Implant-based dental rehabilitation in head and neck cancer patients after maxillofacial reconstruction with a free vascularized fibula flap: the effect on health-related quality of life.

PURPOSE: To evaluate the effect of implant-based dental rehabilitation (IDR) on health-related quality of life (HRQoL) in head and neck cancer (HNC) patients after reconstruction with a free vascularized fibula flap (FFF). METHODS: Eligible patients were identified by retrospectively reviewing the medical records of patients treated in Amsterdam UMC-VUmc. HRQoL data were used from OncoQuest, a hospital-based system to collect patient-reported outcome measures in routine care. Data were used of the EORTC QLQ-C30 and QLQ-H&N 35 before FFF reconstruction (T0) and after completing IDR (T1). Data were statistically analysed with the chi-square test, independent samples t test and linear mixed models. RESULTS: Out of 96 patients with maxillofacial FFF reconstruction between January 2006 and October 2017, 57 patients (19 with and 38 without IDR) had HRQoL data at T0 and T1. In the cross-sectional analysis, patients with IDR scored significantly better at T0 and T1 on several EORTC domains compared to the patients without IDR. Weight loss was significantly different in the within-subject analysis between T0 and T1 for patients with IDR (p = 0.011). However, there were no significant differences in the mean changes of all the EORTC QLQ-C30 and EORTC QLQ-H&N35 scores between the defined timepoints for patients with IDR compared to those without. CONCLUSIONS: In this study, no differences were found in the course of HRQoL in HNC patients who had undergone IDR after maxillofacial FFF reconstruction, compared to those who had not. Patients should be preoperatively informed to have realistic expectations regarding the outcome of IDR.

A Novel Approach for Immediate Implant-Based Oral Rehabilitation in a Sjögren's Syndrome Patient Using Virtual Surgical and Prosthetic Planning.

Patients with Sjögren syndrome (SS) experience difficulties in wearing conventional dentures. After removal of all teeth, the oral rehabilitation is challenging and time consuming using conventional treatment protocols. Although implant-retained overdentures are beneficial for this specific patient group, the average total oral rehabilitation time (TORT) usually takes at least 9 months and needs to be reduced to increase patients' quality of life (QoL). In this paper, we report on a new treatment concept for immediate implant-based oral rehabilitation in a 77-year-old patient with partial edentulous SS. Because of persistent pain, discomfort, and retention problems with the conventional prosthetic devices, full clearance of the remaining mandibular dentition and immediate oral rehabilitation with an implant-retained overdenture were suggested. The treatment protocol included virtual surgical planning (VSP), combining a guided bone reduction of the mandibular alveolar process, immediate dental implant placement, and restoration using a prefabricated bar and placement of the overdenture. This method demands the use of ionizing 3D imaging optionally combined with an optical dental scan or a conventional impression. Furthermore, one needs to gain experience using VSP software. This novel treatment concept for immediate implant-based oral rehabilitation using VSP proved to be feasible and safe in a patient with SS, resulting in a significantly reduced TORT and improved QoL. Further research is needed to what extent this treatment concept could be beneficial to other patient groups, such as patients with head and neck cancer.

The Co-Expression of Kallikrein 5 and Kallikrein 7 Associates with Poor Survival in Non-HPV Oral Squamous-Cell Carcinoma.

OBJECTIVE: Oral squamous-cell carcinoma (OSCC) still has a poor prognosis. Lymph node metastasis (LNM) is a major determinant of treatment decisions and prognosis. Serine protease inhibitor Kazal-type 5 (SPINK5) is the inhibitor of kallikrein 5 (KLK5) and KLK7. SPINK5, KLK5 and KLK7 are three of the genes of a recently validated LNM-predicting gene expression profile in OSCC. This study evaluates their clinicopathological role and value as biomarkers in OSCC. METHODS: Eighty-three patients with primary OSCC, treated surgically between 1996 and 2000, were included. Gene expression data were acquired from a previously reported study. Human papillomavirus (HPV) status was determined by an algorithm for HPV-16. Protein expression for KLK5, KLK7 and SPINK5 was semi-quantitatively determined in all 83 tumours by immunohistochemistry. All expression data were correlated with clinicopathological parameters. RESULTS: Concurrent loss of KLK5 and KLK7 correlates with worse disease-specific and overall survival (DSS and OS). Multivariate analysis proved that co-expression is an independent prognostic factor for DSS (p = 0.029) and OS (p = 0.001). CONCLUSION: This report demonstrates that concurrent loss of KLK5 and KLK7 associates with a poor clinical outcome in OSCC and could therefore serve as prognostic marker in this disease.

