Significance of bisphosphonates on angiogenesis in vivo and their effect under geranyl-geraniol addition - could it alter the treatment of bisphosphonate-associated necrosis of the jaw?

PURPOSE: The aim of this study was to contribute to the understanding of the inhibitory effects of bisphosphonates on tissues, with a special focus on angiogenesis. Referring to bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ), it should be shown that the local addition of the isoprenoid geranyl-geraniol (GGOH) prevents vascularization processes. METHODS: A mouse model with n = 24 animals which received an injection of a collagen matrix was used. In 4 subgroups (n = 6), we examined the effect of zoledronate on the sprouting of capillary-like structures into the matrix, with and without the presence of geranyl-geraniol, as well as testing against control groups with PBS injections or collagen matrix containing PBS instead of GGOH. This was followed by a histological evaluation of the capillary-like structures. RESULTS: Zoledronate inhibits the sprouting of blood vessels into a collagen matrix in vivo; in the presence of GGOH this effect is significantly weakened by a factor of 3.9 (p = 0.00068). CONCLUSION: This work commits to the investigation of the pathophysiology of BP-ONJ and shows a possible causal therapeutic path via the topical application of GGOH.

Isolated Hypoglossal Nerve Palsy as an Early Symptom of a Granular Cell Tumor.

BACKGROUND: Hypoglossal nerve palsy (HNP) is rather common as a neurological disease. However, as an isolated nerve palsy it is an exceedingly rare phenomenon and points at local pathologies along the peripheral course of the nerve. In this communication we report a granular cell tumor (GCT) arising in the submandibular segment of the hypoglossal nerve. CASE-REPORT: Spontaneous isolated HNP was recognized in a female patient. First line MR-imaging identified a clivus-chordoma. However, involvement of the hypoglossal nerve was highly unlikely according to MR-findings. Finally, ultrasonographic investigation revealed a small submandibular mass which, at histological examination, turned out to be a granular cell tumor arising within the hypoglossal nerve. CONCLUSIONS: This is the report of an extremely rare GCT originating within the 12th cranial nerve. The case illustrates that isolated motoric cranial nerve palsy may result from this rare tumor entity. This report also points out the diagnostic value of a simple ultrasonographic investigation to depict pathologic lesions of the submandibular space.

Molecular defects in BRAF wild-type ameloblastomas and craniopharyngiomas-differences in mutation profiles in epithelial-derived oropharyngeal neoplasms.

The aim of this study was to evaluate the mutation profile of BRAF wild-type craniopharyngiomas and ameloblastomas. Pre-screening by immunohistochemistry and pyrosequencing for identifying BRAF wild-type tumors was performed on archived specimens of ameloblastic tumors (n = 20) and craniopharyngiomas (n = 62). Subsequently, 19 BRAF wild-type tumors (nine ameloblastic tumors and ten craniopharyngiomas) were analyzed further using next-generation sequencing (NGS) targeting hot spot mutations of 22 cancer-related genes. Thereby, we found craniopharyngiomas mainly CTNNB1 mutated (8/10), including two FGFR3/CTNNB1-double mutated tumors. Ameloblastic tumors were often FGFR2 mutated (4/9; including one FGFR2/TP53/PTEN-triple mutated case) and rarely CTNNB1/TP53-double mutated (1/9) and KRAS-mutated (1/9). In the remaining samples, no mutation could be detected in the 22 genes under investigation. In conclusion, mutation profiles of BRAF wild-type craniopharyngiomas and ameloblastomas share mutations of FGFR genes and have additional mutations with potential for targeted therapy.

Nasolabial Flap Improves Healing in Medication-Related Osteonecrosis of the Jaw.

PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) is an adverse side effect of antiresorptive and antiangiogenic therapeutic agents that is difficult to treat owing to its high relapse rate. The aim of the present study was to determine whether patients with MRONJ treated using decortication and a nasolabial flap compared with those who underwent decortication with mucoperiosteal flaps have better outcomes regarding stable wound closure. MATERIALS AND METHODS: Two groups of patients with MRONJ and intraoral exposed bone were evaluated in a cohort clinical study retrospectively. The primary predictor variable was the treatment group. The experimental group used the nasolabial flap for wound closure, and the control group used the mucoperiosteal flap for closure. The outcome variable was successful wound closure defined as a symptomless and closed wound after at least 12 months. Other study variables included factors such as perioperative drug holiday, duration of postoperative oral antibiotic administration, and postoperative use of nasogastric feeding tubes. Cox proportional hazard regression analysis and Kaplan-Meier curves were used to determine the factors independently associated with the dependent variable. The Mann-Whitney U test and χ2 test were used for analyses regarding group-related data. RESULTS: Both groups showed similar demographics. The 16 study patients receiving nasolabial flaps had a mean age of 69.9 years, and the 16 control patients receiving mucoperiosteal flaps had a mean age of 71.8 years. Both groups included 10 women and 6 men. Of the 16 patients in each group, 15 had received a bisphosphonate and 1, monoclonal antibody therapy. All evaluated patients underwent combined treatment, including decortication and intravenous antibiotics. Of the 16 patients receiving nasolabial flaps, symptomless intact wound closure was achieved in 68.8%. Of the 16 patients with mucoperiosteal closure, 18.7% achieved wound closure, with 81.2% developing a relapse of MRONJ, a statistically significant difference (P < .001). No statistically significant differences were found between the 2 groups in the demographic variables. The mean interval to relapse for the experimental and control groups was 13.6 ± 7.8 and 8.2 ± 7.9 months, respectively (P = .017). CONCLUSIONS: MRONJ is a complication of antiosteoclastic treatment of mostly oncologic, palliative patients, which requires a very methodical approach to surgical treatment. A variety of different methods have been reported. The use of nasolabial flaps can be considered as a highly reliable option for coverage the bone wound with less morbidity than microvascular free flaps and better long-term results compared with mucoperiosteal flaps.

3D-Printed Simulation Device for Orbital Surgery.

OBJECTIVES: Orbital surgery is a challenging procedure because of its complex anatomy. Training could especially benefit from dedicated study models. The currently available devices lack sufficient anatomical representation and realistic soft tissue properties. Hence, we developed a 3D-printed simulation device for orbital surgery with tactual (haptic) correct simulation of all relevant anatomical structures. DESIGN, SETTING, AND PARTICIPANTS: Based on computed tomography scans collected from patients treated in a third referral center, the hard and soft tissue were segmented and virtually processed to generate a 3D-model of the orbit. Hard tissue was then physically realized by 3D-printing. The soft tissue was manufactured by a composite silicone model of the nucleus and the surrounding tissue over a negative mold model also generated by 3D-printing. The final model was evaluated by a group of 5 trainees in oral and maxillofacial surgery (1) and a group of 5 consultants (2). All participants were asked to reconstruct an isolated orbital floor defect with a titanium implant. A stereotactic navigation system was available to all participants. Their experience was evaluated for haptic realism, correct representation of surgical approach, general handling of model, insertion of implant into the orbit, placement and fixation of implant, and usability of navigated control. The items were evaluated via nonparametric statistics (1 [poor]-5 [good]). RESULTS: Group 1 gave an average mark of 4.0 (±0.9) versus 4.6 (±0.6) by group 2. The haptics were rated as 3.6 (±1.1) [1] and 4.2 (±0.8) [2]. The surgical approach was graded 3.7 (±1.2) [1] and 4.0 (±1.0) [2]. Handling of the models was rated 3.5 (±1.1) [1] and 4 (±0.7) [2]. The insertion of the implants was marked as 3.7 (±0.8) [1] and 4.2 (±0.8) [2]. Fixation of the implants was also perceived to be realistic with 3.6 (±0.9) [1] and 4.2 (±0.45) [2]. Lastly, surgical navigation was rated 3.8 (±0.8) [1] and 4.6 (±0.56) [2]. CONCLUSION: In this project, all relevant hard and soft tissue characteristics of orbital anatomy could be realized. Moreover, it was possible to demonstrate that the entire workflow of an orbital procedure may be simulated. Hence, using this model training expenses may be reduced and patient security could be enhanced.

Cytogenetic and immunohistochemical biomarker profiling of therapy-relevant factors in salivary gland carcinomas.

