Comparison of pharmacodynamic effects of ticagrelor vs prasugrel in type 2 diabetes mellitus patients with coronary heart disease

Summary

What is known and objective

Patients with type 2 diabetes mellitus (T2DM) are at higher risk of thrombotic complications. Studies have indicated that patients with T2DM have impaired clopidogrel-induced antiplatelet effect. Ticagrelor and prasugrel are two latest generation P2Y₁₂ inhibitors with advantageous platelet inhibitory profiles. However, the pharmacodynamic differences between the two drugs in patients with T2DM remain poorly explored.

Methods

This study, involving 140 patients with T2DM following percutaneous coronary intervention (PCI), evaluated the efficacy of aspirin upon concomitant use of prasugrel (10 mg/d) or ticagrelor (90 mg/d). Platelet reactivity was assessed by value of ADP-induced light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) at baseline, 7 and 30 days after randomized P2Y₁₂ inhibitor treatment.

Results

The study showed a decreased platelet reactivity after use of P2Y₁₂ inhibitors (both P < .001). On the basis of comparison between regimens, apart from the prasugrel group having a significantly higher LTA value at the 30-day time point (P = .043), there existed no significant differences in platelet reactivity at separate time points (all P > .05). As for intragroup measurements, when compared with 7-day and 30-day time points, similar platelet reactivity was documented in the ticagrelor group (both P > .05), but LTA tests showed a significant increase with time (days 7-30) in the prasugrel group (P = .050).

What is new and conclusion

Although ticagrelor and prasugrel have similar platelet inhibitory effects in patients with T2DM, if a P2Y₁₂ inhibitor is necessitated in patients with T2DM, ticagrelor might exert a more stable antiplatelet effect with 30-day short-term treatment.

Ticagrelor and prasugrel have similar platelet inhibitory effects in patients with T2DM, but if a P2Y12 inhibitor is necessitated in patients with T2DM, ticagrelor might exert a more stable antiplatelet effect with 30-day short-term treatment.

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Liver injury induced by clomiphene citrate: A case report and literature reviews

Summary

What is known and objective

Clomiphene citrate is used to cause ovulation in females and to increase semen production in males. Clomiphene citrate is well tolerated in most patients and rarely induces liver injury. We report a case of liver injury which is associated with administration of clomiphene citrate in a male patient.

Case summary

A 31-year-old man who was treated by clomiphene citrate for 5 days was transferred to our emergency room with reddish-brown urine and upper abdominal pain. The levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were elevated. Based on the subsequent examination, he was diagnosed with liver injury and cholecystitis. The levels of AST and ALT returned to normal range after discontinuation of clomiphene citrate and symptomatic treatment.

What is new and conclusion

The mechanism of liver injury caused by clomiphene citrate is still unclear. Polymorphism of CYP2D6 may have had an effect. Liver function tests should be performed when there is upper abdominal pain after administration of clomiphene citrate.

A case of liver injury induced by clomiphene citrate in a male patient was reported which may caused by polymorphism of CYP2D6. Liver function tests should be performed after adminitration of clomiphene citrate.

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Four tenants at Devonport

A fully tenanted 1960s retail property, standing beside Devonport's refurbished public library and just a short stroll from its well-used ferry terminal, is for sale through NAI Harcourts. The freehold building at 8 Victoria Rd is scheduled to go to auction on November 30, unless it is sold earlier.

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Two Scientific Awards for papers published in Sleep Medicine

Under the auspices of the World Association of Sleep Medicine (WASM), Elsevier has established two scientific awards for young basic and clinical sleep specialists in honor of Christian Guilleminault and Elio Lugaresi, respectively. The awards are a tribute to Dr. Guilleminault's and Dr. Lugaresi's contributions to establish the field of Sleep Medicine, its journal and its Society.

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Editorial Board

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Effect of laser activated bleaching on the chemical stability and morphology of intracoronal dentin

Publication date: February 2018
Source:Archives of Oral Biology, Volume 86
Author(s): Fabiane Carneiro Lopes, Renato Roperto, Anna Akkus, Ozan Akkus, Regina Guenka Palma-Dibb, Manoel Damião de Sousa-Neto
ObjectivesTo evaluate the effect of the bleaching with 35% hydrogen peroxide either activated or not by a 970nm diode laser on the chemical stability and dentin surface morphology of intracoronary dentin.MethodsTwenty-seven slabs of intracoronary dentin specimens (3×3mm) were distributed into three groups (n=9), according to surface treatment: HP – 35% hydrogen peroxide (1×4'), DL – 970nm diode laser (1×30"/0,8W/10Hz), HP+DL – 35% HP activated with 970nm diode laser (1×30"/0,8W/10Hz leaving the gel in contact to the surface for 4′ after activation). Three Raman spectra from each fragment were obtained to calculate the mean intensity of peaks of inorganic component (a.u.), organic collagen content (a.u.), and the ratio of inorganic/organic content, before and after treatment. Analyses of the samples by confocal laser microscopy were performed to evaluate the surface roughness, percentage of tubules, perimeter and area percentage of tubules, before and after treatment. Data were analyzed by Kruskal-Wallis, Dunn's, and Wilcoxon test (P<0.05).ResultsData analysis showed that HP+DL did not change the inorganic content peaks 8.31 [29.78] or the inorganic/organic ratio 3.37 [14.67] (P>0.05). Similarly, DL did not affect the chemical stability of the dentin surface (P>0.05). However, HP significantly increased inorganic content peaks 10.87 [22.62], as well as the inorganic/organic ratio 6.25 [27.78] (P<0.05). Regarding the morphological alterations, all surface treatments increase tubules exposure; HP treatment significantly increases perimeter and area percentage; and HP+DL increases surface roughness.ConclusionsBleaching HP combined with DL offers an improvement in terms of intracoronal dentin surface protection, yielding better maintenance of dentin chemical stability and morphology.



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Subadditive responses to extremely short blue and green pulsed light on visual evoked potentials, pupillary constriction and electroretinograms

The simultaneous exposure to blue and green light was reported to result in less melatonin suppression than monochromatic exposure to blue or green light. Here, we conducted an experiment using extremely short...

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Life, Positively 2017

Published: November 17, 2017 in A&E / Life&Style , Cover Stories , Featured Stories Updated: November 16, 2017 at 8:02 pm ENGAGE: Write a letter to the editor qnotes is pleased to partner with Affinity Health Center, RAIN, Rosedale Medical, Ballantyne Family Medicine and PowerHouse Project in presenting this special section, "Life, Positively," in recognition of World AIDS Day. Affinity Health Center is a Federally Qualified Community Health Center located in Rock Hill, S.C. Our staff of almost 50 employees is growing to serve the needs of your community with compassion, dignity and respect.

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Letter to the Editor regarding “Robotic or non-robotic transoral laryngectomy”

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Reply to Letter to the Editor regarding “Robotic or non-robotic transoral laryngectomy”

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Pneumoparotitis as a complication of long-term oronasal positive airway pressure for sleep apnea

Abstract

Background

Parotid swelling is rarely caused by pneumoparotitis from retrograde insufflation of air into Stensen's duct. Previous reports have identified occupational exposures, self-induced habits, exercise, spirometry, and short-term positive pressure airway ventilation as causes of salivary duct insufflation.

Methods

We present 2 cases of pneumoparotitis in patients on long-term oronasal continuous positive airway pressure (CPAP) for obstructive sleep apnea.

Results

A diagnosis of pneumoparotitis was made by CT scan in case 1 and sialography in case 2. Patients were advised to transition from oronasal to nasal-only CPAP. One patient was successfully transferred and had good symptomatic improvement, whereas the second patient did not tolerate nasal CPAP and had persistent symptoms on oronasal CPAP.

Conclusion

Long-term use of oronasal CPAP is a potential cause of pneumoparotitis.

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Top 10 research priorities in head and neck cancer: Results of an Alberta priority setting partnership of patients, caregivers, family members, and clinicians

Abstract

Background

The epidemiology, etiology, and management of head and neck cancer are evolving. Understanding the perspectives and priorities of nonresearchers regarding treatment uncertainties is important to inform future research.

Methods

Using the James Lind Alliance approach, patients, caregivers, and clinicians responded to a survey regarding their unanswered questions about treating and managing head and neck cancer. Distinct uncertainties were extracted from responses and sorted into themes. Uncertainties already answered in the literature were removed. Those remaining were ranked by patients and clinicians to develop a short list of priorities, which were discussed at a workshop and reduced to the top 10.

Results

One hundred sixty-one respondents posed 818 uncertainties, culminating in 77 for interim ranking and 27 for discussion at a workshop. Participants reached consensus on the top 10, which included questions on prevention, screening, treatment, and quality of life.

Conclusion

Nonresearchers can effectively collaborate to establish priorities for future research in head and neck cancer.

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Predictive factors for osteoradionecrosis of the jaws: A retrospective study

Abstract

Background

Osteoradionecrosis of the jaw (ORNJ) is a well-recognized complication of radiotherapy. The purpose of this study was to assess predictive factors for the development of ORNJ.

Methods

A retrospective study of 325 patients with head and neck squamous cell carcinoma (HNSCC) treated at one institution between January 1, 1999, and December 31, 2008, was conducted. Outcome measure was the presence/absence of ORNJ. Time to event was recorded and Cox proportional hazard regression analysis was used to determine statistically significant predictive factors.

Results

Fifty-nine patients had ORNJ. Statistical analysis using Cox regression analysis identified several statistically significant variables: dentoalveolar surgery; peri-resective surgery of the jaw; continued tobacco usage after radiotherapy, diabetes mellitus type 2 (DM2); and total radiation dose.

Conclusion

Patients at greater risk of developing ORNJ can be identified and measures can be instituted to reduce its incidence and expedite management when it does occur.

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Prevalence of antibiotic prescription in pediatric outpatients in Italy: the role of local health districts and primary care physicians in determining variation. A multilevel design for healthcare decision support

According to scientific literature, antibacterials are prescribed for common pediatric conditions that do not benefit from antibiotic therapy. The link between antibiotic use and bacterial resistance is well k...

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Risk management of emergency service vehicle crashes in the United States fire service: process, outputs, and recommendations

Emergency service vehicle crashes (ESVCs) are a leading cause of death in the United States fire service. Risk management (RM) is a proactive process for identifying occupational risks and reducing hazards and...

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Assessing the delivery of alcohol screening and brief intervention in sexual health clinics in the north east of England

Risky drinking is associated with risky sexual experiences, however the relationship between alcohol and sex is complex. The aim of the study was to assess the feasibility of delivering alcohol screening and b...

