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.

The analgesic and anti-inflammatory efficacy of diflunisal and codeine after removal of impacted third molars.

A double-blind, randomized trial was carried out in 90 patients to compare the analgesic and anti-inflammatory efficacy of 500 mg diflunisal twice daily with that of 25 mg codeine phosphate 4-times daily and placebo in relieving pain and swelling after surgical removal of impacted third molars. Diflunisal was found to be superior to codeine and placebo on the first post-operative day, but the difference in efficacy of the drugs had diminished by the third post-operative day. In the diflunisal group of 30 patients, 10 (33%) developed 'dry socket' or alveolitis sicca dolorosa. Only 2 patients in the codeine group and 1 patient in the placebo group developed this very painful condition. The possible explanation of 'dry socket' is discussed.

Incidence of pain conditions in dental practice in a Danish county.

From September 1981 to February 1982, an epidemiologic study was carried out on the incidence of pain conditions among patients between 18 and 70 yr of age in 30 dental practices in Ribe County, Denmark. A total of 35 464 patients consulted the 50 participating dentists during the study period. 823 patients consulted the dentist due to pain. The most frequent cause of pain was caries sequelae (pulpitis (35%) and acute apical periodontitis (31%)). There was a significant difference in the distribution of the diagnoses between patients with regular and non-regular dental care. Although the data in the present study may not be representative for the entire Danish population, it seems reasonable to assume that in Denmark there are at least 70 000 annual consultations to a dentist due to pain. Furthermore, a minimum of 4000 patients can be expected to be absent from work annually, due to illness caused by dental pain.

Efficacy of a self-aspirating syringe.

Several self-aspirating syringes have been introduced into dentistry during the last decade. The efficacy of such a self-aspirating system, the EVERS-syringe, has been tested in relation to varying liquid pressure and diameter of the needle. It was found that the EVERS system was able to secure aspiration, irrespective of pressure and needle diameter. The passive back-flow of liquid through the needle, however, did depend on pressure and needle diameter. 3 different brands of local analgetics were evaluated, and it was found that the degree of self-aspiration was identical, regardless of brand and thereby cartridge type.

Efficacy of a fibrin sealant on healing of extraction wounds.

In 61 patients, bilateral lower impacted third molars were removed. In 30 patients, a fibrin sealant was placed in the alveolus on one side immediately following the operation, while the other side functioned as control. In 31 patients, penicillin was added to the fibrin sealant, and the combination was placed in the alveolus on one side, the other side being the control. No difference with regard to bleeding, pain and swelling during the first postoperative week could be found. There was no difference between the sides regarding the incidence of postoperative infection and the healing of the alveoli after a 1-month control period.

A double-blind, randomized study of naproxen and acetylsalicylic acid after surgical removal of impacted lower third molars.

100 patients had an impacted lower 3rd molar surgically removed in a double-blind study. Naproxen (500 mg b.i.d.) or acetylsalicylic acid (ASA) (1 g t.i.d.) were administered to the patients. Paracetamol was allowed as escape medication. 49 patients received naproxen and 51 ASA. 4 patients from each group were excluded because they took other analgesics, took too few tablets, were lost to follow-up or had misunderstood the instructions. There was a significantly better over all analgesic effect of naproxen than ASA (p = 0.004). More patients in the naproxen group than in the ASA group (p less than 0.01) would accept treatment with the same drug again. 4 patients, all from the ASA group, complained spontaneously about side effects.

Complications in patients on therapeutic drugs.

Increasing numbers of patients take more drugs of ever-increasing potency. Dentists today see many of these patients. They should therefore be aware of the connection between drug administration and emergency situations. In certain instances drug-related complications, side-effects and emergencies of both a local and a general nature can arise. Some local complications are destruction of teeth due to the intake of medicines with high sugar content; erosive lesions of the oral mucosa; paraformaldehyde necrosis; and those arising from the use of chlorhexidine. Systemic complications are anaemia due to aspirin misuse; oral ulceration due to antirheumatic drugs; adrenal insufficiency after glucocorticosteroid medication; catecholamine reactions; anticoagulation therapy and bleeding problems; epilepsy; asthma; aplastic anaemia; opportunistic infections; and allergic reactions. The dentists should be prepared to diagnose and manage these complications whether they arise during dental treatment or following it.

Clinical experience in oral surgery with human fibrin sealant.

Fibrin sealant is a two-component product consisting in principle of fibrinogen and thrombin. When it is activated, fibrin (the clot) is formed. Being a natural product, the versatility of its use in the human body is great. No side-effects or complications have been described. It has been tested clinically in oral surgery and found to be very effective in the fixation of mucosal and skin grafts in the oral cavity; as a surgical dressing for the palate or on the lips; in osseous reconstruction after mixture with bone-chips; and finally in the treatment of chronic sclerotizing osteomyelitis of the mandible after the addition of metronidazole. It also has uses in many other fields of surgery.

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.

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.

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.

[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.