M.A.W. Merkx

Validation of a Gene Expression Signature for Assessment of Lymph Node Metastasis in Oral Squamous Cell Carcinoma

PURPOSE Current assessment of lymph node metastasis in patients with head and neck squamous cell carcinoma is not accurate enough to prevent overtreatment. The aim of this study was validation of a gene expression signature for distinguishing metastasizing (N+) from nonmetastasizing (N0) squamous cell carcinoma of the oral cavity (OSCC) and oropharynx (OPSCC) in a large multicenter cohort, using a diagnostic DNA microarray in a Clinical Laboratory Improvement Amendments/International Organization for Standardization-approved laboratory. METHODS A multigene signature, previously reported as predictive for the presence of lymph node metastases in OSCC and OPSCC, was first re-evaluated and trained on 94 samples using generic, whole-genome, DNA microarrays. Signature genes were then transferred to a dedicated diagnostic microarray using the same technology platform. Additional samples (n=222) were collected from all head and neck oncologic centers in the Netherlands and analyzed with the diagnostic microarray. Human papillomavirus status was determined by real-time quantitative polymerase chain reaction. RESULTS The negative predictive value (NPV) of the diagnostic signature on the entire validation cohort (n=222) was 72%. The signature performed well on the most relevant subset of early-stage (cT1-T2N0) OSCC (n=101), with an NPV of 89%. CONCLUSION Combining current clinical assessment with the expression signature would decrease the rate of undetected nodal metastases from 28% to 11% in early-stage OSCC. This should be sufficient to enable clinicians to refrain from elective neck treatment. A new clinical decision model that incorporates the expression signature is therefore proposed for testing in a prospective study, which could substantially improve treatment for this group of patients.

Biomechanics of mandibular reconstruction: a review.

Knowledge of the biomechanics of the mandible allows the surgeon to understand the forces acting on the mandible during function and the resulting deformation that can occur. This allows the appropriate selection and placement of osteosynthesis plates to neutralize these forces. Many methods have been proposed for mandibular reconstruction, each of which has strengths and weaknesses. Most papers evaluating these techniques have focused on survival rates and the quality of the grafted bones, and there have been few studies of the biomechanics (stress distribution and strength) of the various types of reconstructed mandibles. This paper reviews the biomechanics of the mandible and the various methods of reconstruction reported in past studies.

Prevention of thrombosis after microvascular tissue transfer in the head and neck. A review of the literature and the state of affairs in Dutch Head and Neck Cancer Centers

Free vascularized graft or free-flap reconstruction is frequently used in the reconstruction of defects in head and neck oncology patients. A common complication in free-flap surgery is thrombosis. Thrombosis occurs in 8-14% of cases and often leads to flap failure. A review of the literature on this subject was carried out and Dutch head and neck cancer centres were asked to share their guidelines concerning the prevention of thrombosis after free vascularized graft surgery. No consensus in the literature was found on how thrombosis could best be prevented. The Dutch Head and Neck Cancer Centers use routine deep venous thrombosis prophylaxis to prevent thrombosis in the anastomosis. It was also concluded that non-pharmacologic measures for preventing thrombosis, such as meticulous microvascular surgery and smoking cessation prior to the operation, are thought to play an important role in the prevention of thrombosis in microvascular free-flap reconstructions. It has not been determined which pre- and postoperative pharmacologic measure can prevent thrombosis most effectively. A pharmacologic regimen to prevent thrombosis that is customized to the patient is suggested. This should be based on an individual risk profile for the development of thrombosis.

MASTICATION IN PATIENTS TREATED FOR MALIGNANCIES IN TONGUE AND/OR FLOOR OF MOUTH: A 1-YEAR PROSPECTIVE STUDY

People confronted with oral cancer run a high risk of deteriorated masticatory performance. Reduced masticatory function may affect quality of life and food choice. An altered food choice may result in lower intakes for key nutrients and weight loss.

Chromosome instability predicts the progression of premalignant oral lesions

OBJECTIVES One of the main problems in reducing the incidence of oral squamous cell carcinoma (OSCC) is the inability to appropriately deal with leukoplakia. Accurately identifying lesions which will progress to malignancy is currently not possible. The present study aims to establish the value of chromosome instability (CI) detection by DNA image cytometry and FISH analysis for prognosis and monitoring of oral leukoplakia. MATERIALS AND METHODS For this purpose, we included from our archives 102 oral leukoplakia cases, which had been diagnosed between 1991 and 2008. Patient follow-up data were collected and the histopathological diagnosis was revised. CI assessment was carried out on paraffin-embedded tissue sections using both DNA image cytometry (ICM) and dual target FISH for chromosomes 1 and 7. RESULTS 16 of 102 Patients developed carcinoma in situ or OSCC. Both detection methods were found to yield prognostic information independent of the histopathological diagnosis. CI was a strong individual marker of progression, with hazard ratios (HRs) of 7.2 and 6.8 for ICM and FISH respectively. Moreover, this approach seems suitable for monitoring lesions over time (especially ICM). Combining histopathology and CI enables subdivision of patients into three risk groups, with different probabilities of malignant progression. CONCLUSION CI detection seems a reliable method for risk assessment of oral premalignancies and its application may contribute to a better risk-counselling and appropriate treatment regimen or watchfull-waiting approach of patients.

