Alexander Hemprich

Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24.

We conducted a genome-wide association study involving 224 cases and 383 controls of Central European origin to identify susceptibility loci for nonsyndromic cleft lip with or without cleft palate (NSCL/P). A 640-kb region at chromosome 8q24.21 was found to contain multiple markers with highly significant evidence for association with the cleft phenotype, including three markers that reached genome-wide significance. The 640-kb cleft-associated region was saturated with 146 SNP markers and then analyzed in our entire NSCL/P sample of 462 unrelated cases and 954 controls. In the entire sample, the most significant SNP (rs987525) had a P value of 3.34 × 10−24. The odds ratio was 2.57 (95% CI = 2.02–3.26) for the heterozygous genotype and 6.05 (95% CI = 3.88–9.43) for the homozygous genotype. The calculated population attributable risk for this marker is 0.41, suggesting that this study has identified a major susceptibility locus for NSCL/P.

Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate

We conducted a genome-wide association study for nonsyndromic cleft lip with or without cleft palate (NSCL/P) in 401 affected individuals and 1,323 controls, with replication in an independent sample of 793 NSCL/P triads. We report two new loci associated with NSCL/P at 17q22 (rs227731, combined P = 1.07 × 10−8, relative risk in homozygotes = 1.84, 95% CI 1.34–2.53) and 10q25.3 (rs7078160, combined P = 1.92 × 10−8, relative risk in homozygotes = 2.17, 95% CI 1.32–3.56).

Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci

We have conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed associations with all previously identified loci and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22). Analysis of phenotypic variability identified the first specific genetic risk factor for NSCLP (nonsyndromic cleft lip plus palate) (rs8001641; PNSCLP = 6.51 × 10−11; homozygote relative risk = 2.41, 95% confidence interval (CI) 1.84–3.16).

The role of surgical therapy in the management of intravenous bisphosphonates-related osteonecrosis of the jaw

OBJECTIVES Bisphosphonate-related osteonecrosis of the jaw (BRONJ) seems resistant to conventional treatment approaches. We report a study with a surgical concept characterized by resection of the necrotic bone followed by sufficient wound closure. STUDY DESIGN In a clinical study of 24 patients with 33 sites of BRONJ, the surgical basis of the treatment was as follows: (1) conservative treatment with antimicrobiological rinsing, (2) resection of the entire necrotic bone and smoothening of any sharp bone edges, and (3) coverage of the remaining bone by use of a bilayered wound closure. RESULTS In 88% of cases, BRONJ could be treated with success by use of this surgical therapy. Median follow-up was 60 weeks. There was no statistically significant difference between treatment results irrespective of whether or not bisphosphonate treatment was continued. CONCLUSION Because of the high success rate of this surgical technique it seems that patients with BRONJ may benefit from this approach.

Cytologic and DNA-cytometric early diagnosis of oral cancer

Objective. The aim of this prospective study was to report on the diagnostic accuracy of conventional oral exfoliative cytology taken from white‐spotted, ulcerated or other suspicious oral lesions in our clinic. In addition we checked DNA‐image cytometry as an adjuvant diagnostic tool. Our hypothesis is that DNA‐aneuploidy is a sensitive and specific marker for the early identification of tumor cells in oral brushings. Study design. 251 cytological diagnoses obtained from exfoliative smears of 181 patients from macroscopically suspicious lesions of the oral mucosa and from clinically seemingly benign oral lesions which were exisiced for establishing histological diagnoses were compared with histological and/or clinical follow‐ups of the respective patients. Additionally nuclear DNA‐contents were measured after Feulgen restaining using a TV image analysis system. Results. Sensitivity of our cytological diagnosis on oral smears for the detection of cancer cells was 94.6%, specificity 99.5%, positive predictive value 98.1% and negative predictive value 98.5%. DNA‐aneuploidy was assumed if abnormal DNA‐stemlines or cells with DNA‐content greater 9c were observed. On this basis the prevalence of DNA‐aneuploidy in smears of oral squamous cell carcinomas in situ or invasive carcinomas was 96.4%. Sensitivity of DNA‐aneuploidy in oral smears for the detection of cancer cells was 96.4%, specificity 100%, positive predictive value 100% and negative 99.0%. The combination of both techniques increased the sensivity to 98.2%, specificity to 100%, positive predictive value to 100% and negative to 99.5%. Conclusions. Brush cytology of all visible oral lesions, if they are clinically considered as suspicious for cancer, are an easily practicable, cheap, non‐invasive, painless, safe and accurate screening method for detection of oral precancerous lesions, carcinoma in situ or invasive squamous cell carcinoma in all stages. We conclude that DNA‐image cytometry is a very sensitive, highly specific and objective adjuvant tool for the early identification of neoplastic epithelial cells in oral smears.