OBJECTIVES: There is currently no established algorithm for the molecular profiling of therapy-relevant defects in salivary gland carcinomas (SGC). HER2 overexpression in a subfraction of SGC and low frequencies of EGFR mutations are known. Here, we established receptor and cell signalling profiles of 17 therapy-relevant factors and propose a molecular diagnostic algorithm for SGC. MATERIALS AND METHODS: Formalin-fixed and paraffin-embedded tissue samples from SGC (n = 38) were analysed with immunohistochemistry and fluorescence in situ hybridisation (FISH). RESULTS: Two or more expressed receptors and/or receptor gene amplification were detectable in eight of 38 (21%) tumours: HER2 3+/AR 1+, HER3 gene amplification/AR 1+/EGFR 1+, ER 3+/AR 1+, EGFR 2+/PR 1+ and EGFR 2+/PR 1+/AR 1+. No FGFR1-3, MET, ALK1, ROS1, RET, BRAF nor VEGFA defects were detectable, and ERCC1 was not overexpressed. No PD1+ tumour-infiltrating T cells were detectable. CONCLUSION: Personalised therapy of patients with salivary gland carcinomas should include HER2 and EGFR signalling testing and, in negative cases, evaluation of rare potential target molecules. ERCC1 and PD1 do not appear to be reliable markers for the decision for or against chemotherapy or immunotherapy, respectively.

Post-transplant lymphoproliferative disorders with naso- and oropharyngeal manifestation.

The nasopharyngeal/oropharyngeal lymphatic tissues represent the anatomical site of Epstein-Barr virus (EBV) entry. Post-transplant lymphoproliferative disorders (PTLD) are often associated with EBV, but little is known about the characteristics of nasopharyngeal/oropharyngeal mass-forming PTLD. Retrospective evaluation of our own PTLD database (n = 79) and the PubMed(®) database (n = 61) has been performed. Sinonasal/oro-/nasopharyngeal lymphatic masses were early lesions (n = 54/140, 38.5%), polymorphic PTLD (n = 32/140, 23%), monomorphic B-PTLD (n = 47/140, 33.5%) and T-PTLD (n = 7/140, 5%). One-fourth of lesions manifested as masses in the Waldeyer's ring, and in two-thirds of cases, swelling of tonsils was related to manifestation of benign early lesions. Tonsil infiltration by polymorphic PTLD and monomorphic PTLD was present in one-third of cases. Extratonsillar masses were mainly monomorphic PTLD. Meta-analysis of our data in combination with previously published data revealed that lung transplantation and young patients are at a higher risk for earlier manifestation of monomorphic PTLD. Therapy is similar to PTLD therapy strategies, in general reduced immunosuppression and chemotherapy for polymorphic and monomorphic PTLD, and diagnostic and therapeutic surgical gross tumour resection of tonsillar/adenoid lesions. In summary, it is relevant for the clinical differential diagnosis that oro-/nasopharyngeal aggressive PTLD manifested in ~30% as tonsillar masses and >90% at extratonsillar sites.

Aberrant expression of caspase 14 in salivary gland carcinomas.

OBJECTIVES: Caspase 14 is reduced in adenocarcinomas of the stomach and colon. In contrast, breast and lung adenocarcinomas frequently show an overexpression of caspase 14. Salivary gland adenocarcinomas have not been evaluated for potential aberrant caspase 14 expression. MATERIALS AND METHODS: Samples from salivary gland carcinomas (n = 43) were analysed by immunohistochemistry (caspase 14, filaggrin, GATA3 and Ki67) and fluorescence in situ hybridization. RESULTS: Caspase 14 is not expressed in normal salivary glands, while in a subfraction of carcinomas (32%) an aberrant expression was found. Filaggrin could not be detected. Caspase 14 staining was not associated with tumour dedifferentiation, GATA3 expression or amplification of gene locus 19p13. CONCLUSION: In summary, aberrant expression of caspase 14 can be found in a subfraction of salivary gland carcinomas but could not be used as a biomarker for a specific carcinoma subtype of the salivary gland.

Expression of cyclin-dependent kinase inhibitor 2A 16, tumour protein 53 and epidermal growth factor receptor in salivary gland carcinomas is not associated with oncogenic virus infection.