Novel diagnostic modalities for assessment of the clinically node-negative neck in oral squamous-cell carcinoma.

Oral squamous-cell carcinomas arise in mucosal linings of the oral cavity and frequently metastasise to regional lymph nodes in the neck. The presence of nodal metastases is a determinant of prognosis and clinical management. The neck is staged by palpation and imaging, but accuracy of these techniques to detect small metastases is low. In general, 30-40% of patients will have occult nodal disease and will develop clinically detectable lymph-node metastases when the neck is left untreated. The choice at present is either elective treatment or careful observation followed by treatment of the neck in patients who develop manifest metastases. These unsatisfying therapeutic options have been the subject of debate for decades. Recent developments in staging of the neck, including expression profiling and sentinel lymph-node biopsy, will allow more personalised management of the neck.

Oral-Functioning Questionnaires in Patients with Head and Neck Cancer: A Scoping Review.

Background: Oral-functioning impairment can negatively affect the quality of life (QoL) of head and neck cancer (HNC) patients after receiving radiotherapy (RT). Assessment of patient-reported oral functioning throughout treatment can improve patient care. This scoping review aims to propose a definition for oral functioning for HNC patients and to map out the available questionnaires measuring patient-reported oral functioning in RT-treated HNC patients. Methods: A literature search in relevant databases was performed. Each questionnaire was scored on the domains validity, reliability, and responsiveness. Furthermore, the items from the questionnaires were analyzed to define the common denominators for oral functioning in HNC patients. Results: Of the 6434 articles assessed, 16 met the inclusion criteria and employed 16 distinct instruments to evaluate QoL. No questionnaire covered all oral-health-related QoL items nor assessed all aspects of validity, reliability, and responsiveness. Chewing, speaking, and swallowing were the common denominators for oral functioning. Conclusions: Based on the included studies, we suggest using the VHNSS 2.0 questionnaire to assess oral functioning in HNC patients. Furthermore, we suggest to more clearly define oral functioning in HNC patients by focusing on masticatory function (chewing and grinding), mouth opening, swallowing, speaking, and salivation.

The Amsterdam UMC protocol for computer-assisted mandibular and maxillary reconstruction; A cadaveric study.

OBJECTIVES: In this cadaveric study, the accuracy of CAS guided mandibular and maxillary reconstruction including immediate dental implant placement in different Brown defect classes is assessed. MATERIALS AND METHODS: The virtual planning and surgical procedure was conducted according to a newly proposed Amsterdam UMC reconstruction protocol. Postoperative evaluation was performed according to a previously proposed evaluation guideline. RESULTS: Fourteen mandibular and 6 maxillary reconstructions were performed. Average mandibular angle deviations were 1.52°±1.32, 1.85°±1.58, 1.37°±1.09, 1.78°±1.37, 2.43°±1.52 and 2.83°±2.37, respectively for the left and right axial angles, left and right coronal angles and left and right sagittal angles. A total of 62 dental implants were placed in neomandibles with an average dXYZ values of 3.68 ± 2.21 mm and 16 in neomaxillas with an average dXYZ values of 3.24 ± 1.7 mm. CONCLUSION: Promising levels of accuracy were achieved for all mandibular angles. Dental implant positions approached the preoperative preferred positions well, within the margin to manufacture prosthetic devices.

Three-Dimensional Evaluation of Isodose Radiation Volumes in Cases of Severe Mandibular Osteoradionecrosis for the Prediction of Recurrence after Segmental Resection.