Diagnostic value of nucleolar organizer regions (AgNORs) in brush biopsies of suspicious lesions of the oral cavity

Objective: The aim of this retrospective study was to report on the diagnostic accuracy of AgNOR‐analysis as an adjunctive diagnostic tool of conventional oral exfoliative cytology taken from suspicious lesions in our clinic. Study design: Cytological diagnoses obtained from brush biopsies of macroscopically suspicious lesions of the oral mucosa from 75 patients (final diagnoses: 53 histologically proven squamous cell carcinomas, 11 leukoplakias and other inflammatory oral lesions) and from 11 patients with normal mucosa as a negative control group were compared with histological and/or clinical follow‐ups. Five smears were doubtful and seven suspicious for tumor cells in the cytologic report. Number of AgNORs were counted in 100 squamous epithelial cell‐nuclei per slide after silver‐restaining. Results: Sensitivity of our cytological diagnosis alone on oral smears for the detection of squamous carcinomas was 92.5%, specificity 100%, positive predictive value was 100% and negative 84.6%. The best cut‐off value of the mean number of AgNOR dots per nucleus distinguishing benign from malignant cells was 4.8. The percentage of nuclei with more than three AgNORs had a cut‐off level of 70%. Applying these methods to twelve doubtful or suspicious cytological diagnoses we were able to correctly establish the diagnosis of malignancy in ten cases of histologically proven cancers and to reveal benignity in two histologically proven cases. Thus we achieved a positive and negative predictive value of 100% each. Conclusions: Smears from brushings of visible oral lesions, if clinically considered as suspicious for cancer, are an easily practicable, non‐invasive, painless, safe and accurate screening method for detection of oral cancerous lesions. We conclude that AgNOR‐analysis may be a useful adjunct to other methods in routine cytological diagnosis of oral cancer that can help to solve cytologically suspicious or doubtful cases. Colour figures can be viewed on http://www.esacp.org/acp/2003/25‐3/remmerbach.htm.

Management of osteoradionecrosis of the jaws: An analysis of evidence

AIM To review and discuss the management of jaw bone osteoradionecrosis (JORN) based on levels of evidence. METHODS The Medline/PUBMED and Cochrane search was performed to identify all studies on the management of JORN, published in English, French, and German during January 1975-October 2007. Only clinical researches were identified and classified into four levels of evidence before being examined. All references of the retrieved articles were analysed. FINDINGS Seventy three articles and their additional 45 citations were evaluated. Most of the eligible literature provided observational evidence. Hyperbaric oxygen therapy (HBOT) is an adjunct; however, its clinical usefulness remains controversial. A conservative approach should be limited to early-onset JORN, while radical surgery is indicated for an advanced or refractory lesion. Free tissue transfer is the reconstruction of choice for large defects without the need of HBOT. Some new technologies have also been studied, including ultrasound, biological molecules, distraction osteogenesis and antioxidant agents. CONCLUSIONS Most of the reports on the treatment of JORN offer weak evidence. Current information seems insufficient for establishing the definite treatment guideline; thus, well-designed studies with long-term clinical data are encouraged.

Positron-emission tomography imaging in the diagnosis of bisphosphonate-related osteonecrosis of the jaw

OBJECTIVES The purpose of this study was to investigate the sensitivity of F-18 fluoride and F-18 fluorodeoxyglucose (FDG) positron-emission tomography (PET) in the diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ), and to test their suitability for assessing the severity of BRONJ. STUDY DESIGN Nine patients with BRONJ were studied using F-18 fluoride and F-18 FDG PET. For analysis, 8 regions of interest (ROI) were defined in the jaws of each patient. Maximum count rates for each ROI in both PET examinations were analyzed. RESULTS In both studies, increased tracer enhancement was observed in regions with BRONJ. Uptake of fluoride significantly exceeded that of FDG. FDG uptake increased systematically, but not significantly, with increasing severity of BRONJ. CONCLUSION F-18 fluoride PET is a sensitive method for diagnosis of BRONJ. FDG PET could be useful for evaluation of the severity of BRONJ. Further studies are required to prove the specificity of the methods.

The saxon bisphosphonate register - therapy and prevention of bisphosphonate-related osteonecrosis of the jaws.

In 2009, a study group of three Saxon hospitals set up a Saxon register with the aim of including all patients with bisphosphonate (BP) medication. In addition, specific concepts for surgical approach were developed. The target is to define relevant treatment and prevention strategies of bisphosphonate-related osteonecrosis of the jaws (BRONJ) based on high patient population statistics. Since July 2009, all patients with oral or intravenous BP medication have been registered in the 3 Saxon hospitals. Data was systematically acquired in detailed forms. Totally, 258 patients (♂: 83, ♀: 175) were registered by October 2010. 100 patients out of this already had BRONJ which preferably affected the mandible (70%) and was mostly associated with intravenous medication. In 54 cases, treatment was carried out by surgery according to the strategy developed. The criterion for success was absence of symptoms at least for 3 months after surgery. The following stage-dependent success rates were obtained: stage I (13 patients) - 84.6%, stage II (22 patients) - 95.5%, stage III (14 patients) - 85.7%, stage IV (5 patients) - 80%. Under preventive aspects, teeth were extracted after a predefined scheme in 68 of all patients registered as being asymptomatic. No BRONJ was observed in 98.5%; the criterion also being absence of symptoms for a minimum period of 3 months after surgery. Surgical treatment is the treatment of choice in cases of BRONJ. Tooth extractions are rather unproblematic in asymptomatic patients if the predefined scheme is followed.

The role of HPV RNA transcription, immune response-related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer

Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA‐) are similar to HPV‐negative (DNA‐) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response‐related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA‐ tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53‐mutation status for patient stratification and identify associations of an immune response‐related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC.