Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation

Abstract

Constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, has been identified as an alternative mechanism that predisposes to the development of Lynch syndrome. In the present work, we aimed to investigate the prevalence of MLH1 constitutional methylation in colorectal cancer (CRC) patients with abnormal expression of the MLH1 protein in their tumors. In a series of 38 patients who met clinical criteria for Lynch syndrome genetic testing, with loss of MLH1 expression in the tumor and with no germline mutations in the MLH1 gene (35/38) or with tumors presenting the BRAF p.Val600Glu mutation (3/38), we screened for constitutional methylation of the MLH1 gene promoter using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in various biological samples. We found four (4/38; 10.5%) patients with constitutional methylation in the MLH1 gene promoter. RNA studies demonstrated decreased MLH1 expression in the cases with constitutional methylation when compared with controls. We could infer the mosaic nature of MLH1 constitutional hypermethylation in tissues originated from different embryonic germ layers, and in one family we could show that it occurred de novo. We conclude that constitutional MLH1 methylation occurs in a significant proportion of patients who have loss of MLH1 protein expression in their tumors and no MLH1 pathogenic germline mutation. Furthermore, we provide evidence that MLH1 constitutional hypermethylation is the molecular mechanism behind about 3% of Lynch syndrome families diagnosed in our institution, especially in patients with early onset or multiple primary tumors without significant family history.

This work aimed to investigate the prevalence of MLH1 constitutional methylation in colorectal cancer patients with abnormal expression of the MLH1 protein in their tumors and without germline mutations. We provide evidence that MLH1 constitutional hypermethylation is the molecular mechanism behind about 3% of Lynch syndrome families, most likely in patients with early onset or multiple primary tumors without significant family history.

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Impact of preoperative anemia on outcomes in patients undergoing curative resection for gastric cancer: a single-institution retrospective analysis of 2163 Chinese patients

Abstract

We sought to evaluate whether preoperative anemia was an important determinant of survival in gastric cancer (GC). A single institution cohort of 2163 GC patients who underwent curative resection were retrospectively analyzed. Anemia was defined as a preoperative hemoglobin level <120 g/L in males and <110 g/L in females. Overall survival (OS) was analyzed using the Kaplan–Meier method, and a multivariate Cox proportional hazards model was performed to identify the independent prognostic factor. Anemic patients had a poorer OS compared with nonanemic patients after resection for tumor–nodes–metastasis (TNM) stage III tumors (5-year OS rate: 32.2% vs. 45.7%, P < 0.001) but not stage I (P  =  0.480) or stage II (P  =  0.917) tumors. Multivariate analysis revealed that preoperative anemia was an independent prognostic factor in TNM stage III (hazard ratio [HR], 1.771; 95% CI, 1.040–3.015; P = 0.035). In a stage-stratified analysis, preoperative anemia was still independently associated with OS in TNM stages IIIa through IIIc (P < 0.001, P = 0.075, and P = 0.012, respectively), though the association was only marginal in stage IIIb. Of note, preoperative mild anemia had a similar prognostic value in TNM stage III GC. Furthermore, preoperative anemia was significantly associated with more perioperative transfusions, postoperative complications and several nutritional-based indices, including the prognostic nutritional index (PNI), preoperative weight loss and performance status (all P < 0.05). Preoperative anemia, even mild anemia, was an important predictor of postoperative survival for TNM stage III GC.

Preoperative anemia, even mild anemia, is a useful predictor of outcomes in tumor–nodes–metastasis stage III gastric cancer.

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Downregulation of CSN6 attenuates papillary thyroid carcinoma progression by reducing Wnt/β-catenin signaling and sensitizes cancer cells to FH535 therapy

Abstract

The incidence of thyroid cancer has increased worldwide at a rate higher than that of any other cancer. CSN6 is overexpressed in many types of cancers, and such expression is linked to oncogenic activity. However, the detailed biological functions of CSN6 in papillary thyroid cancer (PTC) have not been well characterized. We investigated CSN6 expression in PTC specimens and cell lines. We used short-hairpin RNA-mediated gene silencing to explore the biological effects of CSN6 depletion in PTC cells. The combined effects of CSN6 silencing and FH535 therapy were assessed in terms of cell viability. The mechanism by which CSN6 regulated β-catenin expression was also analyzed. CSN6 levels were determined by real-time polymerase chain reaction (PCR) (mRNA), Western blotting, and immunochemistry (protein). The CCK-8 and migration assays and orthotopic xenograft transplantation were used to investigate the biological effects of CSN6. We assessed the combined effects of CSN6 silencing and FH535 on cell viability in vitro. We also analyzed the relationship between the CSN6 level and clinical pathological status. CSN6 was overexpressed in human PTCs, and loss of CSN6 attenuated tumor proliferation and migration both in vitro and in vivo. CSN6 stabilized β-catenin and facilitated the epidermal-to-mesenchymal transition (EMT) in PTC cells. CSN6 positively regulated β-catenin expression in a β-Trcp-dependent manner and triggered expression of several EMT-related genes regulated by β-catenin. CSN6 silencing sensitized PTC cells to FH535 therapy via downregulation of the Wnt/β–catenin signaling pathway. Finally, in PTC patients, the level of CSN6 was significantly (inversely) correlated with tumor size, the presence of multifocal lesions, and TNM stage. CSN6 overexpression in PTC is a strong indicator of enhanced tumor aggressiveness. CSN6 promotes PTC progression by inducing the EMT. CSN6 knockdown sensitizes PTC cells to FH535 therapy via downregulation of the Wnt/β–catenin signaling pathway.

CSN6 was overexpressed in human PTCs, and loss of CSN6 attenuated tumor proliferation and migration. In PTC patients, the level of CSN6 was significantly (inversely) correlated with tumor size, the presence of multifocal lesions, and TNM stage.

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Clinical outcomes of carbon ion radiotherapy with concurrent chemotherapy for locally advanced uterine cervical adenocarcinoma in a phase 1/2 clinical trial (Protocol 1001)

Abstract

We conducted a phase 1/2 study to evaluate the efficacy and safety of carbon ion radiotherapy (C-ion RT) with concurrent chemotherapy for locally advanced uterine cervical adenocarcinoma. Thirty-three patients were enrolled between April 2010 and March 2014. Treatment consisted of C-ion RT with concurrent weekly cisplatin at a dose of 40 mg/m². In the phase 1 component, the total dose was escalated from 68.0 Gy (relative biological effectiveness [RBE]) to 74.4 Gy (RBE) to determine the maximum tolerated dose of C-ion RT. In the phase 2 component, the efficacy and safety of C-ion RT with concurrent chemotherapy were evaluated using the dose determined in the phase 1 component. The median follow-up duration was 30 months. Two patients did not receive chemotherapy because of anemia or leukocytopenia immediately prior to commencing treatment; 31 patients were analyzed. None of the patients developed dose-limiting toxicities. The recommended dose (RD) was determined to be 74.4 Gy (RBE). In the phase 2 component, two patients developed Grade 3–4 toxicities in the gastrointestinal tract, due to repeated laser coagulation or peritonitis caused by appendicitis. In the patients treated with the RD, the 2-year local control, progression-free survival, and overall survival rates were 71%, 56%, and 88%, respectively. C-ion RT with concurrent weekly cisplatin was well tolerated in patients with locally advanced uterine cervical adenocarcinoma. Our findings support further investigations into the efficacy of this strategy.

The efficacy and safety of carbon ion radiotherapy with concurrent chemotherapy was evaluated in patients with locally advanced uterine cervical adenocarcinoma. This strategy was well tolerated in the majority of patients.

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Mechanism underlying the negative effect of prostate volume on the outcome of extensive transperineal ultrasound-guided template prostate biopsy

Abstract

Previous studies have indicated a possible relationship between increased prostate volume (PV) and decreased biopsy yield, although the mechanism involved is unclear. We evaluated 1650 patients who underwent template biopsy. The distribution of 993 cancer lesions in 302 prostatectomy specimens was compared with the biopsy data to determine whether each lesion was detected. A receiver operating characteristic (ROC) model was used to determine the diagnostic accuracy of prostate-specific antigen (PSA) and related markers. A medical record number (MRN) was used as a negative control. The cancer positive rate did not change as PSA increased in patients with PV ≥50 mL (P = 0.466), although it increased as PSA increased in patients with PV<50 mL (P = 0.001). The detection rate of cancer lesions decreased as the diameter of the lesions decreased (P = 0.018), but remained unchanged with respect to PV. The diameters of the maximum lesions in patients with PV ≥ 50 mL were significantly smaller than those in patients with PV<50 mL (P = 0.003). In patients with PV ≥ 50 mL, the areas under the ROC curves for PSA-related markers did not differ significantly from that for MRN, although they were significantly greater than that for MRN in patients with PV<50 mL (P < 0.001). These results suggest that an increase in PV is associated with a decrease in size and detectability of cancer lesions resulting in a decrease in biopsy yield. Loss of diagnostic accuracy of markers in patients with PV ≥ 50 mL indicates a decrease in serum levels of PSA produced by prostate cancer, which suggests growth inhibition of the cancer.

The currents study indicates that the diameters of maximum cancer lesions in patients with prostate volume ≥ 50 mL were significantly smaller than those in patients with prostate volume <50 mL. Loss of diagnostic accuracy of markers in patients with prostate volume ≥ 50mL indicates a decrease in serum levels of PSA produced by prostate cancer, which suggests growth inhibition of the cancer.