It is known that human papillomavirus (HPV) infection can cause squamous cell neoplasms at several sites, such as cervix uteri carcinoma and oral squamous carcinoma. There is little information on the expression of HPV and its predictive markers in tumours of the major and minor salivary glands of the head and neck. We therefore assessed oral salivary gland neoplasms to identify associations between HPV and infection-related epidermal growth factor receptor (EGFR), cyclin-dependent kinase inhibitor 2A (CDKN2A/p16) and tumour protein p53 (TP53). Formalin-fixed, paraffin-embedded tissue samples from oral salivary gland carcinomas (n=51) and benign tumours (n=26) were analysed by polymerase chain reaction (PCR) analysis for several HPV species, including high-risk types 16 and 18. Evaluation of EGFR, CDKN2A, TP53 and cytomegalovirus (CMV) was performed by immunohistochemistry. Epstein-Barr virus (EBV) was evaluated by EBV-encoded RNA in situ hybridisation. We demonstrated that salivary gland tumours are not associated with HPV infection. The expression of EGFR, CDKN2A and TP53 may be associated with tumour pathology but is not induced by HPV. CMV and EBV were not detectable. In contrast to oral squamous cell carcinomas, HPV, CMV and EBV infections are not associated with malignant or benign neoplastic lesions of the salivary glands.

Modified technique for rehabilitation of facial paralysis using autogenous fascia lata grafts.

PURPOSE: In this retrospective study we used a modified surgical technique for midface reanimation in patients with facial nerve paralysis. Facial atonicity can cause functional impairment regarding speech articulation, oral competence, breathing, and eyelid closure. Furthermore, esthetic and psychological aspects play an important role in patients' emotional interaction and social integration. The chosen rehabilitative technique should offer support against prolapse of facial structures and remedy of functional disabilities and, thereby, prevention of social stigmatization due to disease-related changes in appearance. MATERIALS AND METHODS: Between 2005 and 2013, fascia lata grafts were used as static support in 15 cases of unilateral facial paralysis. Two fascia lata grafts were subcutaneously inserted in the upper and lower lips crossing the midline and sutured at 4 points, including the unaffected part of the orbicularis oris muscle and modiolus. The slings were suspended against the zygomatic arch with an osteosynthesis plate. RESULTS: The patients perceived surgery results as considerably improving their appearance, speech, and alimentation. In 93.3% of cases, no postoperative complications occurred. The follow-up results (8 months to 8 years) remained stable. CONCLUSIONS: This retrospective study showed the advantages of static facial reanimation in appropriate cases. The bony fixated support of the fascial slings allows an immediate improvement of facial symmetry. Additional attachment points including the unaffected part of the orbicularis oris muscle and the use of 2 independent fascia lata slings allow a more accurate adjustment of suspension forces and an incomplete dynamic reanimation of the mouth corner. With respect to its simplicity and minimal invasiveness, this surgical procedure is associated with low morbidity and rapid improvement of the patient's esthetic appearance.

Subperiosteal preparation using a new piezoelectric device: a histological examination.

INTRODUCTION: Subperiosteal preparation using a periosteal elevator leads to disturbances of local immunohistochemistry and periosteal histology due to a microtrauma. Usually soft-tissue damage can be considerably reduced by using piezoelectric technology. For this reason, the effects of a novel piezoelectric device on immunohistochemistry and periosteal histology were examined and compared to conventional preparation of the periosteum using a periosteal elevator. MATERIAL AND METHODS: Lewis rats were randomly assigned to one of five groups (n=50). Subperiosteal preparation was performed using either a piezoelectric device or a periosteal elevator. Immunohistochemical and histological analyses were performed immediately after preparation as well as three and eight days postoperatively. A statistical analysis of the histological colouring was performed offline using analysis of variance (ANOVA) on ranks (p<0.05). RESULTS: At all times, immunohistochemical and histological analysis demonstrated a significantly more homogenous tissue structure in the group of rats that underwent piezosurgery than in the group of rats that underwent treatment with a periosteal elevator. CONCLUSION: The use of a piezoelectric device for subperiosteal preparation is associated with more harmonious immunohistochemical and histological results for the periosteum than the use of a conventional periosteal elevator. As a result, piezoelectric devices can be expected to have a positive effect primarily on soft tissue, in particular of the periosteal as well as on surrounding tissues.

