaemia who shows no signs of improvement with iron supplementation and may require repeated blood transfusions. The absence of haemoptysis does not exclude the diagnosis of IPH in children. An early and prompt diagnosis is recommended in order to start adequate immunosuppressive treatment.

PMID: 27644948 [PubMed - indexed for MEDLINE]

A Multicenter Retrospective Analysis Stressing Importance of Long-Term Follow Up after Hematopoietic Cell Transplantation for Β-Thalassemia.

Tue, 06/20/2017 - 12:45
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A Multicenter Retrospective Analysis Stressing Importance of Long-Term Follow Up after Hematopoietic Cell Transplantation for Β-Thalassemia.

Biol Blood Marrow Transplant. 2017 Jun 13;:

Authors: Chaudhury S, Ayas M, Rosen C, Ma M, Viqaruddin M, Parikh S, Kharbanda S, Chiang KY, Haight A, Bhatia M, Guilcher G, Thompson A, Shenoy S

Abstract
Allogeneic hematopoietic cell transplantation (HCT) is curative in patients with β-thalassemia major. However, the majority of reports on HCT outcomes lack long-term follow-up data with the exception of single center reports. An international multicenter retrospective data collection and analysis was conducted in 176 β-Thalassemia patients who were 1 year or beyond after first HCT to evaluate follow up methods and outcomes at 7 centers- Median age at HCT was 5.5 years (range, 0.6- 18.5) and median follow-up was 7 years (range, 1-20). HCT was predominantly from HLA-matched related donors (91%) with bone marrow as stem cell source (91%) and myeloablative conditioning regimens (88%). Late mortality or persistent chronic graft versus host disease (GVHD) were rare (<2%). Graft rejection was reported in 23% (24% of these occurred beyond 1 year) post-HCT. Of 119 patients with donor chimerism results available for ≥4yrs post HCT, 50% had >95%, 22% had 50-95%, 7% had 20-50% and 25 (21%) had <20% donor chimerism. Organ dysfunction was identified in 10% pre-HCT and in 20% post-HCT even without complete clinical details on all patients. Hypogonadism and elevated creatinine for age were most commonly reported and significantly higher in recipients ≥ 7years at the time of HCT (p=0.007), and in those with pre-existing morbidity before HCT (p=0.02). Outcomes were unaffected by pre- HCT ferritin or GVHD. Mean z-scores for height and weight were low at baseline and remained low post-HCT (79%), confirming that growth impairment from disease lacked recovery post-HCT during this follow-up period.
CONCLUSION: HCT for β-thalassemia has a high rate of cure and low mortality especially in the young, and from HLA-matched related donors. Half the number of recipients live with mixed chimerism that requires continued follow-up due to a risk of late graft rejection (14%). Organ function following HCT when <7 years of age was generally preserved. Hypogonadism, renal dysfunction and growth impairment that failed to correct were late complications identified most frequently in older transplant recipients. Systematic follow-up of individual organs such as lung and heart were inadequate but important. These data support the development of simple measures of uniformly tracking long-term HCT outcomes and organ functions in children and adolescents who undergo HCT for thalassemia, allowing for systematic identification and implementation of standardized surveillance strategies and interventions.

PMID: 28627425 [PubMed - as supplied by publisher]

Landmark cure rate models with time-dependent covariates.

Tue, 06/20/2017 - 12:45
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Landmark cure rate models with time-dependent covariates.

Stat Methods Med Res. 2017 Jan 01;:962280217708681

Authors: Shi H, Yin G

Abstract
We propose a class of landmark cure rate models by incorporating time-dependent covariates. The landmark approach enables us to obtain dynamic predictions of a patient's survival probabilities as new clinical information emerges during the follow-up time. The proposed method extends the landmark model for failure time data with a possible cure fraction. We specify a series of landmark time points, and for each of time point, we construct a landmark data set consisting of only those at-risk individuals at the landmark time. The time-dependent covariates can be fixed at the values evaluated at the landmark time point. Through landmarking, our framework accommodates the Cox proportional hazards model, accelerated failure time model and censored quantile regression model in the presence of a cure proportion. We conduct simulation studies to assess the estimation accuracy of the proposed method, and illustrate it with data from a heart transplant study.

