Glioma-derived extracellular vesicles selectively suppress immune responses

Background

Glioma-related immunosuppression is well documented; however, the mechanisms of suppression are not fully understood. Here we explore a role for glioma extracellular vesicles (EVs) as a means of immune modulation.

Methods

Healthy donor peripheral blood mononuclear cells (PBMCs) were incubated with mitogenic stimuli and various concentrations of glioma-derived EVs. Intracellular signaling and cytokine output were determined by protein microarrays, and phenotypic changes were assessed by flow cytometry. Recall antigen testing, mixed lymphocyte reactions, and migration assays analyzed PBMC functional capacity.

Results

Protein microarray data revealed induction of an immunosuppressive phenotype and cytokine output at high tumor-vesicle concentrations but an activated phenotype at low concentrations. T cell activation antigen expression confirmed differential activation profiles. Functional analyses revealed decreased migratory capacity of PBMCs after incubation with EVs; however, recall antigen and mixed lymphocyte tests indicated that activation capacity is still retained in EV-treated cells.

Conclusion

The differential effects of high and low EV concentrations dictate modulatory effects on PBMCs. These data provide a role for EVs at high concentrations for inducing selective tolerance of an immune response in a tumor setting. This suggests that lymphocytes in patients' circulation are not irreparably impaired, as previously thought, but can be rescued to augment antitumor responses.

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Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study

Background

The colony stimulating factor 1 receptor (CSF1R) ligands, CSF1 and interleukin-34, and the KIT ligand, stem cell factor, are expressed in glioblastoma (GB). Microglia, macrophages, blood vessels, and tumor cells also express CSF1R, and depletion of the microglia reduces tumor burden and invasive capacity. PLX3397 is an oral, small molecule that selectively inhibits CSF1R and KIT, penetrates the blood–brain barrier in model systems, and represents a novel approach for clinical development.

Methods

We conducted a phase II study in patients with recurrent GB. The primary endpoint was 6-month progression-free survival (PFS6). Secondary endpoints included overall survival response rate, safety, and plasma/tumor tissue pharmacokinetics. Exploratory endpoints included pharmacodynamic measures of drug effect in blood and tumor tissue.

Results

A total of 37 patients were enrolled, with 13 treated prior to a planned surgical resection (Cohort 1) and 24 treated without surgery (Cohort 2). PLX3397 was given at an oral dose of 1000 mg daily and was well tolerated. The primary efficacy endpoint of PFS6 was only 8.6%, with no objective responses. Pharmacokinetic endpoints revealed a median maximal concentration (C_max) of 8090 ng/mL, with a time to attain C_max of 2 hour in plasma. Tumor tissue obtained after 7 days of drug exposure revealed a median drug level of 5500 ng/g. Pharmacodynamic changes included an increase in colony stimulating factor 1 and reduced CD14^dim/CD16+ monocytes in plasma compared with pretreatment baseline values.

Conclusion

PLX3397 was well tolerated and readily crossed the blood–tumor barrier but showed no efficacy. Additional studies are ongoing, testing combination strategies and potential biomarkers to identify patients with greater likelihood of response.

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Tumor microenvironment tenascin-C promotes glioblastoma invasion and negatively regulates tumor proliferation

Background

Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor in adults. Recent research on cancer stroma indicates that the brain microenvironment plays a substantial role in tumor malignancy and treatment responses to current antitumor therapy. In this work, we have investigated the effect of alterations in brain tumor extracellular matrix tenascin-C (TNC) on brain tumor growth patterns including proliferation and invasion.

Methods

Since intracranial xenografts from patient-derived GBM neurospheres form highly invasive tumors that recapitulate the invasive features demonstrated in human patients diagnosed with GBM, we studied TNC gain-of-function and loss-of function in these GBM neurospheres in vitro and in vivo.

Results

TNC loss-of-function promoted GBM neurosphere cell adhesion and actin cytoskeleton organization. Yet, TNC loss-of-function or exogenous TNC had no effect on GBM neurosphere cell growth in vitro. In animal models, decreased TNC in the tumor microenvironment was accompanied by decreased tumor invasion and increased tumor proliferation, suggesting that TNC regulates the "go-or-grow" phenotypic switch of glioma in vivo. We demonstrated that decreased TNC in the tumor microenvironment modulated behaviors of stromal cells including endothelial cells and microglia, resulting in enlarged tumor blood vessels and activated microglia in tumors. We further demonstrated that tumor cells with decreased TNC expression are sensitive to anti-proliferative treatment in vitro.

Conclusion

Our findings suggest that detailed understanding of how TNC in the tumor microenvironment influences tumor behavior and the interactions between tumor cells and surrounding nontumor cells will benefit novel combinatory antitumor strategies to treat malignant brain tumors.

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Dropout Rates in Exposure with Response Prevention for Obsessive-Compulsive Disorder: What Do the Data Really Say?

Publication date: Available online 18 March 2016
Source:Journal of Anxiety Disorders
Author(s): Clarissa W. Ong, Joseph W. Clyde, Ellen J. Bluett, Michael E. Levin, Michael P. Twohig
The purposes of this review were to: 1) determine the attrition rates for exposure with response prevention (ERP) for obsessive-compulsive disorder (OCD), 2) compare them to those in other treatments for OCD, and 3) identify predictors of ERP attrition. A systematic literature search of randomized controlled trials for ERP for OCD yielded 22 studies, representing 1,462 participants. Attrition data were extracted for individual treatment conditions. The weighted mean dropout rate for ERP was 15.4% (95% CI [11.9%, 19.1%]). This figure was not statistically different from that of comparison conditions (e.g., cognitive therapy; OR=0.67–2.22, all ps>.15). Only two studies reported refusal rates for ERP (weighted mean=4.0%; 95% CI [0.7%, 9.2%]), which precluded calculation of a reliable refusal rate for ERP. Based on these figures, we estimated an overall attrition rate of 19.4% for ERP. Treatment experience, therapist qualification, and number of treatment sessions did not significantly predict dropout rate. Our review indicates that ERP may have treatment dropout rates similar to other treatments for OCD.



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Stomaching uncertainty: relationships among intolerance of uncertainty, eating disorder pathology, and comorbid emotional symptoms

Publication date: Available online 18 March 2016
Source:Journal of Anxiety Disorders
Author(s): Vidhya Renjan, Peter M. McEvoy, Alicia K. Handley, Anthea Fursland
Intolerance of uncertainty (IU) is proposed to be a transdiagnostic vulnerability factor for various emotional disorders. There is robust evidence for the role of IU in anxiety and depressive disorders, but a paucity of evidence in eating disorders (ED). This study evaluated the factorial validity, internal consistency, and convergent validity of the Intolerance of Uncertainty Scale − Short Form (IUS-12; Carleton, Norton, & Asmundson, 2007), and examined whether IU is associated with ED pathology and comorbid emotional symptoms, in a clinical sample with EDs (N=134). A unitary factor solution provided the best fit. The IUS-12 showed excellent internal validity, and good convergent validity. IU had an indirect effect on dietary restraint, purging, and emotional symptoms via overvaluation of eating, weight, and shape. The indirect effect was not significant for bingeing. Findings provide partial support for the notion that IU is a vulnerability factor for ED pathology and support the notion that IU is a transdiagnostic vulnerability factor for emotional symptoms. Limitations, research implications, and future directions for research are discussed.



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"Ear Nose Throat J"[jour]; +20 new citations

20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Ear Nose Throat J"[jour]

These pubmed results were generated on 2016/03/19

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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TWiEVO 6: Butterflies are free to shuffle

In this month's episode of the science show This Week in Evolution, Nels and I discuss the evolution of butterfly wing patterns. In this study of Amazonian butterflies, the authors show that distinct patterns are a consequence of enhancer shuffling. Enhancers are DNA sequences that control trans...

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Mifepristone Improves Octreotide Efficacy in Resistant Ectopic Cushing's Syndrome.

Mifepristone Improves Octreotide Efficacy in Resistant Ectopic Cushing's Syndrome.

Case Rep Endocrinol. 2016;2016:8453801

Authors: Moraitis AG, Auchus RJ

Abstract
A 30-year-old Caucasian man presented with severe Cushing's syndrome (CS) resulting from ectopic adrenocorticotropin syndrome (EAS) from a metastatic pancreatic neuroendocrine tumor. The patient remained hypercortisolemic despite treatment with steroidogenesis inhibitors, chemotherapy, and octreotide long-acting release (LAR) and was enrolled in a 24-week, phase 3 clinical trial of mifepristone for inoperable hypercortisolemia. After mifepristone was added to ongoing octreotide LAR treatment, EAS symptoms essentially resolved. Cortisol decreased dramatically, despite mifepristone's competitive glucocorticoid receptor antagonist effects. The clinical and biochemical effects reversed upon mifepristone discontinuation despite the continued use of octreotide LAR therapy. Substantial improvement in octreotide LAR efficacy with mifepristone use was noted in this patient with ectopic CS, consistent with upregulation of somatostatin receptors previously downregulated by hypercortisolemia.

PMID: 26989527 [PubMed]

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How do we stage acellular mucin in lymph nodes of colorectal cancer specimens without neo-adjuvant therapy?

