Αρχειοθήκη ιστολογίου

Πέμπτη 7 Δεκεμβρίου 2017

A new T2 lesion in a patient with the clinically isolated syndrome does not necessarily imply a conversion to multiple sclerosis

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Publication date: Available online 7 December 2017
Source:Clinical Neurology and Neurosurgery
Author(s): Fioravante Capone, Marco Puthenparampil, Carlo Augusto Mallio, Alessandra Celia, Lucia Florio, Paolo Gallo, Vincenzo Di Lazzaro
In the follow-up of patients with the clinically isolated syndrome, both clinical and MRI findings should be carefully evaluated by clinicians to avoid misinterpretation and inappropriate diagnosis of multiple sclerosis. We describe a case of a patient with a previous diagnosis of clinically isolated syndrome who developed a new asymptomatic brain lesion at the MRI follow-up. The careful evaluation of clinical history and radiological findings allowed the correct diagnosis of cocaine-associated ischemic stroke. Our case highlights that, in patients with the clinically isolated syndrome, the appearance of a new lesion on MRI does not necessarily imply a conversion to multiple sclerosis. Among "better explanations", ischemic lesions are of relevance and, in patients without typical risk factors for stroke, rarer causes such as cocaine assumption should be considered.



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Multimodality Treatment of Intradural Extramedullary Ewing’s Sarcomas. A Systematic Review

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Publication date: Available online 7 December 2017
Source:Clinical Neurology and Neurosurgery
Author(s): Konstantinos N. Paterakis, Alexandros Brotis, Efthimios Dardiotis, Theofanis Giannis, Christos Tzerefos, Kostas N. Fountas
Ewing's sarcoma (ES) is an aggressive bone and soft tissue sarcoma that usually affects adolescents and young adults. ES occasionally presents as an intradural-extramedullary lesion of the spine. Our aim was to study the role of the multimodality treatment on the survival (overall survival, recurrence-free survival, and metastasis-free survival) of patients with intradural-extramedullary Ewing's sarcoma. Pubmed, EMBASE, Scopus, Web of Science, Cochrane Reviews were searched up to January 2017, using as mesh terms "intradural extramedullary", "Ewing's sarcoma", AND "treatment". The multidisciplinary treatment was recorded in binary variables under the headings of "surgery", "chemotherapy" and "radiotherapy". We also recorded three time-to-event variables, including death, recurrence, and metastasis. We performed survival analysis for all potential combinations. Twenty articles with twenty-three patients were eligible for the current review. The survival curves of GTR did not differ from the equivalent of STR regarding survival (p=0.098), recurrence-free survival (p=0.318), and metastasis-free survival (p=0.089). Patients who received chemotherapy enjoyed longer survival regarding overall survival (p<0.05), recurrence-free survival (p<0.05), and metastasis-free survival (p<0.05), when compared to those who did not receive chemotherapy. Their overall survival of patients who had radiotherapy was marginally superior to those who did not receive (p=0.0653). However, their recurrence-free survival (p<0.05), and metastasis-free survival (p<0.05) were significantly improved in comparison to the latter. In conclusion, the multimodality treatment is mandatory for the management of patients with intradural extramedullary Ewing's sarcomas, with surgery assisting in the diagnosis and decompression the neural elements. However, it is chemotherapy that improves survival, recurrence-free survival, and metastasis-free survival. Radiotherapy is reserved as an adjuvant therapy in the local control, especially in cases with subtotal tumour resection.



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Does radiotherapy prior to surgery improve long term prognosis in pediatric colorectal cancer in lower- and upper-middle income countries with limited resources? Our experience and literature review

Publication date: Available online 7 December 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Yacoob Omar Carrim, Luvo Gaxa, Francisca van der Schyff, Nndweleni Meshack Bida, Fareed Omar, Zarina Lockhat
Colorectal carcinoma in children and adolescents is extremely rare, with an annual incidence <0.3 cases per million, most frequently reported in the second decade of life. It accounts for severe morbidity and poor prognosis owing to the low index of suspicion, delayed diagnosis, advanced stage at presentation and the aggressive tumor nature. Patients present with abdominal pain, vomiting, constipation, abdominal distension, rectal tenesmus, iron-deficiency anemia, change in bowel habit and weight loss. Rectal bleeding is an uncommon presentation in children. Bowel obstruction presents frequently in children compared to adults. In 90% of pediatric cases, colorectal carcinoma occurs sporadically. In 10%, predisposing conditions and syndromes are identified. We present a case study of a 12-year-old female with advanced colorectal cancer without a predisposing disease or syndrome, who received radio-chemotherapy ten weeks prior to radical abdominopelvic surgery, followed by radio-chemotherapy postoperatively, with a positive outcome.



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Downregulation of Caspase 8 in a group of Iranian breast cancer patients – A pilot study

Publication date: Available online 7 December 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Masoumeh Aghababazadeh, Najmeh Dorraki, Fahimeh Afzal Javan, Asieh Sadat Fattahi, Masoumeh Gharib, Alireza Pasdar
PurposeIt is now well known that evading apoptosis, as a cancer hallmark, can lead to tumour initiation, progression and metastasis. As a result of genome wide association studies, an initiator protease in this pathway, caspase 8 (CASP8), has been found to be an important gene regarding breast cancer susceptibility. The alterations of the expression of this gene have been reported in breast cancer cell lines. Given that in previous studies expression analysis of this gene had only been done in breast cancer cell lines, in this study we aimed to evaluate the expression of this gene in breast cancer tissues versus adjacent normal tissues, using real-time quantitative method.MethodsCaspase 8 mRNA expression was quantified using comparative RT-qPCR in 27 fresh frozen breast tumours and 27 adjacent normal tissues. Moreover, relationship between the expression changes of CASP8 in tumour tissue and various clinical and pathological features were evaluated in an Iranian population.ResultsThe present study showed that expression of CASP8 was significantly reduced in tumour tissues compared to neighbouring normal tissues (p = .004). CASP8 expression was significantly correlated with the status of hormone receptors (ER and PR).ConclusionTo the best of our knowledge, this study is the first report on reduced expression of CASP8 in breast cancer versus adjacent normal tissues. Our data support previous results obtained from cell lines and therefore highlights the seminal role of the induction of CASP8 expression, as a novel therapeutic approach, in order to sensitize tumour cells to apoptotic stimuli.



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Cytological diagnosis of a rare case of cutaneous metastasis from transitional cell carcinoma, renal pelvis

Publication date: Available online 7 December 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Pragya Singh, Sachin Kolte, Gunjesh Kumar Singh
Transitional cell carcinoma (TCC) arising from renal pelvis rarely gives rise to cutaneous metastasis. Due to the insufficient literature, the exact incidence is not known till date. Moreover, the diagnosis is confirmed on histopathological examination with the aid of immunohistochemistry wherever needed. We are presenting a case of a 70-year-old female with metastatic TCC from the renal pelvis to the abdominal skin, which was diagnosed on cytology alone along with the cell block preparation. We also highlight the important cytomorphological and immunohistochemical features noted, which need to be known to avoid any diagnostic delay.



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Lymphoepithelioma-like Carcinoma of the Uterine Cervix: Cytomorphologic Features and Diagnostic Pitfalls by Liquid-Based Cytology

Lymphoepithelioma-like carcinoma (LELC) is a rare variant of cervical squamous cell carcinoma with unclear HPV and EBV association. Due to the accompanying and often obscuring lymphocytic inflammation, malignant cells may be difficult to recognize on cytologic samples and can mimic several more common benign and atypical cervical lesions. In this case report, we describe the cytomorphologic findings of LELC by liquid-based cytology in a 59-year-old Caucasian woman who was positive for high risk HPV but had no visible cervical lesions. We also discuss the differential diagnosis, diagnostic pitfalls, and practical considerations for diagnosis.



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Bone Marrow Edema Syndrome Of The Medial Femoral Condyle Treated With Extracorporeal Shock Wave Therapy: A Clinical And MRI Retrospective Comparative Study

Publication date: Available online 7 December 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Matteo Vitali, Nadim Naim Rodriguez, Alberto Pedretti, Andreas Drossinos, Pierluigi Pironti, Gaia Di Carlo, Gianfranco Fraschini
ObjectiveTo determine the validity of Extracorporeal Shock Wave Therapy (ESWT) in the treatment of Bone Marrow Edema (BME) of the medial condyle of the kneeDesignRetrospectiveStudy SettingIRCCS San Raffaele Hospital, Orthopedics Outpatient ClinicParticipantsFifty-six symptomatic patients affected by bone marrow edema of the medial condyle of the knee. Patients were equally divided in a ESWT (Extracorporeal Shock Wave Therapy) treated group and a control group, which was managed conservatively.InterventionsExtracorporeal Shock Wave Therapy delivery to the medial condyle of the affected knee.Main Outcome MeasuresClinical and Functional assessment done with the use of the Knee Society Score (KSS), both clinical and functional scores. Pain was measured with Visual Analog Scale (VAS). Bone marrow edema area was measured with Magnetic Resonance Imaging before treatment and at 4 months follow-up.ResultsClinical evaluation of patients at final follow-up of 4 months post-treatment showed a significant improvement (p< 0.0001) of symptoms and knee functionality, both for range of motion and strength in both groups VAS values saw a significant improvement (p< 0.0001) in both groups; with 3 patients in the ESWT group being pain-free (VAS=0) at 4 months follow-up. At 4 months MRI assessments on both sagittal and coronal views showed a significant reduction in bone marrow edema in the ESWT as compared to the control group.ConclusionOur findings show that this type of therapy has shown to be a valid non-pharmacological and non-invasive therapy in the treatment of spontaneous BME of the medial condyle, producing an improvement of the affected vascular and metabolic state present in this pathology through its metabolic mechanisms of action.



