Response to Cuttler et al. re: “Low-Dose Childhood Radiation Effects to the Thyroid Follow a Linear Dose–Response Trend and Persist Even 45+ Years After Exposure”

Thyroid, Ahead of Print.


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Influence of the width of keratinized tissue on the development and resolution of experimental peri‐implant mucositis lesions in humans

Clinical Oral Implants Research, EarlyView.


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Active and Persistent Cytomegalovirus Infections Affect T Cells in Young Adult HIV Patients Commencing Antiretroviral Therapy

Viral Immunology, Ahead of Print.


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Influenza Vaccination Protects Against Pandemic H1N1 Infection in Sickle Cell Disease Mice

Viral Immunology, Ahead of Print.


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Colorectal Cancer-Associated Spontaneous Tumor Lysis Syndrome: a Case Report and Review of the Current Literature

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Surgico-pathological Outcomes of 148 Radical Cholecystectomies Using Systematic Regional Lymphadenectomy Protocol: a Retrospective Study

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Development of a patient‐centric food allergy research program: A model for action

Allergy, EarlyView.


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Nasal hyperreactivity in rhinitis: a diagnostic and therapeutic challenge

.


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Genetic predisposition to obesity is associated with asthma in US Hispanics/Latinos: Results from the Hispanic Community Health Study/Study of Latinos

Allergy, EarlyView.


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Identification of CPE and GAIT elements in 3’UTR of macrophage migration inhibitory factor (MIF) involved in inflammatory response induced by LPS in Ciona robusta

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Aiti Vizzini, Maria Giovanna Parisi, Felicia Di Falco, Laura Cardinale, Matteo Cammarata, Vincenzo Arizza
Innate immune responses face infectious microorganisms by inducing inflammatory responses. Multiple genes within distinct functional categories are coordinately and temporally regulated by transcriptional 'on' and 'off' switches that account for the specificity of gene expression in response to external stimuli. Mechanisms that control transcriptional and post-transcriptional regulation are important in coordinating the initiation and resolution of inflammation. Macrophage migration inhibitory factor (MIF) is an important cytokine that, in Ciona robusta, is related to inflammatory response. It is well known that in C. robusta, formerly known as Ciona intestinalis, the pharynx is involved in the inflammatory reaction induced by lipopolysaccharide (LPS) injection in the body wall. Using this biological system, we describe the identification of two C. robusta MIFs (CrMIF1 and CrMIF2). The phylogenetic tree and modeling support a close relationship with vertebrate MIF family members. CrMIF1 and CrMIF2 possess two evolutionally conserved catalytic sites: a tautomerase and an oxidoreductase site with a conserved CXXC motif. Real-time PCR analysis shows a prompt expression induced by LPS inoculation in CrMIF1 and a late upregulation of CrMIF2 and in silico analyses of 3'UTR show a cis-acting GAIT element and a CPE element in 3'-UTR, which are not present in the 3'-UTR of CrMIF1, suggesting that different transcriptional and post-transcriptional control mechanisms are involved in the regulation of gene expression of MIF during inflammatory response in C. robusta.



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"Med Oral Patol Oral Cir Bucal"[jour]; +18 new citations

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

"Med Oral Patol Oral Cir Bucal"[jour]

These pubmed results were generated on 2018/04/24

PubMed comprises more than millions of 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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"Med Oral Patol Oral Cir Bucal"[jour]; +18 new citations

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

"Med Oral Patol Oral Cir Bucal"[jour]

These pubmed results were generated on 2018/04/24

PubMed comprises more than millions of 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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Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR

Purpose: Hepatocellular carcinoma (HCC) ranks second in cancer mortality and has limited therapeutic options. We recently described the synergistic effect of allosteric and ATP-site competitive inhibitors against the mammalian target of rapamycin (mTOR) for the treatment of HCC. However, such inhibitors induce glycemia and increase mitochondrial efficiency. Here we determined whether the mitochondrial complex I inhibitor Phenformin could reverse both side effects, impose an energetic-stress on cancer cells and suppress the growth of HCC. Experimental Design: Human HCC cell lines were used in vitro to access the signaling and energetic impact of mTOR inhibitors and Phenformin, either alone or in combination. Next, the therapeutic utility of these drugs alone or in combination was investigated pre-clinically in human orthotopic tumors implanted in mice, by analyzing their impact on the tumor burden and overall survival. Results: We found Phenformin caused mitochondrial dysfunction and fragmentation, inducing a compensatory shift to glycolysis. In contrast, dual inhibition of mTOR impaired cell growth and glycolysis, while increasing mitochondrial fusion and efficiency. In a mouse model of human HCC, dual inhibition of mTOR, together with Phenformin, was highly efficacious in controlling tumor burden. However, more striking, pretreatment with Phenformin sensitized tumors to dual inhibition of mTOR, leading to a dramatic improvement in survival. Conclusion: Treatment of HCC cells in vitro with the biguanide Phenformin causes a metabolic shift to glycolysis, mitochondrial dysfunction and fragmentation, and dramatically sensitizes orthotopic liver tumors to dual inhibition of mTOR. We therefore propose this therapeutic approach should be tested clinically in HCC.

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Immunotherapy for glioblastoma: playing chess, not checkers

Patients with glioblastoma (GBM) exhibit a complex state of immune dysfunction involving multiple mechanisms of local, regional, and systemic immune suppression and tolerance. These pathways are now being identified and their relative contributions explored. Delineating how these pathways are interrelated is paramount to effectively implementing immunotherapy for GBM.

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Validation of a plasma-based comprehensive cancer genotyping assay utilizing orthogonal tissue- and plasma-based methodologies

Purpose: Liquid biopsies are powerful tools that enable non-invasive genotyping of advanced solid tumors; however, comprehensive, structured validation studies employing validated orthogonal comparator methods are lacking. Experimental Design: Analytical validation was conducted according to established principles and guidelines. Blood-to-blood clinical validation comprised blinded external comparison to clinical digital droplet PCR across 222 consecutive biomarker-positive clinical samples. Blood-to-tissue clinical validation comprised comparison of Digital Sequencing calls to those documented in the medical record of 543 consecutive lung cancer patients. Clinical experience was reported from 10,593 consecutive clinical samples. Results: Digital Sequencing technology enabled variant detection down to 0.02%-0.04% allelic fraction/2.12 copies with ≤0.3%/2.24-2.76 copies 95% limits of detection while maintaining high specificity (prevalence-adjusted PPVs >98%). Clinical validation using orthogonal plasma- and tissue-based clinical genotyping across >750 patients demonstrated high accuracy and specificity (PPAs and NPAs >99% and PPVs 92-100%). Clinical use in 10,593 advanced adult solid tumor patients demonstrated high feasibility (>99.6% technical success rate) and clinical sensitivity (85.9%), with high potential actionability (16.7% with FDA-approved on-label treatment options; 72.0% with treatment or trial recommendations), particularly in non-small cell lung cancer where 34.5% of patient samples comprised a directly targetable standard-of-care biomarker. Conclusions: High concordance with orthogonal clinical plasma- and tissue-based genotyping methods supports the clinical accuracy of Digital Sequencing across all four types of targetable genomic alterations. Digital Sequencing's clinical applicability is further supported by high rates of technical success and biomarker target discovery.

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Reciprocal Network between Cancer Stem-Like Cells and Macrophages Facilitates the Progression and Androgen Deprivation Therapy Resistance of Prostate Cancer

Purpose: Cancer stem-like cells (CSCs) contribute to the progression and androgen deprivation therapy (ADT) resistance of prostate cancer. Since CSCs depend on their specific niche, including tumor-associated macrophages (TAMs), elucidating the network between CSCs and TAMs may help to effectively inhibit the progression and ADT resistance of prostate cancer. Experimental Design: The underlying intracellular mechanism that sustains the stem-like characteristics of CSCs in prostate cancer was assessed via RNA-seq, co-IP, ChIP and other assays. A co-culture system and cytokine antibody arrays were employed to examine the interaction network between CSCs and TAMs. In addition, an orthotopic prostate cancer model was established to evaluate the in vivo effects of the combined targeting of CSCs and their interaction with TAMs on ADT resistance. Results: Autophagy-related gene 7 (ATG7) facilitated the transcription of OCT4 via β-catenin which binds to the OCT4 promoter, promoting CSC characteristics in prostate cancer, including self-renewal, tumor initiation and drug resistance. In addition, CSCs remodeled their specific niche by educating monocytes/macrophages towards TAMs, and the CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, progression and ADT resistance of prostate cancer via interleukin 6 (IL6)/STAT3. Furthermore, the combined targeting of CSCs and their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an orthotopic prostate cancer model. Conclusions: Targeting CSCs and their niche may prove to be a more powerful strategy than targeting CSCs alone, providing a rational approach to ameliorating ADT resistance in prostate cancer.

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Tryptophan metabolism contributes to radiation-induced immune checkpoint reactivation in glioblastoma

Purpose: Immune checkpoint inhibitors designed to revert tumor-induced immune suppression have emerged as potent anti-cancer therapies. Tryptophan metabolism represents an immune checkpoint and targeting this pathway's rate limiting enzyme IDO1 is actively being investigated clinically. Here, we studied the intermediary metabolism of tryptophan metabolism in glioblastoma and evaluated the activity of the IDO1 inhibitor GDC-0919, both alone and in combination with radiation (RT).  Experimental Design: LC/GC-MS and expression profiling was performed for metabolomic and genomic analyses of patient-derived glioma. Immune competent mice were injected orthotopically with genetically engineered murine glioma cells and treated with GDC-0919 alone or combined with RT. Flow-cytometry was performed on isolated tumors to determine immune consequences of individual treatments. Results: Integrated cross-platform analyses coupling global metabolomic and gene-expression profiling identified aberrant tryptophan metabolism as a metabolic node specific to the mesenchymal and classical subtypes of glioblastoma. GDC-0919 demonstrated potent inhibition of this node and effectively crossed the blood brain barrier. Although GDC-0919 as a single agent did not demonstrate anti-tumor activity, it had a strong potential for enhancing RT response in glioblastoma, which was further augmented with a hypofractionated regimen. RT response in glioblastoma involves immune stimulation, reflected by increases in activated and cytotoxic T-cells, which was balanced by immune checkpoint reactivation, reflected by an increase in IDO1 expression and Tregs.  GDC-0919 mitigated RT-induced Tregs and enhanced T-cell activation. Conclusion:  Tryptophan metabolism represents a metabolic node in glioblastoma and combining RT with IDO1 inhibition enhances therapeutic response by mitigating RT-induced immune suppression.

