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Growth rates of pulmonary metastases after liver transplantation for unresectable colorectal liver metastases.

Fri, 11/24/2017 - 13:45

Growth rates of pulmonary metastases after liver transplantation for unresectable colorectal liver metastases.

Br J Surg. 2017 Nov 23;:

Authors: Grut H, Solberg S, Seierstad T, Revheim ME, Egge TS, Larsen SG, Line PD, Dueland S

Abstract
BACKGROUND: The previously reported SECA study demonstrated a dramatic 5-year survival improvement in patients with unresectable colorectal liver metastases (CLM) treated with liver transplantation (LT) compared with chemotherapy. The objective of this study was to assess whether immunosuppressive therapy accelerates the growth of pulmonary metastases in patients transplanted for unresectable CLM.
METHODS: Chest CT scans from 11 patients in the SECA study resected for 18 pulmonary metastases were reviewed retrospectively. Tumour diameter, volume and CT characteristics were registered and tumour volume doubling time was calculated. Findings in the SECA group were compared with those of a control group consisting of 12 patients with non-transplanted rectal cancer resected for 26 pulmonary metastases. Disease-free survival (DFS) and overall survival (OS) after first pulmonary resection were determined.
RESULTS: Median doubling time based on tumour diameter and volume in the SECA and control groups were 125 and 130 days (P = 0·658) and 110 and 129 days (P = 0·632) respectively. The metastases in both groups were distributed to all lung lobes and were mostly peripheral. Median DFS after LT in the SECA group and after primary pelvic surgery in the control group was 17 (range 6-42) and 18 (2-57) months respectively (P = 0·532). In the SECA group, estimated 5-year DFS and OS rates after first pulmonary resection were 39 and 51 per cent respectively.
CONCLUSION: Patients treated by LT for unresectable CLM have a good prognosis following resection of pulmonary metastases. Doubling time did not appear to be worse with the immunosuppression used after LT.

PMID: 29168565 [PubMed - as supplied by publisher]

Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.

Fri, 11/24/2017 - 13:45

Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.

Circulation. 2017 Nov 22;:

Authors: da Silva Gonçalves Bos D, Van Der Bruggen CE, Kurakula K, Sun XQ, Casali KR, Casali AG, Rol N, Szulcek R, Dos Remedios C, Guignabert C, Tu L, Dorfmuller P, Humbert M, Wijnker PJM, Kuster DWD, van der Velden J, Goumans MJ, Bogaard HJ, Vonk-Noordegraaf A, de Man FS, Handoko ML

Abstract
Background -Beneficial effects of parasympathetic stimulation have been reported in left heart failure, however, whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in PAH-patients, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase (AchE) inhibition, in experimental pulmonary hypertension (PH). Methods -Heart rate recovery (HRR) after maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction (RVEF) was assessed in 112 PAH-patients. Expression of nicotinic (α-7nAchR) and muscarinic (m2AchR) receptors, and AchE activity were evaluated in RV (n=11) and lungs (n=7) from PAH-patients undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg/day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg; s.c.) injection followed by 4 weeks of hypoxia. In a subgroup sympathetic/parasympathetic modulation was assessed by power spectral analysis. At week 6, PH status was confirmed by echocardiography, and rats were randomized to vehicle or treatment (both n=12). At the end-of-study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological and protein analyses. Results -PAH-patients with lower RVEF (<41%) had a significantly reduced HRR in comparison to patients with higher RVEF. In PAH RV-samples, α-7nAchR was increased and AchE activity was reduced versus controls. No difference in m2AchR expression was observed. Chronic PYR-treatment in PH-rats normalized the cardiovascular autonomic function, demonstrated by an increase in parasympathetic activity and baroreflex sensitivity. PYR improved survival, increased RV contractility, and reduced RV stiffness, RV hypertrophy, RV fibrosis, RV inflammation, as well as RV α-7nAchR and m2AchR expression. Furthermore, PYR reduced pulmonary vascular resistance, RV afterload and pulmonary vascular remodeling, which was associated with reduced local and systemic inflammation. Conclusions -RV dysfunction is associated with reduced systemic parasympathetic activity in PAH-patients, with an inadequate adaptive response of the cholinergic system in the right ventricle. Enhancing parasympathetic activity by PYR improved survival, RV function and pulmonary vascular remodeling in experimental-PH.

PMID: 29167228 [PubMed - as supplied by publisher]

Airway transplantation of adipose stem cells protects against bleomycin-induced pulmonary fibrosis.

Fri, 11/24/2017 - 13:45

Airway transplantation of adipose stem cells protects against bleomycin-induced pulmonary fibrosis.

