Anatomical Examination of Mandibular Condyle Protrusion Into the Middle Cranial Fossa: Cadaveric Dissection

Trauma to the mandible can occasionally be a life-threatening event. Although extremely rare with only 56 reported patients in the English language, fracture of the floor of the middle cranial fossa with protrusion of the mandibular condyle into the middle cranial fossa was first reported in 1963 by Dingman. The authors review the anatomy of the temporomandibular joint in relation to the middle cranial fossa and demonstrate the possible complications due to condylar intrusion with anatomical dissection. Address correspondence and reprint requests to Joe Iwanaga, DDS, PhD, Seattle Science Foundation, 550 17th Ave, James Tower, Suite 600, Seattle, WA 98122; E-mail: joei@seattlesciencefoundation.org Received 13 December, 2017 Accepted 7 January, 2018 The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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Anatomic Study on Sphenoidal Emissary Foramen by Using Cone-Beam Computed Tomography

Objectives: The goal of this retrospective study is to evaluate the radiologic anatomy of sphenoidal emissary foramen (SEF) by using cone-beam computed tomography (CBCT) scans. Methods: Three hundred seventeen (189 female and 128 male) full-head CBCT images were evaluated in this study. Incidence, diameter, shape, confluence to foramen ovale, and distance to anatomic structures of SEF were noted. Results: In the 317 analyzed images, the SEF was identified in 89 (28.1%) images. Of these, 67 (21.1%) were unilateral, 22 were (6.9%) bilateral. The maximum mean diameter of SEF was measured 2.66 mm on the right side and 2.82 mm on the left side (P = 0.16). The most observed SEF shape was oval with the incidence of 68.5% (P ≤ 0.05). Confluence was observed in 23.4% of SEF whereof 84.6% were in the left side (P ≤ 0.05). Conclusion: Observations in this study tender new anatomic parameters regarding SEF incidence, characteristics, and distances to proximate anatomic structures. Knowledge related to SEF variations will be helpful for neurosurgeons and radiologist. Address correspondence and reprint requests to Dr Seval Bayrak, PhD, Department of Dentomaxillofacial Radiology, Faculty of Dentistry, Abant Izzet Baysal University, Bolu, Turkey; E-mail: dtseval@hotmail.com Received 1 November, 2017 Accepted 1 February, 2018 The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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Open Rhinoplasty Using Concealing Incisions for Mild Bifid Nose With Unilateral Mini-Microform Cleft Lip

Bifid nose, an indicator of Tessier No.0, is a rare congenital malformation. Because of its rarity, few cases were reported and the optimal surgical procedure and the best time for surgery have not been widely acknowledged. In this brief report, a 9-year-old girl with mild bifid nose and unilateral mini-microform cleft lip, and its surgical management, is presented. We focused our attention on modifying the shape of the nose through open rhinoplasty without excising the surplus skin on the nasal dorsum and achieved good results. Address correspondence and reprint requests to Jian Li, DDS, Hospital and School of Stomatology Wuhan University, Wuhan 430079, China; E-mail: lijian_hubei@whu.edu.cn Received 25 July, 2017 Accepted 2 February, 2018 The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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Eyebrow Shapes of Chinese Empresses of the Ming and Qing Dynasties

The aim of this study was to analyze eyebrow shapes in portraits of Chinese empresses of Ming and Qing dynasties. The frontal portraits of 20 Ming empresses and 24 of Qing in which the eye and eyebrows were identifiable were measured and analyzed. The arch shape did not differ significantly (P > 0.05) between Ming and Qing. The head-up type (66.6%) was significantly more common (P 

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Parotid Mucoepidermoid Carcinoma Mimicking a Large Mucocele

Mucoepidermoid carcinoma is a malign tumor involving the parotid gland and minor salivary glands. Parotid pure cystic mucoepidermoid carcinoma can also masquerade mucocele, and hence, histopathological examination is crucial to distinguish the 2. Herein, the authors report a patient of mucoepidermoid carcinoma presenting as an asymptomatic mucocele-like cystic parotid mass. A 69-year-old female presented with cystic parotid mass; her examination findings and diagnostic imaging were consistent with that of mucocele. Histological examination revealed mucoepidermoid carcinoma. This case indicates that parotid mucocele-like cysts should be included in the differential diagnosis of malign salivary gland tumors. Address correspondence and reprint requests to Nurdoğan Ata, MD, Department of Otorhinolaryngology, Gaziantep 25 Aralik State Hospital, Sarigüllük Mah. Fevziçakmak bulvari PK: 27060 Şehitkamil, Gaziantep, Turkey; E-mail: nurdoganata@mynet.com Received 5 October, 2017 Accepted 24 November, 2017 The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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Single Session Facial Lipostructure by Using Autologous Fat Mixed With Platelet-Rich Fibrin Injected by Using Facial Autologous Muscular Injection Technique

Aim: This study was designed to evaluate the role of single session autologous facial fat grafting in correcting facial asymmetries after mixing it with platelet-rich fibrin (PRF) and injecting them into rich vascular facial muscular plane. Materials and Methods: Fifteen patients (12 females and 3 males) with age ranging from 18 years to 40 years were included in this study and followed up during 6 months, all the patients were treated in the Al-Shaheed Ghazi Al-Hariri for specialized surgeries hospital (Medical City, Baghdad, Iraq). Autologous fat with PRF injected in facial muscular plane was the standardized method in the treatment of acquired and congenital facial defects. Results were evaluated by 2 plastic surgeons using visual analogue scale. Interexaminer and intraexaminer calibration of the visual analogue scale were carried out by using paired t test. Results: This prospective study showed that the majority of patients (73.3%) needed only a single session for creating a noticeable improvement in facial volumes and contours. Conclusions: Mixing fat with PRF and injecting them by using facial autologous muscular injection technique offers better graft survival by utilizing the growth factors and cytokines in PRF clot together with rich vascular plexus in the muscular layer consequently. Address correspondence and reprint requests to Ahmed Fadhil Al-Quisi, BDS, FIBMS, Lecturer in Oral and Maxilloficial Department, Collage of Dentisty, Baghdad University, Baghdad, Alshaab, 0964, Iraq; E-mail: ahmedquisi@gmail.com Received 27 November, 2016 Accepted 11 November, 2017 The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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Editorial Board

Publication date: April 2018
Source:Dental Materials, Volume 34, Issue 4





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Surface characteristics and biocompatibility of cranioplasty titanium implants following different surface treatments

Publication date: April 2018
Source:Dental Materials, Volume 34, Issue 4
Author(s): Muhanad M. Hatamleh, Xiaohong Wu, Ahmad Alnazzawi, Jason Watson, David Watts
ObjectiveSurface and mechanical properties of titanium alloys are integral for their use in restoring bone defects of skull and face regions. These properties are affected by the method of constructing and surface treatment of the titanium implant. This study aimed to investigate the effects of titanium finishing protocols on the surface morphology, hardness and biocompatibility of TiAl6V4.MethodsSquare shaped TiAl6V4 specimens (ASTM F68) (10×10×0.5mm) were divided into seven groups of different surface treatments (n=10). The treatments included mechanical polishing, sandblasting with AL2O3 (50μm), immersion in different acids, and/or electro-chemical anodization. Weight loss %; 3D micro-roughness; Knoop micro-hardness, and osteoblast cell attachment and proliferation (after 3 days) were determined for each specimen. Data was analysed using one way ANOVA and Dunett T3 post-hoc tests, and t-test (p<0.05).ResultsWeight loss % was in the range of 1.70–5.60 as mechanical polishing produced the highest weight loss, followed by sandblasting, and combined protocol of mechanical polishing and acid treatment (p<0.05). Micro-roughness values (μm) were in the range of 2.81–16.68. It was the highest for control specimens (p<0.05), and smoothest surfaces after combined mechanical polishing and acid treatment; or after electro-chemical treatment (p<0.05). Micro-hardness values (MPa) ranged 170.90–442.15 as sandblasting with/without acid treatment caused statically significantly the highest values (p<0.05) while control and mechanically polished specimens had the lowest values (p<0.05). All treatments produced equally biocompatible surfaces (p>0.05) after 1h or 3 days. Furthermore, osteoblast cell proliferation statistically significantly increased after 3days among each surface treatment (p<0.05).SignificanceDifferent finishing treatments have variable effect on cranioplasty titanium surface loss, micro-roughness and micro-hardness but constant improved biocompatibility effect. Electro-chemical treatment caused less material loss and produced biocompatible smoothest surface of comparable hardness; hence it can be suitable for cranioplasty titanium surface finishing.



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Polymerization efficiency affects interfacial fracture toughness of adhesives

Publication date: April 2018
Source:Dental Materials, Volume 34, Issue 4
Author(s): Pong Pongprueksa, Jan De Munck, Masanao Inokoshi, Bart Van Meerbeek
ObjectiveTo evaluate the effect of the kind and concentration of photo-initiator on the degree of conversion (DC) of adhesives on dentin/glass substrates and their mini-interfacial fracture toughness (mini-iFT) to dentin.MethodsWe tested the adhesive Clearfil S³ Bond Plus and 4 derived experimental 'LUB' ('Leuven Univesity Bond') adhesives (all from Kuraray Noritake), namely 'LUB-CQ/amine_high', 'LUB-CQ/amine_low', 'LUB-TPO_high', and 'LUB-TPO_low', respectively containing 2.0wt% camphorquinone (CQ) and 2.0wt% EDMAB (amine), 0.35wt% CQ and 0.35wt% amine, 2.0wt% TPO, and 0.35wt% TPO. For DC, each adhesive was applied onto glass or dentin prior to being cured (Bluephase 20i; Ivoclar Vivadent: "high mode") for 10s. DC was measured at 5min, 10min, 1h, 24h and 1 week using micro-Raman spectroscopy (SENTERRA; BrukerOptik). For mini-iFT, each adhesive was bonded to 320-grit SiC-paper ground dentin and covered with composite (Z100; 3M ESPE). The restored teeth were cut in sticks (1.5×2.0×16mm), after which a single-gradient notch was prepared at the adhesive-dentin interface using a 150-μm diamond blade. The micro-specimens were loaded until failure in a 4-point bending test and the mini-iFT in term of KQvM was calculated.ResultsDC was higher on dentin than on glass. All adhesives were adequately polymerized at 1 week, except for LUB-TPO_low. DC at 5min was significantly higher for LUB-TPO_high than for both CQ/amine-based adhesives. The highest and most reliable mini-iFT was measured for LUB-CQ/amine_high, despite its 5-min DC was relatively low. No correlation between DC and mini-iFT was found.SignificanceCuring of TPO-based adhesives is faster, but the dark cure of the CQ/amine-containing adhesives is more efficient. The differences in curing profiles do affect the mechanical properties of the resultant interfaces at dentin.



