Publication date: Available online 13 February 2018
Source:Journal of Neuroscience Methods
Author(s): Rimenez R. Souza, Nicole M. Robertson, David T. Pruitt, Lindsey Noble, Eric C. Meyers, Phillip A. Gonzales, Nathaniel P. Bleker, Holle L. Carey, Seth A. Hays, Michael P. Kilgard, Christa K. McIntyre, Robert L. Rennaker
BackgroundFear conditioning (FC) in rodents is the most used animal model to investigate the neurobiology of posttraumatic stress disorder (PTSD). Although research using FC has generated a better understanding of fear memories, studies often rely on mild or moderate FC training and behavioral analysis generally focuses on measuring freezing responses within few test sessions.New methodWe introduce the M-Maze task, a system to measures extinction of conditioned fear using suppression of operant behavior. The apparatus consists of an M-shaped maze where rats are trained to alternate nose poking at two pellet dispensers. Proximity sensors measure the animal's locomotion, as well as the latencies and number of operant behavior. Here we also describe the protracted aversive conditioning (PAC), a rat model of severe fear that induces resistant extinction following a 4-day conditioning protocol that combines delay, unpredictable, and short- and long-trace conditioning.ResultsAn intense one-day auditory FC protocol induced a sharp elevation in transit time and suppression of nose pokes by conditioned cues, but in contrast to what is observed in PTSD patients, fear extinction was rapidly observed. On the other hand, PAC alone or in combination with exposure to single prolonged stress induced persistent extinction impairments in M-Maze tests, as well as enhanced anxiety, and social withdrawal.Comparison with other existing methodsThe M-Maze task is fully automated and allows multiple animals to be tested simultaneously in long-term experiments. Moreover, PAC training can be an alternative approach to study extinction-resistant fear.ConclusionsThe M-Maze task allows rapid and unbiased measurements of fear-induced suppression. We suggest that long-term assessment of extinction impairments would lead to a better understanding of the neurobiology of persistent fear and the screening for new therapies.
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Τρίτη 13 Φεβρουαρίου 2018
The M-Maze task: An automated method for studying fear memory in rats exposed to protracted aversive conditioning
Massively parallel C. elegans tracking provides multi-dimensional fingerprints for phenotypic discovery
Publication date: Available online 13 February 2018
Source:Journal of Neuroscience Methods
Author(s): Michele Perni, Pavan K. Challa, Julius B. Kirkegaard, Ryan Limbocker, Mandy Koopman, Maarten C. Hardenberg, Pietro Sormanni, Thomas Müller, Kadi L. Saar, Lianne W.Y. Roode, Johnny Habchi, Giulia Vecchi, Nilumi W. Fernando, Samuel Casford, Ellen A.A. Nollen, Michele Vendruscolo, Christopher M. Dobson, Tuomas P.J. Knowles
BackgroundThe nematode worm C. elegans is a model organism widely used for studies of genetics and of human disease. The health and fitness of the worms can be quantified in different ways, such as by measuring their bending frequency, speed or lifespan. Manual assays, however, are time consuming and limited in their scope providing a strong motivation for automation.New methodWe describe the development and application of an advanced machine vision system for characterizing the behaviour of C. elegans, the Wide Field-of-view Nematode Tracking Platform (WF-NTP), which enables massively parallel data acquisition and automated multi-parameter behavioural profiling of thousands of worms simultaneously.ResultsWe screened more than a million worms from several established models of neurodegenerative disorders and characterised the effects of potential therapeutic molecules against Alzheimer's and Parkinson's diseases. By using very large numbers of animals we show that the sensitivity and reproducibility of behavioural assays is very greatly increased. The results reveal the ability of this platform to detect even subtle phenotypes.Comparison with existing methodsThe WF-NTP method has substantially greater capacity compared to current automated platforms that typically either focus on characterising single worms at high resolution or tracking the properties of populations of less than 50 animals.ConclusionsThe WF-NTP extends significantly the power of existing automated platforms by combining enhanced optical imaging techniques with an advanced software platform. This approach will further extend the scope and utility of C. elegans as a model organism.
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Treating Immune-Related Epilepsy
Abstract
Purpose of Review
This review explores different treatment modalities for immune-mediated epilepsy, including epilepsy caused by autoantibodies as well as epilepsy in the context of systemic autoimmune disease.
Recent Findings
Autoimmune epilepsy is an increasingly recognized entity. Conventional treatments for epilepsy, such as antiseizure medications and epilepsy surgery, are less successful in treating epilepsy caused by autoimmune disease. Immunomodulatory therapies such as corticosteroids, intravenous immunoglobulin, and plasma exchange are generally more successful in treating immune-mediated epilepsy than conventional epilepsy therapies.
Summary
Autoimmune epilepsy should be considered as a possible etiology for patients with frequent seizures of unknown etiology. The response to immunotherapies is often promising, particularly in patients with antibodies to neuronal cell surface antigens.
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The Neuropsychological Consequences of Armed Conflicts and Torture
Abstract
Purpose of Review
At any point in time, there are hundreds of armed conflicts throughout the world. Neuropsychological disorders are a major cause of morbidity during and after armed conflicts. Conditions such as closed and open head injuries, acute stress disorder, post-traumatic stress disorder, depression, anxiety, and psychosis are prevalent among survivors. Herein, we summarize information on the various forms of torture, the resultant neuropsychological pathology, and treatment strategies to help survivors.
Recent Findings
Strategies to address the needs of individuals who experienced neuropsychological trauma due to armed conflicts and torture include pharmacological and psychological interventions. The former includes antidepressant, antianxiety, and antipsychotic medications. The latter includes narrative exposure therapy and trauma-focused cognitive-behavioral therapy.
Summary
Neuropsychological disorders are major causes of morbidity among survivors of armed conflicts and torture. Treatment strategies must be affordable, applicable across cultures, and deliverable by individuals who understand the victims' psychosocial and ethnic background.
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Neurological Complications of Acute and Chronic Otitis Media
Abstract
Purpose of Review
The aim of this study is to discuss the symptoms, diagnosis, and management of the neurologic complications of acute and chronic otitis media.
Recent Findings
Antibiotic therapy has greatly reduced the frequency of complications of otitis media. However, it is of vital importance to remain aware of the possible development of neurologic complications. There is a trend toward less severe presenting symptoms including otorrhea, headache, nausea, and fever, with altered mental status and focal neurologic deficits presenting later. In order to reduce morbidity, early deployment of a multidisciplinary approach with prompt imaging and laboratory studies is imperative to guide appropriate management.
Summary
Complications of acute and chronic otitis media may present with neurologic signs and symptoms. It is important to recognize the possible otitic origin of such complications to ensure proper management and to decrease overall morbidity and mortality
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Issue Information - Editorial Board
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Meetings of Interest
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Superior and Anterior Hyoid Displacement During Swallowing in Non-Dysphagic Individuals
Abstract
The Dynamic Swallow Study (DSS) is a methodology used to objectively and quantitatively assess swallowing kinematics during Videofluoroscopic Swallow Studies (VFSS). No DSS normative data exist delineating superior and anterior hyoid displacement (Hsup and Hant, respectively), nor the ratio between Hsup and Hant (SAratio). The aims of this study were to (1) establish normative data for Hsup, Hant, and SAratio and (2) assess the effects of age, sex, and bolus size on these measures in non-dysphagic patients, within the context of DSS. VFSSs were reviewed for consecutive elderly (≥ 65 years) and non-elderly (< 65 years) male and female non-dysphagic patients. Measurements of Hsup, Hant, and SAratio were made using a novel measurement methodology within the context of the Dynamic Swallow Study (DSS) protocol. Statistical analysis was performed to establish interaction effects and main effects of age, sex, and bolus size on Hsup, Hant, and SAratio. Descriptive statistics (mean ± standard deviations) are outlined for Hsup, Hant, and SAratio. Hsup was significantly effected by bolus size and age. Additionally, a significant three-way interaction of age, sex, and bolus size was observed. Hant was significantly effected by bolus size and sex, but no two- or three-way interactions were present. Neither bolus size, age, nor sex significantly effected SAratio. Age, sex, and bolus size normative data were established for Hsup, Hant, and SAratio for VFSS kinematic analysis. By outlining these measures, one can more thoroughly evaluate the areas of specific swallowing impairment, better determine the therapy targets, and track changes over time.
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bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM)—the active metabolite of the laxatives bisacodyl and sodium picosulfate—enhances contractility and secretion in human intestine in vitro
Abstract
Background
Stimulant laxatives are widely used to treat constipation. We investigated in human small and large intestinal preparations the effects of bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM), the active metabolite of the laxatives bisacodyl and sodium picosulfate on smooth muscle tone and epithelial secretion.
Methods
Circular and longitudinal muscle tone of small or large intestinal preparations were recorded with isometric force transducers. Epithelial ion flux (ISC) and tissue resistance was measured with Ussing chamber technique after apical and basolateral BHPM application to large intestinal mucosa/submucosa preparations. Studies were performed in macroscopically normal specimens from 79 patients.
Key Results
BHPM concentration-dependently (0.5-5 μM) increased the tone of circular and longitudinal muscle from small to large intestine. The effect was strongest in large intestinal longitudinal muscle and smallest in small intestinal circular muscle. Increase in muscle tone was prevented by the L-type Ca++ channel blocker nifedipine but insensitive to the nerve blocker tetrodotoxin. Apical or basolateral BHPM concentration-dependently decreased or increased ISC, respectively. The KCa1.1 (BK) channel blocker iberiotoxin reversed apical ISC decrease whereas tetrodotoxin reversed basolateral ISC increase. BHPM had no effect on tissue resistance or nerve-mediated secretory or muscle response with one exception: at the highest concentration basolateral BHPM reduced nerve-mediated secretion.
