Evaluating hybrid controls methodology in early-phase oncology trials: A simulation study based on the MORPHEUS-UC trial.

Phase Ib/II oncology trials, despite their small sample sizes, aim to provide information for optimal internal company decision-making concerning novel drug development. Hybrid controls (a combination of the current control arm and controls from one or more sources of historical trial data [HTD]) can be used to increase statistical precision. Here we assess combining two sources of Roche HTD to construct a hybrid control in targeted therapy for decision-making via an extensive simulation study. Our simulations are based on the real data of one of the experimental arms and the control arm of the MORPHEUS-UC Phase Ib/II study and two Roche HTD for atezolizumab monotherapy. We consider potential complications such as model misspecification, unmeasured confounding, different sample sizes of current treatment groups, and heterogeneity among the three trials. We evaluate two frequentist methods (with both Cox and Weibull accelerated failure time [AFT] models) and three different commensurate priors in Bayesian dynamic borrowing (with a Weibull AFT model), and modifications within each of those, when estimating the effect of treatment on survival outcomes and measures of effect such as marginal hazard ratios. We assess the performance of these methods in different settings and the potential of generalizations to supplement decisions in early-phase oncology trials. The results show that the proposed joint frequentist methods and noninformative priors within Bayesian dynamic borrowing with no adjustment on covariates are preferred, especially when treatment effects across the three trials are heterogeneous. For generalization of hybrid control methods in such settings, we recommend more simulation studies.

Immunoadsorption or plasma exchange in steroid-refractory multiple sclerosis and neuromyelitis optica.

BACKGROUND: Plasma exchange (PE) and immunoadsorption (IA) are alternative treatments of steroid-refractory relapses of multiple sclerosis (MS) or neuromyelitis optica (NMO). METHODS: Adverse events and neurological follow-ups in 127 MS- (62 PE, 65 IA) and 13 NMO- (11 PE, 2 IA) patients were retrospectively analyzed. Response was defined by improvements in either expanded disability status scale (EDSS) by at least 1.0 or visual acuity (VA) to 0.5, confirmed after 3 and/or 6 months. RESULTS: Hundred and forty patients were included in safety analysis, 102 patients provided sufficient neurological follow-up-data. There were no significant differences between IA and PE in side effects (3.9% vs 3.6%, P = .96) or response-rate (P = .65). Responders showed significant lower age (P = .02) and earlier apheresis-initiation (P = .01). Subgroup-analysis confirmed significant lower age in patients with relapsing-remitting MS (RRMS) /clinical isolated syndrome (CIS). CONCLUSION: IA and PE seem equally safe and effective in steroid-resistant MS- or NMO-relapses. Early apheresis and low patient age are additional prognostic factors.

Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment. METHODS: We did a randomised, open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada). Eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II-III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0-1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan). We randomly assigned participants (1:1) to receive either trastuzumab emtansine plus pertuzumab or docetaxel, carboplatin, and trastuzumab plus pertuzumab. We did the randomisation via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location. Patients received six cycles (every 3 weeks) of neoadjuvant trastuzumab emtansine plus pertuzumab (trastuzumab emtansine 3·6 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (docetaxel 75 mg/m2; carboplatin area under the concentration-time curve 6 mg/mL × min; trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance doses) plus pertuzumab [same dosing as in the other group]). All treatments were administered intravenously. The primary objective was to compare the number of patients who achieved a pathological complete response (ypT0/is, ypN0), between groups in the intention-to-treat population (two-sided assessment), based on local evaluation of tumour samples taken at breast cancer surgery done between 14 days and 6 weeks after completion of neoadjuvant therapy. Safety was analysed in patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02131064, and follow-up of the adjuvant phase is ongoing. FINDINGS: Between June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44·4%) of 223 patients in the trastuzumab emtansine plus pertuzumab group and 123 (55·7%) of 221 patients in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference -11·3 percentage points, 95% CI -20·5 to -2·0; p=0·016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab, fewer patients receiving trastuzumab emtansine plus pertuzumab had a grade 3-4 adverse event (29 [13%] of 223 vs 141 [64%] of 219) or a serious adverse event (11 [5%] of 223 vs 63 [29%] of 219). The most common grade 3-4 adverse events in the trastuzumab emtansine plus pertuzumab group were decreased platelet count (three [1%] of 223 patients vs 11 [5%] of 219 with docetaxel, carboplatin, and trastuzumab plus pertuzumab), fatigue (three [1%] vs seven [3%]), alanine aminotransferase increase (three [1%] vs four [2%]), and hypokalaemia (three [1%] vs five [2%]). The most common grade 3-4 adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group were neutropenia (55 [25%] of 219 vs one [<1%] of 223 with trastuzumab emtansine plus pertuzumab), diarrhoea (33 [15%] vs 2 [<1%]), and febrile neutropenia (33 [15%] vs 0). No deaths were reported during neoadjuvant treatment. INTERPRETATION: Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab); however, numerically more grade 3-4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted. FUNDING: F Hoffmann-La Roche and Genentech.

