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Prognostic factors and outcomes in Japanese lung transplant candidates with interstitial lung disease.

Sat, 08/12/2017 - 12:45
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Prognostic factors and outcomes in Japanese lung transplant candidates with interstitial lung disease.

PLoS One. 2017;12(8):e0183171

Authors: Ikezoe K, Handa T, Tanizawa K, Chen-Yoshikawa TF, Kubo T, Aoyama A, Motoyama H, Hijiya K, Tokuda S, Nakatsuka Y, Yamamoto Y, Oshima A, Harashima SI, Nagai S, Hirai T, Date H, Chin K

Abstract
OBJECTIVE: Young patients with advanced interstitial lung disease (ILD) are potential candidates for cadaveric lung transplantation. This study aimed to examine clinical features, outcomes, and prognostic factors in Japanese ILD patients awaiting lung transplantation.
METHODS: We investigated the clinical features and outcomes of 77 consecutive candidates with ILD who were referred to Kyoto University Hospital and subsequently actively listed for lung transplant in the Japan Organ Transplant Network between 2010 and 2014.
RESULTS: Of the 77 candidates, 33 had idiopathic pulmonary fibrosis (IPF) and 15 had unclassifiable ILD. During the observational period, 23 patients (30%) received lung transplantations and 49 patients (64%) died before transplantation. Of the 33 patients with IPF, 13 (39%) had a family history of ILD and 13 (39%) had an "inconsistent with usual interstitial pneumonia pattern" on high-resolution computed tomography (HRCT). The median survival time from registration was 16.7 months, and mortality was similar among patients with IPF, unclassifiable ILD, and other ILDs. Using a multivariate stepwise Cox proportional hazards model, 6-min walking distance was shown to be an independent prognostic factor in candidates with ILD (per 10 m, hazard ratio (HR): 0.97; 95% confidence interval (CI): 0.95-0.99, p<0.01), while lower body mass index (HR: 0.83; 95% CI: 0.72-0.95, p < 0.01) independently contributed to mortality in patients with IPF.
CONCLUSIONS: Japanese patients with ILD awaiting transplantation had very poor outcomes regardless of their specific diagnosis. A substantial percentage of IPF patients had an atypical HRCT pattern. 6-min walking distance in ILD patients and body mass index in IPF patients were independent predictors of mortality.

PMID: 28800589 [PubMed - in process]

Anticancer efficacy of the hypoxia-activated prodrug evofosfamide is enhanced in combination with proapoptotic receptor agonists against osteosarcoma.

Sat, 08/12/2017 - 12:45
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Anticancer efficacy of the hypoxia-activated prodrug evofosfamide is enhanced in combination with proapoptotic receptor agonists against osteosarcoma.

Cancer Med. 2017 Aug 10;:

Authors: Liapis V, Zysk A, DeNichilo M, Zinonos I, Hay S, Panagopoulos V, Shoubridge A, Difelice C, Ponomarev V, Ingman W, Atkins GJ, Findlay DM, Zannettino ACW, Evdokiou A

Abstract
Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia also leads to treatment opportunities as demonstrated by the development of compounds that target regions of hypoxia within tumors. Evofosfamide is a hypoxia-activated prodrug that is created by linking the hypoxia-seeking 2-nitroimidazole moiety to the cytotoxic bromo-isophosphoramide mustard (Br-IPM). When evofosfamide is delivered to hypoxic regions of tumors, the DNA cross-linking toxin, Br-IPM, is released leading to cell death. This study assessed the anticancer efficacy of evofosfamide in combination with the Proapoptotic Receptor Agonists (PARAs) dulanermin and drozitumab against human osteosarcoma in vitro and in an intratibial murine model of osteosarcoma. Under hypoxic conditions in vitro, evofosfamide cooperated with dulanermin and drozitumab, resulting in the potentiation of cytotoxicity to osteosarcoma cells. In contrast, under the same conditions, primary human osteoblasts were resistant to treatment. Animals transplanted with osteosarcoma cells directly into their tibiae developed mixed osteosclerotic/osteolytic bone lesions and consequently developed lung metastases 3 weeks post cancer cell transplantation. Tumor burden in the bone was reduced by evofosfamide treatment alone and in combination with drozitumab and prevented osteosarcoma-induced bone destruction while also reducing the growth of pulmonary metastases. These results suggest that evofosfamide may be an attractive therapeutic agent, with strong anticancer activity alone or in combination with either drozitumab or dulanermin against osteosarcoma.

