[On the relevance of histopathology results in oropharyngeal cancer with mandibular involvement and the necessary imaging]. / Relevanz histopathologischer Untersuchungsergebnisse bei Oropharynxkarzinomen mit Unterkieferbeteiligung und die notwendige Bildgebung.

BACKGROUND: Planning of surgical procedures in patients suffering from oropharyngeal cancer requires appropriate imaging, particularly in consideration of the spatial relationship to the mandible. Resection of portions of the mandible (box, marginal, or segmental resection) is often necessary, while simultaneously avoiding overtreatment. Typically, a computed tomography (CT) scan is initially performed. However, the question arises of whether CT alone is adequate for reliable assessment of mandibular involvement. MATERIALS AND METHODS: A patient cohort of 25 individuals aged 44-79 years (mean 62 years) undergoing partial oropharyngeal resection with segmental mandibular resection was examined. The indication for segmental resection was based on the close relationship of the tumor to the mandible observed in imaging. Reconstruction was consistently carried out with a reconstruction plate and free or pedicled flaps. Preoperative radiological findings were compared with histopathology results after decalcification of the mandibular bone. RESULTS: Cortical tumor infiltration was observed in the mandible in 9 patients (36%). Preoperatively, clear bone infiltration had been identified in CT in only 2 of these 9 patients; in the remaining 7, only direct tumor contact with the mandible was evident. Magnetic resonance imaging (MRI) revealed bone infiltration in 1 of these 7 patients. DISCUSSION: Adhering to safety margins requires a radical surgical approach and reliable intraoperative frozen section analysis. However, at the bone level, intraoperative frozen section analysis is technically impractical due to the required decalcification. Only after decalcification can the entire specimen be assessed for tumor infiltration. In our cohort, a significant discrepancy in terms of bone infiltration was noted between preoperative imaging assessments and postoperative histopathology. CT preoperatively identified bone infiltration in only 8% of our patients. In two thirds of the specimens, no bone infiltration was evident after decalcification and histopathological processing, retrospectively indicating overtreatment by segmental resection; box or marginal resections may have been sufficient in these cases. Therefore, when tumors are adjacent to the bone in CT, MRI should also be performed preoperatively to more reliably detect bone infiltration.

Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft Palate.

Nonsyndromic cleft lip with/without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO) are the most frequent subphenotypes of orofacial clefts. A common syndromic form of orofacial clefting is Van der Woude syndrome (VWS) where individuals have CL/P or CPO, often but not always associated with lower lip pits. Recently, ∼5% of VWS-affected individuals were identified with mutations in the grainy head-like 3 gene (GRHL3). To investigate GRHL3 in nonsyndromic clefting, we sequenced its coding region in 576 Europeans with nsCL/P and 96 with nsCPO. Most strikingly, nsCPO-affected individuals had a higher minor allele frequency for rs41268753 (0.099) than control subjects (0.049; p = 1.24 × 10(-2)). This association was replicated in nsCPO/control cohorts from Latvia, Yemen, and the UK (pcombined = 2.63 × 10(-5); ORallelic = 2.46 [95% CI 1.6-3.7]) and reached genome-wide significance in combination with imputed data from a GWAS in nsCPO triads (p = 2.73 × 10(-9)). Notably, rs41268753 is not associated with nsCL/P (p = 0.45). rs41268753 encodes the highly conserved p.Thr454Met (c.1361C>T) (GERP = 5.3), which prediction programs denote as deleterious, has a CADD score of 29.6, and increases protein binding capacity in silico. Sequencing also revealed four novel truncating GRHL3 mutations including two that were de novo in four families, where all nine individuals harboring mutations had nsCPO. This is important for genetic counseling: given that VWS is rare compared to nsCPO, our data suggest that dominant GRHL3 mutations are more likely to cause nonsyndromic than syndromic CPO. Thus, with rare dominant mutations and a common risk variant in the coding region, we have identified an important contribution for GRHL3 in nsCPO.

A matched-pair analysis on survival and response rates between German and non-German cancer patients treated at a Comprehensive Cancer Center.

BACKGROUND: Research shows disparities in cancer outcomes by ethnicity or socio-economic status. Therefore, it is the aim of our study to perform a matched-pair analysis which compares the outcome of German and non-German (in the following described as 'foreign') cancer patients being treated at the Center for Integrated Oncology (CIO) Köln Bonn at the University Hospital of Bonn between January 2010 and June 2016. METHODS: During this time, 6314 well-documented patients received a diagnosis of cancer. Out of these patients, 219 patients with foreign nationality could be matched to German patients based on diagnostic and demographic criteria and were included in the study. All of these 438 patients were well characterized concerning survival data (Overall survival, Progression-free survival and Time to progression) and response to treatment. RESULTS: No significant differences regarding the patients' survival and response rates were seen when all German and foreign patients were compared. A subgroup analysis of German and foreign patients with head and neck cancer revealed a significantly longer progression-free survival for the German patients. Differences in response to treatment could not be found in this subgroup analysis. CONCLUSIONS: In summary, no major differences in survival and response rates of German and foreign cancer patients were revealed in this study. Nevertheless, the differences in progression-free survival, which could be found in the subgroup analysis of patients with head and neck cancer, should lead to further research, especially evaluating the role of infectious diseases like human papillomavirus (HPV) and Epstein-Barr virus (EBV) on carcinogenesis and disease progression.

The role of immediate versus secondary removal of the odontogenic focus in treatment of deep head and neck space infections. A retrospective analysis of 248 patients.

OBJECTIVES: Aim of this study was to investigate conditions and predisposing factors for head and neck infection progress regarding the length of stay (LOS) in hospital, with special emphasis on the time of removal of the odontogenic infection focus. MATERIAL AND METHODS: A 3-year retrospective study reviewed hospital records of 248 subjects who were treated under inpatient conditions with severe odontogenic infections who received surgical incisions, drainage, and intravenous (IV) antibiotics. Outcomes measured included age, gender, involved fascial spaces, LOS, number of infected spaces, antibiotics administered, and comorbidities. We precisely recorded the time between abscess incision and focus extraction. RESULTS: Removal of infection focus (tooth) in the same stay (1 stay, n = 106; group 1; mean 6.5 days ± 3) showed significantly higher (p = 0.042) LOS than extraction in a second stay (2 stays, n = 46; group 2; 5.3 ± 3.1). Group 3 patients showed infection after removal of teeth in outpatient management (1 stay ex-op, n = 96) and presented significantly lower LOS (5.6 ± 2.5) compared to group 1 (p = 0.0216). LOS of group 3 to group 2 patients showed no significance (p = 0.668). Infection expansion and diabetes showed a significant increase of LOS. CONCLUSION: Simultaneous removal of infection focus and abscess incision leads to the lowest LOS. If tooth extraction is performed after incision, subsequent focus extraction performed in a second stay shows lower overall-LOS than extraction at the same stay at later stage. CLINICAL RELEVANCE: Multiple factors tend to increase the LOS of patients with severe head and neck infections of odontogenic origin. Our data reveals the role of removal of odontogenic focus and additionally ranks further parameters that influence the LOS. Based on our findings, decisions regarding the surgical treatment can be recommended.

Eagle Syndrome: a Follow-Up Examination of Four Patients After Surgical Treatment Via Cervical Approach.

OBJECTIVE: Eagle syndrome is a rare pain syndrome caused by an elongated styloid apophysis or an ossified styloid ligament. It is characterized by a complex range of symptoms in head and neck region. The most effective treatment is surgical shortening of the styloid apophysis. The authors report of a follow-up examination of 4 patients after surgical treatment via cervical approach. METHODS: Retrospectively reviewed hospital records of 5 patients (4 females and 1 male), aged from 26 to 59 years old (mean age = 45.5 years) who underwent surgical shortening of the styloid process via cervical approach. Further, a paper-based survey of 4 patients was conducted, including a clinical questionnaire and 4 visual analogue scales, consisting of questions regarding postoperative pain. RESULTS: Period of follow-up ranged from 16 to 79 months (mean 53.75 months). All patients were asymptomatic at follow-up. None of the patients reported a visible scar or hypoesthesia in the affected area. The patients demonstrated low mean visual analogue scales for each item (facial pain: 0.6 ±â€Š1.2, foreign body sensation: 0.725 ±â€Š1.45, pain of throat and neck 1.35 ±â€Š1.58 and limitation of dietary habits: 0.75 ±â€Š1.5). None of the patients reported a resurgence of pain in the head and neck region so far. CONCLUSIONS: Surgical treatment via cervical approach appears to be an effective and safe option with low morbidity and mortality in the treatment of symptomatic Eagle syndrome of adults.

