Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174: 11/06/17

Δευτέρα 6 Νοεμβρίου 2017

Does the reduction of inferior turbinate size affect lower airway functions?

Publication date: Available online 6 November 2017
Source:Brazilian Journal of Otorhinolaryngology
Author(s): Ozlem Unsal, Mehtap Ozkahraman, Mufide Arzu Ozkarafakili, Meltem Akpinar, Arzu Yasemin Korkut, Senem Kurt Dizdar, Berna Uslu Coskun
IntroductionAlthough the nose and lungs are separate organs, numerous studies have reported that the entire respiratory system can be considered as a single anatomical and functional unit. The upper and lower airways affect each other either directly or through reflex mechanisms.ObjectiveIn this study, we aimed to evaluate the effects of the radiofrequency ablation of persistent inferior turbinate hypertrophy on nasal and pulmonary function.MethodsTwenty-seven patients with bilateral persistent inferior turbinate hypertrophy without septal deviation were included in this study. All of the patients were evaluated using anterior rhinoscopy, nasal endoscopy, acoustic rhinometry, a visual analogue scale, and flow-sensitive spirometry on the day before and 4 months after the radiofrequency ablation procedure.ResultsThe post-ablation measurements revealed that the inferior turbinate ablation caused an increase in the mean cross-sectional area and volume of the nose, as well as in the forced expiratory volume in 1s, forced vital capacity, and peak expiratory flow of the patients. These differences between the pre- and post-ablation results were statistically significant. The post-ablation visual analogue scale scores were lower when compared with the pre-ablation scores, and this difference was also statistically significant.ConclusionThis study demonstrated that the widening of the nasal passage after the reduction of the inferior turbinate size had a favorable effect on the pulmonary function tests.

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The hidden benefits of oil pulling

It lasted just a little longer than a week. Three years ago for 10 days, Jennifer Beckinsale woke up each morning, poured a tablespoon of coconut oil into her mouth and swished it around for 20 minutes.

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Intralabyrinthine sporadic endolymphatic sac tumour

Publication date: Available online 6 November 2017
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): C. Lucas, J.-C. Leclère, E. Mornet, R. Marianowski
IntroductionEndolymphatic sac tumours are benign, slowly growing tumours that invade the temporal bone, and present clinically in the form of unilateral hearing loss. They can be sporadic or occur in the context of Von Hippel-Lindau disease (VHL).Case summaryThe authors report a case of endolymphatic sac tumour arising in the utricle presenting histological and immunohistochemical features corresponding to endolymphatic sac tumour in a patient without VHL.DiscussionEndolymphatic sac tumours invade the posterior part of the petrous temporal bone. According to two studies concerning patients with Von Hippel-Lindau disease, endolymphatic sac tumours arise from the endolymphatic duct. This case of intralabyrinthine sporadic endolymphatic sac tumour supports this hypothesis for sporadic forms, indicating the need for labyrinthectomy associated with tumour resection to avoid recurrence.

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The Effect of Visual Contrast on Human Vestibulo-Ocular Reflex Adaptation

AbstractThe vestibulo-ocular reflex (VOR) is the main retinal image stabilising mechanism during rapid head movement. When the VOR does not stabilise the world or target image on the retina, retinal image slip occurs generating an error signal that drives the VOR response to increase or decrease until image slip is minimised, i.e. VOR adaptation occurs. Visual target contrast affects the human smooth pursuit and optokinetic reflex responses. We sought to determine if contrast also affected VOR adaptation. We tested 12 normal subjects, each over 16 separate sessions. For sessions 1 –14, the ambient light level (lx) during adaptation training was as follows: dark, 0.1, 0.2, 0.3, 0.5, 0.7, 1, 2, 8, 16, 32, 64, 128 and 255 lx (light level for a typical room). For sessions 15–16, the laser...

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Tomah VA sued over improper dental care

UNDATED A group of veterans who received dental care at the Tomah VA Medical Center filed a class-action lawsuit over the use of improperly sterilized equipment. The lawsuit, filed by six vets last Wednesday, claims they suffered emotional distress after they were notified that unsterilized dental instruments may have exposed them to illnesses or infection.

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Dental college seeks patients willing to pay a small price for big care

Interim Dental Clinic Director Dr. Gerry Uswak performs a mock check-up at the training clinic at the University of Saskatchewan in Saskatoon on Nov. 2, 2017. The University of Saskatchewan's dental college is home to one of the best-kept secrets in the city - but both staff and students are hoping it doesn't stay that way.

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Medication related osteonecrosis of the jaws associated with targeted therapy as monotherapy and in combination with anti-resorptives. a report of seven cases from the copenhagen ONJ cohort

To report cases of medication related osteonecrosis of the jaws (MRONJ) associated with Targeted Therapy (TT) with and without concomitant anti-resorptive treatment, among The Copenhagen ONJ Cohort, which includes all consecutive cases of MRONJ seen in Copenhagen.

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Effects of single condylar neck fracture without condylar cartilage injury on traumatic heterotopic ossification around temporomandibular joint in mice

In this study, we try to explore the effects of single condylar neck fracture without condylar cartilage injury during the pathogenesis process of traumatic heterotopic ossification around temporomandibular joint (THO-TMJ).

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Clinical pathologic conference: diffuse papillomatous lesions of the gingiva with posterolateral neck skin tags

A 47-year-old Caucasian female initially presented to the General Dentistry Clinic at Vanderbilt University Medical Center with a chief complaint of loose anterior teeth and a need for a dental check-up. The patient was noted to have several carious teeth and moderate, generalized periodontal disease. In addition, she presented with numerous 1-2 mm papillomatous lesions involving attached gingiva and unattached alveolar mucosa. The patient was referred to the Oral & Maxillofacial Surgery Department at Vanderbilt for further evaluation and consultation regarding her intraoral lesions.

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Transcanal endoscopic ear surgery for perilymphatic fistula after electric acoustic stimulation

Transcanal endoscopic ear surgery (TEES) will become a very useful therapeutic option. A perilymphatic fistula (PLF) is defined as sudden sensorineural hearing loss and/or vertigo caused by leakage of the perilymph through a fistula from the oval window and/or round window. We report a case of PLF after electric acoustic stimulation (EAS), a kind of cochlear implant, successfully treated by TEES. A 38-year-old man presented to our hospital with vertigo and hearing loss (HL). His vertigo was induced by Valsalva maneuvers.

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A novel pathogenic variant c.975G>A (p.Trp325*) in the POU3F4 gene in Yakut family (Eastern Siberia, Russia) with the X-linked deafness-2 (DFNX2)

Here, we report a novel hemizygous transition c.975G>A (p.Trp325*) in POU3F4 gene (Xq21) found in two deaf half-brothers from one Yakut family (Eastern Siberia, Russia) with identical inner ear abnormalities ("corkscrew" cochlea with an absence of modiolus) specific to X-linked deafness-2 (DFNX2). Comprehensive clinical evaluation (CT and MR-imaging, audiological and stabilometric examinations) of available members of this family revealed both already known (mixed progressive hearing loss) and additional (enlargement of semicircular canals and postural disorders) clinical DFNX2 features in affected males with c.975G>A (p.Trp325*).

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A novel technique for unilateral supraglottoplasty

Traditional supraglottoplasty for pediatric laryngomalacia is most commonly conducted with either CO2 laser or cold steel instruments. While the procedure enjoys high success rates, serious complications such as excessive bleeding, supraglottic stenosis and aspiration can occur. Unilateral coblation supraglottoplasty may reduce this risk, but data on respiratory and swallowing outcomes are lacking. This study reports our experiences with unilateral coblation supraglottoplasty.

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Recurrent laryngeal nerve reinnervation for management of aspiration in a subset of children

Pediatric aspiration is a multifactorial process that is often complex to manage. Recurrent laryngeal nerve (RLN) injury can cause glottic insufficiency and aspiration. We describe three cases of unilateral vocal fold paralysis resulting in aspiration and the successful use of the RLN reinnervation for its treatment.The theory for utilizing the reinnervation procedure is that when glottic closure improves and a less breathy vocalization occurs, then the larynx is better equipped to protect the lower airway and avoid aspiration.

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Relative rates not relative risks: addressing a wide-spread misinterpretation of hazard ratios

The use of the Cox proportional hazards model is ubiquitous in modern medical research. Despite the wide-spread implementation of this model, the terminology and interpretation that is used to describe the estimate hazard ratio has become loose and, unfortunately, often incorrect. Although some journals offer guidelines that advise against reporting hazard ratios as relative risks, these guidelines are frequently overlooked. Perhaps due to a lack of understanding, authors continue to interpret the resultant hazard ratio as a relative risk–such an interpretation is inappropriate and can be misleading.

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Using reference values to define disease based on the lower limit of normal biased the population attributable fraction, but not the population excess risk: the example of chronic airflow obstruction

The impact of disease on population health is most commonly estimated by the population attributable fraction (PAF). This measurement, an estimate of the proportion of the disease in the population that is attributable to the exposure, is sensitive to the way that the disease is defined. When disease is defined from reference values that are derived from the distribution of values in the "normal" population the PAF is difficult to interpret. Using measures of chronic airflow obstruction as an example, we demonstrate that where normality is defined by centiles (or fractiles) of values in a "normal" population, PAF is strongly influenced by which centile is selected to define normality.

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Recommendations for primary studies evaluating therapeutic medical devices were identified and systematically reported through reviewing existing guidance

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Short- and long-term changes of the pharyngeal airway after surgical mandibular advancement in Class II patients—a three-dimensional retrospective study

To evaluate the short- and long-term impact of mandibular-only advancement on pharyngeal airway space (PAS) changes by using cone-beam computed tomography (CBCT) and a new segmentation software. Furthermore, to determine whether a correlation exists between forward movement and PAS gain.

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Robot-assisted excision of the submandibular gland by a postauricular facelift approach: comparison with the conventional transcervical approach

Various approaches have been described for excision of a submandibular gland including endoscopic and robot-assisted techniques. We present the outcome of excision by a robot-assisted postauricular facelift approach and compare it with the conventional transcervical approach. We studied 30 cases of excision of the gland for benign disease (16 transcervical and 14 robot-assisted), and collected clinical and personal data, and details of patients' satisfaction with the result. The most common conditions were sialadenitis (n=15) and pleomorphic adenoma (n=12).