J Investig Med. 2017 Nov 21;:

Authors: Llontop P, Lopez-Fernandez D, Clavo B, Afonso Martín JL, Fiuza-Pérez MD, García Arranz M, Calatayud J, Molins López-Rodó L, Alshehri K, Ayub A, Raad W, Bhora F, Santana-Rodríguez N

Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis. Adipose-derived stem cells (ADSC) have demonstrated regenerative properties in several tissues. The hypothesis of this study was that airway transplantation of ADSC could protect against bleomycin (BLM)-induced pulmonary fibrosis (PF). Fifty-eight lungs from 29 male Sprague-Dawley rats were analyzed. Animals were randomly divided into five groups: a) control (n=3); b) sham (n=6); c) BLM (n=6); d) BLM+ADSC-2d (n=6); and e) BLM+ADSC-14d (n=8). Animals received 500 µL saline (sham), 2.5 UI/kg BLM in 500 µL saline (BLM), and 2×10(6) ADSC in 100 µL saline intratracheally at 2 (BLM+ADSC-2d) and 14 days (BLM+ADSC-14d) after BLM. Animals were sacrificed at 28 days. Blinded Ashcroft score was used to determine pulmonary fibrosis extent on histology. Hsp27, Vegf, Nfkβ, IL-1, IL-6, Col4, and Tgfβ1 mRNA gene expression were determined using real-time quantitative-PCR. Ashcroft index was: control=0; sham=0.37±0.07; BLM=6.55±0.34 vs sham (P=0.006). BLM vs BLM+ADSC-2d=4.63±0.38 (P=0.005) and BLM+ADSC-14d=3.77±0.46 (P=0.005). BLM vs sham significantly increased Hsp27 (P=0.018), Nfkβ (P=0.009), Col4 (P=0.004), Tgfβ1 (P=0.006) and decreased IL-1 (P=0.006). BLM+ADSC-2d vs BLM significantly decreased Hsp27 (P=0.009) and increased Vegf (P=0.006), Nfkβ (P=0.009). BLM+ADSC-14d vs BLM significantly decreased Hsp27 (P=0.028), IL-6 (P=0.013), Col4 (P=0.002), and increased Nfkβ (P=0.040) and Tgfβ1 (P=0.002). Airway transplantation of ADSC significantly decreased the fibrosis rate in both early and established pulmonary fibrosis, modulating the expression of Hsp27, Vegfa, Nfkβ, IL-6, Col4, and Tgfβ1. From a translational perspective, this technique could become a new adjuvant treatment for patients with IPF.

PMID: 29167193 [PubMed - as supplied by publisher]

Neurological complications of solid organ transplantation.

Thu, 11/23/2017 - 13:45

Neurological complications of solid organ transplantation.

Arq Neuropsiquiatr. 2017 Oct;75(10):736-747

Authors: Pedroso JL, Dutra LA, Braga-Neto P, Abrahao A, Andrade JBC, Silva GLD, Viana LA, Pestana JOM, Barsottini OG

Abstract
Solid organ transplantation is a significant development in the treatment of chronic kidney, liver, heart and lung diseases. This therapeutic approach has increased patient survival and improved quality of life. New surgical techniques and immunosuppressive drugs have been developed to achieve better outcomes. However, the variety of neurological complications following solid organ transplantation is broad and carries prognostic significance. Patients may have involvement of the central or peripheral nervous system due to multiple causes that can vary depending on time of onset after the surgical procedure, the transplanted organ, and the intensity and type of immunosuppressive therapy. Neurological manifestations following solid organ transplantation pose a diagnostic challenge to medical specialists despite extensive investigation. This review aimed to provide a practical approach to help neurologists and clinicians assess and manage solid organ transplant patients presenting with acute or chronic neurological manifestations.

PMID: 29166466 [PubMed - in process]

Intensive care unit patients with lower respiratory tract nosocomial infections: the ENIRRIs project.

Thu, 11/23/2017 - 13:45

Intensive care unit patients with lower respiratory tract nosocomial infections: the ENIRRIs project.

ERJ Open Res. 2017 Oct;3(4):

Authors: De Pascale G, Ranzani OT, Nseir S, Chastre J, Welte T, Antonelli M, Navalesi P, Garofalo E, Bruni A, Coelho LM, Skoczynski S, Longhini F, Taccone FS, Grimaldi D, Salzer HJF, Lange C, Froes F, Artigas A, Díaz E, Vallés J, Rodríguez A, Panigada M, Comellini V, Fasano L, Soave PM, Spinazzola G, Luyt CE, Alvarez-Lerma F, Marin J, Masclans JR, Chiumello D, Pezzi A, Schultz M, Mohamed H, Van Der Eerden M, Hoek RAS, Gommers DAMPJ, Pasquale MD, Civljak R, Kutleša M, Bassetti M, Dimopoulos G, Nava S, Rios F, Zampieri FG, Povoa P, Bos LD, Aliberti S, Torres A, Martín-Loeches I