Nonsyndromic cleft lip with or without cleft palate: Increased burden of rare variants within Gremlin-1, a component of the bone morphogenetic protein 4 pathway.

BACKGROUND: The genes Gremlin-1 (GREM1) and Noggin (NOG) are components of the bone morphogenetic protein 4 pathway, which has been implicated in craniofacial development. Both genes map to recently identified susceptibility loci (chromosomal region 15q13, 17q22) for nonsyndromic cleft lip with or without cleft palate (nsCL/P). The aim of the present study was to determine whether rare variants in either gene are implicated in nsCL/P etiology. METHODS: The complete coding regions, untranslated regions, and splice sites of GREM1 and NOG were sequenced in 96 nsCL/P patients and 96 controls of Central European ethnicity. Three burden and four nonburden tests were performed. Statistically significant results were followed up in a second case-control sample (n = 96, respectively). For rare variants observed in cases, segregation analyses were performed. RESULTS: In NOG, four rare sequence variants (minor allele frequency < 1%) were identified. Here, burden and nonburden analyses generated nonsignificant results. In GREM1, 33 variants were identified, 15 of which were rare. Of these, five were novel. Significant p-values were generated in three nonburden analyses. Segregation analyses revealed incomplete penetrance for all variants investigated. CONCLUSION: Our study did not provide support for NOG being the causal gene at 17q22. However, the observation of a significant excess of rare variants in GREM1 supports the hypothesis that this is the causal gene at chr. 15q13. Because no single causal variant was identified, future sequencing analyses of GREM1 should involve larger samples and the investigation of regulatory elements.

Oral health-related quality of life (OHRQoL) and implant therapy: A prospective multicenter study of preoperative, intermediate, and posttreatment assessment.

The purpose of this multicenter continuation study was to use high patient numbers in order to generate reliable statements regarding the association between different implant indications and OHRQoL. Patients with various types of indication for dental implants, ranging from single tooth loss to edentulous jaws, were included. Quality of life relating to dental implants was assessed through the oral health impact profile (OHIP-G-21), which has a summary score from 0 to 20 in healthy patients. In total, 16 253 patients from 29 centers (European Centers for Dental Implantology (ECDI)) were involved in the study between 2009 and 2021.8251 patients (50.7%) completed the questionnaire after implant insertion, and 4996 patients (30.7%) after prosthodontic treatment. The average age was 54 years (range 18-88 years). Posterior single-tooth gap (28.5%) and free-end gap (27.8%) were the most frequent indications. The preoperative OHIP-G-21 score for all patients was 32.81 (SD 11.92), while the score during the healing period was 30.00 (SD 10.72), and after completion of treatment 27.24 (SD 9.26) (p < 0.001). The most significant improvements in OHIP-G-21 scores were in the indication of edentulous jaw (phase 1, 41.81 (SD 15.53); phase 2, 35.39 (SD 14.22); phase 3, 29.60 (SD 10.12) (p < 0.001). The study revealed significant improvements in the most frequently reported problems (chewing, serious concerns, appearance) (p < 0.001). Insertion of dental implants and prosthodontic rehabilitation led to an improved OHRQoL for patients with all indications for dental implants. Special attention should be paid to patients with edentulous jaw, since in comparison with other indications it had the greatest impact on improving OHRQoL. The psychological dissatisfaction scale of the OHIP-G-21 represented the most important factors for patients, and these scores were substantially influenced by implant therapy. Thus, treating physicians should increase their focus on these factors, in order to avoid dissatisfaction and increase the likelihood of complete implant therapy success.

Modified triaca-style wing osteotomy to correct facial asymmetry in a patient with horizontal growth-type condylar hyperplasia.

In this short communication, we suggest a slight modification of Albino Triaca's chin-wing osteotomy to vertically correct the inferior border of the mandible in a patient with horizontal growth-type facial asymmetry due to condylar hyperplasia.

Human α-defensin (DEFA) gene expression helps to characterise benign and malignant salivary gland tumours.