Abstract

The prognosis and adjuvant treatment of patients with colorectal cancer (CRC) is pivotally dependent on the identification of positive nodal metastatic disease in resected specimens. Whilst the presence of acellular mucin (ACM) at the primary tumour site in patients who have shown complete pathological response after neoadjuvant therapy (NT) for rectal cancer, has been reported as having no impact on oncological outcome¹, local recurrence² and survival^1,2,3,4, less clear is the impact of ACM found within lymph nodes (LN) in patients who have not had NT. We present our encounters with two such patients and discuss the implications of this rare phenomenon.

This article is protected by copyright. All rights reserved.

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Genomic structure and expression of immunoglobulins in Squamata

Publication date: April 2016
Source:Molecular Immunology, Volume 72
Author(s): David N. Olivieri, Elina Garet, Olivia Estevez, Christian Sánchez-Espinel, Francisco Gambón-Deza
The Squamata order represents a major evolutionary reptile lineage, yet the structure and expression of immunoglobulins in this order has been scarcely studied in detail. From the genome sequences of four Squamata species (Gekko japonicus, Ophisaurus gracilis, Pogona vitticeps and Ophiophagus hannah) and RNA-seq datasets from 18 other Squamata species, we identified the immunoglobulins present in these animals as well as the tissues in which they are found. All Squamata have at least three immunoglobulin classes; namely, the immunoglobulins M, D, and Y. Unlike mammals, however, we provide evidence that some Squamata lineages possess more than one Cμ gene which is located downstream from the Cδ gene. The existence of two evolutionary lineages of immunoglobulin Y is shown. Additionally, it is demonstrated that while all Squamata species possess the λ light chain, only Iguanidae species possess the κ light chain.



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How I do it: Anterior pull-through tympanoplasty for anterior eardrum perforations.

How I do it: Anterior pull-through tympanoplasty for anterior eardrum perforations.

Acta Otolaryngol. 2016 Mar 18;:1-6

Authors: Harris JP, Wong YT, Yang TH, Miller M

Abstract
Conclusions This technique is offered as a convenient and reliable method for cases with anterior TM perforation and inadequate anterior remnant. Objectives Chronic otitis media surgery is one of the most common procedures in otology. Anterior tympanic membrane (TM) perforation with inadequate anterior remnant is associated with higher rates of graft failure. It was the goal of this series to evaluate the anatomical and functional outcomes of a modified underlay myringoplasty technique-the anterior pull-through method. Materials and methods In a retrospective clinical study, 13 patients with anterior TM perforations with inadequate anterior remnants underwent tympanoplasty with anterior pull-through technique. The anterior tip of the temporalis fascia was pulled through and secured in a short incision lateral to the anterior part of the annulus. Data on graft take rate, pre-operative, and post-operative hearing status were analyzed. Results A graft success rate of 84.6% (11 out of 13) was achieved, without lateralization, blunting, atelectasia, or epithelial pearls. The air-bone gap was 21.5 ± 6.8 dB before intervention and 11.75 ± 5.7 dB after surgery (p = 0.003).

PMID: 26988908 [PubMed - as supplied by publisher]

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Measurement of Salivary Cortisone to Assess the Adequacy of Hydrocortisone Replacement.

Measurement of Salivary Cortisone to Assess the Adequacy of Hydrocortisone Replacement.

J Clin Endocrinol Metab. 2016 Mar 18;:jc20161228

Authors: Raff H

Abstract
CONTEXT: This Commentary discusses the study of Debono et al (19) and focuses on the potential use of multiple salivary cortisone measurements to evaluate the adequacy of hydrocortisone replacement therapy. Salivary cortisone, typically measured using liquid chromatography-tandem mass spectrometry, accurately reflects plasma free cortisol because of the expression of 11-β -hydroxysteroid dehydrogenase in the salivary gland. Debono et al showed that multiple, sequential salivary cortisone measurements obtained over a 12-hour period correlated with plasma free cortisol in subjects receiving intravenous or oral hydrocortisone (authentic cortisol).
CONCLUSIONS: Hopefully, these studies will lead to a simplified protocol with fewer samples for the measurement of salivary cortisone that can reliably assess the adequacy of hydrocortisone replacement in patients with adrenal insufficiency. This protocol has to be cost-effective and be feasible to obtain timed salivary samples accurately at home. It would be a significant advance to be able to monitor hydrocortisone replacement therapy with as few as one or two salivary cortisone measurements.

PMID: 26990943 [PubMed - as supplied by publisher]

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Evidence for Increased 5α-Reductase Activity During Early Childhood in Daughters of Women with Polycystic Ovary Syndrome.

Evidence for Increased 5α-Reductase Activity During Early Childhood in Daughters of Women with Polycystic Ovary Syndrome.

J Clin Endocrinol Metab. 2016 Mar 18;:jc20153926

Authors: Torchen LC, Idkowiak J, Fogel NR, O'Neil DM, Shackleton CH, Arlt W, Dunaif A

Abstract
CONTEXT: Polycystic ovary syndrome (PCOS) is a heritable, complex genetic disease. Animal models suggest that androgen exposure at critical developmental stages contributes to disease pathogenesis. We hypothesized that genetic variation resulting in increased androgen production produces the phenotypic features of PCOS by programming during critical developmental periods. Although we have not found evidence for increased in utero androgen levels in cord blood in the daughters of women with PCOS (PCOS-d), target tissue androgen production may be amplified by increased 5α-reductase activity analogous to findings in adult affected women. It is possible to noninvasively test this hypothesis by examining urinary steroid metabolites.
OBJECTIVE: We performed this study to investigate whether PCOS-d have altered androgen metabolism during early childhood.
DESIGN, SETTING, AND PARTICIPANTS: Twenty-one PCOS-d, 1-3 years old, and 36 control girls of comparable age were studied at an academic medical center.
MAIN OUTCOME MEASURES: Urinary steroid metabolites were measured by gas chromatography/mass spectrometry. 24-h steroid excretion rates and precursor to product ratios suggestive of 5α-reductase and 11β-hydroxysteroid dehydrogenase activities were calculated.
RESULTS: Age did not differ but weight for length z-scores were higher in PCOS-d compared to control girls (p=0.02). PCOS-d had increased 5α-tetrahydrocortisol:tetrahydrocortisol ratios (p=0.04) suggesting increased global 5α-reductase activity. There was no evidence for differences in 11β-hydroxysteroid dehydrogenase activity. Steroid metabolite excretion was not correlated with weight.
CONCLUSIONS: Our findings suggest that differences in androgen metabolism are present in early childhood in PCOS-d. Increased 5α-reductase activity could contribute to the development of PCOS by amplifying target tissue androgen action.

PMID: 26990942 [PubMed - as supplied by publisher]

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The Incidence and Clinical Features of Dual Thyroid Ectopia in Congenital Hypothyroidism.

The Incidence and Clinical Features of Dual Thyroid Ectopia in Congenital Hypothyroidism.

J Clin Endocrinol Metab. 2016 Mar 18;:jc20153080

Authors: Tucker D, Woods G, Langham S, Biassoni L, Krywawych S, Hindmarsh P, Peters C

Abstract
CONTEXT: Congenital Hypothyroidism (CH) may arise from dual foci thyroid ectopia.
OBJECTIVE: To ascertain the incidence of dual ectopia in CH and compare the phenotype to single ectopia or thyroid agenesis.
DESIGN AND SETTING: Single centre, retrospective study of babies referred through UK Newborn Bloodspot Screening between 2006-2012.
PATIENTS: 837,377 babies were screened for CH with 730 referred for diagnostic confirmation (134 thyroid ectopia; 73 thyroid agenesis).
INTERVENTION: Thyroid isotope scans classified as single or dual ectopia. Biochemical, clinical and sociodemographic data were collected.
MAIN OUTCOME MEASURES: The incidence of thyroid dual ectopia and comparison of clinical parameters with single ectopia and agenesis.
RESULTS: Thyroid ectopia occurs with an incidence of 16 /100,000 births. 21/134 (15.7%) babies with thyroid ectopia had dual foci; an incidence of 2.5 /100,000 births. Dual ectopia infants had lower mean bloodspot TSH compared to single ectopia and agenesis groups (P<0.001). On venous sampling the Ectopia group differences were absent but the difference with the agenesis group remained (TSH P<0.001; FT4: P<0.001). There were no between-group differences for gestation, ethnicity, maternal age or levthyroxine requirements at 12 months.
CONCLUSIONS: Thyroid dual ectopia has an incidence of 2.5 /100,000 births. Early functional activity in the ectopia groups with detectable serum FT4 concentrations, is lost at 12 months when thyroxine requirements are the same as the agenesis group.

