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.

Agenesis of the upper lateral incisors: Study of an orthodontic population and clinical illustration.

In his daily practice, the orthodontist is regularly asked to treat patients with one or more missing teeth. Considering their functional and esthetic specificities, and the relatively high frequency of agenesia, our interest was to focus on the permanent lateral upper incisors. Our study, based on an orthodontic population including 1000 patients, shows that about 7.8% of these patients present agenesis of at least one permanent tooth (out of which 3.6% are agenesis of the upper lateral incisor). Treatment options for these cases are multiple with several decisional factors to consider: the solutions often lead to compromises, and require a multidisciplinary coordination. Therefore, the purpose of this article, was to describe the prevalence of these agenesia based on a retrospective study, and to present two clinical cases: the first case is a bilateral agenesis of the maxillary lateral incisors treated with space opening in order to place two implant-supported restorations. The second case is an agenesis of tooth 12 treated with space reopening and the placement of a cantilever bridge. These clinical cases are presented to illustrate the multidisciplinary approach involving orthodontics, prosthodontics, and periodontology, in order to achieve the most esthetic and functional results possible.

[The smile and dento-facial orthopaedics]. / Sourire et orthopédie dento-faciale.

INTRODUCTION: The mouth is an essential feature of the human body since it is there that the breath and food of life pass. In addition, it bears witness to our emotions. Today, the smile has become a major means of communication and of "self-affirmation". OBJECTIVE: The first task of the orthodontist is to restore correct function while, obviously, also contributing to enhance the patient's appearance. MATERIALS AND METHODS: In this article, we will present six cases to demonstrate that the leading mission of orthodontics is to restore the occlusion and function.

À propos d'un cas de résorptions radiculaires sévères en orthodontie : quelle étiologie et quelle prise en charge?Orthodontics and root resorptions: a clinical case.

INTRODUCTION: Root resorptions are, with white spots, some of the inconveniences caused by orthodontic treatments. Although they are rare, they should not be ignored despite the many benefits gained by orthodontic treatment. Contrary to white spots, which are controllable by good dental hygiene, root resorptions can occur despite patient cooperation. Orthodontists should be aware of this phenomenon and make regular radiologic controls a priority for detection "before, during and after" treatment. MATERIAL AND METHOD: After literary references, the presentation of the case report will illustrate the role of the orthodontist in the preservation and care of teeth damaged by impacted cuspids. DISCUSSION: The discussion will focus on the prevention and the interception of those phenomena, the etiologic research on these cases, on medical supervision and prognostic for damaged teeth. CONCLUSION: Before the conclusion, we will evoke the contribution of the cone-beam in the diagnosis of root resorption.

[Collaboration between periodontics and orthodontics: interest of alveolar corticotomies and piezocision. Review of literature]. / Collaboration parodontie et orthodontie : intérêts des corticotomies alvéolaires et de la piézocision. Revue de la littérature.

INTRODUCTION: Orthodontics in adults must adapt to certain particularities especially related to the decrease or absence of growth and the prevalence of periodontal damage in this population. This review of the literature aims to assess the effects of alveolar corticotomies on accelerating or facilitating tooth movements in different types of orthodontic movements, to compare results obtained by classical technique with those obtained by piezocision and analyze their impact on periodontal tissues in the long term. MATERIAL AND METHODS: Research was performed with Medline, Embase and Cochrane databases, beginning in January 2000. Every study, selected through its title and abstract, was then evaluated through its full content. A total of 65 studies were included. RESULTS: All studies showed that corticotomies temporarily facilitate accelerated orthodontic tooth movement, with minimal complications. No periodontal lesion, loss of pulpal vitality or severe root resorption were reported. DISCUSSION: Only a few studies have examined control groups treated with conventional orthodontics. Corticotomy allows temporary acceleration of orthodontic tooth movement. Piezocision is less invasive and performed in certain indications; it also lightens the postoperative complications. However, the fact that using alveolar corticotomies significantly decreases the treatment time remains uncertain, due to the lack of significant data. Further prospective randomized clinical studies are necessary to analyze more precisely the decrease in the overall treatment time, improved periodontal support and stability of orthodontic treatment results in the long term following the alveolar corticotomies.