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44Ca doped remineralization study on dentin by isotope microscopy

Publication date: April 2018
Source:Dental Materials, Volume 34, Issue 4
Author(s): N. Hiraishi, S. Kobayashi, H. Yurimoto, J. Tagami
ObjectiveThe dental caries is developed as a result of an alternative course of mineral gain and loss. In order to distinguish between intrinsic Ca (tooth-derived mineral) and extrinsic Ca (solution-derived mineral) uptakes, a ⁴⁴Ca doped pH-cycling was performed using ⁴⁴Ca (a stable calcium isotope) remineralization solution.MethodsThe natural abundance of ⁴⁰Ca and ⁴⁴Ca is 96.9% and 2.1%, respectively. The remineralization solution was prepared using ⁴⁴Ca to contain 1.5mmol/L CaCl2 (⁴⁴Ca), 0.9mmol/L KH2PO4, 130mmol/L KCl, 20mmol/L HEPES at pH 7.0. The pH-cycling was conducted on bovine root dentin daily by demineralization (pH 5.0) for 2h, incubation in 0% (control) and 0.2% NaF (900ppm fluoride) for 2h and ⁴⁴Ca doped remineralization for 20h. After 14days pH-cycling, the specimens were sectioned longitudinally. On the sectioned surface, isotope imaging of ⁴⁰Ca and ⁴⁴Ca labeled mineral distribution was observed by a high mass-resolution stigmatic secondary ion 77 (Camera IMS 1270, Gennevilliers Cedex, France).ResultsUptake of ⁴⁴Ca was greater in intensity for the 0.2% fluoride group than the control, especially in the superficial lesions. The control group showed ⁴⁰Ca (intrinsic) distribution in the subsurface lesions and in the superficial lesions, meanwhile the fluoride group showed ⁴⁰Ca distribution limited in subsurface lesions. The total Ca (⁴⁴Ca+⁴⁰Ca) image revealed more homogeneously for the control than the fluoride group.SignificanceSince the fluoride-treated surface is more acid-resistant than intrinsic dentin, alternative minerals were dissolved from the intact intrinsic lesion in the demineralization cycle.

Graphical abstract

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Shining a light on high volume photocurable materials

Publication date: Available online 14 March 2018
Source:Dental Materials
Author(s): William M. Palin, Julian G. Leprince, Mohammed A. Hadis
Spatial and temporal control is a key advantage for placement and rapid setting of light-activated resin composites. Conventionally, placement of multiple thin layers (<2mm) reduces the effect of light attenuation through highly filled and pigmented materials to increase polymerisation at the base of the restoration. However, and although light curing greater than 2mm thick layers is not an entirely new phenomenon, the desire amongst dental practitioners for even more rapid processing in deep cavities has led to the growing acceptance of so-called "bulk fill" (4–6mm thick) resin composites that are irradiated for 10–20s in daily clinical practice. The change in light transmission and attenuation during photopolymerisation are complex and related to path length, absorption properties of the photoinitiator and pigment, optical properties of the resin and filler and filler morphology. Understanding how light is transmitted through depth is therefore critical for ensuring optimal material properties at the base of thick increments. This article will briefly highlight the advent of current commercial materials that rationalise bulk filling techniques in dentistry, the relationship between light transmission and polymerisation and how optimal curing depths might be achieved.



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Percutaneous Dilatational Tracheostomy Using Tube Exchanger

We describe a modified technique for percutaneous dilatational tracheostomy using a 15F tube exchanger or Eschmann catheter. A retrospective review of 1180 procedures using this modified technique demonstrated it to be effective with a failure rate of only 0.25% (3 patients). Moreover, it provides an additional safeguard with the ability to rapidly reintroduce the endotracheal tube into the trachea guided by the exchange catheter in the event of accidental extubation during the procedure. This technique needs no additional special devices or equipment (eg, a bronchoscope). However, a prospective study is needed to better define its complication rate. Accepted for publication January 22, 2018. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Ohad Ronen, MD, Department of Otolaryngology, Head and Neck Surgery, Galilee Medical Center, POB 21, Nahariya 2210001, Israel. Address e-mail to ohadr@gmc.gov.il. © 2018 International Anesthesia Research Society

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Perioperative Cardiac Arrest: Focus on Local Anesthetic Systemic Toxicity (LAST) Erratum

No abstract available

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Burnout in American Anesthetists, Comparison With a French Cohort

No abstract available

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In Response

No abstract available

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Exercise Therapy for Low Back Pain: A Systematic Review

No abstract available

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Response to the Letter to the Editor on ‘The effectiveness of technology-supported exercise therapy for low back pain: A systematic review.’

No abstract available

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A hierarchical linguistic information-based model of English prosody: L2 data analysis and implications for computer-assisted language learning

Publication date: Available online 14 March 2018
Source:Computer Speech & Language
Author(s): Chao-yu Su, Chiu-yu Tseng, Jyh-Shing Roger Jang, Tanya Visceglia
The paper presents a prosody model of native English (L1) continuous speech as corrective prosodic feedback for non-native learners. The model incorporates both hierarchical discourse association and information structure to (1) pinpoint the prosodic features of multi-phrase continuous speech, and (2) simulate native-like expressive speech using corpus of North American and Taiwan L2 English. The bottom-up, additive, data-driven model aims to generate L1-like expressive continuous speech with built-in phonetic and phonological specifications at the lexical level, syntactic/semantic specifications at the next higher phrase and sentence levels, and completed with patterned paragraph associations and prosodic projections of information allocation at higher levels. The hierarchical model successfully allows us to identify L1-L2 differences by prosodic modules/patterns as novel additional features "discourse structure" and "information density" reliably nail down L1-L2 prosodic differences related to phrase association as well as information placement. Our L1 prosodic model with the proposed predictors and optimized model trained from L1 speech corpus showed increase of prediction over existing methods. As a corrective feedback for L2 learners, these predicted L1 prosodic features were compared with a baseline model by objective evaluation (RMS error and correlation) then superimposed onto the L2 speech tokens. Resynthesized L2 tokens were subsequently compared with the original L2 tokens for degrees of perceived accent using subjective evaluation (native-listener perception test). We believe the proposed model can be an effective alternative for implementing computer-assisted language learning (CALL) systems that helps generate L1-like prosody from text, and at the same time serves as corrective feedback for L2 learners.



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Lacosamide monotherapy in clinical practice: A retrospective chart review

Objective

To assess effectiveness and tolerability of first-line and conversion to lacosamide monotherapy for focal seizures.

Materials and Methods

Retrospective, non-interventional chart review of lacosamide monotherapy patients aged ≥16 years in Europe. Outcomes included retention rate at observational point (OP) 3 (12 ± 3 months), seizure freedom rates at OP2 (6 ± 3 months) and OP3 and adverse drug reactions (ADRs).

Results

A total of 439 patients were included (98 first-line and 341 conversion to monotherapy; 128 aged ≥65 years [25 first-line and 103 conversion to monotherapy]). First-line and conversion to monotherapy retention rates were 60.2% (59/98; 95% confidence interval [CI] 49.8%-70.0%) and 62.5% (213/341; 57.1%-67.6%), respectively. Kaplan-Meier estimates of 12-month retention rates were 81.2% and 91.4% for first-line and conversion to monotherapy, respectively. First-line and conversion to monotherapy retention rates in patients aged ≥65 years were 60.0% (38.7%-78.9%) and 68.9% (59.1%-77.7%), respectively. At OP2, 66.3% of first-line and 63.0% of conversion to monotherapy patients were seizure free. At OP3, 60.2% of first-line and 52.5% of conversion to monotherapy patients were seizure free. In the ≥65 years subgroup, seizure freedom rates at OP2 were 72.0% and 68.0% for first-line and converted to monotherapy, respectively, and at OP3, 68.0% and 56.3%, respectively. Overall, 52 of 439 (11.8%) patients reported ADRs (16.4% in ≥65 years subgroup), most commonly dizziness (5.0%), headache (2.1%) and somnolence (1.6%).

Conclusions

Lacosamide was effective and well tolerated as first-line or conversion to monotherapy in a clinical setting in adult and elderly patients with focal seizures.

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Painful musculosceletal disorders and depression among working aged migraineurs

Objective

Musculoskeletal disorders and depression are common among migraineurs. The aim of our study was to evaluate the occurrence of these disorders among working aged migraineurs.

Material and Methods

The risk for fibromyalgia, rheumatoid arthritis (RA), osteoarthrosis (OA), sciatic syndrome, and the occurrence of depression was studied among cases who reported about these conditions and migraine in working aged Finnish population in The Health and Social Support Study (HeSSup) based on postal questionnaire in 2012. Group differences were tested by chi-square test. Odds ratios (ORs with 95% CI) adjusted for age, gender, education level and depression were calculated with logistic regression analysis.

Results

Total of 1505 migraineurs (13%) and 8092 controls were included among the 11 596 responders in 2012. Age and gender adjusted ORs, 2.37 (95% CI 1.81-3.09) for fibromyalgia, 1.46 (1.10-1.95) for RA, 1.58 (1.38-1.80) for OA, and 2.09 (1.84-2.37) for sciatic syndrome, were significant. At least moderate depression was more common among migraineurs (7.3%) than among controls (3.4%) (P < .001).

Conclusion

Recognition of comorbid musculoskeletal disorders and mood disorders among migraineurs needs targeted outreach in working aged population. The acute and preventive treatments to control for neuronal sensitization in migraine and comorbid pain disorders may benefit of individual treatment plan and tailored use of antidepressants.

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Antibody therapy targeting CD19 for B-cell non-Hodgkin lymphoma

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Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients

Abstract

BACKGROUND

Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects.