Conclusions and Interferences
BHPM enhanced mucosal secretion and muscle contractility. Results suggested that the laxative effect of BHPM was a consequence of the increase in muscle tone as well as an increased K+ secretion when acting luminally and a nerve-driven Cl− and HCO3− secretion once acting basolaterally after absorption.
- We identified the action of bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM), the active metabolite of the laxatives bisacodyl and sodium picosulfate, in human intestinal samples.
- BHPM increased muscle tone in small and large intestine. It enhanced K+ secretion when acting luminally and nerve-driven Cl− and HCO3− secretion once acting basolaterally after absorption.
- Increase in muscle activity and epithelial secretion explain the laxative effects of BHPM.
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High expression of DJ-1 promotes growth and invasion via the PTEN-AKT pathway and predicts a poor prognosis in colorectal cancer
Abstract
Cancer cell invasion and unlimited proliferation are key factors in patients with colorectal cancer (CRC). Increased protein deglycase DJ-1 in cancer cells is known to promote tumor growth; however, its role in CRC progression is not well defined. In this study, we investigated 100 CRC patients with disease stages I–IV to determine whether DJ-1 could serve as a prognostic biomarker in CRC. These results showed that DJ-1 expression in CRC tissues was higher than that in normal colon tissues and was associated with the (Tumor Node Metastasis) TNM stage. CRC patients with low DJ-1 expression had a longer overall survival than those with high expression, and multivariate and univariate analyses indicated that DJ-1 expression was an independent prognostic factor for overall survival in CRC. Furthermore, DJ-1 overexpression in two colon cancer cell lines, HCT116 and SW480, activated protein kinase AKT and downregulated tumor suppressor PTEN, whereas DJ-1 knockdown upregulated PTEN expression and effectively suppressed CRC cell invasion and proliferation both in vitro and in vivo, revealing a mechanism underlying DJ-1 pro-oncogenic activity in CRC. Treatment of MK2206, the specific AKT inhibitor, significantly decreased DJ-1-mediated cell proliferation and mobility in vitro. Taken together, these results suggest that DJ-1 may be a novel prognostic biomarker and potential therapeutic target in human CRC.
Our data suggest that DJ-1 may be a novel prognostic biomarker and a potential therapeutic target in human CRC.
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Protein phosphatase 2A (PP2A) inhibitor CIP2A indicates resistance to radiotherapy in rectal cancer
Abstract
Preoperative (chemo)radiotherapy, (C)RT, is an essential part of the treatment of rectal cancer patients, but tumor response to this therapy among patients is variable. Thus far, there are no clinical biomarkers that could be used to predict response to (C)RT or to stratify patients into different preoperative treatment groups according to their prognosis. Overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) has been demonstrated in several cancers and is frequently associated with reduced survival. Recently, high CIP2A expression has also been indicated to contribute to radioresistance in head and neck squamous cell carcinoma, but few studies have examined the connection between CIP2A and radiation response regarding other malignancies. We have evaluated CIP2A protein expression levels in relation to tumor regression after preoperative (C)RT and survival of rectal adenocarcinoma patients. The effects of CIP2A knockdown by siRNA on cell survival were further investigated in colorectal cancer cells exposed to radiation. Patients with low-CIP2A-expressing tumors had more frequently moderate or excellent response to long-course (C)RT than patients with high-CIP2A-expressing tumors. They also had higher 36-month disease-specific survival (DSS) rate in categorical analysis. In the multivariate analysis, low CIP2A expression level remained as an independent predictive factor for increased DSS. Suppression of CIP2A transcription by siRNA was found to sensitize colorectal cancer cells to irradiation and decrease their survival in vitro. In conclusion, these results suggest that by contributing to radiosensitivity of cancer cells, low CIP2A protein expression level associates with a favorable response to long-course (C)RT in rectal cancer patients.
Low CIP2A protein expression level associates with a favorable response to long-course chemoradiotherapy in rectal cancer patients. Suppression of CIP2A transcription by siRNA sensitizes colorectal cancer cells to irradiation and decreases their survival in vitro.
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Knowledge about cervical cancer and barriers toward cervical cancer screening among HIV-positive women attending public health centers in Addis Ababa city, Ethiopia
Abstract
Screening rate for cervical cancer among HIV-infected women and among women overall is low in Ethiopia despite the high burden of the disease and HIV infection, which increases cervical cancer risk. In this paper, we assessed knowledge about cervical cancer symptoms, prevention, early detection, and treatment and barriers to screening among HIV-positive women attending community health centers for HIV-infection management in Addis Ababa. A cross-sectional survey of 581 HIV-positive women aged 21–64 years old attending 14 randomly selected community health centers without cervical cancer screening service in Addis Ababa. We used univariate analysis to calculate summary statistics for each variable considered in the analysis, binary logistic regression analysis to measure the degree of association between dependent and independent variables, and multiple regressions for covariate adjusted associations. Statistical significance for all tests was set at P < 0.05. We used thematic analysis to describe the qualitative data. Of the 581 women enrolled in the study with mean age 34.9 ± 7.7 years, 57.8% of participants had heard of cervical cancer and 23.4% were knowledgeable about the symptoms, prevention, early detection, and treatment of the disease. In multivariate analysis, higher educational attainment and employment were significantly associated with good knowledge about cervical cancer. In addition, only 10.8% of the participants ever had screening and 17% ever received recommendation for it. However, 86.2% of them were willing to be screened if free of cost. Knowledge about cervical cancer is poor and cervical cancer screening rate and provider recommendation are low among HIV-positive women attending community health centers for management and follow-up of their disease in Addis Ababa. These findings underscore the need to scale up health education about cervical cancer prevention and early detection among HIV-positive women as well as among primary healthcare providers in the city.
Knowledge about cervical cancer is poor, and cervical cancer screening rate and recommendation are low among HIV-positive women attending community health centers for management and follow-up of their HIV infection in Addis Ababa. These findings underscore the need to scale up health education about cervical cancer prevention and early detection among HIV-positive women as well as among primary healthcare providers in the city.
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Characteristic findings of high-grade cervical intraepithelial neoplasia or more on magnifying endoscopy with narrow band imaging
Abstract
Background
Colposcopy, which is a standard modality for diagnosing cervical intraepithelial neoplasia (CIN), can have limited accuracy owing to poor visibility. Flexible magnifying endoscopy with narrow band imaging (ME-NBI) has excellent diagnostic accuracy for early gastrointestinal neoplasms and is expected to be highly useful for CIN diagnosis. This study aimed to determine the characteristic findings and evaluate the diagnostic ability of ME-NBI for lesions ≥ CIN 3.
Methods
A well-designed prospective diagnostic case series conducted at multiple tertiary-care centers. A total of 24 patients who underwent cervical conization with a preoperative diagnosis of high-grade squamous cell intraepithelial lesions (HSILs) or lesions ≥ CIN 3 were enrolled. Prior to conization, still images and video of ME-NBI were captured to investigate the cervical lesions. The images were reviewed based on histological examination of the resected specimens.
Results
The NBI-ME images revealed the following abnormal findings: (1) light white epithelium (l-WE), (2) heavy white epithelium (h-WE), and (3) atypical intra-epithelial papillary capillary loop (IPCL). Pathological examination of the resected specimens confirmed cervical lesions ≥ CIN 3 in 21 patients. The ME-NBI findings were classified into four groups: l-WE, l-WE with atypical IPCL, h-WE, and h-WE with atypical IPCL, at rates of 0, 23.8, 9.5, and 66.7%, respectively. Additionally, all 3 patients with micro-invasive carcinoma showed a strong irregularity of IPCLs.
Conclusion
The lesions ≥ CIN 3 demonstrated characteristic ME-NBI findings of h-WE alone, or l-/h-WE with atypical micro-vessels. This study indicates that ME-NBI may have novel value for CIN diagnosis.
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The clinical features of squamous cell lung carcinoma with sensitive EGFR mutations
Abstract
Background
The process of selecting patients on the basis of epidermal growth factor receptor (EGFR) mutations would likely result in a patient population with greater sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, EGFR mutation status is not routinely examined in patients with squamous cell lung cancer (Sq) because of the low incidence of EGFR mutations and the poor clinical response to EGFR-TKIs.
Methods
We retrospectively reviewed the clinical features of patients at our hospital with Sq who carried EGFR-TKI-sensitive EGFR mutations and assessed their responses to EGFR-TKIs.
Results
EGFR mutation status was tested in 23 of 441 patients with Sq (5.2%) admitted to our hospital during the study period. An EGFR mutation (exon 19 deletion 3, L858R 2) was identified in five of the 23 patients (21.7%), all of whom were female never-smokers. Of these five patients, four (4/9; 44.4%) were in the normal lung group, one (1/12; 8.3%) was in the emphysematous lung group, and none (0/2; 0%) in the fibrotic lung group. Two of these five patients with the EGFR mutation received gefitinib and two received afatinib. Although the two patients who were treated with gefitinib did not respond well to treatment (stable disease, 1 patient; progressive disease, 1 patient), the two patients who were treated with afatinib showed a good response (partial response, 2 patients).
Conclusion
The administration of afatinib to Sq patients after selecting patients using the EGFR mutation test based on their underlying pulmonary disease and smoking status would likely result in a population with a greater sensitivity to afatinib.