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Nuclear division cycle 80 promotes malignant progression and predicts clinical outcome in colorectal cancer

Abstract

Colorectal cancer (CRC) is a common human malignancy worldwide and increasing studies have attributed its malignant progression to abnormal molecular changes in cancer cells. Nuclear division cycle 80 (NDC80) is a newly discovered oncoprotein that regulates cell proliferation and cycle in numerous malignancies. However, its clinical significance and biological role in CRC remain unclear. Therefore, in this study, we firstly analyze its expression in a retrospective cohort enrolling 224 CRC patients and find its overexpression is significantly correlated with advanced tumor stage and poor prognosis in CRC patients. In addition, our result reveals it is an independent adverse prognostic factor affecting CRC-specific and disease-free survival. The subgroup analysis indicates NDC80 expression can stratify the clinical outcome in stage II and III patients, but fails in stage I and IV patients. In cellular assays, we find knockdown of NDC80 dramatically inhibits the proliferative ability, apoptosis resistance, cell cycle progression, and clone formation of CRC cells in vitro. Using xenograft model, we further prove knockdown of NDC80 also inhibits the tumorigenic ability of CRC cells in vivo. Finally, the microarray analysis is utilized to preliminarily clarify the oncogenic molecular mechanisms regulated by NDC80 and the results suggest it may promote CRC progression partly by downregulating tumor suppressors such as dual specificity phosphatase 5 and Forkhead box O1. Taken together, our study provides novel evidences to support that NDC80 is not only a promising clinical biomarker but also a potential therapeutical target for CRC precise medicine.

In summary, our results indicate that high NDC80 expression is correlated with advanced tumor stage and unfavorable prognosis in CRC patients. In addition, we also find NDC80 drives malignant progression of CRC cells partly by inactivating DUSP5 and FOXO1. Taken together, these evidences suggest NDC80 is not only a promising clinical biomarker for patient management, but also a potential therapeutical target for CRC diagnosis and treatment.

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Cardiovascular Diseases and Periodontal Disease

Abstract

Purpose of Review

Periodontitis and cardiovascular diseases are both inflammatory conditions. Recent epidemiological studies have associated the effects of periodontitis on cardiovascular disease (CVD) progression. This review aims to summarize the relationship between those two conditions.

Recent Findings

Although there is no evidence of a causal relationship, an association between the two conditions is apparent. The potential factors include bacterial pathway, inflammation, and genetics. Periodontal bacteria affect endothelial cells through interactions that aggravate the atherogenic process. Ulcerated periodontium produces cytokines which increase the production of acute-phase proteins that have been associated with cardiovascular events. Genetic studies have demonstrated the presence of risk alleles in the genes ANRIL and CAMTA1/VAMP3 that are shared between these two diseases.

Summary

This review discusses the current understanding of CVD pathogenesis, underlying mechanisms of periodontitis in CVD, and effects of periodontal therapy on CVD, and provides guidelines for treating patients with CVD risks in respect to periodontal disease.

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Genetic and functional analysis of the RYR1 mutation p.Thr84Met revealed a susceptibility to malignant hyperthermia

Abstract

Purpose

The aim of this study was to analyze the genetic and functional role of a novel RYR1 variant c.251 C > T (p.Thr84Met) identified in a patient with muscle weakness demonstrating MH susceptibility.

Methods

DNA testing of family members was conducted for assessment of pathogenicity of the genetic variant. For functional analysis, Ca²⁺ measurement using patient-derived myotubes and p.Thr84Met RYR1-transfected human embryonic kidney (HEK)-293 cells was performed to evaluate reactivity to RYR1 activators. The half-maximal effective concentration (EC₅₀) values of two RYR1 activators, caffeine and 4-chloro-m-cresol (4CmC), were calculated from the acquired dose–response curves. The EC₅₀ was compared between two groups: for myotubes, the control group and the patient, and for HEK-293 cells, WT and p.Thr84Met.

Results

Dose–response curves for caffeine and 4CmC were shifted to the left in both myotubes and HEK-293 cells compared to controls. The 50% effective concentration values for caffeine and 4CmC were significantly lower in both myotubes and HEK-293 cells compared to controls (P < 0.001 for all comparisons).

Conclusions

Our results of functional testing indicated RYR1 hypersensitivity to caffeine and 4CmC. We conclude that the genetic variant was associated with MH susceptibility.

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News & Announcements

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Issue Information

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Unifying control over the body: consciousness and cross-cueing in split-brain patients

Sir,

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SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency

Abstract

Recessive mutations in the mitochondrial copper-binding protein SCO2, cytochrome c oxidase (COX) assembly protein, have been reported in several cases with fatal infantile cardioencephalomyopathy with COX deficiency. Significantly expanding the known phenotypic spectrum, we identified compound heterozygous variants in SCO2 in two unrelated patients with axonal polyneuropathy, also known as Charcot-Marie-Tooth disease type 4. Different from previously described cases, our patients developed predominantly motor neuropathy, they survived infancy, and they have not yet developed the cardiomyopathy that causes death in early infancy in reported patients. Both of our patients harbour missense mutations near the conserved copper-binding motif (CXXXC), including the common pathogenic variant E140K and a novel change D135G. In addition, each patient carries a second mutation located at the same loop region, resulting in compound heterozygote changes E140K/P169T and D135G/R171Q. Patient fibroblasts showed reduced levels of SCO2, decreased copper levels and COX deficiency. Given that another Charcot-Marie-Tooth disease gene, ATP7A, is a known copper transporter, our findings further underline the relevance of copper metabolism in Charcot-Marie-Tooth disease.

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Peroxiredoxin 4 (PRDX4): Its critical in vivo roles in animal models of metabolic syndrome ranging from atherosclerosis to nonalcoholic fatty liver disease

The peroxiredoxin (PRDX) family, a new family of proteins with a pivotal antioxidative function, is ubiquitously synthesized and abundantly identified in various organisms. In contrast to the intracellular localization of other family members (PRDX1/2/3/5/6), PRDX4 is the only known secretory form and protects against oxidative damage by scavenging reactive oxygen species in both the intracellular (especially the endoplasmic reticulum) compartments and the extracellular space. We generated unique human PRDX4 (hPRDX4) transgenic (Tg) mice on a C57BL/6J background and investigated the critical and diverse protective roles of PRDX4 against diabetes mellitus, atherosclerosis, insulin resistance, and nonalcoholic fatty liver disease (NAFLD) as well as evaluated its role in the intestinal function in various animal models. Our published data have shown that PRDX4 helps prevent the progression of metabolic syndrome by reducing local and systemic oxidative stress and synergistically suppressing steatosis, inflammatory reactions, and/or apoptotic activity. These observations suggest that Tg mice may be a useful animal model for studying the relevance of oxidative stress on inflammation and the dysregulation of lipid/bile acid/glucose metabolism upon the progression of human metabolic syndrome, and that specific accelerators of PRDX4 may be useful as therapeutic agents for ameliorating various chronic inflammatory diseases.

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Transparency-enhancing technology allows three-dimensional assessment of gastrointestinal mucosa: A porcine model

Although high-resolution three-dimensional imaging of endoscopically resected gastrointestinal specimens can help elucidating morphological features of gastrointestinal mucosa or tumor, there are no established methods to achieve this without breaking specimens apart. We evaluated the utility of transparency-enhancing technology for three-dimensional assessment of gastrointestinal mucosa in porcine models. Esophagus, stomach, and colon mucosa samples obtained from a sacrificed swine were formalin-fixed and paraffin-embedded, and subsequently deparaffinized for analysis. The samples were fluorescently stained, optically cleared using transparency-enhancing technology: ilLUmination of Cleared organs to IDentify target molecules method (LUCID), and visualized using laser scanning microscopy. After observation, all specimens were paraffin-embedded again and evaluated by conventional histopathological assessment to measure the impact of transparency-enhancing procedures. As a result, microscopic observation revealed horizontal section views of mucosa at deeper levels and enabled the three-dimensional image reconstruction of glandular and vascular structures. Besides, paraffin-embedded specimens after transparency-enhancing procedures were all assessed appropriately by conventional histopathological staining. These results suggest that transparency-enhancing technology may be feasible for clinical application and enable the three-dimensional structural analysis of endoscopic resected specimen non-destructively. Although there remain many limitations or problems to be solved, this promising technology might represent a novel histopathological method for evaluating gastrointestinal cancers.

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Validation of the digital PCR system in tyrosine kinase inhibitor-resistant EGFR mutant non-small-cell lung cancer

The aim of this study was to compare the accuracy of the QuantStudio 3D Digital polymerase chain reaction (dPCR) system and a PCR-based next generation sequencing (NGS) system for detecting a secondary mutation in the epidermal growth factor receptor (EGFR) gene T790M in non-small cell lung cancer (NSCLC) patients previously diagnosed with EGFR-activating mutations. Twenty-five patients with NSCLC previously treated with EGFR-TKIs were examined. The patients were treated daily with either erlotinib or gefitinib. New biopsies, followed by DNA sequencing on an Ion Torrent systems using the Ion Torrent AmpliSeq Cancer Hotspot Panel and dPCR were performed. A comparison of NGS, sensitive PCR, and dPCR revealed that the sensitivities of NGS and dPCR were similar in this study. As well, T790M was detected in as low as about 5% of mutant allelic frequencies, which represented 5% of the total reads on site mapped reads in NGS and greater than 5% of the dPCR reads, which represented mutant and wild type copies. The strategy in which NGS sequencing is followed by revealed acquired mutation with dPCR may be a reasonable one. We demonstrated the utility of combining NGS and dPCR as a tool for monitoring T790M. NGS and dPCR with formalin-fixed paraffin-embedded (FFPE) specimens might become a standard genomic test for exploring acquired resistance to targeted molecular medicines.