PMID: 28799237 [PubMed - as supplied by publisher]

Prolonged Administration of Twice-Daily Bolus Intravenous Tacrolimus in the Early Phase After Lung Transplantation.

Sat, 08/12/2017 - 12:45
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Prolonged Administration of Twice-Daily Bolus Intravenous Tacrolimus in the Early Phase After Lung Transplantation.

Ann Transplant. 2017 Aug 11;22:484-492

Authors: Hirano Y, Sugimoto S, Mano T, Kurosaki T, Miyoshi K, Otani S, Yamane M, Kobayashi M, Miyoshi S, Oto T

Abstract
BACKGROUND Although administration of tacrolimus, whether by the enteric, sublingual, or continuous intravenous routes, has some limitations, twice-daily bolus intravenous tacrolimus administration has been shown to be beneficial in optimizing efficacy and safety after lung transplantation. However, at present, the duration of bolus intravenous tacrolimus administration is limited, and the effects of prolonged bolus intravenous tacrolimus administration remain unknown. Our study was aimed at assessing the safety and efficacy of prolonged twice-daily bolus intravenous tacrolimus administration in the early phase after lung transplantation. MATERIAL AND METHODS We retrospectively investigated the data of 62 recipients of lung transplantation who had received twice-daily bolus intravenous administration of tacrolimus, followed by oral tacrolimus, after lung transplantation at our institution between January 2011 and October 2015. RESULTS The median duration of bolus intravenous tacrolimus administration was 19 days (4-72 days). The target trough level was achieved in 89% of the patients by day 3. Acute kidney injury occurred in 27% of the patients during bolus intravenous tacrolimus. Two patients (3%) had neurotoxicity, necessitating discontinuation of tacrolimus. Suspected acute rejection requiring steroid pulse therapy occurred in 21% of patients during the follow-up period. Eight patients (13%) developed chronic lung allograft dysfunction during the follow-up period. The 1-year and 5-year survival rates after lung transplantation were 95% and 76%, respectively. CONCLUSIONS These results suggest that prolonged bolus intravenous tacrolimus administration in the early phase after lung transplantation is a safe and effective alternative to enteric, sublingual, or continuous intravenous administration.

PMID: 28798289 [PubMed - in process]

mTOR regulates metabolic adaptation of APCs in the lung and controls the outcome of allergic inflammation.

Sat, 08/12/2017 - 12:45
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mTOR regulates metabolic adaptation of APCs in the lung and controls the outcome of allergic inflammation.

Science. 2017 Aug 10;:

Authors: Sinclair C, Bommakanti G, Gardinassi L, Loebbermann J, Johnson MJ, Hakimpour P, Hagan T, Benitez L, Todor A, Machiah D, Oriss T, Ray A, Bosinger S, Ravindran R, Li S, Pulendran B

Abstract
Antigen-presenting cells (APCs) occupy diverse anatomical tissues, but their tissue-restricted homeostasis remains poorly understood. Here, working in mouse models of inflammation, we found that mTOR-dependent metabolic adaptation was required at discrete locations. mTOR was dispensable for DC homeostasis in secondary lymphoid tissues but necessary to regulate cellular metabolism and accumulation of CD103(+) DCs and alveolar macrophages in lung. Moreover, while numbers of mTOR-deficient lung CD11b(+) DCs were not changed, they were metabolically reprogrammed to skew allergic inflammation from eosinophilic Th2 to neutrophilic Th17 polarity. The mechanism for this change was independent of translational control but dependent on inflammatory DC, which produced IL-23 and increased fatty acid oxidation. mTOR therefore mediates metabolic adaptation of APCs in distinct tissues, influencing the immunological character of allergic inflammation.

PMID: 28798047 [PubMed - as supplied by publisher]

Blockade of Stearoyl-CoA-Desaturase 1 activity reverts resistance to Cisplatin in lung cancer stem cells.

Sat, 08/12/2017 - 12:45
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Blockade of Stearoyl-CoA-Desaturase 1 activity reverts resistance to Cisplatin in lung cancer stem cells.