PATIENTS AND METHODS

In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m² was administered one week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating PBMCs and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRβ sequencing.

RESULTS

Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+immunotherapy. No objective responses were observed, while nine patients presented stable disease (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting stable disease (SD). IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD.

CONCLUSIONS

This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.

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Detection of somatic RAS mutations in circulating tumor DNA from metastatic colorectal cancer patients: are we ready for clinical use?

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Cancer Incidence in Adolescents and Young Adults in 24 Selected Populations of Latin America

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


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Development and Validation of a Gene Signature for Patients with Head and Neck Carcinomas Treated by Postoperative Radio(chemo)therapy

Purpose: The aim of this study was to identify and independently validate a novel gene signature predicting locoregional tumor control (LRC) for treatment individualization of patients with locally advanced HPV-negative head and neck squamous cell carcinomas (HNSCC) who are treated with postoperative radio(chemo)therapy (PORT-C).

Experimental Design: Gene expression analyses were performed using NanoString technology on a multicenter training cohort of 130 patients and an independent validation cohort of 121 patients. The analyzed gene set was composed of genes with a previously reported association with radio(chemo)sensitivity or resistance to radio(chemo)therapy. Gene selection and model building were performed comparing several machine-learning algorithms.

Results: We identified a 7-gene signature consisting of the three individual genes HILPDA, CD24, TCF3, and one metagene combining the highly correlated genes SERPINE1, INHBA, P4HA2, and ACTN1. The 7-gene signature was used, in combination with clinical parameters, to fit a multivariable Cox model to the training data (concordance index, ci = 0.82), which was successfully validated (ci = 0.71). The signature showed improved performance compared with clinical parameters alone (ci = 0.66) and with a previously published model including hypoxia-associated genes and cancer stem cell markers (ci = 0.65). It was used to stratify patients into groups with low and high risk of recurrence, leading to significant differences in LRC in training and validation (P < 0.001).

Conclusions: We have identified and validated the first hypothesis-based gene signature for HPV-negative HNSCC treated by PORT-C including genes related to several radiobiological aspects. A prospective validation is planned in an ongoing prospective clinical trial before potential application in clinical trials for patient stratification. Clin Cancer Res; 24(6); 1364–74. ©2018 AACR.

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Clinical Utility of a STAT3-Regulated miRNA-200 Family Signature with Prognostic Potential in Early Gastric Cancer

Purpose: The majority of gastric cancer patients are diagnosed with late-stage disease, for which distinct molecular subtypes have been identified that are potentially amenable to targeted therapies. However, there exists no molecular classification system with prognostic power for early-stage gastric cancer (EGC) because the molecular events promoting gastric cancer initiation remain ill-defined.

Experimental Design: miRNA microarrays were performed on gastric tissue from the gp130^F/F preclinical EGC mouse model, prior to tumor initiation. Computation prediction algorithms were performed on multiple data sets and independent gastric cancer patient cohorts. Quantitative real-time PCR expression profiling was undertaken in gp130^F/F-based mouse strains and human gastric cancer cells genetically engineered for suppressed activation of the oncogenic latent transcription factor STAT3. Human gastric cancer cells with modulated expression of the miR-200 family member miR-429 were also assessed for their proliferative response.

Results: Increased expression of miR-200 family members is associated with both tumor initiation in a STAT3-dependent manner in gp130^F/F mice and EGC (i.e., stage IA) in patient cohorts. Overexpression of miR-429 also elicited contrasting pro- and antiproliferative responses in human gastric cancer cells depending on their cellular histologic subtype. We also identified a miR-200 family–regulated 15-gene signature that integrates multiple key current indicators of EGC, namely tumor invasion depth, differentiation, histology, and stage, and provides superior predictive power for overall survival compared with each EGC indicator alone.

Conclusions: Collectively, our discovery of a STAT3-regulated, miR-200 family–associated gene signature specific for EGC, with predictive power, provides a molecular rationale to classify and stratify EGC patients for endoscopic treatment. Clin Cancer Res; 24(6); 1459–72. ©2018 AACR.

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CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer

Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and adjuvant chemotherapy have an expected survival of only 2 years due to disease recurrence, frequently in the liver. We investigated the role of liver macrophages in progression of PDAC micrometastases to identify adjuvant treatment strategies that could prolong survival.

Experimental Design: A murine splenic injection model of hepatic micrometastatic PDAC was used with five patient-derived PDAC tumors. The impact of liver macrophages on tumor growth was assessed by (i) depleting mouse macrophages in nude mice with liposomal clodronate injection, and (ii) injecting tumor cells into nude versus NOD-scid-gamma mice. Immunohistochemistry and flow cytometry were used to measure CD47 ("don't eat me signal") expression on tumor cells and characterize macrophages in the tumor microenvironment. In vitro engulfment assays and mouse experiments were performed with CD47-blocking antibodies to assess macrophage engulfment of tumor cells, progression of micrometastases in the liver and mouse survival.

Results: In vivo clodronate depletion experiments and NOD-scid-gamma mouse experiments demonstrated that liver macrophages suppress the progression of PDAC micrometastases. Five patient-derived PDAC cell lines expressed variable levels of CD47. In in vitro engulfment assays, CD47-blocking antibodies increased the efficiency of PDAC cell clearance by macrophages in a manner which correlated with CD47 receptor surface density. Treatment of mice with CD47-blocking antibodies resulted in increased time-to-progression of metastatic tumors and prolonged survival.

Conclusions: These findings suggest that following surgical resection of PDAC, adjuvant immunotherapy with anti-CD47 antibody could lead to substantially improved outcomes for patients. Clin Cancer Res; 24(6); 1415–25. ©2017 AACR.

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Deep Learning-Based Multi-Omics Integration Robustly Predicts Survival in Liver Cancer

Identifying robust survival subgroups of hepatocellular carcinoma (HCC) will significantly improve patient care. Currently, endeavor of integrating multi-omics data to explicitly predict HCC survival from multiple patient cohorts is lacking. To fill this gap, we present a deep learning (DL)–based model on HCC that robustly differentiates survival subpopulations of patients in six cohorts. We built the DL-based, survival-sensitive model on 360 HCC patients' data using RNA sequencing (RNA-Seq), miRNA sequencing (miRNA-Seq), and methylation data from The Cancer Genome Atlas (TCGA), which predicts prognosis as good as an alternative model where genomics and clinical data are both considered. This DL-based model provides two optimal subgroups of patients with significant survival differences (P = 7.13e–6) and good model fitness [concordance index (C-index) = 0.68]. More aggressive subtype is associated with frequent TP53 inactivation mutations, higher expression of stemness markers (KRT19 and EPCAM) and tumor marker BIRC5, and activated Wnt and Akt signaling pathways. We validated this multi-omics model on five external datasets of various omics types: LIRI-JP cohort (n = 230, C-index = 0.75), NCI cohort (n = 221, C-index = 0.67), Chinese cohort (n = 166, C-index = 0.69), E-TABM-36 cohort (n = 40, C-index = 0.77), and Hawaiian cohort (n = 27, C-index = 0.82). This is the first study to employ DL to identify multi-omics features linked to the differential survival of patients with HCC. Given its robustness over multiple cohorts, we expect this workflow to be useful at predicting HCC prognosis prediction. Clin Cancer Res; 24(6); 1248–59. ©2017 AACR.

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Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Metastatic Melanoma

Immune checkpoint inhibitors have revolutionized the treatment of patients with advanced-stage metastatic melanoma, as well as patients with many other solid cancers, yielding long-lasting responses and improved survival. However, a subset of patients who initially respond to immunotherapy, later relapse and develop therapy resistance (termed "acquired resistance"), whereas others do not respond at all (termed "primary resistance"). Primary and acquired resistance are key clinical barriers to further improving outcomes of patients with metastatic melanoma, and the known mechanisms underlying each involves various components of the cancer immune cycle, and interactions between multiple signaling molecules and pathways. Due to this complexity, current knowledge on resistance mechanisms is still incomplete. Overcoming therapy resistance requires a thorough understanding of the mechanisms underlying immune evasion by tumors. In this review, we explore the mechanisms of primary and acquired resistance to immunotherapy in melanoma and detail potential therapeutic strategies to prevent and overcome them. Clin Cancer Res; 24(6); 1260–70. ©2017 AACR.

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Beyond Concurrent Chemoradiation: The Emerging Role of PD-1/PD-L1 Inhibitors in Stage III Lung Cancer

Concurrent chemoradiation (cCRT) with platinum-based chemotherapy is standard-of-care therapy for patients with stage III unresectable non–small cell lung cancer (NSCLC). Although cCRT is potentially curative, 5-year overall survival has hovered around 20%, despite extensive efforts to improve outcomes with increasing doses of conformal radiation and intensification of systemic therapy with either induction or consolidation chemotherapy. PD-1/PD-L1 immune checkpoint inhibitors have demonstrated unprecedented efficacy in patients with stage IV NSCLC. In addition, preclinical and early clinical evidence suggests that chemotherapy and radiation may work synergistically with anti-PD-1/PD-L1 therapy to promote antitumor immunity, which has led to the initiation of clinical trials testing these drugs in patients with stage III NSCLC. A preliminary report of a randomized phase III trial, the PACIFIC trial, demonstrated an impressive increase in median progression-free survival with consolidative durvalumab, a PD-L1 inhibitor, compared with observation after cCRT. Here, we discuss the clinical and translational implications of integrating PD-1/PD-L1 inhibitors in the management of patients with unresectable stage III NSCLC. Clin Cancer Res; 24(6); 1271–6. ©2018 AACR.

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Expanded Genomic Profiling of Circulating Tumor Cells in Metastatic Breast Cancer Patients to Assess Biomarker Status and Biology Over Time (CALGB 40502 and CALGB 40503, Alliance)

Purpose: We profiled circulating tumor cells (CTCs) to study the biology of blood-borne metastasis and to monitor biomarker status in metastatic breast cancer (MBC).

Methods: CTCs were isolated from 105 patients with MBC using EPCAM-based immunomagnetic enrichment and fluorescence-activated cells sorting (IE/FACS), 28 of whom had serial CTC analysis (74 samples, 2–5 time points). CTCs were subjected to microfluidic-based multiplex QPCR array of 64 cancer-related genes (n = 151) and genome-wide copy-number analysis by array comparative genomic hybridization (aCGH; n = 49).

