Further evidence for deletions in 7p14.1 contributing to nonsyndromic cleft lip with or without cleft palate.

BACKGROUND: Nonsyndromic cleft with or without cleft palate (nsCL/P) is a common birth defect. Although genome-wide association studies (GWAS) have identified numerous risk variants, a considerable fraction of the genetic heritability remains unknown. The aim of the present study was to replicate a previous finding that de novo deletions in a 62 kb region of chromosome 7p14 are a risk factor for nsCL/P, using an independent cohort. METHODS: Data from a published case-control GWAS cohort of 399 patients and 1318 controls were used. Copy number variant (CNV) detection in the 62 kb candidate region of 7p14 was performed using QuantiSNP. Putative CNVs in probands were verified and validated by quantitative polymerase chain reaction. Segregation analyses were performed in family members for whom DNA was available. RESULTS: Within the 62 kb candidate region, a deletion of 7.4 kb showed association with nsCL/P (13/387 cases, 20/1300 controls, plowest = 0.024, odds ratio = 2.22). In all families with a sporadic case (n = 3), the deletion occurred de novo. In multiplex families, both incomplete segregation and incomplete penetrance were observed. CONCLUSION: The present data support the hypothesis that deletions at 7p14 are a common risk factor for nsCL/P. Genome-wide CNV analyses in nsCL/P cohorts are warranted to explore the functional relevance of these deletions and their contribution to nsCL/P, and to determine exact breakpoints. Birth Defects Research (Part A) 106:767-772, 2016. © 2016 Wiley Periodicals, Inc.

The importance of early diagnosis in patients with maxillary sinus carcinoma.

There are two major challenges in the early diagnosis of maxillary sinus carcinoma: the maxillary sinus is not susceptible to direct inspection and palpation, and symptoms are uncharacteristic. The aim of this study was to assess the impact of the time interval between first symptoms noticed by the patient and the detection of the tumor on survival. 88 patients with maxillary sinus tumors were included in the retrospective study. Prognostic factors were identified through univariate analysis. Univariate analysis (p = 0.019) revealed a significant impact of the time interval from first symptom to diagnosis on overall survival. With increasing duration of the symptoms 5-year overall survival was reduced from 65 % for duration between 0 and 2 months to 24 % for duration of symptoms longer than 12 months. Furthermore, we found a significant association (p = 0.033) between local extension of the tumor and time interval from first symptom to diagnosis. Early diagnosis is often difficult because of uncharacteristic symptoms, which are identical with benign diseases of the maxillary sinus. The delay between the occurrence of the first symptom and diagnosis often makes a curative treatment impossible.

Implant-based rehabilitation in oncology patients can be performed with high long-term success.

PURPOSE: Radiotherapy and compromised vital bone and/or surrounding soft tissue can be a challenge to the successful osseointegration of dental implants. We evaluated the long-term results of dental implants in patients with oral cancer. MATERIALS AND METHODS: To address the research purpose, we designed and implemented a retrospective cohort study that included patients with oral cancer who had received dental implants from 2003 to 2011. The data were collected from a clinical oncology database. The predictor variables included a set of heterogeneous variables grouped into logical sets of demographics, surgical treatment, dental rehabilitation, radiotherapy type, and tumor entity. The primary outcome variable was implant survival; the secondary outcome variable was peri-implantitis. The descriptive statistics, survival time analysis, Kaplan-Meier implant survival curves, and Cox hazard proportional modeling were computed. RESULTS: The study sample included 59 patients with oral cancer (20 women [33.9%], 39 men [66.1%]; mean age at tumor diagnosis, 55 years), who had had 272 implants placed during the study period. The mean follow-up period was 30.9 months (range 3 to 82). Of the 272 implants, 269 (98.9%) and 264 (97.1%) had survived for 2 and 5 years, respectively. During the observation period, 10 implants were lost (3.7%). Of the implant failures, 82% occurred in transplanted bone (4 fibula flaps, 4 iliac crests, and 2 native mandibles). We observed peri-implantitis caused by insufficiently attached gingiva and bone loss in 182 of the implants (67%). The factors associated with implant failure were peri-implantitis, insufficient soft and hard tissue, muscle dysfunction, and xerostomia. CONCLUSIONS: Implant-based rehabilitation in oncology patients can achieve a high long-term success rate, although risk factors such as impaired muscle function and a high frequency of peri-implantitis can affect healing.

Podoplanin expression in cutaneous head and neck squamous cell carcinoma--prognostic value and clinicopathologic implications.