Occurrence and severity of enamel decalcification adjacent to bracket bases and sub-bracket lesions during orthodontic treatment with two different lingual appliances.

BACKGROUND: Using lingual enamel surfaces for bracket placement not only has esthetic advantages, but may also be suitable in terms of reducing frequencies of enamel decalcifications. OBJECTIVE: To test the null-hypothesis that there is no significant difference in enamel decalcification or cavitation incidence adjacent to and beneath bracket bases between two lingual multi-bracket (MB) appliances that are different in terms of design, material composition, and manufacturing technology (group A: WIN, DW-LingualSystems; group B: Incognito, 3M-Unitek), taking into account patient- and treatment-related variables on white spot lesion (WSL) formation. METHODS: Standardized, digital, top-view photographs of 630 consecutive subjects (16214 teeth; n Incognito = 237/6076 teeth; n WIN = 393/10138 teeth; mean age: 17.47±7.8; m/f 43.2/56.8%) with completed lingual MB treatment of the upper and lower permanent teeth 1-7 were screened for decalcification or cavitation adjacent to and beneath the bracket bases before and after treatment, scored from 0 to 7. Non-parametric ANOVA was used for main effects 'appliance type', 'gender', 'treatment complexity', 'grouped age' (≤16/>16 years), and 'treatment duration' as covariable, at an α-level of 5%. RESULTS: About 2.57% [5.94%] of all teeth in group A [B] developed decalcifications. Subject-related incidence was 9.59% [16.17%] for upper incisors in group A [B], and 12.98% [25.74%] for all teeth 16-46. There were significant effects by gender, age, and treatment duration. CONCLUSION: The null-hypothesis was rejected: sub-bracket lesions were significantly less frequent in group A, while frequencies of WSL adjacent to brackets were not significantly affected by appliance type. In view of the overall low incidences of lingual post-orthodontic white-spot lesions, the use of lingual appliances is advocated as a valid strategy for a reduction of enamel decalcifications during orthodontic treatment.

Spline-based procedures for dose-finding studies with active control.

In a dose-finding study with an active control, several doses of a new drug are compared with an established drug (the so-called active control). One goal of such studies is to characterize the dose-response relationship and to find the smallest target dose concentration d(*), which leads to the same efficacy as the active control. For this purpose, the intersection point of the mean dose-response function with the expected efficacy of the active control has to be estimated. The focus of this paper is a cubic spline-based method for deriving an estimator of the target dose without assuming a specific dose-response function. Furthermore, the construction of a spline-based bootstrap CI is described. Estimator and CI are compared with other flexible and parametric methods such as linear spline interpolation as well as maximum likelihood regression in simulation studies motivated by a real clinical trial. Also, design considerations for the cubic spline approach with focus on bias minimization are presented. Although the spline-based point estimator can be biased, designs can be chosen to minimize and reasonably limit the maximum absolute bias. Furthermore, the coverage probability of the cubic spline approach is satisfactory, especially for bias minimal designs.

Lingual appliances reduce the incidence of white spot lesions during orthodontic multibracket treatment.

INTRODUCTION: The aim of this study was to assess the incidence of white spot lesions (WSLs) in subjects treated with customized lingual multibracket appliances-separately for maxillary anterior teeth 12 to 22 (according to the Fédération Dentaire Internationale numbering system) as well as for tooth groups 15 to 45, 16 to 46, and 17 to 47-and to determine the impact of patient-related and treatment-related variables on the frequencies of new WSLs. METHODS: Of 214 subjects comprehensively treated between June 1, 2011, and May 31, 2014, in 1 orthodontic center (Bad Essen, Germany) with a completely customized lingual appliance (WIN; DW Lingual Systems, Bad Essen, Germany), 174 (47% boys, 53% girls; mean age, 14.35 ± 1.23 years [minimum, 11.35 years; maximum, 17.91 years]) were recruited with inclusion criteria of completed lingual multibracket treatment of their maxillary and mandibular permanent teeth 17 to 47 (4582 teeth in the study), and age less than 18 years at the initial appointment. WSL assessment was accomplished using standardized digital high-resolution maxillary and mandibular occlusal photographs taken before bracketing and after debonding. Nonparametric analysis of variance was performed, taking into account the subjects' grouped ages (≤16 or >16 years), sexes, and treatment durations. RESULTS: Of the total population of subjects, 41.95% developed at least 1 new WSL when all teeth, 17 to 47, were considered, and this incidence was 27.01% for tooth group 16 to 46, or 10.59% of subjects and 4.74% of the maxillary incisors (12 to 22). Of all teeth under consideration, 3.19% developed a WSL during treatment. The frequencies of decalcification were not significantly increased in preadolescents (≤16 years) compared with adolescents (>16 years). Treatment duration had a significant adverse impact on WSL formation in tooth groups 15 to 45 and 16 to 46, and in complete dental arches (teeth 17 to 47). CONCLUSIONS: Subject-related and tooth-related WSL incidences of both single tooth groups and complete dental arches in subjects treated with the lingual WIN appliance were distinctly reduced when compared with previous reports of enamel decalcification after conventional labial multibracket treatment.

Quality of orthodontic care-A multicenter cohort study in a German convenience sample : Part 2: Cross-sectional patient-reported outcomes after orthodontic treatment.

OBJECTIVES: In light of the growing interest in orthodontic care and its effectiveness in Germany, part 2 of this multicenter cohort study evaluated patient-reported outcomes such as oral health-related quality of life (OHRQoL), oral hygiene habits, oral health beliefs, and potential influencing factors. METHODS: Of 586 patients screened from seven German study centers, data from 343 patients were analyzed for this part of the study. At the end of their orthodontic treatment, study participants filled out a questionnaire of either the German long version of the Oral Health Impact Profile (OHIP-G 49) or the German short version of the Child Oral Health Impact Profile (COHIP-19), depending on their age, as well as questions about their oral hygiene behavior and beliefs. Patient-, treatment- and occlusion-related factors were analyzed to account for potential influencing factors with regard to patients' OHRQoL after orthodontic treatment. RESULTS: In all, 222 study participants filled out the OHIP-based and 121 the COHIP-based questionnaire. The mean OHIP-G 49 score was 12.68 and the mean OHIP-G 14 score was 3.09; the mean COHIP-19 score was 6.52 (inverted score 69.48). For OHIP-G 49 scores, a nonsignificant trend towards a higher score for male patients (14.45 vs 11.54; p = 0.061) was detected, while this trend was inverse for the COHIP-19 scores, i.e., female patients reported more impairment (total score 6.99 vs. 5.84; p = 0.099). Analyses suggested a trend towards better OHRQoL for patients who classified for the Peer Assessment Rating (PAR) Index improvement rate group 'greatly improved' as well as for nonsmokers. Oral hygiene habits and beliefs after orthodontic treatment were estimated to be good. CONCLUSION: In this German cohort, OHRQoL proved to be good and was rather unimpaired after orthodontic treatment. Furthermore, self-reported oral hygiene behavior and oral health beliefs represented good health awareness.

Individualized surgery: gamma-probe-guided lymphadenectomy in patients with clinically enlarged lymph node metastases from melanomas.

BACKGROUND: The value of a preoperative lymphoscintigraphy in melanoma patients with clinically evident regional lymph node metastases has not been studied. Therapeutic lymph node dissection (TLND) is regarded as the clinical standard, but the appropriate extent of TLND is controversial in all lymphatic basins. PATIENTS AND METHODS: Of the 115 consecutive patients with surgery on palpable lymph node metastases, 34 received a pre-operative lymphoscintigraphy. Lymphatic drainage to a second nodal basin outside the clinically involved basin was found in 15 cases. In 13 patients, the ectopic tumor-draining lymph nodes were excised as in a sentinel node biopsy. The lymph nodes from the TLND specimens were postoperatively separated and classified as either radioactive or non-radioactive. RESULTS: A total of 493 lymph nodes were examined pathologically. The largest macrometastasis maintained the ability to take up radiotracer in 77% of cases. Radioactively labeled lymph nodes carried a higher risk of being involved with metastasis. The proportions of tumor involvement for radioactive and non-radioactive lymph nodes were 44.5 and 16.9%, respectively (P=0.00002). Of the 13 ectopic nodal basins surgically explored, six harbored clinically occult metastases. CONCLUSION: In patients undergoing TLND for palpable metastases, tumor-draining lymph nodes in a second, ectopic nodal basin should be excised, because they could be affected by occult metastasis. With respect to radioactive lymph nodes situated within the nodal basin of the macrometastasis but beyond the borders of a less-radical lymphadenectomy, further studies are needed.

Durability of esthetic improvement following Icon resin infiltration of multibracket-induced white spot lesions compared with no therapy over 6 months: a single-center, split-mouth, randomized clinical trial.

INTRODUCTION: White spot lesions that form during orthodontic treatment are a problem for patients and clinicians. Lesion infiltration with low-viscosity light-cured resin has been proposed as a treatment to inhibit further demineralization. The purpose of this study was to assess the durability of assimilation of white spot lesions and sound adjacent enamel achieved over 6 months with resin infiltration. METHODS: Twenty-one consecutive subjects with 231 noncavitated, unrestored white spot lesions after multibracket treatment were recruited at the Department of Orthodontics, University of Göttingen (Germany), for lesion infiltration. A simple randomized, split-mouth, controlled design was used to allocate subjects to the treatment and control groups. In the treatment group, white spot lesion infiltration of the anterior teeth was performed with low-viscosity light-cured resin after enamel conditioning with a 15% HCl gel. Color and lightness of the white spot lesions and the sound adjacent enamel were assessed with a spectrophotometer before infiltration and after 1 day, 1 week, 4 weeks, 3 months, and 6 months, using the system of the Commission Internationale de l'Eclairage. Multifactorial analysis of variance with repeated measures and pair-wise comparisons were used to analyze the effects of infiltration and time elapsed on the color differences at an α level of 5% and a power of 80%. RESULTS: Analysis of 20 subjects and 39 quadrants in each group (108 teeth in the control group; 111 teeth in the treatment group) showed that both parameters of treatment and time duration had globally a highly significant influence on the color difference values. Assimilation of white spot lesion color to the surrounding enamel after infiltration was stable with no significant changes over 6 months; the mean color difference of white spot lesions vs sound adjacent enamel (ΔE baseline vs 6 months) was 2.55 (95% confidence interval [CI], 1.431-3.678). The untreated control teeth showed no significant changes over 6 months compared with the baseline: mean (ΔE), 0.29 (95% CI, -0.335-0.928). No important adverse events or side effects were observed. CONCLUSIONS: Resin infiltration improves the esthetic appearance of demineralized teeth. The results showed sufficient durability over 6 months.

Oral health status of patients with acute coronary syndrome--a case control study.

BACKGROUND: The aim of this investigation was to assess the state of oral health of patients with acute coronary syndrome (ACS) and to compare this with that of a provably healthy control group (H). METHODS: 33 patients who were receiving treatment as inpatients following acute myocardial infarction or unstable angina pectoris took part in the study (ACS-group). A healthy control group (H-group) made up of blood donors, was formed following matching for age, gender, and smoking habit with the study patient group.The dental investigation consisted of the dental status (DMF-T), a plaque-Index (PI), an assessment of gingival inflammation (GI) and periodontal situation (Periodontal Screening Index: PSR(®)/PSI), and attachment loss (AL). Statistical evaluation: t-test, Mann-Whitney-test and chi- squared test (level of significance p < 0.05). RESULTS: The mean DMF-T of the ACS-group (18.7 ± 6.8) and the H-group (19.4 ± 5.1) showed no difference (p = 0.7). Although, in the ACS-group the average loss of teeth (M-T: 8.4 ± 5.2) was higher than in the H-group (M-T: 5.8 ± 6.6) the difference was not significant (p = 0.2). Whereas with the PI no difference between the two groups was found (p = 0.9), the ACS-group showed significantly more signs of inflammation (GI) than the H-group (p = 0.045). In the case of PSR(®)/PSI, there was no difference between the two groups (p = 0.7). With regard to AL, no difference was revealed between ACS- and H-group (p = 0.2). CONCLUSION: Although, the state of oral health of the ACS-group differed only insignificantly from that of control, patients with ACS showed more signs of gingival inflammation and a higher loss of teeth.