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Salivary Aerobics

I read with interest the paper by Meng et al, 'Sialoendoscopy combined with an internal stent and postoperative massage as a comprehensive treatment of delayed I131-induced parotitis.'1

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Multiple myeloma of the mandibular condyle: a rare presentation

A 66-year-old man presented to the emergency department with a dull continuous pain in his temporomandibular joint (TMJ). Two days earlier he had been woken up by a sudden sharp pain with a loud click referred to the right ear. A computed tomographic (CT) scan was taken, which showed a radiolucent area that occupied most of his condylar head and neck. The cortical bone was missing or paper-thin (Fig. 1).

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Study of anatomical variations of the zygomaticofacial foramen and calculation of reliable reference points for operation

Dissection on to the facial aspect of the zygoma is common in procedures of the midface for trauma, craniofacial deformity, and cosmesis. These procedures carry the risk of injury to the neurovascular structures that exit from the zygomaticofacial foramen (ZFF). The purpose of this study was to map the ZFF, and to establish reliable reference points from which to identify it before and during operation. We also aimed to compare the anatomy of the ZFF between sexes and among geographical populations.

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Pelagic barite precipitation at micromolar ambient sulfate

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Grants will aid traffic flow on Oak Street

My dentist once told me to keep floss in my car and floss my teeth every time I had to sit at a red light. I might have the cleanest and healthiest teeth in all of Faulkner County simply because I drive down Oak Street about once a week.

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T cells are involve in the induction of macrophage phenotypes in oral leukoplakia and squamous cell carcinoma – a preliminary report

Abstract

Background

The prognosis of human malignancies has been shown to depend on immunological parameters, such as macrophage polarisation (M1 and M2). In the present study, we identify the phenotype of macrophages, and investigate an involvement of infiltrated T cells that participate in the polarization of macrophages, in oral leukoplakia (OLK), and oral squamous cell carcinoma (OSCC).

Methods

Immunohistochemical method was used to examine the number of CD68⁺, CD163⁺ (M2), iNOS⁺ (M1) macrophages, and CD4⁺, CD8⁺, CCR4⁺ (Th2), CCR5⁺ (Th1) cells in 102 cases of OSCC: without metastases – OSCC M(-) (n=54), and with metastases – OSCC M(+) (n=48), 23 cases of OLK, and 18 control cases.

Results

The mean number of CD68⁺, CD163⁺, iNOS⁺, CD4⁺, CCR4⁺, CCR5⁺ cells was significantly increased in OSCC M(+) group compared with OLK, OSCC M(-) and control group. We found positive correlations between the number of CD4⁺ T cells and CD163⁺ and iNOS⁺ macrophages as well as CCR4⁺ and CCR5⁺ cells in both OSCC groups. The mean number of CD8⁺ cells was significantly increased in OSCC M(-) and OLK compared with OSCC M(+) and control group. In OSCC M(+) and OSCC M(-) groups a negative correlation between the number of CD8⁺ cells and CD163⁺ and iNOS⁺ macrophages was found.

Conclusions

The number and co-localization of lymphocytes and macrophages in OLK and OSCC, may indicate that infiltrating cells influence the early and subsequent stage of oral carcinogenesis.

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Antiangiogenic therapy in breast cancer

Summary

Based on a strong rationale for anti-VEGF (vascular endothelial growth factor) treatment in breast cancer and promising preclinical data, great hopes have been placed on the anti-VEGF antibody bevacizumab. Clinical trials, however, reported conflicting results. In metastatic human epidermal growth factor receptor 2(HER2)-negative breast cancer, the addition of bevacizumab to standard chemotherapy improved consistently progression-free survival (PFS), however, without effect on overall survival (OS). In early breast cancer bevacizumab increased the pathologic complete response rate (pCR) after neoadjuvant therapy, but adjuvant trials did not demonstrate an effect on long-term survival. Unfortunately, despite extensive research, there is still no biomarker for bevacizumab efficacy available, making patient selection difficult. This review summarizes all phase III trials investigating efficacy and toxicity of bevacizumab in early, locally advanced and metastatic breast cancer. It recapitulates the main toxicities, gives an overview on biomarker studies and discusses the role and future aspects of antiangiogenic therapy in breast cancer.

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United Natural Trading LLC Announces Voluntary Recall of Dark Chocolate Almonds and Dark Chocolate Cashew Due to Possible Health Risk From an Undeclared Milk Allergen

United Natural Trading LLC, Edison, NJ, is voluntarily recalling Dark Chocolate Cashews and Dark Chocolate Almonds (see below) sold under the Woodstock, Market Basket, Lunds and Byerlys brands due to a possible health risk from an undeclared milk allergen. People who have an allergy or severe sensitivity to milk run the risk of serious or life threatening allergic reaction if they consume these products.

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The Effect of Visual Contrast on Human Vestibulo-Ocular Reflex Adaptation

Abstract

The vestibulo-ocular reflex (VOR) is the main retinal image stabilising mechanism during rapid head movement. When the VOR does not stabilise the world or target image on the retina, retinal image slip occurs generating an error signal that drives the VOR response to increase or decrease until image slip is minimised, i.e. VOR adaptation occurs. Visual target contrast affects the human smooth pursuit and optokinetic reflex responses. We sought to determine if contrast also affected VOR adaptation. We tested 12 normal subjects, each over 16 separate sessions. For sessions 1–14, the ambient light level (lx) during adaptation training was as follows: dark, 0.1, 0.2, 0.3, 0.5, 0.7, 1, 2, 8, 16, 32, 64, 128 and 255 lx (light level for a typical room). For sessions 15–16, the laser target power (related to brightness) was halved with ambient light at 0 and 0.1 lx. The adaptation training lasted 15 min and consisted of left/right active head impulses. The VOR gain was challenged to increment, starting at unity, by 0.1 every 90 s for rotations to the designated adapting side and fixed at unity towards the non-adapting side. We measured active and passive VOR gains before and after adaptation training. We found that for both the active and passive VOR, there was a significant increase in gain only towards the adapting side due to training at contrast level 1.5 k and above (2 lx and below). At contrast level 261 and below (16 lx and above), adaptation training resulted in no difference between adapting and non-adapting side gains. Our modelling suggests that a contrast threshold of ~ 1000, which is 60 times higher than that provided by typical room lighting, must be surpassed for robust active and passive VOR adaptation. Our findings suggest contrast is an important factor for adaptation, which has implication for rehabilitation programs.

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The Effect of Visual Contrast on Human Vestibulo-Ocular Reflex Adaptation

Abstract

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Intensive Treatment for Persisting Rhotic Distortions: A Case Series

Purpose

The study explored changes in accuracy of American English rhotics as a result of an intensive 1-week therapy program for adolescents and young adults with residual speech sound errors that had not resolved with previous therapy.

Method

Four case reports are presented of individuals aged 13, 17, 21, and 22 years with residual /ɹ/ distortions. Each participant attended a 1-week intensive program consisting of pretreatment assessments, 14 hr of therapy, and posttreatment assessment. Treatment sessions included structured motor-based practice, ultrasound visual feedback of the tongue, and auditory speech perception training. To assess generalization, untreated words and sentences with rhotics were recorded before and after therapy; these were rated by listeners who were blind to when the recordings were taken.

Results

All participants showed measurable and statistically significant improvement in speech sound accuracy. Averaged across the 4 participants, rhotic accuracy at the word level improved from 35% to 83%. At the sentence level, rhotic accuracy increased from 11% pretreatment to 66% posttreatment in 1 week.

Conclusion

The promise of an intensive treatment program that includes motor-based practice, biofeedback, and auditory perception training is illustrated by the case presentations in which substantial improvements in speech sound accuracy were observed.

Supplemental Materials

http://ift.tt/2iA3f0l

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The Impact of Expiratory Muscle Strength Training on Speech Breathing in Individuals With Parkinson's Disease: A Preliminary Study

Purpose

The purpose of this study was to examine the impact of expiratory muscle strength training on speech breathing and functional speech outcomes in individuals with Parkinson's disease (PD).

Method

Twelve individuals with PD were seen once a week for 8 weeks: 4 pretraining (baseline) sessions followed by a 4-week training period. Posttraining data were collected at the end of the 4th week of training. Maximum expiratory pressure, an indicator of expiratory muscle strength, and lung volume at speech initiation were the primary outcome measures. Secondary outcomes included lung volume at speech termination, lung volume excursion, utterance length, and vocal intensity. Data were collected during a spontaneous speech sample. Individual effect sizes > 1 were considered significant.

Results

Maximum expiratory pressure increased in a majority of participants after training. Training resulted in 2 main respiratory patterns: increasing or decreasing lung volume initiation. Lung volume termination and excursion, utterance length, and vocal loudness were not consistently altered by training.

Conclusions

Preliminary evidence suggests that the direct physiologic intervention of the respiratory system via expiratory muscle strength training improves speech breathing in individuals with PD, with participants using more typical lung volumes for speech following treatment.

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The Effect of Hand Gesture Cues Within the Treatment of /r/ for a College-Aged Adult With Persisting Childhood Apraxia of Speech

Purpose

Despite the widespread use of hand movements as visual and kinesthetic cues to facilitate accurate speech produced by individuals with speech sound disorders (SSDs), no experimental investigation of gestural cues that mimic that spatiotemporal parameters of speech sounds (e.g., holding fingers and thumb together and "popping" them to cue /p/) currently exists. The purpose of this study was to examine the effectiveness of manual mimicry cues within a multisensory intervention of persisting childhood apraxia of speech (CAS).

Method

A single-subject ABAB withdrawal design was implemented to assess the accuracy of vowel + /r/ combinations produced by a 21-year-old woman with persisting CAS. The effect of manual mimicry gestures paired with multisensory therapy consisting of verbal instructions and visual modeling was assessed via clinician and naïve listener ratings of target sound accuracy.

Results

According to the perceptual ratings of the treating clinician and 28 naïve listeners, the participant demonstrated improved speech sound accuracy as a function of the manual mimicry/multisensory therapy.

Conclusions

These data offer preliminary support for the incorporation of gestural cues in therapy for CAS and other SSDs. The need for continued research on the interaction of speech and manual movements for individuals with SSDs is discussed.

