Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer.

BACKGROUND: Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/ tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/ tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches. METHODS: FIRE-8 ( NCT05007132 ) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m2 body surface area (BSA), orally twice daily on days 1-5 and 8-12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled. DISCUSSION: To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy. TRIAL REGISTRATION: EU Clinical Trials Register (EudraCT) 2019-004223-20 . Registered October 22, 2019, ClinicalTrials.gov NCT05007132 . Registered on August 12, 2021.

Micromorphological evaluation of posterior composite restorations - a 10-year report.

The summarized scanning electron microscopic-supported micromorphologic data of a 10-year longitudinal clinical study of GIC/Hybrid composite posterior restorations is reported. The aim of this study was to compare the results to USPHS-compatible clinical criteria of the CPM index and to analyse the deterioration pattern and the success rate. Out of a total of 194 Class I and Class II fillings 46 restorations were at baseline, after 1, 3, 5, 7 and 10 years. The restorations were micromorphologically examined using gold-sputtered replicas and coded according to the M-criteria of the CPM index. The features for surface roughness, surface texture, marginal integrity, excess of material, marginal fracture, loss of material, marginal leakage and other filling imperfections were assessed. Eighteen fillings showed perfect margins, rapidly deteriorating after the first year of service. Despite poor micromorphologic marginal conditions all restorations retained optimal functional characteristics. Parallel longitudinal micromorphologic and clinical assessment of posterior GIC/Composite restorations revealed fine structure and deterioration patterns of the tooth-biomaterial interface. The layer-technique using GIC as dentine replacement and resin-based composite as enamel replacement results, according to previous biocompatibility testing, and clinical data, in optimal pulp protection and correct anatomic form over a 10-year period. The myth of the need for perfect marginal integrity requires further discussion.

Clinical evaluation of posterior composite restorations: the 10-year report.

PURPOSE: To summarize all clinically relevant data of a 10-year prospective evaluation of posterior glass-ionomer cement/composite restorations (Ketac Bond/Visio-Molar radiopaque). MATERIAL AND METHODS: For this study 194 hybrid composite fillings (115 Class I, 79 Class II) were applied in 73 adult patients. The exposed dentin was covered with glass-ionomer cement. The clinical evaluation was carried out at baseline, after 6 months and at 1-year intervals up to 10 years. The USPHS-compatible CPM Index was used with the C and P criteria presented here for anatomic form, color match, surface quality, wear, marginal integrity, marginal ledge, marginal discoloration, secondary caries, and clinical acceptability. Thermal and electrical sensitivity testing were recorded annually. RESULTS: At baseline, 194 restorations were rated. The drop-out of patients comprised 108 fillings after 10 years. During this time, 24 restorations could not be followed up because of new carious lesions at different sites and/or prosthodontic treatment (drop-out of teeth). Forty-six composite restorations were longitudinally controlled over 10 years, and 16 more fillings failed before the end of the study (3 filling fractures, 7 partial filling losses, 1 total filling loss, 5 cases of secondary caries). Only Class II composite restorations exhibited secondary caries (4 fillings after 7 years and 1 filling after 9 years). After 10 years, the correct anatomic form was preserved in 44 fillings, but all restorations showed rough surface and wear. The majority of restorations (26 fillings) was free of marginal discoloration, and the color match showed only 3 fillings being too dark. The marginal integrity was optimal at baseline and during the first year. During the second year a continuing degradation started and lasted until the end of the study. Thirteen restorations showed optimal marginal integrity after 10 years. CONCLUSION: The USPHS-compatible CPM Index represents a sensitive rating system for long-term observation of posterior composite restorations. The early risk of failure is attributed to bulk fractures and partial loss of filling material. The longevity over 10 years is a maximum of 74.2%, and the very low secondary caries rate and the high percentage of correct anatomical form confirm the clinical safety of posterior composite restorations.

[When and how well does the family physician recognize generalized anxiety disorders and depressions?]. / Wann und wie gut erkennt der Hausarzt Generalisierte Angststörungen und Depressionen?