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Comparison of neuroplastic responses to cathodal transcranial direct current stimulation and continuous theta burst stimulation in subacute stroke

Publication date: Available online 7 December 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Pierre Nicolo, Cécile Magnin, Elena Pedrazzini, Gijs Plomp, Anaïs Mottaz, Armin Schnider, Adrian G. Guggisberg
ObjectiveTo investigate the effects of cathodal transcranial direct current stimulation (tDCS) and continuous theta burst stimulation (cTBS) on neural network connectivity and motor recovery in individuals with subacute stroke.DesignDouble-blinded, randomized, placebo-controlled study.SettingStroke subjects recruited through a university hospital rehabilitation program.ParticipantsStroke inpatients (N=41; mean age 65y, range 28-85; mean weeks poststroke 5, range 2-10) with resultant paresis in the upper extremity (mean Fugl-Meyer score 14, range 3-48).InterventionStroke subjects were randomly assigned to neuronavigated cTBS (N=14), cathodal tDCS (N=14), or sham TMS/sham tDCS (N=13) over the contralesional primary motor area (M1). Each subject completed nine stimulation sessions over three weeks, combined with physical therapy.Main outcome measuresBrain function was assessed with resting-state directed and non-directed functional connectivity based on high-density electroencephalography (EEG) before and after stimulation sessions. Primary clinical endpoint was the change in slope of multifaceted motor score composed of the Upper-Extremity Fugl-Meyer Assessment (UE-FMA), Box and Block test (BBT), Nine Hole Peg Test (NHPT), Jamar dynamometer between the baseline period and the treatment time.ResultsNeither stimulation treatment enhanced clinical motor gains. Cathodal tDCS and cTBS induced different neural effects. Only cTBS was able to reduce transcallosal influences from the contralesional to the ipsilesional M1 during rest. Conversely, tDCS enhanced perilesional beta-band oscillation coherence as compared to cTBS and sham groups. Correlation analyses indicated that the modulation of interhemispheric driving and perilesional beta-band connectivity were not independent mediators for functional recovery across all patients. However, exploratory subgroup analyses suggest that the enhancement of perilesional beta-band connectivity through tDCS might have more robust clinical gains if started within the first 4 weeks after stroke.ConclusionsThe inhibition of the contralesional primary motor cortex or the reduction of interhemispheric interactions was not clinically useful in heterogeneous group of subacute stroke subjects. An early modulation of perilesional oscillation coherence seems to be a more promising strategy for brain stimulation interventions.



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Editorial Board

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Publication date: December 2017
Source:Annales de Chirurgie Plastique Esthétique, Volume 62, Issue 6





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Author Index to Volume 119, 2017

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Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6





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Development of a brief assessment of activity limitations in children with food allergy

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Publication date: Available online 6 December 2017
Source:Annals of Allergy, Asthma & Immunology
Author(s): Catherine C. Peterson, Lauren E. Harrison




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IgG4-related disease presenting as hoarseness and postcricoid ulcer

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Publication date: Available online 6 December 2017
Source:Annals of Allergy, Asthma & Immunology
Author(s): Syeda Hamadani, Beverly Wang, Sudhir Gupta




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Effect of inhaled allergens and air pollutants on childhood rhinitis development

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Publication date: Available online 6 December 2017
Source:Annals of Allergy, Asthma & Immunology
Author(s): Hui Zhou, Xia (Iona) Li, Jeong Hee Kim, Muhammad T. Salam, Hyo Bin Kim, Rob S. McConnell, Rima Habre, Tracy Bastain, Shohreh F. Farzan, Jill Johnston, Frank D. Gilliland




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Information for Readers

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Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6





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Table of Contents

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Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6





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rAsp f 3 and rAsp f 4 are associated with bronchiectasis in allergic fungal airways disease

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Publication date: Available online 7 December 2017
Source:Annals of Allergy, Asthma & Immunology
Author(s): Kerry Woolnough, Michelle Craner, Catherine H. Pashley, Andrew J. Wardlaw




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Instructions for Authors

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Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6





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Toxocara species exposure, symptoms of asthma, and fractional exhaled nitric oxide in the US population

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Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6
Author(s): Funmilola Ogundipe, Edward Christian Anselm Hennis, Alem Mehari, Richard F. Gillum




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Editorial Board

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Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6





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Could calcium channel blockers treat 2 illnesses with 1 pill?

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Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6
Author(s): John Oppenheimer, H. William Kelly




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Baseline asthma burden, comorbidities, and biomarkers in omalizumab-treated patients in PROSPERO

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Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6
Author(s): John J. Oppenheimer, Paul A. Greenberger




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Increasing our knowledge base of asthma

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Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6
Author(s): John J. Oppenheimer, Gailen D. Marshall




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Innate lymphoid cells and allergic disease

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Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6
Author(s): Matthew T. Stier, R. Stokes Peebles




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Rare cause of periorbital and eyelids lesions: Discoid lupus erythematosus misdiagnosed as allergy

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Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6
Author(s): Anzelika Chomiciene, Ruta Stankeviciute, Laura Malinauskiene, Jurate Grigaitiene, Audra Blaziene




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Spectrum and prevalence of reactions to marijuana in a Colorado allergy practice

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Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6
Author(s): William S. Silvers, Tiana Bernard




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Baseline asthma burden, comorbidities, and biomarkers in omalizumab-treated patients in PROSPERO

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Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6
Author(s): Bradley E. Chipps, Robert S. Zeiger, Allan T. Luskin, William W. Busse, Benjamin L. Trzaskoma, Evgeniya N. Antonova, Hooman Pazwash, Susan L. Limb, Paul G. Solari, Noelle M. Griffin, Thomas B. Casale
BackgroundPatients included in clinical trials do not necessarily reflect the real-world population.ObjectiveTo understand the characteristics, including disease and comorbidity burden, of patients with asthma receiving omalizumab in a real-world setting.MethodsThe Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab (PROSPERO) was a US-based, multicenter, single-arm, and prospective study. Patients (≥12 years of age) with allergic asthma initiating omalizumab treatment based on physician-assessed need were included and followed for 12 months. Exacerbations, health care use, adverse events, and Asthma Control Test (ACT) scores were assessed monthly. Biomarkers (blood eosinophils, fractional exhaled nitric oxide, and periostin) were evaluated and patient-reported outcomes (Asthma Quality of Life Questionnaire for 12 Years and Older [AQLQ+12] and Work Productivity and Activity Impairment: Asthma questionnaire [WPAI:Asthma]) were completed at baseline and months 6 and 12. The Mini Rhinoconjunctivitis Quality of Life Questionnaire (MiniRQLQ) was completed at baseline and 12 months.ResultsMost of the 806 enrollees (91.4%) were adults (mean age 47.3 years, SD 17.4), white (70.3%), and female (63.5%). Allergic comorbidity was frequently reported (84.2%), as were hypertension (35.5%) and depression (22.1%). In the 12 months before study entry, 22.1% of patients reported at least 1 asthma-related hospitalization, 60.7% reported at least 2 exacerbations, and 83.3% reported ACT scores no higher than 19 (uncontrolled asthma). Most patients had low biomarker levels based on prespecified cut-points. Baseline mean patient-reported outcome scores were 4.0 (SD 1.4) for AQLQ+12, 2.7 (SD 1.4) for MiniRQLQ, and 47.7 (SD 28.9) for WPAI:Asthma percentage of activity impairment and 33.5 (SD 28.7) for percentage of overall work impairment.ConclusionThe population initiating omalizumab in PROSPERO reported poorly controlled asthma and a substantial disease burden.Trial RegistrationClinicalTrials.gov Identifier: NCT01922037.



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The clinical role of fractional exhaled nitric oxide in asthma control

Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6
Author(s): Suguru Sato, Junpei Saito, Atsuro Fukuhara, Manabu Uematsu, Yasuhito Suzuki, Ryuichi Togawa, Yuki Sato, Takefumi Nikaido, Xintao Wang, Yoshinori Tanino, Mitsuru Munakata
BackgroundThe potential role and characteristics of fractional exhaled nitric oxide (FeNO) remain unclear in the treatment of asthma.ObjectiveTo explore the clinical role of FeNO in asthmatic treatment.MethodsWe evaluated whether the mean or change of FeNO levels in the treatment period is associated with other conventional control parameters and predicted some clinical outcomes of asthma. We retrospectively analyzed the mean and percentage change of FeNO levels in the first 5 measurements at our hospital.ResultsThe study found a significantly strong correlation between FeNO level at diagnosis and the largest changes of FeNO values from diagnosis. No significant correlations were observed between FeNO levels and other parameters (Asthma Control Test [ACT] score or forced expiratory volume in one second [FEV1]) in mean and percentage change of values under treatment of asthma; however, significant positive correlations were found between ACT scores and FEV1. The mean FeNO level revealed a significant negative correlation with an annual change in FEV1 in individuals with asthma who were followed up for more than 2 years. Both the mean ACT score and percent predicted FEV1 revealed a significant negative correlation with occasional use of systemic corticosteroids.ConclusionDuring conventional treatment of asthma, the largest changes of FeNO values from diagnosis were strongly correlated with FeNO levels at diagnosis. As for the unlikely conventional parameters, no significant associations were observed between FeNO levels and deterioration of asthma during the treatment periods. An elevated mean FeNO level may be a marker of decreased lung function in individuals with asthma.



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Burden of skin pain in atopic dermatitis

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Publication date: December 2017
Source:Annals of Allergy, Asthma & Immunology, Volume 119, Issue 6
Author(s): Paras P. Vakharia, Rishi Chopra, Ryan Sacotte, Kevin R. Patel, Vivek Singam, Neha Patel, Supriya Immaneni, Takeshia White, Robert Kantor, Derek Y. Hsu, Jonathan I. Silverberg
BackgroundAtopic dermatitis (AD) is associated with itch, skin inflammation and barrier disruption, and scratching, all of which may be associated with skin pain.ObjectiveTo characterize the patient burden of skin pain in AD.MethodsWe performed a prospective dermatology practice–based study using questionnaires and evaluation by a dermatologist.ResultsOverall, 305 patients (age range, 13–97 years) were included in the study, with 564 encounters. The cohort included 195 females (63.9%) and 193 whites (63.7%). The mean (SD) age at enrollment was 42.3 (18.1) years, and the mean (SD) age of patient-reported AD onset was 29.6 (31.9) years. At baseline, 144 patients (42.7%) reported skin pain in the past week, with 42 (13.8%) reporting severe or very severe pain. Twenty-four (16.8%) thought the skin pain was part of their itch, 16 (11.2%) from scratching, and 77 (72.0%) from both. Patients with skin pain were more likely to describe their itch using terms that resembled neuropathic pain. Prevalence of skin pain was increased in patients with vs without excoriations (72.6% vs 57.6%; χ2 test P = .02) but not other morphologic characteristics. Skin pain severity was most strongly correlated with the Patient-Oriented Eczema Measure (Spearman ρ = 0.54), followed by ItchyQOL (ρ = 0.52), 5-dimensions of itch scale (ρ = 0.47), Dermatology Life Quality Index (ρ = 0.45), numeric rating scale for itch (ρ = 0.43) and sleep (ρ = 0.36), Patient Health Questionnaire 9 (ρ = 0.36), patient-reported global AD severity (ρ = 0.34), Eczema Area and Severity Index (ρ = 0.23), and objective Scoring AD index (ρ = 0.20) (P < .001 for all). Patients with both severe itch and pain vs those with only one or neither symptom being severe had significant increases in all these measures.ConclusionSkin pain is a common and burdensome symptom in AD. Skin pain severity should be assessed with itch severity in AD patients and may be an important end point for monitoring treatment response.