Results: Combined transcriptional and genomic profiling showed that CTCs were 26% ESR1^–ERBB2^–, 48% ESR1⁺ERBB2^–, and 27% ERBB2⁺. Serial testing showed that ERBB2 status was more stable over time compared with ESR1 and proliferation (MKI67) status. While cell-to-cell heterogeneity was observed at the single-cell level, with increasingly stable expression in larger pools, patient-specific CTC expression "fingerprints" were also observed. CTC copy-number profiles clustered into three groups based on the extent of genomic aberrations and the presence of large chromosomal imbalances. Comparative analysis showed discordance in ESR1/ER (27%) and ERBB2/HER2 (23%) status between CTCs and matched primary tumors. CTCs in 65% of the patients were considered to have low proliferation potential. Patients who harbored CTCs with high proliferation (MKI67) status had significantly reduced progression-free survival (P = 0.0011) and overall survival (P = 0.0095) compared with patients with low proliferative CTCs.

Conclusions: We demonstrate an approach for complete isolation of EPCAM-positive CTCs and downstream comprehensive transcriptional/genomic characterization to examine the biology and assess breast cancer biomarkers in these cells over time. Clin Cancer Res; 24(6); 1486–99. ©2018 AACR.

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Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGF{beta}, in Advanced Solid Tumors

Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against programmed death ligand 1 (PD-L1) fused to a TGFβ "trap."

Experimental Design: In the 3+3 dose-escalation component of this phase I study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; in addition, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics, followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics, immunogenicity, and best overall response.

Results: Nineteen heavily pretreated patients with ECOG 0–1 have received M7824. Grade ≥3 treatment-related adverse events occurred in four patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGFβ1, -β2, and -β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including one ongoing confirmed complete response (cervical cancer), two durable confirmed partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid).

Conclusions: M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging, and multiple expansion cohorts are ongoing in a range of tumors. Clin Cancer Res; 24(6); 1287–95. ©2018 AACR.

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Identification of a Novel, EBV-Based Antibody Risk Stratification Signature for Early Detection of Nasopharyngeal Carcinoma in Taiwan

Background. Epstein–Barr virus (EBV) is necessary for the development of nasopharyngeal carcinoma (NPC). By adulthood, approximately 90% of individuals test EBV-positive, but only a fraction develop cancer. Factors that identify which individuals are most likely to develop disease, including differential antibody response to the virus, could facilitate detection at early stages when treatment is most effective.

Methods. We measured anti-EBV IgG and IgA antibody responses in 607 Taiwanese individuals. Antibodies were measured using a custom protein microarray targeting 199 sequences from 86 EBV proteins. Variation in response patterns between NPC cases and controls was used to develop an antibody-based risk score for predicting NPC. The overall accuracy [area under the curve (AUC)] of this risk score, and its performance relative to currently used biomarkers, was evaluated in two independent Taiwanese cohorts.

Findings. Levels of 60 IgA and 73 IgG anti-EBV antibodies differed between stage I/IIa NPC cases and controls (P < 0.0002). Risk prediction analyses identified antibody targets that best discriminated NPC status—BXLF1, LF2,BZLF1, BRLF1, EAd, BGLF2, BPLF1, BFRF1, and BORF1. When combined with currently used VCA/EBNA1 IgA biomarkers, the resulting risk score predicted NPC with 93% accuracy (95% CI, 87%–98%) in the general Taiwanese population, a significant improvement beyond current biomarkers alone (82%; 95% CI, 75%–90%, P ≤ 0.01). This EBV-based risk score also improved NPC prediction in genetically high-risk families (89%; 95% CI, 82%–96%) compared with current biomarkers (78%; 95% CI, 66%–90%, P ≤ 0.03).

Interpretation. We identified NPC-related differences in 133 anti-EBV antibodies and developed a risk score using this microarray dataset that targeted immune responses against EBV proteins from all stages of the viral life cycle, significantly improving the ability to predict NPC. Clin Cancer Res; 24(6); 1305–14. ©2017 AACR.

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Therapeutic Challenge with a CDK 4/6 Inhibitor Induces an RB-Dependent SMAC-Mediated Apoptotic Response in Non-Small Cell Lung Cancer

Purpose: The retinoblastoma tumor suppressor (RB), a key regulator of cell-cycle progression and proliferation, is functionally suppressed in up to 50% of non–small cell lung cancer (NSCLC). RB function is exquisitely controlled by a series of proteins, including the CyclinD–CDK4/6 complex. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function.

Experimental Design and Results: We employed multiple isogenic RB-proficient and -deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo. We demonstrate that while short-term exposure to palbociclib induces cellular senescence, prolonged exposure results in inhibition of tumor growth. Mechanistically, CDK 4/6 inhibition induces a proapoptotic transcriptional program through suppression of IAPs FOXM1 and Survivin, while simultaneously augmenting expression of SMAC and caspase-3 in an RB-dependent manner.

Conclusions: This study uncovers a novel function of RB activation to induce cellular apoptosis through therapeutic administration of a palbociclib and provides a rationale for the clinical evaluation of CDK 4/6 inhibitors in the treatment of patients with NSCLC. Clin Cancer Res; 24(6); 1402–14. ©2018 AACR.

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p53-Reactive T Cells Are Associated with Clinical Benefit in Patients with Platinum-Resistant Epithelial Ovarian Cancer After Treatment with a p53 Vaccine and Gemcitabine Chemotherapy

Purpose: To conduct a phase I trial of a Modified Vaccinia Ankara vaccine delivering wild-type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer.

Experimental Design: Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses.

Results: Eleven patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome, and immunologic response. Toxicity: there were no DLTs, but 3 of 11 patients came off study early due to gemcitabine-attributed adverse events (AE). Minimal AEs were attributed to p53MVA vaccination. Immunologic and clinical response: enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4⁺ and CD8⁺ T-cell compartments in 5 of 11 and 6 of 11 patients, respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression-free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity after therapy. Tumor shrinkage or disease stabilization occurred in 4 patients.

Conclusions: p53MVA was well tolerated, but gemcitabine without steroid pretreatment was intolerable in some patients. However, elevated p53-reactive CD4⁺ and CD8⁺ T-cell responses after therapy correlated with longer PFS. Therefore, if responses to p53MVA can be enhanced with alternative agents, superior clinical responses may be achievable. Clin Cancer Res; 24(6); 1315–25. ©2018 AACR.

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Morphometric properties of the levator scapulae, rhomboid major, and rhomboid minor in human fetuses

Abstract

Purpose

The main objective of this study is to showcase the growth dynamics of levator scapulae, rhomboid major, and rhomboid minor algebraically, to help plan surgeries on newborns and young infants.

Methods

Twenty-five formalin-fixed fetuses (11 male–14 female) with a mean gestational age of 21.80 ± 2.61 (range 18–27) weeks present in the inventory of Mersin University Faculty of Medicine Anatomy Department were dissected. Surface area of levator scapulae, rhomboid major, and rhomboid minor was calculated using digital image analysis software; width and length parameters were measured using digital calipers.

Results

Neither sex nor side significant differences were observed in relation with the numerical data of levator scapulae, rhomboid major, and rhomboid minor (p > 0.05). Algebraic parameters such as surface area, width and length were detected to exhibit a linear growth from 18th to 27th week. Linear functions for levator scapulae, rhomboid major and rhomboid minor surface areas were obtained as y = − 136.871 + 10.598 × age (weeks), y = − 480.567 + 33.147 × age (weeks) and y = − 128.090 + 8.843 × age (weeks), respectively.

Conclusion

The results and data of this study can potentially be beneficial in planning of surgeries for many infancy diseases such as trapezius paralysis, obstetrical brachial plexus palsy, Sprengel's disease, or winged scapula. Linear functions calculated in this study are expected to provide a better understanding of the growth dynamics of levator scapulae, rhomboid major, and rhomboid minor in fetal term and more precise estimation of muscle sizes.

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Microbiome and Esophageal Adenocarcinoma—Letter

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Anti-CD137 Cancer Immunotherapy Suppresses Tumor Growth—Response

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Improved Evaluation of Antivascular Cancer Therapy Using Constrained Tracer-Kinetic Modeling for Multiagent Dynamic Contrast-Enhanced MRI

Dynamic contrast–enhanced MRI (DCE-MRI) is a promising technique for assessing the response of tumor vasculature to antivascular therapies. Multiagent DCE-MRI employs a combination of low and high molecular weight contrast agents, which potentially improves the accuracy of estimation of tumor hemodynamic and vascular permeability parameters. In this study, we used multiagent DCE-MRI to assess changes in tumor hemodynamics and vascular permeability after vascular-disrupting therapy. Multiagent DCE-MRI (sequential injection of G5 dendrimer, G2 dendrimer, and Gd-DOTA) was performed in tumor-bearing mice before, 2 and 24 hours after treatment with vascular disrupting agent DMXAA or placebo. Constrained DCE-MRI gamma capillary transit time modeling was used to estimate flow F, blood volume fraction vb, mean capillary transit time tc, bolus arrival time td, extracellular extravascular fraction ve, vascular heterogeneity index α−1 (all identical between agents) and extraction fraction E (reflective of permeability), and transfer constant Ktrans (both agent-specific) in perfused pixels. F, vb, and α−1 decreased at both time points after DMXAA, whereas tc increased. E (G2 and G5) showed an initial increase, after which, both parameters restored. Ktrans (G2 and Gd-DOTA) decreased at both time points after treatment. In the control, placebo-treated animals, only F, tc, and Ktrans Gd-DOTA showed significant changes. Histologic perfused tumor fraction was significantly lower in DMXAA-treated versus control animals. Our results show how multiagent tracer-kinetic modeling can accurately determine the effects of vascular-disrupting therapy by separating simultaneous changes in tumor hemodynamics and vascular permeability.Significance: These findings describe a new approach to measure separately the effects of antivascular therapy on tumor hemodynamics and vascular permeability, which could help more rapidly and accurately assess the efficacy of experimental therapy of this class. Cancer Res; 78(6); 1561–70. ©2018 AACR.