BACKGROUND: Recognition rates for generalized anxiety disorder (GAS) and depression in primary care and its predictors are reported. METHODS: Based on the results of GAD-P study screening questionnaires, the investigators evaluated how many patients were correctly classified by primary care physicians a) as cases with mental disorders and b) as specific disorder cases. Socio-demographic and illness history variables of patients as well as features of physicians were analyzed as predictors of recognition by regression analyzes. RESULTS: Physicians recognized a mental disorder in more than two thirds of cases with GAS; rates were even higher in patients with comorbid anxiety and depression (85.4%). Recognition of the specific disorder was conspicuously worse in patients with GAS (34.4%) in comparison with patients with depression (64.3%). Only the variables of patients' demographic status and illness (e.g. higher age or, negatively, incident GAS) predicted recognition of a mental disorder. CONCLUSION: Generalized anxiety is often recognized as a mental disorder but seldom as the specific diagnosis of GAS. This is especially true for patients without a history of mental disorders (incident cases). Suggestions for a better recognition are discussed in the light of specific psychopharmacologic and psychotherapeutic treatment demands. The risks of chronicity of this disorder as well as the ascertained predictors of good recognition are also discussed.

Morphology of dental enamel and dentine-enamel junction in osteogenesis imperfecta.

OBJECTIVES: The aim of this study was to examine the morphology of primary and permanent human enamel, and the dentine-enamel junction, in individuals with osteogenesis imperfecta (OI) type I, III and IV in undecalcified sections using polarized light microscopy, microradiography and scanning electron microscopy (SEM), and to relate the findings to the type of OI. SAMPLE AND METHODS: Extracted or exfoliated teeth from 15 patients representing the OI types I, III and IV (12 primary teeth from seven patients, and 11 permanent teeth from eight patients). Ten primary and nine permanent teeth from normal healthy patients served as controls. The teeth were serially cut longitudinally in a bucco-lingual direction and contact microradiographs were made. The sections were examined in polarized light. Sections of primary and permanent teeth were examined by means of SEM. RESULTS: This study shows that the permanent enamel from patients with OI exhibits few structural changes. No relationships were found between enamel morphology and the types of OI (I, III, IV). Primary enamel appeared to be slightly more irregularly mineralized, especially in cases with the additional diagnosis dentinogenesis imperfecta. The major findings were deviations in association with the dentine-enamel junction, and locally a lower degree of mineralization. CONCLUSIONS: The mesodermal disease OI might also be manifested in ectodermal enamel, probably because of suboptimal mesenchymal-ectodermal interactions during amelogenesis.

Aspects of teeth from archaelogic sites in Sweden and Denmark.

The purpose of this study was to examine ground sections of primary second molars and permanent first molars from the same jaws. Teeth from 11 individuals were collected from archaeologic sites in Sweden and Denmark. Longitudinal buccolingual sections were examined in a polarization light microscope and in a Philips scanning electron microscope (SEM). The seven teeth from Sweden appeared to have been subjected to environmental influences at their burial site, which had affected both the dentin and the enamel. The teeth from the Danish sites had a normal color, and no disintegration of the dentin was seen. The general morphologic appearance was normal in all primary and permanent teeth. The position of the neonatal line indicated a normal full-term gestational age. The observed accentuated incremental lines in both the primary and permanent enamel suggested periods of dietary changes, possibly related to periods of illness. SEM images of the surface area of the Swedish teeth showed an extremely porous enamel surface with severe changes in the prism structure as an effect of acid penetration. The Danish teeth did not show any marked changes in the enamel.

Pulp calcifications in traumatized primary incisors. A morphological and inductive analysis study.

The purpose of this study was to investigate histopathological changes in primary teeth following trauma, and to look for possible correlations between the morphology of pulpal calcification and clinical findings. The material consisted of 123 primary teeth from 98 Danish children aged 9-108 months (mean age 33.5 +/- 19.7 months) at the time of injury. The specimens were analyzed by means of light and scanning and transmission electron microscopy. Data from the clinical investigation and from predetermined ranked parameters from the histological analysis were processed in a computerized inductive analysis program. The results, describing patterns of co-variation, are presented as a decision tree. The most common diagnosis was intrusion luxation (54%). In 41% of all teeth, the degree of obliteration was less than 1/4 of the pulpal lumen. In most cases (79%), no denticles were visible. When present, 80% of the denticles had a bone-like appearance. Tissues occluding the pulpal lumen were either dentin-like (49%), bone-like (19%), or fibrotic (9%). It could be concluded that these varying responses could not be correlated with explicit clinical diagnoses. However, in certain combinations, histological parameters could be correlated to clinical findings.

Reactivity of young and old human enamel to demineralization.

