Maximilian Moergel

Overexpression of p63 is associated with radiation resistance and prognosis in oral squamous cell carcinoma

BACKGROUND The tumor suppressor homologue p63 is expressed in basal and parabasal layers of intraoral mucosa. Full length transcripts with transactivational domain (TA forms) present with homology to p53 and implicate functions governing cell proliferation, differentiation and apoptosis control. To date studies show an increase of p63 expression in oral dysplasia and additionally high expression levels correlated with poor prognosis for patients with OSCC, whereas a possible link to radiation resistance of tumors has not been investigated yet. In the present study we tested the hypothesis for p63 being a marker of radioresistance and overall survival in OSCC. METHODS p63 Expression was labeled by immunohistochemistry in pre-treatment biopsies collected from 33 patients with OSCC. Quantification of the labeling index (Li) based on the relation of p63 positive cells to overall tumor cell count. Histological examination of the resection specimen allowed categorization of the radiation response. Statistical analyses of the association between Li and radiation response were performed. Survival analysis utilized Kaplan-Meier estimates and additionally a Cox regression model was built for p63 (Li), T stage, N-stage and chemotherapy and presented as hazard ratios. RESULTS All tumors had enhanced p63 expression. The median Li was 63.1% (range 36-87%). Tumors with a p63 positive cell count>63.1% showed increased resistance to radiation (p=0.027). Overall survival was higher (p=0.001) for patients with low Li (median value) and multivariate Cox regression analysis confirmed the significance of p63 as a prognostic marker of survival. CONCLUSIONS The results of this analysis advocate p63 expression in pre-treatment tumor tissue to be a marker of radiation resistance in OSCC, with high expression levels being associated with poor radiation response and shorter survival. The promising results of this biomarker should now be confirmed by a study with larger patient counts.

Modulation of platelet activation and initial cytokine release by alloplastic bone substitute materials

OBJECTIVES Platelet-derived cytokines play a crucial role in tissue regeneration. In regenerative dental medicine, bone substitute materials (BSM) are widely used. However, initial interactions of BSM and platelets are still unknown. The aim of this study was to evaluate the potential of platelet activation and subsequent initial cytokine release by different commercial alloplastic BSM. MATERIAL AND METHODS Eight commercial BSM of different origins and chemical compositions (tricalcium phosphate, hydroxyapatite, bioactive glass: SiO(2) and mixtures) were incubated with a platelet concentrate (platelet-rich plasma, PRP) of three healthy volunteers at room temperature for 15 min. Platelet count, aggregation, degranulation (activated surface receptor CD62p) and cytokine release (Platelet-derived growth factor, Vascular endothelial growth factor) into the supernatant were quantified. Highly thrombogenic collagen served as a reference. RESULTS The investigated PRP samples revealed different activation patterns when incubated with different BSM. In general, SiO(2)-containing BSM resulted in high platelet activation and cytokine release. In detail, pure bioactive glass promoted platelet activation most significantly, followed by hybrid BSM containing lower ratios of SiO(2). Additionally, we found indications of cytokine retention by BSM of large specific surfaces. CONCLUSIONS Platelet activation as well as consecutive storage and slow release of platelet-derived cytokines are desirable attributes of modern BSM. Within the limits of the study, SiO(2)-containing BSM were identified as promising biomaterials. Further investigations on cytokine adsorption and cytokine release kinetics by the respective BSM have to be conducted.

Effectiveness of adjuvant radiotherapy in patients with oropharyngeal and floor of mouth squamous cell carcinoma and concomitant histological verification of singular ipsilateral cervical lymph node metastasis (pN1-state)--a prospective multicenter randomized controlled clinical trial using a comprehensive cohort design.