Cancer Lett. 2017 Aug 07;:

Authors: Pisanu ME, Noto A, De Vitis C, Morrone S, Scognamiglio G, Botti G, Venuta F, Diso D, Jakopin Z, Fabrizio P, Ricci A, Mariotta S, Giovagnoli MR, Giarnieri E, Amelio I, Agostini M, Melino G, Ciliberto G, Mancini R

Abstract
Poor prognosis in lung cancer has been attributed to the presence of lung cancer stem cells (CSCs) which resist chemotherapy and cause disease recurrence. Hence, the strong need to identify mechanisms of chemoresistance and to develop new combination therapies. We have previously shown that Stearoyl-CoA-desaturase 1 (SCD1), the enzyme responsible for the conversion of saturated to monounsaturated fatty acids is upregulated in 3D lung cancer spheroids and is an upstream activator of key proliferation pathways β-catenin and YAP/TAZ. Here we first show that SCD1 expression, either alone or in combination with a variety of CSCs markers, correlates with poor prognosis in adenocarcinoma (ADC) of the lung. Treatment of lung ADC cell cultures with cisplatin enhances the formation of larger 3D tumor spheroids and upregulates CSCs markers. In contrast, co-treatment with cisplatin and the SCD1 inhibitor MF-438 reverts upregulation of CSCs markers, strongly synergizes in the inhibition of 3D spheroid formation and induces CSCs apoptosis. Mechanistically, SCD1 inhibition activates endoplasmic reticulum stress response and enhances autophagy. These data all together support the use of combination therapy with SCD1 inhibitors to achieve better control of lung cancer.

PMID: 28797843 [PubMed - as supplied by publisher]

Predictors for Permanent Discontinuation of Systemic Immunosuppression in Severely Affected Chronic Graft-Versus-Host Disease Patients.

Sat, 08/12/2017 - 12:45
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Predictors for Permanent Discontinuation of Systemic Immunosuppression in Severely Affected Chronic Graft-Versus-Host Disease Patients.

Biol Blood Marrow Transplant. 2017 Aug 07;:

Authors: Curtis LM, Pirsl F, Steinberg SM, Mitchell SA, Baird K, Cowen EW, Mays J, Buxbaum NP, Pichard DC, Im A, Avila D, Taylor T, Fowler DH, Gress RE, Pavletic SZ

Abstract
Predicting the duration of systemic therapy in patients with chronic graft-versus-host disease (cGVHD) is of critical clinical importance when counseling patients and for treatment planning. CGVHD characteristics associated with this outcome have not been studied in severely affected patients. The National Institutes of Health (NIH) cGVHD scoring provides a standardized set of organ severity measures which could represent clinically useful and reproducible predictive characteristics. We analyzed 227 previously treated patients most with moderate (n=54) or severe (n=170) cGVHD defined by NIH criteria who were prospectively enrolled in a natural history protocol (NCT00092235). Patients received a median of 4 prior systemic therapy regimens and were seen at the NIH for a single time-point visit, then monitored for survival and ability to discontinue cGVHD systemic therapy. With a median follow-up of 71.1 months, the cumulative incidence of systemic therapy discontinuation was 9.5% (95%CI: 6.0-13.9%) at 2 years and 27.7% (95% CI: 20.9-34.8%) by 5 years after the initial visit. Factors which were associated with a higher incidence of immunosuppression discontinuation included lower NIH global severity (p =0.019) and lung (p =0.030) scores, and less extensive deep sclerosis (<37% BSA, p=0.024). Lower patient- and clinician-reported 0-10 severity NIH scores and non-cyclosporine prophylaxis regimens were also associated with higher incidence of immunosuppression discontinuation (p<0.05). In conclusion, we found low success rates for immune suppression discontinuation in previously treated patients who are severely affected with cGVHD. NIH scoring and clinical measures provide new standardized disease specific tools to predict discontinuation of systemic therapy.

PMID: 28797782 [PubMed - as supplied by publisher]

Effect of left ventricular dysfunction on utilization of donor hearts.

Sat, 08/12/2017 - 12:45
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Effect of left ventricular dysfunction on utilization of donor hearts.

J Heart Lung Transplant. 2017 Jul 19;:

Authors: Tryon D, Hasaniya NW, Jabo B, Razzouk AJ, Bailey LL, Rabkin DG

Abstract
BACKGROUND: In this study we investigated modern, non-utilization rates of potential cardiac donors with left ventricular dysfunction (LVD) to clarify this phenomenon's magnitude and the impact of recent studies suggesting these organs can be safely transplanted.
METHODS: Using the United Network for Organ Sharing transplant database, we reviewed all donors evaluated between January 1, 2007 and June 30, 2014. Exclusion criteria included lack of consent and age <13 or >59 years. The number of hearts not transplanted due to non-cardiac causes, structural disease, "other" (previous cardiac surgery, donation after cardiac death, etc.) and isolated LVD was determined and a covariates-adjusted Poisson regression model with robust standard errors was developed to estimate non-utilization relative risk (RR) with 95% confidence interval (CI) for LVD. Heart disposition for potential donor hearts was determined separately for 2 previous eras (1990 to 1999 and 2000 to 2006), and trends were evaluated.
RESULTS: There were 60,789 donors assessed. Of the 44,829 organs meeting the inclusion criteria, 15,654 (34.92%) were transplanted and 29,175 (65.08%) were not. Of the non-utilized hearts, 15,512 (34.60%) were declined for non-cardiac reasons, 1,051 (2.34%) for structural disease, 4,073 (9.09%) for "other" and 8,539 (19.05%) exclusively for LVD. Of this last category, 4,950 (11.04%) lacked documented evidence of LVD. Covariates-adjusted RR for non-utilization showed that, for every 10% increase in LV ejection fraction, the risk of non-utilization decreased by 20% (RR = 0.80, 95% CI 0.79 to 0.81). Analysis of era-effect demonstrated significantly decreased overall utilization of donor hearts, with increases in the number of hearts not transplanted across all categories over time (p < 0.001).
CONCLUSIONS: Roughly 20% of potential cardiac donors are excluded due to LVD. This figure has not been impacted by recent studies indicating that these hearts may be used safely. More complete data are required to understand why 11.04% of hearts that met inclusion criteria were refused for "poor function" without documented evidence.

PMID: 28797760 [PubMed - as supplied by publisher]

Atrial arrhythmias after lung transplantation.

Sat, 08/12/2017 - 12:45
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Atrial arrhythmias after lung transplantation.

Trends Cardiovasc Med. 2017 Aug 01;:

Authors: Roukoz H, Benditt DG

Abstract
Atrial arrhythmias are a common complication after lung transplant (LT), occurring in about 16-46% of LT patients early postoperatively, and in about 14% during longer-term follow-up. They have a significant impact on postoperative in-hospital length of stay and may have an impact on overall mortality. In this report, we review the incidence and risk factors of post lung transplant AA, their pathogenesis and their impact on short- and long-term outcomes. Pharmacological management options are reviewed. In brief, early atrial arrhythmias tend to be mostly atrial fibrillation and are treated acutely with a rate control strategy followed if needed by rhythm control for 4-6 weeks. Late atrial arrhythmias >6 months after LT tend to be more frequently organized atrial flutters amenable to ablation therapy. Long-term anticoagulation is controversial especially in patients with bilateral lung transplant who received surgical pulmonic vein isolation, however anticoagulation is still favored especially in single LT patients. More studies are needed to further document the pathophysiology of early versus late atrial arrhythmias and whether long-term anticoagulation is needed.

PMID: 28797718 [PubMed - as supplied by publisher]

Fungal Infections After Lung Transplantation.

Sat, 08/12/2017 - 12:45
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Fungal Infections After Lung Transplantation.

Clin Chest Med. 2017 Sep;38(3):511-520

Authors: Kennedy CC, Razonable RR

Abstract
Infection remains a significant source of morbidity and mortality after lung transplant, including fungal infection. Various antifungal prophylactic agents are administered for a variable duration after transplant with the goal of preventing invasive fungal infections. Alternatively, some programs target the use of antifungal agents only in those colonized with Aspergillus spp. Despite prophylaxis or preemptive therapy, a significant number of invasive fungal infections occur after lung transplant. Risk factors for fungal infections include single lung transplant, pretransplant Aspergillus colonization, environmental risks, structural lung disease such as cystic fibrosis, augmented immunosuppression, sinus disease, and use of indwelling airway stents.

PMID: 28797492 [PubMed - in process]

A 58-Year-Old Man With Position-Dependent Nocturnal Dyspnea.

Sat, 08/12/2017 - 12:45
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A 58-Year-Old Man With Position-Dependent Nocturnal Dyspnea.