Abstract
The clinical course of intensive care unit (ICU) patients may be complicated by a large spectrum of lower respiratory tract infections (LRTI), defined by specific epidemiological, clinical and microbiological aspects. A European network for ICU-related respiratory infections (ENIRRIs), supported by the European Respiratory Society, has been recently established, with the aim at studying all respiratory tract infective episodes except community-acquired ones. A multicentre, observational study is in progress, enrolling more than 1000 patients fulfilling the clinical, biochemical and radiological findings consistent with a LRTI. This article describes the methodology of this study. A specific interest is the clinical impact of non-ICU-acquired nosocomial pneumonia requiring ICU admission, non-ventilator-associated LRTIs occurring in the ICU, and ventilator-associated tracheobronchitis. The clinical meaning of microbiologically negative infectious episodes and specific details on antibiotic administration modalities, dosages and duration are also highlighted. Recently released guidelines address many unresolved questions which might be answered by such large-scale observational investigations. In light of the paucity of data regarding such topics, new interesting information is expected to be obtained from our network research activities, contributing to optimisation of care for critically ill patients in the ICU.

PMID: 29164144 [PubMed]

Potential Role of Exosomes in Mending a Broken Heart: Nanoshuttles Propelling Future Clinical Therapeutics Forward.

Thu, 11/23/2017 - 13:45

Potential Role of Exosomes in Mending a Broken Heart: Nanoshuttles Propelling Future Clinical Therapeutics Forward.

Stem Cells Int. 2017;2017:5785436

Authors: Dougherty JA, Mergaye M, Kumar N, Chen CA, Angelos MG, Khan M

Abstract
Stem cell transplantation therapy is a promising adjunct for regenerating damaged heart tissue; however, only modest improvements in cardiac function have been observed due to poor survival of transplanted cells in the ischemic heart. Therefore, there remains an unmet need for therapies that can aid in attenuating cardiac damage. Recent studies have demonstrated that exosomes released by stem cells could serve as a potential cell-free therapeutic for cardiac repair. These exosomes/nanoshuttles, once thought to be merely a method of waste disposal, have been shown to play a crucial role in physiological functions including short- and long-distance intercellular communication. In this review, we have summarized studies demonstrating the potential role of exosomes in improving cardiac function, attenuating cardiac fibrosis, stimulating angiogenesis, and modulating miRNA expression. Furthermore, exosomes carry an important cargo of miRNAs and proteins that could play an important role as a diagnostic marker for cardiovascular disease post-myocardial infarction. Although there is promising evidence from preclinical studies that exosomes released by stem cells could serve as a potential cell-free therapeutic for myocardial repair, there are several challenges that need to be addressed before exosomes could be fully utilized as off-the-shelf therapeutics for cardiac repair.

PMID: 29163642 [PubMed]

Cytokine Profiles of Severe Influenza Virus-Related Complications in Children.

Thu, 11/23/2017 - 13:45

Cytokine Profiles of Severe Influenza Virus-Related Complications in Children.

Front Immunol. 2017;8:1423

Authors: Fiore-Gartland A, Panoskaltsis-Mortari A, Agan AA, Mistry AJ, Thomas PG, Matthay MA, PALISI PICFlu Investigators, Hertz T, Randolph AG

Abstract
Rationale: Effective immunomodulatory therapies for children with life-threatening "cytokine storm" triggered by acute influenza infection are lacking. Understanding the immune profiles of children progressing to severe lung injury and/or septic shock could provide insight into pathogenesis.
Objectives: To compare the endotracheal and serum cytokine profiles of children with influenza-related critical illness and to identify their associations with severe influenza-associated complications.
Methods: Children with influenza-related critical illness were enrolled across 32 hospitals in development (N = 171) and validation (N = 73) cohorts (December 2008 through May 2016). Concentrations of 42 cytokines were measured in serum and endotracheal samples and clustered into modules of covarying cytokines. Relative concentrations of cytokines and cytokine modules were tested for associations with acute lung injury (ALI), shock requiring vasopressors, and death/ECMO.
Measurements and main results: Modules of covarying cytokines were more significantly associated with disease severity than individual cytokines. In the development cohort, increased levels of a serum module containing IL6, IL8, IL10, IP10, GCSF, MCP1, and MIP1α [shock odds ratio (OR) = 3.37, family-wise error rate (FWER) p < 10(-4)], and decreased levels of a module containing EGF, FGF2, SCD40L, and PAI-1 (shock OR = 0.43, FWER p = 0.002), were both associated with ALI, shock, and death-ECMO independent of age and bacterial coinfection. Both of these associations were confirmed in the validation cohort. Endotracheal and serum cytokine associations differed markedly and were differentially associated with clinical outcomes.
Conclusion: We identified strong positive and negative associations of cytokine modules with the most severe influenza-related complications in children, providing new insights into the pathogenesis of influenza-related critical illness in children. Effective therapies may need to target mediators of both inflammation and repair.

PMID: 29163498 [PubMed]

SAFETY OF PERITONEAL DIALYSIS AFTER NONRENAL SOLID-ORGAN TRANSPLANTATION.