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Onset of action for loratadine tablets for the symptomatic control of seasonal allergic rhinitis in adults challenged with ragweed pollen in the Environmental Exposure Unit: a post hoc analysis of total symptom score

Loratadine is a second-generation, non-sedating antihistamine used for the relief of allergic rhinitis symptoms. Previous studies reported that when loratadine was encapsulated, the onset of action for symptom...

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Cytological features of mixed adenoneuroendocrine carcinoma of the ampulla of Vater: A case report with immunocytochemical analyses

Mixed adenoneuroendocrine carcinoma (MANEC) is defined as a tumor that has morphologically recognizable both adenocarcinoma and neuroendocrine carcinoma components comprising at least 30% of either components. MANEC occurring in the ampulla of Vater is extremely rare, and only 16 cases have been reported in the English language literature. In the present report, we describe the first case of MANEC of the ampulla of Vater with immunocytochemical analyses. An 82-year-old Japanese male was incidentally found to have a tumorous lesion in the ampulla of Vater. Endoscopic ultrasound-fine needle aspiration (EUS-FNA) of the tumor was performed. The Papanicolaou smear demonstrated the presence of different three components. The most dominant component was cohesive clusters of small round cells with round to oval nuclei with powdery chromatin and scant cytoplasm, which corresponded to small cell carcinoma. The second component was an adenocarcinoma, which was composed of irregularly overlapping clusters of tall columnar cells with large round to oval nuclei containing conspicuous nucleoli. The third component was an adenoma, which was comprised of flat cohesive clusters of columnar cells without atypia. Immunocytochemical analyses demonstrated that synaptophysin was expressed in the small round cells, and cdx-2 was expressed in all three components. Accordingly, a cytodiagnosis of MANEC with adenoma component was made. Preoperative diagnosis of ampullary MANEC is difficult. However, this report clearly demonstrates three different components in the EUS-FNA cytological specimen. Therefore, we suggest that cytological examination is a useful method for diagnosis of MANEC of the ampulla of Vater.

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Iron pill aspiration: Cytologic and histologic findings of a potential life-threatening airway injury. A Case report and literature review

Iron pill-induced injury of bronchial mucosa is a complication following accidental aspiration of an iron tablet. Oral iron supplementation is a common therapy, particularly among advanced-age patients, who are more prone to aspiration. However, iron pill aspiration has been rarely reported in the literature, usually under the format of short case reports, with only 32 cases published in the literature. The cytologic features suspicious for this rare but potentially lethal entity have been seldom described. We report a case of a patient diagnosed with iron pill-induced bronchial injury, after oral ferrous sulfate has been prescribed during a hospital admission for pneumonia. In the bronchial washing specimen, a background of necrotic cell debris and acute inflammation involving extracellular golden-brown fibrils positive for iron stains was seen, along with the yeast forms, which, in this clinical context could confirm the iron pill aspiration. Our aim is to highlight the cytology features associated with iron pill aspiration bronchitis, and to review the literature for the histologic, clinical, bronchoscopy, and treatment aspects.

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Stability, integrity, and recovery rate of cellular nucleic acids preserved in a new liquid-based cytology medium

Background

Liquid-based cytology (LBC) has replaced the conventional Papanicolaou test in cervical cancer screening. The cervical swab specimens collected in LBC media can also be used for additional analyses including high-risk HPV (HR-HPV) test, DNA methylation analysis, and HPV E6/E7 mRNA test.

Methods

The stability, integrity, and recovery rate of cellular DNA and RNA after storage at different conditions were evaluated by a quantitative real-time PCR (qPCR) based HR-HPV test, reverse transcription qPCR (RT-qPCR), and agarose gel electrophoresis. Cervical swab specimens collected in a newly developed LBC medium, VersaMedium, and ThinPrep PreservCyt medium were processed on Hologic ThinPrep 5000 instrument.

Results

Cervical exfoliative cells fixed by VersaMedium exhibited good cellular morphology with intact membranes and delineated chromatin structures. Cellular DNA preserved in VersaMedium exhibited high level of stability at both room temperature and 4°C, and remained mostly intact at 4°C for up to 28 days. Cellular RNA preserved in VersaMedium maintained higher level of stability and integrity at 4°C than at room temperature. VersaMedium also showed no apparent adverse effect on the recovery rate of nucleic acids.

Conclusion

In addition to maintaining cellular morphology, when stored at 4°C, VersaMedium preserves cellular nucleic acids and PreservCyt medium without noticeable adverse effects on the recovery rate during purification. Therefore, VersaMedium is an appropriate LBC medium for the collection and preservation of cervical swab specimens. And VersaMedium preserved cellular nucleic acids are of such high quality that they are suitable for HR-HPV qPCR test and RT-qPCR analyses.

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Evidence-based adequacy criteria for instrumented urine cytology using cytospin preparations

Cytospin preparations of instrumented urine cytology specimens with less than 10 urothelial cells or more than 50 urothelial cells/10 hpfs are both associated with significantly increased false negative rates compared to cases with 10-49 urothelial cells/10 hpfs.

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Cancer-Related Genetic Testing and Personalized Medicine for Adolescents: A Narrative Review of Impact and Understanding

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Educational Needs of Health Professionals Caring for Adolescents and Young Adults with Cancer

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Current Practice Patterns Surrounding Fertility Concerns in Stage I Seminoma Patients: Survey of United States Radiation Oncologists

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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The Graded and Redefined Assessment of Strength, Sensibility, and Prehension Version 2 Provides Interval Measure Properties

Journal of Neurotrauma , Vol. 0, No. 0.


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Exophytic sinonasal papillomas and nasal florid papillomatosis: A retrospective study

Abstract

Background

Sinonasal exophytic papillomas are rare. The multifocal form, florid papillomatosis, has not been yet described in literature. We report on the clinical features and the management of the different forms of exophytic papilloma.

Methods

A retrospective study was conducted that included all patients with exophytic papilloma treated in our center over the past 12 years. We recorded clinical presentation, treatments, recurrences, pathology (p16 expression and human papillomavirus [HPV] status).

Results

We included 13 patients with a mean follow-up of 5 years. The main location of exophytic papilloma was the anterior part of the septum. Lesions were multifocal in 3 patients corresponding to florid papillomatosis. The main treatment was surgery. Cases of HPV-11 or HPV-6 were present in all forms of exophytic papilloma (dysplasia in 4 cases). Late recurrences occurred in 3 patients (2 patients with florid papillomatosis) over a period of 3 years.

Conclusion

Exophytic papilloma has 2 clinical presentations: localized and diffuse. Patients with florid papillomatosis should be monitored closely as recurrence seems to be frequent.

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Endoscopic endonasal approach for sinonasal and anterior skull base malignancies in the elderly

Abstract

Background

The purpose of this study was to report the outcomes of endoscopic transnasal resection for sinonasal and anterior skull-base cancers in elderly patients.

Methods

A retrospective review was performed. The patients were divided into 2 groups, <70 years old and ≥70 years old and compared by univariate analysis. Prognostic factors were evaluated with a multivariate analysis. Survival rates were also calculated.

Results

Two hundred three elderly patients and 397 younger patients were enrolled in this study. The elderly patients reported lower survival rates than the younger patients. When melanoma and esthesioneuroblastoma were censored, the disease-specific survival (DSS) and recurrence-free survival (RFS) were similar. Complication rates were 17.5% without any statistical significance between the groups. Multivariate analysis revealed that histology, stage, surgical margins, and surgical approaches were independent predictors of survival in elderly patients.

Conclusion

The endoscopic transnasal approach reported low mortality and morbidity rates also in geriatric patients, and age itself is not to be considered as a contraindication.

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Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when?

Future Oncology, Ahead of Print.


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Endovascular implantation of 125I seed combined with transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma

Future Oncology, Ahead of Print.


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NrF2/ARE and NF-κB pathway regulation may be the mechanism for lutein inhibition of human breast cancer cell

Future Oncology, Ahead of Print.


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Establishing Correlates of Protection for Vaccine Development: Considerations for the Respiratory Syncytial Virus Vaccine Field

Viral Immunology , Vol. 0, No. 0.


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The Diagnostic Value of Impulse Oscillometry and Plethysmography for the Assessment of Exercise-Induced Bronchoconstriction in Asthmatic Children

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


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Pediatric penile porokeratosis: A case report

Abstract

We present what we believe to be the second case of pediatric penile porokeratosis and the youngest case reported. A 6-year-old boy presented with a pruritic, verrucous growth at the urethral meatus that recurred after two meatotomies. The diagnosis of porokeratosis was confirmed by biopsy. Porokeratosis should be added to the differential diagnosis of chronic hyperkeratotic penile lesions in children.

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Utility of ultrasonography in hair-thread tourniquet syndrome

Abstract

A 2-year-old girl presented with a 2-month history of an erythematous, indurated plaque with well-defined borders on the third toe of the right foot. Bedside high-resolution ultrasonography demonstrated a thickened epidermis overlying a hyperechoic focus within the dermis. Her clinical and sonographic presentation was in keeping with a foreign body causing hair-thread tourniquet syndrome. The foreign body was surgically extirpated without neurovascular sequelae. Ultrasonography expedited accurate diagnosis and is a promising adjunct to clinical evaluation for radiolucent foreign bodies.

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Recurrent terbinafine resistant Trichophyton rubrum infection in a child with congenital ichthyosis

Abstract

Dermatophytosis in children caused by Trichophyton rubrum is preferably treated with topical or systemic terbinafine. We report the first case of terbinafine resistance in a child with recurrent T. rubrum dermatophytosis and congenital ichthyosiform erythroderma.

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The Graded and Redefined Assessment of Strength, Sensibility, and Prehension Version 2 Provides Interval Measure Properties

Journal of Neurotrauma , Vol. 0, No. 0.