Chest. 2017 Aug;152(2):e51-e55

Authors: Schertel A, Horvath CM, Pichler Hefti J, Aubert JD, Brill AK

Abstract
CASE PRESENTATION: A 58-year-old man with idiopathic pulmonary fibrosis, who had received a right-sided single-lung transplant 2 years earlier, was referred to the sleep clinic for the assessment of nocturnal position-dependent episodes of dyspnea and frequent arousals when lying on his right side. There was no subjective worsening of daytime respiratory symptoms, but he complained of fatigue and unrefreshing sleep. His Epworth Sleepiness Scale score was 12/24. After lung transplantation he had a favorable course while receiving immunosuppression with prednisolone, everolimus, and mycophenolate mofetil. In addition, he had received diagnoses of stable coronary artery disease and moderate chronic kidney failure.

PMID: 28797401 [PubMed - in process]

STAT6 Regulates the Development of Eosinophilic versus Neutrophilic Asthma in Response to Alternaria alternata.

Sat, 08/12/2017 - 12:45
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STAT6 Regulates the Development of Eosinophilic versus Neutrophilic Asthma in Response to Alternaria alternata.

J Immunol. 2016 Dec 15;197(12):4541-4551

Authors: Valladao AC, Frevert CW, Koch LK, Campbell DJ, Ziegler SF

Abstract
Human asthma is a heterogeneous disease characterized by the expression of both Th2 and Th17 cytokines. In vitro and in vivo studies have shown a reciprocal regulation between Th2 and Th17 pathways, suggesting a potential induction of neutrophil-promoting Th17 inflammation in the absence of a Th2 response. Alternaria alternata is a clinically relevant allergen that is associated with severe and fatal asthma exacerbations. Exposure to A. alternata is characterized by a predominant Th2 response, but can also induce the production of factors associated with Th17 responses (e.g., CXCL8) from epithelial cells. Using a mouse model, we found that wild-type mice develop an eosinophilic Th2 airway disease in response to A. alternata exposure, whereas IL-4-, IL-13-, and STAT6-deficient mice exhibit a primarily neutrophilic response. Neutrophilic asthma in STAT6(-/-) mice was accompanied by elevated lung levels of TNF-α, CXCL1, CXCL2, and CXCL5, and was steroid resistant. Neutralization of Th17 signaling only partially reduced neutrophil numbers and total airway inflammation. Airway neutrophilia developed in RAG-deficient and CD4-depleted BALB/c mice, suggesting that the suppression of neutrophil responses is dependent on Th2 cytokine production by T cells and that airway neutrophilia is primarily an innate response to allergen. These results highlight the importance of combination therapies for treatment of asthma and establish a role for factors other than IL-17 as targets for neutrophilic asthma.

PMID: 27815425 [PubMed - indexed for MEDLINE]

The epidemiology of medically attended respiratory syncytial virus in older adults in the United States: A systematic review.

Fri, 08/11/2017 - 12:45
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The epidemiology of medically attended respiratory syncytial virus in older adults in the United States: A systematic review.

PLoS One. 2017;12(8):e0182321

Authors: Colosia AD, Yang J, Hillson E, Mauskopf J, Copley-Merriman C, Shinde V, Stoddard J

Abstract
OBJECTIVE: This review was undertaken to assess the historical evidence of the disease incidence and burden of laboratory-confirmed respiratory syncytial virus (RSV) in medically attended older adults.
DESIGN: A qualitative systematic literature review was performed; no statistical synthesis of the data was planned, in anticipation of expected heterogeneity across studies in this population.
METHODS: A literature search of PubMed, Embase, and the Cochrane Library was conducted for studies of medically attended RSV in older adults (≥ 50 years) published in the last 15 years. Two independent reviewers screened titles and abstracts based on predefined inclusion and exclusion criteria.
RESULTS: From 10 studies reporting incidence proportions, RSV may be the causative agent in up to 12% of medically attended acute respiratory illness in older adults unselected for comorbidities, with variations in clinical setting and by year. In multiple studies, medically attended-RSV incidence among older adults not selected for having underlying health conditions increased with increasing age. Of prospectively followed lung transplant recipients, 16% tested positive for RSV. In hospitalized adults with chronic cardiopulmonary diseases, 8% to 13% were infected with RSV during winter seasons (8%-13%) or metapneumovirus season (8%). Hospitalizations for RSV in older adults typically lasted 3 to 6 days, with substantial proportions requiring intensive care unit admission and mechanical ventilation. Among older adults hospitalized with RSV, the mortality rate was 6% to 8%.
CONCLUSIONS: Protection of older adults against RSV could reduce respiratory-related burden, especially as age increases and the prevalence of comorbidities (especially cardiopulmonary comorbidities) grows.