PMID: 28627311 [PubMed - as supplied by publisher]

Ex vivo Generation of Genetically Modified Macrophages from Human Induced Pluripotent Stem Cells.

Tue, 06/20/2017 - 12:45
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Ex vivo Generation of Genetically Modified Macrophages from Human Induced Pluripotent Stem Cells.

Transfus Med Hemother. 2017 Jun;44(3):135-142

Authors: Ackermann M, Kuhn A, Kunkiel J, Merkert S, Martin U, Moritz T, Lachmann N

Abstract
BACKGROUND: Pluripotent stem cells, including induced pluripotent stem cells (iPSCs), have the capacity to differentiate towards all three germ layers and have been highlighted as an attractive cell source for the field of regenerative medicine. Thus, stable expression of therapeutic transgenes in iPSCs, as well as thereof derived progeny of hematopoietic lineage, may lay the foundation for innovative cell replacement therapies.
METHODS: We have utilized human iPSC lines genetically modified by lentiviral vector technology or targeted integration of reporter genes to evaluate transgene expression during hematopoietic specification and differentiation towards macrophages.
RESULTS: Use of lentiviral vectors equipped with an ubiquitous chromatin opening element (CBX3-UCOE) as well as zinc finger nuclease-mediated targeting of an expression cassette into the human adeno-associated virus integration site 1 (AAVS1) safe harbor resulted in stable transgene expression in iPSCs. When iPSCs were differentiated along the myeloid pathway into macrophages, both strategies yielded sustained transgene expression during the hematopoietic specification process including mature CD14+ and CD11b+ macrophages.
CONCLUSION: Combination of human iPSC technology with either lentiviral vector technology or designer nuclease-based genome editing allows for the generation of transgenic iPSC-derived macrophages with stable transgene expression which may be useful for novel cell and gene replacement therapies.

PMID: 28626364 [PubMed - in process]

A Randomized, Placebo-controlled, Double-blinded, Crossover Trial of Pioglitazone for Severe Asthma.

Tue, 06/20/2017 - 12:45
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A Randomized, Placebo-controlled, Double-blinded, Crossover Trial of Pioglitazone for Severe Asthma.

J Allergy Clin Immunol. 2017 Jun 15;:

Authors: Kaler M, Barochia AV, Weir NA, Cuento RA, Stylianou M, Roth MJ, Filie AC, Vaughey EC, Nathan SD, Levine SJ

Abstract
The PPAR-γ agonist, pioglitazone, was associated with significant side effects and did not improve the primary outcome measure of the Juniper Asthma Quality of Life Questionnaire (AQLQ) score in severe asthmatics. We conclude that no further studies should be performed with pioglitazone for severe asthma.

PMID: 28625806 [PubMed - as supplied by publisher]

Invasive mucormycosis in children: an epidemiologic study in European and non-European countries based on two registries.

Tue, 06/20/2017 - 12:45
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Invasive mucormycosis in children: an epidemiologic study in European and non-European countries based on two registries.

BMC Infect Dis. 2016 Nov 10;16(1):667

Authors: Pana ZD, Seidel D, Skiada A, Groll AH, Petrikkos G, Cornely OA, Roilides E, Collaborators of Zygomyco.net and/or FungiScope™ Registries*