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An order effect in English infants’ discrimination of an Urdu affricate contrast

Publication date: March 2018
Source:Journal of Phonetics, Volume 67
Author(s): Mariam Dar, Tamar Keren-Portnoy, Marilyn Vihman
An order effect was found in English infants' discrimination of an Urdu contrast. In Experiment 1 7- and 11-month-old English infants were tested on the Urdu contrast between the affricates /tʃʰ/ and /tʃ/. The order of presentation was counterbalanced: At each age half the infants were habituated to the aspirated and tested on the unaspirated affricate, the other half habituated to the unaspirated and tested on the aspirated. As expected, younger infants discriminated the contrast whereas older infants did not, showing the expected decline in discrimination. Order of presentation seemed to affect the older infants' response. Experiment 2 tested the order effect directly. The results showed no asymmetry in the performance of 7-month olds but clear asymmetry in that of 11-month-olds, who discriminated the contrast only when the non-English-like aspirated affricate was presented first. Experiment 3 tested adult native-speakers of both Urdu and English. Although the English listeners showed a reduced sensitivity to the contrast, there was no effect due to order of presentation of the stimuli in either adult group. The finding of an asymmetry in the infants suggests that infants' perceptual narrowing for speech sounds may be a more complex phenomenon than has generally been assumed.



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Periodontology for Geriatric Patients

Abstract

Purpose of Review

Elderly population represents the fastest growing population segment and target group of many expert organizations developing strategies for successful aging. The substantial increase in man's lifespan together with implementation of preventive dental programs resulted in decreased tooth loss and increased prevalence of periodontal disease. Hence, the present review focused on positioning periodontal health within aging process, characteristic of the senescent periodontium, periodontitis-aging interplay, clinical characteristics, and implications for periodontal care in geriatric patients.

Recent Findings

The senescent periodontium undergoes degenerative changes that are unrelated to progressive destruction in lack of inflammation. The pathological interplay periodontitis-systemic aging is evidenced. Geriatric patients demonstrate comparable treatment outcomes to those of patients ≤ 60 years regarding non-surgical and surgical periodontal treatment and implant therapy as well.

Summary

Adequate oral hygiene and appropriate control of risk factors represent the key pre-conditions for successful periodontal and systemic aging.

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Issue Information

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Anatomical Society Summer Meeting in Galway

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Repurposing tin mesoporphyrin as an immune checkpoint inhibitor shows therapeutic efficacy in preclinical models of cancer

Purpose: Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint molecules. This preclinical study investigates heme oxygenase-1 (HO-1), an immune suppressive enzyme that is expressed in a wide variety of cancers, as a potential immune checkpoint target in the context of a chemotherapy-elicited anti-tumor immune response. We evaluate repurposing tin mesoporphyrin (SnMP), which has demonstrated safety and efficacy targeting hepatic HO in the clinic for the treatment of hyperbilirubinaemia, as an immune checkpoint blockade therapy for the treatment of cancer. Experimental design: SnMP and genetic inactivation of myeloid HO-1 were evaluated alongside 5-fluorouracil in an aggressive spontaneous murine model of breast cancer (MMTV-PyMT). Single-cell RNA sequencing analysis, tumor microarray and clinical survival data from breast cancer patients were used to support the clinical relevance of our observations. Results: We demonstrate that SnMP inhibits immune suppression of chemotherapy-elicited CD8+ T cells by targeting myeloid HO-1 activity in the tumor microenvironment. Microarray and survival data from breast cancer patients reveal that HO-1 is a poor prognostic factor in patients receiving chemotherapy. Single-cell RNA sequencing analysis suggests that the myeloid lineage is a significant source of HO-1 expression, and is co-expressed with the immune checkpoints PD-L1/2 in human breast tumors. In vivo, we therapeutically compared the efficacy of targeting these two pathways alongside immune-stimulating chemotherapy, and demonstrate that the efficacy of SnMP compares favorably to PD-1 blockade in preclinical models. Conclusions: SnMP could represent a novel immune checkpoint therapy, which may improve the immunological response to chemotherapy.

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IDH1/2 mutations sensitize acute myeloid leukemia to PARP inhibition and this is reversed by IDH1/2-mutant inhibitors

Purpose: Somatic mutations in IDH1/2 occur in ~20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2MUT enzymes produce D-2-hydroxyglutarate (D2HG), which associates with increases in DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for IDH1/2MUT AML is not known. Experimental Design: Well-characterized primary IDH1MUT, IDH2MUT and IDH1/2WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation and PARP inhibitors. Results: IDH1/2MUT caused increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib in AML cells. IDH1/2MUT inhibitors protected against these treatments. Combined treatment with a PARP inhibitor and daunorubicin had an additive effect on the killing of IDH1/2MUT AML cells. We provide evidence that the therapy sensitivity of IDH1/2MUT cells was caused by D2HG-mediated downregulation of expression of the DNA damage response gene ATM and not by altered redox responses due to metabolic alterations in IDH1/2MUT cells. Conclusions: IDH1/2MUT AML cells are sensitive to PARP inhibitors as monotherapy but especially when combined with a DNA-damaging agent such as daunorubicin, whereas concomitant administration of IDH1/2MUT inhibitors during cytotoxic therapy decrease the efficacy of both agents in IDH1/2MUT AML. These results advocate in favor of clinical trials of PARP inhibitors either or not in combination with daunorubicin in IDH1/2MUT AML.

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New insights in the relative radiobiological effectiveness of proton irradiation

Proton radiotherapy is a form of charged particle therapy that is preferentially applied for the treatment of tumors positioned near to critical structures due to their physical characteristics, showing an inv...

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Relative Target Affinities of T Cell-Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model

Anti-HER2/CD3, a T cell-dependent bispecific antibody (TDB) construct, induces T cell-mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. While therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy. To our knowledge, no distribution studies have been published using preclinical models wherein the T cell-targeting arm of the TDB is actively bound to T cells. We used a combined approach involving radiochemistry, invasive biodistribution and non-invasive single-photon emission tomographic (SPECT) imaging to measure TDB distribution and catabolism in transgenic mice with human CD3 expression on T cells. Using CD3 affinity variants, we assessed the impact of CD3 affinity on short term pharmacokinetics, tissue distribution and cellular uptake. Our experimental approach determined the relative effects of (i) CD3 targeting to normal tissues, (ii) HER2 targeting to HER2-expressing tumors and (iii) relative HER2/CD3 affinity, all as critical drivers for TDB distribution. We observed a strong correlation between CD3 affinity and distribution to T cell-rich tissues, with higher CD3 affinity reducing systemic exposure and shifting TDB distribution away from tumor to T cell-containing tissues. These observations have important implications for clinical translation of bispecific antibodies for cancer immunotherapy.

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INHIBITION OF FLT3 AND PIM KINASES BY EC-70124 EXERTS POTENT ACTIVITY IN PRECLINICAL MODELS OF ACUTE MYELOID LEUKEMIA

Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myeloid leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations. EC-70124 potently inhibits wild-type and mutant FLT3, and also other important kinases such as Pim kinases. EC-70124 inhibits proliferation of AML cell lines, inducing cell cycle arrest and apoptosis. EC-70124 is orally bioavailable and displays higher metabolic stability and lower human protein plasma binding compared to midostaurin. Both in vitro and in vivo pharmacodynamic analyses demonstrate inhibition of FLT3-STAT5, Akt-mTOR-S6, and Pim-BAD pathways. Oral administration of EC-70124 in FLT3-ITD xenograft models demonstrates high efficacy, reaching complete tumor regression. Ex vivo, EC-70124 impaired cell viability in leukemic blasts, especially from FLT3-ITD patients. Our results demonstrate the ability of EC-70124 to reduce proliferation and induce cell death in AML cell lines, patient derived leukemic blast and xenograft animal models, reaching best results in FLT3 mutants which carry other molecular pathways alterations. Thus, its unique inhibition profile warrants EC-70124 as a promising agent for AML treatment, based on its ability to interfere the complex oncogenic events activated in AML at several levels.

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Cricothyrotomy in Helicopter Emergency Medical Service Transport.

Related Articles

Cricothyrotomy in Helicopter Emergency Medical Service Transport.

Air Med J. 2018 Jan - Feb;37(1):51-53

Authors: High K, Brywczynski J, Han JH

Abstract
OBJECTIVE: Airway management is a requisite skill set for helicopter emergency medical service (HEMS) providers. Cricothyrotomy is a potentially lifesaving skill that is used when other airway maneuvers fail. The authors reviewed all transports by a helicopter program in which cricothyrotomy was performed to assess the frequency, success, and technique.
METHODS: This was a retrospective chart review of air medical patient records from an electronic medical record system over a 112-month period.
RESULTS: During the study period, 22,434 patients were transported, 13 (.057%) of whom underwent cricothyrotomy. The typical patient was a male trauma victim with a mean Glasgow Coma Score of 5 transported from an accident scene with a mean age of 34.3 years. Six (46%) of the patients were alive at 24 hours. All patients (13/100%) received attempted endotracheal intubation; the mean number of attempts per patient was 2. The success rate was 100% with all patients ventilated via cricothyrotomy.
CONCLUSION: This study shows cricothyrotomy is a rarely performed skill but that HEMS providers are able to successfully learn the skill with proper training and oversight.