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Superior and Anterior Hyoid Displacement During Swallowing in Non-Dysphagic Individuals
Abstract
The Dynamic Swallow Study (DSS) is a methodology used to objectively and quantitatively assess swallowing kinematics during Videofluoroscopic Swallow Studies (VFSS). No DSS normative data exist delineating superior and anterior hyoid displacement (Hsup and Hant, respectively), nor the ratio between Hsup and Hant (SAratio). The aims of this study were to (1) establish normative data for Hsup, Hant, and SAratio and (2) assess the effects of age, sex, and bolus size on these measures in non-dysphagic patients, within the context of DSS. VFSSs were reviewed for consecutive elderly (≥ 65 years) and non-elderly (< 65 years) male and female non-dysphagic patients. Measurements of Hsup, Hant, and SAratio were made using a novel measurement methodology within the context of the Dynamic Swallow Study (DSS) protocol. Statistical analysis was performed to establish interaction effects and main effects of age, sex, and bolus size on Hsup, Hant, and SAratio. Descriptive statistics (mean ± standard deviations) are outlined for Hsup, Hant, and SAratio. Hsup was significantly effected by bolus size and age. Additionally, a significant three-way interaction of age, sex, and bolus size was observed. Hant was significantly effected by bolus size and sex, but no two- or three-way interactions were present. Neither bolus size, age, nor sex significantly effected SAratio. Age, sex, and bolus size normative data were established for Hsup, Hant, and SAratio for VFSS kinematic analysis. By outlining these measures, one can more thoroughly evaluate the areas of specific swallowing impairment, better determine the therapy targets, and track changes over time.
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Staying Safe During Gluteal Fat Transplantation
When it comes to patient safety during gluteal augmentation with fat transplantation, what do plastic surgeons need to know?
Plastic and Reconstructive Surgery
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SIEA Flap for a Total Parotidectomy Defect
Is this reconstructive technique a safe and effective option for volume replacement after parotidectomy?
ePlasty, Open Access Journal of Plastic Surgery
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Beasley’s 1981 paper: The power of a well-designed cohort study to drive liver cancer research and prevention
Publication date: Available online 13 February 2018
Source:Cancer Epidemiology
Author(s): Jill Koshiol, Zhiwei Liu, Thomas R. O'Brien, Allan Hildesheim
The 1981 Lancet paper by Beasley et al., "Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22707 men in Taiwan" is a seminal publication that clearly demonstrated that chronic infection with hepatitis B virus (HBV), as measured by seropositivity for the hepatitis B surface antigen (HBsAg), preceded the development of hepatocellular carcinoma (HCC). In doing so, this study paved the way for liver cancer prevention efforts through the implementation of hepatitis B vaccination programs. In this commentary, we will describe the discovery of HBV, which led to the study by Beasley et al.; summarize the major findings of the Beasley paper and its implications; discuss the importance of well-designed cohort studies for prevention activities; and consider the ramifications of the Beasley study and the work that has followed since.
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The Experience of Adolescents and Young Adults Treated for Cancer in an Adult Setting: A Review of the Literature
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Night-shift work increases cold pain perception
Publication date: Available online 13 February 2018
Source:Sleep Medicine
Author(s): Christoph Pieh, Robert Jank, Christoph Waiß, Christian Pfeifer, Thomas Probst, Claas Lahmann, Stefan Oberndorfer
BackgroundAlthough night-shift work (NSW) is associated with a higher risk for several physical and mental disorders, the impact of NSW on pain perception is still unclear. This study investigates the impact of NSW on cold pain perception considering the impact of mood and sleepiness.MethodQuantitative sensory testing (QST) was performed in healthy night-shift workers. Cold pain threshold as well as tonic cold pain was assessed after one habitual night (T1), after a 12-hour NSW (T2) and after one recovery night (T3). Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI) before T1, sleepiness with the Stanford Sleepiness Scale (SSS) and mood with a German short-version of the Profile of Mood States (ASTS) at T1, T2 and T3. Depending on the distribution of the data, ANOVAs or Friedman tests as well as t- or Wilcoxon tests were performed.ResultsN=19 healthy shift-workers (13 females; 29.7 ± 7.5 years old; 8.1 ± 6.6 years in shift work, PSQI: 4.7 ± 2.2) were included. Tonic cold pain showed a significant difference between T1 (48.2 ± 27.5 mm), T2 (61.7 ± 26.6 mm; effect size: Cohen´s d=.49; percent change 28 %), and T3 (52.1 ± 28.7 mm) on a 0 to 100 mm Visual Analog Scale (p= .007). Cold pain threshold changed from 11.0 ± 7.9°C (T1) to 14.5 ± 8.8°C (T2) (p= .04), however, an ANOVA comparing T1, T2, and T3 was not significant (p= .095). Sleepiness (SSS) and mood (ASTS) changed significantly between T1, T2 and T3 (p-values < .01). The change of mood but not of sleepiness correlated with the difference in tonic cold pain from T1 to T2 (R: .53; R2: .29; p=.022).DiscussionNSW increases cold pain perception. The same tonic cold pain stimulus is rated 28 % more painful after NSW and normalizes after a recovery night. Increases in cold pain perception due to NSW appear to be more strongly related to changes in mood as compared to changes in sleepiness.
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Persistence of deep-tendon reflexes during partial cataplexy
Publication date: Available online 13 February 2018
Source:Sleep Medicine
Author(s): Lucie Barateau, Fabio Pizza, Régis Lopez, Elena Antelmi, Giuseppe Plazzi, Yves Dauvilliers
ObjectiveDeep-tendon reflexes are abolished during generalized cataplexy, but whether this is the case in partial cataplexy has remained unknown. Partial cataplexy may mimic other neurologic/psychiatric phenomena, and knowledge of the reflexes status may provide information for differential diagnosis. We assessed whether deep-tendon reflexes are persistent during partial cataplexy.MethodsFive drug-free patients with typical diagnoses of narcolepsy and clear-cut partial cataplexy were diagnosed in Reference Narcolepsy Centers in France and Italy. Bicipital and pattelar reflexes were elicited by physicians in charge and video-documented during cataplexy. Reflexes were assessed several times for each patient in different conditions and for various localizations of cataplexy.ResultsThe absence of tendon reflexes and complete loss of muscle tone during generalized cataplexy was confirmed, but the persistence of those reflexes during several partial cataplectic attacks at different ages, gender, localization of cataplexy (upper limbs, face) and reflexes (bicipital, patellar) in drug-naive or withdrawal conditions was documented.ConclusionThe persistence of tendon reflexes during several partial cataplexy episodes contrasts with their absence during generalized cataplexy. This discovery has clinical implications: the persistence of tendon reflexes does not rule out cataplexy diagnosis for partial attacks, whereas their transient abolishment or persistence during generalized attacks indicates respectively cataplexy or pseudocataplexy.
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Patients with Chronic Insomnia Disorder Have Increased Serum Levels of Neurofilaments, Neuron-Specific Enolase and S100B: Does Organic Brain Damage Exist?
Publication date: Available online 13 February 2018
Source:Sleep Medicine
Author(s): Ping Zhang, Cheng-Wen Tan, Gui-Hai Chen, Yi-Jun Ge, Jing Xu, Lan Xia, Fang Wang, Xue-Yan Li, Xiao-Yi Kong
ObjectivesThe aims of this study were to investigate whether serum levels of neurofilaments heavy chain (NfH) and light chain (NfL), neuron-specific enolase (NSE) and S100 calcium binding protein B (S100B): (1) change, (2) alleviate in post-therapy and (3) are associated with sleep quality and cognitive dysfunction, in patients with chronic insomnia disorder (CID).MethodsForty CID outpatients constituted free-therapy group (ft-CID), in which twenty-four patients completed follow-up after six-month treatment to form re-visiting group (rv-CID), and twenty healthy good sleepers constituted control group (HC). All subjects completed questionnaires, polysomnography, Chinese-Beijing Version of Montreal Cognitive Assessment (MoCA-C) and Nine Box Maze Test (NBMT) to assess sleep and neuropsychological function. The serum levels of NfH, NfL, NSE and S100B were detected using enzyme-linked immunosorbent assay.ResultsThe ft-CID had higher levels of NfH, NfL, NSE and S100B than the HC. Interestingly, the levels of NfH, NfL and NSE significantly reduced in the rv-CID compared to the ft-CID, but not the level of S100B. Principal components analysis revealed that in these serum biomarkers, NfL and S100B had a substantial correlation with subjective and objective sleep parameters.ConclusionsThe CID patients had elevated serum levels of NfH, NfL, NSE and S100B, indicating existence of damaged brain microstructure, including neurons, astrocytes and neuronal terminals, which were associated with the insomniac severity or/and cognitive dysfunction and could significantly reduce after effective therapy apart from the S100B.
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Computed tomography densitometric study of anti-angiogenic effect of regorafenib in colorectal cancer liver metastasis
Future Oncology, Ahead of Print.
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Sluggish dorsally-driven inhibition of return during orthographic processing in adults with dyslexia
Publication date: April 2018
Source:Brain and Language, Volume 179
Author(s): S. Franceschini, S. Mascheretti, S. Bertoni, V. Trezzi, C. Andreola, S. Gori, A. Facoetti
Dyslexia (D) is a neurodevelopmental reading disorder characterized by phonological and orthographic deficits. Before phonological decoding, reading requires a specialized orthographic system for parallel letter processing that assigns letter identities to different spatial locations. The magnocellular-dorsal (MD) stream rapidly process the spatial location of visual stimuli controlling visuo-spatial attention. To investigate the visuo-spatial attention efficiency during orthographic processing, inhibition of return (IOR) was measured in adults with and without D in a lexical decision task. IOR is the delay in responding to stimuli displayed in a cued location after a long cue-target interval. Only adults with D did not showed IOR effect during letter-string recognition, despite the typical left-hemisphere specialization for word identification. A specific deficit in coherent-dot-motion perception confirmed an MD-stream disorder in adults with D. Our results suggest that adults with D might develop an efficient visual word form area, but a dorsal-attentional dysfunction impairs their reading fluency.