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Radioresistant Cervical Cancers Are Sensitive to Inhibition of Glycolysis and Redox Metabolism

Highly glycolytic cervical cancers largely resist treatment by cisplatin and coadministered pelvic irradiation as the present standard of care. In this study, we investigated the effects of inhibiting glycolysis and thiol redox metabolism to evaluate them as alternate treatment strategies in these cancers. In a panel of multiple cervical cancer cell lines, we evaluated sensitivity to inhibition of glycolysis (2-deoxyglucose, 2-DG) with or without simultaneous inhibition of glutathione and thioredoxin metabolism (BSO/AUR). Intracellular levels of total and oxidized glutathione, thioredoxin reductase activity, and indirect measures of intracellular reactive oxygen species were compared before and after treatment. Highly radioresistant cells were the most sensitive to 2-DG, whereas intermediate radioresistant cells were sensitive to 2-DG plus BSO/AUR. In response to 2-DG/BSO/AUR treatment, we observed increased levels of intracellular oxidized glutathione, redox-sensitive dye oxidation, and decreased glucose utilization via multiple metabolic pathways including the tricarboxylic acid cycle. 2-DG/BSO/AUR treatment delayed the growth of tumors composed of intermediate radioresistant cells and effectively radiosensitized these tumors at clinically relevant radiation doses both in vitro and in vivo. Overall, our results support inhibition of glycolysis and intracellular redox metabolism as an effective alternative drug strategy for the treatment of highly glycolytic and radioresistant cervical cancers.Significance: This study suggests a simple metabolic approach to strike at an apparent Achilles' heel in highly glycolytic, radioresistant forms of cervical cancers, possibly with broader applications in cancer therapy. Cancer Res; 78(6); 1392–403. ©2018 AACR.

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Kindlin-1 Promotes Pulmonary Breast Cancer Metastasis

In breast cancer, increased expression of the cytoskeletal adaptor protein Kindlin-1 has been linked to increased risks of lung metastasis, but the functional basis is unknown. Here, we show that in a mouse model of polyomavirus middle T antigen–induced mammary tumorigenesis, loss of Kindlin-1 reduced early pulmonary arrest and later development of lung metastasis. This phenotype relied on the ability of Kindlin-1 to bind and activate β integrin heterodimers. Kindlin-1 loss reduced α4 integrin–mediated adhesion of mammary tumor cells to the adhesion molecule VCAM-1 on endothelial cells. Treating mice with an anti–VCAM-1 blocking antibody prevented early pulmonary arrest. Kindlin-1 loss also resulted in reduced secretion of several factors linked to metastatic spread, including the lung metastasis regulator tenascin-C, showing that Kindlin-1 regulated metastatic dissemination by an additional mechanism in the tumor microenvironment. Overall, our results show that Kindlin-1 contributes functionally to early pulmonary metastasis of breast cancer.Significance: These findings provide a mechanistic proof in mice that Kindin-1, an integrin-binding adaptor protein, is a critical mediator of early lung metastasis of breast cancer. Cancer Res; 78(6); 1484–96. ©2018 AACR.

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Breast Cancer Targeting through Inhibition of the Endoplasmic Reticulum-Based Apoptosis Regulator Nrh/BCL2L10

Drug resistance and metastatic relapse remain a top challenge in breast cancer treatment. In this study, we present preclinical evidence for a strategy to eradicate advanced breast cancers by targeting the BCL-2 homolog Nrh/BCL2L10, which we discovered to be overexpressed in >45% of a large cohort of breast invasive carcinomas. Nrh expression in these tumors correlated with reduced metastasis-free survival, and we determined it to be an independent marker of poor prognosis. Nrh protein localized to the endoplasmic reticulum. Mechanistic investigations showed that Nrh made BH4 domain–dependent interactions with the ligand-binding domain of the inositol-1,4,5-triphosphate receptor (IP3R), a type 1/3 Ca2+ channel, allowing Nrh to negatively regulate ER-Ca2+ release and to mediate antiapoptosis. Notably, disrupting Nrh/IP3R complexes by BH4 mimetic peptides was sufficient to inhibit the growth of breast cancer cells in vitro and in vivo. Taken together, our results highlighted Nrh as a novel prognostic marker and a candidate therapeutic target for late stage breast cancers that may be addicted to Nrh.Significance: These findings offer a comprehensive molecular model for the activity of Nrh/BCL2L10, a little studied antiapoptotic molecule, prognostic marker, and candidate drug target in breast cancer. Cancer Res; 78(6); 1404–17. ©2018 AACR.

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Antitumor Properties of RAF709, a Highly Selective and Potent Inhibitor of RAF Kinase Dimers, in Tumors Driven by Mutant RAS or BRAF

Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here, we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAFV600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF. In cell lines and murine xenograft models, RAF709 demonstrated selective antitumor activity in tumor cells harboring BRAF or RAS mutations compared with cells with wild-type BRAF and RAS genes. RAF709 demonstrated a direct pharmacokinetic/pharmacodynamic relationship in in vivo tumor models harboring KRAS mutation. Furthermore, RAF709 elicited regression of primary human tumor–derived xenograft models with BRAF, NRAS, or KRAS mutations with excellent tolerability. Our results support further development of inhibitors like RAF709, which represents a next-generation RAF inhibitor with unique biochemical and cellular properties that enables antitumor activities in RAS-mutant tumors.Significance: In an effort to develop RAF inhibitors with the appropriate pharmacological properties to treat RAS mutant tumors, RAF709, a compound with potency, selectivity, and in vivo properties, was developed that will allow preclinical therapeutic hypothesis testing, but also provide an excellent probe to further unravel the complexities of RAF kinase signaling. Cancer Res; 78(6); 1537–48. ©2018 AACR.

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E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone Demethylase KDM5C

The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events is poorly understood. Here, we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes EGFR and c-MET. Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bidirectional enhancer RNA transcription. Depletion of KDM5C or HPV16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by HR HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like EGFR and c-MET.Significance: This study suggests a novel explanation for why infections with certain HPV isotypes are associated with elevated cancer risk by identifying an epigenetic mechanism through which E6 proteins expressed by those isotypes can drive expression of key oncogenes. Cancer Res; 78(6); 1418–30. ©2018 AACR.

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Genes Predisposed to DNA Hypermethylation during Acquired Resistance to Chemotherapy Are Identified in Ovarian Tumors by Bivalent Chromatin Domains at Initial Diagnosis

Bivalent chromatin domains containing both active H3K4me3 and repressive H3K27me3 histone marks define gene sets poised for expression or silencing in differentiating embryonic stem (ES) cells. In cancer cells, aberrantly poised genes may facilitate changes in transcriptional states after exposure to anticancer drugs. In this study, we used ChIP-seq to characterize genome-wide positioning of H3K4me3- and H3K27me3-associated chromatin in primary high-grade serous ovarian carcinomas and in normal ovarian surface and fallopian tube tissue. Gene sets with proximal bivalent marks defined in this manner were evaluated subsequently as signatures of systematic change in DNA methylation and gene expression, comparing pairs of tissue samples taken from patients at primary presentation and relapse following chemotherapy. We found that gene sets harboring bivalent chromatin domains at their promoters in tumor tissue, but not normal epithelia, overlapped with Polycomb-repressive complex target genes as well as transcriptionally silenced genes in normal ovarian and tubal stem cells. The bivalently marked genes we identified in tumors before chemotherapy displayed increased promoter CpG methylation and reduced gene expression at relapse after chemotherapy of ovarian cancer. Overall, our results support the hypothesis that preexisting histone modifications at genes in a poised chromatin state may lead to epigenetic silencing during acquired drug resistance.Significance: These results suggest epigenetic targets for intervention to prevent the emergence of cancer drug resistance. Cancer Res; 78(6); 1383–91. ©2018 AACR.

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Role of Chromatin Damage and Chromatin Trapping of FACT in Mediating the Anticancer Cytotoxicity of DNA-Binding Small-Molecule Drugs

Precisely how DNA-targeting chemotherapeutic drugs trigger cancer cell death remains unclear, as it is difficult to separate direct DNA damage from other effects in cells. Recent work on curaxins, a class of small-molecule drugs with broad anticancer activity, shows that they interfere with histone–DNA interactions and destabilize nucleosomes without causing detectable DNA damage. Chromatin damage caused by curaxins is sensed by the histone chaperone FACT, which binds unfolded nucleosomes becoming trapped in chromatin. In this study, we investigated whether classical DNA-targeting chemotherapeutic drugs also similarly disturbed chromatin to cause chromatin trapping of FACT (c-trapping). Drugs that directly bound DNA induced both chromatin damage and c-trapping. However, chromatin damage occurred irrespective of direct DNA damage and was dependent on how a drug bound DNA, specifically, in the way it bound chromatinized DNA in cells. FACT was sensitive to a plethora of nucleosome perturbations induced by DNA-binding small molecules, including displacement of the linker histone, eviction of core histones, and accumulation of negative supercoiling. Strikingly, we found that the cytotoxicity of DNA-binding small molecules correlated with their ability to cause chromatin damage, not DNA damage. Our results suggest implications for the development of chromatin-damaging agents as selective anticancer drugs.Significance: These provocative results suggest that the anticancer efficacy of traditional DNA-targeting chemotherapeutic drugs may be based in large part on chromatin damage rather than direct DNA damage. Cancer Res; 78(6); 1431–43. ©2018 AACR.

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AMPK-Akt Double-Negative Feedback Loop in Breast Cancer Cells Regulates Their Adaptation to Matrix Deprivation

Cell detachment from the extracellular matrix triggers anoikis. Disseminated tumor cells must adapt to survive matrix deprivation, while still retaining the ability to attach at secondary sites and reinitiate cell division. In this study, we elucidate mechanisms that enable reversible matrix attachment by breast cancer cells. Matrix deprival triggered AMPK activity and concomitantly inhibited AKT activity by upregulating the Akt phosphatase PHLPP2. The resultant pAMPKhigh/pAktlow state was critical for cell survival in suspension, as PHLPP2 silencing also increased anoikis while impairing autophagy and metastasis. In contrast, matrix reattachment led to Akt-mediated AMPK inactivation via PP2C-α-mediated restoration of the pAkthigh/pAMPKlow state. Clinical specimens of primary and metastatic breast cancer displayed an Akt-associated gene expression signature, whereas circulating breast tumor cells displayed an elevated AMPK-dependent gene expression signature. Our work establishes a double-negative feedback loop between Akt and AMPK to control the switch between matrix-attached and matrix-detached states needed to coordinate cell growth and survival during metastasis.Significance: These findings reveal a molecular switch that regulates cancer cell survival during metastatic dissemination, with the potential to identify targets to prevent metastasis in breast cancer. Cancer Res; 78(6); 1497–510. ©2018 AACR.