BACKGROUND: Because of the infrequence of salivary gland tumours and their complex histopathological diagnosis it is still difficult to exactly predict their clinical course by means of recurrence, malignant progression and metastasis. In order to define new proliferation associated genes, purpose of this study was to investigate the expression of human α-defensins (DEFA) 1/3 and 4 in different tumour entities of the salivary glands with respect to malignancy. METHODS: Tissue of salivary glands (n=10), pleomorphic adenomas (n=10), cystadenolymphomas (n=10), adenocarcinomas (n=10), adenoidcystic carcinomas (n=10), and mucoepidermoid carcinomas (n=10) was obtained during routine surgical procedures. RNA was extracted according to standard protocols. Transcript levels of DEFA 1/3 and 4 were analyzed by quantitative realtime PCR and compared with healthy salivary gland tissue. Additionally, the proteins encoded by DEFA 1/3 and DEFA 4 were visualized in paraffin-embedded tissue sections by immunohistochemical staining. RESULTS: Human α-defensins are traceable in healthy as well as in pathological altered salivary gland tissue. In comparison with healthy tissue, the gene expression of DEFA 1/3 and 4 was significantly (p<0.05) increased in all tumours - except for a significant decrease of DEFA 4 gene expression in pleomorphic adenomas and a similar transcript level for DEFA 1/3 compared to healthy salivary glands. CONCLUSIONS: A decreased gene expression of DEFA 1/3 and 4 might protect pleomorphic adenomas from malignant transformation into adenocarcinomas. A similar expression pattern of DEFA-1/3 and -4 in cystadenolymphomas and inflamed salivary glands underlines a potential importance of immunological reactions during the formation of Warthin's tumour.

Resequencing of VAX1 in patients with nonsyndromic cleft lip with or without cleft palate.

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all congenital anomalies, and has a multifactorial etiology involving both environmental and genetic factors. Recent genome-wide association studies (GWAS) identified strong association between a locus on chromosome 10q25.3 and NSCL/P in European samples. One gene at 10q25.3, the ventral anterior homeobox 1 (VAX1) gene, is considered a strong candidate gene for craniofacial malformations. The purpose of the present study was to provide further evidence that VAX1 is the causal gene at the 10q25.3 locus through identification of an excess of rare mutations in patients with NSCL/P. METHODS: The 5'UTR, complete coding regions, and adjacent splice sites of the two known VAX1 isoforms were sequenced in 384 patients with NSCL/P and 384 controls of Central European descent. Observed variants were investigated with respect to familial cosegregation or de novo occurrence, and in silico analyses were performed to identify putative effects on the transcript or protein level. RESULTS: Eighteen single-base variants were found, 15 of them rare and previously unreported. In the long VAX1 isoform, predicted functionally relevant variants were observed more often in NSCL/P cases, although this difference was not significant (p = 0.17). Analysis of family members demonstrated incomplete cosegregation in most pedigrees. CONCLUSION: Our data do not support the hypothesis that highly penetrant rare variants in VAX1 are a cause of NSCL/P. To determine whether VAX1 is the causative gene at 10q25.3 further research, in particular into the biologic function of its long isoform, is warranted. Birth Defects Research (Part A), 2012.

Pressure pain threshold and oral health-related quality of life implications of patients with alloplastic temporomandibular joint replacement--a prospective study.

PURPOSE: Alloplastic total temporomandibular joint replacement (TJR) for end-stage disease, congenital disorders, and after ablative surgery has been shown improve function and to decrease pain. The purpose of this study was to evaluate the pain pressure threshold (PPT) and oral health-related quality of life (OHRQoL) in patients undergoing alloplastic TJR. MATERIALS AND METHODS: Subjects requiring TJR from May 2007 through February 2011 were enrolled in the study. The PPT and OHRQoL were measured preoperatively and 2, 6, and 12 months postoperatively. The primary predictor variable was postoperative time (preoperatively and 2, 6, and 12 months postoperatively). The primary outcome variables were the PPT and OHRQoL. RESULTS: Seventeen subjects requiring TJR were enrolled in and completed the required 12-month follow-up. There was no difference in the PPT at any time point. There was a significant improvement in the OHRQoL domain of psychological discomfort (P = .04) at 12 months. Facial pain intensity, temporomandibular joint pain, mandibular function, and diet were also significantly improved at 12 months (P = .001). CONCLUSION: Alloplastic TJR appears to decrease pain, improve function and diet, and decrease psychological discomfort.

