Three-dimensional dentoskeletal changes following minimally invasive surgically assisted rapid palatal expansion: a prospective study.

Dentoskeletal changes in minimally invasive surgically assisted rapid palatal expansion (SARPE) were evaluated using cone beam computed tomography (CBCT). This was a prospective study of 30 patients who underwent minimally invasive SARPE performed under local anaesthesia plus sedation by the same surgeon, in an ambulatory setting. Pre- and postoperative CBCT images were obtained for each patient. A statistically significant increase in the linear transverse dimensions of the maxilla occurred systematically. In the canine region, a mean increase of 5.84 mm occurred at the apex level and 7.82 mm at the crown level. These dimensions were 4.83 mm and 7.68 mm, respectively, in the molar region. The cross-sectional area of the maxilla increased by a mean 12.9 mm2 at the palate level and 23.3 mm2 at the crown level. Dental inclination to the buccal aspect was detected (mean 6.1° at the canines and 8.4° at the first molars). The alveolar process tipped buccally 10° at the molar level. Nasal width increased a mean of 3.0 mm at the canine level. Through a three-dimensional analysis, this study found that minimally invasive SARPE was effective in the correction of transverse maxillary discrepancies> 5 mm in non-growing patients. Although dental inclination to the buccal aspect occurred, significant expansion of the maxilla at the skeletal and dentoalveolar levels was confirmed.

Antibiotic prophylaxis in orthognathic surgery: an overview of systematic reviews.

The purpose of this overview was to assess different antibiotic regimens used in orthognathic surgery and to establish an evidence-based protocol so that beneficial and adverse effects can be determined. A comprehensive literature search for systematic reviews and/or meta-analyses was conducted in MEDLINE (PubMed), EMBASE, and the Cochrane Library until March 2020. Grey literature was investigated in Google Scholar, and a manual search was done of references lists. Two meta-analyses and four systematic reviews met the inclusion criteria. The AMSTAR-2-tool was used to ascertain the potential risk of bias in the included studies, which presented moderate to high methodological quality. Lower infection rates were associated with long-term therapies of penicillin, cefazolin-cephalexin, and amoxicillin-clavulanic-acid, with rates varying from 0% - 3.13%. Higher rates were reported in placebo groups (52.6%) and short-term penicillin therapy (60%). Side effects were reported with cefazolin, clindamycin, and penicillin therapies, including nausea, pain, swelling, headache, vomiting, and skin rash. Evidence suggests that long-term antibiotics can reduce the risk of a surgical site infection (SSI) in orthognathic surgery, but there is uncertainty regarding the effects of one dose of antibiotics preoperatively versus short-term antibiotics. In the same way, intravenous penicillin, cefazolin, clindamycin, and amoxicillin-clavulanic acid kept the infection rates associated with bimaxillary procedures under 3.5%.

Variation between natural head orientation and Frankfort horizontal planes in orthognathic surgery patients: 187 consecutive cases.

The purpose of this study was to assess the relationship between the Frankfort horizontal (FH) and natural head orientation (NHO), their correlation between patients' malocclusion, and the impact of counterclockwise rotation (CCW) on the FH-NHO angle variation after orthognathic surgery. An evaluation of 187 consecutive patients was performed at the Maxillofacial Institute (Teknon Medical Center, Barcelona). FH-NHO° was measured pre- and postoperatively at 1 and 12 months, after three-dimensional (3D) superimposition using a software (Dolphin®). Patients were classified as follows: 3.2%, 48.7% and 48.1%, class I, II and III, respectively. Baseline FH-NHO° was significantly positive for patients with dentofacial deformities (2.73°±4.19 (2.12-3.33°, P<0.001). The impact of orthognathic surgery in FH-NHO° was greater in class II when compared with class III patients, with a variation of 2.04°±4.79 (P<0.001) and -1.20°±3.03 (P<0.001), respectively. FH-NHO° increased when CCW rotational movements were performed (P=0.006). The results of this study suggest that pre- and postoperative NHO differs from FH in orthognathic patients. The angle between FH and NHO is significantly larger in class III than in class II patients at baseline, which converges after orthognathic surgery when CCW rotation is performed. Therefore, NHO should be used as the real horizontal plane when planning for orthognathic surgery.