PMID: 29332778 [PubMed - in process]

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Genes predisposed to DNA hypermethylation during acquired resistance to chemotherapy are identified in ovarian tumors by bivalent chromatin domains at initial diagnosis

Bivalent chromatin domains containing both active H3K4me3 and repressive H3K27me3 histone marks define gene sets poised for expression or silencing in differentiating embryonic stem (ES) cells. In cancer cells aberrantly poised genes may facilitate changes in transcriptional states after exposure to anti-cancer drugs. In this study, we used ChIP-seq to characterize genome-wide positioning of H3K4me3 and H3K27me3-associated chromatin in primary high-grade serous ovarian carcinomas and in normal ovarian surface and fallopian tube tissue. Gene sets with proximal bivalent marks defined in this manner were evaluated subsequently as signatures of systematic change in DNA methylation and gene expression, comparing pairs of tissue samples taken from patients at primary presentation and relapse following chemotherapy. We found that gene sets harboring bivalent chromatin domains at their promoters in tumor tissue, but not normal epithelia, overlapped with Polycomb-repressive complex target genes as well as transcriptionally silenced genes in normal ovarian and tubal stem cells. The bivalently marked genes we identified in tumors before chemotherapy displayed increased promoter CpG methylation and reduced gene expression at relapse after chemotherapy of ovarian cancer. Overall, our results support the hypothesis that pre-existing histone modifications at genes in a poised chromatin state may lead to epigenetic silencing during acquired drug resistance.

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Role of chromatin damage and chromatin trapping of FACT in mediating the anticancer cytotoxicity of DNA-binding small molecule drugs

Precisely how DNA-targeting chemotherapeutic drugs trigger cancer cell death remains unclear, as it is difficult to separate direct DNA damage from chromatin damage in cells. Recent work on curaxins, a class of small molecule drugs with broad anticancer activity, show that they interfere with histone-DNA interactions and destabilize nucleosomes without binding DNA or causing detectable DNA damage. Chromatin unfolding caused by curaxins is sensed by the histone chaperone FACT, which binds unfolded nucleosomes and causes chromatin trapping (c-trapping). In this study, we investigated whether classical DNA-targeting chemotherapeutic drugs also similarly disturbed chromatin to cause c-trapping. Drugs that directly bound DNA induced both chromatin damage and c-trapping. However, chromatin damage occurred in the absence of direct DNA damage and was dependent on how a drug bound DNA, specifically, in the way it bound chromatinized DNA in cells. FACT was sensitive to a plethora of nucleosome perturbations induced by DNA-binding small molecules, including displacement of the linker histone, eviction of core histones, and accumulation of negative supercoiling. Strikingly, we found that the cytotoxicity of DNA-binding small molecules correlated with their ability to cause chromatin damage, not DNA damage. Our results suggest implications for the development of chromatin-damaging agents as selective anticancer drugs.

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AMPK-AKT double negative feedback loop in breast cancer cells regulates their adaptation to matrix deprivation

Cell detachment from the extracellular matrix triggers anoikis. Disseminated tumor cells must adapt to survive matrix deprivation, while still retaining the ability to attach at secondary sites and re-initiate cell division. In this study, we illuminate mechanisms that enable reversible matrix attachment by breast cancer cells. Matrix deprival triggered AMPK activity and concomitantly inhibited AKT activity by upregulating the AKT phosphatase PHLPP2. The resultant pAMPKhigh/pAKTlow state was critical for cell survival in suspension, as PHLPP2 silencing also increased anoikis while impairing autophagy and metastasis. In contrast, matrix re-attachment led to AKT-mediated AMPK inactivation via PP2C-α-mediated restoration of the pAKThigh/pAMPKlow state. Clinical specimens of primary and metastatic breast cancer displayed an AKT-associated gene expression signature, whereas circulating breast tumor cells displayed an elevated AMPK-dependent gene expression signature. Our work establishes a double-negative feedback loop between AKT and AMPK to control the switch between matrix-attached and matrix-detached states needed to coordinate cell growth and survival during metastasis.

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PHD3 controls lung cancer metastasis and resistance to EGFR inhibitors through TGF{alpha}

Lung cancer is the leading cause of cancer-related death worldwide, in large part due to its high propensity to metastasize and develop therapy resistance. Adaptive responses to hypoxia and epithelial-mesenchymal transition (EMT) are linked to tumor metastasis and drug resistance, but little is known about how oxygen sensing and EMT intersect to control these hallmarks of cancer. Here we show that the oxygen sensor PHD3 links hypoxic signaling and EMT regulation in the lung tumor microenvironment. PHD3 was repressed by signals that induce EMT and acted as a negative regulator of EMT, metastasis and therapeutic resistance. PHD3 depletion in tumors, which can be caused by the EMT inducer TGFβ or by promoter methylation, enhanced EMT and spontaneous metastasis via HIF-dependent upregulation of the EGFR ligand TGFα. In turn, TGFα stimulated EGFR which potentiated SMAD signaling, reinforcing EMT and metastasis. In clinical specimens of lung cancer, reduced PHD3 expression was linked to poor prognosis and to therapeutic resistance against EGFR inhibitors such as erlotinib. Re-expression of PHD3 in lung cancer cells suppressed EMT and metastasis and restored sensitivity to erlotinib. Taken together, our results establish a key function for PHD3 in metastasis and drug resistance and suggest opportunities to improve patient treatment by interfering with the feedforward signaling mechanisms activated by PHD3 silencing.

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E6 protein expressed by high-risk HPV activates super-enhancers of the EGFR and c-MET oncogenes by destabilizing the histone demethylase KDM5C

The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events are poorly understood. Here we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes EGFR and c-MET. Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bi-directional eRNA transcription. Depletion of KDM5C or HPV-16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by high-risk HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like EGFR and c-MET.

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Radio-resistant Cervical Cancers Are Sensitive to Inhibition of Glycolysis and Redox Metabolism

Highly glycolytic cervical cancers largely resist treatment by cisplatin and co-administered pelvic irradiation as the present standard of care. In this study, we investigated the effects of inhibiting glycolysis and thiol redox metabolism to evaluate them as alternate treatment strategies in these cancers. In a panel of multiple cervical cancer cell lines, we evaluated sensitivity to inhibition of glycolysis (2-DG) with or without simultaneous inhibition of glutathione and thioredoxin metabolism (BSO/AUR). Intracellular levels of total and oxidized glutathione, thioredoxin reductase activity, and indirect measures of intracellular reactive oxygen species (ROS) were compared before and after treatment. Highly radio-resistant cells were the most sensitive to 2-DG, whereas intermediate radio-resistant cells were sensitive to 2-DG plus BSO/AUR. In response to 2-DG/BSO/AUR treatment, we observed increased levels of intracellular oxidized glutatione, redox-sensitive dye oxidation and decreased glucose utilization via multiple metabolic pathways including the TCA cycle. 2-DG/BSO/AUR treatment delayed the growth of tumors composed of intermediate radio-resistant cells and effectively radio-sensitized these tumors at clinically relevant radiation doses both in vitro and in vivo. Overall, our results support inhibition of glycolysis and intracellular redox metabolism as an effective alternative drug strategy for the treatment of highly glycolytic and radio-resistant cervical cancers.

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The Hippo pathway component TAZ promotes immune evasion in human cancer through PD-L1

The Hippo pathway component WW domain-containing transcription regulator 1 (TAZ) is a transcriptional co-activator and an oncogene in breast and lung cancer. Transcriptional targets of TAZ that modulate immune cell function in the tumour microenvironment are poorly understood. Here, we perform a comprehensive screen for immune-related genes regulated by TAZ and its paralog YAP using NanoString gene expression profiling. We identify the immune checkpoint molecule PD-L1 as a target of Hippo signaling. The upstream kinases of the Hippo pathway, mammalian STE20-like kinase 1 and 2 (MST1/2) and large tumour suppressor 1 and 2 (LATS1/2), suppress PD-L1 expression while TAZ and YAP enhance PD-L1 levels in breast and lung cancer cell lines. PD-L1 expression in cancer cell lines is determined by TAZ activity and TAZ/YAP/TEAD increase PD-L1 promoter activity. Critically, TAZ-induced PD-L1 upregulation in human cancer cells is sufficient to inhibit T cell function. The relationship between TAZ and PD-L1 is not conserved in multiple mouse cell lines, likely due to differences between the human and mouse PD-L1 promoters. To explore the extent of divergence in TAZ immune-related targets between human and mouse cells, we perform a second NanoString screen using mouse cell lines. We show that many targets of TAZ may be differentially regulated between these species. These findings highlight the role of Hippo signaling in modifying human/murine physiological/pathological immune responses and provide evidence implicating TAZ in human cancer immune evasion.

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STAT3/PIAS3 levels serve as "early signature" genes in the development of high-grade serous carcinoma from the fallopian tube

The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 (pSTAT3 Tyr705) and suppression or loss of protein inhibitor of activated STAT3 (PIAS3) in FT likely drive HGSC. We evaluated human tissues-benign normal FT, tubal peritoneal junction (TPJ), p53 signature fallopian tube tissue, tubal intraepithelial lesion in transition (TILT), serous tubal intraepithelial carcinoma (STIC) without ovarian cancer, and HGSC for expression of STAT3/PIAS3 (compared with their known TP53 signature) and their target proliferation genes. We observed constitutive activation of STAT3 and low levels or loss of PIAS3 in the TPJ, p53 signature, TILT, and STIC through advanced stage IV (HGSC) tissues. Elevated expression of pSTAT3 Tyr705 and decreased levels of PIAS3 appeared as early as TPJ and the trend continued until very advanced stage HGSC (compared to high PIAS3 and low pSTAT3 expression in normal benign FT). Exogenous expression of STAT3 in FT cells mediated translocation of pSTAT3 and c-Myc into the nucleus. In vivo experiments demonstrated that overexpression of STAT3 in fallopian tube secretory epithelial cells (FTSEC) promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. Thus we conclude that the STAT3 pathway plays a role in the development and progression of HGSC from its earliest pre-malignant states.

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Primary versus secondary tracheoesophageal puncture: systematic review and meta-analysis.