[Growth and dental implants: assessment and prevention of the long-term aesthetic risk]. / Croissance et implants dentaires : évaluation et prévention du risque esthétique.

Using implant to replace a tooth is a well known treatment. However, the practitioner must keep in mind that osteointegrated implants behave like ankylosed teeth, and their evolution does not follow the alveolar processes of the adjacent teeth during growth. This growth decreases after 20 years, but remains present. This can lead to infraposition functionally and aesthetically failure for the implant therapy. Risk factors, like patient's age, sex and shape of the face must be evaluated. Most palatal implant positioning and use of screwed prosthetic tooth can permit the infraposition treatment during years of aging.

Relocation of Infrapositioned Ankylosed Teeth: Description of Orthodontic Bone Stretching and Case Series.

Different treatments have been proposed to manage the consequences of ankylosed teeth. This clinical report, which includes several different clinical conditions, describes an orthodontic bone-stretching procedure that can be used to relocate ankylosed teeth. The orthodontic bone-stretching technique involves only partial osteotomies, without the mobilization or repositioning of the alveolar segment, combined with orthodontic forces. The applied force facilitates tooth movement to the occlusal plane and can modify the axis of the ankylosed tooth. This relocation is possible because of a bone-stretching phenomenon in the surgical area. In all of the cases, relocation of the ankylosed teeth was successfully performed and the gingival margins were corrected to improve the esthetic results.

[Treatment of ankylosed teeth by segmental corticotomy: the Orthodontic Bone Stretching technique. Preliminary study]. / Traitement des dents ankylosées par corticotomie partielle : l'Orthodontic Bone Stretching. Étude préliminaire.

Ankylosed anterior teeth are associated with infraclusion and can lead to a concomitant significant esthetic defect. After a review of the techniques used move these teeth into the arch, this article describes a new technique to restore occlusion and improve esthetics, or to prepare the case for either a prosthetic or implant treatment, Orthodontic Bone Stretching (OBS). This technic combines partial corticotomy and orthodontic treatment and produces bone stretching. After 8 to 12 weeks of force application, the ankylosed teeth are repositioned into occlusion or, if extraction is necessary, the bone crest is at a level consistent with a prosthetic or implant treatment. OBS technique can be adapted to implant infraclusion, or the vertical regeneration of atrophied ridge.

Preclinical and clinical evidence that Deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography is a reliable tool for the detection of early molecular responses to erlotinib in head and neck cancer.

PURPOSE: There is a clinical need to identify predictive markers of the responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography with computed tomography ((18)FDG-PET/CT) could be a tool of choice for monitoring the early effects of this class of agent on tumor activity. EXPERIMENTAL DESIGN: Using models of human head and neck carcinoma (CAL33 and CAL166 cell lines), we first tested in vitro and in vivo whether the in vivo changes in (18)FDG-PET/CT uptake were associated with the molecular and cellular effects of the EGFR-TKI erlotinib. Then, the pathologic and morphologic changes and the (18)FDG-PET/CT uptake before and after erlotinib exposure in patients were analyzed. RESULTS: Erlotinib strongly inhibited extracellular signal-regulated kinase-1/2 (ERK-1/2) phosphorylation both in the preclinical models and in patients. Western blotting, immunofluorescence, and immunohistochemistry showed that erlotinib did not modify Glut-1 expression at the protein level either in cell line models or in tumor tissue from mouse xenografts or in patients. Phospho-ERK-1/2 inhibition was associated with a reduction in (18)FDG uptake in animal and human tumors. The biological volume was more accurate than the standardized uptake value for the evaluation of the molecular responses. CONCLUSION: These results show that the (18)FDG-PET/CT response is a reliable surrogate marker of the effects of erlotinib in head and neck carcinoma.

In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR.