BackgroundModern radiotherapy plays an important role in therapy of advanced head and neck carcinomas. However, no clinical studies have been published addressing the effectiveness of postoperative radiotherapy in patients with small tumor (pT1, pT2) and concomitant ipsilateral metastasis of a single lymph node (pN1), which would provide a basis for a general treatment recommendation.Methods/DesignThe present study is a non-blinded, prospective, multi-center randomized controlled trial (RCT). As the primary clinical endpoint, overall-survival in patients receiving postoperative radiation therapy vs. patients without adjuvant therapy following curative intended surgery is compared. The aim of the study is to enroll 560 adult males and females for 1:1 randomization to one of the two treatment arms (irradiation/no irradiation). Since patients with small tumor (T1/T2) but singular lymph node metastasis are rare and the amount of patients consenting to randomization is not predictable in advance, all patients rejecting randomization will be treated as preferred and enrolled in a prospective observational study (comprehensive cohort design) after giving informed consent. This observational part of the trial will be performed with maximum consistency to the treatment and observation protocol of the RCT. Because the impact of patient preference for a certain treatment option is not calculable, parallel design of RCT and observational study may provide a maximum of evidence and efficacy for evaluation of treatment outcome. Secondary clinical endpoints are as follows: incidence and time to tumor relapse (locoregional relapse, lymph node involvement and distant metastatic spread), Quality of life as reported by EORTC (QLQ-C30 with H&N 35 module), and time from operation to orofacial rehabilitation. All tumors represent a homogeneous clinical state and therefore additional investigation of protein expression levels within resection specimen may serve for establishment of surrogate parameters of patient outcome.ConclusionThe inherent challenges of a rare clinical condition (pN1) and two substantially different therapy arms would limit the practicality of a classical randomized study. The concept of a Comprehensive Cohort Design combines the preference of a randomized study, with the option of careful data interpretation within an observational study.Trial registrationClinicalTrials.gov: NCT00964977

Platform switch versus platform match in the posterior mandible – 1-year results of a multicentre randomized clinical trial.

Objective The purpose of this ongoing randomized study was to assess differences in bone level changes and success rates using implants supporting single crowns in the posterior mandible either with platform matched or platform switched abutments. Material and Methods Patients aged 18 and above, missing at least two teeth in the posterior mandible and with a natural tooth mesial to the most proximal implant site were enrolled. Randomization followed implant placement. Definitive restorations were placed after a minimum transgingival healing period of 8 weeks. Changes in crestal bone level from surgery and loading (baseline) to 12-month post-loading were radiographically measured. Implant survival and success were determined. Results Sixty-eight patients received 74 implants in the platform switching group and 72 in the other one. The difference of mean marginal bone level change from surgery to 12 months was significant between groups (p < 0.004). Radiographical mean bone gain or no bone loss from loading was noted for 67.1% of the platform switching and 49.2% of the platform matching implants. Implant success rates were 97.3% and 100%, respectively. Conclusions Within the same implant system the platform switching concept showed a positive effect on marginal bone levels when compared with restorations with platform matching.

The Correlation between Chronic Periodontitis and Oral Cancer

Infections are increasingly considered as potential trigger for carcinogenesis apart from risk factors like alcohol and tobacco. The discussion about human papilloma virus (HPV) in oral squamous cell carcinoma (OSCC) points at a general role of infection for the development of oral carcinomas. Furthermore, first studies describe a correlation between chronic periodontitis and OSCC, thus, characterizing chronic inflammation as being a possible trigger for OSCC. In front of this background, we present four well-documented clinical cases. All patients showed a significant anatomical relation between OSCC and clinical signs of chronic periodontitis. The interindividual differences of the clinical findings lead to different theoretical concepts: two with coincidental appearance of OSCC and chronic periodontitis and two with possible de novo development of OSCC triggered by chronic inflammation. We conclude that the activation of different inflammatory cascades by chronic periodontitis negatively affects mucosa and bone. Furthermore, the inflammatory response has the potential to activate carcinogenesis. Apart from a mere coincidental occurrence, two out of four patients give first clinical hints for a model wherein chronic periodontitis represents a potential risk factor for the development of OSCC.