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South Asian Adults' Performance on Executive Function Tests

Purpose

This study compared the performance of South Asian and White adults on the Behavioural Assessment of the Dysexecutive Syndrome (BADS; Wilson, Alderman, Burgess, Emslie, & Evans, 1996) and the Functional Assessment of Verbal Reasoning and Executive Strategies (FAVRES; MacDonald, 2005), tests that can be used by speech-language pathologists to assess executive function (EF).

Method

Twenty South Asian and 20 White participants were administered the BADS and FAVRES. Raw scores were converted to profile scores on the BADS and to standard scores on the FAVRES. Analysis of covariance statistics were calculated to compare EF test performance.

Results

South Asian and White participants did not demonstrate significant performance differences on the BADS. On the FAVRES, Whites had significantly higher accuracy scores on 2 of the 4 subtests and significantly higher rationale scores on 3 subtests. South Asian adults who completed all of their formal education in India had lower accuracy and rationale scores on 2 of the 4 subtests versus South Asian adults who completed at least some of their formal education in North America. No significant differences occurred on the Time scores for any subtest or on the overall Reasoning score.

Conclusions

Performance differences on EF tests may exist between South Asian and White adults. Further research is necessary to determine the impact of cultural and linguistic differences on EF test performance in South Asian adults.

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Smith starts OSU dentistry scholarship -

Local dentist and Gallia Commissioner Dr. David K. Smith has gifted $50,000 to The Ohio State University College of Dentistry to establish a dental scholarship fund. A 1983 graduate of the College of Dentistry, Smith's gift will help support the education of students interested in pursuing a dental career in Gallia County.

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Klebsiella pneumoniae co-producing KPC and RmtG, finally targeting Switzerland

Publication date: Available online 6 November 2017
Source:Diagnostic Microbiology and Infectious Disease
Author(s): Stefano Mancini, Laurent Poirel, Myriam Corthesy, Gilbert Greub, Patrice Nordmann
A carbapenem- and pan-aminoglycoside-resistant Klebsiella pneumoniae strain was isolated from a Brazilian patient hospitalized in a Swiss hospital. The clinical isolate carried genes encoding the KPC-2 carbapenemase and the RmtG 16S rRNA methyltransferase. This is the first report of a carbapenem-resistant K. pneumoniae producing RmtG in Europe.

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Dutch Valley Food Distributors Inc. ISSUES ALLERGY ALERT ON UNDECLARED MILK IN Item # 050605 12/11oz Dark Chocolate Almonds and Item # 050601 12/11oz Dark Chocolate Cashews.

Dutch Valley Food Distributors Inc. of Myerstown, PA is recalling 11oz Dark Chocolate Almonds and 11oz Dark Chocolate Cashews, because it contains undeclared Milk. People who have an allergy or severe sensitivity to Milk run the risk of serious or life-threatening allergic reaction if they consume these products.

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Propensity Scores in Pharmacoepidemiology: Beyond the Horizon

Abstract

Purpose of Review

Propensity score methods have become commonplace in pharmacoepidemiology over the past decade. Their adoption has confronted formidable obstacles that arise from pharmacoepidemiology's reliance on large healthcare databases of considerable heterogeneity and complexity. These include identifying clinically meaningful samples, defining treatment comparisons, and measuring covariates in ways that respect sound epidemiologic study design. Additional complexities involve correctly modeling treatment decisions in the face of variation in healthcare practice and dealing with missing information and unmeasured confounding. In this review, we examine the application of propensity score methods in pharmacoepidemiology with particular attention to these and other issues, with an eye towards standards of practice, recent methodological advances, and opportunities for future progress.

Recent Findings

Propensity score methods have matured in ways that can advance comparative effectiveness and safety research in pharmacoepidemiology. These include natural extensions for categorical treatments, matching algorithms that can optimize sample size given design constraints, weighting estimators that asymptotically target matched and overlap samples, and the incorporation of machine learning to aid in covariate selection and model building.

Summary

These recent and encouraging advances should be further evaluated through simulation and empirical studies, but nonetheless represent a bright path ahead for the observational study of treatment benefits and harms.

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Effectiveness of state climate and energy policies in reducing power-sector CO2 emissions

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Current Concepts of Epigenetics and Its Role in Periodontitis

Abstract

Purpose

The focus of this review is to provide an overview of the recent findings on the role of epigenetic mechanisms in periodontal disease, including disease susceptibility, progression, and as potential treatment options.

Recent Findings

The findings on the influence of oral pathogens on epigenetic regulation of pathogen recognition receptors, such as Toll-like receptors, as well as pro-inflammatory cytokines suggest an important role for epigenetics in the regulation of the host immune response. Recent studies also show that the epigenetic pattern in periodontitis lesions differ from that of healthy and gingivitis tissue. In addition, these patterns differ between tissues in the same individual. Research is also indicating a role for both DNA methylation and histone acetylation on cells osteogenic differentiation and bone regeneration.

Summary

Knowledge of epigenetic pattern in periodontal diseases may add not only to the knowledge of susceptibility of the disease but may also be a diagnostic tool to identify patients at risk to develop the severe form of periodontitis. In addition, recent research within gene therapy and tissue engineering indicate a role for epigenetics also to improve regeneration of periodontal tissues.

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Salivary Aerobics

Publication date: Available online 6 November 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): J.L.B. Carter

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Study of anatomical variations of the zygomaticofacial foramen and calculation of reliable reference points for operation

Publication date: Available online 6 November 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): A. Ferro, S. Basyuni, C. Brassett, V. Santhanam
Dissection on to the facial aspect of the zygoma is common in procedures of the midface for trauma, craniofacial deformity, and cosmesis. These procedures carry the risk of injury to the neurovascular structures that exit from the zygomaticofacial foramen (ZFF). The purpose of this study was to map the ZFF, and to establish reliable reference points from which to identify it before and during operation. We also aimed to compare the anatomy of the ZFF between sexes and among geographical populations. A total of 429 adult skulls from nine geographical sites were used. A cross-line laser was superimposed on to each zygoma to generate consistent landmarks (lines 1 and 2) from which to measure the ZFF, and the number of ZFF on each zygoma was recorded. The site and incidence of ZFF differed significantly among geographical populations, but not between sexes. Of all 858 sides, no foramina were found in 16.3%, one foramen in 49.8%, two foramina in 29%, three in 3.4% and four in 1.4%. A total of 93% of foramina were within a 25mm diameter zone (ZFF zone) centred 5mm anterior to the intersection of lines 1 and 2 on the right zygoma, and 94% were within equivalent measurements on the left. Using these landmarks, we propose a new method of identifying a ZFF zone that is irrespective of sex or geographical population. This technique may be useful in the prevention of iatrogenic damage to the ZFF neurovascular bundle during procedures on the midface and in local nerve blocks.

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Multiple myeloma of the mandibular condyle: a rare presentation

Publication date: Available online 6 November 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): G.B. Bottini, C. Steiner, T. Melchardt, A. Gaggl

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Robot-assisted excision of the submandibular gland by a postauricular facelift approach: comparison with the conventional transcervical approach

Publication date: Available online 6 November 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): R.P. Singh, E.S. Sung, C.M. Song, Y.B. Ji, K. Tae
Various approaches have been described for excision of a submandibular gland including endoscopic and robot-assisted techniques. We present the outcome of excision by a robot-assisted postauricular facelift approach and compare it with the conventional transcervical approach. We studied 30 cases of excision of the gland for benign disease (16 transcervical and 14 robot-assisted), and collected clinical and personal data, and details of patients' satisfaction with the result. The most common conditions were sialadenitis (n=15) and pleomorphic adenoma (n=12). The robot-assisted operations took significantly longer (p=0.045), had more drainage (p<0.001), and a significantly better cosmetic outcome (p=0.002). Robot-assisted excision of the submandibular gland may prove to be a viable option in the treatment of benign conditions for those patients seeking a better cosmetic outcome.

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The efficacy of supplementary sonic irrigation using the EndoActivator® system determined by removal of a collagen film from an ex vivo model

Abstract

Aim

To evaluate the efficacy of sonic irrigation (EndoActivator^®) using various polymer tips and power-settings in a stained collagen ex-vivo model.

Methodology

Fifty human, straight single-rooted extracted teeth were prepared to size 40,.08 taper. The roots were split longitudinally; stained collagen applied to the canal surfaces, photographed and re-assembled. The canals were subjected to syringe without supplementary (Group 1, n = 10), or with supplementary sonic (groups 2–5, n = 10) irrigation. EndoActivator^® tip sizes (size 15, .02 taper for groups 2 & 3, size 35,.04 taper for groups 4 & 5) and power-settings (Low for groups 2 & 4, high for groups 3 & 5) were tested. After irrigation, the canals were re-photographed and the area of residual stained-collagen was quantified using the UTHSCA Image Tool program (Version 3.0). The data were analysed using Wilcoxon signed rank test and General Linear Mixed Models.

Results

Supplementary sonic irrigation using EndoActivator^® resulted in significantly (P < 0.0001) less residual collagen compared with syringe irrigation only. Agitation of irrigant using the large EndoActivator^® tip with high-power resulted in significantly less (22.4% – 29.5%) residual collagen compared to other combinations (large-tip/low-power P = 0.001; small-tip/low-power P = 0.01; small-tip/high-power P = 0.04). There was no significant difference amongst the latter three groups (P > 0.5).

Conclusions

Supplementary sonic irrigation using the EndoActivator^® system was significantly more effective in removing stained collagen from the canal surface than syringe irrigation alone. EndoActivator^® used with large-tip (size 35, .04 taper) and high power-setting in size 40,.08 taper canals was more effective than other combinations.

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Up-regulation of IL-23 expression in human dental pulp fibroblasts by IL-17 via activation of the NF-κB and MAPK pathways

Abstract

Aim

To investigate the effects of the pro-inflammatory and Th17-polarizing mediator IL-17 on HDPFs-mediated IL-23 production and the molecular mechanism involved.