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Trastuzumab emtansine: determining its role in management of HER2+ breast cancer

Future Oncology, Ahead of Print.


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Disrupted circuits in mouse models of autism spectrum disorder and intellectual disability

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Publication date: February 2018
Source:Current Opinion in Neurobiology, Volume 48
Author(s): Carla EM Golden, Joseph D Buxbaum, Silvia De Rubeis
Autism spectrum disorder (ASD) and intellectual disability (ID) are caused by a wide range of genetic mutations, a significant fraction of which reside in genes important for synaptic function. Studies have found that sensory, prefrontal, hippocampal, cerebellar, and striatal regions, as well as the circuits that connect them, are perturbed in mouse models of ASD and ID. Dissecting the disruptions in morphology and activity in these neural circuits might help us to understand the shared risk between the two disorders as well as their clinical heterogeneity. Treatments that target the balance between excitation and inhibition in these regions are able to reverse pathological phenotypes, elucidating this deficit as a commonality across models and opening new avenues for intervention.



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Biography—Q. Ping Dou



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Aesthetic Outcomes in Delayed Breast Reconstruction

Achieving excellent aesthetic outcomes in delayed breast reconstruction can be challenging. Which surgical maneuvers can help attain these results?
Plastic Reconstructive Surgery-Global Open (PRS Global Open)

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Factors necessary for independent walking in patients with thalamic hemorrhage

Thalamic hemorrhages cause motor paralysis, sensory impairment, and cognitive dysfunctions, all of which may significantly affect walking independence. We examined the factors related to independent walking in...

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Anterior sacral meningocele infected with Fusobacterium in a patient with recently diagnosed colorectal carcinoma – a case report

Anterior sacral meningoceles are rare, and usually occur with other malformations of the posterior lower spine. While these are more frequently reported in pediatric cohorts, we report a case in an elderly woman.

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Cross sectional study of serum selenium concentration and esophageal squamous dysplasia in western Kenya

Abstract

Background

Low serum selenium status has been associated with increased risk of esophageal squamous cell carcinoma (ESCC). East Africa is a region of high ESCC incidence and is known to have low soil selenium levels, but this association has not previously been evaluated. In this study we assessed the association of serum selenium concentration and the prevalence of esophageal squamous dysplasia (ESD), the precursor lesion of ESCC, in a cross-sectional study of subjects from Bomet, Kenya.

Methods

294 asymptomatic adult residents of Bomet, Kenya completed questionnaires and underwent endoscopy with Lugol's iodine staining and biopsy for detection of ESD. Serum selenium concentrations were measured by instrumental neutron activation analysis. Odds ratios (OR) and confidence intervals (95% CI) for associations between serum selenium and ESD were calculated using unconditional logistic regression.

Results

The mean serum selenium concentration was 85.5 (±28.3) μg/L. Forty-two ESD cases were identified (14% of those screened), including 5 (12%) in selenium quartile 1 (Q1), 5 (12%) in Q2, 15 (36%) in Q3, and 17 (40%) in Q4. Higher serum selenium was associated with prevalence of ESD (Q4 vs Q1: OR: 3.03; 95% CI: 1.05–8.74) and this association remained after adjusting for potential confounders (Q4 vs Q1: OR: 3.87; 95% CI: 1.06–14.19).

Conclusion

This is the first study to evaluate the association of serum selenium concentration and esophageal squamous dysplasia in an African population at high risk for ESCC. We found a positive association between higher serum selenium concentration and prevalence of ESD, an association contrary to our original hypothesis. Further work is needed to better understand the role of selenium in the etiology of ESCC in this region, and to develop effective ESCC prevention and control strategies.



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Anatomic parameters of the sacral lamina for osteosynthesis in transverse sacral fractures

Abstract

Purpose

To analyze the morphometric parameters of the dorsal sacral lamina and pedicles to determine if there is adequate bony architecture to support plate osteosynthesis.

Methods

Two reviewers performed measurements on 98 randomly selected high-resolution CT scans of the pelvis to quantify the bony anatomy of the sacral lamina. Measurements included the depths of the lamina at each sacral level, the trajectory and depth of the sacral pedicles from the sacral lamina, and the width of the sacral canal. A bone mineral density analysis was performed on the sacral lamina using Hounsfield units (HU) and compared to the L1 and S1 vertebral bodies.

Results

The sacral lamina were found to form peaks and troughs which we refered to as major and minor sections. On average, the thickness was > 4 mm at all major screw starting points, indicating adequate geometry for screw fixation. The sacral pedicle depths were 27, 18, 16, and 14 mm at S2–S5, respectively. The average angulation from midline of this screw path directed laterally to avoid the sacral canal was 20°, 17°, 8°, and − 8° for the S2–5 pedicles, respectively. Average sacral canal diameter was 11 mm for S2 and 8 mm for S3–5. The sacral lamina had an average bone mineral density of 635 HU, which was significantly different from the density of the L5 (220 HU) and S1 (165 HU) vertebral bodies (p < 0.005). This morphometric data was used to pilot a new plating technique.

Conclusions

The sacral lamina offers a novel target for screw fixation and meets the basic geometric and compositional criteria for screw purchase. To our knowledge, this study represents the first morphometric analysis performed on the sacral lamina and pedicles for plate application.



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Comparison of transcanal endoscopic tympanoplasty with sterile acellular dermal allograft to conventional endaural microscopic tympanoplasty with tragal perichondrium

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Publication date: Available online 7 December 2017
Source:American Journal of Otolaryngology
Author(s): Jia Min, Se-Hyung Kim
ObjectivesThis study aimed to compare the outcome of endoscopic tympanoplasty with sterile acellular dermal allograft (ADA) and conventional endaural microscopic tympanoplasty with tragal perichondrium.MethodsThis was a retrospective comparative study of 53 patients (25 males and 28 females) with tympanic membrane perforation who underwent type I tympanoplasty in the department of otorhinolaryngology at a tertiary medical center from March 2011 to April 2017. The subjects were classified into two groups; transcanal endoscopic tympanoplasty with ADA (TET, n=26), conventional endaural microscopic tympanoplasty with autologous tragal perichondrium (EMT, n=27). Demographic data, perforation size of tympanic membrane at preoperative state, pure tone audiometric results preoperatively and 3months postoperatively, operation time, sequential postoperative pain scale, and postoperative graft failure rate were evaluated.ResultsThe perforation size of the tympanic membrane in TET and EMT group was 22.3±10.9% and 23.5±9.7%, respectively (P=0.143). Mean operation time of EMT (92.3±16.5min) was longer than that of the TET (65.3±20.5min) with a statistical significance (P=0.004). Graft success rate in the TET and EMT group were 92.3% and 96.3%, respectively; the values were not significantly different (P=0.610). Pre- and postoperative audiometric results including bone and air conduction thresholds and air-bone gap were not significantly different between the groups. In all groups, the postoperative air-bone gap was significantly improved compared to the preoperative air-bone gap. Pain in the immediate postoperative and day 1 after surgery were significantly less in the TET group.ConclusionWith human cadaveric ADA, minimal invasive endoscopic tympanoplasty can be achieved with similar postoperative results and less pain.



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Is an endoscopic or a microscopic approach optimal for management of attic cholesteatoma?

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Publication date: Available online 8 December 2017
Source:American Journal of Otolaryngology
Author(s): Zhengcai-LouZihan-LouZhenqi-Gong




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Calcification of Thoracic and Abdominal Aneurysms is Associated with Mortality and Morbidity

Publication date: Available online 7 December 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Mohammed M. Chowdhury, Lukasz P. Zieliński, James J. Sun, Simon Lambracos, Jonathan R. Boyle, Seamus C. Harrison, James H.F. Rudd, Patrick A. Coughlin
IntroductionCardiovascular events are common in people with aortic aneurysms. Arterial calcification is a recognised predictor of cardiovascular outcomes in coronary artery disease. Whether calcification within abdominal and thoracic aneurysm walls is correlated with poor cardiovascular outcomes is not known.Patients and methodsCalcium scores were derived from computed tomography (CT) scans of consecutive patients with either infrarenal (AAA) or descending thoracic aneurysms (TAA) using the modified Agatston score. The primary outcome was subsequent all cause mortality during follow-up. Secondary outcomes were cardiovascular mortality and morbidity.ResultsA total of 319 patients (123 TAA and 196 AAA; median age 77 [71–84] years, 72% male) were included with a median follow-up of 30 months. The primary outcome occurred in 120 (37.6%) patients. In the abdominal aortic aneurysm group, the calcium score was significantly related to both all cause mortality and cardiac mortality (odds ratios (OR) of 2.246 (95% CI 1.591–9.476; p < 0.001) and 1.321 (1.076–2.762; p = 0.003)) respectively. In the thoracic aneurysm group, calcium score was significantly related to all cause mortality (OR 6.444; 95% CI 2.574–6.137; p < 0.001), cardiac mortality (OR 3.456; 95% CI 1.765–4.654; p = 0.042) and cardiac morbidity (OR 2.128; 95% CI 1.973–4.342; p = 0.002).ConclusionsAortic aneurysm calcification, in either the thoracic or the abdominal territory, is significantly associated with both higher overall and cardiovascular mortality. Calcium scoring, rapidly derived from routine CT scans, may help identify high risk patients for treatment to reduce risk.