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Enhanced Therapeutic Activity of Non-Internalizing Small Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX in Combination With Targeted Interleukin-2

Purpose: Antibody-drug conjugates and small molecule-drug conjugates have been proposed as alternatives to conventional anti-cancer cytotoxic agents, with the potential to deliver bioactive payloads to the site of disease, helping spare normal tissues. Experimental Design: Here we describe a novel small molecule-drug conjugate, based on a high-affinity ligand specific to carbonic anhydrase IX. The product featured a peptidic linker, suitable for cleavage in the tumor extracellular environment, and monomethyl auristatin E as cytotoxic payload. Results: A potent anti-cancer activity was observed in nude mice bearing SKRC-52 renal cell carcinoma xenografts, but no durable complete responses could be observed in this model. However, when the product was administered together with L19-IL2 (a clinical-stage fusion protein capable of delivering interleukin-2 to the tumor neo-vasculature), all treated mice in the combination group could be rendered tumor-free, in a process which favored the influx of natural killer cells into the tumor mass. The combination of L19-IL2 and the new small molecule-drug conjugate also eradicated cancer in 100% of immunocompetent mice, bearing subcutaneously-grafted CT26 colorectal cancer cells, which stably expressed carbonic anhydrase IX. Conclusions: These findings may be of clinical significance, since carbonic anhydrase IX is over-expressed in the majority of clear-cell renal cell carcinomas and in approximately 30% of colorectal cancers. The targeted delivery of interleukin-2 helps potentiate the action of targeted cytotoxics leading to cancer eradication in models that cannot be cured by conventional chemotherapy.

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Andecaliximab/GS-5745 alone and combined with mFOLFOX6 in advanced gastric and gastroesophageal junction adenocarcinoma: Results from a phase 1 study

Purpose: Matrix metalloproteinase-9 (MMP9) is implicated in pro-tumorigenic processes. Andecaliximab (GS-5745, a monoclonal antibody targeting MMP9) was evaluated as monotherapy and in combination with mFOLFOX6. Experimental Design: Three dosages of andecaliximab monotherapy (200, 600, and 1800 mg IV every 2 weeks [q2w]) were investigated in patients with advanced solid tumors (n=13 in a 3+3 design). After determining a recommended dose, patients with advanced HER2-negative gastric/gastroesophageal junction (GEJ) adenocarcinoma (n=40) received 800 mg andecaliximab + mFOLFOX6 q2w. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed. Results: Andecaliximab monotherapy demonstrated no dose-limiting toxicity (DLT) in any cohort, displaying target-mediated drug disposition at the lowest dose (200 mg) and linear pharmacokinetics at higher doses. Based on target engagement, recommended doses for further study are 800 mg q2w or 1200 mg q3w. Maximal andecaliximab target binding, defined as undetectable andecaliximab-free MMP9 in plasma, was observed in the gastric/GEJ adenocarcinoma cohort. We observed no unusual toxicity, although there were 4 deaths on study not attributed to andecaliximab treatment. In first-line patients (n=36), median progression free survival (PFS) was 9.9 months (95% CI 5-13.9 months) and the overall response rate (ORR) was 50%. Among all patients (n=40), median PFS was 7.8 (90% CI, 5.5-13.9) months and ORR was 48%, with a median duration of response of 8.4 months. Conclusions: Andecaliximab monotherapy achieved target engagement without DLT. Andecaliximab + mFOLFOX6 showed encouraging clinical activity without additional toxicity in patients with HER2-negative gastric/GEJ adenocarcinoma. A phase 3 study evaluating mFOLFOX6 +/- andecaliximab in this setting is ongoing.

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Undifferentiated sarcomas in children harbor clinically-relevant oncogenic fusions and gene copy-number alterations: A report from the Children's Oncology Group

Purpose: A comprehensive analysis of the genomics of undifferentiated sarcomas (UDS) is lacking.  We analyzed copy number alterations and fusion status in patients with UDS prospectively treated on Children's Oncology Group protocol ARST0332. Experimental Design: Copy number alterations were assessed by Oncoscan FFPE Express on 32 UDS. Whole-exome and transcriptome libraries from 8 tumors with sufficient archived material were sequenced on HiSeq (2x100 bp). Targeted RNA-sequencing using Archer chemistry was performed on two additional cases. Results: Five-year overall survival for patients with UDS was 83% (95% CI: 69% to 97%) with risk adapted therapy (surgery, chemotherapy, radiotherapy). Both focal and arm-level copy number alterations were common including gain of 1q (8/32, 25%) and loss of 1p (7/32, 22%), both of which occurred more often in clinically defined high risk tumors. Tumors with both loss of 1p and gain of 1q carried an especially poor prognosis with a five-year event free survival of 20%. GISTIC analysis identified recurrent amplification of FGF1 on 5q31.3 (q=0.03) and loss of CDKN2A and CDKN2B on 9p21.3 (q=0.07). Known oncogenic fusions were identified in 8 of 10 cases analyzed by next generation sequencing. Conclusions: Pediatric UDS generally has a good outcome with risk-adapted therapy. A high-risk subset of patients whose tumors have copy number loss of 1p and gain of 1q was identified with only 20% survival. Oncogenic fusions are common in UDS and next generation sequencing should be considered for children with UDS to refine the diagnosis and identify potentially targetable drivers.

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Metformin targets Mitochondrial Glycerophosphate Dehydrogenase (mGPDH) to control Rate of Oxidative Phosphorylation and growth of thyroid cancer in vitro and in vivo

Purpose: Mitochondrial glycerophosphate dehydrogenase (mGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin (MF) in the liver. There are no data on the expression and role of mGPDH as a metformin target in cancer. In this study, we evaluated mGPDH as a potential target of metformin in thyroid cancer and investigated its contribution in thyroid cancer metabolism. Experimental design: We analyzed mGPDH expression in 253 thyroid cancer and normal tissues by immunostaining and examined its expression and localization in thyroid cancer-derived cell lines (FTC133, BCPAP) by confocal microscopy. The effects of metformin on mGPDH expression were determined by qRT-PCR and western blot.  Seahorse analyzer was utilized to assess the effects of metformin on OXPHOS and glycolysis in thyroid cancer cells. We analyzed the effects of metformin on tumor growth and mGPDH expression in metastatic thyroid cancer mouse models. Results: We show for the first time that mGPDH is overexpressed in thyroid cancer compared with normal thyroid. We demonstrate that mGPDH regulates human thyroid cancer cell growth and OXPHOS rate in vitro. Metformin treatment is associated with downregulation of mGPDH expression and inhibition of OXPHOS in thyroid cancer in vitro. Cells characterized by high mGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin in vitro and growth inhibitory effects of metformin in vitro and in vivo. Conclusion: Our study established mGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin.

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NFATc1 promotes anti-tumoral effector functions and memory CD8+ T cell differentiation during non-small cell lung cancer development

Nuclear factor of activated T cells 1 (NFATc1) is a transcription factor activated by T cell receptor (TCR) and Ca2+-signaling that affects T cell activation and effector function. Upon tumor antigen challenge, TCR and calcium-release-activated channels are induced, promoting NFAT dephosphorylation and translocation into the nucleus. In this study, we report a progressive decrease of NFATc1 in lung tumor tissue and in tumor-infiltrating lymphocytes (TIL) of patients suffering from advanced stage non-small cell lung cancer (NSCLC). Mice harboring conditionally inactivated NFATc1 in T cells (NFATc1ΔCD4) showed increased lung tumor growth associated with impaired T cell activation and function. Furthermore, in the absence of NFATc1, reduced IL 2 influenced the development of memory CD8+ T cells. We found a reduction of effector memory and CD103+ tissue-resident memory (TRM) T cells in the lung of tumor-bearing NFATc1ΔCD4 mice, underlining an impaired cytotoxic T cell response and a reduced TRM tissue-homing capacity. In CD4+ICOS+ T cells, programmed cell death 1 (PD-1) was induced in the draining lymph nodes of these mice and associated with lung tumor cell growth. Targeting PD-1 resulted in NFATc1 induction in CD4+ and CD8+ T cells in tumor-bearing mice and was associated with increased anti-tumor cytotoxic functions. This study reveals a role of NFATc1 in the activation and cytotoxic functions of T cells, in the development of memory CD8+ T cell subsets, and in the regulation of T cell exhaustion. These data underline the indispensability of NFATc1 for successful anti-tumor immune responses in NSCLC patients.

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The inhibitory NKR-P1B:Clr-b recognition axis facilitates detection of oncogenic transformation and cancer immunosurveillance

Natural killer (NK) cells express receptors specific for MHC class I (MHC-I) molecules involved in "missing-self" recognition of cancer and virus-infected cells. Here we elucidate the role of MHC-I-independent NKR-P1B:Clr-b interactions in the detection of oncogenic transformation by NK cells. Ras oncogene overexpression was found to promote a real-time loss of Clr-b on mouse fibroblasts and leukemia cells, mediated in part via the Raf/MEK/ERK and PI3K pathways. Ras-driven Clr-b downregulation occurred at the level of the Clrb (Clec2d) promoter, nascent Clr-b transcripts, and cell surface Clr-b protein, in turn promoting missing-self recognition via the NKR-P1B inhibitory receptor. Both Ras- and c-Myc-mediated Clr-b loss selectively augmented cytotoxicity of oncogene-transformed leukemia cells by NKR-P1B+ NK cells in vitro and enhanced rejection by WT mice in vivo. Interestingly, genetic ablation of either one (Clr-b+/-) or two Clr-b alleles (Clr-b-/-) enhanced survival of Eμ-cMyc transgenic mice in a primary lymphoma model despite preferential rejection of Clr-b-/- hematopoietic cells previously observed following adoptive transfer into naïve wild-type mice in vivo. Collectively, these findings suggest that the inhibitory NKR-P1B:Clr-b axis plays a beneficial role in innate detection of oncogenic transformation via NK cell-mediated cancer immune surveillance, in addition to a pathological role in the immune escape of primary lymphoma cells in Eμ-cMyc mice in vivo. These results provide a model for the human NKR-P1A:LLT1 system in cancer immunosurveillance in lymphoma patients and suggest it may represent a target for immune checkpoint therapy.