Methodology

Interleukin (IL)-17R expression was determined by semi-quantitative reverse transcriptase-polymerase chain reaction and Western blot in cultured human dental pulp fibroblasts (HDPFs). Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay were used to determine IL-23 mRNA and protein levels in IL-17-stimulated HDPFs, respectively. The nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signalling pathways that mediate the IL-17-stimulated production of IL-23 was investigated by using Western blot and specific signalling inhibitor analyses. Statistical tests were performed using Kruskal–Wallis tests followed by the Mann–Whitney U-test. Statistical significance was considered when P value <0.05.

Results

Primary HDPFs steadily expressed IL-17R mRNA and surface-bound protein. IL-17 stimulated the expression of IL-23 mRNA and protein in cultured human dental pulp fibroblasts, which was attenuated by IL-17 or IL-17R neutralising antibodies. In accordance with the enhanced expression of IL-23, IL-17 stimulation resulted in rapid activation of p38 MAPK, extracellular signal-regulated kinase (ERK) 1/2, c-Jun-N-terminal kinase (JNK) and NF-κB in HDPFs. Inhibitors of p38 MAPK, ERK 1/2 or NF-κB significantly suppressed, whereas blocking JNK substantially augmented IL-23 production from IL-17-stimulated HDPFs.

Conclusion

HDPFs expressed IL-17R and responded to IL-17 to produce IL-23 via the activation of the NF-κB and MAPK signalling pathways. The findings provide insights into the cellular mechanisms of the participation of IL-17 in the activation of HDPFs in inflamed pulp tissue.

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Human Periodontal Ligament Fibroblasts synthesize C-Reactive Protein and Th-Related Cytokines in response to Interleukin (IL)-6 trans-signaling

Abstract

Aim

To characterize the potential of human periodontal ligament fibroblasts (HPLF) to synthesize CRP and Th-related cytokines in response to IL-6 in periodontal health and apical inflammation.

Methodology

Primary HPLF stimulated with IL-6, soluble(s) IL-6 receptor (R) and controls were assayed for CRP, Th1, Th2, Th17 and Treg-related cytokines by quantitative real time PCR and ELISA, respectively. IL-6R mRNA expression and its soluble protein levels were screened in HPLF cultures, and ex vivo samples of healthy periodontal ligaments (n=5) and apical lesions (n=13). Data were analyzed with ANOVA or unpaired t-test.

Results

0.5 ng/mL IL-6 plus 1ng/mL of its soluble receptor (sIL-6R) for 24 h were effective in inducing CRP production. IL-6 alone had a mild dose-dependent effect; co-stimulation with sIL-6R significantly enhanced this effect, whereas it was completely abolished by the addition of IL-6R blocking antibody (p<0.05). Similarly, higher mRNA expression and protein levels of Th1, Th17 and partially Treg related cytokines were found for IL-6 combined with its soluble receptor versus the non-stimulated group and IL-6R antibody (p<0.05). IL-6R mRNA expression was slightly induced by IL-6 compared to THP-1 cells, but sILR-6 protein could not be detected in HPLF. High sIL-6R levels were detected in apical lesions and was immunolocalized to mononuclear inflammatory cells and proliferating epithelium.

Conclusions

IL-6 trans-signaling induced Th1 and Th17-related cytokines and represents an extra hepatic mechanism for PCR synthesis in human periodontal ligament fibroblasts, contributing to explain the bone destructive phenotype of apical lesions and eventually its systemic complications.

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White matter fiber bundle lengths are shorter in cART naive HIV: an analysis of quantitative diffusion tractography in South Africa

Abstract

This study examines white matter microstructure using quantitative tractography diffusion magnetic resonance imaging (qtdMRI) in HIV+ individuals from South Africa who were naïve or early in the initiation of antiretroviral therapy. Fiber bundle length (FBL) metrics, generated from qtdMRI, for whole brain and six white matter tracts of interest (TOI) were assessed for 135 HIV+ and 21 HIV− individuals. The association between FBL metrics, measures of disease burden, and neuropsychological performance were also investigated. Results indicate significantly reduced sum of whole brain fiber bundle lengths (FBL, p < 0.001), but not average whole brain FBL in the HIV+ group compared to the HIV− controls. The HIV+ group exhibited significantly shorter sum of FBL in all six TOIs examined: the anterior thalamic radiation, cingulum bundle, inferior and superior longitudinal fasciculi, inferior frontal occipital fasciculus, and the uncinate fasciculus. Additionally, average FBLs were significantly shorter select TOIs including the inferior longitudinal fasciculus, cingulum bundle, and the anterior thalamic radiation. Shorter whole brain FBL sum metrics were associated with poorer neuropsychological performance, but were not associated with markers of disease burden. Taken together these findings suggest HIV affects white matter architecture primarily through reductions in white matter fiber numbers and, to a lesser degree, the shortening of fibers along a bundle path.

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US government approves 'killer' mosquitoes to fight disease

WEB_C0323906-Female_Asian_tiger_mosquito

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The effects of storage time and temperature on the stability of salivary phosphatases, transaminases and dehydrogenase

Publication date: January 2018
Source:Archives of Oral Biology, Volume 85
Author(s): Damaris Raissa dos Santos, Rayne Oliveira Souza, Layani Bertaglia Dias, Tayná Buffulin Ribas, Luis Cezar Farias de Oliveira, Doris Hissako Sumida, Rita Cássia Menegati Dornelles, Ana Cláudia de Melo Stevanato Nakamune, Antonio Hernandes Chaves-Neto
ObjectivesTo investigate the influence of temperature and storage time on salivary acid phosphatase (ACP), tartrate-resistant acid phosphatase (TRAP), alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and lactate dehydrogenase (LDH).DesignUnstimulated whole expectorated saliva was collected from healthy men and women subjects (n=26) between 8 and 10a.m. The saliva samples were centrifuged, and the supernatants were measured for ACP, TRAP, ALP, AST, ALT and LDH activities immediately (without freezing) [baseline values] and after time intervals of 3, 7, 14 and 28days (d) of storage at −20°C and −80°C using spectrophotometric methods The influence of storage time was analyzed by one-way ANOVA followed by the Dunnett post-test, while the paired Student's-t-test was used to compare the differences between the temperature (p<0.05).ResultsThere was significant decline in the activities of all enzymes at −20°C with increasing storage time. This decrease was relevant from day 14 onward for the majority of the enzymes, with the exception of AST. After day 28, the more sensitive enzymes were ALP and LDH, which showed residual activity of 39% and 16%, respectively, compared with baseline values. There were considerable, but insignificant changes, in the activities of all enzymes after storage at −80°C for 28days.ConclusionsFrozen samples should be kept at −80°C to preserve these activities, but there are restrictions for the enzymes ALP, ALT and LDH. Storage of samples at −20°C could introduce high error variance in measured activities.

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Effectiveness of three age estimation methods based on dental and skeletal development in a sample of young Brazilians

Publication date: January 2018
Source:Archives of Oral Biology, Volume 85
Author(s): Marcelo Afonso Machado, Eduardo Daruge Júnior, Mário Marques Fernandes, Igor Felipe Pereira Lima, Graziela Oro Cericato, Ademir Franco, Luiz Renato Paranhos
ObjectiveThis study compared three methods designed for age estimation.MethodsA sample of 468 radiographs (234 panoramic and 234 carpal radiographs) collected from patients ranging from 5 to 14 years old (mean age: 11.27years old±2.27years) was used. Three age estimation methods: were applied: one founded on dental development, one founded on hand and wrist development, and a method combining both measurements. For each method, the mean error (ME), mean absolute error (MAE), root mean square error (RMSE), and mean percentage of absolute error (MPAE) were quantified. The methods: were compared based on their effectiveness for estimating age in relation to sex and age range.ResultsThe data show that the method exclusively using the development of the hand and wrist had the highest error rates (ME: 1.28M, 1.85F; MAE: 1.64M, 1.96F; RMSE: 1.94M, 2.32F) for both males (M) and females (F). In males, the method combining dental and skeletal development obtained outcomes that were slightly better than the method founded on only dental development (MPAE: 6.99% and 7.47%, respectively). In females, the opposite result was observed (MPAE: 8.48% and 6.59%, respectively). The method founded exclusively on skeletal development significantly overestimated (p=0.001) the age (mean chronological and estimated ages: 11.27 and 12.88, respectively).ConclusionThe methods involving dental development provided more accurate age estimates of chronological age. The method exclusively based on hand and wrist development resulted in outcomes that were highly discrepant from the chronological age.

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L-mimosine and hypoxia enhance angiopoietin-like 4 production involving hypoxia-inducible factor-1alpha: Insights from monolayer and spheroid cultures of dental pulp-derived cells and tooth slice cultures

Publication date: January 2018
Source:Archives of Oral Biology, Volume 85
Author(s): Klara Janjić, Umar Alhujazy, Andreas Moritz, Hermann Agis
ObjectiveAngiopoietin-like 4 (Angptl4) is an angiogenesis modulating signaling factor and as such involved in blood vessel formation but also in hard tissue resorption. Here we hypothesized that the hypoxia mimetic agent L-mimosine (L-MIM) and hypoxia stimulate the production of Angptl4 in the dental pulp.Material and methodsMonolayer and spheroid cultures of primary human dental pulp-derived cells (DPC) were treated with L-MIM or hypoxia. Furthermore, tooth slice cultures were performed. The production of Angptl4 was assessed at mRNA and protein levels using reverse transcription qPCR and immunoassays, respectively. To assess the involvement of hypoxia inducible factor (HIF)-1α (HIF-1signaling, inhibitor studies with echinomycin and Western Blot analysis for HIF-1α were performed in DPC monolayer cultures.(HIF-1ResultsL-MIM and hypoxia increased production of Angptl4 at mRNA and protein levels in monolayer cultures of DPC. The increase of Angptl4 was paralleled by an increase of HIF-1α and inhibited by echinomycin. Angptl4 protein levels were also elevated in spheroid cultures. In tooth slice cultures, the pulp tissue expressed and released Angptl4 under normoxic and hypoxic conditions and in the presence of L-MIM. There was a trend for an increase in Angptl4 mRNA levels and a trend for a decrease in the protein levels of the supernatants.ConclusionsOur results suggest that the hypoxia mimetic agent L-MIM and hypoxia can increase Angptl4 production in DPC involving HIF-1α. However, the increase in the cell culture supernatants does not translate in an increased release in tooth slice organ cultures.

