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A Case of Recurrent Pneumoperitoneum and Pneumatosis Intestinalis After Bilateral Lung Transplant.

Wed, 06/07/2017 - 12:45

A Case of Recurrent Pneumoperitoneum and Pneumatosis Intestinalis After Bilateral Lung Transplant.

Exp Clin Transplant. 2017 Jun 05;:

Authors: Beetz O, Kleine M, Vondran FWR, Cammann S, Klempnauer J, Kettler B

Abstract
We report a case of a 60-year-old male patient with recurrent episodes of free gas in the peritoneal and the retroperitoneal cavities as well as pneumatosis intestinalis 3 months after bilateral lung transplant. Interestingly, despite staged laparotomy within the scope of the first episode, no cause for free gas could be found. In a second episode of symptomatically pneumatosis, a conservative treatment with metro_nidazole was performed successfully. Despite several case reports on patients with pneumatosis intestinalis after lung transplant, an effective treatment strategy has not yet been proposed.

PMID: 28585913 [PubMed - as supplied by publisher]

TFE3-rearranged hepatic epithelioid hemangioendothelioma-a case report with immunohistochemical and molecular study.

Wed, 06/07/2017 - 12:45

TFE3-rearranged hepatic epithelioid hemangioendothelioma-a case report with immunohistochemical and molecular study.

APMIS. 2017 Jun 06;:

Authors: Kuo FY, Huang HY, Chen CL, Eng HL, Huang CC

Abstract
A recurrent YAP1-TFE3 gene fusion has been identified in WWTR1-CAMTA1-negative epithelioid hemangioendotheliomas arising in soft tissue, bone, and lung, but not in liver. We present the first case of TFE3-rearranged hepatic epithelioid hemangioendothelioma in a 39-year-old Taiwanese woman. Computed tomography scan revealed multifocal, ill-defined nodules involving both hepatic lobes. She then underwent deceased donor liver transplantation. Histologically, the tumors in the liver explant showed a biphasic growth pattern. One component was composed of dilated and well-formed blood vessels lined by epithelioid cells with abundant eosinophilic cytoplasm, mimicking an alveolar pattern, whereas the other component was composed of cords and single cells, featuring intracytoplasmic vacuoles, separated by a myxoid stroma. The tumor cells showed vesicular nuclei and small indistinct nucleoli with mild to moderate cytologic atypia. Most tumor cells showed factor VIII, CD34, CD31, and TFE3 positivity in immunohistochemical study. Fluorescence in situ hybridization analysis for the tumor cells exhibited TFE3 gene rearrangement. The patient is currently alive, and no post-operative tumor recurrence developed during a 13-year follow-up. Awareness of this rare vasoformative variant and identification of the gene rearrangement would be helpful on differential diagnosis with other high-grade carcinoma and angiosarcoma of liver.

PMID: 28585251 [PubMed - as supplied by publisher]

Diffuse Large B-Cell Lymphoma with Secondary Hemophagocytic Lymphohistiocytosis Presenting as Acute Liver Failure.

Wed, 06/07/2017 - 12:45

Diffuse Large B-Cell Lymphoma with Secondary Hemophagocytic Lymphohistiocytosis Presenting as Acute Liver Failure.

ACG Case Rep J. 2017;4:e68

Authors: Patel R, Patel H, Mulvoy W, Kapoor S

Abstract
Hemophagocytic lymphohistiocytosis (HLH) and newly diagnosed malignant infiltration of liver are rare presentations of acute liver failure associated with poor prognosis. We report a case of a patient with acute liver failure caused by malignant infiltration by diffuse large B-cell lymphoma and secondary HLH.

PMID: 28584842 [PubMed]

Portopulmonary hypertension and hepatorenal syndrome. Two faces of the same coin.

Wed, 06/07/2017 - 12:45

Portopulmonary hypertension and hepatorenal syndrome. Two faces of the same coin.