BACKGROUND: Although most patients are cured by local treatment from cutaneous head and neck squamous cell carcinoma (cHNSCC), a significant number of patients develops metastases to the regional lymph nodes. Recent studies suggest an influence of podoplanin expression on regional lymph node metastases in other head and neck squamous cell carcinoma. The aim of our study was to assess the impact of podoplanin expression on regional lymph node metastasis, locoregional recurrence, and prognosis. METHODS: In this retrospective study, podoplanin expression was examined immunohistochemically in 63 treatment-naive patients with cHNSCC. We analyzed associations of podoplanin expression and clinicopathologic variables. Furthermore, we investigated the effects on overall survival (OS) and locoregional control in univariate and multivariate analysis. RESULTS: In 40 patients (63.5%), podoplanin was expressed in the tumor cells. The χ(2) -test revealed that podoplanin expression was associated with the number of tumorous lymph nodes (P < 0.001). The OS was significantly influenced by podoplanin expression (P < 0.001). None of the patients with high levels of podoplanin expression survived, whereas the 5-year OS for patients with podoplanin-negative tumors was 91.3%. CONCLUSIONS: We concluded that podoplanin is frequently expressed in cHNSCC and might serve as predictor for regional lymph node metastases, locoregional recurrence, and clinical outcome.

Concise review: induced pluripotent stem cells and lineage reprogramming: prospects for bone regeneration.

Bone tissue for transplantation therapies is in high demand in clinics. Osteodegenerative diseases, in particular, osteoporosis and osteoarthritis, represent serious public health issues affecting a respectable proportion of the elderly population. Furthermore, congenital indispositions from the spectrum of craniofacial malformations such as cleft palates and systemic disorders including osteogenesis imperfecta are further increasing the need for bone tissue. Additionally, the reconstruction of fractured bone elements after accidents and the consumption of bone parts during surgical tumor excisions represent frequent clinical situations with deficient availability of healthy bone tissue for therapeutic transplantations. Epigenetic reprogramming represents a powerful technology for the generation of healthy patient-specific cells to replace or repair diseased or damaged tissue. The recent generation of induced pluripotent stem cells (iPSCs) is probably the most promising among these approaches dominating the literature of current stem cell research. It allows the generation of pluripotent stem cells from adult human skin cells from which potentially all cell types of the human body could be obtained. Another technique to produce clinically interesting cell types is direct lineage reprogramming (LR) with the additional advantage that it can be applied directly in vivo to reconstitute a damaged organ. Here, we want to present the two technologies of iPSCs and LR, to outline the current states of research, and to discuss possible strategies for their implementation in bone regeneration.

Impact of anxiety parameters on prospective and experienced pain intensity in implant surgery.

PURPOSE: To investigate the relationship between anxiety and pain perception in the context of implant surgery and to examine the impact of factors such as gender and surgery duration on anxiety and pain levels. METHODS: One hundred twenty-one patients undergoing implant surgery evaluated their anxiety and pain levels by completing a set of 2 questionnaires at different points in time. RESULTS: Both anxiety and pain levels were highest on the day of surgery and showed a significant decrease when evaluated retrospectively (P < 0.01; P < 0.05). Correlations were found between preoperative anxiety and expected pain levels (r = 0.19), pain peak and duration of pain (r = 0.79), and a nearly significant correlation between preoperative anxiety and duration of pain (r = 0.18). Women showed significantly higher levels of preoperative anxiety (P < 0.05) and expected pain (P < 0.05) than men. CONCLUSION: The results confirm a strong negative impact of increased preoperative anxiety levels on pain perception and the recovery process. Therefore, future research should focus on individual patient's sources of dental anxiety to reduce its negative consequences.

Retrospective comparison of split-thickness skin graft versus local full-thickness skin graft coverage of radial forearm free flap donor site.

The study aimed at comparing outcomes between split-thickness skin graft (STSG) and local ipsilateral full-thickness skin graft (FTSG) after radial forearm free flap defect closure. A comprehensive study protocol for objective and subjective assessment was established for this retrospective, single-center study. Clinical examinations were carried out, encompassing measuring wrist and finger range of movement and grip strength, testing skin sensitivity, and evaluating aesthetics using the Patient and Observer Scar Assessment Scale (POSAS). In addition, medical history, and questionnaire, including Cold Intolerance Severity Score (CISS) and 18 items, were used to assess satisfaction, functional limitations, and complaints. 44 patients were examined, and 40 patients included, who had received STSG (group 1; n = 19) respectively local FTSG from the ipsilateral forearm (group 2; n = 21) at least three months previously. Significantly lower values for parameters pigmentation, relief (p = 0.015), overall impression (p = 0.044), as well as mean POSAS observer scale total score (p = 0.046) and no complaints wearing a wristwatch (p = 0.012) were shown in group 2 (FTSG). Within the limitations of the study, it seems that FTSG harvested from the forearm should be preferred over STSG to cover RFFF donor site whenever appropriate, because of beneficial outcomes, while providing single intervention closure and avoiding secondary donor site.