This study aimed to assess the effect of cetuximab (C225, Erbitux, a chimeric anti-epidermal growth factor receptor (EGFR) monoclonal antibody) in combination with oxaliplatin in vitro and in vivo on four colon cancer cell lines (HCT-8; HT-29, SW620, HCT-116) expressing different levels of EGFR. In vitro, cetuximab combined with oxaliplatin significantly decreased the IC50 values of oxaliplatin in HCT-8 (EGF-R moderate) and HT-29 (EGF-R weak) cell lines, while SW620 (EGF-R negative) and HCT-116 (EGFR strong) cell lines remained unresponsive. This combination was synergistic in HCT-8 and HT-29 cell lines while cetuximab induced no major modification of the IC50 of oxaliplatin in HCT-116 or SW620 cell lines. We then determined the effect of cetuximab on the EGF-induced EGFR phosphorylation and we highlight a correlation between the basal level of phospho-EGFR and the response to the combination. In vivo, the combination of cetuximab plus oxaliplatin significantly inhibited tumor growth of HCT-8 and HT-29 (tumor delay or Td = 21.6+/-2.9 and 18.0+/-2.9 days respectively, synergistic effect) compared to either oxaliplatin (Td=12.6+/-2.3 and 14.4+/-3.2 days respectively) or cetuximab (Td=13.4+/-2.9 and 14.5+/-2.4 days, respectively) alone in xenograft models. The combination had no effect on HCT-116 and SW-620 cell lines. The observed responses are strictly dependent on the cell type, and are not correlated with the level of EGFR expression but related to the basal level of phospho-EGFR. This study provides promising preclinical results for a possible clinical investigation of the combination of oxaliplatin plus cetuximab in chemorefractory colorectal tumors.

Phase-I study of a new schedule based on increasing days of topotecan administration associated with dose individualisation.

BACKGROUND: The most commonly prescribed schedule of topotecan administration is daily for five days, every 21 days. Both pre-clinical and clinical studies suggest that a more protracted schedule may increase its therapeutic index. The current study was undertaken to determine the maximum tolerated number of days with 30-minute i.v. infusion of topotecan daily at fixed area under the plasma concentration-time curve (AUC) (i.e., 35 microg/Lxh). PATIENTS AND METHODS: Topotecan was administered i.v. over 30 min. The planned levels of number of days of administration were: 7, 10, 13, 15 and 17. The dose was individualized according to the patient's individual topotecan clearance observed after the first infusion of each cycle. RESULTS: Twenty-three patients were enrolled and received 71 cycles of therapy. The 13-day level was defined as the maximum number of days of administration. The main side effects were thrombocytopenia and anaemia, whereas neutropenia was infrequent. The mean (coefficient of variation) observed AUC was 34.6 (21%), and 33.4 (19%) microg/Lxh, for the last day of cycle 1, and of cycle 2, respectively. Confirmed partial responses were observed in one patient with metastatic desmoplastic tumour and in two patients with small round metastatic endocrine carcinoma. CONCLUSION: The recommended number of topotecan administration is 10 days. Beyond the potential clinical interest of topotecan administered for a 10-day period, this is the first trial showing the feasibility of a phase-I study exploring a number of administrations of daily AUC rather than a total dose in mg/m(2).

Serum cystatin C is a better marker of topotecan clearance than serum creatinine.

PURPOSE: To evaluate plasma cystatin level as a covariate to predict topotecan pharmacokinetics. Cystatin C, a member of the cystatin superfamily of cysteine proteinase inhibitors, has been recently proposed as an alternative endogenous marker of glomerular filtration. Renal function is known as a key factor of topotecan clearance. EXPERIMENTAL DESIGN: Data were obtained from 59 patients who underwent drug monitoring for individual dosing of topotecan. Topotecan plasma concentrations versus time were analyzed using a nonlinear mixed effect model according to a two-compartment pharmacokinetic model and a first-order conditional estimation method. A proportional error model was used for residual and interpatient variabilities. Data-splitting was done randomly to create a model-building data set (44 patients) and a model validation data set (15 patients). RESULTS: Using the building data set, four covariates significantly decreased the objective function value and interindividual variability on topotecan clearance (CL) when tested individually: ideal body weight (IBW), serum creatinine, age, and cystatin C level. The best model was: CL (L/hour) = 20.2 [cystatin C (mg/L) / 1.06](-0.60) [IBW (kg) / 57](0.95). Prospective evaluation using the validation data set confirmed that the model based on cystatin C had a better predictive value than the models based on serum creatinine or body surface area. CONCLUSION: Cystatin C is a marker of drug elimination which is superior to serum creatinine for topotecan. It deserves to be further explored as a promising covariate for drug dosing as well as selection criteria for clinical studies of drugs eliminated mainly or partially by the kidney.