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Re: “Catheter Foam Sclerotherapy of Great Saphenous Vein, with Peri-saphenous Tumescence Infiltration and Saphenous Irrigation”

Publication date: Available online 7 December 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): A. Cavezzi, G. Mosti, F. Campana, L. Tessari, L. Bastiani, S.U. Urso




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A Rare Cause of Critical Limb Ischaemia: An Aneurysmal Persistent Sciatic Artery

Publication date: Available online 7 December 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Gabriele Pagliariccio, Luciano Carbonari




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Late Open Surgical Conversion after Endovascular Abdominal Aortic Aneurysm Repair

Publication date: Available online 7 December 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Vinay Kansal, Sudhir Nagpal, Prasad Jetty
IntroductionLate open surgical conversion following endovascular aneurysm repair (EVAR) may occur more frequently after performing EVAR in anatomy outside the instructions for use (IFU). This study reviews predictors and outcomes of late open surgical conversion for failed EVAR.MethodsThis retrospective cohort study reviewed all EVARs performed at the Ottawa Hospital between January 1999 and May 2015. Open surgical conversions >1 month post EVAR were identified. Variables analysed included indication for conversion, pre-intervention AAA anatomy, endovascular device and configuration, operative technique, re-interventions, complications, and death.ResultsOf 1060 consecutive EVARs performed, 16 required late open surgical conversion. Endografts implanted were Medtronic Talent (8.50.0%), Medtronic Endurant (3.18.8%), Cook Zenith (4.25.0%), and Terumo Anaconda (1.6.2%). Eleven grafts were bifurcated (68.8%), five were aorto-uni-iliac (31.2%). The median time to open surgical conversion was 3.1 (IQR 1.0–5.2) years. There was no significant difference in pre-EVAR rupture status (1.4% elective, 2.1% ruptured, p = .54). Indications for conversion included: Type 1 endoleak with sac expansion (n = 4, 25.0%), Type 2 endoleak with expansion (n = 2, 12.5%), migration (n = 3, 18.8%), sac expansion without endoleak (n = 2, 12.5%), graft infection (n = 3, 18.8%), rupture (n = 2, 12.5%). Nine patients (56.2%) underwent stent graft explantation with in situ surgical graft reconstruction, seven had endograft preserving open surgical intervention. The 30 day mortality was 18.8% (n = 3, all of whom having had endograft preservation). Ten patients (62.5%) suffered major in hospital complications. One patient (6.5%) required post-conversion major surgical re-intervention. IFU adherence during initial EVAR was 43.8%, versus 79.0% (p < .01) among uncomplicated EVARs.ConclusionsOpen surgical conversion following EVAR results in significant morbidity and mortality. IFU adherence of EVARs later requiring open surgical conversion is markedly low. More data are required to elucidate the impact of increasing liberalisation of EVAR outside of IFU.



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Anatomic parameters of the sacral lamina for osteosynthesis in transverse sacral fractures

Abstract

Purpose

To analyze the morphometric parameters of the dorsal sacral lamina and pedicles to determine if there is adequate bony architecture to support plate osteosynthesis.

Methods

Two reviewers performed measurements on 98 randomly selected high-resolution CT scans of the pelvis to quantify the bony anatomy of the sacral lamina. Measurements included the depths of the lamina at each sacral level, the trajectory and depth of the sacral pedicles from the sacral lamina, and the width of the sacral canal. A bone mineral density analysis was performed on the sacral lamina using Hounsfield units (HU) and compared to the L1 and S1 vertebral bodies.

Results

The sacral lamina were found to form peaks and troughs which we refered to as major and minor sections. On average, the thickness was > 4 mm at all major screw starting points, indicating adequate geometry for screw fixation. The sacral pedicle depths were 27, 18, 16, and 14 mm at S2–S5, respectively. The average angulation from midline of this screw path directed laterally to avoid the sacral canal was 20°, 17°, 8°, and − 8° for the S2–5 pedicles, respectively. Average sacral canal diameter was 11 mm for S2 and 8 mm for S3–5. The sacral lamina had an average bone mineral density of 635 HU, which was significantly different from the density of the L5 (220 HU) and S1 (165 HU) vertebral bodies (p < 0.005). This morphometric data was used to pilot a new plating technique.

Conclusions

The sacral lamina offers a novel target for screw fixation and meets the basic geometric and compositional criteria for screw purchase. To our knowledge, this study represents the first morphometric analysis performed on the sacral lamina and pedicles for plate application.



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Can breast cancer patients with HER2 dual-equivocal tumours be managed as HER2-negative disease?

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Publication date: January 2018
Source:European Journal of Cancer, Volume 89
Author(s): Yiwei Tong, Xiaosong Chen, Xiaochun Fei, Lin Lin, Jiayi Wu, Ou Huang, Jianrong He, Li Zhu, Weiguo Chen, Yafen Li, Kunwei Shen
BackgroundIncreasing human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC)/fluorescence in situ hybridisation (FISH) dual-equivocal breast tumours are reported after the 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline update. The aim of this study is to investigate the clinico-pathologic characteristics, treatment patterns and disease outcome of these patients with HER2 dual-equivocal tumours.Patients and methodsPatients with HER2 IHC 2+ and available FISH results were retrospectively analysed from the Comprehensive Breast Health Center, Shanghai Ruijin Hospital. The 2013 ASCO/CAP guideline was applied to define HER2-positive, dual-equivocal and -negative groups. Patient characteristics, systemic treatment patterns and survival were compared among these groups. Reverse transcriptase-polymerase chain reaction-based assays were applied to test HER2 mRNA expression level.ResultsAmong 691 patients included, 133 (19.25%) were HER2 positive, 25 (3.62%) were HER2 dual-equivocal and 533 (77.13%) were HER2 negative. Univariate and multivariate analyses stated that HER2 dual-equivocal tumours shared more similarity with HER2-negative tumours, whereas HER2-positive tumours had rather different clinico-pathologic features. HER2 dual-equivocal tumours had similar HER2 mRNA levels compared with HER2-negative tumours (P = 0.26), which were much less compared with HER2-positive breast cancer. Besides, adjuvant systemic treatment patterns were comparable between HER2-negative and dual-equivocal tumours, and none of HER2 dual-equivocal patients received anti-HER2 treatment. There was no survival difference among these three groups (P = 0.43).ConclusionHER2 dual-equivocal tumours share more similarity with HER2-negative disease in terms of clinico-pathologic features, HER2 mRNA levels, adjuvant systemic treatment patterns and disease outcome, which deserves further clinical evaluation.



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Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: Evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer

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Publication date: January 2018
Source:European Journal of Cancer, Volume 89
Author(s): Andreas Schneeweiss, Stephen Chia, Tamas Hickish, Vernon Harvey, Alexandru Eniu, Maeve Waldron-Lynch, Jennifer Eng-Wong, Sarah Kirk, Javier Cortés
BackgroundWe report long-term efficacy and cardiac safety outcomes in patients with HER2-positive early breast cancer treated with neoadjuvant pertuzumab plus trastuzumab with anthracycline-containing or anthracycline-free chemotherapy.MethodsDescriptive efficacy analyses were conducted in patients randomised to group A (cycles 1–6: trastuzumab [8 mg/kg loading dose and 6 mg/kg maintenance] plus pertuzumab [840 mg loading dose and 420 mg maintenance], plus 5-fluorouracil, epirubicin and cyclophosphamide [FEC] [cycles 1–3; 500 mg/m2 5-fluorouracil/100 mg/m2 epirubicin/600 mg/m2 cyclophosphamide] then docetaxel [cycles 4–6; 75 mg/m2, escalated to 100 mg/m2 if well tolerated]), B (cycles 1–3: FEC, cycles 4–6: trastuzumab plus pertuzumab plus docetaxel as mentioned previously) or C (cycles 1–6: trastuzumab plus pertuzumab plus docetaxel [75 mg/m2, without dose escalation], and carboplatin [AUC 6]), five years after randomisation of the last patient. This study is registered with ClinicalTrials.gov, number NCT00976989.ResultsThree-year Kaplan–Meier survival estimates for disease-free survival (DFS) were 87% (95% confidence interval: 79–95), 88% (80–96) and 90% (82–97) in groups A–C, respectively. Progression-free survival (PFS) rates were 89% (81–96), 89% (81–96) and 87% (80–95). DFS hazard ratio for total pathological complete response (tpCR) versus no tpCR was 0.27 (0.11–0.64). During post-treatment follow-up, 2/72 (2.8%), 3/75 (4.0%) and 4/76 (5.4%) patients in groups A–C had any-grade left ventricular systolic dysfunction; eight (11.1%), 12 (16.0%) and nine (11.8%) patients experienced left ventricular ejection fraction declines ≥10% from baseline to <50%.ConclusionsLong-term DFS and PFS were similar between groups. Patients who achieved tpCR had improved DFS. No new safety signals were identified.



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Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma

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Publication date: January 2018
Source:European Journal of Cancer, Volume 89
Author(s): Maeve A. Lowery, David P. Kelsen, Marinela Capanu, Sloane C. Smith, Jonathan W. Lee, Zsofia K. Stadler, Malcolm J. Moore, Hedy L. Kindler, Talia Golan, Amiel Segal, Hannah Maynard, Ellen Hollywood, MaryEllen Moynahan, Erin E. Salo-Mullen, Richard Kinh Gian Do, Alice P. Chen, Kenneth H. Yu, Laura H. Tang, Eileen M. O'Reilly
PurposeBRCA-associated cancers have increased sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPis). This single arm, non-randomised, multicentre phase II trial evaluated the response rate of veliparib in patients with previously treated BRCA1/2- or PALB2-mutant pancreatic adenocarcinoma (PDAC).MethodsPatients with stage III/IV PDAC and known germline BRCA1/2 or PALB2 mutation, 1–2 lines of treatment, Eastern Cooperative Oncology Group 0–2, were enrolled. Veliparib was dosed at a volume of 300 mg twice-daily (N = 3), then 400 mg twice-daily (N = 15) days 1–28. The primary end-point was to determine the response rate of veliparib; secondary end-points included progression-free survival (PFS), duration of response, overall survival (OS) and safety.ResultsSixteen patients were enrolled; male N = 8 (50%). Median age was 52 years (range 43–77). Five (31%) had a BRCA1 and 11 (69%) had a BRCA2 mutation. Fourteen (88%) patients had received prior platinum-based therapy. No confirmed partial responses (PRs) were seen: one (6%) unconfirmed PR was observed at 4 months with disease progression (PD) at 6 months; four (25%) had stable disease (SD), whereas 11 (69%) had PD as best response including one with clinical PD. Median PFS was 1.7 months (95% confidence interval [CI] 1.57–1.83) and median OS was 3.1 months (95% CI 1.9–4.1). Six (38%) patients had grade III toxicity, including fatigue (N = 3), haematology (N = 2) and nausea (N = 1).ConclusionsVeliparib was well tolerated, but no confirmed response was observed although four (25%) patients remained on study with SD for ≥ 4 months. Additional strategies in this population are needed, and ongoing trials are evaluating PARPis combined with chemotherapy (NCT01585805) and as a maintenance strategy (NCT02184195).



