Targeted next-generation sequencing of adult gliomas for retrospective prognostic evaluation and up-front diagnostics.

AIMS: We aimed to reclassify a population-based cohort of 529 adult glioma patients to evaluate the prognostic impact of the 2016 World Health Organization (WHO) central nervous system tumour classification. Moreover, we evaluated the feasibility of gene panel next-generation sequencing (NGS) in daily diagnostics of 225 prospective glioma patients. METHODS: The retrospective cohort was reclassified according to WHO 2016 criteria by immunohistochemistry for IDH-R132H, fluorescence in situ hybridization for 1p/19q-codeletion and gene panel NGS. All tumours of the prospective cohort were subjected to NGS analysis up-front. RESULTS: The entire population-based cohort was successfully reclassified according to WHO 2016 criteria. NGS results were obtained for 98% of the prospective patients. Survival analyses in the population-based cohort confirmed three major prognostic subgroups, that is, isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas, IDH-mutant astrocytomas and IDH-wildtype glioblastomas. The distinction between WHO grade II and III was prognostic in patients with IDH-mutant astrocytoma. The survival of patients with IDH-wildtype diffuse astrocytomas carrying TERT promoter mutation and/or EGFR amplification overlapped with the poor survival of IDH-wildtype glioblastoma patients. CONCLUSIONS: Gene panel NGS proved feasible in daily diagnostics. In addition, our study confirms the prognostic role of glioma classification according to WHO 2016 in a large population-based cohort. Molecular features of glioblastoma in IDH-wildtype diffuse glioma were linked to poor survival corresponding to IDH-wildtype glioblastoma patients. The distinction between WHO grade II and III retained prognostic significance in patients with IDH-mutant diffuse astrocytic gliomas.

Brain tumour diagnostics using a DNA methylation-based classifier as a diagnostic support tool.

AIMS: Methylation profiling (MP) is increasingly incorporated in the diagnostic process of central nervous system (CNS) tumours at our centres in The Netherlands and Scandinavia. We aimed to identify the benefits and challenges of MP as a support tool for CNS tumour diagnostics. METHODS: About 502 CNS tumour samples were analysed using (850 k) MP. Profiles were matched with the DKFZ/Heidelberg CNS Tumour Classifier. For each case, the final pathological diagnosis was compared to the diagnosis before MP. RESULTS: In 54.4% (273/502) of all analysed cases, the suggested methylation class (calibrated score ≥0.9) corresponded with the initial pathological diagnosis. The diagnosis of 24.5% of these cases (67/273) was more refined after incorporation of the MP result. In 9.8% of cases (49/502), the MP result led to a new diagnosis, resulting in an altered WHO grade in 71.4% of these cases (35/49). In 1% of cases (5/502), the suggested class based on MP was initially disregarded/interpreted as misleading, but in retrospect, the MP result predicted the right diagnosis for three of these cases. In six cases, the suggested class was interpreted as 'discrepant but noncontributory'. The remaining 33.7% of cases (169/502) had a calibrated score <0.9, including 7.8% (39/502) for which no class indication was given at all (calibrated score <0.3). CONCLUSIONS: MP is a powerful tool to confirm and fine-tune the pathological diagnosis of CNS tumours, and to avoid misdiagnoses. However, it is crucial to interpret the results in the context of clinical, radiological, histopathological and other molecular information.

Molecular pathology of tumors of the central nervous system.

Since the update of the 4th edition of the WHO Classification of Central Nervous System (CNS) Tumors published in 2016, particular molecular characteristics are part of the definition of a subset of these neoplasms. This combined 'histo-molecular' approach allows for a much more precise diagnosis of especially diffuse gliomas and embryonal CNS tumors. This review provides an update of the most important diagnostic and prognostic markers for state-of-the-art diagnosis of primary CNS tumors. Defining molecular markers for diffuse gliomas are IDH1/IDH2 mutations, 1p/19q codeletion and mutations in histone H3 genes. Medulloblastomas, the most frequent embryonal CNS tumors, are divided into four molecularly defined groups according to the WHO 2016 Classification: wingless/integrated (WNT) signaling pathway activated, sonic hedgehog (SHH) signaling pathway activated and tumor protein p53 gene (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH-activated. Molecular characteristics are also important for the diagnosis of several other CNS tumors, such as RELA fusion-positive subtype of ependymoma, atypical teratoid rhabdoid tumor (AT/RT), embryonal tumor with multilayered rosettes, and solitary fibrous tumor/hemangiopericytoma. Immunohistochemistry is a helpful alternative for further molecular characterization of several of these tumors. Additionally, genome-wide methylation profiling is a very promising new tool in CNS tumor diagnostics. Much progress has thus been made by translating the most relevant molecular knowledge into a more precise clinical diagnosis of CNS tumors. Hopefully, this will enable more specific and more effective therapeutic approaches for the patients suffering from these tumors.