Eur J Intern Med. 2017 Jun 02;:

Authors: Zardi EM, Zardi DM, Giorgi C, Chin D, Dobrina A

Abstract
Portopulmonary hypertension and hepatorenal syndrome are both severe local hypertensive complications of liver cirrhosis and portal hypertension. Both are characterized by vasoconstrictive manifestations regarding pulmonary and renal vascular network, respectively. This review addresses the mechanisms underlying the development of vasoconstriction that leads to local vascular hypertension in the lung and in the kidney with the result of organ dysfunction. Potential therapeutic options are available for the management of these two syndromes as a bridge for liver transplantation; clinical efficacy depends in part on the time and rapidity of intervention and in part on how serious the chain of events is that has triggered the entire vasoconstrictive process.

PMID: 28583409 [PubMed - as supplied by publisher]

Dose-dependent association between amiodarone and severe primary graft dysfunction in orthotopic heart transplantation.

Wed, 06/07/2017 - 12:45

Dose-dependent association between amiodarone and severe primary graft dysfunction in orthotopic heart transplantation.

J Heart Lung Transplant. 2017 May 20;:

Authors: Wright M, Takeda K, Mauro C, Jennings D, Kurlansky P, Han J, Truby L, Stein S, Topkara V, Garan AR, Yuzefpolskaya M, Colombo P, Naka Y, Farr M, Takayama H

Abstract
BACKGROUND: There is growing concern regarding the association between pre-transplant amiodarone exposure and post-transplant adverse outcomes. We hypothesized that amiodarone use would be associated with the development of severe primary graft dysfunction (PGD) in a dose-dependent manner.
METHODS: This was a retrospective review of 269 adult orthotopic heart transplantation (OHT) recipients at our institution between 2010 and 2014. At the time of OHT, 100 were receiving amiodarone therapy (Group 1) and 169 were not (Group 2).
RESULTS: Pre-OHT creatinine was higher in Group 1 (1.49 ± 0.63 vs 1.27 ± 0.68 mg/dl, p = 0.011). At time of listing, Group 1 had higher frequency of status 2 (42.0% vs 29.0%), and Group 2 had higher frequency of status 1A (20.7% vs 8.0%; p = 0.009). Severe PGD (mechanical circulatory support within 24 hours post-OHT) was significantly higher in Group 1 (20.0% vs 5.3%, p < 0.001). Pre-OHT amiodarone use was an independent risk factor for severe PGD (odds ratio [OR], 6.05; 95% confidence interval [CI], 2.47-14.83; p < 0.001) and in-hospital mortality (OR, 2.88; 95% CI, 1.05-7.88; p = 0.039) in multivariable analysis. Each 100-mg increase in the day-of-OHT amiodarone dose (OR, 1.55; 95% CI, 1.26-1.90) and each 18,300-mg increase in the 6-month cumulative dose (OR, 1.67; 95% CI, 1.31-2.15) was associated with increased odds of developing severe PGD (p < 0.001 for both).
CONCLUSIONS: Amiodarone use pre-OHT is independently associated with increased incidence of severe PGD and in-hospital mortality and linearly associated with increased incidence of severe PGD in a dose-dependent manner.

PMID: 28583372 [PubMed - as supplied by publisher]

Bacterial infections after pediatric heart transplantation: Epidemiology, risk factors and outcomes.

Wed, 06/07/2017 - 12:45

Bacterial infections after pediatric heart transplantation: Epidemiology, risk factors and outcomes.

J Heart Lung Transplant. 2017 May 11;:

Authors: Rostad CA, Wehrheim K, Kirklin JK, Naftel D, Pruitt E, Hoffman TM, L'Ecuyer T, Berkowitz K, Mahle WT, Scheel JN