Mandibular kinematics in patients with alloplastic total temporomandibular joint replacement--a prospective study.

PURPOSE: The purpose was to analyze the mandibular patterns (condylar range of motion during opening; incisal range of motion during opening, lateral excursion, and protrusion; velocity during opening and closing; mandibular rotation angle during opening and closing) in patients with alloplastic total joint replacement (TJR). MATERIALS AND METHODS: Seventeen patients with different diagnoses resulting in condylar hypomobility (8 patients, 15 joints) and condylar instability (9 patients, 12 joints) had undergone alloplastic TJR. Data were recorded preoperatively and 2, 6, and at least 12 months postoperatively. For ordinal data comparison at different time points, the Wilcoxon signed-ranks test was used. RESULTS: Analysis of the kinematic data at least 12 months postoperatively showed in patients with condylar hypomobility a statistically significant increase in all measured data except the incisal range of motion lateral excursion. In patients with condylar instability, the results showed a statistically significant decrease for incisal range of motion protrusion and laterotrusion. A slight increase in condylar range of motion, incisal range of motion linear distance, and velocity during opening and closing was found. CONCLUSIONS: Even after successful alloplastic TJR, a complete restoration of normal joint function is not achievable. Nevertheless, the kinematic data indicate that alloplastic TJR results in an improved function in patients with joint hypomobility and in a decrease of abnormal hypermobility in patients with condylar instability.

Controversial Aspects of Diagnostics and Therapy of Arthritis of the Temporomandibular Joint in Rheumatoid and Juvenile Idiopathic Arthritis-An Analysis of Evidence- and Consensus-Based Recommendations Based on an Interdisciplinary Guideline Project.

Introduction: Due to potentially severe sequelae (impaired growth, condylar resorption, and ankylosis) early diagnosis of chronic rheumatic arthritis of the temporomandibular joint (TMJ) and timely onset of therapy are essential. Aim: Owing to very limited evidence the aim of the study was to identify and discuss controversial topics in the guideline development to promote further focused research. Methods: Through a systematic literature search, 394 out of 3771 publications were included in a German interdisciplinary guideline draft. Two workgroups (1: oral and maxillofacial surgery, 2: interdisciplinary) voted on 77 recommendations/statements, in 2 independent anonymized and blinded consensus phases (Delphi process). Results: The voting results were relatively homogenous, except for a greater proportion of abstentions amongst the interdisciplinary group (p < 0.001). Eighty-four percent of recommendations/statements were approved in the first round, 89% with strong consensus. Fourteen recommendations/statements (18.2%) required a prolonged consensus phase and further discussion. Discussion: Contrast-enhanced MRI was confirmed as the method of choice for the diagnosis of TMJ arthritis. Intraarticular corticosteroid injection is to be limited to therapy-refractory cases and single injection only. In adults, alloplastic joint replacement is preferable to autologous replacement. In children/adolescents, autologous reconstruction may be performed lacking viable alternatives. Alloplastic options are currently still considered experimental.

Risk estimation for a malignant transformation of oral lesions by S100A7 and Doc-1 gene expression.

The objective of this study was the correlation of Doc-1- and S100A7-gene expression in common oral lesions with their cancerous-transformation risk. Biopsies (n = 15 each) of healthy gingiva, irritation fibromas, leukoplakias and Oral squamous cell carcinoma (OSCCs) were obtained, and after RNA-extraction, transcripts of Doc-1 and S100A7 were quantified by RT-PCR. In comparison with the healthy gingiva, the expression of Doc-1 was decreased, whereas the expression of S100A7 was upregulated in all lesions. As the extent of Doc-1-inactivation and S100A7-overexpression is correlated with their biological behavior, the combined investigation of both genes could be a promising marker in intraoral lesions to estimate the risk for their malignant transformation.

Human beta-defensin-1, -2, and -3 exhibit opposite effects on oral squamous cell carcinoma cell proliferation.