Circulating tumor DNA: Opportunities and challenges for pharmacometric approaches.

To support further development of model-informed drug development approaches leveraging circulating tumor DNA (ctDNA), we performed an exploratory analysis of the relationships between treatment-induced changes to ctDNA levels, clinical response and tumor size dynamics in patients with cancer treated with checkpoint inhibitors and targeted therapies. This analysis highlights opportunities for pharmacometrics approaches such as for optimizing sampling design strategies. It also highlights challenges related to the nature of the data and associated variability overall emphasizing the importance of mechanistic modeling studies of the underlying biology of ctDNA processes such as shedding, release and clearance and their relationships with tumor size dynamic and treatment effects.

Class II correction by maxillary en masse distalization using a completely customized lingual appliance and a novel mini-screw anchorage concept - preliminary results.

BACKGROUND: The aim of the study was to evaluate the efficacy of a novel en masse distalization method in the maxillary arch in combination with a completely customized lingual appliance (CCLA; WIN, DW Lingual Systems, Germany). Therefore, we tested the null-hypothesis of a significant deviation from an Angle-Class I canine relationship and a normal overjet defined by an individual target set-up after dentoalveolar compensation in Angle Class II subjects. METHODS: This retrospective study included 23 patients, (m/f 3/20, mean age 29.6 years (min/max, 13.6/50.9 years)), with inclusion criteria of an Angle Class II occlusion of more than half a cusp prior to en masse distalization and treatment completed consecutively with a CCLA in combination with a mini-screw (MS) anchorage for uni- or bilateral maxillary distalization (12 bilateral situations, totalling 35). Plaster casts taken prior to (T0) and following CCLA treatment (T3) were compared with the treatment plan / set-up (TxP, with a Class I canine relationship and a normal overjet as the treatment objective). MSs were placed following levelling and aligning (T1) and removed at the end of en masse distalization at T2. Statistical analysis was carried out using Schuirmann's TOST [two one-sided tests] equivalence test, based on a one-sample t-test with α = 0.025 on each side (total α = 0.05). RESULTS: Ninety-seven percent of planned correction of the canine relationship was achieved (mean 3.6 of 3.7 mm) and also 97 % of the planned overjet correction (mean 3.1 of 3.2 mm), with a statistically significant equivalence (p < 0.0001) for canine relationship and overjet between the individual treatment plan (set-up) and the final outcome. Adverse effects were limited to the loss of n = 2 of 35 mini-screws. However, in each instance, the treatment was completed, as scheduled, without replacing them. Accordingly, the null-hypothesis was rejected. CONCLUSIONS: The technique presented allows for a predictable correction of an Angle-Class II malocclusion via dentoalveolar compensation with maxillary en masse distalization.

Objective treatment outcome assessment of a completely customized lingual appliance: A retrospective study.

