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Paucicellular Fibrointimal Proliferation Characterizes Pediatric Pulmonary Vein Stenosis: Clinicopathologic Analysis of 213 Samples From 97 Patients.

Sun, 06/18/2017 - 12:45
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Paucicellular Fibrointimal Proliferation Characterizes Pediatric Pulmonary Vein Stenosis: Clinicopathologic Analysis of 213 Samples From 97 Patients.

Am J Surg Pathol. 2017 Jun 15;:

Authors: Kovach AE, Magcalas PM, Ireland C, McEnany K, Oliveira AM, Kieran MW, Baird CW, Jenkins K, Vargas SO

Abstract
Pulmonary vein stenosis (PVS) is a luminal narrowing of extrapulmonary pulmonary veins. In pediatric patients, it arises following repair of congenital heart disease, particularly anomalous pulmonary venous return; in lung disease, especially prematurity; and rarely in isolation. The etiology is unknown and the course often fatal without lung transplantation. We hypothesized that systematic clinicopathologic review of pediatric PVS could provide further pathogenic insight. We included patients who underwent first resection of pulmonary venous tissue for symptomatic PVS at our pediatric referral center from 1995 to 2014. Clinical records and hematoxylin and eosin slides were reviewed. Subsets were immunostained for smooth muscle actin, Ki-67, β-catenin, estrogen receptor, and other markers and analyzed for USP6 gene rearrangement. A total of 97 patients (57% male; median age: 6 mo) were identified. Overall, 59 (61%) had prior congenital heart disease repair, 35 involving pulmonary vein manipulation. Samples included 213 separate anatomic sites (median: 2/patient). Histologically, all showed sparsely cellular intimal expansion composed of haphazardly arranged fibroblasts with slender nuclei in myxoid matrix. This tissue merged with underlying collagen. Most samples had a variably continuous sheath of cardiomyocytes. Ancillary tests supported a reactive fibroblastic proliferation; in particular, fibroblasts showed cytoplasmic β-catenin localization, no estrogen receptor expression, and no USP6 rearrangement. At last follow-up (mean: 2.3 y), 46% of patients had died of disease. Pediatric PVS uniformly consists of a paucicellular fibrointimal proliferation, irrespective of clinical scenario. It may be best conceived of as a form of reactive hyperplasia. As with other forms of vascular remodeling, trauma (iatrogenic or occult) is likely an inciting factor. A comprehensive understanding of the surgical pathology of PVS may further inform therapeutic strategies in this lethal disease.

PMID: 28622179 [PubMed - as supplied by publisher]

Organ Dysfunction and Failure Following Brain Death Do Not Preclude Successful Donation.

Sun, 06/18/2017 - 12:45
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Organ Dysfunction and Failure Following Brain Death Do Not Preclude Successful Donation.

World J Surg. 2017 Jun 15;:

Authors: Essien EI, Parimi N, Gutwald-Miller J, Nutter T, Scalea TM, Stein DM

Abstract
BACKGROUND: Organ dysfunction is common after neurologic determination of death (NDD) but before organ collection. Reliable markers for graft success following transplant of these organs would be useful. We sought to determine the relationship between the donor after neurologic determination of death (DNDD) pathophysiology and successful organ donation.
METHODS: Donor information was obtained through the local organ procurement organization. Donor demographics and clinical data points for cardiovascular, renal, respiratory, hepatic, hematological and neuroendocrine systems were reviewed 12 h before and 12 h after neurologic determination of death was declared. The worst values were utilized for analysis and generation of the organ-specific Sequential Organ Failure Assessment (SOFA) scores. SOFA scores were calculated and used to quantify the degree of organ dysfunction. The NDD non-donors for a specific organ were used as a comparison control group. The control group refers to DNDD patients whose specific organs were not transplanted. Lack of use was mostly due to discard by the transplant team as a result of unsuitability of the organ caused by deterioration or possible donor-specific pathology.
RESULTS: One hundred and five organ donors were analyzed. Mean age was 35.0 (± 13.6), 78.1% male, median GCS 3, interquartile range (IQR) 3-4 and median injury severity score 32 (IQR 25-43). Of the successful donors, organ-specific severe dysfunction (SOFA 3 or 4) occurred in 96, 27.5 and 3.3% of cardiac, lung and liver donors, respectively. There was no significant difference between the levels of organ dysfunction in donors versus non-donors except lung donors, in which the median lowest partial pressure of arterial oxygen-to-fraction of inspired oxygen (P/F) ratio in the non-donor was 194 (IQR 121.8-308.3) compared to the median lowest P/F ratio in the donor which was 287 (IQR 180-383.5), p = 0.02. In the recipients, graft failure 6 months after transplantation was reported in one kidney recipient (0.74%) (peak donor creatinine = 1 mg/dL) and in five pancreas recipients (11.4%). The median peak glucose of the pancreas donors in failed recipients was 178 mg/dL (IQR 157-213), whereas in the functioning recipients, the median glucose of their donors was not different (185 mg/dL, IQR 157-216), p = 0.394.
CONCLUSION: Current measures of organ failure and dysfunction do not predict the success of organ donation. Successful donor management in the face of severe organ dysfunction and failure can result in lives saved.