Abstract
BACKGROUND: Bacterial infections represent a major cause of morbidity and mortality in heart transplant recipients. However, data describing the epidemiology and outcomes of these infections in children are limited.
METHODS: We analyzed the Pediatric Heart Transplant Study database of patients transplanted between 1993 and 2014 to determine the etiologies, risk factors and outcomes of children with bacterial infections post-heart transplantation.
RESULTS: Of 4,458 primary transplants in the database, there were 4,815 infections that required hospitalization or intravenous therapy, 2,047 (42.51%) of which were bacterial. The risk of bacterial infection was highest in the first month post-transplant, and the bloodstream was the most common site (24.82%). In the early post-transplant period (<30 days post-transplant), coagulase-negative staphylococci were the most common pathogens (16.97%), followed by Enterobacter sp (11.99%) and Pseudomonas sp (11.62%). In the late post-transplant period, community-acquired pathogens Streptococcus pneumoniae (6.27%) and Haemophilus influenzae (2.82%) were also commonly identified. Patients' characteristics independently associated with acquisition of bacterial infection included younger age (p < 0.0001) and ventilator (p < 0.0001) or extracorporeal membrane oxygenation (p = 0.03) use at time of transplant. Overall mortality post-bacterial infection was 33.78%, and previous cardiac surgery (p < 0.001) and multiple sites of infection (p = 0.004) were independent predictors of death.
CONCLUSIONS: Bacteria were the most common causes of severe infections in pediatric heart transplant recipients and were associated with high mortality rates. The risk of acquiring a bacterial infection was highest in the first month post-transplant, and a large proportion of the infections were caused by multidrug-resistant pathogens.

PMID: 28583371 [PubMed - as supplied by publisher]

Epigenetic activation of SIN1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial-mesenchymal transition.

Wed, 06/07/2017 - 12:45
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Epigenetic activation of SIN1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial-mesenchymal transition.

Biochem Biophys Res Commun. 2017 Jan 29;483(1):645-651

Authors: Hu Z, Wang Y, Wang Y, Zang B, Hui H, You Z, Wang X

Abstract
Stress-activated protein kinase (SAPK) interacting protein 1 (SIN1) is an essential component of mTORC2. Previous studies have shown that SIN1 is a key regulator of Akt pathway which plays an important role in various pathological conditions including cancer. While its effects and mechanisms on the progression of NSCLC remain unknown. In this study, we report that SIN1 is able to promote the growth and migration of NSCLC cells both in vitro and in vivo. Overexpression of SIN1 promoted A549 and H1299 cells proliferation by both MTT and colony formation assays. Consistently, knockdown of SIN1 inhibited the proliferation of these cells. In transwell assay, overexpression of SIN1 increased the migration of A549 and H1299 cells, while SIN1 knockdown reduced their migration. In a tumor xenograft model, overexpression of SIN1 promoted tumor growth of A549 cells in vivo, while SIN1 knockdown suppresses the tumor growth. We also found a mechanistic link between SIN1 and H3K4me3, H3K4me3 is involved in SIN1 upregulation. Moreover, SIN1 can significantly promote the in vitro migration and invasion of NSCLC cells via induction epithelial mesenchymal transition (EMT) process, which subsequently leads to transcriptional downregulation of epithelial marker E-cadherin and upregulation of mesenchymal markers N-cadherin and Vimentin expression. Together, our results reveal that SIN1 plays an important role in NSCLC and SIN1 is a potential biomarker and a promising target in the treatment of NSCLC.

PMID: 27993679 [PubMed - indexed for MEDLINE]

WIP promotes in-vitro invasion ability, anchorage independent growth and EMT progression of A549 lung adenocarcinoma cells by regulating RhoA levels.

Wed, 06/07/2017 - 12:45
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WIP promotes in-vitro invasion ability, anchorage independent growth and EMT progression of A549 lung adenocarcinoma cells by regulating RhoA levels.

Biochem Biophys Res Commun. 2017 Jan 22;482(4):1353-1359

Authors: Salvi A, Thanabalu T

Abstract
Cancer cell migration and invasion involves actin cytoskeleton reorganization, which is regulated by the WASP (Wiskott Aldrich Syndrome Protein) family of proteins such as WASP, N-WASP (Neural-WASP) and WASP interacting protein (WIP). In this study, we found that the expression of WIP was significantly upregulated in metastatic A5-RT3 cells compared to its parental non-tumorigenic HaCaT cells. Using A549 human lung adenocarcinoma cell line as the model system, we found that WIP regulates cell invasion, proliferation and anchorage-independent growth. Expression of WIP was enhanced during TGF-β1 induced epithelial-mesenchymal transition (EMT) and overexpression of WIP accelerated EMT while knocking down WIP attenuated EMT associated morphological changes. Knocking down WIP expression in A549 cells significantly reduced RhoA levels and WIP was found to interact with RhoA suggesting that WIP might be executing its function by regulating RhoA. Acquisition of invasive, proliferative properties and anoikis resistance is the central step in metastasis indicating a novel function of WIP in cancer progression.