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Enlisting the willing: A study of healthcare professional–initiated and opt-in biobanking consent reveals improvement opportunities throughout the registration process

Publication date: January 2018
Source:European Journal of Cancer, Volume 89
Author(s): Elizabeth A. Fradgley, Shu Er Chong, Martine E. Cox, Christine L. Paul, Craig Gedye
Biobanking consent processes should accord with patients' preferences and be offered in a consistent and systematic manner. However, these aims can be difficult to achieve under healthcare professionals' (HCPs) time-constrained workflows, resulting in low participation rates.This current perspective provides a brief overview of HCP involvement in consent and reports new data on participant attrition at each step of the biobanking consent process as experienced by 113 patients at an Australian tertiary cancer centre. To determine attrition in this HCP-driven consent process, we reviewed medical records for the following events: inclusion of biobanking consent forms; visible patient and HCP signatures; consent status selected (decline or accept) and specimen registration with local biobank. Accessible medical records revealed the following data: 75 of 85 records included viewable forms; 22 of 85 records included patient and 19 of 85 included HCP signatures; 15 of 85 records included signed and completed forms and 3 of 85 had samples banked with annotated clinical data. We compared these data with self-reported experiences of being approached to participate by HCPs. Of the 15 participants (17.6%) who successfully completed consent, only five could recall being asked and providing consent.The low enrolment rate is a considerable lost opportunity because most patients (59%) who were not asked to participate indicated they would have consented if asked. Furthermore, in comparing self-reported experiences with medical records, we believe cancer patients' preferences for participation are mismatched with actual biobanking enrolment, which has considerable attrition at each step in the consent process.



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Are pathological high-risk features in locally advanced rectal cancer a useful selection tool for adjuvant chemotherapy?

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Publication date: January 2018
Source:European Journal of Cancer, Volume 89
Author(s): Marloes Swets, Peter J.K. Kuppen, Erik J. Blok, Hans Gelderblom, Cornelis J.H. van de Velde, Iris D. Nagtegaal
BackgroundSeveral histological high-risk factors are used as an indication for adjuvant therapy in stage II colon cancer. Those and other factors, including lymphatic invasion, perineural invasion (PNI), venous invasion and tumour budding are associated with decreased outcome. In this study, we evaluated the prognostic and predictive values of these biomarkers in a cohort of rectal cancer patients.Materials and methodsThe trial-based cohort consisted of 221npTNM stage II–III rectal cancer patients, included in the PROCTOR/SCRIPT trial, a multicentre randomised phase III trial. Patients treated with neoadjuvant radiotherapy and TME surgery were randomised between adjuvant chemotherapy or observation. Lymphatic invasion, PNI, extramural venous invasion, intramural venous invasion and tumour budding were determined in standard tissue slides.ResultsThe presence of PNI (HR 3.36; 95% CI 1.82–6.21), extramural vascular invasion (HR 1.93; 95% CI 1.17–3.19) and tumour budding (HR 1.83, 95% CI 1.11–3.03) was associated with a significant worse overall survival. The presence of ≥2 adverse biomarkers resulted in a stronger prediction of adverse outcome in terms of overall survival (HR 2.82; 95% CI 1.66–4.79), disease-free survival (HR 2.27; 95% CI 1.47–3.48), and distant recurrence (HR 2.51; 95% CI 1.56–4.02). None of these markers alone or combined predicted a beneficial effect of adjuvant chemotherapy.DiscussionWe confirmed that several stage-independent biomarkers were significantly associated with a decreased outcome in rectal cancer patients. More importantly, these markers did not have predictive value and are thus not useful to select for adjuvant therapy in rectal cancer.



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Reviewers 2017

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Publication date: Available online 7 December 2017
Source:European Journal of Cancer





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Eighth American Joint Committee on Cancer (AJCC) melanoma classification: Let us reconsider stage III

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Publication date: Available online 7 December 2017
Source:European Journal of Cancer
Author(s): Jean Jacques Grob, Dirk Schadendorf, Paul Lorigan, Paolo Ascierto, James Larkin, Paul Nathan, Caroline Robert, Axel Hauschild, Jeffrey Weber, Adil Daud, Omid Hamid, Reinhard Dummer, Johan Hansson, Christoph Hoeller, Jacob Schachter, Alexander C.J. Van Akkooi, Claus Garbe




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Long-term adherence with psychiatric treatment among patients with psychogenic nonepileptic seizures

Summary

We conducted a prospective cohort study, examining long-term adherence with psychiatric treatment among patients with psychogenic nonepileptic seizures (PNES). Subjects diagnosed with documented PNES were scheduled for 4 psychiatric visits. Survival analysis was performed, and covariates were assessed for association with time to nonadherence using Cox proportional hazard regression analysis. One hundred twenty-three subjects were recruited and followed for up to 17 months. Eighty percent of subjects attended the first outpatient visit, 42% attended the second, 24% attended the third, and only 14% remained adherent through the fourth visit. Two covariates were associated with nonadherence: (1) a prior diagnosis of PNES (hazard ratio 1.57, P-value .046); (2) a lower score on the Brief Illness Perception Questionnaire (BIPQ), signifying lower concern about one's illness (hazard ratio 0.77 for every 10-point increment on the 80-point scale, P-value .008). Adherence with psychiatric treatment among patients with PNES is initially reasonably good but worsens rapidly over visits 2-4. Risk factors for nonadherence include a history of a prior diagnosis of PNES, and a lower level of concern about the illness as assessed by a lower score on the BIPQ.



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Randomized controlled study comparing the efficacy of rapid and slow withdrawal of antiepileptic drugs during long-term video-EEG monitoring

Summary

Objective

Antiepileptic drugs (AEDs) are routinely withdrawn during long-term video–electroencephalography (EEG) monitoring (LTM), to record sufficient number of seizures. The efficacy of rapid and slow AED taper has never been compared in a randomized control trial (RCT), which was the objective of this study.

Methods

In this open-label RCT, patients aged 2-80 years with drug-resistant epilepsy (DRE) were randomly assigned (1:1) to rapid and slow AED taper groups. Outcome assessor was blinded to the allocation arms. Daily AED dose reduction was 30% to 50% and 15% to <30% in the rapid and slow taper groups, respectively. The primary outcome was difference in mean duration of LTM between the rapid and slow AED taper groups. Secondary outcomes included diagnostic yield, secondary generalized tonic–clonic seizure (GTCS), 4- and 24- hour seizure clusters, status epilepticus, and need for midazolam rescue treatment. The study was registered with Clinical Trial Registry-India (CTRI/2016/08/007207).

Results

One hundred forty patients were randomly assigned to rapid (n = 70) or slow taper groups (n = 70), between June 13, 2016 and February 20, 2017. The difference in mean LTM duration between the rapid and slow taper groups was −1.8 days (95% confidence interval [CI] −2.9 to −0.8, P = .0006). Of the secondary outcome measures, time to first seizure (2.9 ± 1.7 and 4.6 ± 3.0 days in the rapid and slow taper groups respectively, P = .0002) and occurrence of 4-hour seizure clusters (11.9% and 2.9% in the rapid and slow taper groups, respectively, P = .04) were statistically significant. None of the other safety variables were different between the 2 groups. LTM diagnostic yield was 95.7% and 97.1%, in rapid and slow taper groups respectively (P = .46).

Significance

Rapid AED tapering has the advantage of significantly reducing LTM duration over slow tapering, without any serious adverse events.



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Reconstruction Special Edition, Issue 2

The following three articles comprise the second edition of a special series highlighting important aspects of Head and Neck Reconstruction. These peer-reviewed papers highlight current standards, unique practices, and quality and value projects within our field of head and neck reconstruction. The articles are grouped into three different categories: 1) Subsite reconstruction 2) Versatile microvascular free flaps and 3) Perioperative considerations.

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Editorial Board/Aims & Scope



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Psychometric validation of the Center for Epidemiological Studies Depression Scale in Head and Neck Cancer patients

Depression is a common complication in patients with cancer [1]. Studies have shown that patients with head and neck cancer (HNC) experience higher rates of depression than other groups with an incidence of 15–50% as compared to 15–25% in other cancers [2]. Depression associated with cancer treatment in HNC patients has also been shown to contribute to lower quality of life, high levels of fatigue, low motivation, and higher suicide rates [2]. Early detection of depression and treatment would facilitate better treatment outcomes and quality of life [3].

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Hypermethylated ZNF582 and PAX1 genes in oral scrapings collected from cancer-adjacent normal oral mucosal sites are associated with aggressive progression and poor prognosis of oral cancer

The estimated annual incidence of oral squamous cell carcinoma (OSCC) is approximately 275,000 new cases worldwide. OSCC is the eighth most prevalent cancer in the world [1]. In Taiwan, OSCC ranks fifth among the predominant cancers for both sexes and accounts for the fourth most common cancer for males [2]. Development of recurrent cancer and second primary cancer is one of the major causes of the poor 5-year overall survival of OSCC patients [3]. Therefore, it is crucial to find a biomarker that can predict the progression, recurrence, and prognosis of OSCC at its earliest stage.

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Definitive (chemo)radiotherapy is a curative alternative for standard of care in advanced stage squamous cell carcinoma of the oral cavity

Head and neck squamous cell carcinoma is the 7th most common cancer in men and the 9th most common cancer in women in The Netherlands. Per year, 900 out of 2900 head and neck cancer patients are diagnosed with oral cavity carcinoma (OCC) [1]. Although there has been a shift towards organ preservation treatment in other head and neck cancer subsites [2], the standard of care for advanced oral cavity cancer is surgery with adjuvant (chemo)radiotherapy (CRT). However, especially in patients with locally advanced disease, this surgery may lead to extensive mutilation and results in a disappointing 5-year overall survival of 65% in stage III and 37% in stage IV disease [3].

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Differential roles of kallikrein-related peptidase 6 in malignant transformation and ΔNp63β-mediated epithelial-mesenchymal transition of oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) accounts for approximately 3% of all malignancies worldwide [1]. Due to a high rate of local invasion and recurrence, the overall survival rate of OSCC patients has failed to substantially rise over the last decade [2]. Especially, locally advanced OSCC remains refractory and lethal in more than 50% cases [1]. Distant metastases are rarely found on initial presentation; therefore, locoregional disease control and the elucidation of the mechanism underlying OSCC invasion are critical to improving the survival rate of OSCC patients [3].

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Unplanned readmission following transoral robotic surgery

The Hospital Readmissions Reduction Program (HRRP), established by the Affordable Care Act, aims to reduce unplanned hospital readmissions by 20% and requires the Centers for Medicare and Medicaid Services to reduce payments to hospitals that do not meet a certain national benchmark for acceptable readmission rates [1]. Although head and neck oncologic procedures are not yet included in the HRRP, future expansion or iterations may affect otolaryngologists. Moreover, unplanned readmission negatively affects patient quality of life [2].