Clinical, therapeutic and prognostic features of osteosarcoma of the jaws – Experience of 36 cases

INTRODUCTION Osteosarcoma of the jaws (OSJ) differs from osteosarcoma of other skeletal regions due to later development, a high mortality associated with the local disease, fewer incidences of metastases and its extreme rarity. In regard to clinical and pathological parameters as well as therapeutic approaches and prognosis, OSJ has not been specifically examined to date. In order to achieve a better understanding of this special malignancy, an evaluation of incidence, treatment and prognosis of patients with OSJ in our department over the past 38 years was conducted. MATERIALS AND METHODS A retrospective analysis of patients with OSJ between 1972 and 2010 was performed. Information regarding patient characteristics, site of the lesion, main presenting symptoms, latency of initial diagnosis, treatment, histology, local recurrence, development of metastatic disease, duration of follow up and survival was obtained. The data were compared to the literature. RESULTS Thirty-six patients (2-81 years, mean: 33.9, standard deviation: 21.3) were diagnosed and treated for OSJ (maxillar:mandibular nearly 1:2). Initial symptoms were local swelling (81%) and pain (47%). The latency period between fist symptoms and clinical presentation was 3.7 months (1-24). A radical resection alone was conducted in 15 patients. In nine patients, resection and radiotherapy was used. Resection with chemotherapy was the treatment of choice in seven patients. Five patients received a triple combination of resection, chemo- and radiation therapy. The osteoblastic subtype of osteosarcoma was most frequent (42%). In 15 cases (42%) local recurrences, in two cases (5%) metastasis were seen. Of these patients, 13 died within the observation period. One other patient (3%) died as a result of progressive pulmonary metastasis. A mean total survival rate of 61% could be seen whereas the highest survival rate (80%) was found in patients who were treated with neoadjuvant chemotherapy, radical resection and adjuvant radiation. Positive prognostic factors were a younger age and tumour-free resection margins. DISCUSSION OSJ is a highly lethal tumour entity. According to the data at hand, therapy should possibly include chemotherapy, radical resection and irradiation. Nevertheless, due to the rarity of OSJ, information remains limited and the treatment of choice should be within the focus of clinical multi-centre studies.

Local and systemic risk factors influencing the long-term success of angular stable alloplastic reconstruction plates of the mandible

INTRODUCTION After ablative surgery of the mandible, angular stable alloplastic reconstruction plates are commonly employed. The aim of the study was a long-term evaluation of local anatomical, as looking at systemic factors influencing specific complications and the failure rate of such plates. MATERIALS AND METHODS In a retrospective study covering an 11-year period, we reviewed the outcomes of angular stable plates of patients who had a segmental resection of the mandible and subsequent alloplastic reconstruction. Complications and failure rates were assessed and local (anatomical size and localization of resection) as well as systemic risk factors (age, sex, radiation therapy, smoking) evaluated. RESULTS Altogether, 162 plates were reviewed. The overall complication rate was 28% (fractures n = 8, loose screws n = 7, dehiscences n = 31) after an average time of 13 months. Cumulative survival rates of 73% after one, of 67% after 2, of 59% after 3 and of 40% after five years were observed. We found a significant correlation of increasing defect sizes to a rising complication and failure rate. Plate dehiscence occurred more often in defects including the midline (p = 0.005). Though not statistically significant, the occurrence of plate fracture was associated with lateral mandibular defects (7/8, p = 0.113). In smoking patients an earlier failure rate was seen. CONCLUSION The results clearly indicate that the success of alloplastic reconstruction plates of the mandible is dependent on various risk factors. They should--if possible--be used temporarily only. If not done primarily, a secondary approach with bone reconstruction is recommended.