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The acceptability and feasibility of lay-health led interventions for the prevention and early detection of cancer
Abstract
Background
US-based evidence suggests that lay-health worker (LHW) interventions can increase awareness around cancer risk-related lifestyles, symptom recognition and screening programme uptake. The suitability of LHW interventions in the UK and the potential barriers and facilitators for implementation is currently unknown. This study explored the acceptability and feasibility of developing LHW interventions for cancer prevention, screening and early diagnosis.
Methods
Purposive sampling recruited five separate lay groups: a) completed cancer treatment; b) friends/family of cancer patients; c) cancer hospital volunteers; d) cancer charity volunteers; and e) members of the public. Audio-recorded focus groups and semi-structured interviews were transcribed for thematic analysis using framework matrices.
Results
Forty-one people (66% female, aged 23-84 years) participated. Three main themes are reported: i) scope of LHW roles, with a clear remit embedded within communities or primary care practices, ii) defining LHW tasks, with a focus on supporting people overcome barriers including lack of cancer symptom knowledge and non-attendance at screening and iii) clear boundaries, with LHW training and on-going support from healthcare staff seen as key for intervention success. All groups were uncomfortable about having lifestyle-related risk conversations and potentially inflicting guilt. The post-treatment group expressed less concern about the possible emotional impact of discussing cancer symptoms, compared to the other groups.
Conclusions
LHW interventions to promote early diagnosis or screening were generally considered acceptable in a UK context. LHW interventions focussing on reducing cancer risk may be less feasible.
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Relationships between family resilience and posttraumatic growth in breast cancer survivors and caregiver burden
Abstract
Objective
To examine the relationships between family resilience and posttraumatic growth (PTG) of breast cancer survivors and caregiver burden among principal caregivers in China.
Methods
Participants in this cross-sectional study comprised 108 women aged 26–74 years (M = 49, SD = 9) with early-stage breast cancer and 108 principal caregivers. Participants were recruited from a comprehensive cancer center of a public hospital in Shandong Province, China. The principal caregivers completed the Shortened Chinese Version of the Family Resilience Assessment Scale (FRAS-C) and the Chinese Version of the Zarit Caregiver Burden Interview (CZBI); patients completed the Short Form of the Posttraumatic Growth Inventory (PTGI-SF) and questions designed to obtain sociodemographic information. Hierarchical regression analysis was conducted to assess the adjusted association between family resilience and PTG and caregiver burden, while controlling for sociodemographics.
Results
Families showed a slightly elevated level of family resilience since the cancer experience and patients showed a moderate degree of PTG. Principal caregivers reported moderate burden. FRAS-C total score was positively related to PTGI-SF total score (β = .28, P < .01) and was negatively related to CZBI total score (β = -.28, P < .01).
Conclusions
Family resilience impacts PTG of breast cancer survivors and caregiver burden. Our findings indicated the necessity of interventions to facilitate family resilience, promote PTG among breast cancer survivors, and decrease family members' caregiver burden.
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Psychosocial functioning and risk factors among siblings of children with cancer: An updated systematic review
Abstract
Objectives
Siblings' psychosocial adjustment to childhood cancer is poorly understood. This systematic review summarizes findings and limitations of the sibling literature since 2008, provides clinical recommendations, and offers future research directions.
Method
MEDLINE/Pubmed, CINAHL, and PsycINFO were searched for articles related to siblings, psychosocial functioning, and pediatric cancer. After systematic screening, studies meeting inclusion criteria were rated for scientific merit, and findings were extracted and synthesized. In total, 102 studies were included (63 quantitative, 35 qualitative, four mixed-methods).
Results
Methodological limitations are common. Mean levels of anxiety, depression, and general adjustment are similar across siblings and comparisons, but symptoms of cancer-related posttraumatic stress are prevalent. School-aged siblings display poorer academic functioning and more absenteeism but similar peer relationships than peers. Quality of life findings are mixed. Adult siblings engage in higher levels of risky health behaviors and may have poorer health outcomes than comparisons. Risk factors for poor sibling adjustment include lower social support, poorer family functioning, lower income, non-White race, and shorter time since diagnosis, but findings are inconsistent. Qualitative themes include siblings' maturity, compassion, and autonomy, but also strong negative emotions, uncertainty, family disruptions, limited parental support, school problems, altered friendships, and unmet needs.
Conclusion
Despite methodological limitations, research indicates a strong need for sibling support. Clinical recommendations include identifying at-risk siblings and developing interventions to facilitate family communication and increase siblings' social support, cancer-related knowledge, and treatment involvement. Future longitudinal studies focusing on mechanisms and moderators of siblings' adjustment would inform timing and targets of psychosocial care.
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Spanish Translated Abstracts
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Information for Authors
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Academy News – February PM&R
As the primary medical society for the specialty of PM&R, your Academy is focused on moving the specialty and you forward. Academy membership supports initiatives to assist our members with:
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A correlative analysis of PD-L1, PD-1, PD-L2, EGFR, HER2, and HER3 expression in oropharyngeal squamous cell carcinoma
We explored potential associations of the PD-1/PD-L1/PD-L2 pathway with clinical characteristics, outcome, and expression of EGFR, HER2, HER3 in oropharyngeal squamous cell carcinoma (OPSCC) using an institutional database. Protein expression was assessed by immunohistochemistry on tissue microarray sections (EGFR, HER2, HER3) or whole tissue sections (PD-1/PD-L1/PD-L2). Expression of EGFR, HER2, HER3, PD-L1, and PD-L2 was quantified on tumor cells. Maximum density of PD-1 positive lymphocytes was measured on a scale of 0-4 within the tumor mass and peritumoral stroma. Associations between biomarkers and patient outcomes were tested using descriptive and inferential statistics, logistic regression, and Cox proportional hazards models. We analyzed tissue samples from 97 OPSCC cases: median age 59 years, p16+ (71%), male (83.5%), never smokers (18%), stage 3-4 disease (77%). 25% of cases were PD-L1 positive. The proportion of PD-L1+ tumors was higher in p16+ (29%) than p16- OPSCC (11%, p=0.047). There was no correlation between PD-L1, PD-L2, PD-1, EGFR, HER2, or HER3 expression. Positive PD-L1 status correlated with advanced nodal disease on multivariate analysis (OR 5.53 (CI 1.06-28.77), p=0.042). Negative PD-L2 expression was associated with worse survival (HR 3.99 (1.37-11.58), p=0.011) in p16- OPSCC. Lower density of PD-1+ lymphocytes in peritumoral stroma was associated with significantly increased risk of death on multivariate analysis (HR=3.17 (CI 1.03-9.78), p=0.045) after controlling for prognostic factors such as stage and p16 status. PD-L1 expression on tumor cells correlates with p16 status and advanced nodal status in OPSCC. PD-1+ lymphocytes in peritumoral stroma serve as an independent prognostic factor for overall survival.
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In vitro and in vivo activity of IMGN853, an Antibody-Drug Conjugate targeting Folate Receptor Alpha linked to DM4, in biologically aggressive endometrial cancers
Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FR) expression in these biologically aggressive (Type II) endometrial cancers,and evaluate FR as a targetable receptor for IMGN853 (Mirvetuximab soravtansine). The expression of FR was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The in vitro cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FR. In vivo antitumor efficacy of IMGN853 was evaluated in xenograft/patient derived xenograft (PDX) models. Semi-quantitative IHC analysis indicated that 41% of the USC patients overexpress FR. Further, overexpression of FR (ie, 2+) was detected via flow cytometry in 22% (2/9) of primary endometrioid and in 27% (3/11) of primary USC cell lines. Increased cytotoxicity was seen with IMGN853 treatment compared to control in 2+ expressing uterine tumor cell lines. In contrast,tumor cell lines with low FR showed no difference when exposed to IMGN853 versus control. IMGN853 induced bystander killing of FR = 0 tumor cells. In an endometrioid xenograft model (END(K)265), harboring 2+ FR, IMGN853 treatment showed complete resolution of tumors (p< 0.001). Treatment with IMGN853 in USC PDX model (BIO(K)1), expressing 2+ FR, induced 2-fold increase in median survival (p< 0.001). IMGN853 shows impressive anti-tumor activity in biologically aggressive FR 2+ uterine cancers. This preclinical data suggests that patients with chemotherapy resistant/recurrent endometrial cancer overexpressing FR may benefit from this treatment
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A DNA-interacting payload designed to eliminate cross-linking improves the therapeutic index of antibody-drug conjugates (ADCs)
Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar in vitro potency, but improved bystander killing and in vivo efficacy, compared to those of the cross-linker. Thus, the improved in vivo tolerability and anti-tumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment.
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MicroRNA-203 inhibits long noncoding RNA HOTAIR and regulates tumorigenesis through epithelial-to-mesenchymal transition pathway in renal cell carcinoma
This study aims to investigate the role of miR-203-HOTAIR interaction in the suppression of renal cell carcinoma (RCC). We employed series of in vitro assays such as proliferation, invasion, migration and colony formation along with in vivo tumor xenograft model. Profiling of miR-203 and HOTAIR expression revealed that miR-203 was significantly under-expressed whereas HOTAIR was overexpressed in RCC cell-lines and clinical specimens compared to normal cell line and tissue. Both miR-203 and HOTAIR expression significantly distinguished malignant from normal tissues and significantly correlated with clinicopathological characteristics of patients. Overexpression of miR-203 significantly inhibited proliferation, migration and invasion with an induction of apoptosis and cell cycle arrest. Whereas, HOTAIR suppression resulted in the similar functional effects in the same RCC cell lines. In silico RNA-22 algorithm showed a binding site for miR-203 in HOTAIR. We observed a direct interaction between miR-203 and HOTAIR by RNA-immunoprecipitation (RIP) and luciferase reporter assays. We show that miR-203-HOTAIR interaction resulted in the inhibition of epithelial to mesenchymal transition (EMT) and metastatic genes as indicated by induction of key metastasis-suppressing proteins E-cadherin, claudin (epithelial markers) and PTEN along with induction of tumor suppressor genes p21 and p27. A significant decrease in vimentin (mesenchymal-marker), KLF4 and nanog (stemness-markers) was also observed. This is the first report demonstrating miR-203 mediated regulation of HOTAIR induces tumor suppressor effects in RCC by regulating EMT and metastatic pathway genes. Thus, the study suggests that therapeutic regulation of HOTAIR by miR-203 overexpression may provide an opportunity to regulate RCC growth and metastasis.