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KRAS Oncoprotein Expression Is Regulated by a Self-Governing eIF5A-PEAK1 Feed-Forward Regulatory Loop

There remains intense interest in tractable approaches to target or silence the KRAS oncoprotein as a rational therapeutic strategy to attack pancreatic ductal adenocarcinoma (PDAC) and other cancers that overexpress it. Here we provide evidence that accumulation of the KRAS oncoprotein is controlled by a self-regulating feed-forward regulatory loop that utilizes a unique hypusinated isoform of the translation elongation factor eIF5A and the tyrosine kinase PEAK1. Oncogenic activation of KRAS increased eIF5A–PEAK1 translational signaling, which in turn facilitated increased KRAS protein synthesis. Mechanistic investigations show that this feed-forward positive regulatory pathway was controlled by oncogenic KRAS-driven metabolic demands, operated independently of canonical mTOR signaling, and did not involve new KRAS gene transcription. Perturbing eIF5A–PEAK1 signaling, by genetic or pharmacologic strategies or by blocking glutamine synthesis, was sufficient to inhibit expression of KRAS, eIF5A, and PEAK1, to attenuate cancer cell growth and migration, and to block tumor formation in established preclinical mouse models of PDAC. Levels of KRAS, eIF5A, and PEAK1 protein increased during cancer progression with the highest levels of expression observed in metastatic cell populations. Combinatorial targeting of eIF5A hypusination and the RAS–ERK signaling pathway cooperated to attenuate KRAS expression and its downstream signaling along with cell growth in vitro and tumor formation in vivo. Collectively, our findings highlight a new mechanistic strategy to attenuate KRAS expression as a therapeutic strategy to target PDAC and other human cancers driven by KRAS activation.Significance: These findings highlight a new mechanistic strategy to attenuate KRAS expression as a therapeutic strategy to target human cancers driven by KRAS activation. Cancer Res; 78(6); 1444–56. ©2018 AACR.

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Antitumor Effects of Blocking Protein Neddylation in T315I-BCR-ABL Leukemia Cells and Leukemia Stem Cells

Imatinib revolutionized the treatment of chronic myeloid leukemia (CML), but drug resistance and disease recurrence remain a challenge. In this study, we suggest a novel strategy based on blocking protein neddylation to address BCR-ABL point mutations and leukemia stem cells (LSC) that lie at the root of imatinib-resistant recurrences. On the basis of the finding that the NEDD8-activating enzyme subunit NAE1 is overexpressed in CML cells, we hypothesized that the function of certain neddylation-dependent protein substrates might be targeted to therapeutic ends in imatinib-resistant CML cells and LSCs. In support of this hypothesis, we demonstrated that the NAE1 inhibitor MLN4924 induced G2–M-phase arrest and apoptosis in bulk CML cells with wild-type p53, regardless of their T315I mutation status in BCR-ABL. Moreover, MLN4924 inhibited the survival and self-renewal of primary human CML CD34+ cells and LSCs in CML-bearing mice via accumulation of p27kip1 in the nucleus. Notably, p27kip1 silencing attenuated the suppressive effect of MLN4924 on the maintenance of LSCs in CML-bearing mice. Taken together, our findings offer a preclinical proof of concept for targeting protein neddylation as a novel therapeutic strategy to override mutational and LSC-derived imatinib resistance in CML.Significance: These findings highlight a mediator of protein neddylation, a type of protein turnover mechanism, as a viable therapeutic target against imatinib-resistant forms of chronic myelogenous leukemia. Cancer Res; 78(6); 1522–36. ©2018 AACR.

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Genetic Mosaicism and Cancer: Cause and Effect

Increasing theoretical and experimental evidence suggests that the genomes of both normal and cancer cells are subject to continuous changes as a result of copying errors during replication, defects in chromosome segregation during mitosis, and direct chemical attacks by reactive oxygen species. The process of cellular genetic diversification begins during embryonic development and continues throughout life, leading to the phenomenon of somatic mosaicism. New information about the genetic diversity of cells composing the body makes us reconsider the existing concepts of cancer etiology and pathogenesis. Here, I suggest that a progressively deteriorating microenvironment ("soil") generates the cancerous "seed" and favors its development. Cancer Res; 78(6); 1375–8. ©2018 AACR.

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A Novel l-Asparaginase with low l-Glutaminase Coactivity Is Highly Efficacious against Both T- and B-cell Acute Lymphoblastic Leukemias In Vivo

Acute lymphoblastic leukemia (ALL) is the most common type of pediatric cancer, although about 4 of every 10 cases occur in adults. The enzyme drug l-asparaginase serves as a cornerstone of ALL therapy and exploits the asparagine dependency of ALL cells. In addition to hydrolyzing the amino acid l-asparagine, all FDA-approved l-asparaginases also have significant l-glutaminase coactivity. Since several reports suggest that l-glutamine depletion correlates with many of the side effects of these drugs, enzyme variants with reduced l-glutaminase coactivity might be clinically beneficial if their antileukemic activity would be preserved. Here we show that novel low l-glutaminase variants developed on the backbone of the FDA-approved Erwinia chrysanthemi l-asparaginase were highly efficacious against both T- and B-cell ALL, while displaying reduced acute toxicity features. These results support the development of a new generation of safer l-asparaginases without l-glutaminase activity for the treatment of human ALL.Significance: A new l-asparaginase–based therapy is less toxic compared with FDA-approved high l-glutaminase enzymes Cancer Res; 78(6); 1549–60. ©2018 AACR.

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The Balance Players of the Adaptive Immune System

Equilibrium between immune activation and suppression may be necessary to maintain immune homeostasis, because proinflammatory effector T cells (defined as antiregulatory T cells) counteract the functions of regulatory immune cells. These self-reactive T cells recognize human leukocyte antigen (HLA)–restricted epitopes derived from proteins expressed by regulatory immune cells such as IDO, PD-L1, PD-L2, or arginase. The activation of such proinflammatory effector T cells offers a novel way to directly target the tumor microenvironment, potentially giving them considerable clinical value, especially in patients with cancer. Vaccination against genetically stable cells with regular HLA expression is an attractive way to directly target immunosuppressive cells in addition to attracting proinflammatory cells into the tumor microenvironment. Importantly, vaccination toward IDO or PD-L1 to potentiate such T cells have proven safe, with minimal toxicity in the clinical phase I trials conducted thus far.Cancer Res; 78(6); 1379–82. ©2018 AACR.

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Anti-CD137 Cancer Immunotherapy Suppresses Tumor Growth—Letter

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2S protein Ara h 7.0201 has unique epitopes compared to other Ara h 7 isoforms and is comparable to 2S proteins Ara h 2 and 6 in basophil degranulation capacity

Abstract

Background

Screening for specific IgE against 2S albumin proteins Ara h 2 and 6 has good positive predictive value in diagnosing peanut allergy. From the third 2S member Ara h 7, three isoforms have been identified. Their allergenicity has not been elucidated.

Objective

This study investigated the allergenicity of Ara h 7 isoforms compared to Ara h 2 and 6.

Methods

Sensitization of 15 DBPCFC confirmed peanut allergic patients to recombinant Ara h 2.0201, 6.01 and isoforms of recombinant Ara h 7 was determined by IgE immunoblotting strips. A basophil activation test (BAT) was performed in nine patients to determine IgE-crosslinking capacities of the allergens. Sensitivity to the allergens was tested in five patients that were sensitized to at least one Ara h 7 isoform, by a concentration range in the BAT. 3D-prediction models and sequence alignments were used to visualize differences between isoforms and to predict allergenic epitope regions.

Results

Sensitization to Ara h 7.0201 was most frequent (80%) and showed to be equally potent as Ara h 2.0201 and 6.01 in inducing basophil degranulation. Sensitization to Ara h 7.0201 together with Ara h 2.0201 and/or 6.01 was observed, indicating the presence of unique epitopes compared to the other two isoforms. Differences between the three Ara h 7 isoforms were observed in C-terminal cysteine residues, pepsin and trypsin cleavage sites and three single amino acid substitutions.

Conclusion & clinical relevance

The majority of peanut-allergic patients are sensitized to isoform Ara h 7.0201, which is functionally as active as Ara h 2.0201 and 6.01. Unique epitopes are most likely located in the C-terminus or an allergenic loop region which is a known allergenic epitope region for Ara h 2.0201 and 6.01. Due to its unique epitopes and allergenicity, it is an interesting candidate to improve the diagnostic accuracy for peanut allergy.

This article is protected by copyright. All rights reserved.

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A Single Radioactive Iodine Treatment Has a Deleterious Effect on Ovarian Reserve in Women with Thyroid Cancer: Results of a Prospective Pilot Study

Thyroid, Ahead of Print.


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Comment on: A Kidney Conundrum: More or Less?