Advances in assessing the volume of odontogenic cysts and tumors in the mandible: a retrospective clinical trial.

PURPOSE: To compare two methods of creating three-dimensional representations of mandibular cysts and tumors on the basis of computed tomography (CT) and cone beam computed tomography (CBCT) data. METHODS: A total of 71 patients with acquired jaw cysts took part in this retrospective clinical study. CT and CBCT scans were obtained from all patients and saved in the Digital Imaging and Communications in Medicine (DICOM) format. Data were analyzed twice with iPlan software. Analysis was performed manually and using an interpolarization algorithm. The accuracy of the two methods in assessing cyst volume was compared. RESULTS: Manual delineation did not provide more accurate results than the interpolarization algorithm. CONCLUSION: There are no major differences between manual analysis and analysis using the interpolarization algorithm. The use of the algorithm, however, has the advantage of rapidity.

Orbital lymphoma: diagnostic approach and treatment outcome.

BACKGROUND: Lymphomas of the orbit and orbital adnexae are rare tumors, comprising only 1% of all non-Hodgkin's lymphoma. The majority of non-Hodgkin's lymphomas of the orbit are extranodal marginal-zone B-cell lymphomas of mucosa-associated lymphoid tissue type. Because of nonspecific clinical signs and symptoms, some diagnostic delay may occur. The purpose of the study was to evaluate the diagnostic approach in orbital lymphomas and to analyze their treatment outcome. METHODS: In the period from 2005 to 2012, from a group of 135 patients with tumors of the orbit, we identified 11 patients diagnosed with orbital lymphoma. This patient cohort was reviewed retrospectively. RESULTS: The patient group consisted of 11 patients (seven females, male males) with a median age of 57.7 years (range 42 to 88 years). Orbital swelling, pain and motility impairment were the leading clinical symptoms. Diagnosis was confirmed by surgical biopsy. Depending on the anatomic location of the tumor, a surgical biopsy was taken using a blepharoplasty incision, a lateral orbitotomy or a navigation-guided biopsy. The predominant histology was extranodal non-Hodgkin's lymphoma of mucosa-associated lymphoid tissue type (82%). All patients underwent complete clinical staging. These were clinical stage IEA in seven patients, and stages IIEA (n = 2) and IIIEA (n = 2) in four patients . Patients in stage IEA were treated with radiation therapy alone, with radiation doses between 25 and 40 Gy, and patients with stage IIEA received systemic chemotherapy with bendamustin/rituximab. Those two patients diagnosed with diffuse large B-cell lymphoma and mantle cell lymphoma received systemic chemotherapy according to the R-CHOP protocol. CONCLUSIONS: Owing to unspecific clinical symptoms, some diagnostic delay may occur in orbital lymphoma. If unspecific orbital symptoms are present, adequate imaging studies followed by early surgical biopsy will contribute to early diagnosis. Once diagnosis is established and staging is complete, radiation therapy is the recommended treatment for stage IEA patients. Systemic chemotherapy is indicated in selected stage IIEA patients and in patients with stage IIIEA disease.

Optic nerve monitoring.

Orbital and anterior skull base surgery is generally performed close to the prechiasmatic visual pathway, and clear strategies for detecting and handling visual pathway damage are essential. To overcome the common problem of a missed clinical examination because of an uncooperative or unresponsive patient, flash visual evoked potentials and electroretinograms should be used. These electrophysiologic examination techniques can provide evidence of intact, pathologic, or absent conductivity of the visual pathway when clinical assessment is not feasible. Visual evoked potentials and electroretinograms are thus essential diagnostic procedures not only for primary diagnosis but also for intraoperative evaluation. A decision for or against treatment of a visual pathway injury has to be made as fast as possible due to the enormous importance of the time elapsed with such injuries; this can be achieved additionally using multislice spiral computed tomography. The first-line conservative treatment of choice for such injuries is megadose methylprednisolone therapy. Surgery is used to decompress the orbital compartment by exposure of the intracanalicular part of the optic nerve in the case of optic canal compression. Modern craniomaxillofacial surgery requires detailed consideration of the diagnosis and treatment of traumatic visual pathway damage with the ultimate goal of preserving visual acuity.