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High USP6NL levels in breast cancer sustain chronic AKT phosphorylation and GLUT1 stability fueling aerobic glycolysis

USP6NL, also named RN-tre, is a GTPase activating protein (GAP) involved in control of endocytosis and signal transduction. Here we report that USP6NL is overexpressed in breast cancer (BC), mainly of the basal-like/integrative cluster 10 subtype. Increased USP6NL levels were accompanied by gene amplification and were associated with worse prognosis in the METABRIC dataset, retaining prognostic value in multivariable analysis. High levels of USP6NL in BC cells delayed endocytosis and degradation of the epidermal growth factor receptor (EGFR), causing chronic AKT activation. In turn, AKT stabilized the glucose transporter GLUT1 at the plasma membrane, increasing aerobic glycolysis. In agreement, elevated USP6NL sensitized BC cells to glucose deprivation, indicating that their glycolytic capacity relies on this protein. Depletion of USP6NL accelerated EGFR/AKT downregulation and GLUT1 degradation, impairing cell proliferation exclusively in BC cells that harbored increased levels of USP6NL. Overall, these findings argue that USP6NL overexpression generates a metabolic rewiring that is essential to foster the glycolytic demand of BC cells and promote their proliferation.

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Penetrating Foreign Bodies in Head and Neck Trauma: A Surgical Challenge

Cranial Maxillofac Trauma Reconstruction
DOI: 10.1055/s-0038-1642035

Penetrating foreign bodies of different origins in the head and neck are rare and potentially dangerous injuries, which might pose problems for their detection, primary care, and final treatment. Depending on the severity of the underlying trauma, some injuries present a higher risk for the presence of foreign bodies. Minor wounds, including common lacerations, are likely to be contaminated with loose gravel debris or dental fragments, and need to be distinguished from severe wounds caused by impalement, shootings, stabbings, and explosions. Blast injuries resulting from terror attacks are challenging recent therapeutic concepts. Even though these injury patterns are uncommon, they carry the risk of impacted objects with dramatic consequences. Despite improving medical imaging techniques, detection remains a challenge as it is dependent on the material of the foreign body, the affected anatomical site, and the injury severity. Therefore, a detailed history of the circumstances leading to trauma is essential when foreign objects are not visible during clinical examination. Precise detection of the foreign body, its anatomical position, and the affected surrounding structures are vital, especially for impalement injuries of the head and neck area. Therefore, an interdisciplinary planning approach is essential prior to removal of the foreign object. Finally, tension-free anatomical adaptation of the corresponding structures is crucial for maintaining and restoring aesthetic and function. Here, we give an overview of the diagnosis and treatment of cases of foreign body injuries encountered in our department.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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The influence of bone graft procedures on primary stability and bone change of implants placed in fresh extraction sockets

Abstract

Background

This study was to evaluate the effect of bone graft procedure on the primary stability of implants installed in fresh sockets and assess the vertical alteration of peri-implant bone radiographically.

Methods

Twenty-three implants were inserted in 18 patients immediately after tooth extraction. The horizontal gap between the implant and bony walls of the extraction socket was grafted with xenografts. The implant stability before and after graft procedure was measured by Osstell Mentor as implant stability quotient before bone graft (ISQ bbg) and implant stability quotient after bone graft (ISQ abg). Peri-apical radiographs were taken to measure peri-implant bone change immediately after implant surgery and 12 months after implant placement. Data were analyzed by independent t test; the relationships between stability parameters (insertion torque value (ITV), ISQ abg, and ISQ bbg) and peri-implant bone changes were analyzed according to Pearson correlation coefficients.

Results

The increase of ISQ in low primary stability group (LPSG) was 6.87 ± 3.62, which was significantly higher than the increase in high primary stability group (HPSG). A significant correlation between ITV and ISQ bbg (R = 0.606, P = 0.002) was found; however, age and peri-implant bone change were not found significantly related to implant stability parameters. It was presented that there were no significant peri-implant bone changes at 1 year after bone graft surgery.

Conclusions

Bone graft procedure is beneficial for increasing the primary stability of immediately placed implants, especially when the ISQ of implants is below 65 and that bone grafts have some effects on peri-implant bone maintenance.

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"Med Oral Patol Oral Cir Bucal"[jour]; +18 new citations

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

"Med Oral Patol Oral Cir Bucal"[jour]

These pubmed results were generated on 2018/04/24

PubMed comprises more than millions of 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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Challenges in recruiting African-American women for a breast cancer genetics study

Abstract

Background

African-American women, especially in the southern United States, are underrepresented in cancer genetics research. A study was designed to address this issue by investigating the germline mutation rate in African-American women in Arkansas with a personal and/or family history of breast cancer. Women were tested for these mutations using a large panel of breast cancer susceptibility genes. In this analysis, we discuss the challenges encountered in recruiting African-American women from an existing biorepository to participate in this study.

Methods

We attempted to contact 965 African-American women with a personal and/or family history of breast cancer who participated in Spit for the Cure (SFTC) between 2007 and 2013 and provided consent to be recontacted. The SFTC participants were invited by telephone and email to participate in the genetic study. Enrollment required completion of a phone interview to obtain a family and medical history and return of a signed consent form.

Results

Among eligible SFTC participants, 39.6% (382/965) were able to be contacted with the phone numbers and email addresses they provided. Of these, 174 (45.5%) completed a phone interview and returned a signed consent form. Others were not able to be contacted (n = 583), declined to participate (n = 57), did not keep phone interview appointments (n = 82), completed the phone interview but never returned a signed consent (n = 54), were deceased (n = 13), or were too confused to consent to participate (n = 2).

Conclusions

Recruiting African-American women into our breast cancer genetics study proved challenging primarily due to difficulty establishing contact with potential participants. Given their prior participation in breast cancer research, we anticipated that this would be a highly motivated population. Indeed, when we were able to contact SFTC participants, only 14.9% declined to participate in our study. Innovative communication, retention, and recruitment strategies are needed in future studies to address the recruitment challenges we faced.

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An enhanced fresh cadaveric model for reconstructive microsurgery training

Abstract

Background

Performing microsurgery requires a breadth and depth of experience that has arguably been reduced as result of diminishing operating exposure. Fresh frozen cadavers provide similar tissue handling to real-time operating; however, the bloodless condition restricts the realism of the simulation. We describe a model to enhance flap surgery simulation, in conjunction with qualitative assessment.

Methods

The fresh frozen cadaveric limbs used in this study were acquired by the University. A perfused fresh cadaveric model was created using a gelatin and dye mixture in a specific injection protocol in order to increase the visibility and realism of perforating vessels, as well as major vessels. A questionnaire was distributed amongst 50 trainees in order to assess benefit of the model. Specifically, confidence, operative skills, and transferable procedural-based learning were assessed.

Results

Training with this cadaveric model resulted in a statistically significant improvement in self-reported confidence (p < 0.005) and prepared trainees for unsupervised bench work (p < 0.005). Respondents felt that the injected model allowed easier identification of vessels and ultimately increased the similarity to real-time operating. Our analysis showed it cost £10.78 and took 30 min.

Conclusions

Perfusion of cadaveric limbs is both cost- and time-effective, with significant improvement in training potential. The model is easily reproducible and could be a valuable resource in surgical training for several disciplines.

Level of Evidence: Not ratable.

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Pre-operative predictive estimation of abdominal flap volume for breast reconstruction using ultrasound and an anthropometric method

Abstract

Background

The abdominal flap has proven to be an optimal autologous option for breast reconstruction. However, the feasibility of breast reconstruction using an abdominal flap should be determined pre-operatively, especially in lean patients. In order to achieve optimal symmetry when using an abdominal flap for breast reconstruction, a specific amount of abdominal tissue is required and this should be estimated prior to surgery.

Methods

Patients with unilateral modified radical mastectomies requesting delayed breast reconstruction had their abdominal flap volume measured pre-operatively using a measuring tape and ultrasound. Contralateral breast volume was also measured using magnetic resonance imaging and was compared to the abdominal flap volume. Additionally, body mass index was measured for every patient. A correlation between each patient's body mass index, contralateral breast volume, and abdominal flap volume was calculated.

Results

Twenty patients with a mean age of 39 years (range 26–49 years, SD 6) and a mean body mass index of 29 (range 23–35, SD 4) were included in this study. The mean breast volume was 620 cm³, and the mean abdominal flap volume was 770 cm³ (excluding zone IV). The mean breast volume to abdominal flap volume ratio (without zone IV) was 0.8.

Conclusions

Our pre-operative measurements of breast volume, abdominal flap volume, and body mass index enabled us to establish a relationship between these variables and to determine the feasibility of surgery and the need for additional volume enhancement and breast symmetrization procedures in patients seeking breast reconstruction.

Level of Evidence: Level IV, risk/prognostic study.

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Investigating Patients' Perception of Microvascular Free Toe Flap for Reconstruction of Amputated Thumbs: A Guide for Surgeons during Informed Consent

J reconstr Microsurg
DOI: 10.1055/s-0038-1642024

Background After thumb amputations, restoration of function and aesthetic can be accomplished with microvascular free toe flaps. However, many patients in clinical practice do not choose this reconstruction despite positive reported outcomes. This study aims to determine patients' perceptions with respect to free toe flaps to improve areas of informed consent. Methods A retrospective survey was administered to patients with thumb amputations. Participants were required to complete a questionnaire about patient demographics, the Brief Michigan Hand Questionnaire (bMHQ), the standard gamble/time trade-off questionnaires for utility scores, and a questionnaire investigating potential reasons for electing not to undergo a free toe transfer. Results Thirty patients were enrolled in the study wherein 53% underwent a replantation procedure, 27% a revision amputation, and 20% a delayed reconstruction. Mean normalized score on the bMHQ was recorded as 63.54. Utility questionnaires yielded mean measures of 0.8967 and 0.86 on the standard gamble and time trade-off, respectively. From 14 elements, a majority (87%) stated flap failure as a major source of concern, followed by lack of understanding of risks and benefits (80%) and prolonged hospital stay (53%). Cultural/religious beliefs, aesthetic appearance of the foot, and concerns about footwear were not reported as important reasons in 90, 80, and 79% of patients, respectively. Conclusion A better understanding of patients' attitudes and beliefs with respect to free toe flaps will allow surgeons to better address their concerns during informed consent. This study emphasizes the importance to discuss about failure rates, risks, and benefits of the operation and prolonged hospital stay.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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A Prospective Evaluation of Health-Related Quality of Life following Lymphaticovenular Anastomosis for Upper and Lower Extremities Lymphedema

J reconstr Microsurg
DOI: 10.1055/s-0038-1642623

Background Lymphedema is a progressive disease that negatively affects body image and physical, psychological, and social functions. There is lack of evidence in the present literature about the impact of super microsurgical lymphaticovenular anastomosis (LVA) on health-related quality of life (HRQoL). The aim of this prospective study is to report the outcomes of patients' HRQoL after LVA for lower and upper extremities lymphedema. Methods Between September 2015 and February 2017, 74 patients with upper or lower limb lymphedema (ULL or LLL) underwent LVA at our center. Quality of life (QoL) was assessed by lymphedema QoL questionnaire (LyMQoL), which is a validated disease-specific instrument to measure the impact of lymphedema on patient's lives, covering four domains: function, body image, symptoms, and mood. All patients were evaluated preoperatively, 1 month after surgery, and every 3 months up to 1 year. Additionally, we evaluated the episodes of lymphangitis and the need for conservative therapy before and after surgery. Results After a mean follow-up of 8.5 months (range: 2–21 months), we observed an increase of 2.3 points in the overall QoL average for upper limb and 2.6 points for lower limb (p  <  0.001). A statistically significant improvement in all four domains (p  <  0.01) was reported after surgery, being present from the first postoperative months for both upper and lower extremities. Conclusion Our study shows that lymphaticovenular anastomosis improves HRQoL in patients affected by ULL and LLL. Additionally, both a reduction of episodes of lymphangitis and a decrease in the need of conservative therapy were observed in this cohort of patients.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Why EMS agencies should change their definition of intubation success

Sponsored by EMS PRO Jeffrey Jarvis, MD, EMS medical director for Williamson County (Texas) EMS, knew he was passionate about emergency medical services after his first semester at Texas A&M University. While going to school and working for Texas A&M EMS, he progressed through paramedicine and worked in a variety of roles. After 10 years in EMS, he went back to school to continue his EMS career ...

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Combining midfacial degloving, LeFort-I osteotomy and inferiorly extended lateral orbitotomy (Krönlein) for removal of an orbital cavernous haemangioma: a new approach

Orbital tumours, located in the medial extraconal and intraconal compartment of the orbit, represent a challenge, with regard to surgical exposure. In the present paper removal of a cavernous haemangioma, located in the medial intraconal compartment was accomplished by combining lateral orbitotomy, midfacial degloving and LeFort-I osteotomy. Resection of the tumour could be performed under direct vision. Surgical exposure and removal of the lesion were obtained, without causing damage to surrounding tissues.

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Does the instrument used for the implant site preparation influence the bone–implant interface? A systematic review of clinical and animal studies

This systematic review evaluates the influence of the instrument used for the implant site preparation on the bone–implant interface. Any type of clinical or animal study were searched for in MEDLINE/PubMed, ISI Web of Science, and SciVerse Scopus. Two independent reviewers screened titles/abstracts of articles and the full-text of potentially eligible studies. Comparisons of bone to implant contact and crestal bone loss were estimated using pairwise meta-analysis. Twenty-nine studies met the inclusion criteria.

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The impact of chromoendoscopy for surveillance of the duodenum in patients with MUTYH-associated polyposis and familial adenomatous polyposis

Duodenal polyposis and cancer have become a key issue for patients with familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). Almost all patients with FAP will develop duodenal adenomas, with 5% developing cancer. The incidence of duodenal adenomas in MAP appears to be lower than in FAP but the limited available data suggest a comparable increase in the relative risk and lifetime risk of duodenal cancer. Current surveillance recommendations, however, are the same for FAP and MAP, using the Spigelman score--incorporating polyp number, size, dysplasia, and histology--for risk stratification and determination of surveillance intervals.

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Eczema complicated by allergic contact dermatitis to topical medications and excipients

In patients with eczema that is difficult to manage, it is important to consider the possibility that they are allergic to the topical medications or emollients being used to manage their skin disease. This group of patients may have allergic contact dermatitis (ACD) to topical corticosteroids (TCS), antibiotics, or the excipients and preservatives used in their topical medications or emollients being used for skin care. For this group of patients, topical corticosteroids or the excipients in their vehicle may actually worsen their underlying disease and are the focus of this article.

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Lymphoid aggregates in desmoplastic melanoma have features of tertiary lymphoid structures

Desmoplastic melanomas (DM) have unique and challenging clinical presentations and histomorphology. A characteristic feature is the presence of scattered lymphoid aggregates. However, the nature of these aggregates is not defined. We hypothesized that they may be tertiary lymphoid structures (TLS), and may be associated with programmed death ligand 1 (PD-L1) expression. We searched our tissue database for 'pure' DMs and for scars as control tissues, collected clinical information, and reviewed H&E histology. We performed multispectral imaging after staining for CD8, CD20, PNAd, FoxP3, CD83, and Ki67, and assessed PD-L1 expression by immunohistochemistry. Pure DM samples were evaluable in 11 patients. All had desmoplastic stroma and lymphoid aggregates on H&E. The lymphoid aggregates of eight of the 11 (72%) DM samples and only three of the 11 scars contained features of TLS, defined as distinct clusters of B cells and CD8+ T cells, CD83+ dendritic cells in T-cell zones, and PNAd+ vasculature resembling high endothelial venules. PD-L1 was expressed by at least 1% of melanoma cells in six and by at least 5% of immune cells in 10 of the 11 DM samples. We found that most lymphoid aggregates in DM are organized, classical TLS. PD-L1 expression was detected in most cases and was highest in two cases of DM with TLS. However, low PD-L1 expression in some cases suggests that some DM cells may be unresponsive to interferon-γ. TLS support antigen presentation and T-cell responses in chronic inflammation and cancer. Their presence in DM likely reflects an adaptive immune response, which may be enhanced with immune therapies.

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TRAF3-interacting protein 3, a new oncotarget, promotes tumor growth in melanoma

TRAF3-interacting protein 3 (TRAF3IP3) is expressed in the immune system and participates in cell maturation, tissue development, and immune response. In a previous study, we reported that TRAF3IP3 levels were substantially increased in the vasculature of breast cancer tissues, suggesting a proangiogenic role. In this study, we investigated TRAF3IP3 tumorigenic function. TRAF3IP3 protein was present in several cancer cell lines, with highest levels in melanoma. In addition, tumor microarray analysis on 23 primary melanoma and nine positive lymph nodes revealed that 70% of human primary melanoma and 66% of lymph node metastases were positive for TRAF3IP3. Importantly, TRAF3IP3 downregulation correlated with an 83% reduction of tumor growth in a subcutaneous xenograft mouse model (n=10, P=0.005). Immunohistochemistry analysis of the tumors revealed that TRAF3IP3-shRNA tumors had increased apoptosis (n=4, P

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Combination immunotherapies implementing adoptive T-cell transfer for advanced-stage melanoma

Immunotherapy is a promising method of treatment for a number of cancers. Many of the curative results have been seen specifically in advanced-stage melanoma. Despite this, single-agent therapies are only successful in a small percentage of patients, and relapse is very common. As chemotherapy is becoming a thing of the past for treatment of melanoma, the combination of cellular therapies with immunotherapies appears to be on the rise in in-vivo models and in clinical trials. These forms of therapies include tumor-infiltrating lymphocytes, T-cell receptor, or chimeric antigen receptor-modified T cells, cytokines [interleukin (IL-2), IL-15, IL-12, granulocyte-macrophage colony stimulating factor, tumor necrosis factor-α, interferon-α, interferon-γ], antibodies (αPD-1, αPD-L1, αTIM-3, αOX40, αCTLA-4, αLAG-3), dendritic cell-based vaccines, and chemokines (CXCR2). There are a substantial number of ongoing clinical trials using two or more of these combination therapies. Preliminary results indicate that these combination therapies are a promising area to focus on for cancer treatments, especially melanoma. The main challenges with the combination of cellular and immunotherapies are adverse events due to toxicities and autoimmunity. Identifying mechanisms for reducing or eliminating these adverse events remains a critical area of research. Many important questions still need to be elucidated in regard to combination cellular therapies and immunotherapies, but with the number of ongoing clinical trials, the future of curative melanoma therapies is promising.

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Early evolution of BRAFV600 status in the blood of melanoma patients correlates with clinical outcome and identifies patients refractory to therapy

Serial analysis of BRAF mutations in circulating-free DNA (cfDNA) could be of prognostic value in melanoma patients. We collected blood samples from 63 advanced BRAFV600E/K melanoma patients and determined BRAFV600E/K status in cfDNA using a quantitative 5′-nuclease PCR-based assay. Levels of BRAF mutation in pre-cfDNAs were associated significantly with tumour burden, progression-free survival and overall survival. Changes in BRAF status in cfDNA after initiation of treatment (early-cfDNA) had a significant correlation with outcome. In patients with persistent BRAF mutations (n=12), progression-free survival and overall survival were 3.5 months [95% confidence interval (CI): 1.6–4.6] and 5.3 months (95% CI: 3.4–8.1) compared with 16.6 months (95% CI: 8.2–22.3) and 21.9 months (95% CI: 10.2–NR) in patients with BRAF negativization (n=16), and 15.1 months (95% CI: 2.3–NR) and NR (95% CI: 5.1–NR) in patients who maintained their initial negative status (n=12) (P

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Potential clinical and immunotherapeutic utility of talimogene laherparepvec for patients with melanoma after disease progression on immune checkpoint inhibitors and BRAF inhibitors

Talimogene laherparepvec is a genetically modified herpes simplex virus type 1–based oncolytic immunotherapy for the local treatment of unresectable subcutaneous and nodal tumors in patients with melanoma recurrent after initial surgery. We report on two patients with melanoma who, after progression on numerous systemic therapies, derived clinical benefit from talimogene laherparepvec in an expanded-access protocol (ClinicalTrials.gov, NCT02147951). Intralesional talimogene laherparepvec (day 1, ≤4 ml 106 PFU/ml; after 3 weeks, ≤4 ml 108 PFU/ml every 2 weeks) was administered until complete response, no injectable tumors, progressive disease, or intolerance occurred. Patient 1 was 71 years old, had stage IIIB disease, and had previously received granulocyte–macrophage colony-stimulating factor, vemurafenib, metformin, ipilimumab, dabrafenib, trametinib, and pembrolizumab. Patient 2 was 45 years old, had stage IIIC disease, and had previously received nivolumab/ipilimumab combination therapy. There were marked reductions in the number and size of melanoma lesions during treatment with talimogene laherparepvec. Both patients experienced mild-to-moderate nausea and vomiting, which were managed using ondansetron, metoclopramide, and pantoprazole. Both patients completed treatment with talimogene laherparepvec in the expanded-access protocol on 24 November 2015, but received talimogene laherparepvec in clinical practice. Patient 1 continues to receive therapy (>60 weeks); patient 2 experienced a complete response at 23 weeks. Immunohistochemistry of a biopsied dermal metastasis from patient 1 showed a marked infiltration of CD4+ and CD8+ T cells after 1 year of treatment. Talimogene laherparepvec was active in patients with advanced melanoma with disease progression following multiple previous systemic therapies; no new safety signals were identified.

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STAT5 expression correlates with recurrence and survival in melanoma patients treated with interferon-α

Interferons (IFN) have a direct growth-inhibiting effect on tumor cells through Janus kinase-dependent activation of the transcription factor signal transducer and activator of transcription (STAT1). In vitro, signaling through STAT5 has been demonstrated to counteract this effect and lead to IFN resistance of melanoma cell lines. In 32 patients treated with IFN-α in an adjuvant setting, we investigated paraffin-embedded tumor tissue from primary melanomas and melanoma metastases for expression of STAT3 and STAT5, by immunohistochemistry, and for expression of phosphorylated signaling transduction activating transcription factor (pSTAT)3 and pSTAT5, by immunofluorescence. Tumor cell expression levels of these proteins were correlated with patient characteristics and clinical outcomes. The patient cohort consisted of 12 (37.5%) patients at AJCC stage I/II (primary melanoma) and 20 (62.5%) at stage III/IV (metastatic melanoma). Recurrence was observed for 25 (78.1%) either during or after IFN-α therapy. χ2 Correlation of staining intensities with clinical data revealed association of pSTAT3 and STAT5 expression with sex (P=0.003 and 0.016, respectively) and of STAT3 with tumor stage (P=0.019). Recurrence of melanoma was found to be associated with high STAT5 expression (P=0.017). Multivariable regression analysis revealed STAT5 expression as an independent factor for predicting progression-free survival (P

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Sarcoid-like reactions in patients receiving modern melanoma treatment

The development of cancer immunotherapy and targeted therapy has reached an important inflection point in the history of melanoma. Immune checkpoint inhibitors and kinase inhibitors are today's standard of care treatments in advanced melanoma patients. Treatment-related toxicities can be very intriguing and quite challenging. Sarcoidosis is a multisystemic granulomatous disease characterized by an aberrant immune response to unknown antigens, whereas sarcoid-like reactions (SLRs) refer to localized clinical features. We carried out a single-center observational study in patients with stage IIB–IV melanoma treated with BRAF/MEK inhibitors and immune checkpoint inhibitors. A description of the sarcoidosis-related manifestations was provided from patients' records. We observated eight cases of SLRs in a cohort of 200 patients. The clinical courses were characterized by a variety of symptoms, accompanied by cutaneous signs and extracutaneous manifestations such as bilateral, hilar lymphadenopathy. We identified a histologically granulomatous inflammation involving the skin, the lungs, and the lymph nodes. Two patients presented with cutaneous lesions only, and three patients had lung involvement only. Three patients achieved complete and partial response of the melanoma disease, and three patients had stable disease. Disease progression was documented in two patients. The reported immune-related adverse events were mild to severe and in most of the cases were continued without any treatment cessation. SLRs appear during treatment with both kinase and immune checkpoint inhibitors. Awareness of these can avoid misdiagnosis of disease progression and unnecessary treatment changes.

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Three antigen-loading methods in dendritic cell vaccines for metastatic melanoma

In the current era of checkpoint inhibitors, some patients with metastatic melanoma have shown a significant improvement in survival. However, optimization of immunotherapy is an ongoing effort. Monocyte-derived dendritic cell (MODC) vaccines have been shown in clinical trials to be safe and capable of inducing tumor-specific immunity as well as occasional objective clinical responses. Here, we conducted a three-arm pilot clinical study in 15 patients with metastatic melanoma to evaluate three types of MODC vaccines, differing only by strategies of tumor antigen delivery. MODCs were isolated from each patient and loaded with patients' own melanoma cells as sources of antigens. Antigen loading was achieved ex vivo by fusing melanoma cells with MODCs, co-culturing melanoma cells with MODCs, or by pulsing MODCs with melanoma cell lysates. The vaccines were then injected into superficial lymph nodes using high-resolution ultrasound guidance. Primary end points included delayed-type hypersensitivity responses and positive ELISpot result, which measures interferon-γ production. Five of 15 patients achieved delayed-type hypersensitivity responses and six of 15 patients had positive ELISpot results. We demonstrated that the vaccines were safe and well-tolerated by all patients and produced immunological responses in all arms. Although MODC vaccine monotherapy has limited efficacy, combining this vaccine with other immunotherapies, such as checkpoint inhibitors, to engage multiple components of the immune system may be an effective and viable future approach.

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CDKN2A germline alterations in melanoma patients with personal or familial history of pancreatic cancer

CDKN2A germline mutations increase the risk of melanoma development and are present in 20 and 10% of familial and multiple melanoma cases, respectively. Pancreatic cancer has been associated with CDKN2A in some populations and, accordingly, its presence in first-degree or second-degree relatives of a melanoma patient is considered as a criterion for genetic testing. In this study, we show that in an area with low melanoma incidence, CDKN2A germline mutations in patients with melanoma and personal or family history of pancreatic cancer are mainly present in the setting of familial or multiple melanoma cases. In addition, a relatively young age (≤52 years) at pancreatic diagnosis is an additional single criterion that might also be considered.

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Lymph node ratio as a prognostic factor in melanoma: results from European Organization for Research and Treatment of Cancer 18871, 18952, and 18991 studies

The aim of this study was to assess the prognostic importance of lymph node ratio (LNR) in stage III melanoma after complete lymph nodal dissections. From European Organization for Research and Treatment of Cancer randomized trials 18871, 18952, and 18991, 2358 patients had full information on positive and examined lymph nodes (LNs) and were included. Cox proportional hazards models stratified by trial were used to assess the prognostic impact of LNR adjusted for confounders on melanoma-specific survival. Optimal cutoff values for LNR were calculated for each LN dissection site (axillary, inguinal, and neck). LNR (≥ vs.

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Histiocytoid Sweet’s syndrome during combined therapy with BRAF and MEK inhibitors for metastatic melanoma

No abstract available

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Stable Causal Relationships Are Better Causal Relationships

Cognitive Science, EarlyView.


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The Reference of Proper Names: Testing Usage and Intuitions

Cognitive Science, EarlyView.


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The Role of Design and Training in Artifact Expertise: The Case of the Abacus and Visual Attention

Cognitive Science, EarlyView.


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Progression beyond nivolumab: Stop or repeat? Dramatic responses with salvage chemotherapy

Immune check point inhibitors have demonstrated efficacy in squamous cell carcinoma of the head and neck (SCCHN) in cases of recurrence or in a metastatic setting after platinum failure [1]. In many tumors, anti PD1 or anti PDL 1 have increased median overall survival (OS) but have not demonstrated greater median progression free survival (PFS) [1–3]. Recent data has suggested that chemotherapy in post-nivolumab treatment may induce better objective responses than historical data did [4].

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Effects of a Tablet-Based Home Practice Program With Telepractice on Treatment Outcomes in Chronic Aphasia

Purpose

The aim of this study was to determine if a tablet-based home practice program with weekly telepractice support could enable long-term maintenance of recent treatment gains and foster new language gains in poststroke aphasia.

Method

In a pre–post group study of home practice outcomes, 21 individuals with chronic aphasia were examined before and after a 6-month home practice phase and again at follow-up 4 months later. The main outcome measure studied was change in naming previously treated or untreated, practiced or unpracticed pictures of objects and actions. Individualized home practice programs were created in iBooks Author with semantic, phonemic, and orthographic cueing in pictures, words, and videos in order to facilitate naming of previously treated or untreated pictures.

Results

Home practice was effective for all participants with severity moderating treatment effects, such that individuals with the most severe aphasia made and maintained fewer gains. There was a negative relationship between the amount of training required for iPad proficiency and improvements on practiced and unpracticed pictures and a positive relationship between practice compliance and same improvements.

Conclusion

Unsupervised home practice with weekly video teleconferencing support is effective. This study demonstrates that even individuals with chronic severe aphasia, including those with no prior smart device or even computer experience, can attain independent proficiency to continue practicing and improving their language skills beyond therapy discharge. This could represent a low-cost therapy option for individuals without insurance coverage and/or those for whom mobility is an obstacle to obtaining traditional aphasia therapy.

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Remember to blink: Reduced attentional blink following instructions to forget

Abstract

This study used rapid serial visual presentation (RSVP) to determine whether, in an item-method directed forgetting task, study word processing ends earlier for forget words than for remember words. The critical manipulation required participants to monitor an RSVP stream of black nonsense strings in which a single blue word was embedded. The next item to follow the word was a string of red fs that instructed the participant to forget the word or green rs that instructed the participant to remember the word. After the memory instruction, a probe string of black xs or os appeared at postinstruction positions 1–8. Accuracy in reporting the identity of the probe string revealed an attenuated attentional blink following instructions to forget. A yes–no recognition task that followed the study trials confirmed a directed forgetting effect, with better recognition of remember words than forget words. Considered in the context of control conditions that required participants to commit either all or none of the study words to memory, the pattern of probe identification accuracy following the directed forgetting task argues that an intention to forget releases limited-capacity attentional resources sooner than an instruction to remember—despite participants needing to maintain an ongoing rehearsal set in both cases.

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Increased exposure and phonetic context help listeners recognize allophonic variants

Abstract

This study examines the influence of increased exposure and phonetic context on the recognition of words that are produced with nasal flaps in American English (e.g., the word center produced as cenner). Previous work has shown that despite their high frequency of occurrence, words produced with nasal flaps are recognized more slowly and less accurately compared with canonical pronunciation variants produced with /nt/, which occur less frequently. We conducted two experiments in order to investigate how exposure and phonetic context influence this reported processing disadvantage for flapped variants. Experiment 1 demonstrated that the time to recognize flapped variants presented in isolation decreased over the course of the experiment, while accuracy increased. Experiment 2 replicated this finding and showed further that flapped variants that were presented in a casually produced sentence context were recognized faster compared with flapped variants presented in a carefully produced sentence context. Interestingly, the effect of context emerged only in late responses and was present only for flapped but not for canonical variants. Our results thus show that increased exposure and phonetic context help listeners recognize allophonic variants. This finding provides further support for the notion that listeners are flexible and adapt to phonetic variation in speech.

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Object width modulates object-based attentional selection

Abstract

Visual input typically includes a myriad of objects, some of which are selected for further processing. While these objects vary in shape and size, most evidence supporting object-based guidance of attention is drawn from paradigms employing two identical objects. Importantly, object size is a readily perceived stimulus dimension, and whether it modulates the distribution of attention remains an open question. Across four experiments, the size of the objects in the display was manipulated in a modified version of the two-rectangle paradigm. In Experiment 1, two identical parallel rectangles of two sizes (thin or thick) were presented. Experiments 2–4 employed identical trapezoids (each having a thin and thick end), inverted in orientation. In the experiments, one end of an object was cued and participants performed either a T/L discrimination or a simple target-detection task. Combined results show that, in addition to the standard object-based attentional advantage, there was a further attentional benefit for processing information contained in the thick versus thin end of objects. Additionally, eye-tracking measures demonstrated increased saccade precision towards thick object ends, suggesting that Fitts's Law may play a role in object-based attentional shifts. Taken together, these results suggest that object-based attentional selection is modulated by object width.

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Are two spaces better than one? The effect of spacing following periods and commas during reading

Abstract

The most recent edition of the American Psychological Association (APA) Manual states that two spaces should follow the punctuation at the end of a sentence. This is in contrast to the one-space requirement from previous editions. However, to date, there has been no empirical support for either convention. In the current study, participants performed (1) a typing task to assess spacing usage and (2) an eye-tracking experiment to assess the effect that punctuation spacing has on reading performance. Although comprehension was not affected by punctuation spacing, the eye movement record suggested that initial processing of the text was facilitated when periods were followed by two spaces, supporting the change made to the APA Manual. Individuals' typing usage also influenced these effects such that those who use two spaces following a period showed the greatest overall facilitation from reading with two spaces.

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Integration of Transplanted Neural Precursors with the Injured Cervical Spinal Cord

Journal of Neurotrauma, Ahead of Print.


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Multi-dimensional analysis of oral cavity and oropharyngeal defects following cancer extirpation surgery, a cadaveric study

Defects following resection of tumors in the head and neck region are complex; more detailed and defect-specific reconstruction would likely result in better functional and cosmetic outcomes. The objectives of...

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Integration of Transplanted Neural Precursors with the Injured Cervical Spinal Cord

Journal of Neurotrauma, Ahead of Print.


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The discriminative power of STOP-Bang as a screening tool for suspected obstructive sleep apnea in clinically referred patients: considering gender differences

Abstract

Purpose

Obstructive sleep apnea (OSA) is the most commonly seen clinical sleep disorder. STOP-Bang, a widely used screening tool, yields a composite score based on eight dichotomized items including male gender. This study was designed to validate STOP-Bang among clinically referred patients and tested alternative scoring designs on tool performance, with a focus on gender differences in OSA.

Method

STOP-Bang was administered to 403 female and 532 male subjects, followed by comprehensive sleep evaluation that included measurement of apnea-hypopnea indexes. Gender differences in STOP-Bang scores, OSA diagnosis, and severities were explored, and gender-specific alternative score cutoffs evaluated. Optimal operating points (OOP) were tested for female body mass index (BMI) and male neck circumference to inform STOP-Bang threshold refinement. Receiver operating characteristic curves were used to compare conventional and modified STOP-Bang.

Results

STOP-Bang performance by gender showed extremely low specificity in males at the recommended cutoff of ≥3. Better utility was presented at a cutoff of 4 or 5 among clinically referred patients irrespective of gender differences. Screening performance was improved by modifying BMI and/or neck circumference thresholds using gender-triaged OOP estimation. Three gender-based model revisions outperformed conventional STOP-Bang.

Conclusion

Our study suggests that gender-specific consideration needs to be incorporated into the application of STOP-Bang in a clinically referred patient population with a higher risk of OSA. Alternative scoring systems may improve predictive performance of STOP-Bang.

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Low concentrations of 25-hydroxyvitamin D and long-term prognosis of COPD: a prospective cohort study

Abstract

Role and importance of vitamin D deficiency in long-term prognosis of chronic obstructive pulmonary disease (COPD) still remains undetermined. We tested the hypothesis that among individuals with COPD, those with low concentrations of 25-hydroxyvitamin D have a poorer prognosis compared to those with normal concentrations. We studied 35,153 individuals from the general population aged 20–100 years with 25-hydroxyvitamin D measurements and spirometry, the Copenhagen City Heart Study [median follow-up 21 years (range 13 days–36 years)] and the Copenhagen General Population Study [7.1 years (3 days–13 years)]. Spirometric COPD (n = 5178; 15% of all) was defined as forced expiratory volume in 1 s (FEV₁)/forced vital capacity (FVC) < 0.70 in individuals without asthma and clinical COPD (n = 2033; 6%) as FEV₁/FVC < 0.70 and FEV₁ < 80% of predicted in ever-smokers aged > 40 years without asthma and with cumulative tobacco consumption ≥ 10 pack-years. In spirometric COPD, median age at death in years was 70.2 (95% confidence interval [CI] 64.4–71.2) for individuals with 25-hydroxyvitamin D < 12.5 nmol/L and 80.3 (74.4–83.4) for those with ≥ 50 nmol/L. In clinical COPD, corresponding values were 69.0 (63.3–70.9) and 76.2 (73.8–78.0). In spirometric COPD, multivariable adjusted hazard ratios for individuals with 25-hydroxyvitamin D < 12.5 nmol/L versus those with ≥ 50 nmol/L were 1.35 (95% CI 1.09–1.67) for all-cause mortality, 1.63 (1.00–2.64) for respiratory mortality, 1.14 (0.76–1.70) for cardiovascular mortality, 1.37 (0.90–2.06) for cancer mortality, and 1.61 (1.04–2.49) for other mortality. In clinical COPD, corresponding values were 1.39 (1.07–1.82), 1.57 (0.91–2.72), 0.88 (0.51–1.53), 1.63 (0.99–2.67), and 2.00 (1.12–3.56). Low concentrations of 25-hydroxyvitamin D were associated with an increased risk of death in individuals with COPD. No clear pattern of association could be observed for cause of death; however, there may be an increased risk of respiratory, cancer, and other mortality. It is likely that low concentrations of 25-hydroxyvitamin D is a marker of poor health in COPD.

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Quantitative analysis of the perimeniscal position of the inferior lateral genicular artery (ILGA): magnetic resonance imaging study

Abstract

Purpose

The inferior lateral genicular artery (ILGA) passes around the lateral knee joint, adjacent to the lateral meniscus (LM). ILGA injuries in total knee arthroplasty or arthroscopic surgery can result in recurrent hemarthrosis or painful pseudoaneurysms. Detailed information about the perimeniscal position of the ILGA relative to the LM is necessary to avoid these complications.

Methods

3-T MR images of 100 knees (mean age 36.3 ± 11.2 years) were retrospectively reviewed. The perimeniscal area was divided into four regions: the anterior, middle, popliteal hiatus, and posterior zones. In each zone, the ILGA diameter, superoinferior position (assessed as the height of the ILGA from the LM base), and distance between the meniscocapsular junction and the ILGA were measured.

Results

The distance between the ILGA and meniscocapsular junction was significantly smaller in the middle zone than in the other three zones (anterior 5.3 ± 0.8 mm, middle 1.4 ± 0.4 mm, popliteal hiatus 6.1 ± 1.0 mm, and posterior 5.6 ± 1.5 mm, p < 0.05). In the superoinferior position, the height of the ILGA was 3.4 ± 0.9 mm in the anterior zone, 0.4 ± 1.3 mm in the middle zone, − 1.9 ± 1.8 mm in the popliteal hiatus zone, and − 1.3 ± 4.3 mm in the posterior zone. When the LM bottom is the base, the ILGA was located superiorly in the anterior zone, close to the base in the middle zone, and inferiorly in the popliteal hiatus zone.

Conclusions

To avoid ILGA injury, close attention is necessary during surgical procedures involving the meniscocapsular junction of the LM, especially at the meniscal base in the middle zone.

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Acceleration of carboxylesterase-mediated activation of irinotecan to SN-38 by serum from patients with end-stage kidney disease

Abstract

Purpose

Pharmacokinetics and pharmacodynamics of irinotecan have been reported to be altered in cancer patients with end-stage kidney disease (ESKD). Carboxylesterase (CES) has an important role in metabolism of irinotecan to its active metabolite, SN-38, in human liver. The purpose of the present study was to investigate whether CES activity was altered in ESKD patients.

Methods

The present study investigated the effects of uremic serum, uremic toxins, and fatty acids on the hydrolysis of irinotecan and a typical CES substrate, p-nitrophenyl acetate (PNPA), in human liver microsomes. Normal and uremic serum samples were deproteinized by treatment with methanol were used in the present study.

Results

The present study showed that both normal and uremic serum significantly inhibited CES-mediated metabolism of both irinotecan and PNPA. The inhibition by uremic serum was weaker than that by normal serum, suggesting that CES activity may be higher in ESKD patients. Although four uremic toxins did not affect PNPA metabolism, arachidonic acid inhibited it. There was no difference in inhibitory effect of PNPA metabolism between both mixtures of seven fatty acids used at concentrations equivalent to those present in 10% normal or uremic serum. Interestingly, those mixtures had a more pronounced effect than either 10% normal or uremic serum.

Conclusions

The present study showed that the inhibition of CES activity by uremic serum was weaker than that by normal serum, suggesting that an increase in maximum plasma concentration of SN-38 in cancer patients with ESKD can be attributed to an accelerated CES-mediated irinotecan hydrolysis.

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IL-8 regulates the doxorubicin resistance of colorectal cancer cells via modulation of multidrug resistance 1 (MDR1)

Abstract

Cytokines play important roles in tumorigenesis and progression of cancer cells, while their functions in drug resistance remain to be illustrated. We successfully generated doxorubicin (Dox)-resistant CRC HCT-116 and SW480 cells (namely HCT-116/Dox and SW480/Dox, respectively). Cytokine expression analysis revealed that IL-8, while not FGF-2, EGF, TGF-β, IL-6, or IL-10, was significantly increased in Dox-resistant CRC cells as compared with their corresponding parental cells. Targeted inhibition of IL-8 via siRNAs or its inhibitor reparixin can increase the Dox sensitivity of HCT-116/Dox and SW480/Dox cells. The si-IL-8 can decrease the mRNA and protein expression of multidrug resistance 1 (MDR1, encoded by ABCB1), while has no effect on the expression of multidrug resistance-associated protein 1 (ABCC1), in CRC Dox-resistant cells. IL-8 can increase the phosphorylation of p65 and then upregulate the binding between p65 and promoter of ABCB1. BAY 11-7082, the inhibitor of NF-κB, suppressed the recombination IL-8 (rIL-8) induced upregulation of ABCB1. It confirmed that NF-κB is involved in IL-8-induced upregulation of ABCB1. rIL-8 also increased the phosphorylation of IKK-β, which can further activate NF-κB, while specific inhibitor of IKK-β (ACHP) can reverse rIL-8-induced phosphorylation of p65 and upregulation of MDR1. These results suggested that IL-8 regulates the Dox resistance of CRC cells via modulation of MDR1 through IKK-β/p65 signals. The targeted inhibition of IL-8 might be an important potential approach to overcome the clinical Dox resistance in CRC patients.