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Utilization of a pre-bent plate-positioning surgical guide system in precise mandibular reconstruction with a free fibula flap

Extensive repair of mandibular defects is challenging. Reconstructive options have included the use of microvascular free flaps, non-vascularized bone grafts, and alloplastic implants, including titanium reconstruction plates. In 1989, Hidalgo [1] reported the usefulness of free vascularized fibula flaps for mandibular reconstruction. This flap has many advantages, including a long pedicle, wide vessel diameter, sufficient bone components, and the ability to incorporate the skin paddle [2,3]. Since then, the fibula has been commonly chosen as the donor site for mandibular reconstruction.

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Cancer stem cell and its niche in malignant progression of oral potentially malignant disorders

Oral cancer, which is the sixth most common cancer, accounts for 300,000 cases worldwide [1]. A large proportion of oral cancer is preceded by the development of oral leukoplakia [2,3], an oral potentially malignant disorder (OPMD). The histologic progression of OPMD from hyperplasia, different grades of dysplasia to carcinoma-in-situ and invasive carcinoma and the associated genomic changes are well studied [4]. Cancer stem cells (CSCs) have been increasingly implicated in oral carcinogenesis and field cancerization [5], and are known to be regulated by stroma and endothelial cells constituting the CSC-niche [6,7].

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Delayed clinical complete response to intensity-modulated radiotherapy in nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is a common head and neck cancer in China, especially the southern regions, with 60,600 new cases reported in 2015 [1]. Unlike other head and neck cancers, radiotherapy (RT) is the primary treatment modality for non-disseminated NPC due to its anatomical location and sensitivity to radiation. The optimal time-point for assessing the tumor response to RT is very important in NPC, as it determines whether the patient has residual or persistent disease and whether salvage treatment should be initiated [2–4].

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Oncogenic DNA viruses found in salivary gland tumors

Salivary gland tumors (SGTs) are rare, extremely complex entities posing a major challenge for both pathologists and clinicians [1,2]. Despite intensive research beginning in the early '90, the etiology of SGTs is still unclear [3]. Several human DNA viruses, including human papillomaviruses (HPVs), herpes viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), and polyomaviruses, have been implicated in a wide variety of tumors, and the majority of these can be detected in saliva samples [4–7].

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Construction of mass spectra database and diagnosis algorithm for head and neck squamous cell carcinoma

Although complete tumor resection leads to improved prognosis in patients with head and neck squamous cell carcinoma (HNSCC), functional disabilities such as dysphagia and dysphonia are sometimes unavoidable. The risk of these complications can be minimized by careful dissection [1–4]. Intraoperative rapid diagnosis using frozen sections is the standard means of determining appropriate tumor margins [5,6]. This process requires several steps, including tissue freezing, cryosectioning, hematoxylin and eosin (H&E) staining, and microscopic examination, the whole process usually taking >30 min.

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Reconstruction of oral cavity defect using versatile buccinator myomucosal flaps in the treatment of cT2–3, N0 oral cavity squamous cell carcinoma: Feasibility, morbidity, and functional/oncological outcomes

In the surgical management of oral cavity squamous cell carcinoma (OCSCC), radical resection with adequate margins is paramount in achieving local control. To obtain microscopically clear margins >0.5 cm, additional resection of normal tissue >1.0–1.5 cm from the gross tumor border is recommended [1,2]. Therefore, defect size is always significantly larger than the tumor itself, and reconstruction is commonly required to establish form and function in the resected organ, with the exception of some T1 and T2 OCSCCs.

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Prognostic value of masticatory muscle involvement in nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy

In 2017, the UICC/AJCC published the 8th edition of their staging manual for NPC, which has gained universal acceptance. This is a revision based on the UICC/AJCC's 7th edition and the 2008 Chinese staging system. There are three important adjustments for primary tumor site (T) classifications: (1) T0 is added for Epstein-Barr virus (EBV)-positive cancers with cervical lymph node involvement and no identifiable primary tumor; (2) New evidence has confirmed the prognostic value of the prevertebral muscle in NPC patients with tumors designated as T2; (3) The previous T4 criteria of "masticator space" and "infratemporal fossa" are now replaced by a specific description of soft tissue involvement and tumors that invade the medial pterygoid muscle (MP) and/or the lateral pterygoid muscle (LP) are now down-staged as T2 [1].

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A network meta-analysis in comparing prophylactic treatments of radiotherapy-induced oral mucositis for patients with head and neck cancers receiving radiotherapy

Head and neck cancers (HNSCC) account for 5% of all cancers, and squamous cell carcinoma or a variant is the main histologic type in more than 90% of these tumors [1]. Single-modality treatment with surgery or radiotherapy is usually recommended for early disease (stage I or II). Due to complicated anatomy and the wide extension of local or regionally advanced disease, the combined treatment strategy of radical radiotherapy with chemotherapy or cetuximab [2] is a preferred option for unresectable disease.

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Humidification mitigates acute mucosal toxicity during radiotherapy when factoring volumetric parameters. Trans Tasman Radiation Oncology Group (TROG) RadioHUM 07.03 substudy

The rationale for domiciliary humidification during head and neck radiotherapy to ameliorate symptoms associated with mucositis using a high flow rate humidifier with nasal prong interface is based on principles of moist wound care, or in other words to reduce the impact of wound desiccation on tissue injury. This may help mitigate the intense pro-inflammatory environment characteristic of mucositis pathobiology [1,2]. Moisturisation aids nutrient delivery and facilitates migration of cells across epithelial surfaces during wound healing.

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Plasticity of oral mucosal cell sheets for accelerated and scarless skin wound healing

This study examined the potential utility of a newly developed oral mucosal cell sheet in skin excisional wounds. The oral mucosal cell sheet promoted wound healing with early wound closure and less scarring and demonstrated in vivo tissue plasticity through good adaptation in cutaneous wounds.

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Evaluation of the diagnostic efficacy and spectrum of autofluorescence of benign, dysplastic and malignant lesions of the oral cavity using VELscope

In individuals exposed to risk factors; the prevention and early detection of oral cancer play a significant role in increasing the survival rates [1,2]. In the absence of a definitive approach, screening of oral cancer is still largely based on conventional oral examination (COE) and scalpel biopsy in case of suspicious lesions [3,4]. Since visible changes in the oral mucosa are known to precede the development of virtually all oral squamous cell carcinomas (OSCCs), various adjunctive techniques have been introduced with the aim to assist in the detection of early cancerous mucosal changes that can be occult to visual inspection [5,6].

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Head and neck reconstruction with free flaps based on the thoracodorsal system

Evolution in the range of free flaps available for head and neck cancer has facilitated successful reconstructive surgery in increasingly demanding defects. Patients presenting with extensive primary or recurrent tumours, as well as cases of osteoradionecrosis, form a significant part of the head and neck reconstructive surgeon's practice. These cases often incorporate complex three-dimensional defects that include both osseous and soft tissue components as well as more than one epithelial surface (e.g.

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Results of a phase II randomized controlled clinical trial comparing efficacy of Cabazitaxel versus Docetaxel as second line or above therapy in recurrent head and neck cancer

Head and neck squamous cell cancer (SCCHN) is the fifth most common cancer worldwide and is the most common neoplasm in central Asia [1]. Head and neck malignancies are common in regions of the world where tobacco use and alcohol consumption is high [2]. The five-year survival ranges from 20 to 90% depending upon the subsite of origin and the clinical extent of disease [3]. Current therapy consists of surgery, radiotherapy and chemotherapy [3]. More than 60% patients develop recurrence in locally advanced head and neck cancer [4].

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How fast can treatment with overdentures improve the masticatory function and OHRQoL of atrophic edentulous patients? A 1-year longitudinal clinical study

Abstract

Objectives

The aim of this prospective clinical study was to evaluate the masticatory function (MF) and subjective perception of patients with poor denture-bearing tissue in relation to change and the time required to identify an improvement in these parameters after rehabilitation with mandibular overdentures (MO) by two narrow-diameter two-piece implants.

Material and methods

Twenty-three edentulous patients were selected for MO installation. The masticatory function (MF) was evaluated with the masticatory performance (MP) and swallowing threshold (ST) tests. In the MP test, each volunteer was instructed to masticate a portion of Optocal (standardized artificial test food) for 40 masticatory cycles. During the swallowing threshold test, the patients were instructed to chew a new portion of Optocal cubes until they felt the desire to swallow. The MF tests were performed while complete denture (CD) wearers (baseline) and 1, 3, 6, and 12 months after MO loading. In addition, the subjective perception was assessed through the questionnaires Dental Impact on Daily Living (DIDL), Geriatric Oral Health Assessment Index (GOHAI), and Oral Health Impact Profile in Edentulous (OHIP- EDENT) at the baseline and 3, 6, and 12 months after MO loading.

Results

A significant improvement in masticatory function (p < .05) was observed already in the first month of loading. Three months after MO loading, a significant improvement (< .05) was found in the subjective perception of patients. The effect size indicates that the MO had the greatest impact on the domains related to function and comfort of all questionnaires and in relation to psychosocial domain of the GOHAI. The level of patient satisfaction increased significantly after the MO loading and reached >90% satisfied patients at 12 months.

Conclusion

The MO improved both the MF of the patient and their oral health-related quality of life and satisfaction regarding the prosthesis in a short time period.



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PSAT1 is regulated by ATF4 and enhances cell proliferation via the GSK3β/β-catenin/cyclin D1 signaling pathway in ER-negative breast cancer

Abstract

Background

A growing amount of evidence has indicated that PSAT1 is an oncogene that plays an important role in cancer progression and metastasis. In this study, we explored the expression and function of PSAT1 in estrogen receptor (ER)-negative breast cancer.

Method

The expression level of PSAT1 in breast cancer tissues and cells was analyzed using real-time-PCR (RT-PCR), TCGA datasets or immunohistochemistry (IHC). The overall survival of patients with ER-negative breast cancer stratified by the PSAT1 expression levels was evaluated using Kaplan-Meier analysis. The function of PSAT1 was analyzed using a series of in vitro assays. Moreover, a nude mouse model was used to evaluate the function of PSAT1 in vivo. qRT-PCR and western blot assays were used to evaluate gene and protein expression, respectively, in the indicated cells. In addition, we demonstrated that PSAT1 was activated by ATF4 by chromatin immunoprecipitation (ChIP) assays.