Related Articles

Primary versus secondary tracheoesophageal puncture: systematic review and meta-analysis.

J Laryngol Otol. 2018 Jan;132(1):14-21

Authors: Chakravarty PD, McMurran AEL, Banigo A, Shakeel M, Ah-See KW

Abstract
BACKGROUND: Tracheoesophageal puncture represents the 'gold standard' for voice restoration following laryngectomy. Tracheoesophageal puncture can be undertaken primarily during laryngectomy or in a separate secondary procedure. There is no current consensus on which approach is superior. The current evidence comparing primary and secondary tracheoesophageal puncture was assessed.
METHODS: A systematic review and meta-analysis of articles comparing outcomes for primary and secondary tracheoesophageal puncture after laryngectomy were conducted. Outcome measures were: voice success, overall complication rate and pharyngocutaneous fistula rate.
RESULTS: Eleven case series met the inclusion criteria, two prospective and nine retrospective. Meta-analysis did not demonstrate statistically significant differences in overall complication rate or voice outcomes, though it suggested a significantly increased risk of pharyngocutaneous fistula in primary compared to secondary tracheoesophageal puncture.
CONCLUSION: Primary tracheoesophageal puncture is a safe and efficient approach for voice rehabilitation. However, secondary tracheoesophageal puncture should be preferred where there is a higher risk of pharyngocutaneous fistula.

PMID: 29173195 [PubMed - indexed for MEDLINE]

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Microsurgical Resection of Tuberculum Sellae Meningioma through Left Cranio-orbital Approach

J Neurol Surg B
DOI: 10.1055/s-0037-1620240

In this video clip, the authors present the resection of a tuberculum sellae meningioma with compression of the left optic nerve and a chiasm (Fig. 1) through a standard cranial orbital (CO) skull base approach.1 2 3 The key step in the tumor resection was microsurgical dissection of left and right A1 segments of the anterior cerebral artery and the anterior communicating artery and the separation of the tumor from these vascular structures. This was followed by careful separation of the meningioma from both optic nerves, the chiasm and the pituitary stalk. The final step was coagulation and resection of the tumor origin on the dura of the tuberculum sellae, devascularizing the tumor. Once this was achieved, the tumor was removed. Using this approach, an optimal surgical corridor to the sellar area was provided while minimizing the retraction of frontal and temporal lobes.The link to the video can be found at: https://youtu.be/O59Fj2dNXB0.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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

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Endoscopic Transsphenoidal Resection of Craniopharyngioma

J Neurol Surg B
DOI: 10.1055/s-0037-1620243

Objectives To demonstrate, step-by-step, the technique and efficacy of endoscopic transsphenoidal approach in resection of a suprasellar craniopharyngioma. Design The video shows a step-by-step approach to the resection, covering the exposure, access, resection, and confirmation of resection and reconstruction. Setting The surgery was performed in the University of Malaya Medical Centre, a tertiary referral center in the capital of Malaysia. Participants Surgery was performed jointly by Professor Prepageran from the department of otorhinolaryngology and Professor Vicknes Waran from the division of neurosurgery. Both surgeons are from the University of Malaya. Video compilation, editing, and voice narration was done by Dr. Kong Yew Liew. Main Outcome Measures Completeness of resection and avoidance of intra- and postoperative complications. Results Based on intraoperative views and MRI findings, the tumor was completely resected with the patient suffering only transient diabetes insipidus. Conclusion Central suprasellar tumors can be removed completely via an endoscopic transsphenoidal approach with minimal morbidity to the patient.The link to the video can be found at: https://youtu.be/ZNIHfk12cYg.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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

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Microsurgical Resection of Tuberculum Sellae Meningioma via Pterional Craniotomy with Extradural Anterior Clinoidectomy and Optic Unroofing

J Neurol Surg B
DOI: 10.1055/s-0037-1620254

Microsurgical treatment of suprasellar tumors, in particular tuberculum sellae meningiomas, poses significant challenge. These tumors are surrounded by vital neurovascular structures, such as optic apparatus, pituitary stalk, internal carotid artery and its branches, and anterior cerebral arteries. In large and complex cases, early identification and decompression of these structures may facilitate safer dissection and resection. Therefore, extradural anterior clinoidectomy with optic unroofing facilitates the internal carotid artery exposure and optic nerve decompression. In this video, we describe a 37-year-old female patient who presented with new onset of severe headaches. On visual examination, she was found to have bitemporal visual defects. MRI scan of the head showed a large, approximately 3 cm suprasellar tumor consistent with tuberculum sellae meningioma. She underwent surgical resection via pterional craniotomy with extradural anterior clinoidectomy and optic unroofing. Microsurgical gross total resection was achieved and histopathology was WHO grade II meningioma. She had an uneventful postoperative course and visual field examination improved significantly. In this video, surgical technique in performing extradural anterior clinoidectomy and optic unroofing and steps of microsurgical resection are demonstrated.The link to the video can be found at: https://youtu.be/oPZ8NTyvxJc.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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

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Extended Endoscopic Approach for Resection of Craniopharyngiomas

J Neurol Surg B
DOI: 10.1055/s-0037-1620244

Objectives Extended endoscopic approaches are useful for resection of selected craniopharyngiomas. Midline, extraventricular, and predominantly cystic lesions are good candidates for endoscopic resection. In this video, we demonstrate the endoscopic endonasal resection of a large suprasellar craniopharyngioma and discuss the nuances of the surgical technique. Design/Setting Surgical video of an extended endoscopic approach for resection of a suprasellar craniopharyngioma. Results We report the case of a 56-year-old woman who presented with bitemporal hemianopsia and visual acuity deterioration secondary to a large suprasellar solid–cystic lesion. The patient underwent an extended endoscopic transtuberculum approach for resection of the lesion, which was diagnosed as a papillary craniopharyngioma. This video discusses the anatomy and surgical technique applied for endoscopic resection of such lesions. Conclusion Endoscopic endonasal surgery is a useful technique for management of craniopharyngiomas. It is associated with good clinical outcomes in selected cases. Complications, such as postoperative CSF leak, may occur and should be carefully managed.The link to the video can be found at: https://youtu.be/EneOCiQE7yo.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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

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Resection of an Optic Canal Meningioma through a Contralateral Subfrontal Approach with Endoscopic Assistance: A 2D Operative Video

J Neurol Surg B
DOI: 10.1055/s-0037-1620253

Objective To review the use of the contralateral subfrontal approach for the resection of an optic canal meningioma. Design Operative video. Results A meningioma, located in the inferomedial side of the optic canal (Fig. 1), was found to cause significant visual deterioration. The subfrontal route was preferred to expose the tumor without mobilization of the optic nerve. Drilling of the anterior limb of the chiasmatic sulcus (limbus sphenoidale) provided adequate exposure of the medial aspect of the optic canal. Gross total resection (Simpson II) of the tumor was accomplished, and endoscopic assistance allowed identification and coagulation of an infiltrated dura mater in the chiasmatic sulcus and tuberculum sellae. Conclusion The subfrontal approach grants an optimal surgical trajectory to the contralateral chiasmatic sulcus and optic nerve. When the medial side of the optic canal is drilled, tumors extending into the optic canal can be safely resected, under direct visualization of the inferomedial side of the optic nerve. Breach into the sphenoid sinus can occur during drilling of the anterior limb of the chiasmatic sulcus. Endoscopic assistance can provide a better view on blind areas of the surgical field, including the depth of the optic canal (Fig. 2).The link to the video can be found at: https://youtu.be/fS2udUCPH1g.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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

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Extended Endoscopic Endonasal Approach for Craniopharyngioma Removal

J Neurol Surg B
DOI: 10.1055/s-0038-1623527

Objective Endoscopic transsphenoidal extended endoscopic approach (EEA) represents a valid alternative to microsurgery for craniopharyngiomas removal, especially for retrochiasmatic lesions without large parasellar extension. The present video illustrates the salient surgical steps of the EEA for craniopahryngioma removal. Patient A 52-year-old man presented with a bitemporal hemianopia and a bilateral decreased visual acuity. MRI showed a Kassam type III cystic craniopharyngioma with a solid component (Fig. 1, panels A and B). Surgical Procedure The head is rotated 10 degrees toward the surgeons. The nasal step is started through the left nostril with a middle turbinectomy. A nasoseptal flap is harvested and positioned in the left choana. The binostril approach allows a large sphenoidotomy to expose the key anatomic landmarks. The craniotomy boundaries are the planum sphenoidale superiorly, the median opticocarotid recesses, the internal carotid artery laterally and the clival recess inferiorly. After dural opening and superior intercavernous sinus coagulation, the tumor is entirely removed (Fig. 2, panels A and B). Skull base reconstruction is ensured by fascia lata grafting and nasoseptal flap positioning. Results Postoperative MRI showed the complete tumor resection (Fig. 1, panels C and D). At 3 months postoperatively, the bitemporal hemianopia regressed and the visual acuity improved. A novel left homonymous hemianopia developed secondary to optic tract manipulation. Conclusions The extended EEA is a valid surgical approach for craniopharyngioma resection. A comprehensive knowledge of the sellar and parasellar anatomy is mandatory for safe tumor removal with decreased morbidity and satisfactory oncologic results.The link to the video can be found at: https://youtu.be/NrCPPnVK2qA.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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The Posterior Transpetrosal Approach in a Case of Large Retrochiasmatic Craniopharyngioma: Operative Video and Technical Nuances