BACKGROUND: Pre-operative margin planning for the segmental resection of affected bone in mandibular osteoradionecrosis (ORN) is difficult. The aim of this study was to identify a possible relation between the received RT dose, exposed bone volume and the progression of ORN after segmental mandibular resection. METHOD: Patients diagnosed with grade 3-4 ORN for which a segmental resection was performed were included in the study. Three-dimensional reconstructions of RT isodose volumes were fused with postoperative imaging. The primary outcome was the recurrence of ORN after segmental resection. Subsequently, RT exposed mandibular bone volumes were calculated and the location of the bone cuts relative to the isodose volumes were assessed. RESULTS: Five out of thirty-three patients developed recurrent ORN after segmental mandibular resection. All cases with recurrent ORN were resected inside an isodose volume of ≥56 Gy. The absolute mandibular volume radiated with 56 Gy was significantly smaller in the recurrent group (10.9 mL vs. 30.7 mL, p = 0.006), as was the proportion of the mandible radiated with 56 Gy (23% vs. 45%, p = 0.013). CONCLUSION: The volume of radiated bone was not predictive for risk of progression. The finding that recurrent ORN occurred with bone resection margins within the 56 Gy isodose volume suggests that this could serve as a starting point for the pre-operative planning of reducing the risk of ORN recurrence.

Immediate dental implant placement and restoration in the edentulous mandible in head and neck cancer patients: a systematic review and meta-analysis.

PURPOSE OF REVIEW: Oral rehabilitation with dental implants in head and neck cancer (HNC) patients is challenging. After tooth removal prior to radiotherapy, immediate placement of dental implants during panendoscopy or surgery is thought to reduce the oral rehabilitation time improving patients' quality of life. RECENT FINDINGS: There is lack of consensus on the timing of dental implant placement and loading protocols. The aim of this study was to perform a systematic review of the literature regarding the performance and survival rate of immediately inserted dental implants placed prior to radiotherapy. Of 1003 articles, 10 were finally included comparing immediate vs. delayed placement of implants and comparing the effect of radiotherapy on immediately placed implants. Meta-analysis demonstrated a slightly higher survival of immediately placed implants compared with postponed placed implants [risk ratio: 0.92, 95% confidence interval (95% CI): 0.48-1.78, P = 0.81, I2 = 0%]. The other meta-analysis comparing radiotherapy vs. nonradiotherapy showed a clearly better survival of immediately placed implants not having received radiotherapy (risk ratio: 5.02, 95% CI: 0.92-27.38, P = 0.10, I2  = 56%). SUMMARY: Guidelines are recommended for immediate dental implant placement in the edentulous mandible in HNC patients prior to radiotherapy to allow homogeneity regarding the treatment protocols and thus comparison of treatment outcomes.

Accuracy of Computer-Assisted Surgery in Maxillary Reconstruction: A Systematic Review.

Computer-assisted surgery (CAS) in maxillary reconstruction has proven its value regarding more predictable postoperative results. However, the accuracy evaluation methods differ between studies, and no meta-analysis has been performed yet. A systematic review was performed in the PubMed, Embase, and Cochrane Library databases, using a Patient, Intervention, Comparison and Outcome (PICO) method: (P) patients in need of maxillary reconstruction using free osteocutaneous tissue transfer, (I) reconstructed according to a virtual plan in CAS software, (C) compared to the actual postoperative result, and (O) postoperatively measured by a quantitative accuracy assessment) search strategy, and was reported according to the PRISMA statement. We reviewed all of the studies that quantitatively assessed the accuracy of maxillary reconstructions using CAS. Twelve studies matched the inclusion criteria, reporting 67 maxillary reconstructions. All of the included studies compared postoperative 3D models to preoperative 3D models (revised to the virtual plan). The postoperative accuracy measurements mainly focused on the position of the fibular bony segments. Only approximate comparisons of postoperative accuracy between studies were feasible because of small differences in the postoperative measurement methods; the accuracy of the bony segment positioning ranged between 0.44 mm and 7.8 mm, and between 2.90° and 6.96°. A postoperative evaluation guideline to create uniformity in evaluation methods needs to be considered so as to allow for valid comparisons of postoperative results and to facilitate meta-analyses in the future. With the proper validation of the postoperative results, future research might explore more definitive evidence regarding the management and superiority of CAS in maxillary and midface reconstruction.

Long-term outcomes of implant-based dental rehabilitation in head and neck cancer patients after reconstruction with the free vascularized fibula flap.