Thu, 11/23/2017 - 13:45

SAFETY OF PERITONEAL DIALYSIS AFTER NONRENAL SOLID-ORGAN TRANSPLANTATION.

Perit Dial Int. 2017 Nov 21;:

Authors: Buffet A, Guillouët S, Lobbedez T, Ficheux M, Lanot A, Bechade C

Abstract
BACKGROUND: End-stage renal disease is a well-known complication after solid-organ transplantation, mostly as a result of calcineurin-inhibitor therapy. Among recipients of solid-organ transplants other than kidneys, peritoneal dialysis (PD) has been considered an accessory technique as an increased risk of infectious complications has been reported. The aim of our study was to evaluate the outcome of patients with a liver, heart, or lung transplant who underwent PD for replacement therapy.
METHODS: This was a retrospective, monocentric study. Every adult patient starting PD between January 1, 2001, and December 31, 2016, at our center was included. The history of previous solid-organ transplantation was determined. For the statistical analysis, we considered 2 groups of patients: 1 group having a history of transplantation of an organ other than the kidney (lung, heart, liver), and 1 group that was starting dialysis without any prior history of organ transplantation. Patients who had previously undergone kidney transplantation were excluded. The events of interest were the first peritonitis episode, death, and PD failure, defined as transfer to hemodialysis.
RESULTS: A total of 383 patients started PD during this period, 13 of whom had a history of organ transplantation. We found no significant difference between the solid-organ transplantation patients and those without a history of transplantation in terms of the occurrence of peritonitis (HR [hazard ratio] 0.91 [0.37 - 2.22]), death (HR 0.83 [0.26 - 2.63]), and PD failure (HR 1.01 [0.32 - 3.22]).
CONCLUSION: Peritoneal dialysis appears to be an effective replacement therapy for patients with a previous history of solid-organ transplantation.

PMID: 29162679 [PubMed - as supplied by publisher]

Impact of Nocturnal Noninvasive Ventilation on Pulmonary Rehabilitation in Patients with End-Stage Lung Disease Awaiting Lung Transplantation.

Wed, 11/22/2017 - 13:45

Impact of Nocturnal Noninvasive Ventilation on Pulmonary Rehabilitation in Patients with End-Stage Lung Disease Awaiting Lung Transplantation.

Respiration. 2017 Nov 21;:

Authors: Kneidinger N, Gloeckl R, Schönheit-Kenn U, Milger K, Hitzl W, Behr J, Kenn K

Abstract
BACKGROUND: Pulmonary rehabilitation (PR) in patients awaiting lung transplantation is crucial to ensure a transplant benefit. However, PR in patients with end-stage lung disease treated with noninvasive ventilation (NIV) remains an area of uncertainty.
OBJECTIVES: The aim of the study was to assess the potential benefit of PR in patients awaiting lung transplantation treated with NIV.
METHODS: Patients awaiting lung transplantation who underwent comprehensive inpatient PR from 1998 to 2015 were retrospectively analyzed. Success of PR was assessed by comparing admission and discharge. Multivariate regression models were applied to assess the impact of long-term nocturnal NIV on PR success.
RESULTS: In total, 1,044 patients were included in the analysis. Thereof, 296 patients (28%) were treated with NIV. PR in patients treated with NIV resulted in a significant increase in 6-min walk distance (6MWD; from 250 ± 117 to 309 ± 116 m; p < 0.0001) and in various items of the Short Form Health Survey (SF)-36 questionnaire. The increase in 6MWD was higher in patients treated with NIV than in patients without NIV (59 ± 63 vs. 48 ± 55 m; p = 0.003). Furthermore, improvements of various lung function variables were higher in patients with NIV. Finally, multivariate generalized regression analysis revealed that NIV therapy was associated with improvement of 6MWD (p = 0.023) while controlling for various baseline characteristics.
CONCLUSIONS: PR in patients with end-stage lung disease awaiting lung transplantation on nocturnal NIV is feasible and is associated with improvements of exercise capacity and quality of life. Furthermore, despite more advanced lung disease, patients treated with NIV have an increased benefit of PR compared to patients without NIV while awaiting lung transplantation.

PMID: 29161721 [PubMed - as supplied by publisher]

Lung and heart-lung transplantation in pulmonary arterial hypertension.

Wed, 11/22/2017 - 13:45

Lung and heart-lung transplantation in pulmonary arterial hypertension.