PMID: 28620674 [PubMed - as supplied by publisher]

Activin Biology After Lung Transplantation.

Sun, 06/18/2017 - 12:45
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Activin Biology After Lung Transplantation.

Transplant Direct. 2017 Jun;3(6):e159

Authors: Westall GP, Snell GI, Loskot M, Levvey B, O'Hehir R, Hedger MP, de Kretser DM

Abstract
BACKGROUND: Activins A and B, members of the TGF-β superfamily, are produced as part of the physiological response to tissue damage and the resulting proinflammatory response. Given that lung allograft reperfusion results in an inflammatory response, it is likely that the activins and their binding protein follistatin will form part of the regulatory response. There is a need to document the response of these proteins to allograft reperfusion to determine if there is a role for the use of follistatin to control the biological actions of the activins because some of these are potentially damaging.
METHODS: Serum from 48 consecutive patients undergoing lung transplantation (LTx) was collected at 2, 6, 12, and 26 weeks post-LTx. The serum levels of activin A and B and follistatin were measured by enzyme-linked immunosorbent assay and specific radioimmunoassays and compared with clinical events.
RESULTS: Serum activin A and B levels were at the upper limit of the normal ranges at 2 weeks post-LTx decreasing thereafter to 12 weeks post-LTx (P < 0.05). In contrast, serum follistatin levels were unchanged between 2 and 12 weeks, with a late significant increase at 24 week post-LTx (P < 0.01). Patients with primary graft dysfunction had lower serum follistatin levels (7.7 vs 9.5 ng/mL; P = 0.04) and a higher activin A/follistatin ratio (13.1 vs 10.4; P = 0.02) at 2 weeks post-LTx.
CONCLUSIONS: Activin and follistatin levels vary with time form LTX and reflect a proinflammatory environment. Future studies will elucidate associations with chronic lung allograft dysfunction and the therapeutic potential of exogenous follistatin administration.

PMID: 28620643 [PubMed - in process]

Influence of Donor Lung Surfactant-A and -B Protein Expression on the Development of Primary Graft Dysfunction After Lung Transplantation: A Pilot Study.

Sun, 06/18/2017 - 12:45
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Influence of Donor Lung Surfactant-A and -B Protein Expression on the Development of Primary Graft Dysfunction After Lung Transplantation: A Pilot Study.

Ann Transplant. 2017 Jun 16;22:361-369

Authors: Belhaj A, Boven C, Dewachter L, Ruiz Patino M, Sokolow Y, Rondelet B

Abstract
BACKGROUND Primary graft dysfunction (PGD) is responsible of high early mortality in lung transplanted patients. We measured the rate of surfactant proteins in the organ donor, and we observed the occurrence of lung PGD in the recipient. The co-relation between these two parameters was evaluated. MATERIAL AND METHODS In this pilot study, we prospectively collected blood samples and lung biopsies in thirteen donors at the time of recovery of organs before preservation. Gene expression of SP-A, SP-B, SP-D, and CC16 was evaluated by real-time quantitative PCR. Surfactant proteins plasma levels were evaluated by ELISA. Post-transplant assessments included hemodynamic, arterial blood gas measurements, and radiographic evaluation to determine PGD and lung biopsies. RESULTS Nine of the thirteen recipients (69%) developed lung infiltrates and four (31%) developed PGD at either stages 2 or 3. SP-A and SP-B expressions were dramatically reduced in lung allografts of these patients, while lung expression of SP-D and CC16 remained unchanged. Plasma levels of SP-A, SP-B, SP-D, and CC16 did not differ. CONCLUSIONS Primary graft dysfunction may be initiated in the donor. Lung allografts with low lung SP-A and SP-B gene expression prior to implantation are associated with increased incidence of lung infiltrates after transplantation.

PMID: 28620154 [PubMed - in process]

Chronic pulmonary aspergillosis complicating sarcoidosis.

Sun, 06/18/2017 - 12:45
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Chronic pulmonary aspergillosis complicating sarcoidosis.