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Evaluation of the bisphosphonate effect on stem cells derived from jaw bone and long bone rabbit models: A pilot study

Publication date: January 2018
Source:Archives of Oral Biology, Volume 85
Author(s): Jun-Beom Park, Seung-Hyun Cho, InSoo Kim, Won Lee, Seung-Hwan Kang, Heesung Kim
Background and objectiveBisphosphonates have been widely used and the number of patients experiencing medication-related osteonecrosis of the jaw (MRONJ) has been increasing. This study was designed to evaluate the effect of zoledronate on stem cells derived from different tissues.DesignStem cells derived from four different tissues were compared using rabbit models (JPO: periosteum from the jaw bone (mandible), JBM: bone marrow from the jaw bone, LPO: periosteum from long bone (tibia), and LBM: bone marrow from long bone). Stem cells were grown in the presence of zoledronate at final concentrations ranging from 10⁻⁶M to 10⁻¹⁰M. Morphology was viewed under an inverted microscope, and the analysis of cell proliferation was performed using a Cell Counting Kit-8 (CCK-8) on days 1, 2, 4, and 7.ResultsThe CCK-8 results for LBM showed that the increase of CCK-8 values was correlated with a longer incubation time. Compared to the untreated control, growth in the presence of zoledronate at 10⁻¹⁰M and 10⁻⁸M resulted in decreased CCK-8 values for LBM on day 7 (P<0.05). The CCK-8 results for JBM, LPO, and JPO on days 1, 2, 4, and 7 showed that the presence of zoledronate did not produce statistically significant changes compared with the untreated control.ConclusionZoledronate in the tested concentrations from JBM, LPO, and JPO did not produce noticeable alterations in the viability of mesenchymal stem cells. This in vitro experiment suggests that the occurrence of MRONJ solely in the oral cavity is not due to differences in the cellular proliferation of stem cells in the response to zoledronate.

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Three-dimensional mammalian tooth development using diceCT

Publication date: January 2018
Source:Archives of Oral Biology, Volume 85
Author(s): Qamariya Nasrullah, Marilyn B. Renfree, Alistair R. Evans
ObjectiveThis study aims to develop the Diffusible Iodine-based Contrast-Enhanced CT (diceCT) method for non-destructive imaging of both soft and mineralised tissues. We sought to document the 3D spatio-temporal pattern of mammalian tooth development including multiple tooth classes and generations, using the tammar wallaby (Macropus eugenii) as a model species.DesignWe took microCT scans of developing fetuses and pouch young stained using Lugol's Iodine (I2KI) contrast agent. Stained versus unstained specimen comparisons were then made to investigate whether staining had improved visualisation of structures. Scan slices were compared to histological sections to confirm the identity of tissues and structures. Tissue layers were digitally segmented to create 3D models.ResultsDiceCT dramatically enhanced visual contrast of soft tissues, allowing differentiation between epithelial and mesenchymal layers. Subvolume scans at higher magnification achieved single-cell layer resolution within relatively large intact heads. We observed in-situ initiating teeth, which progressed through major stages of tooth development including morphogenesis and mineralisation. In addition, we traced the development of other mineralized and unmineralised tissues, such as the cranial bones and the brain, eye and olfactory system.ConclusionsDiceCT was time- and cost-effective in producing complex 3D models of the entire dentition of the tammar wallaby at each developmental stage with tissue-level resolution. The 3D view of soft and mineralised tooth structures allowed us to define tooth class and generation from a developmental perspective. Additionally, the development of other organs can also be documented using the same scans, demonstrating the efficiency and versatility of this technique.

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Presence of dental signs of congenital syphilis in pre-modern specimens

Publication date: January 2018
Source:Archives of Oral Biology, Volume 85
Author(s): Stella Ioannou, Renata J. Henneberg, Maciej Henneberg
ObjectiveTooth morphology can vary due to genetic factors, infectious diseases and other environmental stresses. Congenital syphilis is known to interrupt tooth formation i.e. odontogenesis and amelogenesis, producing specific dental characteristics. Variation of those characteristics can occur, resulting in dental signs "not typical" of the disease, however, they are described in the 19th century literature. Past treatments of congenital syphilis with mercury also interrupted dental processes resulting in significantly different dental signs. The aim of this study is to examine the dentition of the oldest (pre 15th century) cases attributed to congenital syphilis to determine whether their dental processes have been affected by either congenital syphilis itself, its treatments (mercury) or a combination of both (syphilitic-mercurial).DesignComparisons of dental signs of congenital syphilis and its mercuric treatments as described by Hutchinson, Moon and Fournier in the 1800s and in standardised methods as established by modern studies, are made with the dentition of specimens found in archaeological sites in Mexico, Italy, Turkey and Austria dating back to the Terminal Formative Period, Classical Antiquity, Byzantine times and Middle Ages.ResultsThe dentitions of a child from Oaxaca, Mexico, St. Pölten, Austria, and two juveniles from Classical Antiquity site Metaponto, Italy, show signs attributed to syphilis only. One adolescent from Byzantine site Nicaea, Turkey, shows dental signs characterised as syphilitic-mercurial.ConclusionsDental abnormalities observed in Mediterranean individuals match a range of signs attributable to congenital syphilis and its treatments, more so than the New World case. Therefore, it is likely that these individuals suffered from congenital syphilis.

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TU Delft’s self folding tulip proves 4D printing’s potential in medicine

Professor Amir Zadpoor's team at Delft University of Technology (TU Delft) believes that the self folding ability of 3D printed polymers could have potential for next generation medical devices. In a recent paper for the journal Materials Horizons, the team demonstrate the 3D printing's ability to make flat nets that fold into an array of […]

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Overweight risk and food habits in Portuguese pre-school children

Publication date: Available online 6 November 2017
Source:Journal of Epidemiology and Global Health
Author(s): A.M. Machado-Rodrigues, R.A. Fernandes, Maria-Raquel Silva, A. Gama, I. Mourão, H. Nogueira, V. Rosado-Marques, C. Padez
The relationship between dietary intake and overweight-risk was assessed in 4349 children aged 3–5 years.Eating and sedentary behaviours were assessed by questionnaire. Logistic regressions were used.Children who consumed daily soft-drinks were 1.52 times more likely to be obese, and 72% more likely to be classified as overweight children.

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Interview with Howard Farran: The Benefits of Xylitol

I originally did this interview with Howard Farran back in early January 2017. Reposting for those who may have missed it!

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Sides sink teeth into fluoride debate

Mirror photo by Sean Sauro / Dental hygienists Rachel Leib and Diana Roberts apply fluoride to the teeth of patient Alexandra Dill, 4, on Friday at the Hicks & Dill dental office along Park Street in Ebensburg. As a Cambria County community weighs removing fluoride from its drinking water, dentistry experts and their opponents continue to advocate for different outcomes.

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Warming alters energetic structure and function but not resilience of soil food webs

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Temporal niche expansion in mammals from a nocturnal ancestor after dinosaur extinction

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Phase-resolved X-ray polarimetry of the Crab pulsar with the AstroSat CZT Imager

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Single photon detection of 1.5 THz radiation with the quantum capacitance detector

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Determine the timing

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Orthodontic treatment simultaneous to or after periodontal cause related treatment in periodontally susceptible patients

Abstract

Aim

To compare two treatment strategies regarding the effect of orthodontic treatment on periodontal status in patients with plaque-induced periodontitis.

Subjects and Methods

This was a randomised clinical trial. Fifty periodontal patients were randomly assigned to the test or control groups according to periodontal treatment timing. All patients received supra- and sub-gingival debridement following baseline examination. Control group patients received cause-related periodontal treatment before the start of orthodontic treatment and which was performed simultaneous to orthodontic treatment for the test group patients.

Results

No difference between the test and control groups was found regarding change of clinical attachment level (CAL) after periodontal-orthodontic treatment. Fewer sites with initial pocket depth (PD) of 4-6 mm healed after periodontal-orthodontic treatment in the test group (20.5%, IQR=11.9%) in comparison with controls (30.4%, IQR=27.1%) (p=0.03). Anterior teeth [OR 2.5] and teeth in male patients [OR 1.6] had a greater chance for PD improvement ≥2mm. Total periodontal-orthodontic treatment duration was significantly longer for the control group (p<0.01).

Conclusions

Both groups showed a gain of CAL and a reduction of sites with PD ≥ 4mm.

Orthodontic treatment, simultaneously to the periodontal treatment, could be used in the routine

treatment of patients with plaque-induced periodontitis.

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Quality of questionnaires for the assessment of otitis media with effusion in children

Abstract

Introduction

Audiometric tests provide information about hearing in otitis media with effusion (OME). Questionnaires can supplement this information by supporting clinical history-taking as well as potentially providing a standardized and comprehensive assessment of the impact of the disease on a child. There are many possible candidate questionnaires. This study aimed to assess the quality and usability of parent / child questionnaires in OME assessment.

Methods

Fifteen, published questionnaires, commonly used in audiological departments (ABEL, CHAPS, CHILD, COW, ECLiPS, ELF, FAPC, HL-7, LIFE-R Student, LIFE-UK IHP, LittlEARS, LSQ, OM-6, OMQ-14, PEACH) were assessed according to the following 8 criteria: conceptual clarity, respondent burden, reliability, validity, normative data, item bias, ceiling/ floor effects, and administrative burden.

Results

ECLiPS, LittlEARS and PEACH scored highest overall based on the assessment criteria established for this study. None of the questionnaires fully satisfied all 8 criteria. Although all questionnaires assessed issues considered to be of at least adequate relevance to OME, the majority had weaknesses with respect to the assessment of psychometric properties, such as item bias, floor/ceiling effects or measurement reliability and validity. Publications reporting on the evaluation of reliability, validity, normative data, item bias and ceiling/floor effects were not available for most of the questionnaires.

Conclusion

This formal evaluation of questionnaires, currently available to clinicians, highlights three questionnaires as potentially offering a useful adjunct in the assessment of OME in clinical or research settings. These were the ECLiPS, which is suitable for children aged 6 years and older, and either the LittlEARS or the PEACH for younger children. The latter two are narrowly focused on hearing, whereas ECLiPS has a broader focus on listening, language and social difficulties.