The study aimed at evaluating, comprehensively, implant-based dental rehabilitation in head and neck cancer patients after maxillofacial reconstruction with a vascularized free fibula flap (FFF). Data were obtained by retrospectively reviewing the medical records of patients treated in Amsterdam UMC-VU Medical Center. Dental implant survival and implant success according to the Albrektsson criteria were analyzed. Additionally, prosthetic-related outcomes were studied, with a focus on functional dental rehabilitation. In total, 161 implants were placed in FFFs, with a mean follow-up of 4.9 years (range 0.2-23.4). Implant survival was 55.3% in irradiated FFFs and 96% in non-irradiated FFFs. Significant predictors for implant failure were tobacco use and irradiation of the FFF. Implant success was 40.4% in irradiated FFFs and 61.4% in non-irradiated FFFs, mainly due to implant failure and non-functional implants. Implant-based dental rehabilitation was started 45 times in 42 patients, out of 161 FFF reconstructions (27.9%). Thirty-seven patients completed the dental rehabilitation, 29 of whom achieved functional rehabilitation. Irradiation of the FFF negatively influenced attainment of functional rehabilitation. For patients with functional rehabilitation, the body mass index varied at different timepoints: FFF reconstruction, 24.6; dental implantation 23.5; and after placing dental prosthesis, 23.9. Functional implant-based dental rehabilitation, if started, can be achieved in the majority of head and neck cancer patients after FFF reconstruction. Actively smoking patients with an irradiated FFF should be clearly informed about the increased risk for implant and prosthetic treatment failure.

A Novel Treatment Concept for Advanced Stage Mandibular Osteoradionecrosis Combining Isodose Curve Visualization and Nerve Preservation: A Prospective Pilot Study.

BACKGROUND: Osteoradionecrosis (ORN) of the mandible is a severe complication of radiation therapy in head and neck cancer patients. Treatment of advanced stage mandibular osteoradionecrosis may consist of segmental resection and osseous reconstruction, often sacrificing the inferior alveolar nerve (IAN). New computer-assisted surgery (CAS) techniques can be used for guided IAN preservation and 3D radiotherapy isodose curve visualization for patient specific mandibular resection margins. This study introduces a novel treatment concept combining these CAS techniques for treatment of advanced stage ORN. METHODS: Our advanced stage ORN treatment concept includes consecutively: 1) determination of the mandibular resection margins using a 3D 50 Gy isodose curve visualization, 2) segmental mandibular resection with preservation of the IAN with a two-step cutting guide, and 3) 3D planned mandibular reconstruction using a hand-bent patient specific reconstruction plate. Postoperative accuracy of the mandibular reconstruction was evaluated using a guideline. Objective and subjective IAN sensory function was tested for a period of 12 months postoperatively. RESULTS: Five patients with advanced stage ORN were treated with our ORN treatment concept using the fibula free flap. A total of seven IANs were salvaged in two men and three women. No complications occurred and all reconstructions healed properly. Neither non-union nor recurrence of ORN was observed. Sensory function of all IANs recovered after resection up to 100 percent, including the patients with a pathologic fracture due to ORN. The accuracy evaluation showed angle deviations limited to 3.78 degrees. Two deviations of 6.42° and 7.47° were found. After an average of 11,6 months all patients received dental implants to complete oral rehabilitation. CONCLUSIONS: Our novel ORN treatment concept shows promising results for implementation of 3D radiotherapy isodose curve visualization and IAN preservation. Sensory function of all IANs recovered after segmental mandibular resection.

A Postoperative Evaluation Guideline for Computer-Assisted Reconstruction of the Mandible.

Valid comparisons of postoperative accuracy results in computer-assisted reconstruction of the mandible are difficult due to heterogeneity in imaging modalities, mandibular defect classification, and evaluation methodologies between studies. This guideline uses a step-by-step approach guiding the process of imaging, classification of mandibular defects and volume assessment of three-dimensional (3D) models, after which a legitimized quantitative accuracy evaluation method can be performed between the postoperative clinical situation and the preoperative virtual plan. The condyles and the vertical and horizontal corners of the mandible are used as bony landmarks to define virtual lines in the computer-assisted surgery (CAS) software. Between these lines the axial, coronal, and both sagittal mandibular angles are calculated on both pre- and postoperative 3D models of the (neo)mandible and subsequently the deviations are calculated. By superimposing the postoperative 3D model to the preoperative virtually planned 3D model, which is fixed to the XYZ axis, the deviation between pre- and postoperative virtually planned dental implant positions can be calculated. This protocol continues and specifies an earlier publication of this evaluation guideline.