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Observation and assessment of the nutritional quality of ‘out of school’ foods popular with secondary school pupils at lunchtime

The contemporary Scottish diet is unhealthy and a risk factor for poor health outcomes including obesity. Over a third of Scottish children are at risk of being overweight or obese, and there have been calls t...

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Dentist teaches basics of oral care for police dogs

Roughly 30 area officers learned the basics of oral care for their working police dogs Thursday morning from veterinary dentist Dr. Stephen Juriga, who spoke to the group at the Aurora police headquarters. Juriga said police dogs - typically German shepherds, Belgian malinois or bloodhounds - have a high pain tolerance and won't show signs when their teeth are broken, discolored or otherwise causing pain.

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FLASHBACK: Maxine tries out the DIY dental kit from Barnitts, January 1998

It was a busy newsroom, with two banks of reporters filling the editorial floor and a row of features writers and subs. I had been working as a features writer in London and a sub-editor in Cambridge before my move north and had not been a reporter for a couple of years, having cut my teeth on the Oxford Mail.

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Plant eater

Seymore Krelborn, portrayed by Peyton Smith, talks to his plant for the first time. Plant eater By Chris Strunk Last Updated: November 16, 2017 Valley Center to perform 'Little Shop of Horrors' If 'Little Shop of Horrors" is so gory and gross, why can't audiences stop laughing? The musical, which features a blood-thirsty talking plant and a self-medicating and sadistic dentist, is, at its core, a comedy.

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Use of artificial primary teeth for endodontic laboratory research: experiments related to canal length determination

Abstract

Background

Due to the scarcity of exfoliated/extracted human primary teeth with complete roots, artificial teeth were developed as an alternative to be used for educational and laboratory research purposes. This study aimed to assess the feasibility of using artificial primary teeth for conducting laboratory research through an experiment related to canal length determination, comparing artificial teeth with natural teeth.

Methods

Thirty anterior and 21 posterior artificial teeth, and the same number of natural primary teeth were selected. After preparing the access cavity, the root canal length was determined by two examiners twice using three different methods: radiography and two electronic apex locators. Then, the actual root canal length was measured by inserting a K-file up to the apical foramen (reference standard). Accuracy was calculated using Bland-Altman analysis and intraclass correlation coefficient (ICC). The inter- and intra-examiner reproducibility was also calculated using the ICC.

Results

The methods using the electronic apex locators showed better accuracy in both artificial and natural teeth. Trends observed with artificial primary teeth were similar to those observed with natural teeth, except for the results in artificial anterior teeth.

Conclusions

The model of artificial teeth might be a good alternative for educational purposes; however, improvements are necessary to employ these teeth for research purposes when considering experiments for canal length determination.

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3 Reasons to Visit Your Dentist Regularly

When is the last time you visited our dental office? If it has been more than 6 months since your last routine cleaning, it is time for you to schedule another checkup with Dr. Alina Bergan DDS. While you might think that periodic cleanings are meant to get your teeth bright and white, checkups do more than just keep your teeth clean.

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Association between hepatitis B and hearing status

OBJECTIVE: This study was performed to investigate the correlation between the chronic hepatitis B virus infection and hearing status. This study was performed to investigate the correlation between the chronic hepatitis B virus infection and hearing status.

PATIENTS AND METHODS: This research was based on 76 hepatitis-B infections as the case group (including 35 HBV carriers and 41 chronic hepatitis B (CHB) patients) and 54 normal cases as the control group. They were selected sequentially and audiologic tests were performed on the participants.

RESULTS: The average hearing thresholds (HTs) of control group and hepatitis-B infection were 10.70 and 12.42 dBHL respectively with statistically significant difference (p < 0.01). Frequency-specific HT of 114 ears in control group and hepatitis-B infection were found statistical differences for hearing frequency ranged 250 to 8000 (p < 0.05), and statistically significant differences for 250, 2000 and 4000 Hz (p < 0.01). Significant differences were only measured for HT at 250 Hz frequencies between control and HBV carriers (p < 0.01), while for control and CHB group, the differences were detected for all tested frequency (p < 0.01). The SNR for f2 frequencies (553, 1105, 2211, 3125, 4416, 4416, 6250 Hz) of the CHB patients and HBV carriers were compared with statistical differences (p < 0.01).

CONCLUSIONS: The results showed that the hepatitis-B patients were more prone to hearing loss and that the hepatitis B disease can cause hearing loss. The infection of the inner ear and the pathological changes of the patients with HBV infection still need to be further explored.

L'articolo Association between hepatitis B and hearing status sembra essere il primo su European Review.

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Optimizing functional outcomes in mandibular condyle reconstruction with the free fibula flap using CAD/CAM technology

Publication date: Available online 15 November 2017
Source:Journal of Oral and Maxillofacial Surgery
Author(s): Z-Hye Lee, Tomer Avraham, Casian Monaco, Ashish A. Patel, David L. Hirsch, Jamie P. Levine
IntroductionMandibular defects involving the condyle represent a complex reconstructive challenge for restoring proper function of the temporomandibular joint (TMJ) as it requires precise bone graft alignment for full restoration of joint function. The use of CAD/CAM technology can aid in accurate reconstruction of mandibular condyle defects with a vascularized free fibula flap without the need for additional adjuncts. The purpose of this study is to analyze clinical and functional outcomes following reconstruction of mandibular condyle defects using only a free fibula graft with the help of virtual surgery techniques.MethodsA retrospective review was performed to identify all patients who underwent mandibular reconstruction with only free fibula flap without any TMJ adjuncts after a total condylectomy. Three-dimensional modeling software was used to plan and execute reconstruction for all patients.ResultsBetween 2009 and 2014, total of 14 patients underwent reconstruction of mandibular defects involving the condyle with the aid of virtual surgery technology. The average age was 38.7 (range 11-77) years. The average follow-up period was 2.6 (range 0.8 to 4.2) years. Flap survival was 100% (n=14). All patients reported improved facial symmetry, adequate jaw opening, and normal dental occlusion. In addition, they achieved good functional outcomes including normal, intelligible speech and ability to tolerate a regular diet with solid foods. Maximal intercisal opening range for all patients were 25-38mm with no lateral deviation or subjective joint pain. No patient had progressive joint hypomobility or condylar migration. One patient had ankylosis, which required release.ConclusionTMJ reconstruction poses significant challenges in bone graft alignment for full restoration of joint function. The use of CAD/CAM technology can aid in accurate reconstruction of mandibular condyle defects with a vascularized free fibula flap through precise planning and intra-operative manipulation with optimal functional outcomes.



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Magnetic Resonance Neurography of Traumatic and Non-Traumatic Peripheral Trigeminal Neuropathies

Publication date: Available online 16 November 2017
Source:Journal of Oral and Maxillofacial Surgery
Author(s): John R. Zuniga, Robert V. Walker, Cyrus Mistry, Igor Tikhonov, Riham Dessouky, Avneesh Chhabra
PurposeThe clinical neurosensory testing (NST) is currently the gold-standard for the diagnosis of traumatic and non-traumatic peripheral trigeminal neuropathies (PTN), but exhibits both false positive and negative results when compared to surgical findings and frequently delays treatment decisions. We tested the hypothesis that magnetic resonance neurography (MRN) of PTN can serve as a diagnostic modality by correlating NST, MRN and surgical findings.Materials and MethodsSixty patients with traumatic and non-traumatic PTN of varying etiologies and Sunderland classifications underwent NST followed by MRN on 1.5T and 3.0 T scanners. The protocol included 2D and 3D imaging, including diffusion imaging and isotropic 3D PSIF. The MRN findings were read by two readers in consensus of clinical findings but blinded to the side of abnormality. The MRN results were summarized using Sunderland Classification. In 26 patients, surgery was performed and Sunderland classification was assigned based on surgical photos. Agreement between MRN and NST/Surgical classification was evaluated using kappa statistics. Pearson's Correlation Coefficient (PCC) was used to assess the correlation between continuous measurements of MRN/NST and surgical classification.ResultsNineteen males and 41 females, mean age 41, ranging 12 to 75, with 54 complaints of altered sensation of the lip/chin/or tongue, including 16 with neuropathic pain and 4 with no neurosensory complaint were included. Third molar surgery (n=29) represented the most common cause of traumatic PTN. Assuming one nerve abnormality per patient, the lower class was accepted, a kappa of 0.57 was observed between MRN and NST classification. A kappa of 0.5 existed between MRN and surgical findings with a PCC of 0.67.ConclusionsMRN anatomically maps PTN and stratifies the nerve injury and neuropathies with moderate to good agreement with NST and surgical findings for clinical use.



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Calcified carotid artery atheromas in panoramic radiographs are associated with a first myocardial infarction: a case-control study.

Publication date: Available online 15 November 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): N. Gustafsson, J. Ahlqvist, U. Näslund, P. Wester, K. Buhlin, A. Gustafsson, E. Levring Jäghagen
ObjectiveThe aim of this case-control study was to investigate whether subjects with a first myocardial infarction (MI) had a higher prevalence of calcified carotid artery atheromas (CCAAs) in panoramic radiographs (PRs) than age, gender, and residential area matched controls without MIs.Study designSix hundred ninety-six cases with a first MI and 696 controls, were included in this sub-study of the Swedish multicentre PAROKRANK study. All subjects had PRs that were evaluated for CCAAs.ResultsThe prevalence of CCAAs detected by PR was 33.8% (235/696) in cases and 27.6% (192/696) in controls (odds ratio [OR]: 1.24, 95% CI: 1.04-1.44; p=0.012). Among males, 32.7% (184/562) of cases and 26.5% (149/562) of controls displayed CCAAs in PRs (OR: 1.24, 95% CI: 1.03-1.48; p=0.022). Among both genders, bilateral CCAAs were significantly more common among cases than among controls (p=0.002).ConclusionCases, i.e. subjects with recent MIs, had a significantly higher prevalence of CCAAs in PRs compared to controls, i.e. subjects without MIs. This difference between groups was more pronounced for bilateral CCAAs. These findings supported the contention that CCAA detection could serve as a risk indicator for future MIs.