Influence of moderate and severe hypoxia on the diurnal activity pattern of lesser sandeel Ammodytes tobianus.

The influence of prolonged moderate (c. 60% oxygen saturation) and severe hypoxia (c. 35% oxygen saturation) on the diurnal activity pattern of sandeel Ammodytes tobianus was examined. In moderate hypoxia, the emerging and burying rates were significantly higher compared to that in normoxia, whereas fewer fish (c. 10%) were present in the water column. In contrast, severe hypoxia resulted in twice as many or more fish being present in the water column compared to that in normoxia. The increased number of swimming fish was not just a relative change due to an effect from hypoxia treatment, but the behaviour of the fish was also changed. The summed activity (emerging plus burying events) was lower in severe hypoxia compared to normoxia except during hours of dim light. All fish were buried during night-time, regardless of treatment, with the exception of some in severe hypoxia during the first couple of hours of darkness.

Image quality of two solid-state and three photostimulable phosphor plate digital panoramic systems, and treatment planning of mandibular third molar removal.

OBJECTIVES: The purpose was to evaluate image quality of two solid-state (charge-coupled device (CCD)) and three photostimulable phosphor (PSP) plate digital panoramic systems, and to assess their utility for treatment planning before mandibular third molar removal. METHODS: 433 patients were randomly allocated to five digital systems: Dimax2 and Orthophos Plus (both CCD systems) and DenOptix, DigiDent and Digora (all PSP systems). Image quality was evaluated in six regions on a 4-point scale by three independent observers. In addition, an oral surgeon evaluated image quality in the mandibular third molar region only as well as the utility of the image for treatment planning before removal of that molar. RESULTS: Images from the DenOptix and DigiDent systems had a significantly lower overall quality than images from the Digora, Dimax2 and Orthophos Plus systems (P < 0.005). The oral surgeon's assessment of image utility resulted in rejection rates of 0% for Orthophos Plus, 2% for Digora, 8% for Dimax2, 12% for DigiDent and 14% for DenOptix images. The rates for the DigiDent and DenOptix images were significantly higher than those for the other systems (P < 0.001), and the rate for Dimax2 was significantly higher than that for Orthophos Plus (P = 0.002). CONCLUSIONS: The quality of DenOptix and DigiDent digital panoramic images was found to be inferior to the quality found in images obtained with the Digora, Dimax2 and Orthophos Plus systems. Images from the Digora and Orthophos Plus systems were regarded to be the most useful for treatment planning before mandibular third molar removal.

Accuracy of digital and film panoramic radiographs for assessment of position and morphology of mandibular third molars and prevalence of dental anomalies and pathologies.

OBJECTIVES: To compare the accuracy of digital and film panoramic radiographs for determining (1) the position and morphology of mandibular third molars before surgical removal and (2) the prevalence of dental anomalies and pathologies. METHODS: Three hundred and eighty-eight third mandibular molars were available for examination. Position and morphology of third molars observed on film radiographs and on digital panoramic images from five systems (DenOptix, DigiDent, Digora, Dimax2 and Orthophos Plus) were recorded by two observers and were compared with surgeons' findings at the time of the operation (gold standard). One observer further recorded the prevalence of dental anomalies and pathologies on both imaging modalities. RESULTS: Few differences were found between the digital and film-based panoramic systems in the assessment of accuracy of position and morphology of mandibular third molars. The prevalence of dental anomalies and pathologies determined with the two modalities was roughly similar. CONCLUSION: The five digital panoramic systems evaluated in this study were equally as useful for third molar treatment planning and diagnosis of dental anomalies and pathologies as conventional film-based panoramic radiographs.

Management of acute dento-alveolar trauma--from the viewpoint of an oral surgeon.

Oral and maxillofacial surgeons often deal with acute dento-alveolar trauma in hospital or practice surroundings. They are often called upon by dental colleagues to give their advice or help in a given situation of the acute trauma patient with dental or oral injuries. In this article, the practical viewpoints and clinical experiences of an oral surgeon are offered based upon many years of work in hospital emergency rooms around the world.