J Neurol Surg B
DOI: 10.1055/s-0037-1620252

Objectives To discuss the use of the posterior petrosal approach for the resection of a retrochiasmatic craniopharyngioma. Design Operative video. Results In this case video, the authors discuss the surgical management of a large craniopharyngioma, presenting with mass effect on the third ventricle and optic apparatus. A first surgical stage, through an endoscopic endonasal transtubercular approach, allowed satisfactory decompression of the optic chiasma and nerves in preparation for adjuvant therapy. However, accelerated growth of the tumor, with renewed visual deficits and mass effect on the hypothalamus and third ventricle, warranted a supplementary resection. A posterior transpetrosal1 2 (also called "retrolabyrinthine transtentorial") was performed to obtain a better exposure of the tumor and the surrounding anatomy (floor and walls of the third ventricle, perforating vessels, optic nerves, etc.)3. Nuances of technique and surgical pearls related to the posterior transpetrosal are discussed and illustrated in this operative video, including the posterior mobilization of the transverse–sigmoid sinuses junction, preservation of the venous anatomy during the tentorial incision, identification and preservation of the floor of the third ventricle during tumor resection, and a careful multilayer closure. Conclusion Retrochiasmatic craniopharyngiomas are difficult to reach tumors that often require skull base approaches, either endoscopic endonasal or transcranial. The posterior transpetrosal approach is an important part of the surgical armamentarium to safely resect these complex tumors.The link to the video can be found at: https://youtu.be/2MyGLJ_v1kI.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Tuberculum Meningioma: Orbitopterional Approach

J Neurol Surg B
DOI: 10.1055/s-0037-1618599

This is a case of an extensive tuberculum sella meningioma involving the circle of Willis down to the basilar artery that presented with bilateral visual loss worse on the right than left side. A one-piece right orbitopterional approach along the worse eye was used to gain access to the three cranial fossae. The orbitotomy facilitates access to the midline structures and contralateral base of the tumor with minimal brain retraction. Tumor resection is initiated by first identifying the tumor capsule, followed by piecemeal debulking via ultrasonic aspiration. Early decompression of the ipsilateral optic nerve was performed. Gross total resection of the tumor was achieved through multiple windows as follows: prechiasmatic, opticocarotid, and carotid oculomotor. Sharp dissection is performed around critical neurovascular structures to reduce strain and vascular injury. The circle of Willis including the small perforators was completely preserved. Postoperative examination at follow-up demonstrated improvement in vision less on the right side and resolution of postoperative partial third nerve palsy.The link to the video can be found at: https://youtu.be/XfEh8CjkvA0.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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

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Infrasellar Endoscopic Endonasal Approach for a Pituitary Adenoma Extending into the Third Ventricle, with Anterior Displacement of the Pituitary Gland

J Neurol Surg B
DOI: 10.1055/s-0037-1620261

Objectives The current video presents the nuances of the infrasellar endoscopic endonasal approach for a pituitary adenoma extending into the third ventricle, with anterior displacement of the pituitary gland. Design The video analyzes the presentation, preoperative workup and imaging, surgical steps and technical nuances of the surgery, the clinical outcome, and follow-up imaging. Setting The patient was treated by a skull base team consisting of a neurosurgeon and an ENT surgeon at a teaching academic institution. Participants The case refers to 73-year-old female patient who was found to have a sellar mass after failure of vision to improve with cataract surgery. She also reported a several-month history of progressive loss of vision along with daily retro-orbital headaches. The adenoma extended into the clivus as well as in the retrosellar and suprasellar regions, eroding into the floor of the third ventricle. The normal gland was displaced anteriorly. Main Outcome Measures The main outcome measures consisted of reversal of patient symptoms (headaches and visual disturbance), recurrence-free survival based on imaging, as well as absence of any complications. Results The patient's headaches and visual fields improved. There was no evidence of recurrence. Conclusion The infrasellar endoscopic endonasal approach is safe and effective for pituitary adenomas extending into the third ventricle, with anterior displacement of the pituitary gland.The link to the video can be found at: https://youtu.be/zp_06mEyRvY.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer

The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer

The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer, Published online: 16 January 2018; doi:10.1038/bjc.2017.441

The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer

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How the evolution of multicellularity set the stage for cancer

How the evolution of multicellularity set the stage for cancer

How the evolution of multicellularity set the stage for cancer, Published online: 16 January 2018; doi:10.1038/bjc.2017.398

How the evolution of multicellularity set the stage for cancer

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Phase I open-label study of afatinib plus vinorelbine in patients with solid tumours overexpressing EGFR and/or HER2

Phase I open-label study of afatinib plus vinorelbine in patients with solid tumours overexpressing EGFR and/or HER2

Phase I open-label study of afatinib plus vinorelbine in patients with solid tumours overexpressing EGFR and/or HER2, Published online: 16 January 2018; doi:10.1038/bjc.2017.436

Phase I open-label study of afatinib plus vinorelbine in patients with solid tumours overexpressing EGFR and/or HER2

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Epidermal melanocytes of segmental vitiligo show altered expression of E-cadherin, but not P-cadherin

Abstract

Vitiligo is the most common pigmentation disorder, with a worldwide prevalence of 1%. The loss of melanocytes from the skin is the main clinical feature of patients with vitiligo, resulting in depigmentation macules. Vitiligo has been classified into two major forms: non-segmental vitiligo (NSV) and segmental vitiligo (SV). NSV lesions are generally bilateral or symmetrically scattered over the entire body. Onset may occur at any age, but most patients develop vitiligo before 40 years of age, and the depigmentation evolves over time.

This article is protected by copyright. All rights reserved.

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Reflectance Confocal Microscopy for the Diagnosis of Langerhans Cell Histiocytosis

Abstract

Langerhans cell histiocytosis (LCH) is a rare proliferative disease occurring in young children. The most affected organs are the bones and the skin (1). The diagnosis of LCH relies on histopathology. Reflectance confocal microscopy (RCM) is a non-invasive imaging technique used to diagnose skin cancer (2). We report that in three children RCM examination of cutaneous lesions of LCH showed specific signs correlated to histopathology.

This article is protected by copyright. All rights reserved.

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WHO is in and WHO is out of the mouth, salivary glands, and jaws sections of the 4th edition of the WHO classification of head and neck tumours

This review of changes to the 4th edition of the WHO classification of head and neck tumours focuses on their impact on the surgical care of diseases that affect the salivary glands, jaws, and oral cavity. Updates to the chapter on the salivary glands include the addition of secretory carcinoma and sclerosing polycystic adenosis. The odontogenic cysts are back, and the odontogenic keratocyst is listed among them, as it has now lost its brief and confusing designation as a neoplasm. The newly-defined sclerosing odontogenic carcinoma and primordial odontogenic tumour have been added.

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Sialendoscopy for sialolithiasis in children: 4-8 years follow up

Sialolithiasis is rare in children, there are no guidelines for its treatment, and there are few, if any, long term follow-up studies. We report a retrospective review of medical records of children who were treated for sialolithiasis by sialendoscopy between 1 January 2007 and 31 December 2011, and who have been followed up for 4-8 years. Personal and clinical details, including age, sex, symptoms, whether the lithiasis was parotid or submandibular, the technique of sialendoscopy and complications, were recorded.

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The ability of topical and systemic statins to increase osteogenesis around dental implants: a systematic review of histomorphometric outcomes in animal studies

The purpose of this systematic review was to evaluate the quantitative histomorphometric outcomes of animal studies investigating statins as a pro-osteogenic agent to enhance the osseointegration of dental implants. Some animal studies have suggested a beneficial action of statins on bone tissue. Electronic and manual literature searches, without date or language restriction, ​​were performed by two independent review authors up to February 2017. Eligibility criteria included animal trials quantitatively analysing the pro-osteogenic effect of statins on dental implants.

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Effect of Remote Ischemic Preconditioning on Systemic Toxicity and Ototoxicity Induced by Cisplatin in Rats: Role of TNF-α and Nitric Oxide

Background/Aims: Cisplatin is a chemotherapeutic agent. The use of remote ischemic preconditioning (RIPC) was proposed after the observation that ischemic preconditioning of a cardiac vascular area could protect another completely distinctly. Methods: This is an experimental study. Male Wistar rats were anesthetized, and they underwent a hearing evaluation via measurement of the brainstem auditory evoked potential (BSAEP). Then, cisplatin was administered intraperitoneally (IP) at a dose of 8 mg/kg/day for 4 consecutive days to group 1, whereas saline solution was administered IP to group 2. In groups 3 and 4, ischemia of the right hind paw was performed for 10 min, followed by reperfusion for 30 min, after which cisplatin or saline was administered IP to group 3 or group 4, respectively. Afterwards, all animals were evaluated via the BSAEP. The right cochlea was dissected for immunohistochemistry. Results: RIPC lowered the increase in BSAEP of the animals treated with cisplatin (p = 0.0146). Weight loss decreased in the animals subjected to RIPC (p p Conclusion: RIPC protects against systemic toxicity and ototoxicity induced by cisplatin in rats.
ORL 2017;79:336-346

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Neuroimaging Findings in Patients with Medication Overuse Headache

Abstract

Medication overuse headache (MOH) is a secondary headache syndrome defined as the deterioration of the headache associated with the overuse of analgesics. The prevalence of MOH is 1–2% in the general population and even up to 50% in special clinics. Overuse of abortive medications is highly associated with chronic daily headaches and also a known risk factor for headache evolution. Possible mechanisms include neural plasticity changes such as sensitization and defective endogenous pain inhibition. Psychological studies have suggested dependence, even addiction, in patients with MOH. Neuroimaging studies have provided valuable information concerning MOH pathophysiology. Magnetic resonance imaging analyzed by voxel-based morphometry showed gray matter volume changes in brain areas participating the pain modulations. Changes of brain function at similar areas have been revealed by positron emission tomography and functional magnetic resonance imaging studies. Many of these changes were correlated with either headache and/or analgesics parameters such as frequency and duration. These changes are typically reversible after successful treatment. Though the cause or consequence debate remains unsettled, we are more in favor of these findings as maladaptive changes to the frequent headaches or medication overuse. Of these brain areas involved in MOH, orbitofrontal cortex is of interest in several ways. In an early positron emission tomography study, the hypometabolism persists after successful treatment which implied a causal role. The following morphological studies showed the orbitofrontal cortex volume could predict treatment responses. Functional magnetic resonance imaging studies, task positive and also resting-state ones, also reported changes within the mesocorticolimbic dopamine system, also known as reward system. Important brain areas of this system include ventral tegmental area, striatum, and orbitofrontal cortex. The system plays an important role in decision-making, dependence, and addiction, as implicated in psychological studies of MOH. Further studies on neuromodulation of this system may be considered in the treatment of MOH.