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Evolution of soft palate surgery techniques for Obstructive Sleep Apnea patients: A comparative study for single level palatal surgeries

Abstract

Objectives

to compare the results of tissue preservation techniques of soft palate surgeries including expansion sphincter pharyngoplasty (ESP) and barbed reposition pharyngoplasty (BRP) for patients suffering from obstructive sleep apnea (OSA) with the traditional uvulopalatopharyngoplasty (UPPP).

Design

interventional comparative study.

Setting

Morgagni- Pierantoni Hospital.

Participants

seventy five patients were included in the study, divided into three groups with 25 patients per group: UPPP, ESP or BRP.

Main outcomes measures

Polysomnography was done for all patients pre- and post-operatively, the post-operative results were recorded at least six months after surgery. All patients were assessed pre-operatively using drug induced sleep endoscopy. Epworth Sleepiness scale and body mass index were registered for all patients before and after surgery.

Results

the mean of pre- and post-operative differences of apnea hypopnea index values were higher in BRP group than ESP: 15.76±14.5 Vs 10.13±5.3; P <0.05 and UPPP groups: 15.76± 14.5 Vs 6.08±5.5; P <0.0005. The mean of differences of oxygen desaturation index values was higher in BRP group than UPPP group: 15.09±17.6 Vs 7.13±6.8; P <0.0005, but not significantly higher than ESP group: 15.09± 17.6 Vs 6.48±7.9; P >0.05. The mean of differences of ESS values was higher in BRP group than ESP group: 5.52 ±4.1 Vs 4.84±3.3; P <0.005 and UPPP groups: 5.52 ±4.1Vs 1.36±1.9; P <0.005. Finally, the pre- and post-operative mean of differences of lowest oxygen saturation values were not statistically significant among the three groups (P >0.05).

Conclusion

BRP can be considered an effective procedure on the basis of the post-operative outcomes. ESP still proves to be a good technique especially when performed by experienced surgeons. Both techniques proved to be superior to UPPP.

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Higher prevalence and increased severity of sleep-disordered breathing in male patients with chronic tinnitus: our experience with 173 cases

Tinnitus and sleep are closely related. One of the most important aspects of tinnitus is its association with sleep disturbance. According to the literature, up to 71% of patients with tinnitus report sleep problems (1); furthermore, insomnia is also associated with more distressing tinnitus (2). Conversely, sleep disturbance was proposed as one of the causes of chronic tinnitus (3). The relationship of tinnitus with sleep-disordered breathing (SDB) and obstructive sleep apnea (OSAS) has rarely been mentioned (4). In a recent population-based case-control study, the risk of tinnitus was found to increase 1.36 times in patients with OSAS. However, no detailed grading or severity of SDB (or OSAS) and tinnitus was provided. The purpose of this study was to investigate the exact relationship between tinnitus and SDB and delineate the incidence and severity of SDB in patients with chronic tinnitus; moreover, our study reports the preliminary outcome of tinnitus after intervention with continuous positive airway pressure (CPAP) in selected patients with moderate to severe SDB.

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An ENT smartphone Handbook: adopting new practice for induction

There should be continued support and drive for innovation and implementation of smartphone-based access to local guidelines.

This is the first study, that we're aware of, assessing the use of a smartphone-based clinical handbook in ENT surgery.

Use of a smartphone-based handbook is superior to printed or intranet-based guidelines.

Use of smartphone apps can support junior doctors with delivery of care.

Smartphone-based access to guidelines encourage learning and education to improve the induction process for new doctors.

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Current practices for voice rest recommendations after phonomicrosurgery

ConclusionsThe more common recommendation for complete voice rest is 7 days for nodules, cysts, polyps, and Reinke's edema, and 1 to 4 days for leukoplakia and papilloma. Relative voice rest when recommended is typically recommended for over 8 days. Voice rest recommendations were not affected by surgery type alone, but were determined by either lesion type alone or lesion type combined with surgery type. Levels of Evidence4. Laryngoscope, 2017 (Source: The Laryngoscope)

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Motor and sensory morbidity associated with the anterolateral thigh perforator free flap

ConclusionThe ALT flap offers minimal donor site morbidity. Reduced sensibility of the ALT flap is a common complaint among patients. Quadriceps strength is not significantly affected by an ALT free flap harvest. Level of Evidence4. Laryngoscope, 2017 (Source: The Laryngoscope)

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Pediatric tinnitus: A clinical perspective

ConclusionsThis study distinguishes pediatric tinnitus from adult tinnitus in terms of lower association with underlying hearing loss, lower likelihood of reported anxiety, and higher likelihood of improvement and resolution. There are opportunities for tinnitus prevention in the areas of reducing head injury and noise‐induced hearing loss. Level of Evidence4 Laryngoscope, 2017 (Source: The Laryngoscope)

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The relationship between endolymphatic hydrops in the vestibule and low ‐frequency air‐bone gaps

ConclusionsThe appearance of low‐frequency air‐bone gaps suggests deterioration of endolymphatic hydrops, particularly in ears with Ménière's disease, and could be a useful indicator for evaluating and treating patients with endolymphatic hydrops. Level of Evidence4. Laryngoscope, 2017 (Source: The Laryngoscope)

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Is multidisciplinary team care for head and neck cancer worth it?

(Source: The Laryngoscope)

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Clinical trials in rhinosinusitis: Identifying areas for improvement

ConclusionsThis analysis is the first to characterize rhinosinusitis clinical trials, highlighting the over‐representation of certain drugs and demonstrating an increased focus on clinical trials employing surgical intervention. We provide a framework to discuss prioritization of future studies to guide clinical and research practice. Level of Evidence4. Laryngoscope, 2017 (Source: The Laryngoscope)

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Prediction of mortality and morbidity in head and neck cancer patients 80 years of age and older undergoing surgery

ConclusionPatient and surgical treatment factors predict risk of serious complications and mortality in patients aged 80 years and older undergoing ablative head and neck surgery. Predictive models may guide preoperative discussion with patients. Level of Evidence2b. Laryngoscope, 2017 (Source: The Laryngoscope)

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Vibratory function and healing outcomes after small intestinal submucosa biomaterial implantation for chronic vocal fold scar

ConclusionsSIS implantation into chronic scar reduced the density of collagen I deposits. There was no evidence of a negative impact or complication from SIS implantation. Regardless of treatment type, organization of elastin in the subepithelial region may be important to vibratory outcomes. Level of EvidenceNA Laryngoscope, 2017 (Source: The Laryngoscope)

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Pediatric acute mastoiditis in the era of pneumococcal vaccination

ConclusionsDespite introduction of two pneumococcal vaccines, rates of hospitalization for pediatric acute mastoiditis did not decline between 2000 and 2012. Between 2009 and 2012, however, children 0 to 2 years of age showed declining hospitalization rates, possibly reflecting the protective benefit of the 13‐valent pneumococcal vaccine. Level of Evidence4 Laryngoscope, 2017 (Source: The Laryngoscope)

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Health Corner: Your Top Questions About Going to the Dentist-Answered

Here are some frequently asked questions about going to the dentist. Why do regular dental visits matter? Regular dental visits are important because they can help spot dental health problems early on when treatment is likely to be simpler and more affordable.

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Assessing the role of immune system in cancer progression from minimal residual disease.

Assessing the role of immune system in cancer progression from minimal residual disease.

Oral Oncol. 2017 Oct 26;:

Authors: Raj AT, Patil S, Rajkumar C, Sarode S

PMID: 29102153 [PubMed - as supplied by publisher]

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Gut microbiota and hypertension: From pathogenesis to new therapeutic strategies.

Gut microbiota and hypertension: From pathogenesis to new therapeutic strategies.

Clin Res Hepatol Gastroenterol. 2017 Nov 01;:

Authors: Kang Y, Cai Y

Abstract
Hypertension (HTN) has become a global public health concern and a major risk factor for cardiovascular, cerebrovascular, and kidney diseases. The complex interplay of genetic and environmental influences is important for the development of the disease. Accumulating evidence has illustrated the association of dysbiosis of gut microbiota with hypertension. Certain gut microbial strains may play either a pathogenic or a protective role in the development of hypertension. Oral probiotics can therefore represent a therapeutic approach for hypertension treatment. However, the relevant scientific work has only just begun, and the available data in this field remain limited. Fortunately, recent technological developments that permit identification of microbes and their products using culture-independent molecular detection techniques. In this review, we summarize the role of gut microbiota in hypertension progression, and probiotics in the treatment of hypertension.

PMID: 29102544 [PubMed - as supplied by publisher]

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Rapid onset of osteonecrosis of the jaw in patients switching from bisphosphonates to denosumab.

Rapid onset of osteonecrosis of the jaw in patients switching from bisphosphonates to denosumab.

Oral Surg Oral Med Oral Pathol Oral Radiol. 2017 Sep 28;:

Authors: Yarom N, Lazarovici TS, Whitefield S, Weissman T, Wasserzug O, Yahalom R

Abstract
OBJECTIVE: The aim of this study was to determine whether osteonecrosis of the jaw (ONJ) developed more rapidly in patients who switched from bisphosphonates (BP) treatment to denosumab than in patients who received only denosumab.
STUDY DESIGN: This was a retrospective cohort study conducted at a tertiary referral center. Thirty-one patients with ONJ met the inclusion criteria.
RESULTS: Twenty-two patients who had been on BP were switched to denosumab (BP + D), whereas 9 patients received only denosumab. Both groups were similar for the known ONJ risk factors, that is, age, diabetes mellitus, and smoking. The number and cumulative doses of denosumab before the onset of ONJ symptoms were significantly lower among the BP + D group compared with the denosumab-only group (P = .025 and .018, respectively). In the BP + D group, ONJ symptoms developed in 9 patients (41%) following the administration of ≤3 denosumab doses compared with ONJ developing in only 1 patient (11%) who was naïve to BP. ONJ developed spontaneously without any known triggering event in 72.7% of patients in the BP + D group and in 77.8% of patients in the denosumab-only group.
CONCLUSIONS: Denosumab-induced ONJ might develop rapidly in patients previously treated with BP. ONJ developed spontaneously in most patients treated with denosumab. In light of our sample being small, there is need for further investigation on our conclusions.