PMID: 28797053 [PubMed - in process]

Successful salvage chemotherapy and allogeneic transplantation of an acute myeloid leukemia patient with disseminated Fusarium solani infection.

Fri, 08/11/2017 - 12:45
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Successful salvage chemotherapy and allogeneic transplantation of an acute myeloid leukemia patient with disseminated Fusarium solani infection.

Leuk Res Rep. 2017;8:4-6

Authors: Sheela S, Ito S, Strich JR, Manion M, Montemayor-Garcia C, Wang HW, Oetjen KA, West KA, Barrett AJ, Parta M, Gea-Banacloche J, Holland SM, Hourigan CS, Lai C

Abstract
Disseminated Fusarium infection is associated with high mortality in immunocompromised patients. Patients with acute myeloid leukemia (AML) often have an extended duration of neutropenia during intensive induction chemotherapy, consolidation chemotherapy, and hematopoietic stem cell transplantation (SCT). There is no consensus regarding management of invasive disseminated Fusarium infections in the setting of prolonged neutropenia (Tortorano et al., 2014) [1]. We report a case of disseminated Fusarium in a patient with relapsed AML who underwent successful chemotherapy and haplo-identical allogeneic SCT with administration of granulocyte colony stimulating factor (G-CSF) and granulocyte infusions.

PMID: 28794968 [PubMed]

Perception of symptoms and quality of life - comparison of patients' and physicians' views in the COPD MIRROR study.

Fri, 08/11/2017 - 12:45
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Perception of symptoms and quality of life - comparison of patients' and physicians' views in the COPD MIRROR study.

Int J Chron Obstruct Pulmon Dis. 2017;12:2189-2196

Authors: Celli B, Blasi F, Gaga M, Singh D, Vogelmeier C, Pegoraro V, Caputo N, Agusti A

Abstract
OBJECTIVES: The aim of this study was to compare potential differences between the perception that COPD patients have of their disease and the perception that physicians have of how the disease affects their patients.
METHODS: Surveys in COPD patients and physicians caring for COPD patients were conducted in Spain, Italy, and Germany. Online questionnaires mirrored to explore the same domains, were administered to patients and physicians. Physicians were asked to respond to the questionnaire taking a recently seen patient who represents the majority of COPD patients usually managed, as a reference. Patients with COPD completed a survey containing the same questions offered to the physicians (Medical Investigation of Respiratory COPD Perception [MIRROR] survey). Comparisons between the responses of patients and general practitioners (GPs) and between patients and pulmonologists (PULs) were run separately using the chi-square, Fisher's exact, or Student's t-tests.
RESULTS: A total of 334 COPD patients, 333 GPs, and 333 PULs participated in the surveys. The typical perception that PULs have of the COPD patient was that of an older man with more severe disease and less likely to be a smoker, than the included COPD patients. COPD was regarded as a major health problem by patients and physicians, but its impact on overall quality of life among more severe patients was less strongly perceived by physicians than by patients. Instead, physicians paid more attention to domains related to clinical features (cough, phlegm, and dyspnea), while underestimating COPD impact on leisure and social activities. The majority of patients stated not being completely frank with their doctors during visits. Both GPs and PULs seemed to recognize this issue but underestimated its extent.
CONCLUSION: To improve the doctor-patient communication, a more frank reporting by the patients of their symptoms and feelings and an increased awareness of physicians about the impact on nonconventional domains that patients perceive as importantly affected by COPD should be encouraged.

PMID: 28794623 [PubMed - in process]

Supplemental oxygen and dypsnoea in interstitial lung disease: absence of evidence is not evidence of absence.

Fri, 08/11/2017 - 12:45
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Supplemental oxygen and dypsnoea in interstitial lung disease: absence of evidence is not evidence of absence.

Eur Respir Rev. 2017 Sep 30;26(145):

Authors: Bell EC, Cox NS, Goh N, Glaspole I, Westall GP, Watson A, Holland AE

PMID: 28794146 [PubMed - in process]

Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress tumor growth.

Fri, 08/11/2017 - 12:45
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Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress tumor growth.