PLoS One. 2017;12(11):e0187811

Authors: López-Meseguer M, Quezada CA, Ramon MA, Lázaro M, Dos L, Lara A, López R, Blanco I, Escribano P, Roman A, REHAP Investigators

Abstract
BACKGROUND: Real use of lung (LT) and heart-lung (HLT) transplantation in pulmonary arterial hypertension (PAH) is unknown. The objectives were to describe the indication of these procedures on PAH treatment in a national cohort of PAH patients, and to analyze the potential improvement of its indication in severe patients.
METHODS: Eligibility for LT/HLT was assessed for each deceased patient. Incident patients from REHAP diagnosed between January 2007 and March 2015 and considered eligible for LT/HLT were grouped as follows: those who finally underwent transplantation (LTP) and those who died (D-Non-LT).
FINDINGS: Of 1391 patients included in REHAP, 36 (3%) were LTP and 375 (27%) died. Among those who died, 36 (3%) were D-Non-LT. LTP and D-Non-LT were equal in terms of age, gender, and clinical status. Ten percent of those who died were functional class I-II. Patients functional class IV were less likely to undergo LT (8.3% LTP vs. 30.6% D-Non-LT, p = 0.017). Patients with idiopathic and drug/toxin-associated PAH were more likely to undergo LT (44.4% LTP vs. 16.7% D-Non-LT, p = 0.011).
CONCLUSIONS: The present results show that the use of LT/HLT could double for this indication. Relevant mortality in early functional class reflects the difficulties in establishing the risk of death in PAH.

PMID: 29161284 [PubMed - in process]

Lung necrosectomy in pediatric patients with necrotizing pneumonia.

Wed, 11/22/2017 - 13:45

Lung necrosectomy in pediatric patients with necrotizing pneumonia.

Gen Thorac Cardiovasc Surg. 2017 Nov 20;:

Authors: Bolaños-Morales FV, Gómez-Portugal EP, Aguilar-Mena ME, Santillán-Doherty PJ, Sotres-Vega A, Santibáñez-Salgado JA

Abstract
INTRODUCTION: Necrotizing pneumonia is the consolidation of lung parenchyma with destruction and necrosis, forming solitary or multiloculated radiolucent foci. When antibiotic treatment fails and clinical course does not improve, patients might need lung tissue resection: segmentectomy, lobectomy or bilobectomy. We have performed a more conservative surgical approach in pediatric patients with necrotizing pneumonia, lung necrosectomy: resection of unviable necrotic tissue, to preserve more healthy and potentially recoverable lung parenchyma. The objective of this study is to present the results of our experience with lung necrosectomy.
METHODS: Retrospective review of clinical charts of children with necrotizing pneumonia. The diagnosis was based on physical examination, laboratory data and contrast CT scan. Lung necrosectomy technique includes resection of necrotic tissue with careful debridement technique; air leaks were sutured and/or tissue imbrication.
RESULTS: Twenty-four children were surgically treated for necrotizing pneumonia (18 girls and 6 boys). The mean age was 31.5 ± 13.5 months. All the patients presented productive cough, fever and dyspnea; chest X-rays showed consolidated areas with intraparenchymal cavities and hypoperfusion on the contrasted CT. Surgical treatment included: Lung necrosectomy 17 (70%); lobectomy 3 (12.5%); wedge resection 2 (8.3%); lobectomy + lung necrosectomy 1 (4.1%), and wedge resection + lung necrosectomy 1 (4.1%). The postoperative course was uneventful in 23 patients; mean postoperative hospital stay was 6.3. One patient died because of sepsis.
CONCLUSIONS: Lung necrosectomy is a conservative, effective surgical treatment, which solves lung necrotizing infection avoiding resection of healthy lung parenchyma.

PMID: 29159658 [PubMed - as supplied by publisher]

Young donor white blood cell immunotherapy induces extensive tumor necrosis in advanced-stage solid tumors.

Wed, 11/22/2017 - 13:45

Young donor white blood cell immunotherapy induces extensive tumor necrosis in advanced-stage solid tumors.

Heliyon. 2017 Oct;3(10):e00438

Authors: Maharaj D, Vianna PG, Ward W, Messina AJ, Rayborn T, Gouvea JV, Hammer RD, Cui Z

Abstract
Background: In the past decade, a variety of immunotherapy approaches focused predominantly on the adaptive immune system have shown unprecedented responses in patients with advanced-stage malignancies. However, studies in spontaneous regression/complete resistance (SR/CR) mice and humans have shown a novel innate cancer-killing activity mediated by granulocytes, which is completely transferable for prevention or therapy against established malignancies.
Methods: Three patients with advanced, relapsed or refractory solid tumors for which no standard therapy was available or was refused were enrolled into this ongoing combined phase I/II open label clinical trial testing the safety, dose tolerance, and possible antineoplastic efficacy of sequential infusions of HLA-mismatched non-irradiated allogeneic white cells (68-91% granulocytes) collected by leukapheresis from young, healthy donors (age 18-35) following mobilization with granulocyte colony stimulating factor (G-CSF) and dexamethasone.
Results: Besides fevers and flushing, no infusional toxicities were observed. All patients remained clinically stable following infusions with mild cytokine release syndrome and no evidence of transfusion-associated graft-versus-host disease, acute tumor lysis syndrome,or transfusion-associated acute lung injury. Pathological examination of all cases post-mortem revealed extensive tumor necrosis up to 80% in patients 1-2, 40-50% in patient 3, and leukocyte infiltration in all cases, which could not be attributed to disease progression.
Conclusions: Allogeneic white cell immunotherapy (AWIT) from young, healthy donors is well tolerated with minimal side effects and shows antitumor activity against advanced-stage solid tumors. AWIT represents a novel, safe, and cost-effective immunotherapy that can be administered in an outpatient cancer clinic.