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Yoga Face-toning Might Compete With Fillers and Facelifts

To his toolbox of Botox, fillers and plastic surgery, cosmetic dermatologist Dr. Murad Alam has added a new, low-cost, noninvasive anti-aging treatment: facial yoga.
Reuters Health Information

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Bidirectional and context-dependent changes in theta and gamma oscillatory brain activity in noradrenergic cell-specific Hcrtr1 KO mice

Introduction: Noradrenaline (NA) and hypocretins (Hcrt) and their cognate receptors modulate the electrical properties of brain circuits that dynamically sculpt wakefulness and define mnesic traces. Locus coeruleus NA cells (LC-NA) respond to salient environmental changes, and, through widespread NA release, 'reset' networks to mediate behavioral adaptation. Among other inputs, they receive dense projections from hypothalamic Hcrt neurons. The range of behaviors that the Hcrt-to-LC-NA neuronal connection implements, remains incompletely defined.

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Taste sensitivity in older adults and their relationship to sleep quality

Introduction: Aging may cause some physiological changes, including loss of taste sensitivity, especially for bitter and salty flavors, as well as modifications in sleep architecture, such as increased sleep latency, awakenings at night, reduction in sleep efficiency and greater daytime sleepiness, which may culminate in changes in the sleep quality. Some studies relate the taste sensitivity to sleep disorders, but the researches are still scarce, and the controversial results. In this sense, the aim of the present study was to evaluate the taste sensitivity, the sleep pattern, and verify if was correlation between them, in the older adults population.

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Childhood narcolepsy and autism spectrum disorders – an underdiagnosed neuropsychiatric association?

Introduction: Childhood narcolepsy is associated with various emotional, behavioural and cognitive dysfunctions as well as with psychiatric and neurodevelopmental disorders: anxiety, depression, attention deficit hyperactivity disorder and psychosis. A relationship between these conditions is not clear–comorbidity as well as similar pathophysiological mechanisms can be suggested. The aim of our study is to describe four children with narcolepsy type 1 (NT1) and new comorbidity of autism spectrum disorder (ASD)–Asperger syndrome.

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An objective description of sleep: tracking continuous oscillation dynamics in the sleep EEG

Introduction: Sleep is a dynamic, continuous process in every physiological and behavioral system studied thus far. The ability to accurately describe these dynamics is therefore essential to understanding the way in which healthy and pathological brain activity evolves during sleep. Current clinical staging, however, discretizes the continuum of sleep into 30-second epochs through subjectively visual inspection. By representing sleep as a coarsely discretized progression of stages, vital information on the neurophysiological dynamics is lost, and we are unable to properly account for activity that does not fit into a single stage definition.

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Compact optical fiber-type sleep apnea syndrome sensor

Introduction: We have developed an optical Fiber-type Sleep Apnea Syndrome sensor (F-SAS sensor) that can detect a change in lateral pressure as a signal light beam change and apply it to hotel and medical checkups. We have succeeded in downsizing the F-SAS sensor and have recognized that it highly correlates with PSG and PLSX.

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Differences in sleep quality and clinical characteristics of patients studied in a sleep unit according to gender

Introduction: Patients referred to sleep units for the study of OSAS are mostly men. It is not known if there are differences in the structure of sleep according to gender, well established clinical differences or comorbidities. To analyze the differences according to gender, polysomnographic variables, clinical characteristics and comorbidities in patients referred to our Sleep Unit for suspected OSAS.

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Can we truly change from polysomnography to polygraphy in obstructive sleep apnea? A comparison between these to levels of sleep studies in a population of patients with obstructive sleep apnea

Introduction: Polygraphy (PG) or polysomnography (PSG)–sleep studies level III and I, respectively, can be used to diagnose sleep apnea. The first focuses exclusively on respiratory parameters that are analyzed as if the entire study was done with the patient sleeping. The second involves a multi-parameter monitoring, in which respiratory variables are analyzed only during sleep, excluding wakefulness in the apnea/hypopnea index (AHI) and respiratory disturbance index (RDI) determination.

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Accuracy of newly developed portable PSG device for detection of sleep bruxism-related masseter EMG muscle activity

Introduction: Sleep bruxism (SB) is defined as a repetitive jaw muscle activity characterized by clenching or grinding of the teeth, which is classified as a sleep-related movement disorder according to the American Academy of Sleep Medicine. While laboratory-based video-polysomnographic (vPSG) recording is the gold standard for quantification of SB severity, such recordings are not feasible for dental patients because they require patients to sleep at laboratory. We recently modified a commercially available portable PSG device (Sleep Profiler™; Advanced Brain Monitoring, Inc., USA) in order to record the SB-related masseter EMG muscle activity for multiple nights in the patient's home environment at minimal expense.

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The market value of sleep: using economic input-output analysis to shift society's views on sleep loss

Introduction: Modern society is driven by economic profit and output. Sleep loss is considered to impact profit and output via fatigue related accidents. However, the consequences of sleep loss are not limited to these short term performance decrements. Sleep loss also impacts physical and mental health, contributing to the prevalence of many diseases and social issues. These burden society with increased medical and social welfare costs. Fatigue Risk Management Systems and prescriptive legislation do not directly address these consequences.

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An open-label study of the efficacy, safety and tolerability of oral BTD-001 in adults with idiopathic hypersomnia or narcolepsy type 2

Introduction: Recent research suggests that an endogenous agent in the central nervous system of idiopathic hypersomnia (IH) and narcolepsy type-2 (Na-2) patients acts as a GABA agonist and may be a key driver of debilitation. We assessed the efficacy and safety of BTD-001, a GABAA receptor (GABAAR) antagonist in IH and Na-2 in a pilot clinical study.

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Sleep disorders and sleep-wake cycle in undergraduate students attending morning and afternoon school shifts

Introduction: The aim of this study was to analyze sleep disorders and sleep-wake cycle in undergraduate students attending morning and afternoon shifts.

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CUED memory reactivation during slow wave sleep selectively improves auditory discrimination

Introduction: Slow wave sleep (SWS) is known to play an important role in the off-line consolidation of memory. During SWS some memories are randomly reactivated at neuronal level as a part of consolidation process. Moreover, targeted presentation of memory-associated cues in SWS stage may reactivate declarative and procedural memory and improve its consolidation. As little is known about the effect of sleep at consolidation of sensory memory, we aimed to study an effect of auditory memory reactivation during SWS on explicit auditory discrimination during subsequent wakefulness.

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Melanin-concentrating hormone (MCH) in the median raphe nucleus: fibers, receptors and cellular effects

Introduction: Hypothalamic neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator project to several regions of the central nervous system including the median raphe nucleus (MnR). The serotonergic neurons of the MnR and the MCH-containing neurons have been involved in the control of REM sleep and mood; in fact, microinjections of MCH into the MnR promote a depressive-like state.

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Apnea bye, first app to treat sleep disorder breathing

Introduction: Apnea Bye is the first app to treat sleep apnea and snoring. Apnea Bye is based on myofunctional therapy. Patient interacts with the Phone performing oropharyngeal exercises. The main advantage for this app is that provide feedback with the patient about the accuracy of the exercises, and the doctor is aware about the adherence of this exercises.

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Polysomnographic findings in restless legs syndrome (RLS) patients with severe augmentation

Introduction: An increasing number of RLS patients with severe augmentation due to dopaminergic therapy are currently reported in Germany. With L-DOPA 68% of RLS patients may develop augmentation depending on dosage and the duration of the studies. Polysomnographic (PSG) data of augmented RLS patients are scarce.

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Morningness is associated with lower sleep spindle amplitudes and intensities during adolescence

Introduction: Circadian preference, reflected in the circadian timing of sleep onset and awakening times, and nighttime sleep spindle characteristics show marked variation between individuals, but are fairly consistent biological features during adulthood. These both have been associated with similar behavioral phenotypes related to cognitive function and mental health. However, there are no previous explorative studies on whether spindle characteristics would differ by circadian preference.

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The relationship between slow wave activity increase across acute and chronic sleep loss and vigilance impairments

Introduction: Individuals vary in the extent of sleep loss induced deterioration of neurobehavioral functioning. Such individual vulnerabilities have been shown to be comparable across acute and chronic sleep loss paradigms. The homeostatic increase in slow wave activity (SWA) during initial parts of sleep reflects elevated sleep pressure in the sleep electroencephalogram (EEG). We aimed at assessing

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Sleep instability among adults with non-refractory temporal lobe epilepsy

Introduction: Temporal lobe epilepsy (TLE) is a prevalent epileptic syndrome with partial complex seizures in adults, and the non refractory TLE patients, despite of their seizures control, still remain with cognitive complaints. The cyclic alternating pattern (CAP) is an EEG pattern in NREM sleep that has been associated with sleep instability. CAP affects the epileptiform activity, and distribution of discharges occurring during the phase A of CAP. The effect of CAP in temporal lobe epilepsies still remains unclear.

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