Blood. 2017 Aug 03;130(5):567-580

Authors: Michael JV, Wurtzel JGT, Mao GF, Rao AK, Kolpakov MA, Sabri A, Hoffman NE, Rajan S, Tomar D, Madesh M, Nieman MT, Yu J, Edelstein LC, Rowley JW, Weyrich AS, Goldfinger LE

Abstract
Platelet-derived microparticles (PMPs) are associated with enhancement of metastasis and poor cancer outcomes. Circulating PMPs transfer platelet microRNAs (miRNAs) to vascular cells. Solid tumor vasculature is highly permeable, allowing the possibility of PMP-tumor cell interaction. Here, we show that PMPs infiltrate solid tumors in humans and mice and transfer platelet-derived RNA, including miRNAs, to tumor cells in vivo and in vitro, resulting in tumor cell apoptosis. MiR-24 was a major species in this transfer. PMP transfusion inhibited growth of both lung and colon carcinoma ectopic tumors, whereas blockade of miR-24 in tumor cells accelerated tumor growth in vivo, and prevented tumor growth inhibition by PMPs. Conversely, Par4-deleted mice, which had reduced circulating microparticles (MPs), supported accelerated tumor growth which was halted by PMP transfusion. PMP targeting was associated with tumor cell apoptosis in vivo. We identified direct RNA targets of platelet-derived miR-24 in tumor cells, which included mitochondrial mt-Nd2, and Snora75, a noncoding small nucleolar RNA. These RNAs were suppressed in PMP-treated tumor cells, resulting in mitochondrial dysfunction and growth inhibition, in an miR-24-dependent manner. Thus, platelet-derived miRNAs transfer in vivo to tumor cells in solid tumors via infiltrating MPs, regulate tumor cell gene expression, and modulate tumor progression. These findings provide novel insight into mechanisms of horizontal RNA transfer and add multiple layers to the regulatory roles of miRNAs and PMPs in tumor progression. Plasma MP-mediated transfer of regulatory RNAs and modulation of gene expression may be a common feature with important outcomes in contexts of enhanced vascular permeability.

PMID: 28500171 [PubMed - indexed for MEDLINE]

Pericardial Conduit for Pulmonary Artery Reconstruction by Surgical Stapling.

Fri, 08/11/2017 - 12:45
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Pericardial Conduit for Pulmonary Artery Reconstruction by Surgical Stapling.

Ann Thorac Surg. 2017 May;103(5):e469-e471

Authors: Matsutani N, Kanai E, Hanawa R, Takahashi Y, Uehara H, Iinuma H, Kawamura M

Abstract
Pulmonary artery reconstruction in lung cancer surgery is an effective surgical method to avoid pneumonectomy that leads to longer survival times with few adverse effects. The pericardium is often used for the interposition of a prosthetic conduit. A pericardial conduit can be easily and precisely constructed by surgical stapling, which facilitates pulmonary artery reconstruction. In this report, the process and pitfalls of surgical stapling are described.

PMID: 28431731 [PubMed - indexed for MEDLINE]

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression.

Fri, 08/11/2017 - 12:45
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Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression.

Antioxid Redox Signal. 2017 Apr 10;26(11):563-582

Authors: Klein D, Steens J, Wiesemann A, Schulz F, Kaschani F, Röck K, Yamaguchi M, Wirsdörfer F, Kaiser M, Fischer JW, Stuschke M, Jendrossek V

Abstract
AIMS: Radiation-induced normal tissue toxicity is closely linked to endothelial cell (EC) damage and dysfunction (acute effects). However, the underlying mechanisms of radiation-induced adverse late effects with respect to the vascular compartment remain elusive, and no causative radioprotective treatment is available to date.
RESULTS: The importance of injury to EC for radiation-induced late toxicity in lungs after whole thorax irradiation (WTI) was investigated using a mouse model of radiation-induced pneumopathy. We show that WTI induces EC loss as long-term complication, which is accompanied by the development of fibrosis. Adoptive transfer of mesenchymal stem cells (MSCs) either derived from bone marrow or aorta (vascular wall-resident MSCs) in the early phase after irradiation limited the radiation-induced EC loss and fibrosis progression. Furthermore, MSC-derived culture supernatants rescued the radiation-induced reduction in viability and long-term survival of cultured lung EC. We further identified the antioxidant enzyme superoxide dismutase 1 (SOD1) as a MSC-secreted factor. Importantly, MSC treatment restored the radiation-induced reduction of SOD1 levels after WTI. A similar protective effect was achieved by using the SOD-mimetic EUK134, suggesting that MSC-derived SOD1 is involved in the protective action of MSC, presumably through paracrine signaling.
INNOVATION: In this study, we explored the therapeutic potential of MSC therapy to prevent radiation-induced EC loss (late effect) and identified the protective mechanisms of MSC action.
CONCLUSIONS: Adoptive transfer of MSCs early after irradiation counteracts radiation-induced vascular damage and EC loss as late adverse effects. The high activity of vascular wall-derived MSCs for radioprotection may be due to their tissue-specific action. Antioxid. Redox Signal. 26, 563-582.