Tooth eruption through autogenous and xenogenous bone transplants: a histological and radiographic evaluation in beagle dogs

The effect of implanting autogenous and xenogenous (Bio-Oss) bone transplants into metabolically active sites within beagle dog mandibles during permanent premolar tooth eruption was examined. Ten 14-week-old beagles were used. Before commencing the radiographic experiments, metal bone markers were placed in the caudal margin of the mandible at the age of 10 weeks. The deciduous first and third molar teeth were extracted and their sockets over the permanent second and fourth premolars were implanted with autogenous particulate enchondral iliac crest bone, autogenous particulate membraneous mandibular body bone, xenogenous bovine anorganic bone mineral spongiosa granules (1-2mm3) (Bio-Oss, Geistlich Pharma, Switzerland) of left empty. The third premolar served as control site. Standardized oblique lateral radiographs were taken once a week. A number of coordinates of defined points and structures were determined by means of a coordinate digitizing system. Animals were killed 4, 10 and 16 weeks after bone transplantation for histological examination of the transplantation sites. All premolars showed no delay in eruption or disruption of crown and root development. On histology, the Bio-Oss particles were not resorbed or integrated in the alveolar bone but were pushed forward into the gingiva. We have demonstrated that there is on difference in the eruption curve of the permanent premolars in the four groups (ANOVA P > 0.5) and that bone transplantation has no inhibitory effect on eruption (ANOVA P > 0.3) and crown development of the underlying permanent premolar but that Bio-Oss does not have the same resorbable or integrating capability as autogenous bone grafts.

Biocompatibility and bone formation with porous modified PMMA in normal and irradiated mandibular tissue

UNLABELLED A cemented mandibular endoprosthesis is a potentially viable option for mandibular reconstruction after ablative surgery. The commonly used PMMA cement has the inherent weakness of a lack of bioactivity. Improvement by the addition of porosities and bioactive compounds like calcium phosphates may resolve this issue. OBJECTIVE The objective of this study was to assess the bone and tissue response to two modified PMMA cements with post-operative radiation as an additional influencing factor. MATERIALS & METHODS An in vivo animal study was performed using a mandibular rabbit model. A porous PMMA cement (A) and a porous cement incorporated with Beta-tricalcium phosphate particles (b-TCP) (B) were placed in bilateral mandibular defects with exposed roots and mandibular nerve of 20 animals. Half of the animals underwent additional post-operative radiation. RESULTS The animals were healthy with only a minor complication in one rabbit. Temperature analysis showed no significant risk of thermal necrosis with the maximal in vivo cement temperature at 37.8°C. Histology demonstrated: (1) good bone ingrowth around the defect as well as within the pores of the cement and defect bridging was achieved in 70% of the specimens after 12-15 weeks of implantation, (2) no pulpal injury with minor secondary cementum response, (3) an intact mandibular nerve with no inflammation, (4) extensive degradation and resorption of the b-TCP particles by 12-15 weeks, and (5) presence of an intervening thin fibrous tissue at the bone-to-cement interface. Histomorphometrical analysis revealed that there was no difference between the different cements and the presence or absence of post-operative radiation. The 12-15 weeks specimens showed significantly more bone ingrowth and bone maturity than the 4-7 weeks specimens. CONCLUSION Both modified PMMA cements have good biocompatibility, bioactivity and support bone ingrowth and additional post-operative radiation did not show any negative effects.

Trends in oral cavity cancer incidence, mortality, survival and treatment in The Netherlands

Information on epidemiology is essential to evaluate care for the growing group of oral cancer patients. We investigated trends in incidence, mortality and relative survival rates for oral cavity cancer (OCC) and its subsites in the Netherlands from 1991 to 2010, and relate these to changes in stage and treatment. Patient (age, sex), tumour (subsite, stage) and treatment characteristics of patients diagnosed with OCC (ICD‐O‐3: C02‐C06) in 1991–2010 were extracted from the Netherlands Cancer Registry. Incidence, mortality and 5‐year relative survival rates over time are presented, as well as trends in type of treatment. The incidence of OCC increased with +1.2% (95%CI: +0.9%;+1.6%) per year: more strongly in women, stage I and IV disease, and in cancers of the tongue and gum. The mortality rate slightly rose (+0.8%, 95%CI: +0.3%;+1.3% per year), but differed by subsite. The 5‐year relative survival improved from 57% in 1991–1995 to 62% in 2006–2010. The 5‐year relative survival was better for women compared with men (64% and 55%, respectively), decreased with increasing stage, was the best for tongue cancer (63%) and the worst for cancer of the gum (56%) and floor of mouth cancer (55%). The relative excess risk of dying was higher for non‐surgery‐based treatments. Surgery was the main treatment option and the proportion of “surgery only” rose in stage I and III disease. The incidence and, to a lesser extent, mortality of OCC are increasing and therefore, even with slightly improving survival rates, OCC is an increasingly important health problem.

Oral squamous cell carcinoma and a clinically negative neck: The value of follow-up

In squamous cell carcinoma of the oral cavity (SCCOC), regular follow‐up comprises 5 years of prescheduled visits, irrespective of tumor stage/classification and/or treatment. We analyzed our standard treatment and follow‐up protocol in patients with a preoperative clinically negative neck (cN0) in SCCOC.

Fracture of costochondral graft in temporomandibular joint reconstructive surgery: an unexpected complication

The case of a 35-year-old woman with a history of several temporomandibular joint (TMJ) operations, including condylectomy, is reported. She presented with myofacial pain and partial fibrous ankylosis of her right TMJ. The ankylosis was released and an autogenous costochondral graft was used to restore the vertical dimension of the ramus. About 3 months after surgery, a fracture of the graft occurred during physical therapy. The cause of this complication is discussed with reference to the literature.