Combined-modality treatment in advanced oral squamous cell carcinoma: Primary surgery followed by adjuvant concomitant radiochemotherapy.

BACKGROUND: The efficacy of adjuvant radiochemotherapy (RCT) in patients with advanced stage head and neck carcinoma has been proven in prospective randomized trials. However, these trials focused on different head and neck sites. Specific analyses for treatment effects in squamous cell carcinoma of the oral cavity (OSCC) are missing. We evaluated our experiences with adjuvant concomitant RCT in advanced OSCC to compare the results with other treatment schemes using adjuvant RCT. PATIENTS AND METHODS: A total of 183 patients with OSCC of UICC stages II-IVb were reviewed retrospectively. All patients were treated with radical surgery followed by adjuvant, conventional fractionated concomitant RCT using carboplatin. Overall survival was plotted by Kaplan-Meier analysis. Prognostic factors were identified through univariate and multivariate analysis. RESULTS: Univariate analysis showed a significant impact of T, N, and UICC stage, histopathologic grading, surgical margins, extracaspular spread (ECS), and lymphangiosis carcinomatosa on overall survival (Table 3). Patients with stage IVa had a higher 5-year overall survival rate (42.8%) than patients with stage IVb (25.0%) (Figure 1). The differences were significant in multivariate analysis (p = 0.033) (Table 4). CONCLUSION: Adjuvant concomitant RCT is an effective treatment in patients with advanced stage OSCC. However, it remains unclear, which patients should be treated with adjuvant RCT. For patients with stage IVb, adjuvant RCT yields poor results. Prospective randomized trials are needed to confirm which patients should be treated with adjuvant RCT.

Prognostic value of the sixth edition of the UICC's TNM classification and stage grouping for oral cancer.

BACKGROUND: Carcinoma of the oral cavity is classified according to the TNM staging system of the UICC. The staging system is under continuous revision. The aim of our study was to assess the prognostic value of the UICC sixth edition for oral cancer, which was established in 2003. METHODS: Three-hundred treatment-naive patients with oral squamous cell carcinoma (OSCC) of stages I-IVb were reviewed retrospectively. Patients with stage-I disease were treated solely surgically, and patients with stage II-IVb received a multimodal treatment. Overall survival was plotted by Kaplan-Meier analysis. Prognostic factors were identified through univariate and multivariate analysis. RESULTS: Univariate analysis showed a significant impact of T stage (P = 0.009), N stage (P < 0.001), and UICC stage (P < 0.001) on overall survival. However, no statistical differences were observed between stages T4a and T4b (P = 0.176) and UICC stages IVa and IVb (P = 0.306). CONCLUSIONS: T stage, N stage, and UICC stage grouping are good predictors of overall survival in patients with OSCC. Neither the division of stage T4 into T4a and T4b in the sixth edition nor the split of stage IV into IVa and IVb showed significant differences in overall survival between the subgroups.

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.

Further evidence for the involvement of MYH9 in the etiology of non-syndromic cleft lip with or without cleft palate.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common birth defects and has a multifactorial etiology that includes both genetic and environmental components. MYH9, the gene coding for the heavy chain of non-muscle myosin II, has been considered as a good candidate gene in NSCL/P on the basis of its expression profile during craniofacial morphogenesis. Reports in an Italian sample, as well as in an ethnically mixed North American sample, of a positive association between single-nucleotide polymorphisms in the MYH9 gene and NSCL/P have provided further support for the role of MYH9 in the development of NSCL/P. In the present study, we aimed to replicate these findings by conducting a family-based association study with seven single nucleotide polymorphisms in MYH9 using a sample of 248 NSCL/P patients and their parents. Single marker analysis resulted in a highly significant association for rs7078. In haplotype analysis, the most significant result was obtained for the SNP combination (rs7078; rs2071731; rs739097; rs5995288). Our results thus confirm the potential involvement of MYH9 in the etiology of NSCL/P in our patients of Central European origin, although further studies are warranted to determine its exact pathogenetic role.

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.

Comparison of torque measurements and clinical handling of various surgical motors.