PMID: 27939884 [PubMed - indexed for MEDLINE]

Long-term adaptation to hypoxia preserves hematopoietic stem cell function.

Wed, 06/07/2017 - 12:45
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Long-term adaptation to hypoxia preserves hematopoietic stem cell function.

Exp Hematol. 2016 Sep;44(9):866-873.e4

Authors: Chen J, Kang JG, Keyvanfar K, Young NS, Hwang PM

Abstract
Molecular oxygen sustains aerobic life, but it also serves as the substrate for oxidative stress, which has been associated with the pathogenesis of disease and with aging. Compared with mice housed in normoxia (21% O2), reducing ambient oxygen to 10% O2 (hypoxia) resulted in increased hematopoietic stem cell (HSC) function as measured by bone marrow (BM) cell engraftment onto lethally irradiated recipients. The number of BM c-Kit(+)Sca-1(+)Lin(-) (KSL) cells as well as the number of cells with other hematopoietic stem and progenitor cell markers were increased in hypoxia mice, whereas the BM cells' colony-forming capacity remained unchanged. KSL cells from hypoxia mice showed a decreased level of oxidative stress and increased expression of transcription factor Gata1 and cytokine receptor c-Mpl, consistent with the observations of increased erythropoiesis and enhanced HSC engraftment. These observations demonstrate the benefit of a hypoxic HSC niche and suggest that hypoxic conditions can be further optimized to preserve stem cell integrity in vivo.

PMID: 27118043 [PubMed - indexed for MEDLINE]

Electroporation-mediated gene delivery of surfactant protein B (SP-B) restores expression and improves survival in mouse model of SP-B deficiency.

Tue, 06/06/2017 - 18:45

Electroporation-mediated gene delivery of surfactant protein B (SP-B) restores expression and improves survival in mouse model of SP-B deficiency.

Exp Biol Med (Maywood). 2017 Jan 01;:1535370217713000

Authors: Barnett RC, Lin X, Barravecchia M, Norman RA, de Mesy Bentley KL, Fazal F, Young JL, Dean DA

Abstract
Surfactant Protein B Deficiency is a rare but lethal monogenetic, congenital lung disease of the neonate that is unresponsive to any treatment except lung transplantation. Based on the potential that gene therapy offers to treat such intractable diseases, our objective was to test whether an electroporation-based gene delivery approach could restore surfactant protein B expression and improve survival in a compound knockout mouse model of surfactant protein B deficiency. Surfactant protein B expression can be shut off in these mice upon withdrawl of doxycycline, resulting in decreased levels of surfactant protein B within four days and death due to lung dysfunction within four to seven days. Control or one of several different human surfactant protein B-expressing plasmids was delivered to the lung by aspiration and electroporation at the time of doxycycline removal or four days later. Plasmids expressing human surfactant protein B from either the UbC or CMV promoter expressed surfactant protein B in these transgenic mice at times when endogenous surfactant protein B expression was silenced. Mean survival was increased 2- to 5-fold following treatment with the UbC or CMV promoter-driven plasmids, respectively. Histology of all surfactant protein B treated groups exhibited fewer neutrophils and less alveolar wall thickening compared to the control groups, and electron microscopy revealed that gene transfer of surfactant protein B resulted in lamellar bodies that were similar in the presence of electron-dense, concentric material to those in surfactant protein B-expressing mice. Taken together, our results show that electroporation-mediated gene delivery of surfactant protein B-expressing plasmids improves survival, lung function, and lung histology in a mouse model of surfactant protein B deficiency and suggest that this may be a useful approach for the treatment of this otherwise deadly disease. Impact statement Surfactant protein B (SP-B) deficiency is a rare but lethal genetic disease of neonates that results in severe respiratory distress with no available treatments other than lung transplantation. The present study describes a novel treatment for this disease by transferring the SP-B gene to the lungs using electric fields in a mouse model. The procedure is safe and results in enough expression of exogenous SP-B to improve lung histology, lamellar body structure, and survival. If extended to humans, this approach could be used to bridge the time between diagnosis and lung transplantation and could greatly increase the likelihood of affected neonates surviving to transplantation and beyond.