PMID: 29159318 [PubMed]

Use of ceftolozane-tazobactam in a cystic fibrosis patient with multidrug-resistant pseudomonas infection and renal insufficiency.

Wed, 11/22/2017 - 13:45

Use of ceftolozane-tazobactam in a cystic fibrosis patient with multidrug-resistant pseudomonas infection and renal insufficiency.

Respir Med Case Rep. 2018;23:8-9

Authors: Stokem K, Zuckerman JB, Nicolau DP, Wungwattana M, Sears EH

Abstract
We report the successful use of ceftolozane/tazobactam (C/T) to treat a pulmonary exacerbation in a 35 year old female, post lung transplant, with cystic fibrosis (CF), malnutrition, chronic kidney disease, and multi-drug resistant Pseudomonas aeruginosa infection (MDR PSA). Given the complexity of the clinical profile, we measured drug levels of C/T during treatment of her current exacerbation to determine pharmacokinetics. The patient achieved an estimated ceftolozane peak of 174.1 μg/mL and trough of 9.2 μg/mL. Serum half-life was found to be slightly shorter than previously reported in normal subjects, (2.3 hr. vs. 2.6 hr.) despite the presence of renal insufficiency. Treatment resulted in improvement in serum inflammatory markers and symptoms and was well-tolerated.

PMID: 29159032 [PubMed]

DNA Methylation of miR-7 is a Mechanism Involved in Platinum Response through MAFG Overexpression in Cancer Cells.

Wed, 11/22/2017 - 13:45

DNA Methylation of miR-7 is a Mechanism Involved in Platinum Response through MAFG Overexpression in Cancer Cells.

Theranostics. 2017;7(17):4118-4134

Authors: Vera O, Jimenez J, Pernia O, Rodriguez-Antolin C, Rodriguez C, Sanchez Cabo F, Soto J, Rosas R, Lopez-Magallon S, Esteban Rodriguez I, Dopazo A, Rojo F, Belda C, Alvarez R, Valentin J, Benitez J, Perona R, De Castro J, Ibanez de Caceres I

Abstract
One of the major limitations associated with platinum use is the resistance that almost invariably develops in different tumor types. In the current study, we sought to identify epigenetically regulated microRNAs as novel biomarkers of platinum resistance in lung and ovarian cancers, the ones with highest ratios of associated chemo-resistance. Methods: We combined transcriptomic data from microRNA and mRNA under the influence of an epigenetic reactivation treatment in a panel of four paired cisplatin -sensitive and -resistant cell lines, followed by real-time expression and epigenetic validations for accurate candidate selection in 19 human cancer cell lines. To identify specific candidate genes under miRNA regulation, we assembled "in silico" miRNAs and mRNAs sequences by using ten different algorithms followed by qRT-PCR validation. Functional assays of site-directed mutagenesis and luciferase activity, miRNAs precursor overexpression, silencing by antago-miR and cell viability were performed to confirm their specificity in gene regulation. Results were further explored in 187 primary samples obtained from ovarian tumors and controls. Results: We identified 4 candidates, miR-7, miR-132, miR-335 and miR-148a, which deregulation seems to be a common event in the development of resistance to cisplatin in both tumor types. miR-7 presented specific methylation in resistant cell lines, and was associated with poorer prognosis in ovarian cancer patients. Our experimental results strongly support the direct regulation of MAFG through miR-7 and their involvement in the development of CDDP resistance in human tumor cells. Conclusion: The basal methylation status of miR-7 before treatment may be a potential clinical epigenetic biomarker, predictor of the chemotherapy outcome to CDDP in ovarian cancer patients. To the best of our knowledge, this is the first report linking the regulation of MAFG by miRNA-7 and its role in chemotherapy response to CDDP. Furthermore, this data highlights the possible role of MAFG as a novel therapeutic target for platinum resistant tumors.

PMID: 29158814 [PubMed - in process]

Lung transplantation and survival outcomes in patients with oxygen-dependent COPD with regard to their alpha-1 antitrypsin deficiency status.

Wed, 11/22/2017 - 13:45

Lung transplantation and survival outcomes in patients with oxygen-dependent COPD with regard to their alpha-1 antitrypsin deficiency status.