Eur Respir J. 2017 Jun;49(6):

Authors: Uzunhan Y, Nunes H, Jeny F, Lacroix M, Brun S, Brillet PY, Martinod E, Carette MF, Bouvry D, Charlier C, Lanternier F, Planès C, Tazi A, Lortholary O, Baughman RP, Valeyre D

Abstract
Chronic pulmonary aspergillosis (CPA) complicating sarcoidosis (SA) is associated with high mortality, and there is a lack of clarity regarding the relative contributions of SA or CPA.This was a retrospective single-centre study on CPA-SA.In total, 65 patients (44 men), aged 41.4±13.5 and 48.3±11.9 years at the time of SA and CPA diagnoses, respectively, were included between 1980 and 2015. Of these, 64 had fibrocystic SA, most often advanced, with composite physiological index (CPI) >40 (65% of patients) and pulmonary hypertension (PH) (31%), and 41 patients (63%) were treated for SA (corticosteroids or immunosuppressive drugs). Chronic cavitary pulmonary aspergillosis (CCPA) was the most frequent CPA pattern. Regarding treatment, 55 patients required long-term antifungals, 14 interventional radiology, 11 resection surgery and two transplantation. Nearly half of the patients (27; 41.5%) died (mean age 55.8 years); 73% of the patients achieved 5-year survival and 61% 10-year survival. Death most often resulted from advanced SA and rarely from haemoptysis. CPI, fibrosis extent and PH predicted survival. Comparison with paired healthy controls without CPA did not show any difference in survival, but a higher percentage of patients had high-risk mould exposure.CPA occurs in advanced pulmonary SA. CPA-SA is associated with high mortality due to the underlying advanced SA rather than to the CPA. CPI, fibrosis extent and PH best predict outcome.

PMID: 28619957 [PubMed - in process]

Risk stratification to determine the impact of induction therapy on survival, rejection and adverse events after pediatric heart transplant: A multi-institutional study.

Sun, 06/18/2017 - 12:45
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Risk stratification to determine the impact of induction therapy on survival, rejection and adverse events after pediatric heart transplant: A multi-institutional study.

J Heart Lung Transplant. 2017 May 11;:

Authors: Castleberry C, Pruitt E, Ameduri R, Schowengerdt K, Edens E, Hagin N, Kirklin JK, Naftel D, Urschel S

Abstract
BACKGROUND: Induction therapy is increasingly being used in pediatric heart transplantation. General versus risk-adapted use remains controversial. We aimed to determine the impact of induction therapy on outcomes after stratifying patients by diagnosis and risk.
METHODS: The Pediatric Heart Transplant Study (PHTS) database was used to identify patients (age ≤18 years) who underwent transplantation between January 1, 2001 and December 31, 2014. Patients were excluded if they survived <48 hours or received multiple induction agents. Patients were stratified using a multivariable model to predict 1-year mortality. Patients within the top 25% risk of predicted mortality were defined as high risk (HR) and the bottom 75% as low risk (LR).
RESULTS: Of the 2,860 patients studied, 1,370 received anti-lymphocyte antibody (ALA), 707 received an interleukin-2 receptor antagonist (IL-2RA) and 783 received no induction (NI) therapy. Overall, patients with NI had lower survival (p < 0.01); however, multivariable analysis did not demonstrate an association with graft loss. Freedom from rejection was greater among LR congenital heart disease (CHD) and all cardiomyopathy (CMP) patients who received induction therapy (p < 0.01, for both), as confirmed in a multivariable analysis for CMP patients. Frequency of graft vasculopathy was higher in LR CMP patients who received NI. Freedom from infection was lower with IL-2RA in the LR groups.
CONCLUSIONS: Pediatric heart transplant survival has improved in the recent era, in concert with increased use of induction therapy. Although induction therapy is associated with decreased rejection, it was not found to directly influence survival on multivariable analysis. Lower risk patients may benefit the most from induction therapy, particularly IL-2RA, which may be correlated with decreased infection and rejection in this cohort.

PMID: 28619384 [PubMed - as supplied by publisher]

Cardiac rehabilitation and readmissions after heart transplantation.

Sun, 06/18/2017 - 12:45
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Cardiac rehabilitation and readmissions after heart transplantation.

J Heart Lung Transplant. 2017 May 23;:

Authors: Bachmann JM, Shah AS, Duncan MS, Greevy RA, Graves AJ, Ni S, Ooi HH, Wang TJ, Thomas RJ, Whooley MA, Freiberg MS

Abstract
BACKGROUND: Exercise-based cardiac rehabilitation (CR) is under-utilized. CR is indicated after heart transplantation, but there are no data regarding CR participation in transplant recipients. We characterized current CR utilization among heart transplant recipients in the United States and the association of CR with 1-year readmissions using the 2013-2014 Medicare files.
METHODS: The study population included Medicare beneficiaries enrolled due to disability (patients on the transplant list are eligible for disability benefits under Medicare regulations) or age ≥65 years. We identified heart transplant patients by diagnosis codes and cumulative CR sessions occurring within 1 year after the transplant hospitalization.
RESULTS: There were 2,531 heart transplant patients in the USA in 2013, of whom 595 (24%) received Medicare coverage and were included in the study. CR utilization was low, with 326 patients (55%) participating in CR programs. The Midwest had the highest proportion of transplant recipients initiating CR (68%, p = 0.001). Patients initiating CR attended a mean of 26.7 (standard deviation 13.3) sessions, less than the generally prescribed program of 36 sessions. Transplant recipients age 35 to 49 years were less likely to initiate CR (odds ratio [OR] 0.39, 95% confidence interval [CI] 0.23 to 0.66, p < 0.001) and attended 8.2 fewer sessions (95% CI 3.5 to 12.9, p < 0.001) than patients age ≥65 years. CR participation was associated with a 29% lower 1-year readmission risk (95% CI 13% to 42%, p = 0.001).
CONCLUSIONS: Only half of cardiac transplant recipients participate in CR, and those who do have a lower 1-year readmission risk. These data invite further study on barriers to CR in this population.