PMID: 28581337 [PubMed - as supplied by publisher]

Extended Bridge to Heart and Lung Transplantation Using Pumpless Extracorporeal Lung Assist.

Tue, 06/06/2017 - 18:45

Extended Bridge to Heart and Lung Transplantation Using Pumpless Extracorporeal Lung Assist.

Can J Cardiol. 2017 Mar 25;:

Authors: Vasanthan V, Garg M, Maruyama M, Michelakis E, Freed DH, Nagendran J

Abstract
In end-stage idiopathic pulmonary artery hypertension (iPAH), centrally cannulated Novalung (Novalung GmbH, Hechingen, Germany) pumpless extracorporeal lung assist (pECLA) decompresses the pulmonary artery for bridge to transplantation. We report placing a 45-year-old man with end-stage iPAH and right heart failure on centrally cannulated pECLA for 82 days as a bridge to heart and double-lung transplantation (HLTx). To our knowledge, this is the longest reported bridge to transplantation in Canada and the first successful bridge to HLTx. We demonstrate how pECLA permits mobility, facilitating physiotherapy to ensure fitness for transplantation. Considering the irreversible right heart failure, HLTx remains suitable in iPAH.

PMID: 28579162 [PubMed - as supplied by publisher]

Bleeding and thrombosis associated with ventricular assist device therapy.

Tue, 06/06/2017 - 18:45

Bleeding and thrombosis associated with ventricular assist device therapy.

J Heart Lung Transplant. 2017 May 11;:

Authors: Shah P, Tantry US, Bliden KP, Gurbel PA

Abstract
Over the past decade, continuous-flow rotary pumps have dramatically improved survival for patients with advanced systolic heart failure. Bleeding and thrombosis, however, continue to be the Achilles heel of left ventricular assist device (LVAD) therapy. There is a dynamic and complex interaction between the patient and pump. The net effect of a variety of hematologic derangements, such as hemolysis, high-molecular-weight von Willebrand degradation, platelet activation and diminished pulsatility, is poorly understood. A combination of these factors mediates the common adverse events of gastrointestinal bleeding, device thrombosis and stroke. In this review we incorporate information from translational investigations in LVAD patients to understand how continuous-flow pumps activate the coagulation system and platelets predisposing to thrombosis, while, in parallel, degrade high-molecular-weight von Willebrand factor and trigger abnormal angiogenesis predisposing to bleeding. Finally, we propose novel strategies to develop a personalized approach to anti-thrombotic monitoring and titration of anti-coagulants to minimize the bleeding and thrombotic event rates of future LVAD recipients.

PMID: 28579115 [PubMed - as supplied by publisher]

Potential impact of a shock requirement on adult heart allocation.

Tue, 06/06/2017 - 18:45

Potential impact of a shock requirement on adult heart allocation.

J Heart Lung Transplant. 2017 May 17;:

Authors: Parker WF, Garrity ER, Fedson S, Churpek MM

PMID: 28579114 [PubMed - as supplied by publisher]

Waitlist outcomes in pediatric lung transplantation: Poor results for children listed in adult transplant programs.

Tue, 06/06/2017 - 18:45

Waitlist outcomes in pediatric lung transplantation: Poor results for children listed in adult transplant programs.