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MI130004, a novel antibody-drug conjugate combining trastuzumab with a molecule of marine origin, shows outstanding in vivo activity against HER2 expressing tumors
In the search for novel payloads to design new antibody-drug conjugates (ADCs), marine compounds represent an interesting opportunity given their unique chemical features. PM050489 is a marine compound that binds β-tubulin at a new site and disrupts the microtubule network hence leading to mitotic aberrations and cell death. PM050489 has been conjugated to trastuzumab via Cys residues through a non-cleavable linker and the resulting ADC, named MI130004, has been studied. Analysis of MI130004 delivered data consistent with the presence of two molecules of PM050489 per antibody molecule, likely bound to both sides of the intermolecular disulfide bond connecting the antibody light and heavy chains. The antitumor activity of MI130004 was analyzed in vitro and in vivo in different cell lines of diverse tumor origin (breast, ovary, and gastric cancer) expressing different levels of HER2. MI130004 showed very high in vitro potency and good selectivity for tumor cells that overexpressed HER2. At the cellular level, MI130004 impaired tubulin polymerization, causing disorganization and disintegration of the microtubule network which ultimately led to mitotic failure, mirroring the effect of its payload. Treatment with MI130004 in mice carrying histologically diverse tumors expressing HER2 induced a long-lasting antitumor effect with statistically significant inhibition of tumor growth coupled with increases in median survival time compared to vehicle or trastuzumab. These results strongly suggest that MI130004 is endowed with remarkable anticancer activity and confirm the extraordinary potential of marine compounds for the design of new ADCs.
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PIM kinases are a potential prognostic biomarker and therapeutic target in neuroblastoma
The majority of high-risk neuroblastoma patients are refractory to, or relapse on current treatment regimens, resulting in 5-year survival rates of less than 50%. This emphasizes the urgent need to identify novel therapeutic targets. Here, we report that high PIM kinase expression is correlated with poor overall survival. Treatment of neuroblastoma cell lines with the pan-PIM inhibitors AZD1208 or PIM-447 suppressed proliferation through inhibition of mTOR signaling. In a panel of neuroblastoma cell lines, we observed a marked binary response to PIM inhibition, suggesting that specific genetic lesions control responses to PIM inhibition. Using a genome-wide CRISPR-Cas9 genetic screen, we identified NF1 loss as the major resistance mechanism to PIM kinase inhibitors. Treatment with AZD1208 impaired the growth of NF1 wild type xenografts, while NF1 knock out cells were insensitive. Thus, our data indicate that PIM inhibition may be a novel targeted therapy in NF1 wild type neuroblastoma.
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A Spatio-temporal Model of Macrophage-mediated Drug Resistance in Glioma Immunotherapy
The emergence of drug resistance is often an inevitable obstacle that limits the long-term effectiveness of clinical cancer chemotherapeutics. Although various forms of cancer cell-intrinsic mechanisms of drug resistance have been experimentally revealed, the role and the underlying mechanism of tumor microenvironment in driving the development of acquired drug resistance remain elusive, which significantly impedes effective clinical cancer treatment. Recent experimental studies have revealed a macrophage-mediated drug resistance mechanism in which the tumor microenvironment undergoes adaptation in response to macrophage-targeted colony-stimulating factor-1 receptor (CSF1R) inhibition therapy in gliomas. In this study, we developed a spatio-temporal model to quantitatively describe the interplay between glioma cells and CSF1R inhibitor-targeted macrophages through CSF1 and IGF1 pathways. Our model was used to investigate the evolutionary kinetics of the tumor regrowth and the associated dynamic adaptation of the tumor microenvironment in response to the CSF1R inhibitor treatment. The simulation result obtained using this model was in agreement with the experimental data. The sensitivity analysis revealed the key parameters involved in the model, and their potential impacts on the model behavior were examined. Moreover, we demonstrated that the drug resistance is dose-dependent. In addition, we quantitatively evaluated the effects of combined CSFR inhibition and IGF1 receptor (IGF1R) inhibition with the goal of designing more effective therapies for gliomas. Our study provides quantitative and mechanistic insights into the microenvironmental adaptation mechanisms that operate during macrophage-targeted immunotherapy and has implications for drug dose optimization and the design of more effective combination therapies.
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NEO212 Inhibits Migration and Invasion of Glioma Stem Cells
Glioblastoma multiforme is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature, suggesting that cell migration plays an important role in tumor progression. The poor prognosis in GBM is associated with a high rate of tumor recurrence, and resistance to the standard of care chemotherapy, temozolomide (TMZ). The novel compound NEO212, a conjugate of TMZ and perillyl alcohol (POH), has proven to be 10 fold more cytotoxic to glioma stem cells (GSCs) than TMZ, and is active against TMZ-resistant tumor cells. In this study, we show that NEO212 decreases migration and invasion of primary cultures of patient-derived GSCs, in both mesenchymal USC02 and proneural USC04 populations. The mechanism by which NEO212 reduces migration and invasion appears to be independent of its DNA alkylating effects, which cause cytotoxicity during the first hours of treatment, and is associated with a decrease in the FAK/Src signaling pathway, an effect not exhibited by TMZ. NEO212 also decreases the production of matrix metalloproteinases MMP2 and MMP9, crucial for GSC invasion. Gene expression analysis of epithelial and mesenchymal markers suggests that NEO212 increases the expression of epithelial-like characteristics, suggesting a reversion of the epithelial-to-mesenchymal transition (EMT) process. Furthermore, in an in vivo orthotopic glioma model, NEO212 decreases tumor progression by reducing invasion of GSCs, thereby increasing survival time of mice. These studies indicate that NEO212, in addition to cytotoxicity, can effectively reduce migration and invasion in GSCs, thus exhibiting significant clinical value in the reduction of invasion and malignant glioma progression.
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Small molecule-mediated activation of RAS elicits biphasic modulation of phospho ERK levels that are regulated through negative feedback on SOS1
Oncogenic mutation of RAS results in aberrant cellular signaling and is responsible for more than 30% of all human tumors. Therefore, pharmacological modulation of RAS has attracted great interest as a therapeutic strategy. Our laboratory has recently discovered small molecules that activate Son of Sevenless (SOS)-catalyzed nucleotide exchange on RAS and inhibit downstream signaling. Here we describe how pharmacologically targeting SOS1 induced biphasic modulation of RAS-GTP and ERK phosphorylation levels, which we observed in a variety of cell lines expressing different RAS mutant isoforms. We show that compound treatment caused an increase in phosphorylation at ERK consensus motifs on SOS1 that was not observed with the expression of a non-phosphorylatable S1178A SOS1 mutant or after pretreatment with an ERK inhibitor. Phosphorylation at S1178 on SOS1 is known to inhibit the association between SOS1 and GRB2 and disrupt SOS1 membrane localization. Consistent with this, we show that wild-type SOS1 and GRB2 dissociated in a time dependent fashion in response to compound treatment, and conversely, this interaction was enhanced with the expression of a S1178A SOS1 mutant. Furthermore, in cells expressing either S1178A SOS1 or a constitutively membrane-bound CAAX box tagged SOS1 mutant, we observed elevated RAS-GTP levels over time in response to compound, as compared to the biphasic changes in RAS-GTP exhibited in cells expressing wild-type SOS1. These results suggest that small molecule targeting of SOS1 can elicit a biphasic modulation of RAS-GTP and phospho ERK levels through negative feedback on SOS1 that regulates the interaction between SOS1 and GRB2.
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The Balance Players of the Adaptive Immune System
Equilibrium between immune activation and suppression may be necessary to maintain immune homeostasis, because proinflammatory effector T cells (defined as antiregulatory T cells) counteract the functions of regulatory immune cells. These self-reactive T cells recognize human leukocyte antigen (HLA)–restricted epitopes derived from proteins expressed by regulatory immune cells such as IDO, PD-L1, PD-L2, or arginase. The activation of such proinflammatory effector T cells offers a novel way to directly target the tumor microenvironment, potentially giving them considerable clinical value, especially in patients with cancer. Vaccination against genetically stable cells with regular HLA expression is an attractive way to directly target immunosuppressive cells in addition to attracting proinflammatory cells into the tumor microenvironment. Importantly, vaccination toward IDO or PD-L1 to potentiate such T cells have proven safe, with minimal toxicity in the clinical phase I trials conducted thus far.Significance: Autoreactive effector T cells that specifically recognize regulatory cells might be useful to harness for cancer immunotherapy to target the immune-suppressive tumor microenvironment. Cancer Res; 1–4. ©2018 AACR.
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SPON2 Promotes M1-like Macrophage Recruitment and Inhibits Hepatocellular Carcinoma Metastasis by Distinct Integrin-Rho GTPase-Hippo Pathways
Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis. SPON2-α4β1 integrin signalling activated RhoA and Rac1, increased F-actin reorganization, and promoted M1-like macrophage recruitment. F-actin accumulation also activated the Hippo pathway by suppressing LATS1 phosphorylation, promoting YAP nuclear translocation, and initiating downstream gene expression. However, SPON2-α5β1 integrin signaling inactivated RhoA and prevented F-actin assembly, thereby inhibiting HCC cell migration; the Hippo pathway was not noticeably involved in SPON2-mediated HCC cell migration. In HCC patients, SPON2 levels correlated positively with prognosis. Overall, our findings provide evidence that SPON2 is a critical factor in mediating the immune response against tumor cell growth and migration in HCC.