PMID: 26990941 [PubMed - as supplied by publisher]

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Tackling probiotic and gut microbiota functionality through proteomics

Publication date: Available online 18 March 2016
Source:Journal of Proteomics
Author(s): Lorena Ruiz, Claudio Hidalgo, Aitor Blanco-Míguez, Anália Lourenço, Borja Sánchez, Abelardo Margolles
Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. Many strains exert their beneficial effects after transiently colonizing the human gut, where they interact with the rest of the intestinal microorganisms and with the host mucosa. Indeed the human gut harbours a huge number of microorganisms also known as gut microbiota. Imbalances in the relative abundances of the individual components of the gut microbiota may determine the health status of the host and alterations in specific groups have been related to different diseases and metabolic disorders.Proteomics provide a set of high-throughput methodologies for protein identification that are extremely useful for studying probiotic functionality and helping in the assessment of specific health-promoting activities, such as their immunomodulatory activity, the intestinal colonization processes, and the crosstalk mechanisms with the host. Furthermore, proteomics have been used to identify markers of technological performance and stress adaptation, which helps to predict traits such as behaviour into food matrices and ability to survive passage through the gastrointestinal tract. The aim of this review is to compile studies in which proteomics have been used to assess probiotic functionality and to identify molecular players supporting their mechanisms of action.SignificanceProbiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. Molecular basis underlying the functional properties of probiotic bacteria responsible for the health promoting effects have been in the background for many years. Breakthrough of omics technologies in the probiotic and microbiota fields has had a very relevant impact in the elucidation of probiotic mechanisms and in the procedures to select these microorganisms, based on solid scientific evidence. It is unquestionable that, in the near future, the evolution of proteomic techniques will play a pivotal role in the generation of knowledge about the functions of probiotics and gut commensals, still a pending issue in the field of intestinal microbiomics.



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Comparison of early results of anterior cruciate ligament tear reconstruction with transtibial and anatomical single-bundle technique by using autogenous hamstring tendon graft.

Comparison of early results of anterior cruciate ligament tear reconstruction with transtibial and anatomical single-bundle technique by using autogenous hamstring tendon graft.

Int J Surg. 2016 Mar 14;

Authors: Kılınç BE, Kara A, Oc Y, Celik H, Camur S, Bilgin E, Erten YT, Sahinkaya T, Eren OT

Abstract
INTRODUCTION: Most of the ACL reconstruction is done with isometric single-band technique. Traditionally, surgeons were trained to use the transtibial technique (TT) for drilling the femoral tunnel. Our study compared the early postoperative period functional and clinical outcomes of patients who had ACL reconstruction with TT and patients who had ACL reconstruction with anatomical single-bundle technique (AT).
MATERIAL METHOD: Fifty-five patients who had ACL reconstruction and adequate follow-up between January 2010-December 2013 were included the study. Patients were grouped by their surgery technique. 28 patients included into anatomical single-bundle ACL reconstruction surgery group (group 1) and 27 patients were included into transtibial AC reconstruction group (group 2). Average age of patients in group 1 and group 2 was 28,3±6, and 27,9±6,4, respectively. Lachman and Pivot-shift tests were performed to patients. Laxity was measured by KT-1000 arthrometer test with 15, 20 and 30 pound power. All patients' muscle strength between both extremities were evaluated with Cybex II (Humac) at 60°/sec, 240°/sec frequencies with flexion and extension peak torque. The maximum force values of non-operated knee and the operated knee were compared to each other. Groups were evaluated by using International Knee Documentation Committee (IKDC) knee ligament healing Standard form, IKDC activity scale, modified Lysholm and Cincinnati evaluation forms. Return to work and exercise time of patients were compared. Functional and clinical outcomes of two groups were compared. NCSS 2007 and PASS 2008 Statistical Software programs were used for statistical analysis.
RESULT: There was no statistically significant difference between Lachman and Pivot-shift results (p>0,01). Positive value of Pivot-shift test and incidence of anterior translation in Lachman test were higher in the patients who had TT. Lysholm activity level of patients who had TT, 33.3% (n = 9) were excellent, 51.9% (n = 14) were good and 14.8%(n =4) were moderate; patients who had AT, 57.1% (n =16) were excellent, 39.3%(n =11) were good and 3.6% (n =1) was good level. There was no statistically significant difference between Lysholm Activity level of the patients (p<0.01). Lysholm Activity level of patients who had AT significantly higher than TT. There was no statistically significant difference between Modified Cincinnati activity level of the patients (p<0,05). Modified Cincinnati activity level of patients who had AT were significantly higher than those had TT. There was no statistically significant difference between two groups with post treatment IKDC activity level (p<0.01). Intense activity after treatment rate of patient who had AT was significantly higher than those had TT. There was statistically significant difference between Cybex extension-flexion 60 measurement and extension 240 measurement of the patients (p<0.01). KT-1000 arthrometer test results with AT was better than the TT in antero-posterior translation of the knee kinematics at 20 and 30 pound of forces. Return to exercise time of patients who had TT was significantly higher than those had AT (p <0.01). There was no statistically significant difference between return to work time of patients (p>0,05).
CONCLUSION: Single band anatomic ACL reconstruction was better than the TT in term of clinical, functional, and laboratory results. We believe that AT ACL reconstruction will increase in use and traditional method which is TT ACL reconstruction surgery will decrease in the long term. Theoretically, anatomic relocation of the ACL can provide better knee kinematics.

PMID: 26987514 [PubMed - as supplied by publisher]

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The surgical treatment of esophageal cancer in Sudan.

The surgical treatment of esophageal cancer in Sudan.

Int J Surg. 2016 Mar 14;

Authors: Ahmed ME, Mahdi SI, Ali BM

Abstract
OBJECTIVE: Esophageal cancer is the most common gastrointestinal (GI) cancer in The Sudan. This study aimed to evaluate the outcome of the surgical management.
METHODS: A 100 consecutive patients who underwent esophagectomy in Shaab Hospital in Khartoum during the period June 2003- Aug 2007 were studied. .
RESULTS: The mean age was 55 ± 14 years with an equal sex ratio. Fifty five per cent of patients presented with stage III&IV locally advanced and or metastatic disease. Sixty seven percent of the patients underwent a 2-stage resection, Lewis Tanner type while 27% underwent a 3-stage resection, McKeon operation and 6% had total gastrectomy with distal esophagectomy and roux-en-y reconstruction. The 30 days postoperative mortality was 10%. In 75 patients who could be traced, the overall 5 years survival was 21% (n=16) and the 10 years survival was 8% (n=6).
CONCLUSION: There was great improvement in the early postoperative mortality from 27% in 1986 to 10% in this series. The surgical treatment offered a rapid symptoms relief which suited most patients coming from distant locations and couldn't afford to stay for long in the Capital as will be required if chemo-radiotherapy was used as sole or as a neo-adjuvant treatment.

PMID: 26987513 [PubMed - as supplied by publisher]

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Clinical Implications of Assisted Peak Cough Flow Measured with External Glottic Control Device for Tracheostomy Decannulation in the Patients with Neuromuscular Diseases and Cervical Spinal Cord Injuries: A Pilot Study

Publication date: Available online 19 March 2016
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Seong-Woong Kang, Won Ah Choi, Yu Hui Won, Jang-Woo Lee, Hoo Young Lee, Dong Jin Kim
ObjectiveTo investigate the clinical usefulness and significance of an external control device substituting glottic function in determining feasibility of decannulation in tracheostomized patients with neuromuscular diseases or cervical spinal cord injuries, whose assisted peak cough flows (APCFs) were unmeasurable or lower than 160L/min.DesignBefore-after trialSettingInpatient setting in a university hospitalParticipantsSixteen tracheostomized subjects, 11 with neuromuscular diseases and 5 with cervical spinal cord injuries were recruited.InterventionsUnassisted and assisted peak cough flows (PCFs) were measured with and without an external glottic control device. Among the patients whose APCFs without the device were lower than 160L/min, if their APCFs with the device were measured as 160L/min or higher, they were decannulated. After decannulation, unassisted and assisted PCFs were measured again.Main Outcome MeasuresAPCF with and without an external glottic control device, and APCF after decannulation.ResultsAfter successful decannulation, the APCFs were equal to or higher than those measured with the device before decannulation. No patients received intubation or re-tracheostomy, and there were no respiratory complications.ConclusionsThe external glottic control device substituting for innate glottic function is beneficial for determining tracheostomy decannulation. It provides an objective and accurate APCF. It is particularly helpful for patients whose APCFs are 160L/min or more while using the device, even if the APCFs are lower than 160L/min without it.



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Effects of singing on voice, respiratory control and quality of life in persons with Parkinson's disease.

Effects of singing on voice, respiratory control and quality of life in persons with Parkinson's disease.

Disabil Rehabil. 2016 Mar 17;:1-7

Authors: Stegemöller EL, Radig H, Hibbing P, Wingate J, Sapienza C

Abstract
Purpose Interventions focused on singing may provide additional benefits to established voice and respiratory therapies, due to their greater emphasis on the respiratory muscle control system in those with Parkinson's disease (PD) progresses. The purpose of this study was to examine if singing can improve voice, respiratory pressure and quality of life (QOL) in persons with PD. Methods This pilot study measured the effects of a singing intervention in 27 participants with PD. Participants were assigned to a high (met twice weekly) or low (met once weekly) dosage group. Voice, respiratory and QOL measures were recorded before and after an 8-week singing intervention. Sessions were led by board-certified music therapists and included a series of vocal and articulation exercises and group singing. Results Both groups demonstrated significant improvements in maximum inspiratory and expiratory pressure, as well as phonation time. While other voice measures improved, they did not reach statistical significance. Voice QOL and whole health QOL also significantly improved. Conclusion These results suggest singing may be a beneficial and engaging treatment choice for improving and maintaining vocal function and respiratory pressure in persons with PD. Implications for Rehabilitation In a small sample, group singing proved beneficial for improving voice and respiratory impairment in persons with Parkinson's disease. Completing group singing one time per week for 8 weeks was as effective as completing group singing two times per week for 8 weeks in persons with Parkinson's disease. Group singing is an effective means of improving overall quality of life in persons with Parkinson's disease.

PMID: 26987751 [PubMed - as supplied by publisher]

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Evaluation and comparison of type I tympanoplasty efficacy and histopathological changes to the tympanic membrane in dry and wet ear: a prospective study.

Evaluation and comparison of type I tympanoplasty efficacy and histopathological changes to the tympanic membrane in dry and wet ear: a prospective study.

J Laryngol Otol. 2016 Apr;130(4):413

Authors: Mills R

PMID: 26991879 [PubMed - as supplied by publisher]

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Evaluation and comparison of type I tympanoplasty efficacy and histopathological changes to the tympanic membrane in dry and wet ear: a prospective study.

Evaluation and comparison of type I tympanoplasty efficacy and histopathological changes to the tympanic membrane in dry and wet ear: a prospective study.

J Laryngol Otol. 2016 Apr;130(4):412

Authors: Lou ZC

PMID: 26991878 [PubMed - as supplied by publisher]

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Active middle-ear implant fixation in an unusual place: clinical and audiological outcomes.

Active middle-ear implant fixation in an unusual place: clinical and audiological outcomes.

J Laryngol Otol. 2016 Apr;130(4):404-407

Authors: Polanski JF, Soares AD, Dos Santos ZM, Mendonça Cruz OL

Abstract
OBJECTIVE: The Vibrant Soundbridge is an active middle-ear implant for hearing rehabilitation that is usually placed in the long process of the incus or round window. This study reports on the unusual implant attachment to the short process of the incus in a patient with ear malformation, and describes their audiological and clinical outcomes.
METHODS: Case report and literature review.
RESULTS: Audiological evaluation with the Vibrant Soundbridge implant showed a pure tone average of 31 dB. The speech test, at 65 dB HL, revealed correct recognition of 92 per cent of disyllabic words. The Glasgow Hearing Aid Benefit Profile showed high levels of satisfaction, hearing aid use and benefit.
CONCLUSION: Fixation of the Vibrant Soundbridge implant on the short process of the incus is a feasible option, with good clinical and audiological outcomes. Coupling the floating mass transducer to the short process of the incus is a good surgical option, especially when the long process and the oval or round window are inaccessible.

PMID: 26991877 [PubMed - as supplied by publisher]

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A murine model of subglottic granulation.

A murine model of subglottic granulation.

J Laryngol Otol. 2016 Apr;130(4):380-387

Authors: Ghosh A, Leahy KP, Singhal S, Einhorn E, Howlett P, Cohen NA, Mirza N

Abstract
OBJECTIVE: This study aimed to develop a functional model of subglottic stenosis by inducing direct airway irritation in transplanted mouse laryngotracheal complexes.
METHODS: Laryngotracheal complexes from C57BL/6 mice were harvested and divided into three groups: uninjured, mechanically injured and chemically injured. Donor laryngotracheal complexes from each group were placed in dorsal subcutaneous pockets of recipient mice. Each week, the transplanted laryngotracheal complexes were harvested, and tissues were fixed, sectioned, and stained with haematoxylin and eosin. Representative slides were reviewed by a blinded pathologist, to determine the formation of granulation tissue, and graded as to the degree of granulation formation.
RESULTS: Direct airway irritation induced granulation tissue formation under the disrupted epithelium of airway mucosa; this was seen as early as two weeks after chemical injury.
CONCLUSION: Results indicate that granulation tissue formation in a murine model may be an efficient tool for investigating the development and treatment of subglottic stenosis.

PMID: 26991876 [PubMed - as supplied by publisher]

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Impact of unilateral carbon dioxide laser posterior transverse cordotomy on vocal and aerodynamic parameters in bilateral vocal fold paralysis.

Impact of unilateral carbon dioxide laser posterior transverse cordotomy on vocal and aerodynamic parameters in bilateral vocal fold paralysis.

J Laryngol Otol. 2016 Apr;130(4):373-379

Authors: Asik MB, Karasimav O, Birkent H, Merati AL, Gerek M, Yildiz Y

Abstract
OBJECTIVES: Carbon dioxide laser posterior transverse cordotomy is a common option for bilateral vocal fold paralysis. This study prospectively evaluated aerodynamic and acoustic effects of unilateral carbon dioxide laser posterior transverse cordotomy in bilateral vocal fold paralysis patients.
METHODS: The study comprised 11 bilateral vocal fold paralysis patients (9 females, 2 males), with a mean age of 46.6 ± 14.1 years. All patients were treated by laser posterior transverse cordotomy. Pre-operative and two-month post-operative assessments were conducted, including: dyspnoea scales, maximum phonation time measurement, spirometry and bicycle ergometry.
RESULTS: All subjective and objective aerodynamic parameters showed statistically significant improvements between the pre- and post-operative period. Objective spirometric and ergometric parameters showed a significant increase post-operatively. The changes in objective voice parameters (fundamental frequency (f0), jitter, shimmer, soft phonation index and noise-to-harmonic ratio) were statistically non-significant; however, there was a significant improvement in subjective voice parameters post-operatively, as assessed by the voice handicap index and grade-roughness-breathiness-asthenia-strain scale (p = 0.026 and p = 0.018 respectively).
CONCLUSION: Unilateral carbon dioxide laser posterior transverse cordotomy is an effective procedure that results in improved dyspnoea and aerodynamic performance with some worsening of voice parameters.

PMID: 26991875 [PubMed - as supplied by publisher]

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Comparison of Carina active middle-ear implant with conventional hearing aids for mixed hearing loss.

Comparison of Carina active middle-ear implant with conventional hearing aids for mixed hearing loss.

J Laryngol Otol. 2016 Apr;130(4):340-343

Authors: Savaş VA, Gündüz B, Karamert R, Cevizci R, Düzlü M, Tutar H, Bayazit YA

Abstract
OBJECTIVE: To compare the auditory outcomes of Carina middle-ear implants with those of conventional hearing aids in patients with moderate-to-severe mixed hearing loss.
METHODS: The study comprised nine patients (six males, three females) who underwent middle-ear implantation with Carina fully implantable active middle-ear implants to treat bilateral moderate-to-severe mixed hearing loss. The patients initially used conventional hearing aids and subsequently received the Carina implants. The hearing thresholds with implants and hearing aids were compared.
RESULTS: There were no significant differences between: the pre-operative and post-operative air and bone conduction thresholds (p > 0.05), the thresholds with hearing aids and Carina implants (p > 0.05), or the pre-operative (mean, 72.8 ± 19 per cent) and post-operative (mean, 69.9 ± 24 per cent) speech discrimination scores (p > 0.05). One of the patients suffered total sensorineural hearing loss three months following implantation despite an initial 38 dB functional gain. All except one patient showed clinical improvements after implantation according to quality of life questionnaire (Glasgow Benefit Inventory) scores.
CONCLUSION: Acceptance of Carina implants is better than with conventional hearing aids in patients with mixed hearing loss, although both yield similar hearing amplification. Cosmetic reasons appear to be critical for patient acceptance.

PMID: 26991874 [PubMed - as supplied by publisher]

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New anticoagulants, a new book and old gags.

New anticoagulants, a new book and old gags.

J Laryngol Otol. 2016 Apr;130(4):323

Authors: Youngs R, Fisher E, Hussain M, Fishman J

PMID: 26991873 [PubMed - as supplied by publisher]

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Editorial.

Editorial.

J Laryngol Otol. 2016 Jan;130 Suppl 1:S1

Authors: Harvey RJ

PMID: 26988865 [PubMed - in process]

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An outbreak of respiratory syncytial virus (RSV) infection in immunocompromised adults on a haematology ward.

An outbreak of respiratory syncytial virus (RSV) infection in immunocompromised adults on a haematology ward.

J Med Virol. 2016 Mar 17;

Authors: Jensen TO, Stelzer-Braid S, Willenborg C, Cheung C, Andresen D, Rawlinson W, Clezy K

Abstract
We describe an outbreak of respiratory syncytial virus (RSV) infection on a haematology ward without allogeneic stem cell transplant patients. Twelve patients and one staff member infected with RSV were identified from the laboratory database. Five patients had lower respiratory tract infection, seven had upper respiratory tract infection, one was asymptomatic and there were two (15.4%) deaths. Most patients had overlapping periods of potential infectiousness on the ward. Sequencing was possible on eight specimens and five of these had identical sequences. Results were consistent with transmission occurring both on the ward and by introduction of RSV from the community. This article is protected by copyright. All rights reserved.

PMID: 26990584 [PubMed - as supplied by publisher]

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Human rhinovirus in experimental infection after peroral Lactobacillus rhamnosus GG consumption, a pilot study.

Human rhinovirus in experimental infection after peroral Lactobacillus rhamnosus GG consumption, a pilot study.

Int Forum Allergy Rhinol. 2016 Mar 17;

Authors: Tapiovaara L, Kumpu M, Mäkivuokko H, Waris M, Korpela R, Pitkäranta A, Winther B

Abstract
BACKGROUND: Data has emerged on possible beneficial effects of probiotics in respiratory tract viral infections, but it is unclear if the promising positive effects evidenced are due to a reduced viral load during infections. The aims of this work were to investigate the effect of peroral probiotic Lactobacillus rhamnosus GG (American Type Culture Collection [ATCC], Accession No. 53103) consumption on human rhinovirus (HRV) load in nasopharyngeal lavage samples in experimental HRV infection, and to correlate viral load to clinical symptoms.
METHODS: Intranasal HRV A39 inoculation was performed on 59 adults, who had consumed juice enriched with live or heat-inactivated L. rhamnosus GG or control juice for 3 weeks prior to inoculation in a randomized, controlled, pilot trial setting. Nasopharyngeal lavage samples and symptom data were analyzed on day 0 before inoculation, and on days 2 and 5. Samples were subjected to quantitative HRV detection by polymerase chain reaction (PCR).
RESULTS: Before inoculation 9 of 59 (15%) samples presented with another HRV strain than the studied A39. There was a tendency toward the lowest HRV loads in the L. rhamnosus GG groups and the highest in placebo group (log10 copies/mL, 95% confidence interval [CI], 6.20 [5.18 to 7.40] in live, 6.30 [4.91 to 7.08] in inactivated L. rhamnosus GG, and 7.25 [5.81 to 7.52] in placebo group, p = 0.57 in day 2) in the wild-type excluded population. The HRV load positively correlated with the symptom scores on days 2 and 5 (correlation coefficient 0.61 [p < 0.001] and 0.28 [p = 0.034], respectively).
CONCLUSION: Results did not show statistical differences in viral loads in subjects using L. rhamnosus GG when compared to placebo. HRV load positively correlated with the total symptom scores.

PMID: 26990147 [PubMed - as supplied by publisher]

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Host-directed therapies for antimicrobial resistant respiratory tract infections.

Host-directed therapies for antimicrobial resistant respiratory tract infections.

Curr Opin Pulm Med. 2016 Mar 17;

Authors: Maeurer M, Rao M, Zumla A

Abstract
PURPOSE OF REVIEW: Antimicrobial-resistant respiratory tract infections (AMR-RTIs) are increasing, presenting important management challenges worldwide. Current management of AMR-RTI patients focuses on pathogen-directed antimicrobial treatment. Overt lung inflammation, parenchymal damage, and ineffective immune activation perpetrate increased patient morbidity and mortality. Immunomodulatory and tissue-regenerative host-directed therapies (HDT) may improve treatment outcomes. HDTs under investigation for improving AMR-RTI treatment outcomes are reviewed.
RECENT FINDINGS: Various HDTs are being developed or evaluated for adjunctive AMR-RTI treatment. α-1 antitrypsin was shown to reduce Pseudomonas aeruginosa burden in the airways of cystic fibrosis patients. Cellular therapy by reinfusing autologous bone marrow-derived MSCs into MDR/XDR-TB patients shows promise, whereas adjunctive T cell-based therapies are considered. Cytotoxic therapy using etoposide, a topoisomerase II-inhibiting anticancer drug extends survival of patients with severe influenza H1N1 infection-induced hemophagocytic lymphohistiocytosis. Two other novel HDT candidates, DAS181 and resveratrol show antiinfluenza effects. Novel kinase inhibitors SB203580 (MAPK-2 antagonist) and LY294002 (phosphoinositide-3 kinases antagonist) exhibit promising anti-MERS-CoV activity. Palivizumab, an anti-RSV monoclonal antibody, effectively prevents RSV infection in high-risk paediatric populations. T-cell therapy is currently considered for adjunctive HDT of azole-resistant pulmonary aspergillosis.
SUMMARY: Novel HDTs may revolutionize future treatment regimens for AMR-RTIs. Well designed multisite clinical trials are now necessary to accelerate progress.

PMID: 26989822 [PubMed - as supplied by publisher]

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Primary Glial and Neuronal Tumors of the Ovary or Peritoneum: A Clinicopathologic Study of 11 Cases.

Primary Glial and Neuronal Tumors of the Ovary or Peritoneum: A Clinicopathologic Study of 11 Cases.

Am J Surg Pathol. 2016 Mar 17;

Authors: Liang L, Olar A, Niu N, Jiang Y, Cheng W, Bian XW, Yang W, Zhang J, Yemelyanova A, Malpica A, Zhang Z, Fuller GN, Liu J

Abstract
Primary glial and neuronal tumors of the ovary or peritoneum are rare neuroectodermal-type tumors similar to their counterparts in the central nervous system. We retrospectively reviewed 11 cases. These cases included 4 ependymomas, 6 astrocytic tumors, and 1 neurocytoma. Patients' age ranged from 9 to 50 years (mean, 26 y; median, 24 y). All ependymal tumors with detailed clinical history (n=3) were not associated with any other ovarian neoplasm. In contrast, all astrocytic tumors were associated with immature teratoma (n=4), mature cystic teratoma (n=1), or mixed germ cell tumor (n=1). The neurocytoma arose in association with mature teratomatous components in a patient with a history of treated mixed germ cell tumor. Immunohistochemical staining showed that 7 of 7 ependymal and astrocytic tumors (100%) were positive for glial fibrillary acidic protein, and 2 of 2 ependymomas (100%) were positive for both estrogen and progesterone receptors. The neurocytoma was positive for synaptophysin and negative for S100 protein, glial fibrillary acidic protein, and SALL4. No IDH1-R132H mutation was detected in 2 of 2 (0%) astrocytomas by immunohistochemistry. Next-generation sequencing was performed on additional 2 ependymomas and 2 astrocytomas but detected no mutations in a panel of 50 genes that included IDH1, IDH2, TP53, PIK3CA, EGFR, BRAF, and PTEN. Follow-up information was available for 8 patients, with the follow-up period ranging from 4 to 59 months (mean, 15 mo; median, 8.5 mo), of which 3 had no evidence of disease and 5 were alive with disease. In conclusion, primary glial and neuronal tumors of the ovary can arise independently or in association with other ovarian germ cell tumor components. Pathologists should be aware of these rare tumors and differentiate them from other ovarian neoplasms. Even though an IDH1 or IDH2 mutation is found in the majority of WHO grade II and III astrocytomas, and in secondary glioblastomas arising from them, such mutations were not identified in our series, suggesting that these tumors are molecularly different from their central nervous system counterparts despite their morphologic and immunophenotypic similarities.

PMID: 26990854 [PubMed - as supplied by publisher]

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A unexpected growth arising within nevus sebaceous of Jadassohn.

A unexpected growth arising within nevus sebaceous of Jadassohn.

Dermatol Online J. 2016;22(1)

Authors: Chan SA, Hejmadi R, Webster K, Kaur MR

Abstract
The predisposition to epithelial neoplasms in nevus sebaceous is well established; most tumors occur in adults and are benign. Hidradenoma is a relatively rare benign tumor of sweat gland origin that can rarely arise within a nevus sebaceous. We present an interesting case of a hidradenoma and sebaceoma arising within a nevus sebaceous and present a literature review of the 2 conditions. Even though hidradenoma is a benign tumor, we would advocate complete excision given the potential for malignant transformation.

PMID: 26990478 [PubMed - as supplied by publisher]

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Diagnostics and Early Diagnosis of Esophageal Cancer.

Diagnostics and Early Diagnosis of Esophageal Cancer.

Viszeralmedizin. 2015 Oct;31(5):315-8

Authors: Meves V, Behrens A, Pohl J

Abstract
In the esophagus two different kinds of primary neoplasias may arise: squamocellular carcinomas (SCC) and esophageal adenocarcinomas (EAC). Although both types of carcinoma are rare diseases, especially the incidence of EAC rose in the last years. The management of esophageal cancer is challenging. There are no specific symptoms of early esophageal cancers. Due to this fact, most of the esophageal cancers are found incidentally, and only 12.5% of esophageal tumors are endoscopically resectable. Gastroscopy is the gold standard for the diagnosis of esophageal cancer. The sensitivity of detecting early-stage carcinoma may be improved by adjunct techniques such as chromoendoscopy, virtual chromoendoscopy, magnification endoscopy, and other advanced endoscopic imaging techniques. The diagnosis of esophageal cancer can be verified with targeted biopsies. Accurate staging information is crucial for establishing appropriate treatment choices for esophageal cancer, while the depth of the tumor determines the feasibility of therapy. In terms of staging, endosonography, abdominal ultrasound, and computed tomography scan of the thorax and abdomen should thus be performed before initiation of therapy.

PMID: 26989385 [PubMed]

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Exsanguinating Hemorrhage during Open Biopsy in a Primary Breast Angiosarcoma: A Case Report.

Exsanguinating Hemorrhage during Open Biopsy in a Primary Breast Angiosarcoma: A Case Report.

Iran J Med Sci. 2016 Mar;41(2):154-156

Authors: Akrami M, Mohammadipour M, Mokhtari M, Dayani M

Abstract
Angiosarcomas are endothelial cell neoplasms in the lining of the blood vessel wall and account for about 0.04% of all breast malignancies with a high rate of error in primary diagnosis. The breast angiosarcoma is a rare and uncommon pathology and has been described mostly as case reports. Indeed, only a limited number of cases have been published. Accordingly, the natural history of this tumor and its clinical course remain unclear, and as a consequence, no uniform treatment strategy exists. We present the clinical course and challenges in the diagnosis of a primary angiosarcoma of the breast in a young woman, presenting with a mass in her left breast. Fine-needle aspiration and core needle biopsy failed to confer a correct diagnosis. She suffered severe bleeding at the time of open biopsy and underwent total mastectomy, followed by adjuvant chemotherapy. Young women with solid breast tumors, especially those that are highly vascular, should be considered malignant until proven otherwise. Accurate diagnosis may be difficult. Open biopsy can be diagnostic, although exsanguinating bleeding may occur. Thus, performing open biopsy in locations other than equipped operating rooms may be hazardous and should be avoided.