J Heart Lung Transplant. 2017 Apr 24;:

Authors: Scully BB, Goss M, Liu H, Keuht ML, Adachi I, McKenzie ED, Fraser CD, Melicoff E, Mallory GB, Heinle JS, Rana A

Abstract
BACKGROUND: Low case volume has been associated with lower survival after pediatric lung transplantation. Our aim was to analyze waitlist outcomes among pediatric lung transplant centers in the USA.
METHODS: We studied a cohort of 1,139 pediatric candidates listed in the Organ Procurement and Transplantation Network for lung transplantation between 2002 and 2014. Of these candidates, 720 (63.2%) received a transplant. Candidates were divided into groups according to the clinical activity of the center of listing: high-volume pediatric (≥4 transplants per year); low-volume pediatric (<4 transplants per year); and adult (transplant volume predominantly in adults). We used multivariate Cox regression analysis to identify independent risk factors for waitlist mortality. We also determined the transplant rate-or likelihood of transplant after listing-over the study period.
RESULTS: Fifty-eight percent of the children and adolescents were listed in adult centers where the resultant transplant rate was low-only 42% received a transplant compared with 93% in pediatric programs. Listing in an adult program was also the most significant risk factor for death on the waiting list (hazard ratio 15.6, 95% confidence interval 5.8 to 42.1).
CONCLUSIONS: Most children (58%) are listed for lung transplantation in adult centers and have a reduced rate of transplantation and a greater chance of waitlist mortality.

PMID: 28579113 [PubMed - as supplied by publisher]

Early mortality after heart transplantation related to IgA anti-β2-glycoprotein I antibodies.

Tue, 06/06/2017 - 18:45

Early mortality after heart transplantation related to IgA anti-β2-glycoprotein I antibodies.

J Heart Lung Transplant. 2017 May 19;:

Authors: Delgado JF, Serrano M, Morán L, Enguita AB, Martínez-Flores JA, Ortiz-Bautista C, Rodríguez-Chaverri A, de Antonio IP, García Cosio MD, Castro Panete MJ, Cortina JM, Serrano A

Abstract
BACKGROUND: The presence of pre-formed IgA anti-β2-glycoprotein I antibodies (IgA-aB2GP1ab) has been related to early graft loss after kidney transplant. Because β2-glycoprotein I is produced in both the kidney and heart, we aimed to assess whether the presence of these antibodies may also be associated with poor outcomes after heart transplantation (HT).
METHODS: A 2-year follow-up retrospective analysis of 151 consecutive patients who underwent HT between 2004 and 2012 was performed to assess the role of this pre-formed antibody type in HT. The population was divided into 2 groups according to the presence of IgA: Group 1 was positive for IgA-aB2GP1ab (47 patients, 31.1%), and Group 2 was negative for IgA-Ab2GP1ab (104 patients, 68.9%).
RESULTS: Early mortality rates within the first 3 months were higher in Group 1 (27.7%) than in Group 2 (9.6%). No differences in donor and recipient characteristics or in causes of death were observed between groups. Multivariate analysis identified the presence of IgA-aB2GP1ab, female gender and blood type A as independent risks factors for early mortality after HT. A greater incidence of thrombotic events during the first 3 months post-HT in Group 1 (23.4% vs 5.8%) and a greater presence of risk factors for thrombotic events, which may have exacerbated them, were observed. After this period, no increase in mortality or in thrombotic events was found when the 2 groups were compared.
CONCLUSION: Pre-transplant presence of IgA-aB2GP1ab is associated with both increased early mortality rates and higher thrombotic events after HT.

PMID: 28579112 [PubMed - as supplied by publisher]

Incremental shuttle walk test distance and autonomic dysfunction predict survival in pulmonary arterial hypertension.

Tue, 06/06/2017 - 18:45

Incremental shuttle walk test distance and autonomic dysfunction predict survival in pulmonary arterial hypertension.