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Considerations in the diagnosis of oral hairy leukoplakia – an institutional experience

Publication date: Available online 15 November 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Andres Flores-Hidalgo, Si On Lim, Alice E. Curran, Ricardo J. Padilla, Valerie Murrah
ObjectiveWe report the 10-year experience with oral hairy leukoplakia (OHL) at the Division of Oral and Maxillofacial Pathology at the University of North Carolina at Chapel Hill.Study DesignAll the associated hematoxylin and eosin (H&E) and EBV encoding region in-situ hybridization (EBER ISH) slides of OHL cases between January 1, 2008 and February 1, 2017 were retrieved and reviewed. Collected demographics, clinical presentation, medical and social history were reviewed and reported.ResultsSix ISH-confirmed OHL cases showed predilection for the lateral tongue. There were three females and three males. The mean age was 50.5 years, with a range of 29 -70 years. One patient had known HIV-positive status prior to the biopsy. Three patients had reported a history of heavy smoking. Other medical conditions reported were history of breast cancer, a long history of corticosteroid inhalers use for asthma treatment, high cholesterol, diabetes and hypertension.ConclusionThese findings demonstrate the need to include OHL as a potential entity in the differential diagnosis of leukoplakic tongue lesions, regardless of the HIV status. Also, the presence of OHL in patient can promote the investigation of various explanations of EBV infection including immunosuppression due to HIV infection or chronic steroid use.



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Comparison between peri-implant bone level changes of implants placed during and 3 months after iliac bone grafting

Publication date: Available online 15 November 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Emre Tosun, Canseda Avağ, Özgür Başlarlı, Serkan Kiriş, Anıl Öztürk, Murat Akkocaoğlu
ObjectiveThe aim of this study was to compare the peri-implant bone level changes of implants placed during and 3 months after bone grafting from the iliac crest.Study DesignA total of 103 implants were placed; 42 during the grafting, and 61 three months after the grafting procedure. All patients were grafted with iliac bone from the anterior superior iliac crest. Bone resorption was evaluated with cone-beam computed tomography, in all patients, at their last control visit. Periodontal health was assessed via the gingival and plaque indices and pocket depths around the dental implants.ResultsMean bone resorption values at the buccal, lingual, mesial, and distal sides of the implants were 1.08 mm, 0.36 mm, 0.30 mm, and 0.25 mm in the delayed group, and 1.87 mm, 1.25 mm, 0.92 mm, and 1.23 mm in the simultaneous group, respectively; the differences between the groups were significant. There were no significant between-group differences in the gingival or plaque indices, or pocket depths. The mean follow-up period was 29 months.ConclusionFor reconstructing atrophic jaws, bone grafting from the iliac crest and implant placement after 3 months is a reliable technique with a high success rate and less bone resorption.



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Performance of five different displays in the detection of artificial incipient and recurrent caries-like lesions

Publication date: Available online 15 November 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Shawn Chancy Countryman, Saulo Leonardo Sousa Melo, Manuella Dias Furtado Belem, Francisco Haiter-Neto, Marcos A. Vargas, Veeratrishul Allareddy
ObjectivesTo assess whether auto-calibrating medical-grade monitors perform better than off-the-shelf monitors and tablet computers in detecting artificial incipient and recurrent caries-like lesions.Materials & Methods60 extracted teeth (30 premolars and 30 molars) were selected. All molars received class II amalgam and composite restorations. A 7mm² area on the crowns of half of the teeth was demineralized. Phantoms consisting of four teeth were created. Three observers using a five-point scale evaluated digital periapical radiographs for the presence of caries on five displays: two auto-calibrating medical-grade monitors, two tablets, and an off-the-shelf monitor. Sensitivity, specificity, accuracy, and ROC data were calculated and verified through ANOVA and Tukey tests. Cohen's kappa assessed observer agreements.ResultsIntraobserver agreement ranged from 0.347-0.612 (molars) and 0.617-0.811 (premolars). Interobserver agreement ranged from 0.239-0.559 (molars) and 0.657-0.858 (premolars). The performances of tablets and the off-the-shelf monitor were similar to medical monitors when the same tooth groups were compared. Medical monitors presented fewer statistically significant differences when different lesions where compared within the same display and restorative material.ConclusionEvaluations of similar lesions were not significantly different between the 3 types of displays. However, the auto-calibrating medical-grade monitors performed better when incipient and recurrent lesions were compared.



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Use of integra in oral reconstruction: a case series

Publication date: Available online 15 November 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): L. Rúa Gonzálvez, L. de Villalaín Álvarez, A. Novoa Gómez, J.C. de Vicente Rodríguez, I. Peña González
Purpose: Small intraoral defects are usually reconstructed using skin autografts. However, the goal of this research was to describe an alternative to the classical techniques using artificial dermis (Integra®) in the reconstruction of these types of injuries. Materials and Methods: Four patients with small intraoral lesions in different locations underwent resection. The created defects were covered with a bilayer of Integra®; then, a chlorhexidine stent cure (Laboratorios Salvat, Barcelona, Spain) was applied. The patients were followed-up daily during the first week to detect any signs of infection, dehiscence or loss of the lamina. Thereafter, they were followed-up once per week for one month. Results: None of the patients presented with infections or a loss of the dermis. When the silicon sheet was detached, granulation tissue was detected, with complete re-epithelialization of the lesion in the postsurgical third through fourth weeks. Conclusion: The use of the Integra® allowed for the rapid reconstruction of slight intraoral defects, while preventing the morbidity associated with classical techniques. In this research, no complications were observed.



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Modifiable health-related factors (smoking, physical activity and body mass index) and health care use and costs among adult cancer survivors

Abstract

Objective

To examine the associations between modifiable health-related factors, such as smoking, low physical activity and higher body mass index (BMI), and annual health care visits and expenditures among adult cancer survivors in the United States.

Methods

Using data from the 2010–2014 Medical Expenditures Panel Survey, we identified 4920 cancer survivors (aged 18–64 years) and a matched comparison group. Our outcomes were number of annual health care visits [i.e., outpatient/office-based, hospital discharges and emergency department (ED) visits] and total health care expenditures. We examined health-related factors, demographics, insurance and health status (i.e., comorbidity and mental distress). Bivariate and multivariable analyses examined the associations between outcomes and health-related factors.

Results

Of survivors, approximately 21% were current smokers, 52% reported low physical activity and 35% were obese, vs. 19.6, 49.5 and 36.7%, respectively, of the comparison group. These factors were associated with greater comorbidity and mental distress in both groups. Current smokers among survivors were less likely to have outpatient visits [marginal effect on the number of visits (ME) = −3.44, 95% confidence interval (CI) −5.02 to −1.86, P < 0.001] but more likely to have ED visits (ME = 0.11, 95% CI 0.05–0.18, P = 0.001) than non-smokers. Physically active individuals in both groups had fewer ED visits, and lower total expenditures than those who reported low physical activity.

Conclusion

Regular assessments of health-related factors should be incorporated in survivorship care to reduce the burden of cancer. Modification of survivors' health-related factors (e.g., low physical activity) may help improve their health outcomes and reduce financial burden.

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Identification of prognostic markers of high grade prostate cancer through an integrated bioinformatics approach

Abstract

Purpose

Prostate cancer is one of the leading causes of cancer death for male. In the present study, we applied an integrated bioinformatics approach to provide a novel perspective and identified some hub genes of prostate cancer.

Method

Microarray data of fifty-nine prostate cancer were downloaded from Gene Expression Omnibus. Gene Ontology and pathway analysis were applied for differentially expressed genes between high and low grade prostate cancer. Weighted gene coexpression network analysis was applied to construct gene network and classify genes into different modules. The most related module to high grade prostate cancer was identified and hub genes in the module were revealed. Ingenuity pathway analysis was applied to check the chosen module's relationship to high grade prostate cancer. Hub gene's expression profile was verified with clinical samples and a dataset from The Cancer Genome Atlas project.

Result

3193 differentially expressed genes were filtered and gene ontology and pathway analysis revealed some cancer- and sex hormone-related results. Weighted gene coexpression network was constructed and genes were classified into six modules. The red module was selected and ingenuity pathway analysis confirmed its relationship with high grade prostate cancer. Hub genes were identified and their expression profile was also confirmed.

Conclusion

The present study applied integrate bioinformatics approaches to generate a holistic view of high grade prostate cancer and identified hub genes could serve as prognosis markers and potential treatment targets.

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Meeting report of the 6th Heidelberg Myeloma Workshop: current status and developments in diagnosis and therapy of multiple myeloma

Abstract

Purpose

The 6th Heidelberg Myeloma Workshop was held on May 5th and 6th, 2017 in the lecture hall of the University Hospital Heidelberg.

Methods and results

Main topics of the meeting were (1) biology and genomics of multiple myeloma, (2) diagnostics and prognostic factors, (3) role of immunotherapy in multiple myeloma, as well as (4) therapy of multiple myeloma—drugs and treatment strategies.

Conclusion

The landscape for the treatment of newly diagnosed and relapsed disease has significantly changed since the last Heidelberg Myeloma Workshop in 2015. Updates on the current developments were presented at the meeting.

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The more from East-Asian, the better: risk prediction of colorectal cancer risk by GWAS-identified SNPs among Japanese

Abstract

Background

Little is known about the difference of genetic predisposition for CRC between ethnicities; however, many genetic traits common to colorectal cancer have been identified. This study investigated whether more SNPs identified in GWAS in East Asian population could improve the risk prediction of Japanese and explored possible application of genetic risk groups as an instrument of the risk communication.

Methods

558 Patients histologically verified colorectal cancer and 1116 first-visit outpatients were included for derivation study, and 547 cases and 547 controls were for replication study. Among each population, we evaluated prediction models for the risk of CRC that combined the genetic risk group based on SNPs from GWASs in European-population and a similarly developed model adding SNPs from GWASs in East Asian-population. We examined whether adding East Asian-specific SNPs would improve the discrimination.

Results

Six SNPs (rs6983267, rs4779584, rs4444235, rs9929218, rs10936599, rs16969681) from 23 SNPs by European-based GWAS and five SNPs (rs704017, rs11196172, rs10774214, rs647161, rs2423279) among ten SNPs by Asian-based GWAS were selected in CRC risk prediction model. Compared with a 6-SNP-based model, an 11-SNP model including Asian GWAS-SNPs showed improved discrimination capacity in Receiver operator characteristic analysis. A model with 11 SNPs resulted in statistically significant improvement in both derivation (P = 0.0039) and replication studies (P = 0.0018) compared with six SNP model. We estimated cumulative risk of CRC by using genetic risk group based on 11 SNPs and found that the cumulative risk at age 80 is approximately 13% in the high-risk group while 6% in the low-risk group.

Conclusion

We constructed a more efficient CRC risk prediction model with 11 SNPs including newly identified East Asian-based GWAS SNPs (rs704017, rs11196172, rs10774214, rs647161, rs2423279). Risk grouping based on 11 SNPs depicted lifetime difference of CRC risk. This might be useful for effective individualized prevention for East Asian.

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Survival benefit of pelvic and paraaortic lymphadenectomy in high-grade endometrial carcinoma: a retrospective population-based cohort analysis

Abstract

Objective

The standard therapy for high-grade endometrial cancer is surgery but the therapeutic effects of pelvic and paraaortic lymph node dissection (LND) are poorly investigated. In this study, we retrospectively evaluated overall survival, recurrence rates and recurrence-free survival among patients with high-grade type I and II endometrial carcinoma who underwent LND.