PMID: 29102242 [PubMed - as supplied by publisher]

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EXTH-15. RADIATION-INDUCED LATE MALIGNANT MENINGIOMA TRANSFORMATION: CDK 4/6 INHIBITOR THERAPY

Abstract

Meningiomas are the most common primary brain tumor reported in the United States each year and account for approximately 30% of primary neoplasms. Though in most cases the etiology of meningiomas is unclear, prior exposure to radiation is responsible for a subset of meningiomas. Some have speculated that there may be a relationship between pretreatment characteristics and radiotherapy parameters in the development of radiation-induced meningiomas (RIM). Compared with their sporadic counterparts, currently, the clinical treatment involves is similar with radiation used as a first line therapy. Novel therapeutic agents being investigated in the treatment of these tumors, rely on the direct or cell cycle-mediated induction of DNA damage to promote cellular apoptosis. Our pre-clinical data showed that disruption of p16INK4a-Cdk4-Rb (retinoblastoma) pathways plays a significant role in the development of RIM in Rb+ low-gradelow-grade meningioma cells. These observations highlight the critical role of the p16INK4a-Cdk4-Rb pathway in RIM and suggest that targeting this pathway might be a promising strategy to improve the therapeutic efficacy among RIM patients. Pretreatment characteristics and radiotherapy parameters which may influence the time interval for development of radiation-induced Rb+ meningiomas (RIM) were identified. Our results also demonstrated that CDK 4/6 Inhibitor, significantly suppresses radiation induced malignant transformation and prolonged survival in a cell-free, slice culture model and xenograft model of meningioma. Success of the proposed therapeutic strategies in both in vitro and in vivo models may form the basis for future research.

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ACTR-02. DCC-2618, A NOVEL pan-KIT AND PDGFRa KINASE SWITCH CONTROL INHIBITOR, SHOWS ENCOURAGING SIGNAL IN A PATIENT (PT) WITH GLIOBLASTOMA (GBM)

Abstract

BACKGROUND

Non-clinical data suggest that PDGFRa plays an important role in the development and progression of human gliomas. To date, few PDGFRa inhibitors with CNS activity have been available. DCC-2618 was designed to potently inhibit the broadest range of mutations (mut) in KIT & PDGFRa kinases that emerge during tumor progession or on treatment.

METHODS

In a dose-escalation study (NCT# 02571036) of oral DCC-2618 (QD or BID q28 days), pts with advanced malignancies with a molecular rationale for activity were eligible. MRI scans were performed initially every 2 cycles then every 3 cycles.

RESULTS

We enrolled 4 GBM pts and 1 anaplastic astrocytoma (AA) pt with PDGFRa muts/ amplifications who had progressed after standard temozolomide chemoradiation (GBM) or temozolomide only (AA) and had received 0 to 5 salvage therapies. Three pts (2 GBM and 1 AA) had a triple amplification of PDGFRa, KIT and KDR (4q12 amplicon). Two GBM pts had activating PDGFRa mutations. Pts were treated at 20 mg (1 pt), 50 mg BID (2 pts) or 100 mg QD (2 pts). The per-protocol population (N=48) received doses up to 200 mg BID and DCC-2618 was well tolerated. One GBM pt with mut PDGFRa progressed after 6 weeks and one stopped treatment due to a tumor-related hemaorrhage on C1D12. Two of the three pts with triple amplifications progressed after 2 cycles while the third pt (GBM, 20 mg BID) achieved a PR per RANO after 9 cycles. This pt is currently in cycle 20 with a remarkable 94% tumor reduction.

CONCLUSIONS

The durable partial response of >18 months in a GBM patient (94% tumor reduction) warrants further evaluation of DCC-2618 in gliomas. An expansion cohort for pts with KIT- and PDGFRa driven tumors was initiated to be able to better select the patient population with a likely benefit.

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SCDT-20. NEW THERAPEUTIC APPROACH FOR BRAINSTEM GLIOMA: INTRANASAL DELIVERY OF NANOLIPOSOMAL SN-38

Abstract

INTRODUCTION

Children with diffuse intrinsic pontine gliomas (DIPGs) die within 2 years after initial diagnosis. The infiltrative nature and anatomic location of DIPGs in an eloquent area of the brain preclude surgical resection, and the blood-brain barrier (BBB) reduces the availability of systemically administered agents. In order to improve outcomes for patients with DIPG, new drug delivery approach circumventing the BBB are greatly needed. Intranasal delivery (IND) is a practical, noninvasive method to deliver therapeutic agents into the brain along with the olfactory and trigeminal nerves pathway. With the advantages of reducing systemic side effects and convenient self-administration for patients, IND is an alternative to systemic (intravenous) and/ or direct invasive (intraparechymal) drug delivery.

METHODS

Two human DIPG cell lines were treated with hydrophobic fluorophore (DiI)-labeled nanoparticle liposomes containing CPT-11 (nanoliposomal CPT-11) and SN-38. Cell viability was determined by MTS assay and intracellular localization was imaged by confocal microscopy. For in vivo study, mice bearing human brainstem gliomas were randomly assigned to 3 groups: 1. empty nanoliposomes, 2. nanoliposomal CPT-11, 3. nanoliposomal SN-38, administrating by IND for 3 weeks. In vivo distribution was determined by DiI-labeled nanoliposomal SN-38 into the tumor bearing mice. Tumor growth and response to therapy were quantitatively measured by bioluminescence imaging, and efficacy was assessed by survival analysis.

RESULTS

DiI-fluorescence were detected at 30 minutes and peaked at 24 hours following treatment with DiI nanoliposomal SN-38. Nanoliposomal SN-38 induced dose dependent inhibition of the growth of DIPG cells, that is greater inhibition than nanoliposomal CPT-11. IND of nanoliposomal SN-38 showed significant reduction of the growth rate in compared to IND of empty nanoliposome. Results from animal survival will be reported at the meeting.

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ACTR-03. INDUCING FACTORS OF MALIGNANT RECURRENCE IN LOW-GRADE GLIOMA

Abstract

Low-grade glioma patients have relatively long life expectancy for gliomas, but once they recur in malign, their prognosis can be poor. We analyzed factors corresponding to malignant recurrence by uni- and multi-variate analysis applying their treatment backgrounds. SUBJECTS: 261 newly diagnosed WHO grade 2 adults gliomas in 2004 to 2014. Malignant recurrence was determined by pathological diagnosis if the patient had a surgery (69% of the recurrent patients), otherwise contrast T1WI or 11C- methionine PET images if the patient was unable to undergo any surgery or biopsy.

RESULTS

Age average 41 years old, the 10-year survival rate in all patients was 75%, and the mean of progression-free survival time was 7.8 years. Relapse event occurred in 115 cases (44%), and 67 % of them developed malignant glioma sometime. The 10-year survival rate for the patients who relapsed in malign was 37%, on the contrary, the patients who had recurrence but staying in low grade was 71% (p=0.0389). When they were categorized by 1p19q deletion and IDH1 mutation status, IDH wild type diffuse astrocytoma patients had significantly developed malignant glioma compared to oligodendroglioma and IDH mutant type diffuse astrocytoma (p<0.0001). The factors related to malignant progression were extracted as; recurrence in 2 years, 6% and over in MIB-1 index, no intervention longer than 18 months since the disease revealed, 1p19q non-co-deletion, less than 90% of tumor resection rate, and IDH wild type. In the 1p19q non-deletion patients, who were provisionally defined as diffuse astrocytoma patients here, the factors were resection rate, MIB-1 index, and duration between discovered the disease and the first surgery, but not the IDH mutant status (p＜0.0001, p=0.0015, p=0.0478 respectively).

CONCLUSION

Recurrence in malign form low-grade glioma can be avoided by early intervention in 18 months from diagnosis and resection over 90% of volume of the tumor.

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SURG-28. KYPHO-IORT: A NEW TREATMENT PARADIGM FOR PATHOLOGICAL FRACTURES

Abstract

OBJECTIVE

This is a prospective single institution study to assess the safety and efficacy of Kypho-intraoperative radiation therapy (Kypho-IORT) for potentially mechanically unstable metastatic disease to the spine in reducing pain.

METHODS

Patients with symptomatic osteolytic vertebral body metastasis underwent Kypho-IORT: kyphoplasty procedures and intraoperative radiotherapy with the ZEISS INTRABEAM System followed by cement augmentation. Tumors were limited to vertebral body using the International Spine Radiosurgery Consortium (ISRC) anatomic classification system, SINS scores of 7-12 (potentially unstable), and Bilsky grade 0. Intraoperative CT delineation of gross tumor volume, needle applicator tip, and OAR delineation were done with deformable image registration, integrating pre-operative CT and MRI images. 10 Gy was prescribed to a distance from the source tip to the distal boundary. The prescription was limited by a maximum dose limit to the spinal cord of 12 Gy. Preoperative and postoperative pain scores were assessed with the numerical rating pain scale (NRPS). The involved spine will be imaged at 3-month intervals up to one year.

RESULTS

7 vertebral levels were treated. All patients were discharged home within 12 hours of the Kypho-IORT procedure. There was a statistically significant reduction in patient reported NPRS scores from preoperative baseline within 2 weeks (6.57 ± 2.82 preoperative versus 4.00 ± 2.16 postoperatively; p=0.0349). After 3 months, one patient with metastatic rectal cancer suffered local progression. No patients experience neurological deterioration postoperatively.

CONCLUSIONS

Kypho-IORT is a safe treatment option for potentially unstable spinal metastases. Patient reported pain scores significantly improve within two weeks, enhancing the patient's quality of life. Long-term follow up is necessary to further evaluate efficacy.

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ACTR-44. AUTOPSY STUDY ON THE EFFECTS OF TUMOR TREATMENT FIELDS IN RECURRENT GLIOBLASTOMA: PRELIMINARY RESULTS AND TRIAL DESIGN

Abstract

BACKGROUND

Optune therapy with tumor treatment fields (TTFields) is approved for the treatment of recurrent glioblastoma due to a recent clinical trial that showed better quality of life and comparable overall survival to conventional therapy. In the newly diagnosed setting, the addition of TTFields to standard therapy consisting of surgery, radiation and temozolomide has also been shown to prolong tumor progression and improve overall survival. TTFields are low-intensity, alternating frequency electric fields that have been shown to disrupt cell division and subsequently tumor growth. Apoptosis and cell cycle arrest have been seen in vitro, and shown in mice and rabbit tumor models. Though preclinical studies are ongoing, glioblastoma patients who have undergone TTFields therapy have not yet been assessed at autopsy to determine both the pathological signature of TTFields therapy, and the pattern of failure.