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A DDX31/mutant-p53/EGFR axis promotes multistep progression of muscle invasive bladder cancer
The p53 and EGFR pathways are frequently altered in bladder cancers, yet their contributions to its progression remain elusive. Here we report that DEAD box polypeptide 31 (DDX31) plays a critical role in the multistep progression of muscle invasive bladder cancer (MIBC) through its sequential interactions with mutant p53 (mutp53) and EGFR. In early MIBC cells, nuclear DDX31 bound mutp53/SP1 and enhanced mutp53 transcriptional activation, leading to migration and invasion of MIBC. Cytoplasmic DDX31 also bound EGFR and phospho-nucleolin (p-NCL) in advanced MIBC, leading to EGFR-Akt signaling activation. High expression of both cytoplasmic DDX31 and p53 proteins correlated with poor prognosis in patients with MIBC, and blocking the DDX31-NCL interaction resulted in downregulation of EGFR-Akt signaling, eliciting an in vivo anti-tumor effect against bladder cancer. These findings reveal that DDX31 cooperates with mutp53 and EGFR to promote progression of MIBC, and inhibition of DDX31-NCL formation may lead to potential treatment strategies for advanced MIBC.
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The FACT inhibitor CBL0137 synergizes with cisplatin in small cell lung cancer by increasing NOTCH1 expression and targeting tumor-initiating cells
Traditional treatments of small cell lung cancer (SCLC) with cisplatin, a standard of care therapy, spare the tumor-initiating cells (TIC) that mediate drug resistance. Here we report a novel therapeutic strategy that preferentially targets TIC in SCLC in which cisplatin is combined with CBL0137, an inhibitor of the histone chaperone facilitates chromatin transcription (FACT), which is highly expressed in TIC. Combination of cisplatin and CBL0137 killed patient-derived and murine SCLC cell lines synergistically. In response to CBL0137 alone, TIC were more sensitive than non-TIC, in part because CBL0137 increased expression of the tumor suppressor NOTCH1 by abrogating the binding of negative regulator SP3 to the NOTCH1 promoter, and in part because treatment decreased the high expression of stem cell transcription factors. The combination of cisplatin and CBL0137 greatly reduced the growth of a patient-derived xenograft in mice and also the growth of a syngeneic mouse SCLC tumor. Thus, CBL0137 can be a highly effective drug against SCLC, especially in combination with cisplatin.
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Highly Efficient Cuprous Oxide Nanocrystals Assisted with Graphene for Decolorization Using Visible Light
Abstract
The preparation of rhombic dodecahedral cuprous oxide (rdCu2O) decorated with various amounts of reduced graphene oxide (rGO) is carried out by using a wet-chemical route. The resultant nanocomposites (denoted as rdCu2O-xrGO, x = amounts of rGO) possess unique crystal facets of Cu2O and superior electronic properties of rGO, which are tested as photocatalysts in the degradation of methyl orange (MO) under visible light irradiation. Among all the rdCu2O-xrGO photocatalysts, the rdCu2O-1rGO is found to degrade ca. 98% of MO in the presence of very low catalyst concentration (0.0625 g L−1) within 120 min under visible light illumination. This obtained result may be owing to the well interfacial contact of rhombic dodecahedral Cu2O nanoparticles with high electronic conductivity of rGO sheets that can increase the separation of photo-induced electron-hole pairs, stabilize the Cu2O, and enhance MO adsorption, which are proofed by using X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy, photoluminescence, and UV-Vis diffuse reflection spectroscopy. Most importantly, these efficient photocatalysts can be reusable and retain surpassing photoactivity in terms of MO degradation after cyclic tests, which may provide a possible opportunity for practical applications in purifying wastewater via direct sunlight.
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Bronchoalveolar Lavage Fluid in Children: Comparative Proteomic Analysis in Infectious and Non-Infectious Lung Disease
Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.
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UW launches new training program for children’s oral health
A University of Washington Health Sciences team led by the School of Dentistry is launching an interprofessional training program to improve access to dental care for children ranging in age from the first year of life through 5 years.
The post UW launches new training program for children's oral health appeared first on UW School of Dentistry.
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Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel
Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel
Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel, Published online: 13 February 2018; doi:10.1038/bjc.2017.486
Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel
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Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology
Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology
Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology, Published online: 13 February 2018; doi:10.1038/bjc.2017.485
Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology
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IKKα is required in the intestinal epithelial cells for tumour stemness
IKKα is required in the intestinal epithelial cells for tumour stemness
IKK<i>α</i> is required in the intestinal epithelial cells for tumour stemness, Published online: 13 February 2018; doi:10.1038/bjc.2017.459
IKKα is required in the intestinal epithelial cells for tumour stemness
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Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection
Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection
Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection, Published online: 13 February 2018; doi:10.1038/bjc.2017.473
Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection
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A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424
A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424
A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424, Published online: 13 February 2018; doi:10.1038/bjc.2017.484
A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424
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Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer
Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer
Regulation of ITGA3 by the dual-stranded <i>microRNA</i>-199 family as a potential prognostic marker in bladder cancer, Published online: 13 February 2018; doi:10.1038/bjc.2017.439
Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer
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A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma
A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma
A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma, Published online: 13 February 2018; doi:10.1038/bjc.2017.495
A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma
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An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma
An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma
An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma, Published online: 13 February 2018; doi:10.1038/bjc.2018.3
An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma
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Lymphaticovenular anastomosis for breast cancer treatment-related lymphedema: three-line strategy for an optimal outcome
The approach to lymphaticovenular anastomosis (LVA) for breast cancer treatment-related lymphedema should differ from that performed for secondary lower extremity lymphedema (LEL) because upper extremity lymphedema (UEL) and LEL differ in terms of the areas affected, imaging features, and postoperative improvements.
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Aesthetic and functional outcomes of radial forearm flap donor site reconstruction with biosynthetic skin substitutes
The radial forearm fasciocutaneous flap (RFFF) is a workhorse flap in reconstructive microsurgery that is favoured for its thinness, reliable vascularity, consistent anatomy, and ability to be harvested concurrently during oncologic resection (1). Despite its popularity, RFFF elevation may lead to wound healing complications, wrist stiffness, weakened grip, sensory impairment, and a visible, potentially stigmatizing forearm scar (2). Various strategies have been investigated to reduce donor site morbidity, including suprafascial dissection, full thickness skin grafting, primary closure with local flaps, and the use of alternative flaps (3).
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BY7Jdy
Feasibility of EUS-guided Nd:YAG laser ablation of unresectable pancreatic adenocarcinoma
Endoscopic ultrasound (EUS) has become an interventional technique in which a needle may be used as a vehicle to deliver therapeutic agents. Laser ablation (LA) has been used to treat many primary and secondary neoplasms. This study aimed to assess the feasibility of EUS-guided LA for unresectable (UR) pancreatic cancer.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2F21i7E
Clinical outcomes and factors related with colonic perforations in patients receiving self-expandable metal stent insertion for malignant colorectal obstruction
Although colonic perforation is a dreadful adverse event associated with stent placement, data on this topic are sparse. We aimed to investigate the clinical outcomes of colonic perforation and factors related with its occurrence in patients who receiving self-expanding metal stents (SEMSs) for malignant colorectal obstruction.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2o5Kgxl
Chondromyxoid Fibroma Arising in Craniofacial Sites: A Clinicopathologic Analysis of 25 Cases
Chondromyxoid fibroma (CMF) is a rare benign tumor, usually arising in the metaphysis of long bones in young adults. Occurrence in craniofacial bones presents a particular diagnostic challenge given its unusual location and resemblance to malignant mimics. We describe the clinicopathologic features of 25 cases of craniofacial CMF identified between 1999 and 2017. Patients were 14 men and 11 women, with median age of 44 years (range, 5 to 83 y). Sites of involvement were sphenoid (7), ethmoid (5), maxilla (3), occipital (2), nasal septum (2), palatine (2), temporal (2), orbit (1), and undisclosed skull (1). Tumor size ranged from 0.8 to 6.0 cm (median, 2.0 cm). Of the 21 tumors with available radiology, 15 arose on the bone surface with expansion into adjacent sinuses; 6 were intraosseous. Bony erosion/destruction was present in most (13/16) cases, and 7/12 showed calcification on imaging. Microscopically, most tumors showed a lobulated growth pattern with hypocellular central chondromyxoid areas and peripheral hypercellularity, though many samples were fragmented. Tumor cells had ovoid to tapered nuclei and abundant palely eosinophilic cytoplasm, frequently with stellate cell processes. Mitoses ranged from 0 to 2 per 10 high-power fields (median count, 0). None showed necrosis. Significant atypia was present in 2 cases, 1 of which was a previously radiated recurrence. Bone infiltration was present in 6 cases. Thirteen tumors had focal calcification, and 2 had foci of hyaline cartilage. All tumors were negative for keratin and GFAP (0/24), with frequent positivity for SMA (7/7) and occasional staining for EMA (5/24) and S-100 (2/24). Most patients underwent piecemeal excision or curettage (5/5 positive margins when reported). Follow-up data were available for 15 patients, and 5 suffered local recurrence. Craniofacial CMF poses diagnostic pitfalls including frequent aggressive radiologic features and lack of a specific immunophenotype. Tumors may recur, largely due to the difficulty of obtaining clear surgical margins in this anatomic region. Furthermore, propensity for local destruction and invasion can create significant morbidity.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BWdM2e