PMID: 26989288 [PubMed - as supplied by publisher]

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Aggressive Calcifying Epithelial Odontogenic Tumor of the Maxillary Sinus with Extraosseous Oral Mucosal Involvement: A Case Report.

Aggressive Calcifying Epithelial Odontogenic Tumor of the Maxillary Sinus with Extraosseous Oral Mucosal Involvement: A Case Report.

Iran J Med Sci. 2016 Mar;41(2):145-149

Authors: Rani V, Masthan MK, Aravindha B, Leena S

Abstract
Calcifying epithelial odontogenic tumors are benign odontogenic neoplasms whose occurrence in the maxillary sinus is rare. Maxillary tumors tend to be locally aggressive and may rapidly involve the surrounding vital structures. We report a case of a large calcifying epithelial odontogenic tumor of the maxilla, involving the maxillary sinus in a 48-year-old woman. The tumor was largely intraosseous. In the canine and first premolar regions, the loss of bone could be palpated but the oral mucosa appeared normal. Histologically, the tumor tissue could be seen in the connective tissue below the oral epithelium. The most significant finding was the presence of an intraosseous tumor with an extraosseous involvement in a single tumor, indicating aggressive behavior and warranting aggressive treatment. In this article, we discuss the rare presentation of the tumor and its radiological appearance and histological features. We also highlight the importance of a detailed histopathological examination of the excised specimen.

PMID: 26989286 [PubMed - as supplied by publisher]

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Impairment of Immune Function in Children with Familial Hemophagocytic Lymphohistiocytosis.

Impairment of Immune Function in Children with Familial Hemophagocytic Lymphohistiocytosis.

Adv Exp Med Biol. 2016 Mar 18;

Authors: Popko K, Jasińska J, Górska E, Demkow U, Balwierz W, Maciejka-Kembłowska L, Badowska W, Wachowiak J, Drabko K, Malinowska I

Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a severe systemic syndrome associated with hyperactivation of macrophages and impaired regulation of the immune system. Two forms of HLH are currently recognized: genetically determined or familial (FHLH), and secondarily developed in the course of primary diseases, like autoimmune disorders, rheumatoid disorders, cancers, or infections. In the Polish population, FHLH is rather rare. The aim of the present study was to assess the immune function in a group of children with clinical symptoms suggesting FHLH. Forty five children with suspected HLH of the median age of 4 years and 15 healthy children, taken as a control group, were enrolled into the study. All presented results were obtained with the use of flow cytometry. In the HLH group, there were only three cases identified with the UNC13D gene mutation responsible for the FHLH3 phenotype. Another four children, without known mutation, were classified as FHLH because of frequent recurrence of the disease. In all cases of FHLH, cell cytotoxicity was impaired compared with healthy children (p = 0.003). Perforin expression in FHLH was normal or higher than that observed in controls (p = 0.09). In case of patients with mutation in the Munc13 protein, degranulation was lower than that in healthy children (<5 %). The findings of this study demonstrate that children with known mutations responsible for the FHLH development are immunocompromised. However, it requires further elucidation whether the presence of currently unknown mutations could lead to a similar phenotype.

PMID: 26987330 [PubMed - as supplied by publisher]

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Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia.

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Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia.

Blood. 2015 Nov 26;126(22):2484-90

Authors: Churpek JE, Pyrtel K, Kanchi KL, Shao J, Koboldt D, Miller CA, Shen D, Fulton R, O'Laughlin M, Fronick C, Pusic I, Uy GL, Braunstein EM, Levis M, Ross J, Elliott K, Heath S, Jiang A, Westervelt P, DiPersio JF, Link DC, Walter MJ, Welch J, Wilson R, Ley TJ, Godley LA, Graubert TA

Abstract
Familial clustering of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) can be caused by inherited factors. We screened 59 individuals from 17 families with 2 or more biological relatives with MDS/AML for variants in 12 genes with established roles in predisposition to MDS/AML, and identified a pathogenic germ line variant in 5 families (29%). Extending the screen with a panel of 264 genes that are recurrently mutated in de novo AML, we identified rare, nonsynonymous germ line variants in 4 genes, each segregating with MDS/AML in 2 families. Somatic mutations are required for progression to MDS/AML in these familial cases. Using a combination of targeted and exome sequencing of tumor and matched normal samples from 26 familial MDS/AML cases and asymptomatic carriers, we identified recurrent frameshift mutations in the cohesin-associated factor PDS5B, co-occurrence of somatic ASXL1 mutations with germ line GATA2 mutations, and recurrent mutations in other known MDS/AML drivers. Mutations in genes that are recurrently mutated in de novo AML were underrepresented in the familial MDS/AML cases, although the total number of somatic mutations per exome was the same. Lastly, clonal skewing of hematopoiesis was detected in 67% of young, asymptomatic RUNX1 carriers, providing a potential biomarker that could be used for surveillance in these high-risk families.

PMID: 26492932 [PubMed - indexed for MEDLINE]

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Distinct Acute Lymphoblastic Leukemia (ALL)-associated Janus Kinase 3 (JAK3) Mutants Exhibit Different Cytokine-Receptor Requirements and JAK Inhibitor Specificities.

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Distinct Acute Lymphoblastic Leukemia (ALL)-associated Janus Kinase 3 (JAK3) Mutants Exhibit Different Cytokine-Receptor Requirements and JAK Inhibitor Specificities.

J Biol Chem. 2015 Nov 27;290(48):29022-34

Authors: Losdyck E, Hornakova T, Springuel L, Degryse S, Gielen O, Cools J, Constantinescu SN, Flex E, Tartaglia M, Renauld JC, Knoops L

Abstract
JAK1 and JAK3 are recurrently mutated in acute lymphoblastic leukemia. These tyrosine kinases associate with heterodimeric cytokine receptors such as IL-7 receptor or IL-9 receptor, in which JAK1 is appended to the specific chain, and JAK3 is appended to the common gamma chain. Here, we studied the role of these receptor complexes in mediating the oncogenic activity of JAK3 mutants. Although JAK3(V674A) and the majority of other JAK3 mutants needed to bind to a functional cytokine receptor complex to constitutively activate STAT5, JAK3(L857P) was unexpectedly found to not depend on such receptor complexes for its activity, which was induced without receptor or JAK1 co-expression. Introducing a mutation in the FERM domain that abolished JAK-receptor interaction did not affect JAK3(L857P) activity, whereas it inhibited the other receptor-dependent mutants. The same cytokine receptor independence as for JAK3(L857P) was observed for homologous Leu(857) mutations of JAK1 and JAK2 and for JAK3(L875H). This different cytokine receptor requirement correlated with different functional properties in vivo and with distinct sensitivity to JAK inhibitors. Transduction of murine hematopoietic cells with JAK3(V674A) led homogenously to lymphoblastic leukemias in BALB/c mice. In contrast, transduction with JAK3(L857P) induced various types of lymphoid and myeloid leukemias. Moreover, ruxolitinib, which preferentially blocks JAK1 and JAK2, abolished the proliferation of cells transformed by the receptor-dependent JAK3(V674A), yet proved much less potent on cells expressing JAK3(L857P). These particular cells were, in contrast, more sensitive to JAK3-specific inhibitors. Altogether, our results showed that different JAK3 mutations induce constitutive activation through distinct mechanisms, pointing to specific therapeutic perspectives.

PMID: 26446793 [PubMed - indexed for MEDLINE]

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Testicular metastasis from gastric carcinoma: A case report.

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Testicular metastasis from gastric carcinoma: A case report.

World J Gastroenterol. 2015 Jun 7;21(21):6764-8

Authors: Li B, Cai H, Kang ZC, Wu H, Hou JG, Ma LY

Abstract
Gastric cancer (GC) is the most prevalent malignancy in the world, especially in China. GC has been postulated to spread via several different routes, including through hematogenous channels, lymphatic vessels, the seeding of peritoneal surfaces, direct extension through the gastric wall, and retrograde extension through the vas deferens or lymphatics. Testicular metastasis is rare. We show here a 53-year-old patient with GC who underwent a radical total gastrectomy approximately 22 mo ago after he presented with a sensation of heaviness and swelling of the right hemiscrotum. The diagnosis of metastatic adenocarcinoma was made after a right-side orchiectomy. We report the first case of testicular metastasis from gastric adenocarcinoma in mainland China and summarize the clinicopathologic features of the disease based on previously published papers.

PMID: 26074716 [PubMed - indexed for MEDLINE]

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Decreased level of phosphatidylcholine (16:0/20:4) in multiple myeloma cells compared to plasma cells: a single-cell MALDI-IMS approach.

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Decreased level of phosphatidylcholine (16:0/20:4) in multiple myeloma cells compared to plasma cells: a single-cell MALDI-IMS approach.