Atypical protein kinase C stimulates nucleotide excision repair activity.

Nucleotide excision repair (NER) deals with bulky DNA damages. However, the regulation of this process is still unclear. Here, we show that both cell resistance to genotoxic agents that generate DNA lesions corrected by NER and in vitro NER activity are correlated with atypical protein kinase C (PKC) zeta expression levels. Moreover, repair intermediates are produced and eliminated more rapidly in UV-irradiated PKCzeta-overexpressing cells. The expression levels of XPC and hHR23B, two NER proteins, are correlated with PKCzeta expression. Altogether, these results strongly suggest that PKCzeta could act as a modulator of NER activity by regulating the expression of XPC/hHR23B heterodimer.

Toxicity patterns of cytotoxic drugs.

Toxicity is a major concern for anticancer drugs. These compounds present a narrow therapeutic index, with a small difference between the dose required for an antitumor effect and that responsible for unacceptable toxicity. Their recommended doses are determined according to the toxicity endpoint. Moreover, toxicity is observed earlier than the therapeutic effect, so, toxic effects represent a major endpoint for pharmacodynamic studies of cytotoxic drugs. Knowledge of toxicity patterns and main factors of toxicity of anticancer drugs is required before modeling data of these studies. Hematological toxicities represent the main toxicity of the cytotoxic. However, non-hematological toxicities have become more important than hematological toxicities as pharmacodynamic endpoints in some circumstances such as high-dose chemotherapy associated with bone marrow transplantation. This paper will describe the main toxicity of the cytotoxic drugs, and its factors of both inter- and intra-patient variability. The toxicity pattern of topotecan will be examined as an example. Knowledge of the toxicity pattern of a drug constitutes a prerequirement before modeling its pharmacodynamics.

Population pharmacokinetics of oxaliplatin.

The objective of this study was to explore correlations between a variety of covariates and oxaliplatin ultrafilterable and blood pharmacokinetic parameters. Data from 40 patients receiving oxaliplatin combined with 5-fluorouracil and levofolinic acid as standard treatment for advanced colorectal cancer were analysed. Plasma ultrafilterable, blood, and urine platinum concentrations were determined by flameless atomic absorption spectrophotometry. Data were analysed according to a population pharmacokinetic method using the NONMEM program. The best fit for oxaliplatin plasma ultrafilterable clearance (CL) was given by the following equation, which considers four covariates: body surface area (BSA, in metres squared), age (in years), sex (0 if male, 1 if female), and serum creatinine (Scr, in micromoles per liter): CL (l/h)=5.49xBSA+4.55xBSAx(140-AGE)x(1-0.15xSEX)/Scr. By taking into account these covariates, the interindividual variability in CL decreased from 43% to 33%. Renal clearance represented 34% of the overall elimination. This value was obtained by recovering urine over only 5 h from the beginning of the infusion and modelling the data using NONMEM. We would recommend the use of this methodology for pharmacokinetic studies in oncology in which renal clearances of the drug are presently rarely explored. The oxaliplatin blood concentrations versus time observed during the three-cycle period were well-described by a three-compartment model with first-order elimination from the central compartment. No significant intrapatient pharmacokinetic variability was observed between cycles. The relationship we obtained using the population approach between oxaliplatin CL and covariates may allow rational reduction of oxaliplatin dose in cases of elevated serum creatinine levels.

Contribution of apoptosis in the cytotoxicity of the oxaliplatin-irinotecan combination in the HT29 human colon adenocarcinoma cell line.