Spectrum of Indications for Palatal Implants in Treatment Concepts Involving Immediate and Conventional Loading

Aim:To analyze the spectrum of indications for second-generation palatal implants in relation to two different loading concepts in a prospective, multicenter, randomized controlled trial (RCT).Patients and Methods:Forty-one patients were recruited to the study from 2006 to 2009. All implants (Orthosystem®, Straumann, Basel, Switzerland; dimensions: 4.1 mm × 4.2 mm) were inserted in the median or paramedian region of the anterior palate, and each patient was randomized to one of two loading groups (immediate loading within the first week after insertion versus conventional loading after a 12-week healing phase). In this interim evaluation, we report preliminary results obtained six months after functional loading.Results:All palatal implants were primarily stable at the time of insertion. One implant loss (12 weeks after surgical insertion) was documented in the cohort subjected to conventional loading, and one patient dropped out of the immediate-loading group. At the time of this investigation, 39 palatal implants are experiencing functional loads. Using both loading concepts, we had various orthodontic objectives, such as intrusion of anterior and/or posterior teeth, and the mesialization and distalization of posterior teeth. Both loading groups presented nearly identical indications, and the distribution of direct vs. indirect anchorage forms was also very similar during the active treatment.Conclusion:Comparison of the two treatment concepts revealed no clinical differences in implant stability. Patients undergoing immediate-loading therapy were subject to no limitations regarding indications at 6 months after functional loading compared with the patients who experienced conventional loading.ZusammenfassungZiel:Im Rahmen einer prospektiven multizentrischen RCT-Studie (Randomized Controlled Trial) wird das Indikationsspektrum von Gaumenimplantaten der zweiten Generation bei zwei verschiedenen Belastungskonzepten analysiert.Patienten und Methodik:Im Zeitraum von 2006 bis 2009 wurden insgesamt 41 Patienten in die Untersuchung eingeschlossen. Alle Implantate (Orthosystem®; Straumann, Basel, Schweiz; Dimension: 4,1 mm × 4,2 mm) wurden im medianen bzw. paramedianen Bereich des anterioren Gaumens inseriert und über eine Randomisierung auf zwei Belastungsgruppen (Frühbelastung innerhalb der ersten Woche nach Insertion vs. Spätbelastung nach einer Einheilphase von 12 Wochen) verteilt. In dieser Zwischenauswertung berichten wir über erste Ergebnisse 6 Monate nach funktioneller Belastung.Ergebnisse:Alle Gaumenimplantate waren bei der Insertion primär stabil. In der Gruppe der Spätbelastung gab es einen Implantatverlust (12. Woche nach chirurgischer Insertion) und einen Drop-out in der Gruppe der Sofortbelastung. 39 Gaumenimplantate befanden sich zum Zeitpunkt dieser Untersuchung unter funktioneller Belastung. In beiden Belastungskonzepten wurden verschiedene kieferorthopädische Behandlungsaufgaben (z.B. Intrusion von Front- und/oder Seitenzähnen, Mesialisieren und Distalisieren von Seitenzähnen) gelöst. In den Belastungsgruppen war die Verteilung der Indikationen sowie von direkten und indirekten Verankerungsformen in der aktiven Behandlungszeit annähernd gleich.Schlussfolgerung:Der Vergleich beider Belastungskonzepte ergab klinisch keine Unterschiede bezüglich der Implantatstabilität. Das frühzeitige Belastungskonzept zeigte gegenüber der Spätbelastung keine Indikationseinschränkungen 6 Monate nach funktioneller Belastung.

Effectiveness of postoperative radiotherapy in patients with small oral and oropharyngeal squamous cell carcinoma and concomitant ipsilateral singular cervical lymph node metastasis (pN1)