OBJECTIVE: To assess the outcome quality of subjects treated with a completely customized lingual appliance (CCLA) in a postgraduate university program, using the ABO Objective Grading System (OGS), by testing the null-hypothesis of a significant proportion of post-treatment cases exceeding an adjusted 'exam failure' threshold value of OGS=24. MATERIALS AND METHODS: This retrospective single-arm study included 66 consecutively debonded CCLA cases (m/f 19/47; mean age: 25.1±9 years) treated at Hannover Medical School (MHH, Hannover, Germany). The discrepancy index (DI) was assessed on initial plaster casts. The OGS of the cast-radiograph evaluation was scored for both set-up and post-treatment casts, including the seven components of alignment/rotation, marginal ridges, buccolingual inclination, overjet, occlusal contacts, occlusal relationships and interproximal contacts, to parameterize differences between those. RESULTS: DI score distribution (≥20, <20) was 25 (37.9%)/41 (62.1%) subjects. Mean initial DI was 17.3±8.5. Mean set-up OGS was 10.4±4.4 (min-max: 3-21), mean final OGS was 17.7±5.9 (min-max: 7-33), and the difference 7.3 (post-treatment - set-up) was statistically significant (p<0.0001; 95% CI [5.8, 8.7]). The null-hypothesis was rejected: A statistically significant proportion of the final casts (n=58; 87.8%) scored below OGS=24 by exact binomial test (P<0.0001; 95% CI [77.5%, 94.6%]). The rate of a final OGS score<24 was not significantly different (P=0.98) between both DI (≥20, <20) groups. CONCLUSIONS: The outcome quality of the CCLA treatment in this postgraduate university setting was high and therefore sufficient for a vast majority of treated cases to pass the ABO-OGS clinical examination.

Controlling incisor torque with completely customized lingual appliances.

PURPOSE: To test the null hypothesis of no significant deviation between the center of rotation (CROT) and the center of resistance (CRES) during space closure in Angle class II division 2 subjects achieved using a completely customized lingual appliance (CCLA) in combination with class II elastics and elastic chains. METHODS: This retrospective study included 29 patients (male/female 11/18; mean age 15.6 [13-27] years) with inclusion criteria of an Angle class II/2 occlusion of least of half of a cusp, maxillary dental arch spacing, completed CCLA treatment (WIN, DW Lingual Systems, Bad Essen, Germany) in one center with a standardized archwire sequence and use of class II elastics and elastic chains only. Maxillary incisor root inclination was assessed by X­ray superimpositions of the maxilla at the beginning (T1) and the end (T3) of CCLA treatment. Using Keynote software (Apple®, Cupertino, CA, USA), the incisor's CROT was assessed with the point of intersection of the incisor axes (T1; T3) following vertical correction of overbite changes. CRES was defined at 36% of the incisor's apex-incisal edge distance. RESULTS: The null hypothesis was rejected: the mean CROT - CRES difference was 52.6% (p < 0.001). The mean CROT was located at 88.6% (min-max 51-100%) of the incisor's apex-incisal edge distance. Although 6.9% of CROT were located between the CRES and the alveolar crest, the vast majority (93.1%) were assessed between the alveolar crest and the incisal edge, or beyond. CONCLUSION: CCLAs can create upper incisor palatal root torque even in cases in which lingually oriented forces applied incisally to the center of resistance of the upper incisors counteract these intended root movements.

Incorrect measurements and misleading conclusions in the article "Comparison of the efficacy of tooth alignment among lingual and labial brackets: an in vitro study".

BACKGROUND/OBJECTIVE: To reproduce the methods and results of the study by Alobeid et al. (2018) in which the efficacy of tooth alignment using conventional labial and lingual orthodontic bracket systems was assessed. MATERIALS/METHODS: We used the identical experimental protocol and tested (i) regular twin bracket (GAC-Twin [Dentsply]) and lingual twin bracket systems (Incognito [3M]), (ii) together with NiTi 0.014" wires (RMO), and (iii) a simulated malocclusion with a displaced maxillary central incisor in the x-axis (2 mm gingivally) and in the z-axis (2 mm labially). RESULTS: The method described by Alobeid et al. (2018) is not reproducible, and cannot be used to assess the efficacy of tooth alignment in labial or lingual orthodontic treatment. Major flaws concern the anteroposterior return of the Thermaloy-NiTi wire ligated with stainless steel ligatures. The reproduced experimental setting showed that a deflected Thermaloy-NiTi wire DOES NOT move back at all to its initial stage (= 0 per cent correction) because of friction and binding (see supplemented video), neither with the tested labial nor with the lingual brackets. Furthermore, an overcorrection of up to 138 per cent, which the authors indicate for some labial bracket-wire combinations and which deserves the characterization "irreal", stresses the inappropriateness of the method of measurement.Further flaws include: a) incorrect interpretation of the measurement results, where a tooth tripping around (overcorrection) is interpreted as a better outcome than a perfect 100 per cent correction; b) using a statistical test in an inappropriate and misleading way; c) uncritical copying of text passages from older publications to describe the method, which do not correspond to this experimental protocol and lead to calculation errors; d) wrong citations; e)differences in table and bar graph values of the same variable; f) using a lingual mushroom shaped 0.013" Thermaloy-NiTi wire which does not exist; g) drawing uncritical conclusions of so called "clinical relevance" from a very limited in vitro testing. CONCLUSIONS: Clinical recommendations based on in vitro measurements using the Orthodontic Measurement and Simulation System (OMSS) should be read with caution.