PURPOSE: Modern implant dentistry requires the application of torque during various treatment steps. This study investigated seven different surgical motors for the accuracy of the applied torque and their reliability. MATERIALS AND METHODS: The following surgical motors were evaluated: Chiropro 980 (Bienair), INTRAsurg 300 and INTRAsurg 500 (KaVo), Osseocare (Nobel Biocare), Surgic XT (NSK), Elcomed SA-200 C (W and H), and Osseo System (XO Dentalcare). The torque was measured during typical surgical and prosthetic procedures using a special load transfer mechanism for a torque gauge. For each setting, 30 measurements were made and means were calculated. RESULTS: The highest percentage shortfall was 20.5% at a set torque of 11.4 Ncm (absolute deviation of -2.4 Ncm). The highest percentage by which a torque was exceeded was 54.6% (absolute deviation of 5.5 Ncm). The lowest value for absolute shortfall was found to be -5.6 Ncm at a set torque of 45 Ncm. The highest absolute exceeded was 15 Ncm at a set torque of 40 Ncm. Potentially problematic torque values were identified in the low-torque-value setting, as the implant position may be changed if a machine driver applies excessive torque to the first-stage healing screw. In addition, in the indication of immediate loading in the high-set-torque group, torque values above the critical value of 50 Ncm may be unwittingly applied while working with a set torque of 40 Ncm. CONCLUSION: For most of the clinically relevant torque settings, precise values were measured, although a few devices delivered potentially problematic torque values for some of the indications.

Current concepts in cleft care: A multicenter analysis.

The current surgical techniques used in cleft repair are well established, but different centers use different approaches. To determine the best treatment for patients, a multi-center comparative study is required. In this study, we surveyed all craniofacial departments registered with the German Society of Maxillofacial Surgery to determine which cleft repair techniques are currently in use. Our findings revealed much variation in cleft repair between different centers. Although most centers did use a two-stage approach, the operative techniques and timing of lip and palate closure were different in every center. This shows that a retrospective comparative analysis of patient outcome between the participating centers is not possible and illustrates the need for prospective comparative studies to establish the optimal technique for reconstructive cleft surgery.

Influence of the volume of soft tissue herniation on clinical symptoms of patients with orbital floor fractures.

INTRODUCTION: One of the most important complications of orbital floor fractures is diplopia and restricted ocular movement. The role of the volume of soft tissue herniation on these clinical symptoms after orbital floor fractures is unclear and potentially may predict development of persistent clinical symptoms. Therefore the aim of this study was to assess pre- and postoperative complications associated to the volume of soft tissue herniation, with special interest to diplopia and bulbus motility impairment. MATERIAL AND METHODS: 204 untreated patients with orbital floor fractures from 2009 to 2011 were included in this retrospective study. Contingency tables and χ2-test were performed to analyze associations between two qualitative variables. p-Values p < 0.05 were considered as significant. Volume measurement was performed in a semiautomatic segmentation method with the software "ITK-Snap". RESULTS: The volume of soft tissue herniation correlated significantly with pre- and postoperative diplopia (p = 0.003; p = 0.002), persistent diplopia (p = 0.009) as well as pre- and postoperative bulbus motility impairment (both p < 0.001). Furthermore we found out significant associations between the volume of soft tissue herniation and pre- and postoperative complications depending on fracture type and reconstruction technique. CONCLUSIONS: Volume measurement of soft tissue herniation may help to predict postoperative complications, particularly bulbus motility restriction and persistent diplopia. The risk for these symptoms rises with increasing volume of soft tissue herniation after orbital floor fractures. Therefore we recommend for these patients within indication an early repair and/or closer observation.

Autofluorescence imaging in recurrent oral squamous cell carcinoma.