Background:The positive effect of radiation therapy for patients with advanced oropharyngeal squamous cell carcinoma (OSCC) has been substantially verified. The present work investigated whether a meta-analysis of current data is able to evaluate the effectiveness of postoperative radiotherapy (PORT) in patients with small OSCC (pT1, pT2) and a single ipsilateral lymph node metastasis (pN1).Methods:The meta-analysis comprises randomized and non-randomized studies. High-risk tumors were excluded and defined by size ≥ pT3/pT4, lymph node involvement ≥ pN2, or presence of additional histological risk factors, e.g., involved positive resection margins, extra nodal spread of the disease, or lymphangiosis carcinomatosa. The primary outcome analyzed mortality between the different treatment arms.Results:Only one prospective randomized clinical trial and six retrospective observational studies were adequate for evaluation. Descriptive analysis revealed a marginally higher mortality in the irradiation group (44% vs. 34%). In contrast, a forest plot presentation of two of seven studies with and without events in the control and therapy arms presented an advantage for the irradiation group with the limitation of large heterogeneity and a lack of statistical significance.Conclusion:Present data are poor and exhibit limited internal and external validity; thus, direct comparison was not possible with the eligible studies. Therefore, a meta-analysis of present data may not serve as the basis for a general treatment recommendation but underlines the need of prospective, randomized, controlled clinical trials.Hintergrund:Der positive Effekt der Strahlentherapie für Patienten mit fortgeschrittenem Plattenepithelkarzinom im Kopf-Hals-Bereich ist wissenschaftlich gut belegt. Die vorliegende Arbeit überprüft, ob eine Meta-Analyse publizierter Daten die Wirksamkeit der postoperativen Strahlentherapie auch bei Patienten mit kleinem oralen oder oropharyngealen Plattenepithelkarzinom (pT1, pT2) und gleichzeitiger solitärer Lymphknotenmetastase (pN1) bewerten kann.Methoden:In die Meta-Analyse wurden randomisierte und nicht-randomisierte Studien eingeschlossen. Patienten mit hohem Risikoprofil wurden primär von der Studie ausgeschlossen und sind definiert durch Tumorgröße ≥ pT3/pT4, positivem Lymphknotenbefall ≥ pN2 oder Vorhandensein zusätzlicher histologischer Risikofaktoren, wie z.B. R1-Status, Lymphknotenkapseldurchbruch oder Lymphangiosis carcinomatosa. Das Primärziel war die Sterblichkeit zwischen den Behandlungsarmen.Ergebnisse:Lediglich eine prospektiv randomisierte Studie und sechs retrospektive Beobachtungsstudien standen zur Verfügung. Die deskriptive Analyse erbrachte eine leicht erhöhte Mortalität im Bestrahlungsarm (44% vs. 34%). Demgegenüber erbrachte die Forest-Plot-Darstellung von zwei Studien, die Ereignisse sowohl in Kontroll- und Therapiearm besaßen, einen begrenzten Vorteil für die Bestrahlungsgruppe, jedoch mit der Einschränkung großer Heterogenität und einem Mangel an statistischer Signifikanz.Schlussfolgerung:Es gibt nur wenige Publikationen zum Thema mit geringer interner und externer Validität, so dass ein direkter Vergleich nur eingeschränkt möglich ist. Die Meta-Analyse ist daher derzeit keine geeignete Basis für eine allgemeine Behandlungsempfehlung und unterstreicht die Notwendigkeit von prospektiv randomisierten klinischen Studien.

Effect of platform switching on crestal bone levels around implants in the posterior mandible: 3 years results from a multicentre randomized clinical trial

Abstract Objective Evaluation of differences in the clinical performance and crestal bone levels between implants restored with single crowns with platform‐matched or platform‐switched abutments after 3 years. Material and Methods The study enrolled adult patients missing two or more adjacent teeth in the posterior mandible with natural teeth mesial to the implant site. Randomization followed open‐flap implant insertion and the corresponding matching or switching healing abutments placed at surgery. Conventional loading was made with cemented crowns. Clinical follow‐up took place annually after loading up to 3 years. Bone level changes were measured in standardized radiographs as the variation in crestal bone from one evaluation to the next. Results Sixty‐three patients with a total of 135 implants (66 platform matching, 69 platform switching) were analysed. From surgery to 36 months, mean bone loss was 0.28 ± 0.56 mm for the platform‐switching group and 0.68 ± 0.64 mm for the platform‐matching group. A statistically significant difference was found between groups (p = 0.002) with an estimate of 0.39 mm (0.15–0.64, 95% CI) in favour of platform switching. Conclusions After 3 years, platform‐switching restorations showed a significant effect in the preservation of marginal bone levels compared to platform‐matching restorations.