Methods

This study included 284 patients who are recorded in the German Tumor Centre Regensburg form 1998 to 2015 and were selected by cancer grading, the absence of secondary tumors, primary surgery including hysterectomy and available follow-up. 244 of the 284 patients in this cohort were unequivocally classified as R0 after resection.

Results

A significantly increased overall survival was observed for systematic LND of 25 or more paraaortic and pelvic lymph nodes versus patients who did not undergo such intervention (p < 0.001) or had elective LND of 1–24 lymph nodes both in univariable (p = 0.016) and multivariable (p = 0.014) analysis. A similar observation was made for recurrence-free survival of patients in the cohort who underwent complete tumor resection (R0). In addition, a reduced cumulative recurrence rate was observed for patients with systematic LND.

Conclusions

Our study provides evidence that the systematic removal of 25 or more pelvic and paraaortic lymph nodes reduces the recurrence rate and that it is beneficial for the long-term overall and recurrence-free survival of patients with high-grade endometrial cancer.

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Prognostic stratification of patients with metastatic nasopharyngeal carcinoma using a clinical and biochemical scoring system

Abstract

Purpose

Metastatic nasopharyngeal cancer (NPC) is known to have poor survival outcomes. Clinical and biochemical parameters may impact survival outcomes among patients with metastatic NPC and may be used for prognostication.

Methods

One-hundred and fifty-eight patients with metastatic NPC treated at a single tertiary institution were analyzed retrospectively. Multivariate analysis was carried out on patients who were given disease control treatment (n = 135). A numerical score derived from the regression coefficients of each identified independent variable was used to create prognostic groups (PG). A p value of less than 0.05 was considered significant.

Results

Independent negative prognostic factors included ECOG status >1, LDH level >580 U/L, hemoglobin level <12.0 g/dL and having more than one metastatic organ involvement. Three PGs were obtained: low risk (total score = 0), intermediate risk (1–2) and high risk (3–4). Median survivals of the 3 groups (low, intermediate and high risk) were 57.1, 18.1 and 8.0 months for the three different risk groups, respectively (p < 0.001).

Conclusion

Risk stratification of patients with metastatic nasopharyngeal cancer is possible using a prognostic scoring system based on clinical and biochemical parameters. Patients with low-risk score may achieve good metastatic survival and may benefit from additional therapy for disease control.

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Human cancer stem cells are a target for cancer prevention using (−)-epigallocatechin gallate

Abstract

Purpose

Our previous experiments show that the main constituent of green-tea catechins, (−)-epigallocatechin gallate (EGCG), completely prevents tumor promotion on mouse skin initiated with 7,12-dimethylbenz(a)anthracene followed by okadaic acid and that EGCG and green tea extract prevent cancer development in a wide range of target organs in rodents. Therefore, we focused our attention on human cancer stem cells (CSCs) as targets of cancer prevention and treatment with EGCG.

Methods

The numerous reports concerning anticancer activity of EGCG against human CSCs enriched from cancer cell lines were gathered from a search of PubMed, and we hope our review of the literatures will provide a broad selection for the effects of EGCG on various human CSCs.

Results

Based on our theoretical study, we discuss the findings as follows: (1) Compared with the parental cells, human CSCs express increased levels of the stemness markers Nanog, Oct4, Sox2, CD44, CD133, as well as the EMT markers, Twist, Snail, vimentin, and also aldehyde dehydrogenase. They showed decreased levels of E-cadherin and cyclin D1. (2) EGCG inhibits the transcription and translation of genes encoding stemness markers, indicating that EGCG generally inhibits the self-renewal of CSCs. (3) EGCG inhibits the expression of the epithelial-mesenchymal transition phenotypes of human CSCs. (4) The inhibition of EGCG of the stemness of CSCs was weaker compared with parental cells. (5) The weak inhibitory activity of EGCG increased synergistically in combination with anticancer drugs.

Conclusions

Green tea prevents human cancer, and the combination of EGCG and anticancer drugs confers cancer treatment with tissue-agnostic efficacy.

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Validity of eleven prognostic scores with respect to intra- and extrahepatic recurrence of hepatocellular carcinoma after liver transplantation

Abstract

Introduction

Tumor recurrence is the most frequent cause of death after liver transplantation for hepatocellular carcinoma. We selected ten other prognostic classifications to evaluate their potential to predict the risk of recurrence after LT for HCC as compared to the Milan classification. All of the other scores have not been compared with one another in a single cohort.

Methods

Data of 147 consecutive patients transplanted at our department between 1996 and 2014 were analyzed and staged for morphological and functional scores of underlying liver disease. For long-term follow-up, we analyzed intrahepatic (within the liver ± distant metastases) and extrahepatic (distant metastases only) recurrence separately.

Results and conclusions

The median survival time for all patients was 106 months. The 5- and 10-year observed survival rates were 61 and 43%, respectively. The observed cumulative 5- and 10-year recurrence rates were 37 and 39%, respectively, 10-year intrahepatic and extrahepatic recurrence rates were 12 and 27%, respectively. Median survival time after diagnosis of first recurrence was 7.5 (0–120) months; 2 and 18 months for all, intra- and extrahepatic recurrence, respectively. UCSF-, up to seven-, Shanghai Fudan- or Duvoux classifications can identify patients with a cumulative 10-year recurrence rate below 20%. The pre-therapeutic AFP level should be considered in addition to the geometry of the intrahepatic lesions.

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Prescribing of NOACs has outnumbered warfarin: exploring how physicians choose anticoagulant treatments

Abstract

Purpose

The development of non-vitamin K-dependent oral anticoagulants (NOACs) is a new alternative to treatment with warfarin. The purpose of this study was to explore drug prescription decisions of NOACs or warfarin from hospital physicians in cardiovascular departments.

Methods

A qualitative study with focus group interviews was conducted in three different hospitals. The interview guide explored the background of prescribing anticoagulants (warfarin, dabigatran, rivaroxaban, and apixaban) and experiences with effect and side-effects they had observed in patients.

Results

The systematic text condensation eluded four main themes: when to prescribe NOACs, concern about side-effects, pharmaceutical properties and patient adherence, and prescribing policy and intra-professional communication. All available anticoagulants were prescribed. However, no specific NOAC was preferred. Factors perceived as contraindications for NOACs varied among the doctors. Most had observed side-effects of NOACs; however, these rarely influenced prescribing decisions due to small differences in safety profiles. Few drug-drug interactions and fixed daily doses made NOACs easy to prescribe; but some doctors had experienced lack of drug effect for some patients. Non-adherence with NOACs was harder to spot. Some different prescribing cultures had evolved between the different hospitals and between general practitioners.

Conclusion

The hospital physicians chose anticoagulants based on patient conditions as renal function, bleeding risks, and drug interactions being the most common taken into account. They could not say which NOAC was best, and wish that future studies could compare the different NOACs, and not just compare with warfarin.

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Association between a single-nucleotide polymorphism in the GREM1 gene and nonsyndromic orofacial cleft in the Chinese population

Abstract

Background

Nonsyndromic orofacial cleft (NSOC) is a common craniofacial deformity among newborns. The GREM1 gene is correlated with orofacial development. The aim of our study was to investigate the association between a single-nucleotide polymorphism in the GREM1 gene and this malformation in the Chinese population.

Methods

The SNaPshot mini sequencing technique was used to genotype the locus rs1258763 of the GREM1 gene in 331 patients with NSOC and 271 individuals in a control group.

Results

For GREM1 rs1258763, there was a significant difference between the NSOC case group and control group (P=0.022). Children carrying GA and GA/AA genotypes had an increased risk of NSOC (OR=1.62, 95%CI: 1.15-2.30; OR=1.52, 95%CI: 1.09-2.12). In the cleft subgroup, we found that the GREM1 rs1258763 GA genotype might contribute to the elevated risk of the cleft lip with or without cleft palate (CL/P) (P=0.029). Nonsignificant differences were found between the cleft palate only (CPO) and control groups (P=0.077).

Conclusion

Our findings revealed that the GREM1 polymorphism was significantly associated with the risk of NSOC in the Chinese population.

This article is protected by copyright. All rights reserved.

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All you need to know about angular cheilitis

A look at angular cheilitis, a condition where pain occurs in the corners of the mouth. Included is detail on risk factors, complications, and diagnosis.

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Prenatal famine exposure, adulthood obesity patterns and risk of type 2 diabetes

Abstract

Background

Prenatal exposure to famine and adulthood obesity have been independently related to the risk of type 2 diabetes; however, little is known about the joint effects of these risk factors at different stages of life on adulthood diabetes risk.

Methods

The analysis included 88 830 participants of the China Kadoorie Biobank, who were born around the time of the Chinese Great Famine and without diabetes, cardiovascular diseases, or cancer at baseline. We defined famine exposure subgroups as nonexposed (born between 1 October 1962 and 30 September 964), fetal-exposed (born between 1 October 1959 and 30 September 1961) and early-childhood exposed (born between 1 October 1956 and 30 September 1958). General obesity was assessed by body mass index (BMI: overweight ≥ 24.0, obesity ≥ 28.0) and abdominal obesity assessed by waist-to-hip ratio (WHR, men/women: moderate ≥ 0.90/0.85, high ≥ 0.95/0.90).

Results

During a median 7.3 years (642 552 person-years) of follow-up, we identified 1372 incident cases of type 2 diabetes. Compared with nonexposed and early-childhood exposed participants combined as a single comparison group, fetal-exposed participants showed an increased risk of diabetes in adulthood [hazard ratio (HR) = 1.25; 95% confidence interval (CI): 1.07–1.45]. The association between general obesity and diabetes was consistent across subgroups according to famine exposure (P for interaction > 0.05). A stronger association between abdominal obesity and diabetes was observed in the fetal-exposed subgroup than in other subgroups (P for interaction = 0.025 in the whole population). This interaction was more obvious in women (P = 0.013) but not in men (P = 0.699). Compared with normal-BMI and -WHR participants, those with both general (BMI ≥ 24.0) and abdominal (WHR ≥ 0.90/0.85) obesity in adulthood had 5.32 (95% CI: 3.81–7.43)-, 3.13 (2.48–3.94)- and 4.43 (3.45–5.68)-fold higher risks if these were carried during, before and after times of famine, respectively.

Conclusions

Coexistence of prenatal experience of undernutrition and abdominal obesity in adulthood was associated with a higher risk of type 2 diabetes.

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Family history of gastric mucosal abnormality and the risk of gastric cancer: a population-based observational study

Abstract

Background

An increased prevalence of gastric premalignant abnormalities was reported among relatives of gastric cancer (GC) patients, with rather unexplored clinical significance.

Methods

In Swedish computerized pathology registers, we identified, as 'index' persons 232 681 patients who were born after 1931 and underwent endoscopic examination with stomach biopsy between 1979 and 2014. Through linkage with the Multi-Generation Register, we compiled a cohort consisting of 903 337 first-degree relatives of these biopsied patients. The relatives were grouped according to their 'family histories', defined as the first gastric mucosal diagnosis of the index person or GC family history known before that. Standardized incidence ratios (SIRs) provided comparisons with the matched general population. For internal comparisons with relatives with 'normal/minor changes' mucosal family history, hazard ratios (HRs) were derived from adjusted Cox regression modelling.

Results

During follow-up, 1302 relatives developed GC. Crude incidence rates of non-cardia GC were 7.7 × 10⁻⁵ year⁻¹ for the 'normal/minor changes' family history group (SIR = 1.0), 11.2 to 12.6 × 10⁻⁵ year⁻¹ for precancerous changes groups (atrophic gastritis/intestinal metaplasia/dysplasia, SIR = 1.5 to 1.6), and 18.4 × 10⁻⁵ year⁻¹ for those with a family history of GC (SIR = 2.3). HRs derived from Cox models corroborated the family history-related risk pattern, with the most conspicuous trend observed among siblings—a family history of any precancerous changes and GC was associated with, respectively, a 2.5-fold and a 3.8-fold increment in non-cardia GC hazard, compared with siblings of index persons with 'normal/minor mucosal changes'.

Conclusions

The precancerous mucosal abnormalities recorded in a person's first-degree relatives may improve GC risk stratification for this person.

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Vorbereitung zur Facharztprüfung HNO

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LTBK-03 MULTICENTER RANDOMIZED PLACEBO CONTROLLED TRIAL OF AUTOLOGOUS FORMALIN FIXED TUMOR VACCINE FOR NEWLY DIAGNOSED GLIOBLASTOMAS

Abstract

BACKGROUND

Unlike immune checkpoint inhibitors, various vaccines have failed to demonstrate sufficient evidence in phase III studies due to the multiple antigenicity of neoplasms. Autologous formalin-fixed tumor vaccine (AFTV) from paraffin-embedded tissue is stable, and contains multiple tumor peptides, which are designed to induce killer lymphocytes in vivo (Nat Med 1995, 1996). We conducted three AFTV trials of Phase Ib or IIa for recurrent and newly-diagnosed glioblastoma (ndGBM), which demonstrate promising results. (Clin Cancer Res 2004; J Neurosurg 2011, 2013). In addition, a multicenter double-blind Phase IIb/III trial has been initiated.

METHODS

Patients from 16 to 75 years of age with supratentorial ndGBM, extensive resection, KPS of at least 60, and no prolonged steroids, were eligible. Planned patient enrollment was 120. AFTV or placebo, including for adjuvant treatment, was administered intradermally 3 times preceding (1) temozolomide chemoradiotherapy, (2) first and (3) second courses of adjuvant temozolomide.

RESULTS

In 30 months, 63 patients were registered for phase IIb and 61 cases were analyzed (mean age, 61 years). Median resection rate was 95%, median KPS was 80. In the whole cohort, median OS and progression-free survival (PFS) was 31.5 and 14.5 months, respectively. Comparison of the AFTV group (median OS, 25.6 months; 3-year OS rate, 38%) and the placebo group (median OS, 31.5 months; 3-year OS rate, 41%) did not reveal a significant difference in OS (HR, 1.19; 95% CI, 0.57 - 2.47; P = 0.64). Median PFS was 13.5 months in both groups (P = 0.98). According to a subgroup analysis of tumors with negative p53 immunostaining, 3-year OS of AFTV and placebo was 79% and 43%, respectively (P = 0.072). Surprisingly, for patients undergoing total resection of tumors, 3-year PFS of AFTV and placebo was 81% and 46%, respectively (P = 0.067). There were no severe adverse effects.

CONCLUSIONS

Phase IIb of AFTV trial for ndGBM did not demonstrate obvious survival impact in the whole cohort. However, subgroup analyses of tumors with negative p53 immunostaining or after total resection revealed possible better outcomes after AFTV therapy. These results will be investigated further in the Phase III part of the study.

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LTBK-04 FIRST RESULTS OF THE RANDOMIZED PHASE II STUDY ON DEPATUX –M ALONE, DEPATUX-M IN COMBINATION WITH TEMOZOLOMIDE AND EITHER TEMOZOLOMIDE OR LOMUSTINE IN RECURRENT EGFR AMPLIFIED GLIOBLASTOMA: FIRST REPORT FROM INTELLANCE 2/EORTC TRIAL 1410

Abstract

BACKGROUND

Depatux-m is a tumor-specific antibody-drug-conjugate consisting of antibody (ABT-806) bound to the toxin monomethylauristatin-F. We investigated depatux-m in EGFR-amplified recurrent glioblastoma (40–50% of glioblastoma).

METHODS

EORTC-1410-BTG (NCT02343406) is a randomized open label phase II study. Eligible were patients with centrally confirmed EGFR-amplified glioblastoma at first recurrence after temozolomide chemo-irradiation, occurring ≥3 months after radiotherapy. After stratification for WHO status and time of relapse (<16 or ≥16 weeks after the first day of the last temozolomide cycle), patients were randomized to either a) treatment with depatux-m 1.0 mg/kg every 2 weeks intravenously, or b) the same treatment combined with temozolomide 150–200 mg/m2 day 1–5 every 4 weeks, or c) either lomustine or temozolomide (TMZ/LOM) depending on the time of relapse. Primary endpoint was overall survival (OS); 240 patients/170 events were needed to detect a HR reduction of 0.54 in the depatux-m arms.

RESULTS

Between March 2015 and July 2016 260 patients were randomized. With 199 events observed, for the primary comparison of depatux-m in combination with TMZ versus TMZ/LOM a HR of 0.71 was observed (95%CI [0.50, 1.02]; p = 0.031 one-sided; median OS 9.6 months versus 8.2 months, 1-year OS rate 39.7% versus 28.2%). No OS difference was observed between depatux-m monotherapy (median OS 7.9 months) and TMZ/LOM (HR 1.04; 95%CI [0.73, 1.48]. In patients with relapse ≥16 weeks after end of 1stline TMZ treatment, combined depatux-m/TMZ was associated with improved OS (HR 0.45, 95%CI [0.23, 0.87]; median OS 14.9 months versus 9.5 months). The main toxicity observed in depatux-m treated patients was ocular (grade 3: 27.9%, grade 4: 1%).

CONCLUSION

Although the primary endpoint was not met, depatux-m in combination with TMZ might improve OS in EGFR amplified recurrent glioblastoma. Outcome for depatux-m monotherapy was similar to LOM/TMZ control. Ocular events observed were consistent with earlier studies.

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CMET-26. DIAGNOSTIC VALUE OF FDG-PET/CT FOR PATIENTS WITH BRAIN METASTASIS FROM UNKNOWN PRIMARY SITE

Abstract

OBJECTIVE

In 30% of patients with brain metastasis (BM), BM are the first clinical manifestation of systemic malignancy, referred to as BM from cancer of unknown primary site (BM-CUPS). The value of 18F-fluordesoxyglucose positron emission tomography (FDG-PET)/CT in the work-up of BM-CUPS patients remains to be defined.

METHODS

We screened 566 patients operated for BM at the University Hospital Zurich between 2004 and 2014 and identified 127 BM-CUPS patients. A validation cohort from two independent centers (n=100 and 120 patients) was available.

RESULTS

FDG-PET/CT was not superior to CT in localizing the primary lesion (FDG-PET/CT: 73/78, 93.6%; CT: n=70/78, 89.7%; p=0.25, McNemar's test). Thirty-six of 64 patients (56.3%) showed the same result in spotting the primary tumor. FDG-PET/CT identified additional lesions suspicious for extracranial metastases in 28 patients (43.7%). The graded prognostic assessment (GPA) score was determined post-hoc to objectify clinical relevance of additional findings. Information from CT only or FDG-PET/CT was used to assess extracranial metastases. Median GPA was 3 for CT vs. 2.5 for PET/CT (p= 3.8x10-5, McNemar's test), resulting in a predicted survival of 5.3 vs. 3.8 months (p= 6.1x10-5; Wilcoxon's test). Sensitivity of CT and FDG-PET/CT and staging capabilities were comparable in all cohorts.

CONCLUSION

FDG-PET/CT shows similar sensitivity to detect the primary tumor in BM-CUPS patients as CT, but may improve the accuracy of staging by detecting of more metastases. GPA scores and predicted survival differ significantly when calculated based on CT versus FDG-PET/CT. FDG-PET/CT should be prioritized for planning the diagnostic algorithm of BM-CUPS patients and redundant CT imaging should be avoided. Further, randomized trials on BM patients should standardize the methods when stratifying for GPA.

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ACTR-01. RETROSPECTIVE ANALYSIS OF OLIGODENDROGLIOMA TREATMENT AT A SINGLE INSTITUTION

Abstract

BACKGROUND

Recently published results of randomized prospective clinical trials have demonstrated benefit from sequential radiation and chemotherapy after surgery for oligodendroglial tumors (RTOG 9802, 9402; EORTC 26951). We aimed to investigate whether such a benefit could be demonstrated in a retrospective cohort treated at our institution.

METHODS

Patients were identified from the quality control database in the Section of Neuro-Oncology, Yale Cancer Center. Histologic, clinical, imaging, treatment, and outcome data was reviewed. Patients who were 18 to 39 years old and had undergone gross total resection of a WHO II lesion were deemed low-risk (LR). High-risk patients were those ≥40 years old or who had undergone an incomplete resection or those with anaplastic tumors. Primary outcome measure is progression-free survival (PFS). Secondary outcome measure is overall survival (OS). PFS and OS are analyzed in high-risk patients who at initial diagnosis received sequential therapy (HR-SEQ) compared to individuals who only underwent surgery alone or combined with one adjuvant treatment modality (HR-DEL). Survival estimates are based on Kaplan Meier method and survival distributions are compared using the log-rank test.

RESULTS

We identified 150 consecutive biopsy-confirmed oligodendroglioma cases who were treated at Yale Cancer Center between 2002 and 2016. Forty-one patients (27%) are deceased. Thirty patients were considered low risk (1p/19q intact, n=14; co-deletion, n=14; 1p-deleted, n=2). Amongst the high-risk patients, 99 were in the SEQ group (1p/19q intact, n=46; co-deletion, n=47; 1p-deleted, n=2; 19q-deleted, n=4) and 21 in the DEL group (1p/19q intact, n=9; co-deletion, n=8; 1p-deleted, n=3; 19q-deleted, n=1). Median OS was 15.1 years for LR, 6.75 years for HR-SEQ, and 16.95 years for HR-DEL.