J Heart Lung Transplant. 2017 Apr 24;:

Authors: Billings CG, Hurdman JA, Condliffe R, Elliot CA, Smith IA, Austin M, Armstrong IJ, Hamilton N, Charalampopoulos A, Sabroe I, Swift AJ, Rothman AM, Wild JM, Lawrie A, Waterhouse JC, Kiely DG

Abstract
BACKGROUND: To ensure effective monitoring of pulmonary arterial hypertension (PAH), a simple, reliable assessment of exercise capacity applicable over a range of disease severity is needed. The aim of this study was to assess the ability of the incremental shuttle walk test (ISWT) to correlate with disease severity, measure sensitivity to change, and predict survival in PAH.
METHODS: We enrolled 418 treatment-naïve patients with PAH with baseline ISWT within 3 months of cardiac catheterization. Clinical validity and prognostic value of ISWT distance were assessed at baseline and 1 year.
RESULTS: ISWT distance was found to correlate at baseline with World Health Organization functional class, Borg score, and hemodynamics without a ceiling effect (all p < 0.001). Walking distance at baseline and after treatment predicted survival; the area under the receiver operating characteristic curve for ability of ISWT distance to predict mortality was 0.655 (95% confidence interval 0.553-0.757; p = 0.004) at baseline and 0.737 (95% confidence interval 0.643-0.827; p < 0.001) at 1 year after initiation of treatment. Change in ISWT distance also predicted survival (p = 0.04). Heart rate (HR) and systolic blood pressure (SBP) parameters reflecting autonomic response to exercise (highest HR, change in HR, HR recovery at 1 minute >18 beats/min, highest SBP, change in SBP, and 3-minute SBP ratio) were significant predictors of survival (all p < 0.05).
CONCLUSIONS: In patients with PAH, the ISWT is simple to perform, allows assessment of maximal exercise capacity, is sensitive to treatment effect, predicts outcome, and has no ceiling effect. Also, measures of autonomic function made post-exercise predict survival in PAH.

PMID: 28579006 [PubMed - as supplied by publisher]

Genetic disorders of surfactant protein dysfunction: when to consider and how to investigate.

Tue, 06/06/2017 - 18:45
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Genetic disorders of surfactant protein dysfunction: when to consider and how to investigate.

Arch Dis Child. 2017 Jan;102(1):84-90

Authors: Gupta A, Zheng SL

Abstract
Genetic mutations affecting proteins required for normal surfactant protein function are a rare cause of respiratory disease. The genes identified that cause respiratory disease are surfactant protein B, surfactant protein C, ATP binding cassette number A3 and thyroid transcription factor-1. Surfactant protein dysfunction syndromes are highly variable in their onset and presentation, and are dependent on the genes involved and environmental factors. This heterogeneous group of conditions can be associated with significant morbidity and mortality. Presentation may be in a full-term neonate with acute and progressive respiratory distress with a high mortality or later in childhood or adulthood with signs and symptoms of interstitial lung disease. Genetic testing for these disorders is now available, providing a non-invasive diagnostic test. Other useful investigations include radiological imaging and lung biopsy. This review will provide an overview of the genetic and clinical features of surfactant protein dysfunction syndromes, and discuss when to suspect this diagnosis, how to investigate it and current treatment options.

PMID: 27417306 [PubMed - indexed for MEDLINE]

Invasive Fusariosis: A Single Pediatric Center 15-Year Experience.

Tue, 06/06/2017 - 18:45
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Invasive Fusariosis: A Single Pediatric Center 15-Year Experience.

J Pediatric Infect Dis Soc. 2015 Jun;4(2):163-70

Authors: Schwartz KL, Sheffield H, Richardson SE, Sung L, Morris SK

Abstract
Invasive fungal infection (IFI) is an important cause of mortality in immunocompromised children, particularly after hematopoietic stem cell transplantation. We describe 5 cases of Fusarium IFI in immunocompromised children seen at our institution over a 15-year period. A summary of all published pediatric cases of invasive Fusarium infection is presented. A focus on antifungal management challenges in these patients will be discussed.

PMID: 26407418 [PubMed - indexed for MEDLINE]

The components of somatostatin and ghrelin systems are altered in neuroendocrine lung carcinoids and associated to clinical-histological features.

Mon, 06/05/2017 - 12:45

The components of somatostatin and ghrelin systems are altered in neuroendocrine lung carcinoids and associated to clinical-histological features.