PMID: 28619383 [PubMed - as supplied by publisher]

Human adipose-derived mesenchymal stem cells alleviate obliterative bronchiolitis in a murine model via IDO.

Sun, 06/18/2017 - 12:45
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Human adipose-derived mesenchymal stem cells alleviate obliterative bronchiolitis in a murine model via IDO.

Respir Res. 2017 Jun 15;18(1):119

Authors: Zheng G, Qiu G, Ge M, He J, Huang L, Chen P, Wang W, Xu Q, Hu Y, Shu Q, Xu J

Abstract
BACKGROUND: Long-term survival of lung transplantation is hindered by the development of obliterative bronchiolitis (OB). Adipose-derived stem cells (ASCs) were documented to have more potent immunosuppressive ability than mesenchymal stem cells (MSCs) from bone marrow and placenta. The goal of our study is to evaluate the effect of repeated administration of ASCs on OB and the involvement of indoleamine 2,3-dioxygenase (IDO) mediating the protective effect of ASCs in a heterotopic tracheal transplantation (HTT) model.
METHODS: For studies in vitro, ASCs were treated with interferon-γ (IFN-γ). For in vivo study, tracheas from BALB/c or C57BL/6 donors were transplanted into C57BL/6 recipients to create a HTT model. On days 0, 1, 3, 5, 8, 12, 15, 20 and 25 post-transplant, the allogeneic recipient mice were administered intravenously with phosphate buffered saline, 1 × 10(6) human ASCs, or 1 × 10(6) human ASCs plus 1-methyltryptophan (1-MT), an IDO inhibitor. On days 3, 7, 14 and 28, serum, trachea and spleen samples were harvested for analysis.
RESULTS: ASCs homed to heterotopic tracheal grafts after infusion. Multiple doses of ASCs significantly increased tracheal IDO levels in allografts. There were significant increases in graft and serum IFN-γ levels in allografts compared with isografts. IFN-γ elevated IDO expression and activity in ASCs in vitro. ASCs alleviated OB in allografts as evidenced by reduced epithelial loss, epithelial apoptosis, and intraluminal obstruction. The effects of ASCs on OB were blocked by 1-MT. 1-MT also blocked the alterations in pro and anti-inflammatory cytokines as well as CD3+ T cell infiltration induced by ASCs. ASCs induced not only splenic levels of CD4+CD25+Foxp3+ regulatory T cells (Treg) but also IL-10 and TGF-β-producing Treg. Furthermore, IDO inhibition abolished the changes of splenic Treg induced by ASCs. In addition, Treg reduction by cyclophosphamide treatment did not alter the effects of ASCs on tracheal IDO expression in allografts confirming Treg induction is downstream of IDO.
CONCLUSIONS: Repeated doses of ASCs are capable of ameliorating OB. ASCs act at least in part via elevating IDO expression. ASCs promote the generation of Treg and suppress T cell infiltration via an IDO-dependent mechanism.

PMID: 28619045 [PubMed - in process]

CME: Konservative und invasive Behandlungsmethoden in der Therapie des Lungenemphysems.

Sun, 06/18/2017 - 12:45
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CME: Konservative und invasive Behandlungsmethoden in der Therapie des Lungenemphysems.

Praxis (Bern 1994). 2016 Nov;105(22):1293-1299

Authors: Gautschi F, Franzen D

PMID: 27805852 [PubMed - indexed for MEDLINE]

Herpes simplex virus-2 transmission following solid organ transplantation: Donor-derived infection and transplantation from prior organ recipients.

Fri, 06/16/2017 - 12:45

Herpes simplex virus-2 transmission following solid organ transplantation: Donor-derived infection and transplantation from prior organ recipients.