Nasolabial soft tissue effects of segmented and non-segmented Le Fort I osteotomy using a modified alar cinch technique-a cone beam computed tomography evaluation.

The aim of this study was to verify soft tissues changes and the effect of a minimally invasive surgical technique in the nasolabial region after segmented and non-segmented Le Fort I osteotomy, using cone beam computed tomography (CBCT) evaluation of three-dimensional (3D) volume surfaces. Two groups were evaluated: group 1, bimaxillary surgery with maxillary segmentation (n=40); group 2, bimaxillary surgery without maxillary segmentation (n=40). In both groups, a specific alar cinching technique was used to control nasal base broadening. CBCT evaluation was performed at three different treatment time points: T0, 1 month before surgery; T1, 1 month after surgery; T2, 1year after surgery. The results showed statistically significant differences in the nasolabial area (P<0.001). For group 1, the mean change in alar base width (Alinf-Alinf) was 1.31±1.40mm at T1 and 0.93±1.77mm at T2; for group 2 these values were 1.12±2.01mm at T1 and 0.54±1.54mm at T2. For group 1, the mean changes in inter-alar width (Al-Al) were 1.68±1.46mm at T1 and 1.49±1.33mm at T2; for group 2, they were 2.22±1.93mm at T1 and 1.34±1.79mm at T2. The alar cinch technique proposed here appears to be effective in controlling nasolabial soft tissue widening.

Three-dimensional analysis of nasolabial soft tissue changes after Le Fort I osteotomy: a systematic review of the literature.

A systematic review was conducted to investigate the three-dimensional (3D) effect of Le Fort I osteotomy on the nasolabial soft tissues. The literature search was conducted using the MEDLINE (accessed via PubMed), Embase, and Cochrane electronic databases until January 2018. A total of 333 studies were identified (PubMed, n=292; Embase, n=41; Cochrane Library, n=0). Seventeen met the inclusion criteria. The studies were essentially retrospective. The risk of bias was considered high in 15 studies, medium in one study, and low in one study. 3D soft tissue analysis was performed at least 6months after surgery (mean 8.3months). The main image acquisition technique reported was cone beam computed tomography (CBCT), associated or not with 3D photography. Approximately 50% of the studies performed two-jaw surgery, 25% performed maxillary surgery only, and the other 25% included heterogeneous intervention groups. The most reported nasolabial changes were anterior and lateral movements of the nasomaxillary soft tissues and upper lip, together with anterior and superior movement of the nasal tip. The alar cinch suture and V-Y closure technique seemed to have little effect in counteracting the undesirable postoperative nasolabial changes. CBCT superimposition presented a reliable 3D assessment for simultaneous measurement of skeletal and soft tissue changes.

Alveolar corticotomies for accelerated orthodontics: A systematic review.

INTRODUCTION: It has been suggested that alveolar corticotomies may accelerate tooth movement, broaden the scope of malocclusion types that can be treated orthodontically, decrease the need for extractions, and support long-term stability. Several techniques have been proposed, although the indications, ideal design and technical characteristics, potential complications, and objective clinician and patient satisfaction remain unclear. This systematic review aimed to provide scientific support to validate alveolar corticotomies as a reliable approach to accelerated orthodontics. MATERIAL & METHODS: A literature search was conducted using MEDLINE (via PubMed), Cochrane, and EMBASE electronic databases until December, 2016. Articles written in any language other than English, Spanish, French, German, and Portuguese were excluded. Randomized controlled trials, controlled clinical trials, and case series involving healthy adult patients, with a sample size of at least 5 patients, and using alveolar corticotomy techniques were included. Two reviewers extracted the data independently. RESULTS: Three randomized clinical trials, 2 prospective randomized clinical trials, 6 case series and 1 randomized controlled split-mouth study were included. No clinical trials were retrieved. Mean total treatment time in corticotomy-facilitated orthodontic cases was 8.85 months (range, 4-20 months); control groups treatment duration was 16.4 months (range, 7.8-28.3 months). Complications such as pain, swelling, and dentin hypersensitivity were reported. Few studies mentioned patient/clinician satisfaction. The faster and less invasive procedures appeared to be well tolerated. However, the methodological quality of the selected studies was low, with only low to moderate scientific evidence. CONCLUSIONS: Corticotomy-facilitated orthodontics resulted in decreased treatment time. Few complications and low morbidity were found. More solid evidence-based research is required to support these results.