Interactions between the topoisomerase I inhibitor irinotecan (CPT-11) and the platinum derivative oxaliplatin (L-OHP) were investigated in HT29 colon cancer cell line. Synergism was observed when cells were simultaneously exposed to drugs or when cells were first exposed to CPT-11. Flow cytometric studies showed a G(2)/M accumulation when cells were exposed to the simultaneous and CPT-11-->L-OHP combinations whereas a persistent S phase delay was observed when cells were first exposed to L-OHP. We characterised the cytotoxic effect by assessing the induction of apoptosis. Irinotecan induced substantial DEVDase activity and poly(ADP-ribose) polymerase cleavage while this activity was moderate and delayed after exposure to L-OHP. Combination experiments showed a sequence-dependent onset of apoptosis, the CPT-11-->L-OHP schedule being the earliest and the most effective; on the other hand the apoptotic signaling generated by CPT-11 was partly inhibited in the simultaneous combination and in the L-OHP-->CPT-11 sequence. Cell death studies using a dual staining technique showed a shift from apoptosis to necrosis when combining these drugs at high concentrations. Synergistic interactions observed using CPT-11 before L-OHP may be linked to an early apoptotic signaling while the L-OHP-induced S phase block could account for the observed additive effect in the reverse sequence. An additional phenomenon might work towards synergism for the simultaneous combination.

Non-linear pharmacokinetics of irinotecan in mice.

Irinotecan (CPT-11) is a topoisomerase I inhibitor used in the treatment of metastatic colorectal cancer. Its conversion by carboxyl esterases is necessary to form the active metabolite SN-38. The aims of the study were to evaluate the linearity of CPT-11 pharmacokinetics and the influence of the schedule of administration of CPT-11 in mice, using a population pharmacokinetic approach with the NON-linear Mixed Effects Model (NONMEM) program. Mice were treated using two doses and two schedules of administration [10 mg/kg/day (dailyx5)x2 or 50 mg/kg/day on days 1 and 12]. Plasma concentrations of both CPT-11 and SN-38 were determined by HPLC. A pharmacokinetic model based on both immediate conversion of CPT-11 to SN-38 for a fraction of the administered dose and saturable process for the remaining fraction fitted the data well. Refinements of the model allowed us to evaluate both the impacts of the dose and the schedule of administration on the pharmacokinetic parameters. We conclude that the pharmacokinetics of CPT-11 is not linear in mice. Extrapolation of both pharmacokinetic and pharmacodynamic preclinical results to humans may be limited by species particularities for this drug.

Individual adaptive dosing of topotecan in ovarian cancer.

PURPOSE: To take into account relationships between topotecan area under the plasma concentration (AUC) versus time curve and percentage decrease of neutrophil count previously shown when topotecan is administered on a 5-day, daily schedule. A multicentric clinical trial with individualized dosing of topotecan was performed in patients with platinum-refractory ovarian cancer. The primary goal of this study was to evaluate the toxicity of topotecan when the interindividual variability in plasma drug exposure is decreased. EXPERIMENTAL DESIGN: A total of 39 patients were evaluable. In cycle 1, the daily dose for the last 2 days was dependent on the observed topotecan AUC at day 1; the general objective was to constrain the overall AUC (i.e., from day 1 to day 5) within 37,500-75,000 nM.min. A pharmacokinetic study was also performed on day 5 of cycle 1 and day 1 of cycle 2 to evaluate the intrapatient pharmacokinetic variability both within cycle 1 and between cycles. RESULTS: The dose of topotecan was decreased for 20 patients and increased for only 1 patient within cycle 1. The total administered dose was correlated to the creatinine clearance. The dose adjustments allowed control of the topotecan exposure: mean (+/-SD) observed AUC of 70,697 (+/-12,364) nM.min. Fourteen cases of dose-limiting toxicity were observed, mainly in patients who previously received two different regimens of chemotherapy without a washout period before topotecan treatment. An overall response rate of 21% was observed in the 33 patients evaluable. CONCLUSION: Dose adjustments are required not only in patients with creatinine clearance below 40 ml/min, but also in those with values between 40 and 60 ml/min (recommended starting dose is 1.2 mg/m(2)). By performing drug monitoring and taking into consideration the past treatment of each patient, better dose individualization can be obtained.