Transpl Infect Dis. 2017 Jun 15;:

Authors: Macesic N, Abbott IJ, Kaye M, Druce J, Glanville AR, Gow PJ, Hughes PD, Korman TM, Mulley WR, O'Connell PJ, Opdam H, Paraskeva M, Pitman MC, Setyapranata S, Rawlinson WD, Johnson PDR

Abstract
BACKGROUND: Owing to limited availability of donor organs, previous solid organ transplant (SOT) recipients are increasingly considered as potential organ donors. We report donor-derived transmission of herpes simplex virus type-2 (HSV-2) to two clusters of SOT recipients with transmission from the original donor and an HSV-2-infected recipient who subsequently became a donor.
METHODS: We reviewed medical records of the donors and recipients in both clusters. Pre-transplant serology and virological features of HSV-2 were characterized. Genotyping of HSV-2 isolates to determine potential for donor transmission of HSV-2 through transplantation of organs from prior organ recipients was performed.
RESULTS: A kidney-pancreas recipient died day 9 post transplant. Following confirmation of brain death, the lungs and recently transplanted kidney were donated to two further recipients. The liver was not retrieved, but biopsy confirmed HSV-2 infection. Testing on the original donor showed negative HSV-2 polymerase chain reaction and HSV immunoglobulin (Ig)M, but positive HSV-2 IgG. The liver recipient from the original donor developed HSV-2 hepatitis and cutaneous infection that responded to treatment with intravenous acyclovir. In the second cluster, lung and kidney recipients both developed HSV-2 viremia that was successfully treated with antiviral therapy. Genotyping of all HSV-2-positive samples showed 100% sequence homology for three recipients.
CONCLUSIONS: Donor-derived HSV infection affected two clusters of recipients because of transplantation of organs from a prior organ recipient. HSV should be considered as a possible cause of illness in febrile SOT recipients in the immediate post-transplant period and may cause disseminated disease and re-infection in HSV-2-seropositive recipients. Testing of HSV serology and prophylaxis may be considered in SOT recipients not receiving cytomegalovirus prophylaxis. This article is protected by copyright. All rights reserved.

PMID: 28618165 [PubMed - as supplied by publisher]

Clinical outcome of cystic fibrosis patients colonized by Scedosporium species following lung transplantation: A single-center 15-year experience.

Fri, 06/16/2017 - 12:45

Clinical outcome of cystic fibrosis patients colonized by Scedosporium species following lung transplantation: A single-center 15-year experience.

Transpl Infect Dis. 2017 Jun 15;:

Authors: Parize P, Boussaud V, Poinsignon V, Sitterlé E, Botterel F, Lefeuvre S, Guillemain R, Dannaoui E, Billaud EM

Abstract
BACKGROUND: Fungi of the genus Scedosporium are emerging pathogens responsible for severe infections in lung transplant recipients. These infections are associated with poor prognosis and some centers consider now Scedosporium species colonization as a contraindication to lung transplantation (LT) even though no published evidence demonstrates that Scedosporium species colonization is associated with higher morbidity or mortality after LT.
METHODS: Here we aim to describe characteristics and outcome of cystic fibrosis (CF) lung transplant recipients colonized with Scedosporium species in a single center over a 15-year period.
RESULTS: During the study period, 14 patients had scedosporial colonization reported. Only one patient, colonized before transplantation by Lomentospora prolificans, developed scedosporial disease. Among the eight patients colonized before transplantation by Scedosporium apiospermum complex, the median survival was 1.92 year (range 0.21-12.5). All these patients except one became free of fungal colonization after transplantation with antifungal prophylaxis including voriconazole or posaconazole. For the five patients colonized after LT, including two with L. prolificans, the median survival was 1.75 years (range 0.1-13); three of them are still alive.
CONCLUSIONS: It appears to us that scedosporial colonization may not be a contraindication for LT in CF patients, as long as S. apiospermum complex is involved and a life-long azole prophylaxis prescribed. This article is protected by copyright. All rights reserved.

PMID: 28618155 [PubMed - as supplied by publisher]

Challenges in Providing Timely Physiotherapy and Opportunities to Influence Outcomes for Potential Lung Donors.

Fri, 06/16/2017 - 12:45

Challenges in Providing Timely Physiotherapy and Opportunities to Influence Outcomes for Potential Lung Donors.

Prog Transplant. 2017 Jun;27(2):112-124

Authors: Raios C, Keating JL, Stitt N, Opdam HI, Skinner EH

Abstract
CONTEXT: There is a critical shortage of donor lungs however, considerable ethical considerations are associated with the conduct of research to optimize care of the potential organ donor.
OBJECTIVE: To investigate pathways of consent, respiratory care by physiotherapists and donation rates to contextualize future research on physiotherapy effects on donor lung suitability for procurement.
DESIGN: Retrospective audit.
SETTING: Australian tertiary hospital.
PATIENTS: Potential organ donors (defined as patients who may have been eligible to donate organs for transplantation via either brain death or circulatory death) 75 years or younger presenting to the emergency department or the intensive care unit (ICU) between September 2011 and December 2012.
MAIN OUTCOME MEASURES: Donation rates, timing of organ procurement from initial hospital presentation, number of persons designated to make health-care decisions approached for and consenting to donation and clinical research, and number of patients assessed and/or treated by physiotherapists.
RESULTS: Records of 65 potentially eligible donors were analyzed. Eighteen (28%) of the 65 became donors. Organ procurement occurred at a median of 48 hours (interquartile range: 34-72 hours) after ICU admission. All decision-makers approached regarding participation in clinical research (4 [6%] of the 65) consented. Physiotherapists assessed 48 (74%) of the 65 patients at least once and provided 28 respiratory treatments to 18 (28%) of the 65 patients, including lung hyperinflation and positioning. Limitations were the retrospective, single-center design and the "potential organ donor" definition.
CONCLUSION: Organ procurement occurs early. There is potential for early intervention to improve lung donor rates. Randomized controlled trials investigating protocolized respiratory packages of care may increase the potential donor pool and transplantation rates.