Reappraisal of Morphologic Differences Between Renal Medullary Carcinoma, Collecting Duct Carcinoma, and Fumarate Hydratase–deficient Renal Cell Carcinoma
Renal medullary carcinomas (RMCs) and collecting duct carcinomas (CDCs) are rare subsets of lethal high-stage, high-grade distal nephron-related adenocarcinomas with a predilection for the renal medullary region. Recent findings have established an emerging group of fumarate hydratase (FH)-deficient tumors related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC-RCCs) syndrome within this morphologic spectrum. Recently developed, reliable ancillary testing has enabled consistent separation between these tumor types. Here, we present the clinicopathologic features and differences in the morphologic patterns between RMC, CDC, and FH-deficient RCC in consequence of these recent developments. This study included a total of 100 cases classified using contemporary criteria and ancillary tests. Thirty-three RMCs (SMARCB1/INI1-deficient, hemoglobinopathy), 38 CDCs (SMARCB1/INI1-retained), and 29 RCCs defined by the FH-deficient phenotype (FH−/2SC+ or FH±/2SC+ with FH mutation, regardless of HLRCC syndromic stigmata/history) were selected. The spectrum of morphologic patterns was critically evaluated, and the differences between the morphologic patterns present in the 3 groups were analyzed statistically. Twenty-five percent of cases initially diagnosed as CDC were reclassified as FH-deficient RCC on the basis of our contemporary diagnostic approach. Among the different overlapping morphologic patterns, sieve-like/cribriform and reticular/yolk sac tumor–like patterns favored RMCs, whereas intracystic papillary and tubulocystic patterns favored FH-deficient RCC. The tubulopapillary pattern favored both CDCs and FH-deficient RCCs, and the multinodular infiltrating papillary pattern favored CDCs. Infiltrating glandular and solid sheets/cords/nested patterns were not statistically different among the 3 groups. Viral inclusion–like macronucleoli, considered as a hallmark of HLRCC-RCCs, were observed significantly more frequently in FH-deficient RCCs. Despite the overlapping morphology found among these clinically aggressive infiltrating high-grade adenocarcinomas of the kidney, reproducible differences in morphology emerged between these categories after rigorous characterization. Finally, we recommend that definitive diagnosis of CDC should only be made if RMC and FH-deficient RCC are excluded.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BVTgi8
Clear Cell Carcinoma of Salivary Glands Is Frequently p16 Positive: A Pitfall in the Interpretation of Oropharyngeal Biopsies
Clear cell carcinoma (CCC) is a low-grade malignancy that commonly arises in minor salivary glands of the oropharynx and other sites. EWSR1-ATF1 gene fusions seem to be specific for this salivary neoplasm. Testing for EWSR1-ATF1 has expanded the histologic spectrum of CCC. As one important example, many CCCs have a predominantly squamous phenotype with few clear cells, a finding that can cause confusion with squamous cell carcinoma (SqCC). P16 immunohistochemical staining to determine human papillomavirus (HPV) status has become standard practice for all oropharyngeal carcinomas showing squamous differentiation. The purpose of this study was to determine whether this practice could contribute to the difficulty in distinguishing CCC from p16-positive SqCC. The authors' surgical pathology archives were searched for cases of CCC. All cases were evaluated with p16 immunohistochemistry, high-risk HPV RNA in situ hybridization (ISH), and EWSR1 gene break-apart fluorescence ISH. Sixteen CCCs were identified. All harbored an EWSR1 rearrangement. Eleven patients were women and 5 were men. They ranged in age from 30 to 85 years (mean, 58 y). The CCCs arose in the oropharynx (tongue base or tonsil) (n=8, 50%), oral cavity (n=4, 25%), and nasopharynx (n=4, 25%). Each case demonstrated clear cells, but the proportion was highly variable (10% to 90%, mean 48%), with 7 of 16 cases havingfrom #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BWaFYa
Clinicopathologic Features and Prognostic Impact of Lymph Node Involvement in Patients With Breast Implant-associated Anaplastic Large Cell Lymphoma
Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a rare T-cell lymphoma that arises around breast implants. Most patients manifest with periprosthetic effusion, whereas a subset of patients develops a tumor mass or lymph node involvement (LNI). The aim of this study is to describe the pathologic features of lymph nodes from patients with BI-ALCL and assess the prognostic impact of LNI. Clinical findings and histopathologic features of lymph nodes were assessed in 70 patients with BI-ALCL. LNI was defined by the histologic demonstration of ALCL in lymph nodes. Fourteen (20%) patients with BI-ALCL had LNI, all lymph nodes involved were regional, the most frequent were axillary (93%). The pattern of involvement was sinusoidal in 13 (92.9%) cases, often associated with perifollicular, interfollicular, and diffuse patterns. Two cases had Hodgkin-like patterns. The 5-year overall survival was 75% for patients with LNI and 97.9% for patients without LNI at presentation (P=0.003). Six of 49 (12.2%) of patients with tumor confined by the capsule had LNI, compared with LNI in 8/21 (38%) patients with tumor beyond the capsule. Most patients with LNI achieved complete remission after various therapeutic approaches. Two of 14 (14.3%) patients with LNI died of disease compared with 0/56 (0%) patients without LNI. Twenty percent of patients with BI-ALCL had LNI by lymphoma, most often in a sinusoidal pattern. We conclude that BI-ALCL beyond capsule is associated with a higher risk of LNI. Involvement of lymph nodes was associated with decreased overall survival. Misdiagnosis as Hodgkin lymphoma is a pitfall.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2sq2m2P
The AFIP/ARP Atlases of Pathology Past, Present, and Future
The AFIP (Armed Forces Institute of Pathology) Atlases (Fascicles) have been in continuous publication for nearly 75 years and have enjoyed a highly regarded reputation for their excellence. Throughout this time period, more than 130 volumes, encompassing the 1st to 4th series have been published. Since their inception in the 1940's, the Fascicles have evolved from loose-leafed atlases illustrated with black and white images, to hardbound monographs with full color images and expansion of scope, including relevant clinical information, cytopathology, and the most recent advances in immunohistochemistry and molecular diagnostics. Each of the volumes undergoes a rigorous review process by the Editor-in-Chief, Associate Editors, members of the Editorial Advisory Board, and external reviewers. The 5th series, under the editorial direction of Drs. Elizabeth Montgomery and Jason Hornick, is well underway and will include an Epub version and a virtual slide box, in addition to the hardbound book. The Atlases of Nontumor Pathology will also continue to be published. With the closure of the AFIP in 2011, the American Registry of Pathology (ARP) has assumed full responsibility for the publication of both the Tumor and Nontumor Fascicles.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2sviHD4
The Significance of Spermatic Cord Involvement by Testicular Germ Cell Tumors: Should We Be Staging Discontinuous Invasion From Involved Lymphovascular Spaces Differently From Direct Extension?
The recent 8th edition of the American Joint Committee on Cancer (AJCC) staging manual had multiple changes concerning how pathologists should stage germ cell tumors (GCTs) of the testis. A significant one concerns the impact of different types of spermatic cord involvement, specifically direct tumor extension versus discontinuous involvement by invasion through lymphovascular spaces. We compared clinicopathologic findings and outcome data between 2 cohorts with these findings to evaluate the validity of the change in the AJCC 8th edition manual. GCTs (seminomatous and nonseminomatous) of the testis were identified that had previously been staged as pT3 due to involvement of the spermatic cord. Pathologic, radiographic, and clinical findings were reviewed. Tumors were restaged based on AJCC 8th edition criteria and the cohorts were split into direct extension by tumor into the spermatic cord (pT3), spermatic cord soft tissue invasion via spread from discontinuously involved lymphovascular spaces (pT2pM1), or a combination of both (pT3pM1). One hundred cases of primary GCTs of the testis, previously classified as pT3 by the AJCC 6th or 7th cancer staging manuals from 2007 to 2015, were selected. Mixed malignant GCTs were the predominant tumor type, comprising 66% of all cases. Pure tumor morphologies included embryonal carcinoma (n=17), seminoma (n=14), teratoma (n=2), and yolk sac tumor (n=1). The tumors either directly invaded into the spermatic cord (n=78), involved the cord discontinuously via spread from lymphovascular spaces (n=18), or had both findings (n=4). Overall, 93% of patients presented at advanced clinical stage (CS). Using the AJCC 8th parameters, 12% of all tumors were upstaged. Changes included CSI (n=1) and CSII (n=11) tumors being reclassified as prognostic stage group III. Clinical and/or pathologic recurrence was identified in 19% of all patients, including 12 pT3 and 7 pM1 patients (P=0.11). Overall mean time to recurrence was 24.6 months, with a mean of 28.0 months for pT3 tumors and 18.9 months for pM1 tumors. Five patients were dead at the time of this study, including 3 (4%) with pT3 tumors and 2 (9%) in the pM1 cohort. Our findings support that seminomatous and nonseminomatous GCTs with spermatic cord invasion have a high frequency of advanced CS at presentation, regardless of involvement by direct extension or discontinuous spread via invasion from lymphovascular spaces. By designating the latter as M1, a spurious upstaging to prognostic stage group III is required by the AJCC 8th edition. We were unable to identify statistically significant difference between the 2 groups as it pertained to CS at presentation and likelihood of recurrence. Conversely, statistical trends favor that pM1 patients have more likely recurrence and worse prognosis than pT3 patients.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BWaKLs