Genotype-outcome correlations in pediatric AML: the impact of a monosomal karyotype in trial AML-BFM 2004.

We conducted a cytogenetic analysis of 642 children with de novo acute myeloid leukemia (AML) treated on the AML-Berlin-Frankfurt-Münster (BFM) 04 protocol to determine the prognostic value of specific chromosomal aberrations including monosomal (MK+), complex (CK+) and hypodiploid (HK+) karyotypes, individually and in combination. Multivariate regression analysis identified in particular MK+ (n=22) as a new independent risk factor for poor event-free survival (EFS 23±9% vs 53±2% for all other patients, P=0.0003), even after exclusion of four patients with monosomy 7 (EFS 28±11%, P=0.0081). CK+ patients without MK had a better prognosis (n=47, EFS 47±8%, P=0.46) than those with MK+ (n=12, EFS 25±13%, P=0.024). HK+ (n=37, EFS 44±8% for total cohort, P=0.3) influenced outcome only when t(8;21) patients were excluded (remaining n=16, EFS 9±8%, P<0.0001). An extremely poor outcome was observed for MK+/HK+ patients (n=10, EFS 10±10%, P<0.0001). Finally, isolated trisomy 8 was also associated with low EFS (n=16, EFS 25±11%, P=0.0091). In conclusion, monosomal karyotype is a strong and independent predictor for high-risk pediatric AML. In addition, isolated trisomy 8 and hypodiploidy without t(8;21) coincide with dismal outcome. These results have important implications for risk stratification and should be further validated in independent pediatric cohorts.

Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia.

Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1's critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias.

KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia.

High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.

Computer-aided planning in orthognathic surgery-systematic review.

The aim of this study was to conduct a systematic review to evaluate the accuracy and benefits of computer-aided planning in orthognathic surgery. The search was performed in PubMed, EMBASE, Cochrane Library, LILACS, and SciELO. The articles identified were assessed independently and in a blinded manner by two authors using selection criteria and eligibility criteria. The database search yielded 375 studies. Following the application of search and eligibility criteria, a final nine studies were included in the systematic review. The level of agreement between the authors in the study selection process was substantial (κ=0.767) and study eligibility was considered excellent (κ=0.863). The accuracy of translation was <1.2mm in the maxilla (vertical) and <1.1mm in the mandible (sagittal), and for rotation was <1.5° in the maxilla (pitch) and <1.8° in the mandible (pitch). Two studies showed a medium potential risk of bias and six studies showed a high potential risk of bias. Computer-aided planning in orthognathic surgery was considered accurate for the studies included in this systematic review. However, the low quality of these studies means that randomized clinical trials are needed to compare computer-aided planning to conventional planning in orthognathic surgery.

Minimal residual disease-based treatment is adequate for relapse-prone childhood acute lymphoblastic leukemia with an intrachromosomal amplification of chromosome 21: the experience of the ALL-BFM 2000 trial.