Publication date: Available online 14 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Arjun Sahgal




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Predictors of Hypothyroidism in Hodgkin Lymphoma Survivors after Intensity-Modulated versus 3-Dimensional Radiation Therapy

Publication date: Available online 14 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Chelsea C. Pinnix, Laura Cella, Therese Y. Andraos, Zeina Ayoub, Sarah A. Milgrom, Jillian Gunther, Sonali Thosani, Christine Wogan, Manuel Conson, Vittoria D'Avino, Yasuhiro Oki, Michelle Fanale, Hun J. Lee, Sattva Neelapu, Luis Fayad, Frederick Hagemeister, M. Alma Rodriguez, Loretta J. Nastoupil, Yago Nieto, Wei Qiao, Roberto Pacelli, Bouthaina Dabaja
PurposeTo identify predictors of hypothyroidism after chemoradiation for Hodgkin lymphoma (HL) and to compare outcomes after intensity-modulated radiation therapy RT (IMRT) with those after 3-dimensional conformal RT (3D-CRT).Patients and MethodsNinety patients given involved-site IMRT in 2009–2014 were evaluated for treatment-induced hypothyroidism, defined as elevated thyroid-stimulating hormone (TSH) or decreased free thyroxine (fT4) levels or both. Receiver operating characteristic curve analysis identified individuals at low vs. high risk based on dosimetric variables. Dosimetric cutoff points were verified with an external dataset of 50 patients given 3D-CRT.ResultsMost patients given IMRT (75 [83%]) had stage II HL and the median prescribed dose was 30.6 Gy; in the 3D-CRT group 32 (64%) had stage II HL and the median prescribed dose was 32.0 Gy. No differences were found in proportions of patients with bilateral (P=0.982) or unilateral neck involvement (P=0.074) between either group. Hypothyroidism rates were marginally higher in the IMRT group, with estimated 3-year rates of freedom from hypothyroidism of 56.1% for the 3D-CRT group and 40% for the IMRT group (P=0.057). Univariate analysis showed that smaller thyroid volume and higher thyroid dose were associated with hypothyroidism in both groups (P<0.05). In the IMRT group, V25 and the absolute volume of thyroid spared from 25 Gy (VS25Gy) were the strongest predictors of hypothyroidism (P=0.001 and P<0.001). Cutoff points of 63.5% (V25) and 2.2 mL (VS25Gy) classified patients as high-risk (80%-82%) or low-risk (37%-44%) (P<0.001). Use of a thyroid avoidance structure reduced the incidence of hypothyroidism (P<0.05) in the IMRT group.ConclusionsThe percentage of thyroid receiving 25 Gy and the volume of thyroid spared from 25 Gy predicted risk of hypothyroidism after either IMRT or 3D-CRT for HL. IMRT may confer a higher risk than 3D-CRT unless a treatment avoidance structure is used during planning.

Teaser

In this comprehensive evaluation of risk factors associated with hypothyroidism after IMRT and involved-site RT for HL, identified variables included thyroid V25 and V30 and both absolute thyroid volume (cut point 11.2 mL) and volume spared from ≥25 Gy (≥2.2 mL). We further recommend contouring the thyroid and using thyroid avoidance structures in treatment planning when they do not compromise target coverage.


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Corticothalamic axon morphologies and network architecture

Abstract

Recent commentaries on the role of the thalamus consider a wide sphere of influence beyond sensory-motor transformation, to include task-relevant cognitive processes. In this short review, I reconsider known anatomic features of corticothalamic connectivity, primarily for macaque monkey, and discuss these as part of an intricate network architecture consistent with multiple connectional re-combinations and a diversity of functional tasks. Drawing mainly on results from single axon analysis for the two broad classes of corticothalamic (CT) connections, I review the strikingly complementary spatial parameters of their extrinsic CT arbors in relation to intrinsic cortical collaterals. That is, CT neurons in layer 5 (class II) have spatially compact (low divergent) thalamic fields, but highly spatially divergent cortical collaterals. In contrast, CT neurons in layer 6 (class I) have highly divergent thalamic fields, but delimited, low divergent cortical collaterals. CT convergence in the thalamus is technically more difficult to analyze; but one can infer a low convergence of terminations from layer 5, in contrast with CT terminations from layer 6, which are highly convergent. Reciprocating thalamocortical (TC) axons have multiple clustered and divergent arbors. What to conclude from these relationships requires further investigation of activity patterns and networks under different conditions. Specific parameters are suggestive of selective recruitment of distributed postsynaptic networks and ordered activity sequences; but are these separable systems, operating cooperatively or in parallel (L.5 low divergent/low convergent vs. L. 6 high divergent/high convergent)?

This article is protected by copyright. All rights reserved.

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Poor Motor-Function Recovery after Spinal Cord Injury in Anxiety-Model Mice with Phospholipase C-Related Catalytically Inactive Protein Type 1 Knockout

Journal of Neurotrauma, Ahead of Print.


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Valproic Acid Treatment Decreases Serum Glial Fibrillary Acidic Protein and Neurofilament Light Chain Levels in Swine Subjected to Traumatic Brain Injury

Journal of Neurotrauma, Ahead of Print.


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The Feasibility of Telephone-Administered Cognitive Testing in Individuals 1 and 2 Years after Inpatient Rehabilitation for Traumatic Brain Injury

Journal of Neurotrauma, Ahead of Print.


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Parallel Evaluation of Two Potassium Channel Blockers in Restoring Conduction in Mechanical Spinal Cord Injury in Rat

Journal of Neurotrauma, Ahead of Print.


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Functional Status Examination in Patients with Moderate-to-Severe Traumatic Brain Injuries

Journal of Neurotrauma, Ahead of Print.


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Poor Motor-Function Recovery after Spinal Cord Injury in Anxiety-Model Mice with Phospholipase C-Related Catalytically Inactive Protein Type 1 Knockout

Journal of Neurotrauma, Ahead of Print.


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Critical Thresholds of Intracranial Pressure-Derived Continuous Cerebrovascular Reactivity Indices for Outcome Prediction in Noncraniectomized Patients with Traumatic Brain Injury

Journal of Neurotrauma, Ahead of Print.


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Valproic Acid Treatment Decreases Serum Glial Fibrillary Acidic Protein and Neurofilament Light Chain Levels in Swine Subjected to Traumatic Brain Injury

Journal of Neurotrauma, Ahead of Print.


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The Feasibility of Telephone-Administered Cognitive Testing in Individuals 1 and 2 Years after Inpatient Rehabilitation for Traumatic Brain Injury

Journal of Neurotrauma, Ahead of Print.


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Parallel Evaluation of Two Potassium Channel Blockers in Restoring Conduction in Mechanical Spinal Cord Injury in Rat

Journal of Neurotrauma, Ahead of Print.


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Esophageal Paget’s Disease Secondary to Hypopharyngeal Carcinoma: a Case Report

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Electroretinogram evaluation for the treatment of proliferative diabetic retinopathy by short-pulse pattern scanning laser panretinal photocoagulation

Abstract

Panretinal photocoagulation (PRP) is a standard method for proliferative diabetic retinopathy (PDR) treatment. However, conventional PRP usually significantly damages the retinal structure and vision. Retinal pattern scanning laser (PASCAL) photocoagulation has emerged as a new technique with fewer complications for the treatment of retinal disorders. This study compares the therapeutic effects of short-pulse PASCAL to conventional single-spot PRP for PDR. Fifty-two PDR patients (104 eyes) were randomly assigned into a short-pulse PASCAL-PRP treatment (SP) group and a conventional PRP treatment (TP) group. The best corrected visual acuity (BCVA) and full-field flash electroretinogram (ERG) data were evaluated before and after the two treatments. The BCVA data between before and after the PRP treatments did not show any significant difference. After the PRP treatment, the b-wave amplitude (b-A) in the dark-adapted 3.0 ERG (p = 0.0005) and the amplitude in the light-adapted 3.0 flicker ERG (p = 0.009) were significantly higher in the SP group compared with that of the TP group. In addition, after the PRP treatment, the a-wave implicit time (a-T) of light-adapted 3.0 ERG prolonged significantly in the TP group compared to the SP group. Compared with the parameters before the treatments, the a-A and b-A under dark-adapted 3.0 ERG and the b-A under the light-adapted 3.0 ERG in both TP and SP groups after the treatments decreased significantly (p < 0.05). Short-pulse PASCAL-PRP significantly attenuated partial vision damage compared to conventional PRP, although it still caused limited retinal injury and mild reduction in retinal function. These findings suggest that short-pulse PASCAL-PRP is a promising technique for PDR treatment.

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PRRT2 controls neuronal excitability by negatively modulating Na+ channel 1.2/1.6 activity

Abstract

Proline-rich transmembrane protein 2 (PRRT2) is the causative gene for a heterogeneous group of familial paroxysmal neurological disorders that include seizures with onset in the first year of life (benign familial infantile seizures), paroxysmal kinesigenic dyskinesia or a combination of both. Most of the PRRT2 mutations are loss-of-function leading to haploinsufficiency and 80% of the patients carry the same frameshift mutation (c.649dupC; p.Arg217Profs*8), which leads to a premature stop codon. To model the disease and dissect the physiological role of PRRT2, we studied the phenotype of neurons differentiated from induced pluripotent stem cells from previously described heterozygous and homozygous siblings carrying the c.649dupC mutation. Single-cell patch-clamp experiments on induced pluripotent stem cell-derived neurons from homozygous patients showed increased Na⁺ currents that were fully rescued by expression of wild-type PRRT2. Closely similar electrophysiological features were observed in primary neurons obtained from the recently characterized PRRT2 knockout mouse. This phenotype was associated with an increased length of the axon initial segment and with markedly augmented spontaneous and evoked firing and bursting activities evaluated, at the network level, by multi-electrode array electrophysiology. Using HEK-293 cells stably expressing Na_v channel subtypes, we demonstrated that the expression of PRRT2 decreases the membrane exposure and Na⁺ current of Na_v1.2/Na_v1.6, but not Na_v1.1, channels. Moreover, PRRT2 directly interacted with Na_v1.2/Na_v1.6 channels and induced a negative shift in the voltage-dependence of inactivation and a slow-down in the recovery from inactivation. In addition, by co-immunoprecipitation assays, we showed that the PRRT2-Na_v interaction also occurs in brain tissue. The study demonstrates that the lack of PRRT2 leads to a hyperactivity of voltage-dependent Na⁺ channels in homozygous PRRT2 knockout human and mouse neurons and that, in addition to the reported synaptic functions, PRRT2 is an important negative modulator of Na_v1.2 and Na_v1.6 channels. Given the predominant paroxysmal character of PRRT2-linked diseases, the disturbance in cellular excitability by lack of negative modulation of Na⁺ channels appears as the key pathogenetic mechanism.

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Reply to ‘Comment on ‘BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses’’

Reply to 'Comment on 'BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses''

Reply to 'Comment on 'BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses'', Published online: 15 March 2018; doi:10.1038/s41416-018-0032-y

Reply to 'Comment on 'BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses''

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Comment on ‘BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses'

Comment on 'BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses'

Comment on 'BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses', Published online: 15 March 2018; doi:10.1038/s41416-018-0023-z

Comment on 'BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses'

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Repair of a perforated sinus membrane with an autogenous periosteal graft: a study in 24 patients

We describe a technique for repairing a perforation of the sinus membrane with a periosteal graft. Of 117 patients who had augmentation of the sinus floor, the sinus membrane perforated in 24, and these were repaired with autogenous periosteal grafts. Patients were followed up daily for the first 10days and monthly for the next six months, and clinical and radiographic variables were recorded. Patients had to be free of complications such as wound dehiscence, sinus infections, exposure of the graft, local inflammation, or pain.

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Survivin Monoclonal Antibodies Detect Survivin Cell Surface Expression and Inhibit Tumor Growth in vivo

Purpose: Survivin is an inhibitor of apoptosis protein (IAP) that is highly expressed in many cancers and represents an attractive molecule for targeted cancer therapy. Although primarily regarded as an intracellular protein with diverse actions, survivin has also been identified in association with circulating tumor exosomes. Experimental Design: We have reported that active specific vaccination with a long peptide surviving immunogen leads to the development of survivin-specific CD8-mediated tumor cell lysis and prolongation of survival in tumor-bearing mice. In addition to cellular antitumor responses, circulating anti-survivin antibodies are detected in the serum of mice and human glioblastoma patients following vaccination with the survivin immunogen. Results: Here we demonstrate that survivin is present on the outer cell membrane of a wide variety of cancer cell types, including both murine and human glioma cells. In addition, antibodies to surviving that are derived from the immunogen display antitumor activity against murine GL261 gliomas in both flank and intracranial tumor models and against B16 melanoma as well. Conclusion: In addition to immunogen-induced, CD8-mediated tumor cell lysis, antibodies to the survivin immunogen have antitumor activity in vivo. Cell-surface survivin could provide a specific target for antibody-mediated tumor immunotherapeutic approaches.

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STAT3/HOTAIR signaling axis regulates HNSCC growth in an EZH2-dependent manner

Purpose: Phosphotidylinositol-3-kinase (PI3K)and signal transducers and activators of transcription 3 (STAT3) are frequently activated in cancer progression. However, little is known about the underlying mechanisms by which PI3K and STAT3 regulate HNSCC growth. The lncRNA HOX transcript antisense RNA (HOTAIR) was found to modulate the progression of head and neck squamous cell cancer (HNSCC). In this study, we attempted to establish the correlation of PI3K-STAT3-HOTAIR signaling with the progression of HNSCC and its sensitivity towards platinum-based and targeted anti-EGFR combination therapy. Experimental Design: We first analyzed the STAT3/HOTAIR and PI3K/AKT level in human HNSCC samples. We then activated or suppressed STAT3/HOTAIR and determined the effects on HNSCC cell proliferation in vitro and the growth of UM1 xenograft tumor, an orthotopic model of HNSCC. The sensitivity of HNSCC cells towards cisplatin and cetuximab was determined by in vitro assays. Results: HNSCC samples showed significantly robust expression/activation of STAT3, HOTAIR, PI3K, and AKT, compared with normal squamous epithelium. STAT3 inhibition with WP1066 decreased HOTAIR level and sensitized HNSCC to cisplatin or cetuximab. STAT3 promoted HOTAIR transcription and its interaction with pEZH2-S21, resulting in enhanced growth of HNSCC cells. In addition, overexpression of HOTAIR promoted the growth of UM1 xenograft tumors in vivo. Conclusions: Our results suggest that STAT3 signaling promotes HNSCC progression via regulating HOTAIR and pEZH2-S21 in HNSCC with PI3K overexpression/activation. These findings provide a rationale to target the STAT3/HOTAIR/pEZH2-S21 regulatory axis for treating patients with HNSCC.

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Mucoepidermoid carcinoma of the parotid gland: A National Cancer Database study

To describe the demographics, tumor characteristics, and prognostic features of mucoepidermoid carcinoma of the parotid gland.

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Are surgeons overdosing patients with lidocaine?

Local anesthetics have long been used since the 1850s following the first pure extraction of cocaine from coca leaves. Cocaine was a potent anesthetic, however, it led to deaths and addictions for health care members and patients alike [1]. Other local anesthetics such as tetracaine, tropocaine, lidocaine, bupivacaine and more recently, ropivacaine, were synthesized to minimize the cocaine toxicity. These newer anesthetic agents included both ester and amide preparationswith varying degrees of cardiovascular and neurotoxicity [1].

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MPO promoter polymorphism rs2333227 enhances malignant phenotypes of colorectal cancer by altering the binding affinity of AP-2{alpha}

Myeloperoxidase (MPO) promoter single nucleotide polymorphisms (SNPs) rs2243828 (-764T>C) and rs2333227 (G-463A) program malignant phenotypes by regulating MPO transcriptional activity. In this study, we enrolled a total of 1,175 controls and 1,078 colorectal cancer (CRC) patients with comprehensive clinical and survival information to assess whether these SNPs could affect the susceptibility and development of CRC. The MPO rs2333227 TT genotype significantly increased the risk of CRC and decreased the overall survival time of patients. CRC cells with the rs2333227 TT genotype exhibited enhanced proliferation, migration, and invasion capacity in vitro and in vivo. Mechanistically, we found that MPO SNP rs2333227 C to T mutation altered the binding affinity of the transcription factors AP-2α to the rs2333227 mutation region, sequentially enhancing expression levels of MPO and activating further IL23A-MMP9 axis-mediated oncogenic signaling. Taken together, our findings indicate that MPO SNP rs2333227 serves as a marker of enhanced risk for development of CRC.

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Molecular alterations of newly formed mandibular bone caused by zoledronate

Bone quality is defined by structural and material characteristics. Most studies on the mandible have focused on the analysis of structural characteristics, with insufficient investigation of material characteristics. This study tested whether zoledronate affects the material characteristics of newly formed mandibular bone. Thirty-six female Wistar rats were assigned to three groups: sham-ovariectomized rats (SHAM, n=12), ovariectomized rats (OVX, n=12), and ovariectomized rats treated with zoledronate (ZOL, n=12).

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Myocardial Infarction Injury in Patients with Chronic Lung Disease Entering Pulmonary Rehabilitation: Frequency and Association with Heart Rate Parameters

Myocardial infarction (MI) remains under-recognized in chronic lung disease (CLD) patients. Rehabilitation health professionals need accessible clinical measurements to identify the presence of prior MI in order to determine appropriate training prescription.

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Sex Differences in Common Sports Injuries

Common sports injuries include bone stress injuries (BSI), anterior cruciate ligament injuries (ACL), and concussions. Less commonly recognized are the specific sex differences in epidemiology, risk factors, and outcomes of these conditions by sex. An understanding of these factors can improve their clinical management, from prescribing appropriate prehabilitation to guiding post injury rehabilitation and return to play. This narrative review summarizes the sex differences in the diagnosis and management of BSI, ACL injuries, and concussions.

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Rhythmic Neck Muscle Spasms and Upper Limb Muscle Myoclonic Jerks as an Unusual Initial Presentation of Posttraumatic Cervicothoracic Syringomyelia: A Case Report

Posttraumatic syringomyelia with an initial presentation of involuntary movement is rare. We describe a 25-year-old patient who sustained complete traumatic spinal cord injury at the thoracic level and presented with rhythmic neck muscle spasms and upper limb muscle myoclonic jerks 1 month after trauma. Magnetic resonance imaging revealed syrinx formation between C3 and T1. Lumbar-peritoneal shunt and decompression were performed. The symptoms completely disappeared after surgery. This report highlights that rhythmic neck muscle spasms and upper limb muscle myoclonic jerks can be the initial and only manifestations of syringomyelia.

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Characteristics and outcomes of children with conversion disorder admitted to a single inpatient rehabilitation unit, a retrospective study

Conversion disorder (CD) can lead to impaired functioning. Few studies present demographic and outcome data for pediatric patients. Many have had success with rehabilitation, however further details are not known.

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The Specialty of Hope: How Physiatry Made Boston Strong

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Pharmacological Treatment for Depression at Injury is associated with Fewer Clinician Visits for Persistent Symptoms after Mild Traumatic Brain Injury: A Medical Record Review Study

Depression and traumatic brain injury (TBI) substantially contribute to the United States healthcare burden. Depression is a known risk factor for prolonged recovery after TBI. However, the effect of depression treatment on health care utilization has yet to be studied.

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Functional Outcomes of an Interdisciplinary Outpatient Rehabilitation Program for Patients with Malignant Brain Tumors

Malignant brain tumors cause significant impairments in function due to nature of the disease. Patients with malignant brain tumors can make functional gains equivalent to those with stroke and traumatic brain injury in the inpatient rehabilitation setting. However, the efficacy of outpatient rehabilitation in this population has received little study.

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Increasing the Representation of Minority Students in the Biomedical Workforce: the ReTOOL Program

Abstract

With the growing burden of cancer in minority populations and limited progress in eliminating cancer disparities, it has become important to develop a diverse oncology workforce in basic, clinical, and behavioral research who will address cancer disparities and increase the participation of minority populations in clinical trials. To address the lack of well-trained underrepresented minority cancer scientists in Florida, the University of Florida collaborated with Florida A&M University in 2012 to establish the Florida Prostate Cancer Research Training Opportunities for Outstanding Leaders (ReTOOL) Program. Since 2012, the ReTOOL program has expanded to (1) cover all areas of cancer disparities; (2) offer training opportunities to minority students from all historically Black colleges and universities (HBCUs) in Florida; and (3) successfully secure both intramural and extramural federal funding to continuously provide research training opportunities for minority students in Florida. Focusing primarily on training Black students, the ReTOOL model includes culturally sensitive recruitment, mentorship, didactic curriculum, networking, and hands on experience in cancer research. This paper discusses the lessons learned from administering the ReTOOL program for 5 years, which includes having the right inputs (such as majority-minority institutions partnership, funding, faculty advisors, committed mentors, culturally competent staff, and standardized program requirements) and processes (such as pipeline approach, structured applications system, didactic curriculum, research experience, and continuous mentoring) for an effective research training program. The program impact is an increase in the pool of underrepresented minority candidates with scientific and academic career progression paths focused on reducing cancer health disparities.

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