Long-term follow-up of camouflage effects following resin infiltration of post orthodontic white-spot lesions in vivo.

OBJECTIVES: To reassess the long-term camouflage effects of resin infiltration (Icon, DMG, Hamburg, Germany) of white spot lesions (WSL) and sound adjacent enamel (SAE) achieved in a previous trial. The null hypothesis was tested that there were no significantly different CIE-L*a*b*-ΔE-values between WSL and SAE areas of assessment after at least 24 months (T24) compared to those at baseline (T0). MATERIALS AND METHODS: Of twenty subjects who received previous resin infiltration treatment of nteeth = 111 nonrestored, noncavitated postorthodontic WSL after multibracket treatment during a randomized controlled trial and were contacted 20 months after baseline, eight subjects (trial teeth nteeth = 40; m/f ratio 1/7; age range (mean; SD) 12-17 [15.25; 2.12] years); response rate: 40%) were available for follow-up after at least 24 months (T24). CIE-L*a*b* differences between summarized color and lightness values (ΔEWSL/SAE) of WSL and SAE were assessed using a spectrophotometer and compared to baseline data assessed prior to infiltration (T0), and those after 6 (T6), and 12 (T12) months using paired t tests at a significance level of α = 5%. RESULTS: T24 assessments were performed after a mean 33.86 (SD: 8.64; Min: 24; Max: 45) months following T0. Mean (SD) ΔEWSL/SAE units of available teeth were 8.76 (5.33) at baseline; 5.5 (2.75) at T6; 5.2 (2.41) at T12; and 5.57 (2.6) at T24. Comparisons of T6, T12, and T24 with T0 yielded highly significant differences, whereas T6-T24 and T12-T24 differences were found to be not significant. CONCLUSIONS: Assimilation of infiltrated WSL to the color of adjacent enamel by resin infiltration is considered to be suitable for the long-term improvement in the esthetic appearance of postorthodontic WSL.

Comparison of potential long-term costs for preventive dentistry treatment of post-orthodontic labial versus lingual enamel cavitations and esthetically relevant white-spot lesions: a simulation study with different scenarios.

BACKGROUND: Post-orthodontic white-spot lesions (WSL) in esthetically relevant incisor and canine areas impair dentofacial esthetics, and preventive dentistry treatment is definitely required in case of enamel cavitations. The incidence of lingual post-orthodontic WSL and cavitation following lingual MB treatment has been reported to be distinctively decreased compared to labial MB treatment. Moreover, lingual WSL do not impair dentofacial esthetics. It was the objective of this study to calculate consequential costs of preventive dental care necessary to recover labial or lingual post-orthodontic cavitations as well as esthetically relevant WSL following either labial or lingual MB interventions. METHODS: MB treatments (labial / lingual) were simulated in 1,000,000 patients between the ages of 12-18Y, with a median residual life time expectancy of 58Y based on local mortality tables. Range of MB Tx duration was 9-45 mo. Frequencies of post-orthodontic (labial / lingual) enamel damages were derived from large-scale WSL incidence studies. Anterior composite survival rates were based on a systematic review on the subject. Within the context of the German dental fee system (GOZ 2.3 and 3.5 fee increments), simulation of costs for enamel damage treatment and re-treatment (maximum: 5x) were based on single-surface composite restorations for lingual or labial cavitations and labial WSL treatment; and lingual WSL fluoridation. RESULTS: Overall mean total costs for Tx and re-Tx of both WSLs and cavitations may sum up to 1718.91 Eur in the high-cost (GOZ 3.5) scenario for conventional MB cases, versus 19.94 Eur for lingually treated cases, given that renewal of simulated single-surface restorations takes place at 15-year intervals. When focussing on patients diagnosed with least of one WSL, and/or cavitation, these mean costs increase up to 2332.35 Eur for conventionally treated MB patients, or 65.03 Eur for lingual MB patients. CONCLUSION: Costs for repeated treatment of post-orthodontic enamel damages produced by conventional vestibular fixed appliances may easily exceed the initially higher costs associated with lingual orthodontic treatment. Judged economically in the long term, lingual MB Tx may be considered as a more cost-effective solution for a correction of malocclusion.