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Low concentrations of 25-hydroxyvitamin D and long-term prognosis of COPD: a prospective cohort study

Abstract

Role and importance of vitamin D deficiency in long-term prognosis of chronic obstructive pulmonary disease (COPD) still remains undetermined. We tested the hypothesis that among individuals with COPD, those with low concentrations of 25-hydroxyvitamin D have a poorer prognosis compared to those with normal concentrations. We studied 35,153 individuals from the general population aged 20–100 years with 25-hydroxyvitamin D measurements and spirometry, the Copenhagen City Heart Study [median follow-up 21 years (range 13 days–36 years)] and the Copenhagen General Population Study [7.1 years (3 days–13 years)]. Spirometric COPD (n = 5178; 15% of all) was defined as forced expiratory volume in 1 s (FEV₁)/forced vital capacity (FVC) < 0.70 in individuals without asthma and clinical COPD (n = 2033; 6%) as FEV₁/FVC < 0.70 and FEV₁ < 80% of predicted in ever-smokers aged > 40 years without asthma and with cumulative tobacco consumption ≥ 10 pack-years. In spirometric COPD, median age at death in years was 70.2 (95% confidence interval [CI] 64.4–71.2) for individuals with 25-hydroxyvitamin D < 12.5 nmol/L and 80.3 (74.4–83.4) for those with ≥ 50 nmol/L. In clinical COPD, corresponding values were 69.0 (63.3–70.9) and 76.2 (73.8–78.0). In spirometric COPD, multivariable adjusted hazard ratios for individuals with 25-hydroxyvitamin D < 12.5 nmol/L versus those with ≥ 50 nmol/L were 1.35 (95% CI 1.09–1.67) for all-cause mortality, 1.63 (1.00–2.64) for respiratory mortality, 1.14 (0.76–1.70) for cardiovascular mortality, 1.37 (0.90–2.06) for cancer mortality, and 1.61 (1.04–2.49) for other mortality. In clinical COPD, corresponding values were 1.39 (1.07–1.82), 1.57 (0.91–2.72), 0.88 (0.51–1.53), 1.63 (0.99–2.67), and 2.00 (1.12–3.56). Low concentrations of 25-hydroxyvitamin D were associated with an increased risk of death in individuals with COPD. No clear pattern of association could be observed for cause of death; however, there may be an increased risk of respiratory, cancer, and other mortality. It is likely that low concentrations of 25-hydroxyvitamin D is a marker of poor health in COPD.

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Moderators of angiogenesis in muscle flaps: a non-randomised animal study

Publication date: Available online 23 April 2018
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): K. Bradshaw, M. Wagels
IntroductionA muscle flap can survive a pedicle injury under favourable conditions. In the reconstruction of compound limb injuries, the wound milieu is variable and may affect the rate and manner of neovascularisation. Our aim is to determine the effect of some key clinical variables on neovascularisation in muscle flaps in an animal model.MethodologyPectoralis profundus was raised in 60 rats and covered with skin graft. Fifteen cases were allocated to groups: separation of the flap from the skin inset (S), inflammation by inoculation with Staphylococcus aureus (I), flap elevation with Harmonic Scalpel (H), preservation of the motor nerve (N) and compared to controls (C). Graft-take and wound complications were assessed five days later, as well as perfusion before and after pedicle ligation, using Laser Doppler Flowmetry and neovascularisation using barium angiography.ResultsFlaps with an intact motor nerve had significantly higher graft take than controls (59% vs 29%). Perfusion changed less than controls in all study groups, though the extent of flap necrosis was not significantly different. Only flaps raised with the harmonic scalpel generated more new vessels than controls at the inset (9.6 vs 3.2), particularly at the origin of the muscle (1.10 vs 0.19).ConclusionsAll study groups were less dependant on their pedicle for perfusion than controls. The use of the harmonic scalpel and increased inflammation seem pro-angiogenic, though they do not reduce flap necrosis after simulated pedicle injury. Neovascularisation will preferentially bridge to skin at the inset rather than tissues in the base of the wound. It is likely that flap necrosis is the result of a combination of unfavourable variables rather than one in isolation.



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Tumor-originated exosomal lncUEGC1 as a circulating biomarker for early-stage gastric cancer

Abstract

Conventional tumor markers for non-invasive diagnosis of gastric cancer (GC) exhibit insufficient sensitivity and specificity to facilitate detection of early gastric cancer (EGC). We aimed to identify EGC-specific exosomal lncRNA biomarkers that are highly sensitive and stable for the non-invasive diagnosis of EGC. Hence, in the present study, exosomes from the plasma of five healthy individuals and ten stage I GC patients and from culture media of four human primary stomach epithelial cells and four gastric cancer cells (GCCs) were isolated. Exosomal RNA profiling was performed using RNA sequencing to identify EGC-specific exosomal lncRNAs. A total of 79 and 285 exosomal RNAs were expressed at significantly higher levels in stage I GC patients and GCCs, respectively, than that in normal controls. Through combinational analysis of the RNA sequencing results, we found two EGC-specific exosomal lncRNAs, lncUEGC1 and lncUEGC2, which were further confirmed to be remarkably up-regulated in exosomes derived from EGC patients and GCCs. Furthermore, stability testing demonstrates that almost all the plasma lncUEGC1 was encapsulated within exosomes and thus protected from RNase degradation. The diagnostic accuracy of exosomal lncUEGC1 was evaluated, and lncUEGC1 exhibited AUC values of 0.8760 and 0.8406 in discriminating EGC patients from healthy individuals and those with premalignant chronic atrophic gastritis, respectively, which was higher than the diagnostic accuracy of carcinoembryonic antigen. Consequently, exosomal lncUEGC1 may be promising in the development of highly sensitive, stable, and non-invasive biomarkers for EGC diagnosis.

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The discriminative power of STOP-Bang as a screening tool for suspected obstructive sleep apnea in clinically referred patients: considering gender differences

Abstract

Purpose

Obstructive sleep apnea (OSA) is the most commonly seen clinical sleep disorder. STOP-Bang, a widely used screening tool, yields a composite score based on eight dichotomized items including male gender. This study was designed to validate STOP-Bang among clinically referred patients and tested alternative scoring designs on tool performance, with a focus on gender differences in OSA.

Method

STOP-Bang was administered to 403 female and 532 male subjects, followed by comprehensive sleep evaluation that included measurement of apnea-hypopnea indexes. Gender differences in STOP-Bang scores, OSA diagnosis, and severities were explored, and gender-specific alternative score cutoffs evaluated. Optimal operating points (OOP) were tested for female body mass index (BMI) and male neck circumference to inform STOP-Bang threshold refinement. Receiver operating characteristic curves were used to compare conventional and modified STOP-Bang.

Results

STOP-Bang performance by gender showed extremely low specificity in males at the recommended cutoff of ≥3. Better utility was presented at a cutoff of 4 or 5 among clinically referred patients irrespective of gender differences. Screening performance was improved by modifying BMI and/or neck circumference thresholds using gender-triaged OOP estimation. Three gender-based model revisions outperformed conventional STOP-Bang.

Conclusion

Our study suggests that gender-specific consideration needs to be incorporated into the application of STOP-Bang in a clinically referred patient population with a higher risk of OSA. Alternative scoring systems may improve predictive performance of STOP-Bang.

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Quantitative analysis of the perimeniscal position of the inferior lateral genicular artery (ILGA): magnetic resonance imaging study

Abstract

Purpose

The inferior lateral genicular artery (ILGA) passes around the lateral knee joint, adjacent to the lateral meniscus (LM). ILGA injuries in total knee arthroplasty or arthroscopic surgery can result in recurrent hemarthrosis or painful pseudoaneurysms. Detailed information about the perimeniscal position of the ILGA relative to the LM is necessary to avoid these complications.

Methods

3-T MR images of 100 knees (mean age 36.3 ± 11.2 years) were retrospectively reviewed. The perimeniscal area was divided into four regions: the anterior, middle, popliteal hiatus, and posterior zones. In each zone, the ILGA diameter, superoinferior position (assessed as the height of the ILGA from the LM base), and distance between the meniscocapsular junction and the ILGA were measured.

Results

The distance between the ILGA and meniscocapsular junction was significantly smaller in the middle zone than in the other three zones (anterior 5.3 ± 0.8 mm, middle 1.4 ± 0.4 mm, popliteal hiatus 6.1 ± 1.0 mm, and posterior 5.6 ± 1.5 mm, p < 0.05). In the superoinferior position, the height of the ILGA was 3.4 ± 0.9 mm in the anterior zone, 0.4 ± 1.3 mm in the middle zone, − 1.9 ± 1.8 mm in the popliteal hiatus zone, and − 1.3 ± 4.3 mm in the posterior zone. When the LM bottom is the base, the ILGA was located superiorly in the anterior zone, close to the base in the middle zone, and inferiorly in the popliteal hiatus zone.

Conclusions

To avoid ILGA injury, close attention is necessary during surgical procedures involving the meniscocapsular junction of the LM, especially at the meniscal base in the middle zone.

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Digitale Pathologie

Zusammenfassung

Hintergrund

Die Bildverarbeitung und das Scannen von histologischen Präparaten konnte in den vergangenen Jahren für die Mikroskopie so weit entwickelt werden, dass Systeme für den Routinealltag zur Verfügung stehen, die das Potenzial haben in der Routinediagnostik das Mikroskop zu ersetzen.

Ziel der Arbeit

Darstellung der Erfahrungen in der Digitalen Pathologie im Routinealltag.