BACKGROUND: Recently, the UK CCLG and COG reported that an intrachromosomal amplification of chromosome 21 (iAMP21) in acute lymphoblastic leukemia (ALL) loses its adverse prognostic impact with intensified therapy. PATIENT AND METHODS: We evaluated the prognosis of iAMP21 among patients from the ALL-BFM (Berlin-Frankfurt-Münster) 2000 trial with 46 of 2 637 (2%) patients iAMP21+. RESULTS: 8-year event-free-survival (EFS, 64 ± 8% vs. 81 ± 1%, p=0.0026) and cumulative incidence of relapse (CIR, 29 ± 8% vs. 14 ± 1%, p=0.008) of the iAMP21 cases were significantly worse compared with non-iAMP21 patients. Within the MRD low-risk group, iAMP21 cases (n=14) had an inferior 8-year EFS (76 ± 12% vs. 92 ± 1%, p=0.0081), but no increased CIR (10 ± 10% vs. 6 ± 1%, p=0.624). Within the MRD intermediate-risk group, iAMP21 cases (n=27) had a worse 8-year EFS (56 ± 11% vs. 78 ± 2%, p=0.0077) and CIR (44 ± 11% vs. 20 ± 2%, p=0.003) with 6/10 relapses occurring after 2 years. CONCLUSIONS: Conclusively, we believe that there is no necessity for enrolling all iAMP21 patients into the high-risk arm of ongoing ALL-BFM trials because MRD low-risk patients have a moderate relapse risk under current therapy. Whether the increased relapse risk in MRD intermediate-risk patients can be avoided by late treatment intensification remains to be answered by the AIEOP-BFM ALL 2009 trial randomly using protracted pegylated L-asparaginase during delayed intensification and early maintenance.

An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome.

Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). To date, fluorescence in situ hybridisation (FISH), with probes specific for the RUNX1 gene, provides the only reliable detection method (five or more RUNX1 signals per cell). Patients with iAMP21 are older (median age 9 years) with a low white cell count. Previously, we demonstrated a high relapse risk when these patients were treated as standard risk. Recent studies have shown improved outcome on intensive therapy. In view of these treatment implications, accurate identification is essential. Here we have studied the cytogenetics and outcome of 530 iAMP21 patients that highlighted the association of specific secondary chromosomal and genetic changes with iAMP21 to assist in diagnosis, including the gain of chromosome X, loss or deletion of chromosome 7, ETV6 and RB1 deletions. These iAMP21 patients when treated as high risk showed the same improved outcome as those in trial-based studies regardless of the backbone chemotherapy regimen given. This study reinforces the importance of intensified treatment to reduce the risk of relapse in iAMP21 patients. This now well-defined patient subgroup should be recognised by World Health Organisation (WHO) as a distinct entity of BCP-ALL.

Soft and hard tissue changes in skeletal Class III patients treated with double-jaw orthognathic surgery-maxillary advancement and mandibular setback.

The soft tissues of the facial profile may change after skeletal movement in orthognathic surgery. The aim of this study was to evaluate and compare the differences and correlation between hard and soft tissues after double-jaw surgery in skeletal Class III subjects. Radiographs from the following time points were assessed using Dolphin Imaging software: preoperative (T0), 2-4 months postoperative (T1), and 6-12 months postoperative (T2). Eleven hard and soft tissue points of the facial profile were evaluated. The Student's t-test was used to assess the significance of differences between the time intervals; Pearson's correlation coefficient was used to assess the significance of correlation existing between these points; significance was set at P<0.05. In the sample of 58 subjects, the correlation between hard and soft tissues in the mandible was greater than in the maxilla. Similarly, the correlations only between hard tissues and only between soft tissues presented a greater correlation in the mandible. The results are similar to those found in studies on single-jaw surgery for both the maxilla and the mandible. The influence of movements in hard tissues was restricted to the soft tissues of the same jaw, although there were exceptions.

Blocking ETV6/RUNX1-induced MDM2 overexpression by Nutlin-3 reactivates p53 signaling in childhood leukemia.