Lung Cancer. 2017 Jul;109:128-136

Authors: Herrera-Martínez AD, Gahete MD, Sánchez-Sánchez R, Salas RO, Serrano-Blanch R, Salvatierra Á, Hofland LJ, Luque RM, Gálvez-Moreno MA, Castaño JP

Abstract
BACKGROUND: Lung carcinoids (LCs) are rare tumors that comprise 1-5% of lung malignancies but represent 20-30% of neuroendocrine tumors. Their incidence is progressively increasing and a better characterization of these tumors is required. Alterations in somatostatin (SST)/cortistatin (CORT) and ghrelin systems have been associated to development/progression of various endocrine-related cancers, wherein they may become useful diagnostic, prognostic and therapeutic biomarkers.
OBJECTIVES: We aimed to evaluate the expression levels of ghrelin and SST/CORT system components in LCs, as well as to explore their putative relationship with histological/clinical characteristics.
PATIENTS AND METHODS: An observational retrospective study was performed; 75 LC patients with clinical/histological characteristics were included. Samples from 46 patients were processed to isolate mRNA from tumor and adjacent non-tumor region, and the expression levels of SST/CORT and ghrelin systems components, determined by quantitative-PCR, were compared to those of 7 normal lung tissues.
RESULTS: Patient cohort was characterized by mean age 53±15 years, 48% males, 34% with tobacco exposure; 71.4/28.6% typical/atypical carcinoids, 21.7% incidental tumors, 4.3% functioning tumors, 17.7% with metastasis. SST/CORT and ghrelin system components were expressed at variable levels in a high proportion of tumors, as well as in adjacent non-tumor tissues, while a lower proportion of normal lung samples also expressed these molecules. A gradation was observed from normal non-neoplastic lung tissues, non-tumor adjacent tissue and LCs, being SST, sst4, sst5, GHS-R1a and GHS-R1b overexpressed in tumor tissue compared to normal tissue. Importantly, several SST/CORT and ghrelin system components displayed significant correlations with relevant clinical parameters, such as necrosis, peritumoral and vascular invasion, or metastasis.
CONCLUSION: Altogether, these data reveal a prominent, widespread expression of key SST/CORT/ghrelin system components in LCs, where they display clinical-histological correlations, which could provide novel, valuable markers for NET patient management.

PMID: 28577942 [PubMed - in process]

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML.

Sun, 06/04/2017 - 10:06
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Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML.

Blood. 2017 Jun 02;:

Authors: Yoshimi A, Balasis ME, Vedder A, Feldman K, Ma Y, Zhang H, Lee SC, Letson C, Niyongere S, Lu SX, Ball M, Taylor J, Zhang Q, Zhao Y, Youssef S, Chung YR, Zhang XJ, Durham BH, Yang W, List AF, Loh ML, Klimek V, Berger MF, Stieglitz E, Padron E, Abdel-Wahab O

Abstract
Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to GM-CSF. Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, IL-3, and SCF in a NOD/SCID-IL2Rγ(null) background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML. Xenotransplantation of CD34(+) cells (n=8 patients) or unfractionated bone marrow (BM) or peripheral blood mononuclear cells (n=10 additional patients) resulted in robust engraftment of CMML in BM (25-96% human chimerism), spleen (9-85%), liver (34-97%), and lung (11-83%) of recipients (n=82 total mice). Engrafted cells were myeloid-restricted and matched the immunophenotype, morphology, and genetic mutations of the corresponding patient. Similar levels of engraftment were seen upon serial transplantation of human CD34(+) cells in secondary NSGS recipients (2/5 patients, 6/11 mice), demonstrating the durability of CMML grafts and functionally validating CD34(+) cells as harboring the disease-initiating compartment in vivo. Successful engraftments of JMML primary samples were also achieved in all NSGS recipients (n=4 patients, n=12 mice). Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and lethality in recipients, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo. These data reveal that NSGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in vivo, allowing creation of genetically-accurate preclinical models of these disorders.

PMID: 28576879 [PubMed - as supplied by publisher]

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