The aim of this study was to determine the susceptibility of newly erupted and old permanent teeth to artificial, caries-like attacks. Two groups of caries-free teeth were used. Group 1 consisted of 38 teeth extracted for orthodontic reasons (9-12-yr-old children); group 2, of 40 teeth extracted for periodontal reasons (45-65-yr-old patients). After thorough cleaning, a test window was isolated on the incisal two-thirds of the buccal surface. After demineralization with 6% HEC gel at pH 4.9 for 8 days, longitudinal ground sections were prepared for imbibition studies in polarized light and for secondary ion mass spectrometry (SIMS). In the young teeth, the lesions appeared to be uniform in their extension in the enamel, whereas the old teeth showed less marked and thinner surface zones and greater depth of the positively birefringent body of the lesion. Polarized light microscopy and SIMS data support the hypothesis that there are different enamel pathways in the initiation of the natural carious process.

[The micromorphology of the superficial remineralization of the dental enamel]. / Mikromorphologie der superfiziellen Remineralisation des Zahnschmelzes.

The remineralization process in the oral environment is the presumption of enamel structural integrity and function. Strong or frequent acid attacks may be followed by pathological alterations. Remineralization of human enamel after phosphoric acid demineralization was investigated. 4 subjects were selected for in-vivo experiments using specialized oral applicators with 52 etched enamel specimen, incorporated for 10 or 28 days and 59 probes remineralized in a synthetic mineral solution over the same period. Mineral deposition and rehardening took place. After 28 days the reparation of acid defects was incomplete. The in-vitro remineralization is less pronounced and does not reflect the complex remineralization mechanism in vivo.

[Biological testing and clinical assessment of composite restorations]. / Biologische Prüfung und klinische Bewertung von Komposit-Füllungen.

The vital-microscopic acute pulp test in rat incisors did not show any toxic effects of the light-curing composite material Lux-a-fill, independent of the remaining dentin thickness. The clinically controlled 2-year study of restorations of cavity class I, III, IV and V have yielded good results in the front teeth region. In addition to the clinical study a micromorphological follow-up study of the surface morphology was performed in cavity class I, and small restorations have been found clinically acceptable after 2 years. Despite of the good results further medium term studies are needed for extended restorations in posterior teeth. The combination of biological application tests in an adequate animal experiment and highly standardized clinical studies is a important prerequisite for the introduction of new filling materials.

[Exposit in a biological test]. / Exposit im biologischen Test.

The biocompatibility of the composite resin materials Exposit and Evicrol was tested by functional studies of the rat incisor and the biological test of the dental pulp of pigs. Exposit shows mainly reversible reactions of the vascular connective tissue both in the vital-microscopical examination of the immediate reaction and in short-term tests (24 hours, 7 days), where positive adaptation reactions (new vessels and revascularization) are to be observed. Evicrol causes distinct and irreversible damages in the pulp of the rat incisor. The results of the vital-microscopical examination are proven by histological checks of the rat incisor. In the morphological picture Exposit shows in pig teeth mainly slight and partly moderate inflammatory pulpal reactions after a period of 30 and 90 days. For Evicrol, however, severe reactions with a massive accumulation of inflammatory cells is to be observed after a period of 30 days. Despite an acceptable and, compared to Evicrol, a better biocompatibility of Exposit there is a demand for an exact pulp protection.

A new experimental restoration model in man for studying enamel reactions.

A new model of experimental restoration is suggested for testing the marginal imperfections of composite resin, for examining the surface morphology of composite restorations and of sound, etched and remineralized enamel. Enamel-dentine samples with standardized cavities and composite restorations were placed on lower removable partial dentures using the etching technique. After 12 and 28 days the specimens were examined in a scanning electron microscope (SEM), operated at 15 kV. After 12 days the examination of the conventional composite resin by SEM showed extremely rough structures. The use of the enamel etch techniques produces acceptable marginal conditions with tags and some minor gaps. Etching the enamel emphasizes its prismatic structure and reveals the typical pattern of demineralization, involving prism cores and the preferential dissolution of prism peripheries. After 12 days the SEM appearance of uncovered etched enamel suggested that incomplete remineralization had occurred. After 28 days the mineral recoating, which had progressed further, predominantly involved prism-orientated repair. The experimental model described here is more accurate, highly standardizable and easily accessible, compared with conventional clinical and replica techniques.