Int J Chron Obstruct Pulmon Dis. 2017;12:3281-3287

Authors: Ekström M, Tanash H

Abstract
Background: Individuals with severe alpha-1 antitrypsin deficiency (AATD) have an increased risk of developing COPD. However, outcomes during long-term oxygen therapy (LTOT) in patients with severe AATD and hypoxemia are unknown.
Patients and methods: This was a prospective, population-based, consecutive cohort study of patients on LTOT due to COPD in the period from January 1, 1987, to June 30, 2015, in the Swedish National Registry for Respiratory Failure (Swedevox). Severe AATD was identified using the Swedish AATD registry and confirmed by isoelectric focusing. Data on lung transplantation (LTx) were obtained from the two lung transplantation centers in Sweden. Mortality and causes of death were assessed based on the National Causes of Death Registry and analyzed using multivariable Cox regression.
Results: A total of 14,644 patients who started LTOT due to COPD were included in this study. No patient was lost to follow up. Patients with AATD were younger, included more males and more never smokers, and had fewer comorbidities. During a median follow-up of 1.6 years (interquartile range [IQR], 2.7) on LTOT, patients without severe AATD had a higher mortality, hazard ratio [HR] 1.53 (95% CI, 1.24-1.88), adjusting for age, sex, smoking status, body mass index, performance status, level of hypoxemia, and comorbidities. Cardiovascular deaths were increased. A higher proportion of AATD patients underwent LTx, 53 (19%) vs 118 (1%). Survival after LTx was similar for AATD and non-AATD patients and was predicted by age.
Conclusion: In oxygen-dependent COPD, patients with severe AATD have a longer survival time on LTOT, but they have a similar prognosis after lung transplantation compared with patients without AATD.

PMID: 29158672 [PubMed - in process]

Development and electronic validation of the revised Cystic Fibrosis Questionnaire (CFQ-R Teen/Adult): New tool for monitoring psychosocial health in CF.

Wed, 11/22/2017 - 13:45

Development and electronic validation of the revised Cystic Fibrosis Questionnaire (CFQ-R Teen/Adult): New tool for monitoring psychosocial health in CF.

J Cyst Fibros. 2017 Nov 17;:

Authors: Solé A, Olveira C, Pérez I, Hervás D, Valentine V, Baca Yepez AN, Olveira G, Quittner AL

Abstract
BACKGROUND: The Cystic Fibrosis Questionnaire-Revised (CFQ-R+14) is a disease-specific, health-related quality of life instrument for cystic fibrosis (CF) patients ≥14years. We have developed a Spanish electronic version of the CFQ-R (e-CFQ-R+14 Spain). Our aim was to compare the paper and electronic versions and to validate the electronic version.
METHODS: Fifty CF patients completed the study. All answered the paper and electronic versions on day 1 and repeated the e-CFQR version 15days later.
RESULTS: Concordance between the electronic and paper copy versions was high, with correlations above 0.9 in all domains. Test-retest reliability of the e-CFQ-R results was strong, with coefficients ranging from 0.8 to 0.9.
CONCLUSIONS: The e-CFQ-R version is reliable and valid and can replace the paper copy, thus simplifying the assessment of quality of life. It also provides immediate results with no errors in scoring. It is a useful new tool in CF care.

PMID: 29157922 [PubMed - as supplied by publisher]

Ischemic stroke and subsequent thrombosis within a HeartMate 3 left ventricular assist system: A cautionary tale.

Wed, 11/22/2017 - 13:45

Ischemic stroke and subsequent thrombosis within a HeartMate 3 left ventricular assist system: A cautionary tale.

J Heart Lung Transplant. 2017 Nov 06;:

Authors: Netuka I, Mehra MR

PMID: 29157603 [PubMed - as supplied by publisher]

Can Youthful Mesenchymal Stem Cells from Wharton's Jelly Bring a Breath of Fresh Air for COPD?

Wed, 11/22/2017 - 13:45
Related Articles

Can Youthful Mesenchymal Stem Cells from Wharton's Jelly Bring a Breath of Fresh Air for COPD?

Int J Mol Sci. 2017 Nov 18;18(11):

Authors: Janczewski AM, Wojtkiewicz J, Malinowska E, Doboszyńska A

Abstract
Chronic obstructive pulmonary disease (COPD) is a major global cause of morbidity and mortality, projected to become the 3rd cause of disease mortality worldwide by 2020. COPD is characterized by persistent and not fully reversible airflow limitation that is usually progressive and is associated with an abnormal chronic inflammatory response of the lung to noxious agents including cigarette smoke. Currently available therapeutic strategies aim to ease COPD symptoms but cannot prevent its progress or regenerate physiological lung structure or function. The urgently needed new approaches for the treatment of COPD include stem cell therapies among which transplantation of mesenchymal stem cells derived from Wharton's jelly (WJ-MSCs) emerges as a promising therapeutic strategy because of the unique properties of these cells. The present review discusses the main biological properties of WJ-MSCs pertinent to their potential application for the treatment of COPD in the context of COPD pathomechanisms with emphasis on chronic immune inflammatory processes that play key roles in the development and progression of COPD.