METHODS

Whole brain samples were acquired and analyzed pathologically from two recurrent GBM patients at autopsy. One patient served as a control and one considered a test patient who had undergone TTFields therapy. Tissue samples were acquired from regions suspicious of tumor and treatment effects. Samples were paraffin embedded and hematoxylin and eosin (H&E) stained, and pathologically reviewed by a board certified pathologist. Samples were then compared.

RESULTS

The patient who underwent TTFields therapy showed regions of necrosis and increased cellular debris compared to the control patient who had pseudo-palisading and radiation necrosis.

CONCLUSION

These findings suggest there is increased apoptosis in patients treated with TTFields compared to those on chemoradiation alone. Recruitment is ongoing for expansion of this study to include 10 patients treated with TTFields at recurrence and 10 at treated at initial diagnosis. Patients will be recruited from brain donation. Pathology will be compared to control patients naïve of TTFields therapy.

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CMET-47. PRECLINICAL VALIDATION OF NOVEL THERAPEUTICS TARGETING A BMIC POPULATION IN HUMAN BRAIN METASTASES

Abstract

Brain Metastases (BM) are the most common neoplasm to affect the adult central nervous system, occurring at a rate 10 times greater than that of primary brain cancers. Despite the prevalence and severe lethality of BM, therapeutic strategies remain limited. Advancements in in vivo modelling of metastasis presents a useful platform to aid in the advance and screening of novel targeting therapeutics, though currently few models exist that properly recapitulate the clinical progression of brain metastasis. Utilizing primary patient samples of BMs, we have characterized a subpopulation of CSC-like cells, termed brain metastasis-initiating cells (BMICs), which are responsible for initiating BMs. Through injections of BMICs isolated from lung BMs into NOD-SCID mice, we have generated a novel patient-derived xeno-transplantation (PDXT) model of BM that allows for interrogation of each phase of the metastatic process from lung to brain. We then expanded our model to incorporate BMICs derived from breast and melanoma BMs. BMICs were harvested from primary sites and corresponding BMs, and RNA submitted for sequencing to identify metastatic and tissue-specific gene signatures. BMICs were found to possess a unique genomic profile as compared to BMICs isolated from full primary tumors and complete macro-metastases, exhibiting dysregulated expression in over 13,000 genes, including those involved in stem cell, epithelial-to-mesenchymal transition, and quiescence properties. In silico analysis was used to generate a list of therapeutics targeting this unique BMIC population. In vitro and in vivo screening has identified a subset of compounds with no previously known efficacy in cancer treatment that inhibits BMIC growth and metastasis. Ultimately, we aim to transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.

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ACTR-45. A PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF MARIZOMIB (MRZ) WITH TEMOZOLOMIDE (TMZ) AND RADIOTHERAPY (RT) IN NEWLY DIAGNOSED WHO GRADE IV MALIGNANT GLIOMA (GLIOBLASTOMA, ndGBM)

Abstract

Proteasome inhibition sensitizes glioma cells to TMZ and RT, providing a novel therapeutic strategy for ndGBM. MRZ -- an irreversible, brain-penetrant, pan-proteasome inhibitor with anti-glioma preclinical activity -- is being evaluated in ndGBM patients (NCT02903069). The phase 1 study (MRZ at 0.55, 0.7, 0.8, 1.0, and 1.2 mg/m²) is accruing in separate concomitant (MRZ+TMZ+RT) and adjuvant (MRZ+RT) treatment cohorts (3 + 3 design), followed by dose-expansion at the recommended phase 2 dose in concomitant followed by adjuvant treatment cohorts. Concomitant treatment (42 days (D)): MRZ (10 min IV infusion) D1, 8, 15, 29, 36; RT total dose 60 Gy; TMZ (75 mg/m², PO QD). Adjuvant treatment (28D-cycle): MRZ D1, 8, 15; TMZ (150–200 mg/m², PO QDX5). Tumor response (RANO criteria) measured at beginning and end of concomitant treatment, and every other cycle during adjuvant treatment; MRZ and TMZ PK in concomitant treatment D1-2, 8–9. Mean age 55 yrs (60% male) for 20 patients in 14Apr2017 interim analysis (cohorts 1–3 have completed accrual in concomitant treatment, cohorts 1 and 2 have completed accrual and 2 patients are enrolled in adjuvant cohort 3); one DLT (fatigue) in the 0.7 mg/m² adjuvant cohort. Most common treatment-related AEs (≥4 pts): fatigue, nausea, vomiting, decreased appetite, dizziness, hallucination; three Grade 3 SAEs (fatigue, hallucination, vomiting; all MRZ-related); two Grade 2 SAEs (nausea, confusional state, MRZ-related). Seventeen of the 20 patients included in this interim analysis remain on study: 7 of 9 concomitant patients are continuing in adjuvant treatment (longest beginning adjuvant cycle 7); of 11 adjuvant pts, two beginning cycle 9. The study is ongoing at 1.0 mg/m² for both concomitant and adjuvant dose-escalation cohorts. Together the data demonstrate that the combination of MRZ with standard of care in ndGBM is well tolerated and may provide novel therapeutic benefit in this unmet need.

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STEM-11. A MAPK-DRIVEN miR-124-SOX9 AXIS IS CRITICAL FOR STEM CELL MAINTENANCE, PROGRESSION, AND THERAPY-RESISTANCE IN GLIOBLASTOMA

Abstract

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor. Genetic alterations in growth factor signaling pathways are found in 90% of GBMs. Advances in developmental and glioma biology suggest that common down-stream effector molecules in growth factor signaling pathways are critical for stem cell maintenance in the normal brain and GBM cells. It remains unclear whether differentiation therapies will be of therapeutic value for GBM patients. Here, we demonstrate that constitutive mitogen activated protein kinase (MAPK) activation in stem cells drives GBM formation and blocks neurogenesis in mice. Pharmacological inhibition of MAPK signaling restored neurogenesis in vivo and induced neuronal differentiation in GBM tumorspheres cultures established from murine GBMs and patient-derived tumors. Inhibition of MAPK signaling depleted SOX9 protein expression, and to a lesser extent SOX9 mRNA levels, in GBM cells. MicroRNA profiling experiments demonstrated that MAPK signaling regulates genome-wide expression of miRNAs, including the neuronal determinant miR-124. Pharmacological inhibition of MAPK signaling increased miR-124 levels in SOX9-expressing GBMs, but not SOX10-expressing proneural tumors. Using a doxycycline-inducible approach in vitro and in vivo, we demonstrated that miR-124 overexpression blocks SOX9 expression and induces neuronal differentiation in an EGFRvIII-driven GBM model and patient-derived xenografts. Neuronal differentiation resulted in apoptosis, reduced DNA repair capacity, and radiosensitized GBM cells. Doxycycline-mediated miR-124 overexpression resulted in complete regression for 1/3 of patient-derived xenografts. Mechanistic studies showed that SOX9 was a direct target of miR-124 and a major regulator of stem cell maintenance in GBM. Preliminary data showed that MAPK activation regulates transcriptional networks in SOX10-expressing proneural glioma, suggesting that distinct miRNAs regulate glioma aggressiveness in a subtype-specific manner. In conclusion, our results provide a mechanistic explanation for MAPK-dependent expansion of the stem cell pool during GBM initiation and demonstrate that enforcing neuronal differentiation represents a viable therapeutic strategy in glioma.

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ACTR-46. AG-120, A FIRST-IN-class MUTANT IDH1 INHIBITOR IN PATIENTS WITH RECURRENT OR PROGRESSIVE IDH1 MUTANT GLIOMA: UPDATED RESULTS FROM THE PHASE 1 NON-ENHANCING GLIOMA POPULATION

Abstract

INTRODUCTION

Isocitrate dehydrogenase 1/2 (IDH1/2) mutations occur in >70% of low-grade gliomas (LGG) and lead to an altered metabolic state associated with production of D-2-hydroxyglutarate (2-HG), resulting in genetic/epigenetic dysregulation and oncogenesis. AG-120 is a potent oral inhibitor of mutant IDH1 (mIDH1) under clinical evaluation in an ongoing phase 1 study that treated 66 pretreated (median 2 prior systemic therapies) glioma patients in dose escalation and expansion cohorts. Safety and preliminary results were presented previously (SNO2016). We present updated results from the non-enhancing glioma patient population.

METHODS

Key eligibility: mIDH1 recurrent or progressive disease, ECOG 0–1, no surgery/radiation within 6 months. MRI response was assessed every 8 weeks using RANO and LGG-RANO criteria by local and independent central review. Exploratory analyses: change in tumor growth rate (FLAIR tumor volume, non-enhancing glioma expansion cohort) and pharmacodynamic evaluations of tissue and serum.

RESULTS

As of 10March2017, 35 patients with non-enhancing glioma were enrolled in dose escalation (n=11) and expansion (n=24), and 51% (n=18) remain on AG-120. M/F 23/12, median age 38 years, 1p19q intact in 54% (n=19) of patients, 74% reported anticonvulsant use. Frequent (≥5 patients) adverse events (AEs) grade 1–2: diarrhea (26%), headache (26%), nausea (20%), anemia (17%), neutrophil decrease (17%), and vomiting (17%). 7 (20%) patients experienced a grade 3–4 AE (hypophosphatemia most frequent, n=2, unrelated), with no dose reduction due to AEs. 73% and 88% of patients achieved stable disease as best response in the dose escalation (RANO) and expansion (LGG-RANO) cohorts, respectively. Median duration on AG-120 was 14.7 months (range 1.4–25.0); 63% remained on AG-120 for ≥1 year. Updated safety, response, and exploratory imaging analyses will be presented.

CONCLUSIONS

AG-120 monotherapy is associated with a favorable safety profile and prolonged stable disease in a previously treated non-enhancing mIDH1 glioma patient population, and warrants further clinical evaluation.

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Αρχειοθήκη ιστολογίου

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Δευτέρα 6 Νοεμβρίου 2017

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