CONCLUSIONS

PFS and subgroup analysis based on molecular markers is ongoing. We reserve our conclusions until the analysis is complete. The cohort is likely too small for detailed subgroup analysis.

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TMOD-48. SNAIL1 REGULATES GLIOMAGENESIS INDEPENDENT OF ITS MESENCHYMAL TRANSFORM FUNCTION

Abstract

BACKGROUND

Master mesenchymal factors such as Snail1 have long been implicated in local invasion and metastasis of various cancers including malignant brain tumors such as glioblastoma (GBM). However, mesenchymal factors are expressed early in tumorigenesis, well before first evidence of metastatic cells, suggesting that these factors have other critical functions independent of their mesenchymal regulation.

METHODS

We used a highly penetrant, retrovirally-delivered, PDGFB-induced mouse model of gliomagenesis in a conditional PTEN and/or P53 knockout background to produce GBM tumors of the proneural subtype, in which Snail1 expression is much lower compared to the mesenchymal subtype. We then examined the effect of conditional KO of Snail1 in glial cells when PDGFB overexpression occurred, using in vitro and in vivo loss-of-function experiments augmented by RNAseq expression profiling and computational network analysis.

RESULTS

Snail1 expression peaked early in gliomagenesis although its expression is downregulated once PDGFB-induced proneural tumors are formed. In an immune intact background, Snail1-null GBM developed at a much slower pace. Snail1 cooperated with oncogene activity to promote higher transformative capacity and to influence the cancer stem cell compartment.

CONCLUSION

Our data confirms a dual role for Snail1 in GBM progression, in which it cooperates with oncogenes to promote early transformation while independently also regulating mesenchymal changes at later stages of tumor development. Our platform combining RNAseq expression profiling and computational network analysis with biological validation provides a potentially powerful tool to study mechanistic events as gliomagenesis and proneural subtype GBM transformed into mesenchymal subtype GBM.

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SURG-11. LASER INTERSTITIAL THERMOTHERAPY (LITT) FOR NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA: ASSOCIATION BETWEEN TIME TO INITIATION OF CHEMOTHERAPY POST-PROCEDURE AND OUTCOME

Abstract

BACKGROUND

LITT is used for cytoreduction of unresectable glioblastoma and is associated with blood brain barrier disruption with an increased permeability peak at 2 weeks. We investigated if time to initiation of chemotherapy post-LITT was associated with progression free survival (PFS) and overall survival (OS).

METHODS

Records of glioblastoma patients who underwent LITT at our institution between 2013-2017 were reviewed. Patients with inadequate follow-up or no further treatment after LITT were excluded. A time-to-event analysis was performed to investigate the association between PFS, OS and the time to initiation of chemotherapy after LITT.

RESULTS

The study included 21 patients; 17 recurrent glioblastoma (rGBM) (6 secondary glioblastoma), 4 newly diagnosed glioblastoma (nGBM). Median age was 53.6 (19.8-64.9) years. Three patients (14%) had isocitrate dehydrogenase (IDH)-1 mutation by immunohistrochemistry and two patients had unknown IDH status. Pre- and post-operative median KPS were 90 (60-100) and 80 (40-100) respectively. Eleven patients had difficulty weaning steroids (4 patients initiated steroids peri-operatively, 7 patients prior to surgery). For rGBM post-LITT median PFS was 3.36 months (95% CI (0.21, 0.51)) and median OS was 18.48 months (95% CI (0.66,NA)) with 5 deaths. Median PFS and OS for nGBM has not been reached. Eighteen patients (86%) received post-LITT chemotherapy of which eight initiated treatment >3 weeks post-LITTdue to poor functionality (6), pregnancy (1), and patient choice (1). Among the patients receiving chemotherapy, time to initiation of chemotherapy was not associated with PFS or OS. Chemotherapy in rGBM cohort included lomustine (6), temozolomide (5), bevacizumab (3), bevacizumab + lomustine (1), lapatinib (1), and Novo-TTF (1). Median time to initiation ofi bevacizumab (4 patients) after LITT was 30.5 (17-45) days, without complications.

CONCLUSIONS

LITT may be an effective cytoreductive treatment for glioblastoma. Timing of onset of chemotherapy after LITT for glioblastoma is not associated with PFS or OS.

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EPID-13. A SINGLE INSTITUTION ANALYSIS: DETERMINING GENETIC VARIATION AND SURVIVAL OUTCOMES AMONG ASIAN AND NON-ASIAN NEUROSURGERY PATIENTS

Abstract

BACKGROUND

Globally, brain cancer compromises 2% of all total emerging cancers, yet has one of the lowest survival five-year survival rates. Differences in clinical outcomes between brain tumor patients of different races remains poorly understood.

METHODS

A retrospective chart review was performed on brain tumor resection patients 18 years old. Demographics, treatment variables, and survival outcomes were collected. Primary outcomes were recurrence rate, progression free survival (PFS), and overall survival (OS).

RESULTS

A total of 666 patients were included in final analysis. Females and males had nearly a 1:1 ratio (n = 345 and n = 321, respectively). Mean age was 51.3 (± 17.2) years. Females composed 64.3% (n = 54) of Asians patients; males constituted 35.7% (n = 30). Mean age of the Asians was 53.5 (± 16.5) years. Tumor pathologies included meningioma (n = 210 total) and glioblastoma (n = 192 total). There were 210 meningioma patients, of which Non-Asian patients comprised 81.43% of the group (n = 171) and Asian patients composed 18.57% (n = 39). We identified 192 glioblastoma patients in total. Non-Asian patients made up 92.7% of the glioblastoma cohort (n = 178) with the remaining 7.3% (n = 14) composed of Asian patients. There were no statistically significant differences between these groups in both cohorts in recurrence (P = .9052 and P = .7894, respectively), PFS (P = .6953 and P = .845, respectively), or OS (P = 1.0 and P = .9126, respectively).

CONCLUSION

Studies evaluating the survival between patients of different racial backgrounds against several tumor varieties are rare. Patients of certain racial backgrounds may need additional care consideration despite the same mutational composition as their counterparts. Repeated studies using national databases, such as the SEER database, may yield more conclusive results.

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TMIC-36. CROSSTALK OF GLIOMA STEM CELLS WITH VASCULAR ENDOTHELIAL CELLS PERSISTS THEIR PRONEURAL PHENOTYPE AND THERAPY RESISTANCE VIA ENDOCAN-CD11A INTERACTION

Abstract

GBM cells tend to invade into adjacent normal brain tissues and cannot be completely resected surgically. These remaining tumor cells are the "seeds" to escape post-surgical therapies, hence contributing to tumor recurrence. The exact mechanisms by which these seeds confer to therapy resistance remains elusive. Several studies have shown the functional contribution of tumor microenvironment to glioma stemness and highlighted the importance of vascular endothelial(VE) cells in tumor initiation and progression. Here, we aim to determine the role of crosstalk of VE cells with glioma stem cells (GSCs) to develop GBM recurrence. We first assessed the effect of VE conditioned media (VE-CM) on patient-derived GBM neurospheres in vitro and in vivo. Culturing GBM neurospheres with VE-CM or their coculturing with VE cells promoted growth and migration of GBM neurospheres. Mice coinjected with VE cells and GBM neurospheres resulted in an increase of tumor growth compared to the injection of GBM neurospheres alone. To understand the mechanism of action, we performed RNA sequencing with CD31+ VE cells and A2B5+ GSCs directly isolated from patients with therapy-refractory epilepsy or GBM to identify factors secreted by these cells. We identified that Endocan is upregulated in VE cells, whereas CD11a – a receptor for Endocan, is upregulated in GSCs. Preferential expression of CD11a in perivascular region of GBM tissues was observed by immunohistochemistry. Irradiating VE cells substantially increased ESM1, by which VE cells provide extrinsic signals for elevated malignancy of GSCs after radiation therapy. Functionally, adding VE-CM or recombinant ESM1 protected GBM neurospheres from undergoing irradiation induced apoptosis and mesenchymal transition. We are currently investigating exact mechanism by which Endocan secretion from VE cells promotes GSC malignancy after radiation. Taking these data together, targeting ESM1 in VE cells or CD11a in GBM cells may provide a novel and effective strategy for preventing GBM recurrence.

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ATIM-20. CLINICAL OUTCOMES WITH IPILIMUMAB IN COMBINATION WITH BEVACIZUMAB IN PATIENTS WITH RECENTLY DIAGNOSED GLIOBLASTOMA - A RETROSPECTIVE COHORT REVIEW

Abstract

BACKGROUND

Median survival for patients with glioblastoma remains under a year. Whilst there is accumulating interest in the role of checkpoint inhibitors in newly diagnosed glioblastoma, the results of clinical trials are awaited to establish clinical efficacy. We have previously presented clinical outcomes in patients with relapsed glioblastoma treated with the anti-CTLA-4 monoclonal antibody ipilimumab in combination with the anti-VEGF monoclonal antibody bevacizumab.

METHODS

We retrospectively identified patients with newly diagnosed WHO grade IV glioma who received treatment with ipilimumab and bevacizumab at our centre between March 2015 and March 2017. Baseline demographics, tumour characteristics, concurrent therapy, radiological responses, and survival data were analysed.

RESULTS

Nineteen patients were identified, 18 with glioblastoma and one with a glioneuronal tumour (Grade IV). Median age was 52 years (range 22–85) and 79% were male. 5% (1/19) had an IDH mutation, and 38% (6/16) had MGMT promotor methylation. Ipilimumab (3mg/kg, 3 weekly, 4 cycles) and bevacizumab (10mg/kg 2 weekly), given with concurrent G-CSF or GM-CSF were commenced after radiotherapy (except in one patient who did not receive radiotherapy). 58% of patients had prior surgical debulking (42% biopsy only), 79% had prior radical radiotherapy with concomitant temozolomide, 16% had short course radiotherapy, and 5% did not receive radiotherapy. 84% of patients received adjuvant temozolomide, and 89% received concurrent valganciclovir. In those with visible disease on pre-treatment MRI, 62% (8/13) had a radiological response. At time of analysis, 63% of patients remained alive, and 58% were alive and progression free. Median follow up was 15 months. Median survival in patients who had had debulking surgery was 23 months, and median survival in those who had a biopsy only was 16 months.

CONCLUSION

This combination requires prospective evaluation in clinical trials to formally determine efficacy. Data on this cohort continues to be collected and will be updated.

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CSIG-41. UPREGULATED EXPRESSION OF THE ARYL HYDROCARBON RECEPTOR PATHWAY IN BRAIN METASTASES FROM MALIGNANT MELANOMA

Abstract

OBJECTIVE

The Aryl-hydrocarbon-receptor (AHR) is a ligand activated transcription factor linked to exogenic carcinogenic agents such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In 2011, the tryptophan (TRP) catabolite kynurenine (KYN) was identified as an endogenous ligand for AHR. The AHR is involved in several crucial processes such as cell migration, tumorigenesis, and immune function. Dysregulation of AHR, its nuclear translocator (ARNT), its repressor AHRR and the KYN building Enzyme TRP-2,3-dioxygenase 2 (TDO) has been linked to poor survival in patients with Glioblastoma. We aimed to evaluate the AHR-pathway in brain metastases.

METHODS

Using qRT-PCR, gene expression was analyzed in 19 brain-metastases of melanoma patients, 10 control tissues from peritumoral brain and 10 glioblastoma (GBM) samples. Differences in the expression of AHR, ARNT, AHRR, TDO as well as the AHR/AHRR ratio between tumor tissue and control were analyzed. Results are depicted in mean values with standard deviation (SD) and in Arbitrary Units (AU). p<.05 was considered significant.

RESULTS

Both, AHR and ARNT were massively overexpressed in metastatic tissues (p<.01) (6- and 4.5-fold) in comparison to control (AHR: 3.64 ± 2.32 vs. .58 ±.50; p<0.01 and ARNT: 3.81 ± 2.25 vs. .83 ±.48, p<.01). AHRR and TDO where not significantly upregulated (.73 ±.88 vs. .41 ±.35; p=.31 and .37 ±.61 vs. .14 ±.09; p=.46). The ratio of AHR and its repressor AHRR (AHRR/AHR) was significantly different between metastases and control, hinting at a distinct regulatory imbalance (.55 ± 1.09 vs. .18 ± 1.60 p<.01). The difference of AHR expression in metastases and GBM did not quite reach significance (3.64 ± 2.32 vs. 1.27 ± 1.89; p=.055). ARNT was significantly elevated in metastases compared to GBM (3.81 ± 2.25 vs. 1.7 ±.1.15, p<.01).

CONCLUSION

The AHR pathway is significantly upregulated in melanoma brain metastases and might play a pathophysiological role in growth and progression of brain metastases.

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EXTH-59. THE IDH1 MUTANT INHIBITOR AG-120 SHOWS STRONG INHIBITION OF 2-HG PRODUCTION IN AN ORTHOTOPIC IDH1 MUTANT GLIOMA MODEL IN VIVO

Abstract

Mutations in isocitrate dehydrogenase (IDH) 1 and 2 result in accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which drives multiple oncogenic processes, including increased histone and DNA methylation, leading to a block in cellular differentiation. IDH1/2 mutations occur in >70% of diffuse low-grade gliomas (LGG). Standard of care treatment for patients with diffuse LGG involves combined modality approaches including surgery, radiation, and chemotherapy. Here we present preclinical data from studies using AG-120, a potent, orally available inhibitor of the mIDH1 protein currently in clinical trials. In an orthotopic mouse xenograft model of a human mIDH1-R132H glioma, strong inhibition of 2-HG production in brain tumor samples (>77% inhibition) was observed when AG-120 was dosed orally at 150 mg/kg twice daily. Pharmacokinetic analysis revealed that AG-120 was detectable in the brain and brain-tumor tissues of the mice, although at much lower exposures than in the plasma, indicating that AG-120 is highly potent against the mIDH1-R132H protein in vivo. Results from ongoing preclinical studies testing the potential activity of AG-120 combined with radiation therapy in an orthotopic human mIDH1-R132H glioma model will also be shared.

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STEM-21. CONTEXT-SPECIFIC TUMOR SUPPRESSIVE FUNCTION OF THE CANONICAL Wnt PATHWAY IN PEDIATRIC MEDULLOBLASTOMA HIGHLIGHTS A THERAPEUTIC STRATEGY FOR TREATMENT-REFRACTORY SUBGROUPS

Abstract

Current molecular subgroups of childhood medulloblastoma (MB) recognize distinct disease entities of which activated Wnt signaling is associated with a distinct subgroup and the best overall outcome. In contrast, non-Wnt MBs are characterized by metastatic disease, increased rate of recurrence, and poor overall survivorship. Given the excellent clinical outcome in Wnt-driven MB, we aimed to convert treatment-resistant MB subgroups 3 and 4 into an ostensibly benign tumor. Activated Wnt signaling by way of Wnt agonists decreased in vitro self-renewal of primary MB cells. Comparative RNA-sequencing of control and transgenic lines containing a stabilized beta-catenin mutant demonstrated a reduction in self-renewal genes following beta-catenin overexpression, including Sox2 and Bmi1. In order to validate the therapy-sensitive nature of Wnt-activated cells, we developed stable human Group 3 and 4 patient-derived lines containing a 7XTOPFlash reporter to determine the presence of endogenous Wnt signaling. Rare subclonal Wnt-active cells demonstrated a reduced self-renewal and tumor-initiating capacity through in vivo limiting dilution assays when compared to bulk Wnt-inactive cells from Group 3 and 4 MBs. The therapeutic relevance of these findings were demonstrated with an in vivo survival advantage in mice with orthotopic injections of cells containing stabilized beta-catenin overexpression or endogenous Wnt-active cells. Resulting xenograft tumors were smaller in size, maintained a lower rate of proliferation, and reduction in MB self-renewal genes. To develop a rationale clinical therapeutic, we used a novel substrate-competitive peptide inhibitor for GSK. Treatment with our peptide inhibitor showed a significant reduction in tumor burden and metastatic disease with a corresponding increase in survival of patient-derived Group 3 and 4 tumors that were otherwise treatment-resistant. Our work establishes activated Wnt signaling as a novel treatment paradigm in childhood MB, identifies a rationale therapeutic approach for recurrent MB, and provides evidence for the context-specific tumor suppressive function of the canonical Wnt pathway.

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TMIC-06. IMMUNE MICROENVIRONMENT IN CYSTIC GBM

Abstract

The study objective was to characterize the immune microenvironment in cystic glioblastoma (GBM). We retrospectively reviewed the records of 298 consecutive newly diagnosed and recurrent adult GBM patients treated at our hospital from Jan 2011 to Jun 2017. 23 (7.7%) had cystic tumors and 17 had cystic tumor components. We were able to analyze 23 of these cystic GBM (cGBM) cases. We observed that overall survival in cGBM group is longer than in noncystic counterparts. In 17 samples, 16 were PTEN+, and all of these had TILS CD3, CD4, CD8 within the tumor and in surrounding vessels, 7/17 cGBM were PDL-1+ (>1%). T cells (CD8+, CD4+, and CD8+CD4+), B cells and NK cells were detected in the cystic fluid of cGBM cases. T memory cells (CD4+CD25-CD127+) but not Treg cells were also detected in the cystic fluid. The proportion of active T cells (CD69+) in the cystic fluid was higher than in control PBMC. Immunosuppressive cells Treg and MDSC populations were lower in the cystic fluid than in PBMC. The ProcartaPlex Human Cytokine Panel (34 plex) and IPA data analysis a variety of chemokines were detected in the GBM cyst fluid. IL-6, GRO-alpha, IL-8, IP-10, MCP-1, TNF-a, IL-4, IL-27 were higher in the peripheral blood serum cGBM patients versus non-cystic GBM patients; however, the inhibitory cytokine IL-10 is lower in cyst fluid or PB serum. These results suggest that the mechanism of cystic formation in cGBM could be due to activation of the host immune system. Higher levels of chemokines in the cystic fluid of cGBM patients could enhance recruitment of lymphocytes into the tumor. Intact PTEN status as observed in 16/17 cGBM patients in our study, is critical for anti-glioma immune function and may have played a role in improved survival in our study.

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TMOD-19. SOMATIC GENOME EDITING WITH THE RCAS-CRISPR/Cas9 SYSTEM FOR PRECISION GLIOMA MODELING

Abstract

It has been gradually established that the vast majority of human tumors are extraordinarily heterogeneous at a genetic level. To accurately recapitulate this complexity, it is now evident that in vivo animal models of cancers will require to recreate not just a handful of simple genetic alterations, but possibly dozens and increasingly intricate. Here we have combined the RCAS/tv-a system with the CIRSPR/Cas9 genome editing tools to somatically target neural stem cells (NSCs) for precise modeling of human glioma. We show that deletion, both in pups and adult mice, of a variety of known tumor suppressor genes (Trp53, Cdkn2a and Pten), in combination with the expression of an oncogene driver, leads to high-grade glioma formation. Moreover, by simultaneously delivery into NSCs of pairs of gRNAs we show for the first time that the Bcan-Ntrk1 gene fusions, is able to induce high-grade gliomas. We further established that cells derived from Bcan-Ntrk1 tumors are remarkably sensitive to a Pan-Ntrk inhibitor. Lastly, using homology directed repair (HDR), we generated the Braf V600E mutation into NSCs and we demonstrated that it's sufficient to induce glioma tumor formation. In summary, we have developed an extremely powerful and versatile mouse model for in vivo somatic genome editing. Our system will elicit the generation of more accurate glioma models, particularly suitable for preclinical testing.

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SCDT-30. SURGICAL IMPLANTATION OF AN OSMOTIC PUMP FOR CONVECTION ENHANCED DELIVERY INTO DIPG XENOGRAFT MURINE MODELS

Abstract

INTRODUCTION

Diffuse intrinsic pontine gliomas (DIPG) are fatal, high-grade tumors arising in the pons of children. Convection-enhanced delivery (CED) is a method for directly delivering agents into the tumor, bypassing the blood brain barrier. CED can achieve effective long-term continuous administration when connected to an osmotic pump filled with chemotherapeutic agents. Our objective is to optimize the technique for placement of the CED cannula carrying an osmotic pump into the tumor of preclinical DIPG mouse models.

METHODS

Using agarose gel, Evans blue dye (EBD) was injected at various rates to determine area of distribution. Then, an osmotic pump with a capacity to infuse 100ml over 28 days was used in two cohorts of mice. A cannula was stereotactically implanted into the pons in both cohorts and connected to a subcutaneously placed osmotic pump loaded with EBD or DII. The first cohort assessed the feasibility of implantation into the pons. The second cohort was transplanted with murine DIPG cells and allowed to develop pontine tumors before cannula implantation. The EBD/DII signal was evaluated and compared to tumor cell location to assess delivery to targeted site and distribution.

RESULTS

We have established a methodology for surgical implantation of a cannula attached to an osmotic pump into mouse pons, and assessed the distribution of EBD/DII in healthy as well as tumor bearing murine models of DIPG. We also show that CED cannula installation does not affect the overall survival of the mouse.

CONCLUSION

We show that precise pontine delivery of cargo (dye) has optimal distribution within the pons, tissue integrity is not compromised, and more importantly, does not alter overall survival. This technique will serve as a platform for rapid assessment of tumor response to therapeutic agents. An effective agent can then be translated in clinical setting through upcoming clinical trials.

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CBIO-29. ACOT7 REGULATES COLONIZATION OF BREAST CANCER CELLS IN THE BRAIN BY REGULATING ENDOPLASMIC RETICULUM STRESS RESPONSE

Abstract

Colonization of cancer cells in a foreign organ is the key for establishment of metastases. To identify the genes that are responsible for colonization of breast cancer cells in the brain, we conducted an in silico analysis using a NKI dataset and identified ACOT-7 to be negatively correlated with patient survival. ACOT-7 is normally expressed in the brain and is responsible for maintaining the cellular pool of coenzyme-A by catalyzing the conversion of acyl-CoA to free fatty acid and CoA. The resulting CoA can be used for anabolic reactions. ACOT-7 was found to be overexpressed in microdissected brain metastases as compared to primary breast cancer tissues, and it was also upregulated in brain metastasis models CN34/CN34BrM2 and BT-474/BT-474BrM3. To understand the role of brain specific protein ACOT-7 in brain metastasis, ACOT-7 knockdown studies were conducted. ACOT7 knockdown in CN34Br cells reduced their ability to grow in the brain, which subsequently resulted in increased median survival by 60% in a preclinical mouse model. To understand the role of ACOT-7, we conducted a whole proteome analysis and found reduced expression of genes responsible for unfolded protein response (UPR)/Endoplasmic reticulum (ER)-stress. The results were confirmed using quantitative RT-PCR and western blotting. ACOT-7 knockdown cells also exhibited increased sensitivity to thapsigargin (an ER stress inducer). In conclusion, ACOT-7 is aberrantly expressed in brain metastases arising from breast cancer, and it regulates the ability of cells to counter ER stress. Hence unfolded protein response/ER stress proteins will be a novel therapeutic target for the treatment of breast cancer brain metastases.

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CSIG-08. MUTANT IDH1 CO-OPERATES WITH ATRX LOSS TO DRIVE THE ALTERNATIVE LENGTHENING OF TELOMERE (ALT) PHENOTYPE IN GLIOMA

Abstract

A subset of human tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT activation. In these tumors, which include lower-grade astrocytomas (LGA) and secondary glioblastoma (sGBM), the ALT phenotype is associated with loss-of-function mutations in p53 and ATRX, although these mutations alone are insufficient to drive the process. Because LGA and sGBM also exhibit R132H IDH1 mutations, we examined the possible role of mutant IDH1 in driving ALT-based gliomagenesis. In p53/pRb-deficient human astrocytes, we found that neither expression of mutant IDH1 nor genetic deletion of ATRX was sufficient to drive the ALT phenotype. Combined expression of mutant IDH1 and loss of ATRX, however, resulted in the creation of tumorigenic cells with the ALT phenotype. The tumorigenic IDH1-mutant, ATRX-deficient ALT cells, as well as human IDH1-mutant LGA xenograft cells, consistently downregulated both RAP1 and XRCC1. Furthermore, exogenous re-expression of XRCC1 and/or RAP1 suppressed the ALT phenotype and tumor cell viability. Mechanistically, suppression of RAP1, a component of the telomere-capping shelterin complex, caused telomere dysfunction. Downregulation of XRCC1, a key component of the alternative non-homologous end joining (aNHEJ) pathway, suppressed aNHEJ-mediated lethal fusion of dysfunctional telomeres, and instead allowed IDH1-mutant, ATRX-deficient cells to use homologous recombination and ALT to resolve telomeric dysfunction and escape cell death. These studies show that mutant IDH1 expression initiates telomeric dysfunction and alters DNA repair pathway preference at telomeres, and in doing so co-operates with p53 and ATRX loss to allow cells to overcome a critical bottleneck in gliomagenesis. Agents that alter the linkage between mutant IDH1 and DNA repair pathway preference may therefore be of particular interest in mutant IDH1 driven glioma.

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DRES-05. IDENTIFYING DRIVERS OF CHEMORESISTANCE IN GROUP 3 MEDULLOBLASTOMA THROUGH A GENOME-WIDE CRISPR/Cas9 ACTIVATION SCREEN

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for nearly 20% of all pediatric brain cancers. Based on transcriptional profiling studies, MB has been characterized into four molecular subgroups--WNT, SHH, Group 3, and Group 4--that have distinct genetics, patient demographics, histology, and clinical outcomes. Group 3 MB carries the worst prognosis, with 5-year survival rates of 50%. Current therapy for MB consists of maximal safe surgical resection, radiation, and chemotherapy, with cisplatin and cyclophosphamide as mainstays in many chemotherapy regimens. However, Group 3 MB commonly develops resistance and becomes refractory to standard therapy. As these mechanisms of resistance remain poorly understood, I used the CRISPR/Cas9-based synergistic activation mediator (SAM) system to conduct a genome-wide, gain-of-function, positive selection screen to identify the specific drivers of chemoresistance in Group 3 MB. I cloned and sequenced a library consisting of 70,290 single-guide RNAs (sgRNAs) targeting each of the 23,430 coding isoforms from the human RefSeq database. I transduced this library into a Group 3 MB patient-derived model stably expressing the other SAM components (dCas9, VP64, MS2, p65, and HSF1) and then selected with cisplatin and 4-hydroperoxycyclophosphamide. Modulators of chemotherapy sensitivity will be prioritized by sgRNAs that have activated genes conferring chemoresistance, and I have performed next-generation sequencing to identify these sgRNAs. I will validate the top hits from our screen and also cross-reference them with recently published whole-genome sequencing data on six pairs of human diagnostic and post-therapy Group 3 MBs. These findings will provide insights into the mechanisms of resistance in Group 3 MB and inform novel therapeutic targets that may sensitize the tumor to chemotherapy and improve future treatment response.

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EXTH-31. RNA NANOPARTICLE-BASED TARGETED GENE THERAPY FOR GLIOBLASTOMA

Abstract

Systemic administration of therapeutic siRNA/microRNA for targeted treatment of glioblastoma, one of the most deadly cancers, requires robust and efficient delivery platform without immunogenicity. Here we report newly emerged multivalent naked RNA nanoparticle (RNP), named FA-pRNA-3WJ, based on pRNA 3-way-junction (3WJ) from bacteriophage phi29 to target glioblastoma cells with folate (FA) ligand and deliver siRNA/microRNA for tumor cell killing. Systemically injected FA-pRNA-3WJ RNPs successfully targeted and delivered siRNA into brain tumor cells in mice, and efficiently reduced luciferase reporter gene expression (4-fold lower than control). The FA-pRNA-3WJ RNP also can target human patient-derived glioblastoma stem cells, thought to be responsible for tumor initiation and deadly recurrence, without accumulation in adjacent normal brain cells, nor other major internal organs. FA-3WJ-LNA-miR21 specifically targeted and delivered anti-miR-21 LNA and knocked down miR-21 expression in glioblastoma cells in vitro and in vivo with favorable biodistribution. Systemically injected FA-3WJ-LNA-miR21 RNP efficiently rescued PTEN and PDCD4, resulting in glioblastoma cell apoptosis and tumor growth regression. This RNA nanotechnology was employed even to regulate the anchoring of nanoparticles on the surface of extracellular vesicles (EVs) for specific cancer targeting and intracellular trafficking. Taking advantage of the RNA aptamer ligand for specific targeting and EVs for efficient membrane fusion, EGFRapt-pRNA-3WJ RNP was constructed and anchored onto EVs loaded with survivin siRNA. In the preliminary animal tests, systemic administration of the EV-siSurvivin coated with EGFRapt-pRNA-3WJ RNP inhibited tumor growth in orthotopic breast cancer xenograft mouse model by successfully downregulating the Survivin expression. The studies are indicative of the clinical benefit of FA-3WJ RNP based tumor targeting and gene therapy for the successful targeted therapy of primary and recurrent glioblastoma.

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GENE-04. COMPREHENSIVE GENOMIC CHARACTERIZATION OF AGGRESSIVE MENINGIOMAS IDENTIFIES MOLECULAR SIGNATURES THAT PREDICT CLINICAL OUTCOMES

Abstract

BACKGROUND

Current pathological grading schemes do not fully predict meningioma behavior, and the molecular basis for meningioma is incompletely understood. Here, we perform whole exome sequencing (WES), DNA methylation arrays, RNA-seq, NanoString (NS), and immunohistochemistry using tissue microarrays (TMAs) on meningiomas to elucidate molecular drivers of aggressive behavior and identify clinically relevant biomarkers.

METHODS

We constructed a database containing clinical data and tissue from 283 patients who underwent resection of meningioma between 1990 and 2015. Histology was re-evaluated using current grading criteria. We conducted WES (n=24), methylation arrays (n=26), and RNA-seq (n=42) in a discovery cohort composed of 14 grade I, 23 grade II and 5 grade III meningiomas. We further carried out NS profiling of 282 cancer-associated transcripts (n=96), and TMAs (n=241) in an independent validation cohort composed of 132 grade I, 87 grade II and 22 grade III meningiomas. WES data was analyzed via the bcbio pipeline with the ensemble method and CNVkit, methylation data was processed in the minfi Bioconductor package, and RNA-seq data was analyzed with the DESeq2 Bioconductor package. Hierarchical clustering and statistics were performed in R. 

RESULTS

WES demonstrated increased somatic mutation burden was associated with decreased overall survival (OS) (p=0.005). Unsupervised hierarchical clustering of methylation arrays segregated meningioma samples into three groups with significant differences in OS (p=0.0465) and age (p=0.0123). RNA-seq showed enrichment of a FOXM1 mediated transcriptional network with an overrepresentation of cell division genes. High FOXM1 mRNA expression was associated with decreased local recurrence free survival (LRFS) (p=0.004). Consistently, high FOXM1 mRNA expression in NS samples was associated with decreased LRFS (p=0.001) and OS (p=0.006), and high FOXM1 protein expression was associated with decreased LRFS in TMA samples (p=0.049).

CONCLUSION

Comprehensive genomic characterization of aggressive meningiomas identifies molecular signatures associated with poor outcomes, suggesting novel prognostic markers and therapeutic targets.

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