PMID: 28617166 [PubMed - in process]

Insomnia and Relationship With Immunosuppressant Therapy After Lung Transplantation.

Fri, 06/16/2017 - 12:45

Insomnia and Relationship With Immunosuppressant Therapy After Lung Transplantation.

Prog Transplant. 2017 Jun;27(2):167-174

Authors: Rohde KA, Schlei ZW, Katers KM, Weber AK, Brokhof MM, Hawes DS, Radford KL, Francois ML, Menninga NJ, Cornwell R, Benca R, Hayney MS, Dopp JM

Abstract
BACKGROUND: Lung transplant recipients are at high risk of developing sleep disorders such as insomnia, but the prevalence and features are currently poorly characterized within this population. Since these disorders are associated with increased morbidity and mortality, it is important to identify them to optimize the care of lung transplant recipients. We sought to evaluate the prevalence of insomnia within our university-based lung transplant clinic and determine whether a relationship exists between insomnia and exposure to immunosuppressant medications following transplantation.
METHODS: Participants were recruited through the University of Wisconsin Hospital and Clinics Lung Transplant Clinic (N = 125). Participants (n = 92) completed the adult sleep history questionnaire, which included the Insomnia Severity Index (ISI) to assess for insomnia (defined as ISI score >10). Cumulative tacrolimus exposure was determined in 73 patients by performing an area under the curve calculation to assess for a potential relationship between tacrolimus exposure and insomnia.
RESULTS: The prevalence of insomnia was 40% within this population. Although no difference in time since transplant was found, cumulative mean ± standard error of the mean tacrolimus exposure was significantly higher in patients with insomnia versus those without insomnia (17 190 ± 1673 ng·d/mL vs 12 130 ± 1630 ng·d/mL, respectively; P = .04). Estimated tacrolimus exposure was not greater with increasing frequency of insomnia complaints (analysis of variance P = .54).
CONCLUSION: In our population, insomnia is common after lung transplantation, with prevalence greater than the general population. Higher cumulative exposure to tacrolimus may contribute to insomnia in this group. Future research should investigate the relationship between immunosuppressant therapy and development of sleep disorders.

PMID: 28617161 [PubMed - in process]

Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction.

Fri, 06/16/2017 - 12:45
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Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction.

Sci Transl Med. 2017 Jun 14;9(394):

Authors: Zheng Z, Chiu S, Akbarpour M, Sun H, Reyfman PA, Anekalla KR, Abdala-Valencia H, Edgren D, Li W, Kreisel D, Korobova FV, Fernandez R, McQuattie-Pimentel A, Zhang ZJ, Perlman H, Misharin AV, Scott Budinger GR, Bharat A

Abstract
Primary graft dysfunction is the predominant driver of mortality and graft loss after lung transplantation. Recruitment of neutrophils as a result of ischemia-reperfusion injury is thought to cause primary graft dysfunction; however, the mechanisms that regulate neutrophil influx into the injured lung are incompletely understood. We found that donor-derived intravascular nonclassical monocytes (NCMs) are retained in human and murine donor lungs used in transplantation and can be visualized at sites of endothelial injury after reperfusion. When NCMs in the donor lungs were depleted, either pharmacologically or genetically, neutrophil influx and lung graft injury were attenuated in both allogeneic and syngeneic models. Similar protection was observed when the patrolling function of donor NCMs was impaired by deletion of the fractalkine receptor CX3CR1. Unbiased transcriptomic profiling revealed up-regulation of MyD88 pathway genes and a key neutrophil chemoattractant, CXCL2, in donor-derived NCMs after reperfusion. Reconstitution of NCM-depleted donor lungs with wild-type but not MyD88-deficient NCMs rescued neutrophil migration. Donor NCMs, through MyD88 signaling, were responsible for CXCL2 production in the allograft and neutralization of CXCL2 attenuated neutrophil influx. These findings suggest that therapies to deplete or inhibit NCMs in donor lung might ameliorate primary graft dysfunction with minimal toxicity to the recipient.

PMID: 28615357 [PubMed - in process]

Risk of second malignancies in solid organ transplant recipients who develop keratinocyte cancers.

Fri, 06/16/2017 - 12:45
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Risk of second malignancies in solid organ transplant recipients who develop keratinocyte cancers.