Abstract
BACKGROUND: Mucormycosis has emerged as a rare but frequently fatal invasive fungal disease. Current knowledge on paediatric mucormycosis is based on case reports and small series reported over several decades. Contemporary data on a large cohort of patients is lacking.
METHODS: Two large international registries (Zygomyco.net and FungiScope™) were searched for mucormycosis cases in ≤19 year-old patients. Cases enrolled between 2005 and 2014 were extracted, and dual entries in the two databases merged. Epidemiology, clinical characteristics, diagnostic procedures, therapeutic management and final outcome were recorded and analysed with SPSS v.12.
RESULTS: Sixty-three unique cases (44 proven and 19 probable) were enrolled from 15 countries (54 in European and 9 in non-European countries). Median age was 13 years [Interquartile Range (IQR) 7.7] with a slight predominance (54.1 %) of females. Underlying conditions were haematological malignancies (46 %), other malignancies (6.3 %), haematopoietic stem cell transplantation (15.9 %), solid organ transplantation, trauma/surgery and diabetes mellitus (4.8 % each) and a variety of other diseases (7.9 %); in 9.5%, no underlying medical condition was found. Neutropenia was recorded in 46 % of the patients. The main sites of infection were lungs (19 %), skin and soft tissues (19 %), paranasal sinus/sino-orbital region (15.8 %) and rhino-cerebral region (7.9 %). Disseminated infection was present in 38.1 %. Mucormycosis diagnosis was based on several combinations of methods; culture combined with histology was performed in 31 cases (49.2 %). Fungal isolates included Rhizopus spp. (39.7 %), Lichtheimia spp. (17.5 %), Mucor spp. (12.7 %), Cunninghamella bertholletiae (6.3 %) and unspecified (23.8 %). Treatment comprised amphotericin B (AmB) monotherapy in 31.7 % or AmB in combination with other antifungals in 47.7 % of the cases, while 14.3 % received no antifungals. Surgery alone was performed in 6.3 %, and combined with antifungal therapy in 47.6 %. Crude mortality at last contact of follow-up was 33.3 %. In regression analysis, disseminated disease and prior haematopoietic stem cell transplantation were associated with increased odds of death, whereas the combination of systemic antifungal therapy with surgery was associated with improved survival.
CONCLUSION: Paediatric mucormycosis mainly affects children with malignancies, presents as pulmonary, soft tissue, paranasal sinus or disseminated disease and is highly lethal. Outcome is improved when active antifungal therapy and surgery are combined.

PMID: 27832748 [PubMed - indexed for MEDLINE]

Methods to increase reproducibility in differential gene expression via meta-analysis.

Tue, 06/20/2017 - 12:45
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Methods to increase reproducibility in differential gene expression via meta-analysis.

Nucleic Acids Res. 2017 Jan 09;45(1):e1

Authors: Sweeney TE, Haynes WA, Vallania F, Ioannidis JP, Khatri P

Abstract
Findings from clinical and biological studies are often not reproducible when tested in independent cohorts. Due to the testing of a large number of hypotheses and relatively small sample sizes, results from whole-genome expression studies in particular are often not reproducible. Compared to single-study analysis, gene expression meta-analysis can improve reproducibility by integrating data from multiple studies. However, there are multiple choices in designing and carrying out a meta-analysis. Yet, clear guidelines on best practices are scarce. Here, we hypothesized that studying subsets of very large meta-analyses would allow for systematic identification of best practices to improve reproducibility. We therefore constructed three very large gene expression meta-analyses from clinical samples, and then examined meta-analyses of subsets of the datasets (all combinations of datasets with up to N/2 samples and K/2 datasets) compared to a 'silver standard' of differentially expressed genes found in the entire cohort. We tested three random-effects meta-analysis models using this procedure. We showed relatively greater reproducibility with more-stringent effect size thresholds with relaxed significance thresholds; relatively lower reproducibility when imposing extraneous constraints on residual heterogeneity; and an underestimation of actual false positive rate by Benjamini-Hochberg correction. In addition, multivariate regression showed that the accuracy of a meta-analysis increased significantly with more included datasets even when controlling for sample size.

PMID: 27634930 [PubMed - indexed for MEDLINE]

Hepatocyte Growth Factor Is Required for Mesenchymal Stromal Cell Protection Against Bleomycin-Induced Pulmonary Fibrosis.

Tue, 06/20/2017 - 12:45
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Hepatocyte Growth Factor Is Required for Mesenchymal Stromal Cell Protection Against Bleomycin-Induced Pulmonary Fibrosis.