Ergebnisse und Schlussfolgerung

Ein digitales Pathologiesystem bietet eine Reihe von Vorteilen: 1) Die Objektträger sind keine Unikate mehr. 2) Auf die Scans kann standortunabhängig zugegriffen werden. 3) Digitale Bildverarbeitung kann genutzt werden. 4) Der Zugriff auf archivierte Scans ist einfach und fallbezogen. Daraus resultieren sekundäre Vorteile: a) Die Fallzusammenstellung und die Zuteilung zum befundenen Arzt ist schneller und ohne Fehler. b) Laufwege für die Verteilung der Schnittpräparate fallen weg, papierloses Arbeiten wird möglich. c) Schnittpräparate können für eine konsiliarische Begutachtung oder in Satellitenstandorten zugängig gemacht werden. d) Schnittpräparate für Konsilien können gescannt werden und stehen nach Rücksendung im Zentrum noch zur Verfügung. e) Bereitstellung von Bildmaterial in Tumorkonferenzen. f) Der Arbeitstisch ist aufgeräumt! g) Homeoffice ist möglich. Für die Einführung ist eine umfassende Workflowanalyse vorab notwendig, welche die Bedürfnisse und Wünsche des Instituts abklärt. Um die speziellen Erfordernisse eines Instituts optimal abzudecken sind offene Plattformen von Vorteil, die Scanner von unterschiedlichen Herstellern einbinden können. Weitere Entwicklungen der Bildanalyse wie etwa die virtuelle Rekonstruktion mit Darstellung der räumlichen Bezüge könnten zukünftig die Diagnostik verfeinern und die Behandlungsqualität verbessern.

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Anforderungen an eine standortübergreifende Biobanken-IT-Infrastruktur

Zusammenfassung

Hintergrund

Die große Zahl an Biobanken innerhalb Deutschlands resultiert in einer hohen Heterogenität hinsichtlich der verwendeten IT-Komponenten an den jeweiligen Standorten. Im Rahmen der German Biobank Alliance (GBA) implementieren 13 Biobanken harmonisierte Prozesse zur Bereitstellung von Biomaterial und zugehörigen Daten.

Zielsetzung

Die Vernetzung der individuellen Biobanken und die damit verbundene Harmonisierung der IT-Infrastruktur soll die Zusammenstellung von Biomaterial und zugehörige klinische Daten für die Forschung über Standorte hinweg erleichtern.

Methode

Hierzu wurden zunächst die relevanten Zielgruppen identifiziert, um deren Anforderungen an zu entwickelnde IT-Lösungen im Rahmen eines Workshops zu erheben.

Ergebnisse

Von 7 identifizierten Interessengruppen wurden zunächst die Biobankleiter und -manager sowie IT-Mitarbeiter der Biobanken zu einer ersten Diskussionsrunde eingeladen. Aus dem dort geäußerten Stakeholderinput ging ein Anforderungskatalog in Hinblick auf die IT-Unterstützung bei (i) einer Proben- und Datenanfrage, (ii) der Handhabung von Patienteneinwilligungen und -einbezug sowie (iii) der nachgelagerten Evaluation der Proben- und Datenanfrage hervor.

Schlussfolgerungen

Die IT-Lösungen werden anhand der genannten Anforderungen im nächsten Schritt als Prototypen konzipiert. Parallel dazu werden weitere Nutzergruppen befragt, um die Vorgaben für die Entwicklung auch von breiteren Nutzergruppen zu berücksichtigen.

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CXCL9/10/11, a regulator of PD-L1 expression in gastric cancer

Abstract

Background

Programmed death-ligand 1 (PD-L1) is an immunosuppressor that plays an important role in cancer treatments. Although majority of the studies demonstrated that PD-L1 expression was regulated by cellular intrinsic and extrinsic controls, and IFN-γ was a key molecule of extrinsic control, other studies imply that other cytokines play important roles in PD-L1 expression. In this study, we investigated the regulation of PD-L1 by chemokine signaling pathway in gastric cancer (GC) cells.

Methods

Bioinformatics was used to explore the PD-L1-related genes in GC and propose a hypothesis. PD-L1 and CXCR3 expression were detected by western blot in SGC7901 and MKN74 cell lines. Meanwhile, PD-L1 and CXCR3 expressions were immunohistochemically assessed for their relevance. Moreover, PD-L1, pSTAT3 and pAkt were detected after treatment with CXCL9/10/11. Furthermore,PD-L1, pSTAT3 and pAkt were evaluated after blocking chemokine signaling in SGC7901 cells.

Results

Based on online database analysis, CXCL9/10/11-CXCR3 is proposed to upregulate PD-L1 expression by activating the STAT and PI3K-Akt pathways. This hypothesis was confirmed by in vitro and vivo experiments. CXCR3 and PD-L1 were expressed in GC cell lines and tissues, and the expression of CXCR3 and PD-L1 was positively related. PD-L1 was upregulated after treatment with CXCL9/10/11, accompanied by activation of STAT3 and Akt. After blocking chemokine signaling, upregulation of PD-L1 and activation of STAT3 and Akt were diminished.

Conclusions

CXCL9/10/11-CXCR3 upregulated the expression of PD-L1 by activating the STAT and PI3K-Akt signaling pathways in GC cells. There was a significant positive correlation between the expression of PD-L1 and CXCR3 in gastric cancer patient tissues.

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Severe, eosinophilic asthma in primary care in Canada: a longitudinal study of the clinical burden and economic impact based on linked electronic medical record data

Stratification of patients with severe asthma by blood eosinophil counts predicts responders to anti-interleukin (IL)-5 (mepolizumab and reslizumab) and anti-IL-5 receptor α (benralizumab) therapies. This stud...

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Standardtherapie von Plattenepithelkarzinomen der Mundhöhle gemäß Leitlinien

Zusammenfassung

Das chirurgische Vorgehen beim Plattenepithelkarzinom der Mundschleimhaut ist, die Operabilität des Patienten vorausgesetzt, die tragende Therapiesäule mit stadienabhängiger adjuvanter Radiotherapie und (Radio)chemotherapie. Obwohl es viele offene Fragen gibt, ist die Datenlage zur Effektivität der operativen Behandlung insgesamt gut, sowohl was die Resektion des Primärtumors als auch die Behandlung der abführenden Lymphwege angeht. Entscheidender Prognosefaktor ist neben dem Lymphknotenstatus der erreichte Sicherheitsabstand und Resektionsstatus, womit der Qualität der chirurgischen Resektion die wesentliche Bedeutung zukommt. Auch zur Frage der Unterkieferresektion liegen Daten vor, wobei hier Aussagen auf hohem Evidenzniveau schwieriger sind. Für die niedrigen bis mittleren Tumorstadien ist die operative Behandlung auch hinsichtlich der posttherapeutischen Funktionalität und Lebensqualität der Maßstab.

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Favourable response of serum prostate-specific antigen to conjugated oestrogen in castrate-resistant prostate cancer in Jamaica

Andrew Condappa, Maxine Gossell-Williams and William Aiken

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The current state of prostate cancer treatment in Trinidad and Tobago

Satyendra Persaud, Maliza Persaud, Lester Goetz and Dylan Narinesingh

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Oncological and reproductive outcomes of adenocarcinoma in situ of the cervix managed with the loop electrosurgical excision procedure

Abstract

Background

The standard treatment for cervical adenocarcinoma in situ (AIS) is hysterectomy, which is a more aggressive treatment than that used for squamous intraepithelial lesions. Several previous studies have primarily demonstrated that the loop electrosurgical excision procedure (LEEP) is as safe and effective as cold knife cone (CKC) biopsy when AIS is unexpectedly found in a loop excision. This study evaluated the safety of LEEP as the initial treatment for patients with AIS who were strictly selected and evaluated before and after loop resection.

Methods

The oncological and reproductive outcomes of a series of AIS patients who underwent LEEP as the initial treatment between February 2006 and December 2016 were retrospectively evaluated.

Results

A total of 44 women were eligible for analysis. The mean age at diagnosis was 36.1 years, and 14 patients were nulliparous. Multiple lesions were identified in 4 (9.1%) patients. Either hysterectomy (6 patients) or repeat cone biopsies (3 patients) were performed in 8 of the 10 patients who presented positive or not evaluable surgical resection margins (SMs) on the initial LEEP specimens. Residual disease was detected in two patients. All patients were closely followed for a mean of 36.9 months via human papillomavirus testing, PAP smears, colposcopy, and endocervical curettage when necessary. No recurrences were detected. Of the 16 patients who desired to become pregnant, 8 (50%) successfully conceived, and the full-term live birth rate was 83.3% among this subgroup.

Conclusions

LEEP with negative SMs was a safe and feasible fertility-sparing surgical procedure for patients with AIS, and the obstetric outcome was satisfactory. However, long-term follow-up is mandatory.

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Radiogenic angiosarcoma of the breast: case report and systematic review of the literature

Abstract

Background

Radiogenic angiosarcoma of the breast (RASB) is a rare late sequela of local irradiation of the breast or chest wall after breast cancer. The prognosis of women with RASB is poor and there is no standardized therapy for this type of malignancy.

Case presentation

We present the case of a 54 year old woman with RASB (poorly differentiated angiosarcoma of the left breast; pT1, pNX, M0, L0, V0) and a history of invasive-ductal cancer of the left breast (pT1b, G2, pN0, ER positive, PR positive, HER-2/neu negative) treated in July 2012 with breast-conserving surgery, adjuvant chemotherapy with 6 cycles of epirubicin and cyclophosphamide, adjuvant irradiation of the left breast with 50 Gray, and adjuvant endocrine therapy with an aromatase inhibitor. In August 2016, a bilateral salpingo-oophorectomy was performed to remove a tumor of the left ovary, which was diagnosed as breast cancer recurrence. At the same time, a small, purple skin lesion of 1.2 cm in diameter was noted in the inner upper quadrant of the right breast. RASB was diagnosed by punch biopsy and the tumor was excised with clear margins. Imaging studies showed no evidence of further metastases. A systemic chemotherapy with 6 cycles of liposomal doxorubicin was initiated. Five months later, a local recurrence of RASB was diagnosed and mastectomy was performed. Six months later, the patient is alive with no evidence of disease.

Three hundred seven cases of RASB were identified. The pooled incidence rate of RASB was 1/3754 women. The most common treatment of RASB was mastectomy in 83% of cases. Adjuvant radiotherapy or chemotherapy were rarely used with 6 and 4%, respectively, whereas in case of recurrence, chemotherapy was the mainstay of treatment, used in 58% of cases. Radiotherapy and repeated surgery were also common with 30 and 33% of cases, respectively. Overall, the prognosis of women with RASB was poor and the recurrence-free survival was short with a mean of 15.9 months. Mean overall survival was 27.4 months.

Conclusion

RASB is a rare late complication of breast irradiation. The prognosis of women with RASB is poor. Surgery is the mainstay of treatment for localized disease while systemic chemotherapy and re-irradiation are appropriate for women with disseminated or recurrent RASB.

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