The survival of patients with oral cancer is decreased by locoregional recurrence after an initial multimodal treatment. In order to identify lesions in the oral cavity for a possible recurrence, clinical evaluation as well as MRI or CT scanning is advised. The evaluation of mucosa lesions is hampered by changes related to radio- and chemotherapy as well as reconstruction with tissue flaps. Several techniques for easier identification of tissue abnormalities in the oral cavity have been advocated as adjuncts in order to facilitate identification. Especially methods using altered tissue fluorescence have gained much interest during the last decade. The aim of our prospective study was to evaluate fluorescence properties of undiagnosed mucosa lesions with the VELscope device in patients with multimodal treated oral cancer prior to histological confirmation. In total, 41 patients with a history of oral squamous cell carcinomas (OSCC) (19 females and 22 males) with undiagnosed mucosa lesions where included in the study. After clinical evaluation, examination and documentation using the VELscope® device were performed. Then, an incisional biopsy was performed. An autofluorescence loss indicating a malignant or dysplastic mucosa condition could be detected in six patients (14.6 %); however, only one OSCC and one SIN revealed a complete autofluorescence loss. In four patients, OSCC was present in lesions with retained autofluorescence. Sensitivity and specificity for the VELscope® examination to identify malignant oral lesions by autofluorescence were 33.3 and 88.6 %, respectively. The positive and negative predictive values were 33.3 and 88.6 %, respectively. No statistical correlation between gender and lesion appearance versus autofluorescence loss could be detected. In contrast to mucosa lesions in patients with no prior treatment, the autofluorescence evaluation with the VELscope reveals no additional information in our analysis. Accordingly, invasive biopsies as gold standard are still needed to get sufficient evidence regarding potential malignancy in patients after multimodal treatment for oral cancer.

Clinical and histopathological staging in oral squamous cell carcinoma - Comparison of the prognostic significance.

BACKGROUND: In oral cancer the prognostic significance of clinical staging (cTNM) is regarded inferior to histopathologic staging (pTNM) after surgery. This is mainly due to the point that the quality of the cTNM strongly depends on the clinical and radiological examination techniques applied and the physician's experience. The aim of this study was to evaluate the prognostic quality of cTNM and pTNM in a single center cohort. METHODS: This retrospective study included 392 patients with treatment-naive oral squamous cell carcinoma (OSCC). All patients received primary surgery including a neck dissection. According to tumor stage and histopathologic risk factors patients received adjuvant radiotherapy (RT) or radiochemotherapy (RCT). Prognostic factors were identified in univariate analysis by using the log rank test and in multivariate analysis through Cox regression. RESULTS: Clinical and histopathologic staging showed concordance in 62% for the primary tumor and 59% for cN- and pN-classification. In 58% of the cases of discordance the primary tumor was overstaged. In case of discordance of metastatic spread to the cervical lymph nodes, lymph node involvement showed overstaging in 78%. In univariate analysis cT-, cN-, cT- and pT-classification had a significant impact (p<0.05) on overall survival (OS). In multivariate analysis only pT- and pN-classification had a significant impact on OS. CONCLUSION: Despite advances and modern radiologic techniques, pTNM has a higher prognostic quality than cTNM. Discordance between clinical and histopathologic staging was observed in up to 40%. When discordance was observed overstaging for clinical T-stage and clinical N-stage was more likely than understaging.

Moving the mandible in orthognathic surgery - A multicenter analysis.

Orthognathic surgery has always been a classical focus of maxillofacial surgery. Since more than 100 years, various surgical techniques for mandibular repositioning have been developed and clinically tested. Since the establishment of plate and screw osteosynthesis, orthognathic surgery became more stable and safe. Nowadays, different surgical methods for mobilising the mandible are existing. This international multicenter analysis (n = 51 hospitals) is providing first evidence based data for the current use of different surgical methods. The dominating techniques were Obwegeser/dal Pont (61%) followed by Hunsuck/Epker (37%) and Perthes/Schlössmann (29%). The main osteosynthesis materials were plates (82%), bicortical screws (23.5%), or a combination of both (5.9%). 47% of all centers reported to use several surgical methods at the same time, depending on the anatomical problem and the surgeon's preference. This shows that different surgical methods seem to work as comparable, safe, and reliable procedures in everydays clinical practise. On this basis, further prospective studies could evaluate possible advantages for our patients.

Effects of various chair-side surface treatment methods on dental restorative materials with respect to contact angles and surface roughness.

Available chair-side surface treatment methods may adversely affect prosthetic materials and promote plaque accumulation. This study investigated the effects of treatment procedures on three resin restorative materials, zirconium-dioxide and polyetheretherketone in terms of surface roughness and hydrophobicity. Treatments were grinding with silicon carbide paper or white Arkansas stone, blasting with prophylaxis powder and polishing with diamond paste. Surface roughness was assessed using confocal laser scanning. Hydrophobicity as measured by water contact angle was determined by computerized image analysis using the sessile drop technique. All of the specific surface treatments performed led to significant changes in contact angle values and surface roughness (Ra) values. Median contact angle values ranged from 51.6° to 114°. Ra values ranged from 0.008 µm to 2.917 µm. Air-polishing as well as other polishing procedures increased surface roughness values in all materials except zirconium dioxide. Polyetheretherketone displayed greatest change in contact angle values after air-polishing treatment.