Stem Cells Transl Med. 2016 10;5(10):1307-1318

Authors: Cahill EF, Kennelly H, Carty F, Mahon BP, English K

Abstract
: The incidence of idiopathic pulmonary fibrosis is on the rise and existing treatments have failed to halt or reverse disease progression. Mesenchymal stromal cells (MSCs) have potent cytoprotective effects, can promote tissue repair, and have demonstrated efficacy in a range of fibrotic lung diseases; however, the exact mechanisms of action remain to be elucidated. Chemical antagonists and short hairpin RNA knockdown were used to identify the mechanisms of action used by MSCs in promoting wound healing, proliferation, and inhibiting apoptosis. Using the bleomycin induced fibrosis model, the protective effects of early or late MSC administration were examined. The role for hepatocyte growth factor (HGF) in MSC protection against bleomycin lung injury was examined using HGF knockdown MSC. Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling assay was performed on ex vivo lung sections to examine the effects of MSC on apoptosis. MSC conditioned media (CM) enhanced wound closure and inhibited apoptosis of pulmonary cells in vitro. HGF was required for MSC CM enhancement of epithelial cell proliferation and inhibition of apoptosis. In contrast, MSC required COX-2 for CM to inhibit fibroblast proliferation. In a murine model, early administration of MSC protected against bleomycin induced lung fibrosis and correlated with reduced levels of the proinflammatory cytokine interleukin-1β, reduced levels of apoptosis, and significantly increased levels of HGF. These protective effects were in part mediated by MSC derived HGF as HGF knockdown MSC were unable to protect against fibrosis in vivo. These findings delineate the mechanisms of MSC protection in a preclinical model of fibrotic lung disease.
SIGNIFICANCE: The mechanisms used by mesenchymal stromal cells (MSCs) in mediating protective effects in chronic models of lung disease are not understood and remain to be elucidated. These findings from in vitro studies highlight an important role for the MSC-derived soluble factors hepatocyte growth factor (HGF) and prostaglandin E2 in promoting wound healing and inhibiting apoptosis. Furthermore, this study translates these findings demonstrating an important role for HGF in the protective effects mediated by MSC in vivo in the bleomycin model. These findings support a targeted approach to enhancing MSC therapy for fibrotic disease and highlight the importance of timing of MSC therapy.

PMID: 27388243 [PubMed - indexed for MEDLINE]

Concurrent Longitudinal EPR Monitoring of Tissue Oxygenation, Acidosis, and Reducing Capacity in Mouse Xenograft Tumor Models.

Tue, 06/20/2017 - 12:45
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Concurrent Longitudinal EPR Monitoring of Tissue Oxygenation, Acidosis, and Reducing Capacity in Mouse Xenograft Tumor Models.

Cell Biochem Biophys. 2017 Jun;75(2):247-253

Authors: Bobko AA, Evans J, Denko NC, Khramtsov VV

Abstract
Tissue oxygenation, extracellular acidity, and tissue reducing capacity are among crucial parameters of tumor microenvironment (TME) of significant importance for tumor pathophysiology. In this paper, we demonstrate the complementary application of particulate lithium octa-n-butoxy-naphthalocyanine and soluble nitroxide paramagnetic probes for monitoring of these TME parameters using electron paramagnetic resonance (EPR) technique. Two different types of therapeutic interventions were studied: hypothermia and systemic administration of metabolically active drug. In summary, the results demonstrate the utility of EPR technique for non-invasive concurrent longitudinal monitoring of physiologically relevant chemical parameters of TME in mouse xenograft tumor models, including that under therapeutic intervention.

PMID: 27193607 [PubMed - indexed for MEDLINE]

Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features.

Mon, 06/19/2017 - 12:45

Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features.

Gastroenterology. 2017 Jun 14;:

Authors: Sia D, Jiao Y, Martinez-Quetglas I, Kuchuk O, Villacorta-Martin C, Castro de Moura M, Putra J, Camprecios G, Bassaganyas L, Akers N, Losic B, Waxman S, Thung SN, Mazzaferro V, Esteller M, Friedman SL, Schwartz M, Villanueva A, Llovet JM