A randomized trial comparing limited-excision conisation to Large Loop Excision of the Transformation Zone (LLETZ) in cervical dysplasia patients.

OBJECTIVE: To show noninferiority of a limited-excision (resection of the dysplastic lesion only) vs. classical Large Loop Excision of the Transformation Zone (LLETZ). METHODS: In this prospective, randomized, multicenter trial, women with human papillomavirus (HPV) positive cervical intraepithelial neoplasia grade 3 were randomized into two groups (1:1). Primary outcome was the rate of negative HPV tests after 6 months, secondary outcomes included cone size, complete resection rates as well as cytological and histological results after 6 and 12 months. A sample size of 1,000 was calculated to show noninferiority of the limited-excision compared to the LLETZ group using a noninferiority margin of 5%. Enrollment was stopped after 100 patients due to slow accrual. RESULTS: Patients in the limited-excision group did not show a lower number of negative HPV tests (78% [LLETZ]-80% [limited-excision]=-2%; 90% confidence interval=-15%, 12%). The limited-excision resulted in a substantially lower cone size (LLETZ: 1.97 mL vs. limited-excision: 1.02 mL; p<0.001) but higher numbers of involved margins (LLETZ: 8% vs. limited-excision: 20%). Although postoperative cytological results slightly differed, histological results were similar in both groups. One limited-excision patient received immediate re-conisation, whereas one patient in each group was scheduled for re-conisation after 6 months. CONCLUSION: The limited-excision could represent a promising option to reduce the surgical extent of conisations while maintaining oncological safety. The trial was not sufficiently powered to reach statistical significance due to early termination. Nevertheless, the study provides important insights in the feasibility of a limited-excision and could serve as a pilot study for future trials. TRIAL REGISTRATION: German Clinical Trials Register Identifier: DRKS00006169.

Interaction between deglutition, tongue posture, and malocclusion: A comparison of intraoral compartment formation in subjects with neutral occlusion or different types of malocclusion.

OBJECTIVE: To test the null hypothesis of no significant difference in terms of intraoral pressure curve characteristics assessed simultaneously at the subpalatal space (SPS) and the vestibular space (VS), during different oral postures, between four groups with either an Angle Class II/1 (II1), Angle Class II/2 (II2), anterior open bite (O) malocclusion, or a neutral occlusion control group (I). MATERIALS AND METHODS: Intraoral pressure recordings were performed simultaneously in the VS and SPS of 69 consecutive subjects (nII1  =  15; nII2  =  17; nO  =  17; nI  =  20; mean age/standard deviation 18.43/6.60 years). Assessments included defined sections of open mouth posture (OMP, 30 seconds), anteriorly closed mouth condition (60 seconds), dynamics by a tongue-repositioning maneuver (TRM, 60 seconds), swallowing, and positive pressure generation (PP, 10 seconds). Interactions of malocclusion, compartment location, and posture on pressure curve characteristics were analyzed by Kruskal-Wallis and Mann-Whitney U-tests, adopting an α level of 5%. RESULTS: Globally significant group differences were detected at the VS (plateau duration and median peak heights during TRM; area under pressure curve [AUC] during PP) and SPS (AUC during TRM and PP). Subjects with anteriorly nonopen dental configurations (groups I and II2) were able to keep negative pressure levels at the VS for longer time periods during TRM, compared to groups O and II1. CONCLUSIONS: The null hypothesis was rejected for mean VS plateau durations and peak heights and for SPS AUC. Negative pressures at the VS may stabilize outer soft tissues passively and may explain the dental arch form shaping effect by mimic muscles.