[Colonic ileus caused by a giant gallstone]. / Galdestensbetinget colonileus forårsaget af en monstrøs galdesten.

Gallstone induced colonic ileus is a rare disease. An enormous gallstone was found as the cause of ileus in a previously healthy ninety year-old man. A laparotomy was carried out, and a gallstone measuring 6 x 8 cm was removed from the sigmoideum in a normal looking colon. The stone had been wedged at the ligament of Told after having formed a fistula from the gallbladder to the colon. The fistula was left untouched and the patient was discharged after making a full recovery. A year later the patient developed icterus. Ultrasound examination revealed choledocus stones, which were removed by ERCP papillotomy.

Efficacy of a topical anesthetic on pain and unpleasantness during scaling of gingival pockets.

The efficacy of a topical anesthetic on pain and unpleasantness provoked by scaling of gingival pockets was investigated in 20 patients with mild chronic periodontitis. A eutectic mixture of local anesthetics (EMLA) and a placebo cream, both occluded by Orahesive Oral Bandages, were applied in a balanced, randomized, double-blind, split-mouth design, which enabled within-subject comparison of the anesthetic and the placebo in the upper and the lower jaw. Pretreatment interviews showed that approximately two-thirds of the patients considered gingival scaling to be associated with some degree of pain and unpleasantness. Pain intensity and unpleasantness were evaluated on 100-mm visual analog scales (VAS). Application of EMLA reduced both pain intensity and unpleasantness significantly compared to placebo cream. Median reductions in VAS pain intensity in the upper and lower jaw were 58.9% and 61.9%, and corresponding reductions in VAS unpleasantness were 31.9% and 25.6%, respectively. Generally, the patients accepted the anesthetic procedure well. The residual perception of pain and unpleasantness following topical anesthesia may be dependent on activation of nonanesthetized nociceptive fibers in the tooth pulp. However, the present study clearly demonstrates the efficacy of a topical anesthetic in a clinical situation, which may be recommended as a simple pharmacologic strategy to reduce pain and unpleasantness during scaling procedures.

The effect of an ibuprofen-codeine combination for the treatment of patients with pain after removal of lower third molars.

A double-blind randomized crossover analgesic trial was carried out on 70 patients undergoing surgical removal of one lower third molar at each visit. The analgesic efficacy of a two-dose regimen of the combination ibuprofen-codeine, 400 to 60 mg, was compared with ibuprofen, 400 mg. Each of the two doses was taken when the patient needed pain relief and the pain intensity was measured on a visual analog scale during the 10-hour period after the first medication. Because of carryover effects between periods 1 and 2, the analysis was carried out only for period 1 according to a parallel group design. Of the 60 patients who were evaluated for analgesic effect, the mean pain reduction of dose 1 was 63% for the 29 patients given ibuprofen-codeine and 50% for the 31 patients given ibuprofen; the mean duration of effect was 7.5 and 6.3 hours, respectively. The difference in pain reduction index (pain reduction X duration of effect) between the two treatments was significant in favor of the combination, whereas the separate variables of pain reduction and duration of effect were not significantly different. The mean pain reduction was 67% after doses 1 and 2 for patients on ibuprofen-codeine and 52% for those on ibuprofen; the mean duration of effect was 9.4 and 9.2 hours, respectively. For doses 1 and 2, the difference in pain reduction index per dose between the two treatments was significant but not the difference for the separate variables, pain reduction, and duration of effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetic effect of EMLA occluded with Orahesive oral bandages on oral mucosa. A placebo-controlled study.

The efficiency of a topical anesthetic occluded with Orahesive Oral Bandage was investigated. Experimental pain was provoked by needle insertions into two palatal test areas in 20 healthy subjects. Pain, estimated on a 100-mm visual analogue scale (VAS), decreased significantly from 23.5 mm to 10.5 mm at the greater palatine foramen and from 51.5 mm to 35.0 mm at the incisive foramen after application of a eutectic mixture of local anesthetics (EMLA). No significant change in pain perception was obtained after placebo application. The EMLA cream and the Orahesive Oral Bandages were well accepted by the subjects, as only two out of 20 subjects experienced slight gagging reflexes and only three considered the taste unpleasant. No other adverse reactions were observed. Occlusion of topical anesthetics seems to be a useful technique for achieving superficial mucosal anesthesia.