Abstract
BACKGROUND AND AIMS: Agents that induce an immune response against tumors by altering T-cell regulation have increased survival times of patients with advanced-stage tumors, such as melanoma or lung cancer. We aimed to characterize molecular features of immune cells that infiltrate hepatocellular carcinomas (HCCs) to determine whether these types of agents might be effective against liver tumors.
METHODS: We analyzed HCC samples from 956 patients. We separated gene expression profiles from tumor, stromal, and immune cells using a non-negative matrix factorization algorithm. We then analyzed the gene expression pattern of inflammatory cells in HCC tumors samples. We correlated expression patterns with the presence of immune cell infiltrates and immune regulatory molecules, determined by pathology and immunohistochemical analyses, in a training set of 228 HCC samples. We validated the correlation in a validation set of 728 tumor samples. Using data from 190 tumors in the Cancer Genome Atlas, we correlated immune cell gene expression profiles with numbers of chromosomal aberrations (based on single-nucleotide polymorphism array) and mutations (exome sequence data).
RESULTS: We found approximately 25% of HCCs to have markers of an inflammatory response, with high expression levels of the CD274 molecule (PD-L1) and programmed cell death 1 (PD-1), markers of cytolytic activity, and fewer chromosomal aberrations. We called this group of tumors the Immune class. It contained 2 subtypes, characterized by markers of an adaptive T-cell response or exhausted immune response. The exhausted immune response subclass expressed many genes regulated by transforming growth factor beta 1 (TGFB) that mediate immunosuppression. We did not observe any differences in numbers of mutations or expression of tumor antigens between the immune-specific class and other HCCs.
CONCLUSIONS: In an analysis of HCC samples from 956 patients, we found almost 25% to express markers of an inflammatory response. We identified 2 subclasses, characterized by adaptive or exhausted immune responses. These findings indicate that some HCCs might be susceptible to therapeutic agents designed to block the regulatory pathways in T cells, such as PD-L1, PD-1, or TGFB inhibitors.

PMID: 28624577 [PubMed - as supplied by publisher]

Heart transplant centers with multidisciplinary team show a higher level of chronic illness management - Findings from the International BRIGHT Study.

Mon, 06/19/2017 - 12:45

Heart transplant centers with multidisciplinary team show a higher level of chronic illness management - Findings from the International BRIGHT Study.

Heart Lung. 2017 Jun 14;:

Authors: Cajita MI, Baumgartner E, Berben L, Denhaerynck K, Helmy R, Schönfeld S, Berger G, Vetter C, Dobbels F, Russell CL, De Geest S, BRIGHT Study Team

Abstract
OBJECTIVES: The objectives of this study were to: (1) explore the proportion of HTx centers that have a multidisciplinary team and (2) assess the relationship between multidisciplinarity and the level of chronic illness management (CIM).
BACKGROUND: The International Society for Heart and Lung Transplantation (ISHLT) recommends a multidisciplinary approach in heart transplant (HTx) follow-up care but little is known regarding the proportion of HTx centers that meet this recommendation and the impact on patient care. HTx centers with a multidisciplinary team may offer higher levels of CIM, a care model that has the potential to improve outcomes after HTx.
METHODS: We conducted a secondary analysis of the BRIGHT study, a cross-sectional study in 11 countries. Multidisciplinarity in the 36 HTx centers was assessed through HTx director reports and was defined as having a team that was composed of physician(s), nurse(s), and another healthcare professional (either a social worker, psychiatrist, psychologist, pharmacist, dietician, physical therapist, or occupational therapist). CIM was assessed with the Patient Assessment of Chronic Illness Care (PACIC). Multiple linear regression assessed the relationship between multidisciplinarity and the level of CIM.
RESULTS: Twenty-nine (80.6%) of the HTx centers had a multidisciplinary team. Furthermore, multidisciplinarity was significantly associated with higher levels of CIM (β = 5.2, P = 0.042).
CONCLUSION: Majority of the HTx centers follows the ISHLT recommendation for a multidisciplinary approach. Multidisciplinarity was associated with CIM and point toward a structural factor that needs to be in place for moving toward CIM.

PMID: 28624338 [PubMed - as supplied by publisher]

Applying rigor and reproducibility standards to assay donor-derived cell-free DNA as a non-invasive method for detection of acute rejection and graft injury after heart transplantation.

Mon, 06/19/2017 - 12:45

Applying rigor and reproducibility standards to assay donor-derived cell-free DNA as a non-invasive method for detection of acute rejection and graft injury after heart transplantation.