Results

mRNA expression of PSAT1 was up-regulated in ER-negative breast cancer. A tissue microarray that included 297 specimens of ER-negative breast cancer was subjected to an immunohistochemistry assay, which demonstrated that PSAT1 was overexpressed and predicted a poor clinical outcome of patients with this disease. Our data showed that PSAT1 promoted cell proliferation and tumorigenesis in vitro and in vivo. We further found that PSAT1 induced up-regulation of cyclin D1 via the GSK3β/β-catenin pathway, which eventually led to the acceleration of cell cycle progression. Furthermore, ATF4 was also overexpressed in ER-negative breast cancers, and a positive correlation between the ATF4 and PSAT1 mRNA levels was observed in ER-negative breast cancers. We further demonstrated that knockdown of ATF4 by siRNA reduced PSAT1 expression. Finally, chromatin immunoprecipitation (ChIP) assays showed that PSAT1 was a target of ATF4.

Conclusions

PSAT1, which is overexpressed in ER-negative breast cancers, is activated by ATF4 and promotes cell cycle progression via regulation of the GSK3β/β-catenin/cyclin D1 pathway.



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Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxel

Abstract

Background

Docetaxel-based chemotherapy failure in advanced prostate carcinoma has partly been attributed to the resistance of prostate cancer (PC) cells to docetaxel-induced apoptosis. Hence, there is an urgent need to identify mechanisms of docetaxel chemoresistance and to develop new combination therapies.

Methods

miR-193a-5p level was evaluated by qPCR in prostate tissues and cell lines, and its expression in the tissues was also examined by in situ hybridization. PC cell line (PC3 cell) was transfected with miR-193a-5p mimic or its inhibitor, and then cell apoptosis and the expression of its downstream genes Bach2 and HO-1 were detected by TUNEL staining and Western blotting. Luciferase reporter assay was used to detect the effect of miR-193a-5p and Bach2 on HO-1 expression. Xenograft animal model was used to test the effect of miR-193a-5p and docetaxel on PC3 xenograft growth.

Results

miR-193a-5p was upregulated in PC tissues and PC cell lines, with significant suppression of PC3 cell apoptosis induced by oxidative stress. Mechanistically, miR-193a-5p suppressed the expression of Bach2, a repressor of the HO-1 gene, by directly targeting the Bach2 mRNA 3′-UTR. Docetaxel treatment modestly decreased Bach2 expression and increased HO-1 level in PC3 cells, whereas a modest increase of HO-1 facilitated docetaxel-induced apoptosis. Notably, docetaxel-induced miR-193a-5p upregulation, which in turn inhibits Bach2 expression and thus relieves Bach2 repression of HO-1 expression, partly counteracted docetaxel-induced apoptosis, as evidenced by the increased Bcl-2 and decreased Bax expression. Accordingly, silencing of miR-193a-5p enhanced sensitization of PC3 cells to docetaxel-induced apoptosis. Finally, depletion of miR-193a-5p significantly reduced PC xenograft growth in vivo.

Conclusions

Silencing of miR-193a-5p or blockade of the miR-193a-5p-Bach2-HO-1 pathway may be a novel therapeutic approach for castration-resistant PC.



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Targeting the cross-talk between Urokinase receptor and Formyl peptide receptor type 1 to prevent invasion and trans-endothelial migration of melanoma cells

Abstract

Background

Accumulating evidence demonstrates that the Urokinase Receptor (uPAR) regulates tumor cell migration through its assembly in composite regulatory units with transmembrane receptors, and uPAR88–92 is the minimal sequence required to induce cell motility through the Formyl Peptide Receptor type 1 (FPR1). Both uPAR and FPR1 are involved in melanoma tumor progression, suggesting that they may be targeted for therapeutic purposes. In this study, the role of the uPAR-FPR1 cross-talk to sustain melanoma cell ability to invade extracellular matrix and cross endothelial barriers is investigated. Also, the possibility that inhibition of the uPAR mediated FPR1-dependent signaling may prevent matrix invasion and transendothelial migration of melanoma cells was investigated.

Methods

Expression levels of uPAR and FPR1 were assessed by immunocytochemistry, Western Blot and qRT-PCR. Cell migration was investigated by Boyden chamber and wound-healing assays. Migration and invasion kinetics, trans-endothelial migration and proliferation of melanoma cells were monitored in real time using the xCELLigence technology. The agonist-triggered FPR1 internalization was visualized by confocal microscope. Cell adhesion to endothelium was determined by fluorometer measurement of cell-associated fluorescence or identified on multiple z-series by laser confocal microscopy. The 3D–organotypic models were set up by seeding melanoma cells onto collagen I matrices embedded dermal fibroblasts. Data were analyzed by one-way ANOVA and post-hoc Dunnett t-test for multiple comparisons.

Results

We found that the co-expression of uPAR and FPR1 confers to A375 and M14 melanoma cells a clear-cut capability to move towards chemotactic gradients, to cross extracellular matrix and endothelial monolayers. FPR1 activity is required, as cell migration and invasion were abrogated by receptor desensitization. Finally, melanoma cell ability to move toward chemotactic gradients, invade matrigel or fibroblast-embedded collagen matrices and cross endothelial monolayers are prevented by anti-uPAR84–95 antibodies or by the RI-3 peptide which we have previously shown to inhibit the uPAR84–95/FPR1 interaction.

Conclusions

Collectively, our findings identify uPAR and FPR1 as relevant effectors of melanoma cell invasiveness and suggest that inhibitors of the uPAR84–95/FPR1 cross-talk may be useful for the treatment of metastatic melanoma.



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FAM198B is Associated with Prolonged Survival and Inhibits Metastasis in Lung Adenocarcinoma via Blockage of ERK-Mediated MMP-1 Expression

Purpose: The comprehensive understanding of mechanisms involved in the tumor metastasis is urgently needed for discovering novel metastasis-related genes for developing effective diagnoses and treatments for lung cancer. Experimental Design: FAM198B was identified from an isogenic lung cancer metastasis cell model by microarray analysis. To investigate the clinical relevance of FAM198B, the FAMB198B expression of 95 Taiwan lung adenocarcinoma patients was analyzed by quantitative real-time PCR and correlated to patients' survivals. The impact of FAM198B on cell invasion, metastasis and tumor growth was examined by in vitro cellular assays and in vivo mouse models. Additionally, the N-glycosylation-defective FAM198B mutants generated by site-directed mutagenesis was used to study protein stability and subcellular localization of FAM198B. Finally, the microarray and pathway analysis were used to elucidate the underlying mechanisms of FAM198B-mediated tumor suppression. Results: We found that the high expression of FAM198B was associated with favorable survival in Taiwan lung adenocarcinoma patients and in a lung cancer public database. Enforced expression of FAM198B inhibited cell invasion, migration, mobility, proliferation and anchorage-independent growth and FAM198B silencing exhibited opposite activities in vitro. FAM198B also attenuated tumor growth and metastasis in vivo. We further identified MMP-1 as a critical downstream target of FAM198B. The FAM198B-mediated MMP-1 downregulation was via inhibition of the phosphorylation of extracellular signal-regulated kinase (ERK). Interestingly Deglycosylation nearly eliminated the metastasis suppression activity of FAM198B due to a decrease of protein stability. Conclusions: Our results implicate FAM198B as a potential tumor suppressor and to be a prognostic marker in lung adenocarcinoma.



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The Impact of Smoking and TP53 mutations in lung adenocarcinoma patients with targetable mutations - the Lung Cancer Mutation Consortium (LCMC2)

PURPOSE Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas. PATIENTS AND METHODS Sixteen U.S. institutions enrolled 1367 lung cancer patients in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and immunohistochemistry. RESULTS The use of targeted therapies in patients with EGFR, ERBB2, or BRAF p.V600E mutations, ALK, ROS1 or RET rearrangements, or MET amplification was associated with a survival increment of 1.5 years compared to those with such mutations not receiving targeted therapy; and 1.0 year compared to those lacking a targetable driver. Importantly, 60 patients with a history of smoking derived similar survival benefit from targeted therapy for alterations in EGFR ALK/ROS1, when compared to 75 never smokers with the same alterations. In addition, co-existing TP53 mutations were associated with shorter survival among patients with EGFR, ALK, or ROS1 alterations. CONCLUSION Patients with adenocarcinoma of the lung and an oncogenic driver mutation treated with effective targeted therapy have a longer survival, regardless of prior smoking history. Molecular testing should be performed on all individuals with lung adenocarcinomas irrespective of clinical characteristics. Routine use of massively parallel sequencing enables detection of both targetable driver alterations and tumor suppressor gene and other alterations that have potential significance for therapy selection and as predictive markers for the efficacy of treatment.



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T cells expressing checkpoint receptor TIGIT are enriched in follicular lymphoma tumors and characterized by reversible suppression of T-cell receptor signaling

Purpose: T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing co-inhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets. Experimental Design: Surface expression of 9 co-inhibitory receptors governing T-cell function was characterized in T-cell subsets from FL lymph node tumors and from healthy donor tonsils and peripheral blood samples, using high-dimensional flow cytometry. The results were integrated with T-cell receptor (TCR)-induced signaling and cytokine production. Expression of TIGIT ligands were detected by immunohistochemistry. Results: TIGIT was a frequently expressed co-inhibitory receptor in FL, expressed by the majority of CD8 T effector memory cells, which commonly co-expressed exhaustion markers such as PD-1 and CD244. CD8 FL T cells demonstrated highly reduced TCR-induced phosphorylation (p) of ERK and reduced production of IFN-, while TCR proximal signaling (p-CD3, p-SLP76) was not affected. The TIGIT ligands CD112 and CD155 were expressed by follicular dendritic cells in the tumor microenvironment. Dysfunctional TCR signaling correlated with TIGIT expression in FL CD8 T cells, and could be fully restored upon in vitro culture. The co-stimulatory receptor CD226 was downregulated in TIGIT+ compared to TIGIT-CD8 FL T cells, further skewing the balance towards immunosuppression. Conclusions: TIGIT blockade is a relevant strategy for improved immunotherapy in FL. A deeper understanding of the interplay between co-inhibitory receptors and key T-cell signaling events can further assist in engineering immunotherapeutic regimens to improve clinical outcomes of cancer patients.



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First-in-human phase I study of single-agent vanucizumab, a first-in-class bi-specific anti-Ang-2/anti-VEGF antibody, in adult patients with advanced solid tumors

Purpose: Vanucizumab is an investigational anti-angiogenic, first-in-class, bi-specific monoclonal antibody targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies. Experimental Design: Patients received escalating bi-weekly (q2w; 3-30 mg/kg) or weekly (qw; 10-30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control. Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally-located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg q2w dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related Grade ≥3 toxicities. Toxicity was generally higher with qw than q2w dosing. A maximum tolerated dose of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6-9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in KTRANS (measured by dynamic contrast-enhanced-MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2000 mg q2w dose (phamacokinetically equivalent to 30 mg/kg q2w) was recommended for further investigation. Conclusion: Bi-weekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging anti-tumor activity in this heterogeneous population.