Anal Bioanal Chem. 2015 Jul;407(18):5273-80

Authors: Hossen MA, Nagata Y, Waki M, Ide Y, Takei S, Fukano H, Romero-Perez GA, Tajima S, Yao I, Ohnishi K, Setou M

Abstract
Lipid metabolic changes under diseased conditions, particularly in solid tumors, are attracting increased attention. However, in non-solid tumors, including most hematopoietic tumors, lipid analyses are scarce. Multiple myeloma (MM) is a plasma cell disorder arising from bone marrow, and the lipid status of MM cells has not been reported yet. In this study, we analyzed flow cytometry-sorted single MM cells and normal plasma cells (NPCs) using matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS), a two-dimensional label-free mass spectrometry technique for biomolecular analysis, to obtain specific lipid information. We isolated 1.31-5.77% of MM cells and 0.03-0.24% of NPCs using fluorescence-activated cell sorting (FACS). Analysis of purified cells using MALDI-IMS at the single-cell level revealed that the peak intensity and ion signals of phosphatidylcholine [PC (16:0/20:4) + H](+) at m/z 782.5 were significantly decreased in MM cells compared to NPCs. By examining particular cell populations rather than cell mixtures, our method can become a suitable tool for the analysis of rare cell populations at the single-cell level and advance the understanding of MM progression.

PMID: 25957845 [PubMed - indexed for MEDLINE]

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Epigenetics markers of metastasis and HPV-induced tumorigenesis in penile cancer.

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Epigenetics markers of metastasis and HPV-induced tumorigenesis in penile cancer.

Clin Cancer Res. 2015 Mar 1;21(5):1196-206

Authors: Feber A, Arya M, de Winter P, Saqib M, Nigam R, Malone PR, Tan WS, Rodney S, Lechner M, Freeman A, Jameson C, Muneer A, Beck S, Kelly JD

Abstract
PURPOSE: Penile cancer is a rare malignancy in the developed world with just more than 1,600 new cases diagnosed in the United States per year; however, the incidence is much higher in developing countries. Although HPV is known to contribute to tumorigenesis, little is known about the genetic or epigenetic alterations defining penile cancer.
EXPERIMENTAL DESIGN: Using high-density genome-wide methylation arrays, we have identified epigenetic alterations associated with penile cancer. Q-MSP was used to validate lymph node metastasis markers in 50 cases. A total of 446 head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESCC) samples were used to validate HPV-associated epigenetic alterations.
RESULTS: We defined 6,933 methylation variable positions (MVP) between normal and tumor tissue, which includes 997 hypermethylated differentially methylated regions associated with tumor supressor genes, including CDO1, AR1, and WT1. Analysis of penile cancer tumors identified a 4 gene epi-signature which accurately predicted lymph node metastasis in an independent cohort (AUC of 89%). Finally, we explored the epigenetic alterations associated with penile cancer HPV infection and defined a 30 loci lineage-independent HPV specific epi-signature which predicts HPV status and survival in independent HNSCC, CESC cohorts. Epi-signature-negative patients have a significantly worse overall survival [HNSCC P = 0.00073; 95% confidence interval (CI), 0.021-0.78; CESC P = 0.0094; HR = 3.91, 95% CI = 0.13-0.78], HPV epi-signature is a better predictor of survival than HPV status alone.
CONCLUSIONS: These data demonstrate for the first time genome-wide epigenetic events involved in an aggressive penile cancer phenotype and define the epigenetic alterations common across multiple HPV-driven malignancies.

PMID: 25538261 [PubMed - indexed for MEDLINE]

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Extrarenal nephroblastomatosis in children: a report of two cases.

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Extrarenal nephroblastomatosis in children: a report of two cases.

BMC Pediatr. 2014;14:255

Authors: Wu Y, Zhu X, Wang X, Wang H, Cao X, Wang J

Abstract
BACKGROUND: Extrarenal nephroblastomatosis is a rare entity which occurs in retroperitoneum and inguinal region predominantly. Here we report two cases of primary extrarenal nephroblastomatosis of Han Chinese in Asian in unusual locations, one is located in testis and paratestis, and the other is paraspinal cord.
CASE PRESENTATION: Patient 1 was a 19-month-old boy with a hard and nodular mass adherent to the left testis in inguinal region. Patient 2 was a 9-month-old boy with a 1 × 0.7 × 0.4 cm mass in spinal canal at the midline thoracolumbar region. Histological examinations of the two patients after operations revealed extrarenall nephroblastomatosis with multiple nephrogenic foci, composed of immature glomeruli, tubules and blastemal cells.Then the patients were closely monitored without adjuvant chemotherapy, and has been alive and well without any recurrence for >6 months.
CONCLUSIONS: Most nephrogenic rests remain subclinical, and thus, complete excision of the lesion with conservative treatment is recommended. Otherwise, nephrogenic rests are close associated with Wilms tumor and regular follow-up is required to ensure early detection of malignant transformation.

PMID: 25288411 [PubMed - indexed for MEDLINE]

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Clinical course and progression-free survival of adult intracranial and spinal ependymoma patients.

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Clinical course and progression-free survival of adult intracranial and spinal ependymoma patients.

Neuro Oncol. 2015 Mar;17(3):440-7

Authors: Vera-Bolanos E, Aldape K, Yuan Y, Wu J, Wani K, Necesito-Reyes MJ, Colman H, Dhall G, Lieberman FS, Metellus P, Mikkelsen T, Omuro A, Partap S, Prados M, Robins HI, Soffietti R, Wu J, Gilbert MR, Armstrong TS, CERN Foundation

Abstract
BACKGROUND: Ependymomas are rare CNS tumors. Previous studies describing the clinical course of ependymoma patients were restricted to small sample sizes, often with patients at a specific institution.
METHODS: Clinically annotated ependymoma tissue samples from 19 institutions were centrally reviewed. Patients were all adults aged 18 years or older at the time of diagnosis. Potential prognostic clinical factors identified on univariate analysis were included in a multivariate Cox proportional hazards model with backwards selection to model progression-free survival.
RESULTS: The 282 adult ependymoma patients were equally male and female with a mean age of 43 years (range, 18-80y) at diagnosis. The majority were grade II (78%) with the tumor grade for 20 cases being reclassified on central review (half to higher grade). Tumor locations were spine (46%), infratentorial (35%), and supratentorial (19%). Tumor recurrence occurred in 26% (n = 74) of patients with a median time to progression of 14 years. A multivariate Cox proportional hazards model identified supratentorial location (P < .01), grade III (anaplastic; P < .01), and subtotal resection, followed or not by radiation (P < .01), as significantly increasing risk of early progression.
CONCLUSIONS: We report findings from an ongoing, multicenter collaboration from a collection of clinically annotated adult ependymoma tumor samples demonstrating distinct predictors of progression-free survival. This unique resource provides the opportunity to better define the clinical course of ependymoma for clinical and translational studies.

PMID: 25121770 [PubMed - indexed for MEDLINE]

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Prostate tumor overexpressed-1 in conjunction with human papillomavirus status, predicts outcome in early-stage human laryngeal squamous cell carcinoma.

Prostate tumor overexpressed-1 in conjunction with human papillomavirus status, predicts outcome in early-stage human laryngeal squamous cell carcinoma.

Oncotarget. 2016 Mar 15;

Authors: Yang L, Wang H, Wang Y, He Z, Chen H, Liang S, He S, Wu S, Song L, Chen Y

Abstract
In human cancer, molecular markers combined with clinical characteristics are used increasingly to predict prognosis. Prostate tumor overexpressed-1 (PTOV1), first identified in prostate cancer, is a key factor in tumor progression and correlates with unfavorable clinical outcomes. HPV infection status was tested by HPV E6-targeted multiplex real-time PCR and p16 immunohistochemistry (IHC). Real-time PCR and western blotting analyses were used to examine the mRNA and protein expression levels of PTOV1 in eight paired LSCC samples. IHC was performed to assess PTOV1 protein expression in 196 paraffin-embedded, archived LSCC samples. PTOV1 protein and mRNA expression was increased in LSCC tissues compared with adjacent non-cancerous tissue samples. High expression of PTOV1was significantly associated with advanced TNM stage by the χ2 test. Multivariate analysis revealed that PTOV1 and HPV status were independent prognostic indicators of overall survival (OS) and progression-free survival (PFS) (P = 0.001, P = 0.009 for OS, P = 0.005, P = 0.012 for PFS, respectively). Our study provides the first evidence that the combination of PTOV1 expression level and HPV status provides more prognostic information compared with HPV status alone with the significance still exists in the HPV negative subgroup.

PMID: 26992242 [PubMed - as supplied by publisher]

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BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21.

BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21.