J Heart Lung Transplant. 2017 May 20;:

Authors: Agbor-Enoh S, Tunc I, De Vlaminck I, Fideli U, Davis A, Cuttin K, Bhatti K, Marishta A, Solomon MA, Jackson A, Graninger G, Harper B, Luikart H, Wylie J, Wang X, Berry G, Marboe C, Khush K, Zhu J, Valantine H

Abstract
BACKGROUND: Use of new genomic techniques in clinical settings requires that such methods are rigorous and reproducible. Previous studies have shown that quantitation of donor-derived cell-free DNA (%ddcfDNA) by unbiased shotgun sequencing is a sensitive, non-invasive marker of acute rejection after heart transplantation. The primary goal of this study was to assess the reproducibility of %ddcfDNA measurements across technical replicates, manual vs automated platforms, and rejection phenotypes in distinct patient cohorts.
METHODS: After developing and validating the %ddcfDNA assay, we subjected the method to a rigorous test of its reproducibility. We measured %ddcfDNA in technical replicates performed by 2 independent laboratories and verified the reproducibility of %ddcfDNA patterns of 2 rejection phenotypes: acute cellular rejection and antibody-mediated rejection in distinct patient cohorts.
RESULTS: We observed strong concordance of technical-replicate %ddcfDNA measurements across 2 independent laboratories (slope = 1.02, R(2) > 0.99, p < 10(-6)), as well as across manual and automated platforms (slope = 0.80, R(2) = 0.92, p < 0.001). The %ddcfDNA measurements in distinct heart transplant cohorts had similar baselines and error rates. The %ddcfDNA temporal patterns associated with rejection phenotypes were similar in both patient cohorts; however, the quantity of ddcfDNA was significantly higher in samples with severe vs mild histologic rejection grade (2.73% vs 0.14%, respectively; p < 0.001).
CONCLUSIONS: The %ddcfDNA assay is precise and reproducible across laboratories and in samples from 2 distinct types of heart transplant rejection. These findings pave the way for larger studies to assess the clinical utility of %ddcfDNA as a marker of acute rejection after heart transplantation.

PMID: 28624139 [PubMed - as supplied by publisher]

Sevoflurane preconditioning protects from posttransplant injury in mouse lung transplantation.

Mon, 06/19/2017 - 12:45

Sevoflurane preconditioning protects from posttransplant injury in mouse lung transplantation.

J Surg Res. 2017 Jun 15;214:270-277

Authors: Yamada Y, Laube I, Jang JH, Bonvini JM, Inci I, Weder W, Beck Schimmer B, Jungraithmayr W

Abstract
BACKGROUND: Although sevoflurane (Sevo) had been shown to ameliorate posttransplant injury in various organs, data available are inconsistent, particularly in the context of lung transplantation (Tx). We here investigated if preconditioning by Sevo can protect from posttransplant injury regarding both, primary graft dysfunction (PGD) and acute rejection (AR) after experimental lung Tx, thereby focusing on two important clinical outcome parameters.
MATERIALS AND METHODS: Three experimental approaches were used: (1) BALB/c mice were preconditioned for 2 h with Sevo or a fentanyl cocktail (Control; n = 10); (2) syngeneic (Syn) mouse lung Tx (C57BL/6) with a Sevo-preconditioned graft followed by 18 h storage to mimic PGD (Syn-Tx, n = 12) versus controls (fentanyl cocktail); and (3) allogeneic (Allo) Tx (BALB/c, donor; C57BL/6, recipient) to mimic AR (Allo-Tx, n = 12) versus controls (fentanyl cocktail). Syn-Tx grafts were harvested on Day 1, Allo-Tx grafts on Day 3 and analyzed for histology, immunohistochemistry, blood gas analysis, and inflammatory cytokines (enzyme-linked immunosorbent assay or reverse transcription polymerase chain reaction).
RESULTS: Evaluating the preconditioning effect of Sevo only showed significantly better oxygenation (P = 0.03) and a tendency toward lower levels of lung tissue messenger RNA for tumor necrosis factor-α. In Syn-Tx recipients, the Sevo group had histologically a tendency toward an attenuation of PGD and showed significantly lower levels of interleukin 6 (P = 0.01) in plasma, but higher levels of interleukin 10 (P < 0.01) in lungs. Allo-Tx grafts in Sevo Tx recipients showed attenuated AR with histologically significantly lower rejection scores (P = 0.03), fewer classical macrophages (F4/80+; P < 0.01), but more anti-inflammatory activated macrophages (M2, CD206+; P < 0.01). Functionally, the Sevo group had a tendency toward improved oxygenation.
CONCLUSIONS: We demonstrated that Sevo preconditioning has protective effects on lung transplants in both, PGD and AR. The observed amelioration may be attributed to suppressed inflammatory cytokines during PGD and the induction of alternatively activated macrophages during AR. These promising data could set the base for using Sevo preconditioning in donor lungs for a human trial.

PMID: 28624055 [PubMed - in process]

Lung transplantation with lungs from older donors: an analysis of survival in elderly recipients.

Mon, 06/19/2017 - 12:45

Lung transplantation with lungs from older donors: an analysis of survival in elderly recipients.

J Surg Res. 2017 Jun 15;214:109-116

Authors: Katsnelson J, Whitson BA, Tumin D, Ravi Y, Kilic A, Tobias JD, Sai-Sudhakar CB, Hayes D

Abstract
BACKGROUND: The average ages of lung transplant (LTx) recipients and donors are increasing. With older recipients considered to be especially at high risk of posttransplant mortality, we sought to determine whether the use of allografts from older donors affects survival among older patients undergoing LTx.
METHODS: The United Network for Organ Sharing registry was used to identify patients aged 65-80 y receiving a first-time LTx between 1987 and 2013. Survival analysis examined implications of a donor-recipient age difference >10 y using Cox proportional hazards regression.
RESULTS: The cohort selected for analysis included 3227 elderly LTx recipients, of whom 263 (8.15%) had donors within 10 y of their age at transplantation. Univariate Cox models found no differences with LTx involving donors at least 10 y younger than the recipient with respect to overall survival (hazard ratio = 0.979; 95% confidence interval [CI] = 0.807-1.188; P = 0.831) or conditional survival past 1 y (hazard ratio = 1.067; 95% CI = 0.819-1.391; P = 0.629) relative to LTx involving donors within 10 y of an elderly recipient's age. These findings were substantiated in multivariate analysis adjusting for potential confounders.
CONCLUSIONS: In elderly LTx recipients aged 65-80 y at transplantation, intermediate-term survival was not influenced by donor age. For the viable elderly LTx candidate, a carefully selected older donor should be considered to increase donor availability.

PMID: 28624031 [PubMed - in process]

Cathepsin K in Lymphangioleiomyomatosis: LAM Cell-Fibroblast Interactions Enhance Protease Activity by Extracellular Acidification.

Sun, 06/18/2017 - 12:45
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Cathepsin K in Lymphangioleiomyomatosis: LAM Cell-Fibroblast Interactions Enhance Protease Activity by Extracellular Acidification.

Am J Pathol. 2017 Jun 14;:

Authors: Dongre A, Clements D, Fisher AJ, Johnson SR

Abstract
Lymphangioleiomyomatosis (LAM) is a rare disease in which clonal LAM cells infiltrate the lungs and lymphatics. In association with recruited fibroblasts, LAM cells form nodules adjacent to lung cysts. It is hypothesized that LAM nodule-derived proteases lead to cyst formation. On protease gene-expression profiling in whole-lung tissue, cathepsin K was 40-fold overexpressed in LAM compared with control lungs (P ≤ 0.0001). Immunohistochemistry confirmed cathepsin K protein in LAM nodules but not in control lungs. Cathepsin K gene expression and protein and protease activity were detected in LAM-associated fibroblasts but not in LAM cell line 621-101. In lung nodules, cathepsin K immunoreactivity predominantly co-localized with LAM-associated fibroblasts. In vitro, extracellular cathepsin K activity was minimal at pH 7.5 but was significantly enhanced in fibroblast cultures at pH 7 and 6. 621-101 cells reduced extracellular pH by 0.5 units over 24 hours. Acidification was dependent on 621-101 mechanistic target of rapamycin activity and net hydrogen ion transporters, particularly sodium bicarbonate co-transporters and carbonic anhydrases, which were also expressed in LAM lung tissue. In LAM cell-fibroblast co-cultures, acidification paralleled cathepsin K activity, and both were inhibited by sodium bicarbonate co-transporter (P ≤ 0.0001) and carbonic anhydrase inhibitor (P = 0.0021). Our findings suggest that cathepsin K activity is dependent on LAM cell-fibroblast interactions; inhibitors of extracellular acidification may be potential therapies for LAM.