Surgical treatment of bisphosphonate-associated osteonecrosis of the jaw: technical report and follow up of 21 patients.

INTRODUCTION: Bisphosphonates are used to reduce skeletal related events in patients with bone consuming diseases such as osteoporosis and bone metastases. However recently there has been an increased awareness of bisphosphonate-associated necrosis of the jaws (BP-ONJ). Many authors propose conservative management in these cases but invariably the problem is not treated successfully allowing the bone defect to worsen. Recently there has been a move to treat this problem surgically. The aim of this retrospective study was to provide a surgical solution for patients suffering from BP-ONJ. MATERIALS AND METHODS: All patients presenting with BP-ONJ were treated with bone debridement of the affected area and multilayer wound closure. The considered variables were: gender, age, underlying diagnosis, type of bisphosphonate (BP) used, duration of bisphosphonate use, route of administration, location of the osteonecrosis, clinical symptoms, association with dental treatment and surgical outcome. RESULTS: Nineteen cases of a total of 21 demonstrated no recurrence of osteonecrosis during follow up (Mean 16 months - Range 12-24 months). One patient with a bilateral defect showed a dehiscence on one side and a small fistula on the contralateral side 6 weeks post-operatively and required revision surgery. Another patient developed a fistula after 4 weeks that was treated successfully with antibiotics and curettage. No patients had evidence of exposed bone, bland mucosa nor pain at the surgical site. CONCLUSION: The technique described can be recommended for patients with BP-ONJ if a conservative treatment fails.

Bisphosphonate-associated osteonecrosis of the mandible: reliable soft tissue reconstruction using a local myofascial flap.

For the treatment of bisphosphonate-associated osteonecrosis of the jaw (BP-associated ONJ), poor cure rates are reported. In many cases, repeated osseous exposition and infection may occur. The currently recommended management of affected patients is antibiotic treatment and bony decortication, which is often complicated by soft tissue deficits due to chronic infection. In severe cases osteonecrosis can be managed often only by continuity resections of the mandible. For this purpose, we developed a new surgical procedure, which allows an effective closure of difficult jaw wounds in the lateral mandible. In the last 3 years, 20 patients with BP-associated osteonecrosis of the lower jaw were treated successfully with a modified defect-covering method using a myofascial flap. A mylohyoid muscle flap was detached from mylohyoid line and used to cover the bony defect. During 19 months mean follow-up, 90% of patients were asymptomatic, the oral mucosa was intact, and no exposed bone was observed. In consequence, we are able to demonstrate that a mylohyoid muscle flap provides a reliable wound closure in the lower jaw in patients treated with BPs. Although there are still no consensual therapy guidelines for patients affected by BP-associated ONJ, the results of the presented study provide evidence for an effective surgical therapy with long-term success. Covering compromised bone with well-vascularized tissue, a muscle flap, increased healing chances by enabling and supporting the necessary nutrition and defense against opportunistic infections. This therapy concept showed a good clinical outcome.

Treatment of mandibular high-flow vascular malformations: report of 2 cases.

Two cases of high-flow vascular malformations affecting the mandible are presented. Manifesting mainly in childhood, intraosseous arteriovenous malformations are extremely rare morphologic errors of vascular morphogenesis that can lead to life-threatening hemorrhage without appropriate treatment. A dentist referred an 8-year-old girl with radiolucency in the left mandible and supraocclusion of the mandibular left first molar. During biopsy, massive bleeding occurred. Computed tomographic scan with contrast medium showed a vascular malformation. Arterial embolization was performed followed by surgical resection. Autologous bone transplantation and resorbable osteosynthesis plates were used for reconstruction. The second patient, a 15-year-old girl, had intense bleeding from the periodontal space of a highly mobile right mandibular second molar. Intraoral clinical examination showed a painless pulsatile swelling in the right buccal vestibule. Computed tomographic angiogram displayed an extensive vascular malformation involving the right mandible. After successful selective embolization, surgical resection, and reconstruction with autologous bone, transplantation was performed. Preoperative embolization is a low-risk procedure in highly vascularized lesions. It is a recommended procedure to avoid the increased risk of an emergency operation, to minimize blood loss during surgery, and to better plan reconstructive surgery.