Cancer Res. 2017 Jun 14;:

Authors: Zamoiski R, Yanik EL, Gibson TM, Cahoon EK, Madeleine MM, Lynch CF, Gustafson S, Goodman MT, Skeans M, Israni A, Engels EA, Morton LM

Abstract
Solid organ transplant recipients have increased risk for developing keratinocyte cancers (KC), including cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), in part as a result of immunosuppressive medications administered to prevent graft rejection. In the general population, KC are associated with increased risks of subsequent malignancy, however, the risk in organ transplant populations has not been evaluated. We addressed this question by linking the U.S. Scientific Registry of Transplant Recipients, which includes data on KC occurrence, with 15 state cancer registries. Risk of developing malignancies after KC was assessed among 118,440 Caucasian solid organ transplant recipients using multivariate Cox regression models. Cutaneous SCC occurrence (n=6169) was associated with 1.44-fold increased risk [95% confidence interval (CI): 1.31-1.59] for developing later malignancies. Risks were particularly elevated for non-cutaneous SCC, including those of the oral cavity/pharynx [hazard ratio (HR)=5.60, 95%CI: 4.18-7.50] and lung (HR=1.66, 95%CI: 1.16-2.31). Cutaneous SCC was also associated with increased risk of human papillomavirus-related cancers, including anal cancer (HR=2.77, 95%CI: 1.29-5.96) and female genital cancers (HR=3.43, 95%CI: 1.44-8.19). In contrast, BCC (n=3669) was not associated with overall risk of later malignancy (HR=0.98, 95%CI: 0.87-1.12) including any SCC. Our results suggest that transplant recipients with cutaneous SCC, but not BCC, have an increased risk of developing other SCC. These findings somewhat differ from those for the general population and suggest a shared etiology for cutaneous SCC and other SCC in the setting of immunosuppression. Cutaneous SCC occurrence after transplantation could serve as a marker for elevated malignancy risk.

PMID: 28615224 [PubMed - as supplied by publisher]

Internet-based perioperative exercise program in patients with Barrett's carcinoma scheduled for esophagectomy [iPEP - study] a prospective randomized-controlled trial.

Fri, 06/16/2017 - 12:45
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Internet-based perioperative exercise program in patients with Barrett's carcinoma scheduled for esophagectomy [iPEP - study] a prospective randomized-controlled trial.

BMC Cancer. 2017 Jun 14;17(1):413

Authors: Pfirrmann D, Tug S, Brosteanu O, Mehdorn M, Busse M, Grimminger PP, Lordick F, Glatz T, Hoeppner J, Lang H, Simon P, Gockel I

Abstract
BACKGROUND: Patients undergoing surgery for esophageal cancer have a high risk for postoperative deterioration of lung function and pulmonary complications. This is partly due to one-lung ventilation during thoracotomy. This often accounts for prolonged stay on intensive care units, delayed postoperative reconvalescence and reduced quality of life. Socioeconomic disadvantages can result from these problems. Physical preconditioning has become a crucial leverage to optimize fitness and lung function in patients scheduled for esophagectomy, in particular during the time period of neoadjuvant therapy.
METHODS/STUDY DESIGN: We designed a prospective multicenter randomized-controlled trial. The objective is to evaluate the impact of an internet-based exercise program on postoperative respiratory parameters and pneumonia rates in patients with Barrett's carcinoma scheduled for esophagectomy. Patients are randomly assigned to either execute internet-based perioperative exercise program (iPEP), including daily endurance, resistance and ventilation training or treatment as usual (TAU). During neoadjuvant therapy and recovery, patients in the intervention group receive an individually designed intensive exercise program based on functional measurements at baseline. Personal feedback of the supervisor with customized training programs is provided in weekly intervals.
DISCUSSION: This study will evaluate if an intensive individually adapted training program via online supervision during neoadjuvant therapy will improve cardiorespiratory fitness and reduce pulmonary complications following esophagectomy for Barrett's cancer.
TRIAL REGISTRATION: NCT02478996 , registered 26 May 2015.

PMID: 28615010 [PubMed - in process]

PCAF-mediated acetylation of transcriptional factor HOXB9 suppresses lung adenocarcinoma progression by targeting oncogenic protein JMJD6.

Fri, 06/16/2017 - 12:45
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PCAF-mediated acetylation of transcriptional factor HOXB9 suppresses lung adenocarcinoma progression by targeting oncogenic protein JMJD6.

Nucleic Acids Res. 2016 Dec 15;44(22):10662-10675

Authors: Wan J, Xu W, Zhan J, Ma J, Li X, Xie Y, Wang J, Zhu WG, Luo J, Zhang H

Abstract
HOXB9 is a homeobox domain-containing transcription factor, playing an important role in embryonic development and cancer progression. However, the precise post-translational modifications (PTMs) of HOXB9 and the corresponding roles are unclear. Here, we report that acetyltransferase p300/CBP-associated factor (PCAF) interacts with and acetylates HOXB9 both in vivo and in vitro Conversely, the acetylation of HOXB9 can be reversed by deacetylase SIRT1. Furthermore, we found that HOXB9 is acetylated at lysine 27 (AcK27). Functionally, in contrast to the wild type HOXB9, AcK27-HOXB9 decreased its capacity in promoting lung cancer cell migration and tumor growth in mice. Mechanistically, AcK27-HOXB9 suppresses the transcription of its target gene Jumonji domain-containing protein 6 (JMJD6) by direct occupying the promoter of JMJD6 gene. For clinical relevance, elevated HOXB9 acetylation at K27 predicts a better prognosis in lung adenocarcinoma patients. Taken together, we identified the first PTM of HOXB9 by demonstrating that HOXB9 can be acetylated and AcK27-HOXB9 counteracts the role of the wild-type HOXB9 in regulating lung adenocarcinoma progression.

PMID: 27613418 [PubMed - indexed for MEDLINE]

Trajectories of Self-Care Agency and Associated Factors in Lung Transplant Recipients over the First 12-months Following Transplantation.

Wed, 06/14/2017 - 12:45

Trajectories of Self-Care Agency and Associated Factors in Lung Transplant Recipients over the First 12-months Following Transplantation.

Clin Transplant. 2017 Jun 13;:

Authors: Hu L, Lingler JH, DeVito Dabbs A, Dew MA, Sereika SM

Abstract
Self-care agency (SCA), defined as one's ability and willingness to engage in self-care behaviors, can influence actual performance of self-care behaviors in lung transplant recipients (LTRs). Understanding patterns of SCA over time may inform the design of interventions to promote self-care in LTRs. Using group-based trajectory modeling, we sought to identify patterns and correlates of SCA among 94 LTRs over the first 12-months post-transplant. Baseline measures of sociodemographic, clinical, and psychosocial factors, and longitudinally assessed psychological distress were examined for their associations with predicted trajectory group membership. Three distinct stable (i.e., zero slope) SCA trajectories were identified: persistently low, persistently moderate, and persistently high. Based on the final multivariate model, requiring a re-intubation after transplant (p=.043), discharged to a facility rather than home (p=.048), and reporting a higher level of baseline anxiety (p=.001) were significantly associated with lower SCA. Linear mixed models revealed that higher levels of anxiety and depression were associated with lower SCA in the persistently moderate and low SCA groups over the 12-month time period (ps<.05). LTRs who require a re-intubation after transplant and are discharged to a facility other than home, and report high psychological distress, may need additional assistance to engage in post-transplant self-care behaviors. This article is protected by copyright. All rights reserved.

PMID: 28609813 [PubMed - as supplied by publisher]

2017 ACC/AHA/HFSA/ISHLT/ACP Advanced Training Statement on Advanced Heart Failure and Transplant Cardiology (Revision of the ACCF/AHA/ACP/HFSA/ISHLT 2010 Clinical Competence Statement on Management of Patients With Advanced Heart Failure and Cardiac...

Wed, 06/14/2017 - 12:45

2017 ACC/AHA/HFSA/ISHLT/ACP Advanced Training Statement on Advanced Heart Failure and Transplant Cardiology (Revision of the ACCF/AHA/ACP/HFSA/ISHLT 2010 Clinical Competence Statement on Management of Patients With Advanced Heart Failure and Cardiac Transplant): A Report of the ACC Competency Management Committee.

Circ Heart Fail. 2017 Jun;10(6):

Authors: Jessup M, Drazner MH, Book W, Cleveland JC, Dauber I, Farkas S, Ginwalla M, Katz JN, Kirkwood P, Kittleson MM, Marine JE, Mather P, Morris AA, Polk DM, Sakr A, Schlendorf KH, Vorovich EE

PMID: 28607153 [PubMed - in process]

Can immunosuppression be stopped after liver transplantation?

Wed, 06/14/2017 - 12:45

Can immunosuppression be stopped after liver transplantation?

Lancet Gastroenterol Hepatol. 2017 Jul;2(7):531-537

Authors: Clavien PA, Muller X, de Oliveira ML, Dutkowski P, Sanchez-Fueyo A

Abstract
Liver transplantation has improved dramatically over the past three decades, mainly as a result of advances in surgical techniques and management of post-transplant complications. The focus has now turned towards rescuing additional organs in the face of scarce organ supply, or prevention of long-term toxicity associated with immunosuppression. The liver appears to be privileged in terms of immune tolerance, with a low incidence of antibody-mediated rejection, which is in sharp contrast to other solid organ transplants, such as kidney, lung, and heart transplants. However, tolerogenic processes remain poorly understood, and strategies for complete drug withdrawal should be selected carefully to avoid graft rejection. In this Review, we summarise the current understanding of liver-specific immune responses and provide an outlook on future approaches.

PMID: 28606879 [PubMed - in process]

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