ETV6/RUNX1 (E/R) is the most common fusion gene in childhood acute lymphoblastic leukemia. It is responsible for the initiation of leukemia but also indispensable for disease maintenance and propagation, although its function in these latter processes is less clear. We therefore investigated the effects of the perceived p53 pathway alterations in model cell lines and primary leukemias and, in particular, how E/R upregulates MDM2, the predominant negative regulator of p53. We found that E/R transactivates MDM2 in both p53(+/+) and p53(-/-) HCT116 cells by binding to promoter-inherent RUNX1 motifs, which indicates that this activation occurs in a direct and p53-independent manner. Treatment of E/R-positive leukemic cell lines with Nutlin-3, a small molecule that inhibits the MDM2/p53 interaction, arrests their cell cycle and induces apoptosis. These phenomena concur with a p53-induced expression of p21, pro-apoptotic BAX and PUMA, as well as caspase 3 activation and poly ADP-ribose polymerase cleavage. The addition of DNA-damaging and p53-activating chemotherapeutic drugs intensifies apoptosis. Moreover, Nutlin-3 exposure leads to an analogous p53 accumulation and apoptotic surge in E/R-positive primary leukemic cells. Our findings clarify the role of p53 signaling in E/R-positive leukemias and outline the potential basis for its therapeutic exploitation in this setting.

Evaluation of tissue response and genotoxicity of poly(L/D-lactic acid) disks implanted in rat calvarium.

The aim of the present study was to evaluate local and cytotoxicity systemic tissue reaction in the skull of rats using the implantation of disks of poly (lactic L/D-acid) and evaluate its genotoxicity. 25 males Wistar rats were used, 20 animals underwent surgical procedures and had the discs implanted in the parietal bone, and 5 animals received postoperative medication in the same way, serving as a control group for genotoxicity. The results were subjected to statistical evaluation by analysis of variance (ANOVA). In histological evaluation, between periods of 90 and 120 days in the control group, a new formation at the edges of the defect was noticed. In the experimental group, there was new bone formation at the edges of the defect, migrating below the site occupied by the disk, an absence of inflammatory infiltrate. Regarding the evaluation of genotoxicity, a significant reduction in the frequency of polychromatic erythrocytes in relation to negative control or significant increase in the polychromatic erythrocytes with micronuclei was not detected. So, the material used in this study is biocompatible and well tolerated by the tissues studied, and found to be negative for chromosomal mutagenicity.

CREBBP HAT domain mutations prevail in relapse cases of high hyperdiploid childhood acute lymphoblastic leukemia.

Despite their apparently good prognosis ∼15% of high hyperdiploid (HD) childhood acute lymphoblastic leukemia (ALL) cases relapse. To search for responsible risk factors we determined copy number aberrations as well as copy neutral loss of heterozygosity (LOH) in 13 matched diagnosis and relapse samples and added the data of the only three available cases from the literature. Deletions and copy neutral LOH in 3 and 2 of the 16 cases directed us to the histone-modifying CREB-binding protein (CREBBP) gene, whose functional impairment is implicated in drug resistance. We therefore screened all samples for mutations in this gene and discovered 9 acquired sequence mutations in 7/16 cases, leading to an overall frequency of somatic CREBBP aberrations in HD ALL relapse cases of 63% that is considerably higher than that of the reported, mainly non-HD ALL (18.3%). Moreover, mutations in HD cases occur almost exclusively in the HAT domain (8/9; 89%). Hot spot mutations are present at diagnosis in 18.8% of relapsing HD ALL cases but in none of 40 respective cases remaining in long-term remission. Thus, the particular high incidence of CREBBP mutations in relapse-prone HD ALL cases could eventually be exploited for refined risk stratification and customized treatment in this genetic subgroup.

Concurrent FOXP3- and CTLA4-associated genetic predisposition and skewed X chromosome inactivation in an autoimmune disease-prone family.

CLTA4 is relevant for FOXP3(+)Treg cells, and the link between skewed X chromosome inactivation (XCI) and autoimmunity is recognized. The observation of immune dysregulation polyendocrinopathy enteropathy X-linked syndrome and multiorgan endocrine autoimmune phenomena in various members of one family, associated with a CTLA4 polymorphism and skewed XCI, provides an in vivo model of how mechanisms of immune dysregulation may cooperate.