PMID: 29156550 [PubMed - in process]

Cancer Stem Cell-Like Population is Preferentially Suppressed by EGFR-TKIs in EGFR-mutated PC-9 Tumor Models.

Tue, 11/21/2017 - 13:45

Cancer Stem Cell-Like Population is Preferentially Suppressed by EGFR-TKIs in EGFR-mutated PC-9 Tumor Models.

Exp Cell Res. 2017 Nov 14;:

Authors: Yang F, Li Y, Liu B, You J, Zhou Q

Abstract
AIMS: Although the epidermal growth factor receptor (EGFR) and Wnt/β-catenin signaling systems synergistically regulate many essential developmental and regenerative processes in lung cancer, the mechanisms of their crosstalk remain poorly defined. Our study aimed to investigate an interaction between EGFR and the β-catenin signal.
RESULTS: In this study, we described a potent activation of β-catenin by EGFR, which is dependent of the PtdIns3K/AKT pathway. We found EGF activated β-catenin signaling via phosphorylation of EGFR and AKT in EGFR-mutated PC-9 lung cancer cells. Meanwhile, EGFR tyrosine kinase inhibitors (EGFR-TKIs) regulated cancer stem-like cells (CSCs) by inhibiting autophosphorylation of EGFR and downstream signaling proteins, as well as β-catenin. Further, β-catenin depletion by RNA interference virtually eliminated cancer stem cell-like population in PC-9 cells in vitro. The nude mice transplantation model was also performed to confirm EGFR-TKIs strongly inhibited the β-catenin signal and decreased CSCs. Importantly, the reduction of CSCs that sorted out by side population (SP) cells significantly reduced the migration capability. Thus, our results improved the understanding of this process to provide insights into mechanisms of responding to EGFR-TKIs.
CONCLUSIONS: Our discoveries raise an intriguing question of the role of β-catenin in EGFR-TKIs-treated cancer stem cell-like population(s) and its potential as a new therapeutic target for NSCLC in the future.

PMID: 29154817 [PubMed - as supplied by publisher]

Impact of age, sex, therapeutic intent, race and severity of advanced heart failure on short-term principal outcomes in the MOMENTUM 3 trial.

Tue, 11/21/2017 - 13:45

Impact of age, sex, therapeutic intent, race and severity of advanced heart failure on short-term principal outcomes in the MOMENTUM 3 trial.

J Heart Lung Transplant. 2017 Nov 03;:

Authors: Goldstein DJ, Mehra MR, Naka Y, Salerno C, Uriel N, Dean D, Itoh A, Pagani FD, Skipper ER, Bhat G, Raval N, Bruckner BA, Estep JD, Cogswell R, Milano C, Fendelander L, O'Connell JB, Cleveland J, MOMENTUM 3 Investigators

Abstract
BACKGROUND: Primary outcomes analysis of the Multicenter Study of MagLev Technology in Patients Undergoing MCS Therapy With HeartMate 3 (MOMENTUM 3) trial short-term cohort demonstrated a higher survival rate free of debilitating stroke and reoperation to replace/remove the device (primary end-point) in patients receiving the HeartMate 3 (HM3) compared with the HeartMate (HMII). In this study we sought to evaluate the individual and interactive effects of pre-specified patient subgroups (age, sex, race, therapeutic intent [bridge to transplant/bridge to candidacy/destination therapy] and severity of illness) on primary end-point outcomes in MOMENTUM 3 patients implanted with HM3 and HMII devices.
METHODS: Cox proportional hazard models were used to analyze patients enrolled in the "as-treated cohort" (n = 289) of the MOMENTUM 3 trial to: (1) determine interaction of various subgroups on primary end-point outcomes; and (2) identify independent variables associated with primary end-point success.
RESULTS: Baseline characteristics were well balanced among HM3 (n = 151) and HMII (n = 138) cohorts. No significant interaction between the sub-groups on primary end-point outcomes was observed. Cox multivariable modeling identified age (≤65 years vs >65 years, hazard ratio 0.42 [95% confidence interval 0.22 to 0.78], p = 0.006]) and pump type (HM3 vs HMII, hazard ratio 0.53 [95% confidence interval 0.30 to 0.96], p = 0.034) to be independent predictors of primary outcomes success. After adjusting for age, no significant impact of sex, race, therapeutic intent and INTERMACS profiles on primary outcomes were observed.
CONCLUSIONS: This analysis of MOMENTUM 3 suggests that younger age (≤65 years) at implant and pump choice are associated with a greater likelihood of primary end-point success. These findings further suggest that characterization of therapeutic intent into discrete bridge-to-transplant and destination therapy categories offers no clear clinical advantage, and should ideally be abandoned.

PMID: 29154131 [PubMed - as supplied by publisher]

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