PMID: 28623674 [PubMed - as supplied by publisher]

Allele-level HLA matching for umbilical cord blood transplantation for non-malignant diseases in children: a retrospective analysis.

Sun, 06/18/2017 - 12:45
Related Articles

Allele-level HLA matching for umbilical cord blood transplantation for non-malignant diseases in children: a retrospective analysis.

Lancet Haematol. 2017 Jun 13;:

Authors: Eapen M, Wang T, Veys PA, Boelens JJ, Martin AS, Spellman S, Bonfim CS, Brady C, Cant AJ, Dalle JH, Davies SM, Freeman J, Hsu KC, Fleischhauer K, Kenzey C, Kurtzberg J, Michel G, Orchard PJ, Paviglianiti A, Rocha V, Veneris MR, Volt F, Wynn R, Lee SJ, Horowitz MM, Gluckman E, Ruggeri A

Abstract
BACKGROUND: The standard for selecting unrelated umbilical cord blood units for transplantation for non-malignant diseases relies on antigen-level (lower resolution) HLA typing for HLA-A and HLA-B, and allele-level for HLA-DRB1. We aimed to study the effects of allele-level matching at a higher resolution-HLA-A, HLA-B, HLA-C, and HLA-DRB1, which is the standard used for adult unrelated volunteer donor transplantation for non-malignant diseases-for umbilical cord blood transplantation.
METHODS: We retrospectively studied 1199 paediatric donor-recipient pairs with allele-level HLA matching who received a single unit umbilical cord blood transplantation for non-malignant diseases reported to the Center for International Blood and Marrow Transplant Research or Eurocord and European Group for Blood and Marrow Transplant. Transplantations occurred between Jan 1, 2000, and Dec 31, 2012. The primary outcome was overall survival. The effect of HLA matching on survival was studied using a Cox regression model.
FINDINGS: Compared with HLA-matched transplantations, mortality was higher with transplantations mismatched at two (hazard ratio [HR] 1·55, 95% CI 1·08-2·21, p=0·018), three (2·04, 1·44-2·89, p=0·0001), and four or more alleles (3·15, 2·16-4·58, p<0·0001). There were no significant differences in mortality between transplantations that were matched and mismatched at one allele (HR 1·18, 95% CI 0·80-1·72, p=0·39). Other factors associated with higher mortality included recipient cytomegalovirus seropositivity (HR 1·40, 95% CI 1·13-1·74, p=0·0020), reduced intensity compared with myeloablative conditioning regimens (HR 1·36, 1·10-1·68, p=0·0041), transplantation of units with total nucleated cell dose of more than 21 × 10(7) cells per kg compared with 21 × 10(7) cells per kg or less (HR 1·47, 1·11-1·95, p=0·0076), and transplantations done in 2000-05 compared with those done in 2006-12 (HR 1·64, 1·31-2·04, p<0·0001). The 5-year overall survival adjusted for recipient cytomegalovirus serostatus, conditioning regimen intensity, total nucleated cell dose, and transplantation period was 79% (95% CI 74-85) after HLA matched, 76% (71-81) after one allele mismatched, 70% (65-75) after two alleles mismatched, 62% (57-68) after three alleles mismatched, and 49% (41-57) after four or more alleles mismatched transplantations. Graft failure was the predominant cause of mortality.
INTERPRETATION: These data support a change from current practice in that selection of unrelated umbilical cord blood units for transplantation for non-malignant diseases should consider allele-level HLA matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1.
FUNDING: National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute for Allergy and Infectious Diseases; US Department of Health and Human Services-Health Resources and Services Administration; and US Department of Navy.

PMID: 28623181 [PubMed - as supplied by publisher]

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