PMID: 27572073 [PubMed - indexed for MEDLINE]

Controlled donation after circulatory death in the Netherlands: more organs, more efforts.

Fri, 08/11/2017 - 12:45
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Controlled donation after circulatory death in the Netherlands: more organs, more efforts.

Neth J Med. 2016 Aug;74(7):285-91

Authors: Leiden H, Haase-Kromwijk B, Hoitsma A, Jansen N

Abstract
BACKGROUND: The Netherlands was one of the first countries in Europe to stimulate controlled donation after circulatory death (cDCD) at a national level in addition to donation after brain death (DBD). With this program the number of organ transplants increased, but it also proved to have challenges as will be shown in this 15-year review.
METHODS: Data about deceased organ donation in the Netherlands, from 2000 until 2014, were analysed taking into account the whole donation process from donor referral to the number of organs transplanted.
RESULTS: Donor referral increased by 58%, from 213 to 336 donors per year, and the number of organs transplanted rose by 42%. Meanwhile the contribution of cDCD donors increased from 14% in 2000 to 54% in 2014 among all referrals. The organs were transplanted from 92-99% of referred DBD donors, but this percentage was significantly lower for cDCD donors and also decreased from 86% in 2000-2002 to 67% in 2012-2014. In 16% of all referred cDCD donors, organs were not recovered because donors did not die within the expected two-hour time limit after withdrawal of life- upporting treatment. Furthermore, cDCD is more often performed at a higher donor age, which is associated with a lower percentage of transplanted organs.
CONCLUSION: Although cDCD resulted in more transplants, the effort in donor recruitment is considerably higher. Important challenges in cDCD that need further attention are the time limit after withdrawal of life-supporting treatment and donor age, as well as the possibilities to stimulate non-renal transplants including the heart by machine preservation.

PMID: 27571943 [PubMed - indexed for MEDLINE]

Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT).

Thu, 08/10/2017 - 12:45
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Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT).

Front Immunol. 2017;8:807

Authors: Deripapa E, Balashov D, Rodina Y, Laberko A, Myakova N, Davydova NV, Gordukova MA, Abramov DS, Pay GV, Shelikhova L, Prodeus AP, Maschan MA, Maschan AA, Shcherbina A

Abstract
BACKGROUND: Nijmegen breakage syndrome (NBS) is a combined primary immunodeficiency with DNA repair defect, microcephaly, and other phenotypical features. It predominantly occurs in Slavic populations that have a high frequency of carriers with the causative NBN gene c.657_661del5 mutation. Due to the rarity of the disease in the rest of the world, studies of NBS patients are few. Here, we report a prospective study of a cohort of Russian NBS patients.
METHODS: 35 Russian NBS patients of ages 1-19 years, referred to our Center between years 2012 and 2016, were prospectively studied.
RESULTS: Despite the fact that in 80% of the patients microcephaly was diagnosed at birth or shortly thereafter, the average delay of NBS diagnosis was 6.5 years. Though 80% of the patients had laboratory signs of immunodeficiency, only 51% of the patients experienced significant infections. Autoimmune complications including interstitial lymphocytic lung disease and skin granulomas were noted in 34%, malignancies-in 57% of the patients. T-cell excision circle (TREC)/kappa-deleting recombination excision circle (KREC) levels were low in the majority of patients studied. Lower KREC levels correlated with autoimmune and oncological complications. Fifteen patients underwent hematopoietic stem cell transplantation (HSCT), 10 of them were alive and well, with good graft function. Three patients in the HSCT group and five non-transplanted patients died; tumor progression being the main cause of death. The probability of the overall survival since NBS diagnosis was 0.76 in the HSCT group and 0.3 in the non-transplanted group.
CONCLUSION: Based on our findings of low TRECs in most NBS patients, independent of their age, TREC detection can be potentially useful for detection of NBS patients during neonatal screening. KREC concentration can be used as a prognostic marker of disease severity. HSCT is a viable treatment option in NBS and should be especially considered in patients with low KREC numbers early on, before development of life-threatening complications.

PMID: 28791007 [PubMed]

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