The objective of this study was to investigate the impact of human beta-defensins (hBDs) on oral squamous cell carcinoma (OSCC) proliferation and hBD expression in vitro. BHY-OSCC cell lines were stimulated with hBD-1, -2, and -3. Proliferation of BHY cells was ascertained and hBD-mRNA expression was evaluated by real-time PCR. Proliferation of BHY cells decreased by 25% in response to hBD-1 stimulation but increased after stimulation with hBD-2 and -3. HBD-1 stimulation enhanced hBD-3 expression, whereas HBD-2 stimulation decreased early hBD-3 expression. HBD-3 stimulation enhanced hBD-1 expression. HBDs profoundly impact on OSCC proliferation and hBD expression in vitro. Therefore, hBD-1 might function as a tumor suppressor gene in OSCCs, while hBD-2 and -3 might be protooncogenes.

High α-defensin and S100A7 expression and missing DOC-1 down-regulation characterize irritation fibromas of the oral cavity and may counteract malignant transformation.

PURPOSE: The purposes of this study were to analyze the gene expression pattern of antimicrobial peptides, tumor suppressors, growth factors, matrix metalloproteases, and inflammatory cytokines and chemokines in oral irritation fibromas and to identify genes with protective effects against malignant transformation in benign proliferating tumors of the oral mucosa. MATERIALS AND METHODS: Biopsies of irritation fibromas (n = 15) and healthy gingiva (n = 15) were obtained during routine surgical procedures. RNA was extracted according to standard protocols, and transcription levels of CCL20, DEFA 1/3, DEFA 4, S100A7, DOC-1, interleukin (IL) 1ß, IL-6, IL-8, IL-10, tumor necrosis factor α, Cox-2, matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-3, MMP-8, MMP-9, transforming growth factor ß1, transforming growth factor α, and keratinocyte growth factor were analyzed by real-time polymerase chain reaction. In addition, immunostaining was performed to visualize the transcription products of the genes of interest in fibroma tissue as well as in healthy gingiva. RESULTS: The gene expression of S100A7 was 11.3-fold and that of DEFA 1/3 was 14-fold higher in irritation fibromas than in healthy gingiva, whereas the expression of MMP-3 and of inflammation markers IL-1ß, IL-6, IL-8, tumor necrosis factor α, and Cox-2 was reduced. Profound down-regulation of DOC-1 gene expression, characteristic for proliferating malignant tumors of the oral cavity, was in irritation fibromas not verifiable. CONCLUSIONS: Changes in the expression pattern of S100A7, DEFA 1/3, and MMP-3 seem to be involved in the development of irritation fibromas, whereas chronic inflammation might be of less importance. Overexpression of S100A7, but missing down-regulation of the tumor-suppressor gene DOC-1, might exert protective effects and counteract malignant transformation of benign, proliferating lesions of the oral cavity.

Digitally designed, personalized bone cement spacer for staged TMJ and mandibular reconstruction - Introduction of a new technique.

The aim of this paper is to introduce an innovative workflow for staged reconstruction of the mandible, including the temporomandibular joint (TMJ), using a temporary, patient-specific spacer. In cases of partial mandibular resection including disarticulation, sometimes needed to treat inflammatory bone disease, the spacer is intended to retain symmetry of the hard tissues, to preserve the soft tissues, and to act as a bactericidal agent. When complete healing of the affected surrounding tissues has occurred, final reconstruction using a patient-matched total TMJ endoprosthesis, in combination with an autogenous free bone flap, can be performed as a second-stage procedure. The crucial steps of the workflow are virtual surgical planning, manufacturing of a two-part silicone mold, and chairside manufacturing of the spacer using an established bone cement with gentamycin. The method was first introduced in two patients suffering from therapy-resistant chronic osteomyelitis. The presented protocol of staged surgery allows a much safer and predictable reconstruction compared with immediate reconstruction. The workflow also minimizes the potential risk of endoprosthesis infection - one of the major risks of implant failure.

Genome-wide linkage scan of nonsyndromic orofacial clefting in 91 families of central European origin.

Orofacial clefts are among the most common of all congenital disorders. Nonsyndromic cases of cleft lip with or without cleft palate (NSCL/P) and cleft palate only (NSCPO) are considered to have a multifactorial etiology which involves both genetic and environmental factors. We present the results of a genome-wide linkage scan in 91 families of central European descent with nonsyndromic orofacial clefts (NSC). The sample included 74 NSCL/P families, 15 NSCPO families, and 2 mixed families (a total of 217 affected and 230 unaffected individuals were genotyped). We genotyped 542 microsatellite markers (average intermarker distance = 6.9 cM). Multipoint nonparametric linkage analysis was performed using Allegro 2.0f. In addition to the factors investigated in previous genome-wide linkage analyses, we searched for sex-specific susceptibility loci, loci demonstrating parental imprinting and loci that are shared by NSCL/P and NSCPO. Several genomic regions likely to contain susceptibility loci for NSC were identified at the level of nominal significance. Some of these overlap with regions identified in previous studies. Suggestive evidence of linkage was obtained for the loci 4q21-q26 and 1p31-p21, with the chromosome 1 locus showing a male-specific genetic effect. Our study has identified promising chromosomal regions for the identification of NSC-associated genes, and demonstrates the importance of performing detailed statistical analyses which take into account complex genetic mechanisms such as sex-specific effects and genomic imprinting. Further research in large patient samples is necessary to identify factors common to NSCL/P and NSCPO.

IRF6 gene variants in Central European patients with non-syndromic cleft lip with or without cleft palate.

Variants in the interferon regulatory factor 6 (IRF6) gene have repeatedly been associated with non-syndromic cleft lip with or without cleft palate (NSCL/P). A recent study has suggested that the functionally relevant variant rs642961 is the underlying cause of the observed associations. We genotyped rs642961 in our Central European case-control sample of 460 NSCL/P patients and 952 controls. In order to investigate whether other IRF6 variants contribute independently to the etiology of NSCL/P, we also genotyped the non-synonymous coding variant V274I (rs2235371) and five IRF6-haplotype tagging single nucleotide polymorphisms (SNPs). A highly significant result was observed for rs642961 (P = 1.44 x 10(-6)) in our sample. The odds ratio was 1.75 [95% confidence interval (CI): 1.38-2.22] for the heterozygous genotype and 1.94 (95% CI: 1.21-3.10) for the homozygous genotype, values that are similar to those reported in a previously published family-based study. Our results thus confirm the involvement of the IRF6 variant, rs642961, in the etiology of NSCL/P in the Central European population. We also found evidence suggestive of an independent protective effect of the coding variant V274I. In order to understand fully the genetic architecture of the IRF6 locus, it will be necessary to conduct additional SNP-based and resequencing studies using large samples of patients.

A mathematical approach improves the predictability of length of hospitalization due to acute odontogenic infection: A retrospective investigation of 303 patients.

PURPOSE: Increasing rates of hospitalization of patients diagnosed with acute odontogenic infection have become a burden for public health care, with significant economic concerns. The aim of this study was to investigate factors that tend to prolong hospital length of stay (LOS) in the treatment of severe infections. We present a statistical model that enables the prediction of LOS by exposing the feasibility of the essential statistical determinants. MATERIALS AND METHODS: A 5-year retrospective study investigated records of 303 in-hospital patients with abscess of odontogenic origin. Time-to-event models were used to analyse data where the outcome variable is the time to the occurrence of a specific event. Here, the focus is on a statistical model for the prediction of LOS of patients. RESULTS: The group of all patients (n = 303) was analysed by considering seven characteristics of the patients (age, gender, spreading of infection, localization of infection focus, type of administered antibiotics, diagnosed diabetes mellitus, and existence of a remaining infection focus). Age (p = 0.049; rc = -0.007) and spreading of infection (p < 0.001; rc = -0.965) showed a significant impact on the LOS. Subjects were divided into two groups. Group A (n = 185) consisted of patients who presented with a severe odontogenic infection and not yet removed infection focus; group B were patients having undergone outpatient operative tooth removal (n = 118). To group A patients' data, two new risk factors ("days between abscess incision and removal of infection focus" = dbir and "removal of infection focus during the same stay as abscess incision" = riss) replaced the risk factors "remaining infection focus." A significant impact on the LOS was detected for dbir (p < 0.001; rc = -0.15) and riss (p < 0.001; rc = -1.76). Our statistical model explicitly describes how the probability for discharge depends on the time and how specific characteristics affect the LOS. We observed a significantly higher LOS in older patients and subjects with infection spreading. In group A patients, dbir and riss had a highly significant impact on the LOS. CONCLUSION: Predicting the LOS may promote transparency to costs and management of patients under inpatient treatment. Our statistical model describes the probability of a discharge at time t compared to a discharge later than t (a LOS longer than t). Furthermore, the model enables a prediction of the LOS of each patient for practitioners in an easy way.