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Merkel cell carcinoma in the age of immunotherapy: Facts and hopes

Merkel cell carcinoma (MCC) is a rare (~2,000 US cases/year) but aggressive neuroendocrine tumor of the skin. For advanced MCC, cytotoxic chemotherapy only infrequently (<10% of cases) offers durable clinical responses (>1 year) suggesting a great need for improved therapeutic options. In 2008, the Merkel cell polyomavirus (MCPyV) was discovered and is clonally integrated in ~80% of MCC tumors. The remaining 20% of MCC tumors have large numbers of UV-associated mutations. Importantly, both the UV-induced-neoantigens in virus-negative tumors and the MCPyV T antigen oncogenes that are required for virus-positive tumor growth are immunogenic. Indeed, antigen-specific T cells detected in patients are frequently dysfunctional/'exhausted' and the inhibitory ligand, PD-L1, is often present in MCC tumors. These findings led to recent clinical trials involving PD-1 pathway blockade in advanced MCC. The combined data from these trials, involving three PD-1 pathway blocking agents (avelumab, pembrolizumab, and nivolumab) indicated a high frequency of durable responses in treated patients. Of note, prior treatment with chemotherapy was associated with decreased response rates to PD-1 checkpoint blockade. Over the past year, these striking data led to major changes in advanced MCC therapy, including the first-ever FDA drug approval for this disease. Despite these successes, ~50% of MCC patients do not persistently benefit from PD-1 pathway blockade, underscoring the need for novel strategies to broaden anti-tumor immune responses in these patients. Here we highlight recent progress in MCC including the underlying mechanisms of immune evasion and emerging approaches to augment the efficacy of PD-1 pathway blockade.



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Anti-cytokine autoantibodies in a patient with a heterozygous NFKB2 mutation

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Publication date: Available online 7 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Kesava A. Ramakrishnan, William Rae, Gabriela Barcenas-Morales, Yifang Gao, Reuben J. Pengelly, Sanjay V. Patel, Dinkantha S. Kumararatne, Sarah Ennis, Rainer Döffinger, Saul N. Faust, Anthony P. Williams

Teaser

We report a family with a heterozygous NFKB2 mutation in which anti-cytokine autoantibodies were identified in one individual. Rituximab therapy for autoantibodies led to a reduction in anti-cytokine autoantibodies and a marked improvement in infectious susceptibility.


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Autophagy deficiency in myeloid cells exacerbates eosinophilic inflammation in chronic rhinosinusitis

Publication date: Available online 7 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Go Eun Choi, Seung-Yong Yoon, Ji-Yun Kim, Do-Young Kang, Yong Ju Jang, Hun Sik Kim
BackgroundEosinophilic inflammation is a major pathologic feature of chronic rhinosinusitis and is frequently associated with severe refractory disease. Prostaglandin D2 level is elevated in chronic rhinosinusitis and is an important contributing factor to eosinophilic inflammation. Autophagy has a pleiotropic effect on immune responses and disease pathogenesis. Recent studies suggest the potential involvement of autophagy in chronic rhinosinusitis and the prostaglandin pathway.ObjectiveTo investigate whether altered function of autophagy is associated with eosinophilic inflammation and dysregulated production of prostaglandin D2 in chronic rhinosinusitis.MethodsWe used myeloid cell-specific deletion of Atg7, which is vital for autophagy, and investigated the effects of impaired autophagy on eosinophilic inflammation in a murine model of eosinophilic chronic rhinosinusitis. The effect of autophagy on prostaglandin D2 production and gene expression profiles associated with allergy and the prostaglandin pathway were assessed.ResultsWe found that impaired autophagy in myeloid cells aggravated eosinophilia, epithelial hyperplasia, and mucosal thickening in eosinophilic chronic rhinosinusitis mice. This aggravation was associated with gene expression profiles that favor eosinophilic inflammation, Th2 response, mast cell infiltration, and prostaglandin D2 dysregulation. Supporting this, prostaglandin D2 production was also significantly increased by impaired autophagy. Among other myeloid cells, macrophages were associated with autophagy deficiency, leading to elevated IL-1β levels. Macrophage depletion or blockade of IL-1 receptor led to alleviation of eosinophilic inflammation and sinonasal anatomic abnormalities associated with autophagy deficiency.ConclusionOur results suggest that impaired autophagy in myeloid cells, particularly macrophages, has a causal role in eosinophilic inflammation and eosinophilic chronic rhinosinusitis pathogenesis.

Graphical abstract

image

Teaser

Autophagy deficiency in myeloid cells, particularly macrophages, is linked to augmented production of PGD2 and eosinophilic inflammation in a murine model of ECRS. Thus, autophagy dysfunction has a causal role in the development of ECRS.


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CCL5-CCR5 interactions modulate metabolic events during tumor onset to promote tumorigenesis

Abstract

Background

In earlier studies we have shown that CCL5 activation of CCR5 induces the proliferation and survival of breast cancer cells in a mechanistic target of rapamycin (mTOR)-dependent manner and that this is in part due to CCR5-mediated increases in glycolytic metabolism.

Methods

Using the MDA-MB-231 triple negative human breast cancer cell line and mouse mammary tumor virus – polyomavirus middle T-antigen (MMTV-PyMT) mouse primary breast cancer cells, we conducted in vivo tumor transplant experiments to examine the effects of CCL5-CCR5 interactions in the context of regulating tumor metabolism. Additionally, we employed Matrix-Assisted Laser Desorption/Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry imaging (MALDI-FTICR-MSI) to evaluate tumor utilization of cellular metabolites.

Results

We provide evidence that, in the absence of CCR5, the early events associated with rapid tumor growth in the MMTV-PyMT mouse model of spontaneous breast cancer development, are diminished, as demonstrated by a delay in tumor onset. In tumor transplant studies into immunocompromised mice we identify a direct correlation between reduced tumor proliferation and decreased metabolic activity, specifically associated with tumor expression of CCR5. The reduction in tumorigenesis is accompanied by decreases in glucose uptake, glucose transporter-1 (GLUT-1) cell surface expression, intracellular ATP and lactate levels, as well as reduced CCL5 production. Using MALDI-FTICR-MS, we show that the rapid early tumor growth of CCR5+/+ triple negative breast cancer cells in vivo is attributable to increased levels of glycolytic intermediates required for anabolic processes, in contrast to the slower growth rate of their corresponding CCR5−/− cells, that exhibit reduced glycolytic metabolism.

Conclusions

These findings suggest that CCL5-CCR5 interactions in the tumor microenvironment modulate metabolic events during tumor onset to promote tumorigenesis.



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Improved Tumor Penetration and Single-Cell Targeting of Antibody Drug Conjugates Increases Anticancer Efficacy and Host Survival

Current antibody-drug conjugates (ADC) have made advances in engineering the antibody, linker, conjugation site, small molecule payload and drug-to-antibody ratio (DAR). However, the relationship between heterogeneous intratumoral distribution and efficacy of ADC is poorly understood. Here we compared trastuzumab and ado-trastuzumab emtansine (T-DM1) to study the impact of ADC tumor distribution on efficacy. In a mouse xenograft model insensitive to trastuzumab, co-administration of trastuzumab with a fixed dose of T-DM1 at 3:1 and 8:1 ratios dramatically improved ADC tumor penetration and resulted in twice the improvement in median survival compared to T-DM1 alone. In this setting, the effective DAR was lowered, decreasing the amount of payload delivered to each targeted cell but increasing the number of cells that received payload. This result is counterintuitive because trastuzumab acts as an antagonist in vitro and has no single-agent efficacy in vivo, yet improves the effectiveness of T-DM1 in vivo. Novel dual-channel fluorescence ratios quantified single-cell ADC uptake and metabolism and confirmed that the in vivo cellular dose of T-DM1 alone exceeded the minimum required for efficacy in this model. Additionally, this technique characterized cellular pharmacokinetics with heterogeneous delivery after one day, degradation and payload release by two days, and in vitro cell killing and in vivo tumor shrinkage 2-3 days later. This work demonstrates that the intratumoral distribution of ADC - independent of payload dose or plasma clearance - plays a major role in ADC efficacy.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2Amtbs0

Radiotherapy-activated cancer-associated fibroblasts promote tumor progression through paracrine IGF-1R activation

Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer (RC), a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAF are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer (CRC) cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell cycle arrest, and secretion of paracrine mediators including insulin-like growth factor-1 (IGF-1). Subsequently, RT-activated CAF promoted survival of CRC cells as well as a metabolic switch favoring glutamine consumption through IGF-1 receptor (IGF-1R) activation. RT followed by IGF-1R neutralization in orthotopic CRC models reduced the number of mice with organ metastases. Activation of the downstream IGF-1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from RC patients after neoadjuvant chemoRT. Taken together, our data support the notion that paracrine IGF-1/IGF-1R signaling initiated by RT-activated CAF worsen CRC progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BgrJYs

SIRT6 is a target of regulation by UBE3A that contributes to liver tumorigenesis in an ANXA2-dependent manner

UBE3A is an E3 ubiquitin ligase well known for its role in the proteasomal degradation of p53 in human papillomavirus (HPV)-associated cancers. Here we report that UBE3A ubiquitylates and triggers degradation of the tumor suppressive sirtuin SIRT6 in hepatocellular carcinoma. UBE3A ubiquitylated the highly conserved Lys160 residue on SIRT6. FOXO1-mediated transcriptional repression of UBE3A was sufficient to stabilize SIRT6 and epigenetically repress ANXA2, a key mediator of UBE3A oncogenic function. Thus, UBE3A-mediated SIRT6 degradation promoted the proliferative capacity, migration potential and invasiveness of cells. In mouse models of hepatocellular carcinoma, SIRT6 downregulation and consequent induction of ANXA2 were critical for UBE3A-mediated tumorigenesis. Furthermore, in clinical specimens, increased UBE3A levels correlated with reduced SIRT6 levels and elevated ANXA2 levels in increasing tumor grades. Overall, our findings show how the tumor suppressor SIRT6 is regulated in hepatocellular carcinoma and establish the mechanism underlying UBE3A-mediated tumorigenesis in this disease.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2AkgkXn