Oncotarget. 2016 Mar 15;

Authors: Hyemin L, Dai F, Zhuang L, Xiao ZD, Kim J, Zhang Y, Ma L, You MJ, Wang Z, Gan B

Abstract
BAF180 (also called PBRM1), a subunit of the SWI/SNF complex, plays critical roles in the regulation of chromatin remodeling and gene transcription, and is frequently mutated in several human cancers. However, the role of mammalian BAF180 in tumor suppression and tissue maintenance in vivo remains largely unknown. Here, using a conditional somatic knockout approach, we explored the cellular and organismal functions of BAF180 in mouse. BAF180 deletion in primary mouse embryonic fibroblasts (MEFs) triggers profound cell cycle arrest, premature cellular senescence, without affecting DNA damage response or chromosomal integrity. While somatic deletion of BAF180 in adult mice does not provoke tumor development, BAF180 deficient mice exhibit defects in hematopoietic system characterized by progressive reduction of hematopoietic stem cells (HSCs), defective long-term repopulating potential, and hematopoietic lineage developmental aberrations. BAF180 deletion results in elevated p21 expression in both MEFs and HSCs. Mechanistically, we showed that BAF180 binds to p21 promoter, and BAF180 deletion enhances the binding of modified histones associated with transcriptional activation on p21 promoter. Deletion of p21 rescues cell cycle arrest and premature senescence in BAF180 deficient MEFs, and partially rescues hematopoietic defects in BAF180 deficient mice. Together, our study identifies BAF180 as a critical regulator of cellular senescence and HSC homeostasis, which is at least partially regulated through BAF180-mediated suppression of p21 expression. Our results also suggest that senescence triggered by BAF180 inactivation may serve as a failsafe mechanism to restrain BAF180 deficiency-associated tumor development, providing a conceptual framework to further understand BAF180 function in tumor biology.

PMID: 26992241 [PubMed - as supplied by publisher]

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Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells.

Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells.

Oncotarget. 2016 Mar 15;

Authors: Cornet-Masana JM, Moreno-Martínez D, Lara-Castillo MC, Nomdedeu M, Etxabe A, Tesi N, Pratcorona M, Esteve J, Risueño RM

Abstract
Acute myeloid leukemia (AML) is an hematologic neoplasia characterized by the accumulation of transformed immature myeloid cells in bone marrow. Although the response rate to induction therapy is high, survival rate 5-year after diagnosis is still low, highlighting the necessity of new novel agents. To identify agents with the capability to abolish the self-renewal capacity of AML blasts, an in silico screening was performed to search for small molecules that induce terminal differentiation. Emetine, a hit compound, was validated for its anti-leukemic effect in vitro, ex vivo and in vivo. Emetine, a second-line anti-protozoa drug, differentially reduced cell viability and clonogenic capacity of AML primary patient samples, sparing healthy blood cells. Emetine treatment markedly reduced AML burden in bone marrow of xenotransplanted mice and decreased self-renewal capacity of the remaining engrafted AML cells. Emetine also synergized with commonly used chemotherapeutic agents such as ara-C. At a molecular level, emetine treatment was followed by a reduction in HIF-1α protein levels. This study validated the anti-leukemiceffect of emetine in AML cell lines, a group of diverse AML primary samples, and in a human AML-transplanted murine model, sparing healthy blood cells. The selective anti-leukemic effect of emetine together with the safety of the dose range required to exert this effect support the development of this agent in clinical practice.

PMID: 26992240 [PubMed - as supplied by publisher]

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MRP1-CD28 bi-specific oligonucleotide aptamers: target costimulation to drug-resistant melanoma cancer stem cells.

MRP1-CD28 bi-specific oligonucleotide aptamers: target costimulation to drug-resistant melanoma cancer stem cells.

Oncotarget. 2016 Mar 15;

Authors: Soldevilla MM, Villanueva H, Casares N, Lasarte JJ, Bendandi M, Inoges S, López-Díaz de Cerio A, Pastor F

Abstract
In this work we show a clinically feasible strategy to convert in situ the own tumor into an endogenous vaccine by coating the melanoma cancerous cells with CD28 costimulatory ligands. This therapeutic approach is aimed at targeting T-cell costimulation to chemotherapy-resistant tumors which are refractory and been considered as untreatable cancers. These tumors are usually defined by an enrichment of cancer stem cells and characterized by the higher expression of chemotherapy-resistant proteins. In this work we develop the first aptamer that targets chemotherapy-resistant tumors expressing MRP1 through a novel combinatorial peptide-cell SELEX. With the use of the MRP1 aptamer we engineer a MRP1-CD28 bivalent aptamer that is able to bind MRP1-expressing tumors and deliver the CD28 costimulatory signal to tumor-infiltrating lymphocytes. The bi-specific aptamer is able to enhance costimulation in chemotherapy-resistant tumors. Melanoma-bearing mice systemically treated with MRP1-CD28 bivalent aptamer show reduced growth, thus proving an improved mice survival.Besides, we have designed a technically feasible and translational whole-cell vaccine (Aptvax). Disaggregated cells from tumors can be directly decorated with costimulatory ligand aptamers to generate the vaccine Aptvax. CD28Aptvax made of irradiated tumor cells coated with the CD28-agonistic aptamer attached to MRP1 elicits a strong tumor- cell immune response against melanoma tumors reducing tumor growth.

PMID: 26992239 [PubMed - as supplied by publisher]

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Decreased MALL expression negatively impacts colorectal cancer patient survival.

Decreased MALL expression negatively impacts colorectal cancer patient survival.

Oncotarget. 2016 Mar 15;

Authors: Wang X, Fan J, Yu F, Cui F, Sun X, Zhong L, Yan D, Zhou C, Deng G, Wang B, Qi X, Wang S, Qu L, Deng B, Pan M, Chen J, Wang Y, Song G, Tang H, Zhou Z, Peng Z

Abstract
The aim of the present study was to determine whether MALL expression is associated with colon cancer progression and patient survival. MALL mRNA expression was reduced in the tumor tissues of 70% of the colon cancer patients and 75% of the rectal cancer patients as compared to their normal tissues. MALL protein was also significantly reduced in the tumor tissues of colon cancer patients (P < 0.001). Increased LOH and methylation of MALL was observed in tumor tissues as compared to normal tissues. Reduced MALL expression was associated with vessin invasion, disease recurrence and metastasis or death (P ≤ 0.027). Furthermore, patients with MALL-negative tumors had significantly decreased overall survival (OS) and disease-free survival (DFS) (P < 0.008 and P < 0.011, respectively). Univariate analysis indicated that MALL expression was significantly associated with OS and DFS. Finally, overexpression of MALL suppressed HCT116 and SW480 cell proliferation and inhibited HCT116 migration. MALL may play a role in colorectal cancer progression as suppression of its expression in tumor tissues negatively impacts colorectal cancer patient survival. Further analyses are required to determine if reduced MALL expression is due to LOH and/or methylation.

PMID: 26992238 [PubMed - as supplied by publisher]

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Safety of two-year caloric restriction in non-obese healthy individuals.

Safety of two-year caloric restriction in non-obese healthy individuals.

Oncotarget. 2016 Mar 15;

Authors: Romashkan SV, Das SK, Villareal DT, Ravussin E, Redman LM, Rochon J, Bhapkar M, Kraus WE, CALERIE Study Group

Abstract
BACKGROUND: The extent to which sustained caloric restriction (CR) in healthy non-obese adults is safe has not been previously investigated.
OBJECTIVE: Assess the safety and tolerability of sustained two-year CR intervention in healthy, non-obese adults.
DESIGN: A multi-center, randomized controlled trial. Participants were randomized using a 2:1 allocation in favor of 25% CR vs. Ad-Libitum intake (AL). Adverse and serious adverse events (AE, SAE), safety laboratory tests, and other safety parameters were closely monitored.
RESULTS: Three participants were withdrawn from the CR intervention because of the safety concerns. No deaths and one SAE was reported by participants in the CR group. Although the difference in AE between AL and CR groups was not significant, within the CR group, the incidence of nervous system (p = 0.02), musculoskeletal (p = 0.02) and reproductive system (p = 0.002) disorders was significantly higher in the normal-weight than in the overweight participants. At months 12 and 24, bone mineral densities at the lumbar spine, total hip, and femoral neck of participants in the CR group were significantly lower than in those in the AL group.
CONCLUSIONS: Two-years of CR at levels achieved in CALERIE was safe and well tolerated. Close monitoring for excessive bone loss and anemia is important.

PMID: 26992237 [PubMed - as supplied by publisher]

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Cellular evidence for nano-scale exosome secretion and interactions with spermatozoa in the epididymis of the Chinese soft-shelled turtle, Pelodiscus sinensis.

Cellular evidence for nano-scale exosome secretion and interactions with spermatozoa in the epididymis of the Chinese soft-shelled turtle, Pelodiscus sinensis.

Oncotarget. 2016 Mar 15;

Authors: Chen H, Yang P, Chu X, Huang Y, Liu T, Zhang Q, Li Q, Hu L, Waqas Y, Ahmed N, Chen Q

Abstract
The epididymis is the location of sperm maturation and sperm storage. Recent studies have shown that nano-scale exosomes play a vital role during these complicated processes. Our aim was to analyze the secretory properties of epididymal exosomes and their ultrastructural interaction with maturing spermatozoa in the Chinese soft-shelled turtle. The exosome marker CD63 was primarily localized to the apices of principal cells throughout the epididymal epithelium. Identification of nano-scale exosomes and their secretory processes were further investigated via transmission electron microscopy. The epithelium secreted epididymal exosomes (50~300 nm in diameter) through apocrine secretion and the multivesicular body (MVB) pathway. Spermatozoa absorbed epididymal exosomes through endocytosis or membrane fusion pathways. This study shows, for the first time, that nano-scale exosomes use two secretion and two absorption pathways in the reptile, which may be contribute to long-term sperm storage.

PMID: 26992236 [PubMed - as supplied by publisher]

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