Substantial Interobserver Agreement in the Diagnosis of Dysplasia in Barrett Esophagus Upon Review of a Patient’s Entire Set of Biopsies
The pathologic diagnosis of dysplasia in Barrett esophagus (BE) suffers from interobserver disagreement. Many of the studies demonstrating disagreement in the diagnosis of dysplasia have pathologists review individual biopsy slides in isolation. To more closely mimic daily practice, 3 pathologists reviewed hematoxylin and eosin slides made from 549 individual biopsy jars obtained from 129 unique patients with a diagnosis of BE. Each pathologist reviewed the entirety of a given patient's biopsy material. The grade of dysplasia present in each biopsy jar was given as well as an overall highest grade of dysplasia from the patient's entire set of biopsies. The interobserver agreement in the diagnosis of dysplasia per biopsy jar and per patient's set of biopsies was measured by Fleiss κ statistic for multiple raters. The κ values for each diagnosis was higher in the per patient analysis compared with the per biopsy jar analysis indicating that pathologists are more likely to agree on the overall grade of dysplasia compared with the grade in an individual biopsy jar. In the per patient analysis, the interobserver agreement in the diagnosis of nondysplastic BE and high-grade dysplasia were substantial (κ=0.66; 95% confidence interval [CI], 0.56-0.76 and κ=0.76; 95% CI, 0.66-0.86, respectively). The interobserver agreement in the diagnosis of low-grade dysplasia (LGD) was fair (κ=0.31; 95% CI, 0.21-0.42). When LGD and high-grade dysplasia were collapsed into 1 category of positive for dysplasia, the interobserver agreement in the per patient analysis remained substantial (κ=0.70; 95% CI, 0.60-0.80), suggesting that much of the disagreement in LGD is not due to lack of recognition of dysplastic Barrett's mucosa, but rather the degree of dysplasia. These results indicate that pathologists can reliably distinguish between nondysplastic BE and dysplastic BE when a patient's entire set of biopsies is reviewed as a group. When second opinions are obtained, all available slides from that endoscopic procedure should be sent for review.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BWaEU6
SWI/SNF Chromatin-remodeling Complex Status in SMARCB1/INI1-preserved Epithelioid Sarcoma
The SWI/SNF chromatin-remodeling complex, which is composed of evolutionarily conserved core subunits such as SMARCB1/INI1 (INI1), SMARCA4/BRG1 (BRG1), SMARCC1/BAF155 (BAF155), and SMARCC2/BAF170 (BAF170), can be viewed as the prototype of an epigenetic regulator of gene expression that is involved in tumor suppression. Epithelioid sarcoma, which classified as a tumor of uncertain differentiation, shows an almost complete loss of INI1. However, some cases of epithelioid sarcoma have preserved INI1, and the clinicopathologic features of these cases are uncertain. To date, there has been no investigation focused on the SWI/SNF chromatin-remodeling complex in INI1-preserved epithelioid sarcoma cases. First, an investigation of INI1 immunoexpression statuses in 60 formalin-fixed paraffin-embedded epithelioid sarcoma specimens (proximal type, 29 cases; conventional type, 31 cases) was performed. In the available INI1-preserved epithelioid sarcoma cases, we analyzed the BRG1, BAF155, and BAF170 protein expressions. INI1 preservation was observed in 6 of 29 (21%) proximal-type and 2 of 31 (6%) conventional-type epithelioid sarcoma cases. Six cases of INI1-preserved epithelioid sarcomas of proximal type were available for further immunohistochemical study. One proximal type showed loss of BAF170, and 2 proximal-type cases revealed loss of BRG1 with preservation of the other remaining core subunit proteins. One proximal-type case showed a mosaic pattern of BRG1 and loss of BAF155. However, in the remaining 2 proximal-type cases, all core subunit proteins were preserved. Overall, these results suggest that loss of expression of SWI/SNF chromatin-remodeling complex proteins has an important role in tumorigenesis. The remaining 2 INI1-preserved epithelioid sarcoma cases may have had other abnormalities causing dysfunction of SWI/SNF chromatin remodeling.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BpWLfw
Dermatofibrosarcoma Protuberans of Distal Extremities and Acral Sites: A Clinicopathologic Analysis of 27 Cases
Dermatofibrosarcoma protuberans (DFSP) of the distal extremities and acral sites are extremely rare and incompletely characterized. Twenty-seven DFSP occurring in these sites were retrieved from our collective archives and reevaluated. Tumors occurred in 16 males and 11 females. Median age at presentation was 42.5 years (range, 7 to 78 y). Lesions involved the foot (18 with 6 in the toes and 2 on the plantar foot), distal ankle (4), hand (4 with 2 in the thumbs), and wrist (1). All cases showed predominantly classic DFSP morphology and were diffusely CD34 positive. Myxoid change, melanin pigmented, and giant cell fibroblastoma foci were each present in 1 case, respectively. Fibrosarcomatous change was present in 3 cases. Fluorescent in situ hybridization demonstrated PDGFB gene rearrangement in 9 of 10 tested cases. Clinical follow-up was available in 21 cases (median, 36.1 mo; range, 1 to 152 mo) and revealed 4 local recurrences. Four patients underwent digital amputation for unresectable recurrent disease. An additional patient underwent multiple resections with positive margins and elected to receive imatinib mesylate therapy. After a 2-year course, the patient has no evidence of residual disease (40 mo). No metastases were documented in any of the cases studied. The natural history of DFSP of distal extremities and acral sites is similar to that of its counterparts elsewhere. A high index of suspicion, careful morphologic examination for key histologic features of DFSP, and in selected cases, molecular studies to identify the pathognomonic COL1A1-PDGFB gene fusion should facilitate the distinction of these rare, locally aggressive neoplasms from morphologic mimics that may arise in distal extremities and acral sites.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BXwzdy
MYB Translocation Status in Salivary Gland Epithelial-Myoepithelial Carcinoma: Evaluation of Classic, Variant, and Hybrid Forms
Epithelial-myoepithelial carcinoma (EMC) is a malignant salivary gland neoplasm comprised of a biphasic arrangement of inner luminal ductal cells and outer myoepithelial cells. Adenoid cystic carcinoma (AdCC) is also a biphasic tumor comprised of ductal and myoepithelial cells, but these components tend to be arranged in a more cribriform pattern. The occurrence of "hybrid carcinomas" that show mixed patterns of EMC and AdCC raises questions about the relationship of these morphologically overlapping but clinically distinct tumors. AdCCs frequently harbor MYB-NFIB gene fusions. Mapping of EMCs (including hybrid forms with an AdCC component) for this fusion could help clarify the true nature of EMC as a distinct entity or simply as some variant form of AdCC. Twenty-nine cases of EMC were evaluated including 15 classic low-grade EMCs, 7 intermediate-grade EMCs, 2 EMCs with myoepithelial anaplasia, 1 EMC with high-grade transformation, and 4 hybrid EMCs with an AdCC component. Break apart fluorescence in situ hybridization for MYB was performed, as was MYB immunohistochemistry. For the hybrid carcinomas and those with high-grade transformation, the divergent tumor components were separately analyzed. A MYB translocation was identified in 5 of 28 (18%) tumors including 3 of 4 (75%) hybrid carcinomas and 2 of 7 (29%) intermediate-grade EMCs. For the positive hybrid carcinomas, the fusion was detected in both the EMC and AdCC components. The MYB fusion was not detected in any of the classic EMCs (0/15) or in any of the EMCs with myoepithelial anaplasia (0/2) or high-grade transformation (0/1). The fluorescence in situ hybridization assay was unsuccessful in 1 case. MYB immunostaining was seen in 5 of 5 fusion-positive cases, and also 9 of 23 fusion-negative tumors. Classic low-grade EMCs are genetically distinct from AdCCs in that they do not harbor MYB fusions. The presence of a MYB fusion in EMCs showing hybrid features of AdCC or exhibiting highly infiltrative growth points to a subset of these tumors that may well be true AdCCs masquerading as EMCs.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BWaJam
Prognostic Significance of Periadnexal Extension in Cutaneous Melanoma and its Implications for Pathologic Reporting and Staging
Tumor thickness is the strongest predictor of outcome for clinically localized melanoma. Therefore, accurate assessment is critical for appropriate staging, reliable estimation of prognosis, and management. When melanoma extends alongside skin adnexal structures more deeply than the main tumor mass (periadnexal extension), it is currently unknown whether the prognosis is more accurately reflected by the deepest point of periadnexal tumor extension or the main tumor mass. This study sought to address this question. Survival outcomes of 257 primary cutaneous melanoma patients with periadnexal extension diagnosed between 2005 and 2015 and managed at Melanoma Institute Australia were identified and compared with a control cohort of 514 patients who were matched for tumor thickness, sex, age, mitotic rate, ulceration status, and year of diagnosis but lacked periadnexal extension. The incidence of periadnexal extension at Melanoma Institute Australia was 1.5% (257/16,692 cutaneous melanomas diagnosed between 2005 and 2015). The patient characteristics between the 2 groups were otherwise very similar; median Breslow thickness was 0.9 mm for the periadnexal group and 1.0 mm for the control group. The median extension beyond the Breslow thickness in the tumors with periadnexal extension was 0.45 mm (mean, 0.4 mm). Median follow-up was 46 months for the periadnexal group and 44 months for the control group. Measures of clinical outcomes all showed trends for improved survival in the periadnexal extension group; these were melanoma-specific survival (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.44, 1.38), overall survival (HR, 0.91; 95% CI, 0.59, 1.41), disease-free survival (HR, 0.68; 95% CI, 0.45, 1.03), and distant disease-free survival (HR, 0.69; 95% CI, 0.4, 1.17), although none were statistically significant. There was a higher rate of sentinel lymph node (SLN) metastasis in the periadnexal group versus the control group in patients whose tumors were >1 mm thick (24/100=24% vs. 23/187=12.3%). Periadnexal extension was significantly associated with SLN metastasis on univariate logistic regression analysis (odds ratio [95% CI], 2.25 [1.20, 4.24], P=0.01). If the periadnexal extension had been included in the measurement of tumor thickness, 42.8% of patients would have been upstaged to a higher American Joint Committee on Cancer T category. The findings of this study indicate that periadnexal involvement that extends more deeply than the thickness of the main tumor mass increases the risk of SLN metastasis in tumours >1 mm thick, however, does not worsen clinical outcomes overall, and tumor thickness measurements should not include deeper foci of periadnexal tumor.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BrwbTu