Downregulation of SERPINB13 expression in head and neck squamous cell carcinomas associates with poor clinical outcome.

Tumorigenesis of head and neck squamous cell carcinomas (HNSCC) is associated with various genetic changes such as loss of heterozygosity (LOH) on human chromosome 18q21. This chromosomal region maps a gene cluster coding for a family of intracellular serine protease inhibitors (serpins), including SERPINB13. As SERPINB13 expression in HNSCC has recently been shown to be downregulated both at the mRNA and protein levels, here we investigated if such a low SERPINB13 expression is associated with histopathological and clinical parameters of HNSCC tumors and patient survival. By generating specific antibodies followed by immunohistochemistry on a well-defined cohort of 99 HNSCC of the oral cavity and oropharynx, SERPINB13 expression was found to be partially or totally downregulated in 75% of the HNSCC as compared with endogenous expression in non-neoplastic epithelial cells. Downregulation of SERPINB13 protein expression in HNSCC was significantly associated with the presence of LOH at the SERPINB13 gene in the tumors (p = 0.006), a poor differentiation grade of the tumors (p = 0.001), the presence of a lymph node metastasis (p = 0.012), and a decreased disease-free (p = 0.033) as well as overall (p = 0.018) survival of the patients. This is the first report demonstrating that downregulation of SERPINB13 protein expression in HNSCC is positively associated with poor clinical outcome. Therefore, SERPINB13 seems to act as an important protease inhibitor involved in the progression of HNSCC.

Accuracy of computer-assisted surgery in mandibular reconstruction: A postoperative evaluation guideline.

Comparing accuracy results for mandibular reconstructions using computer-assisted surgery (CAS) is limited due to heterogeneity in image acquisition, extent of mandibular resection, and evaluation methodologies between studies. We propose a practical, feasible and reproducible guideline for standardizing evaluation methods to allow valid comparisons of postoperative results and facilitate meta-analyses in the future. It offers a guide to imaging, data comparison, volume assessment of 3-dimensional models, classification of defects, and it also contains a quantitative accuracy evaluation method.

Accuracy of computer-assisted surgery in mandibular reconstruction: A systematic review.

Computer-assisted surgery (CAS) for mandibular reconstruction was developed to improve conventional treatment methods. In the past years, many different software programs have entered the market, offering numerous approaches for preoperative planning and postoperative evaluation of the CAS process of mandibular reconstruction. In this systematic review, we reviewed planning and evaluation methods in studies that quantitatively assessed accuracy of mandibular reconstruction performed with CAS. We included 42 studies describing 413 mandibular reconstructions planned and evaluated using CAS. The commonest software was Proplan/Surgicase CMF (55%). In most cases, the postoperative virtual 3-dimensional model was compared to the preoperative 3-dimensional model, revised to the virtual plan (64%). The commonest landmark for accuracy measurements was the condyle (54%). Accuracy deviations ranged between 0 mm and 12.5 mm and between 0.9° and 17.5°. Because of a lack of uniformity in planning (e.g., image acquisition, mandibular resection size) and evaluation methodologies, the ability to compare postoperative outcomes was limited; meta-analysis was not performed. A practical and simple guideline for standardizing planning and evaluation methods needs to be considered to allow valid comparisons of postoperative results and facilitate meta-analysis in the future.

Nodal metastasis and survival in oral cancer: Association with protein expression of SLPI, not with LCN2, TACSTD2, or THBS2.

BACKGROUND: Gene expression profiling revealed a strong signature predicting lymph node metastases in oral squamous cell carcinoma (OSCC). Four of the most predictive genes are secretory leukocyte protease inhibitor (SLPI), lipocalin-2 (LCN2), thrombospondin-2 (THBS2), and tumor-associated calcium signal transducer 2 (TACSTD2). This study correlates their protein expression with lymph node metastases, overall survival (OS), and disease-specific survival (DSS). METHODS: Two hundred twelve patients with OSCC were included for protein expression analysis by immunohistochemistry. RESULTS: SLPI expression correlates with lymph node metastases in the whole cohort, not in a subgroup of cT1 to 2N0. SLPI expression correlates with OS (hazard ratio [HR] = 0.61) and DSS (HR = 0.47) in multivariate analysis. LCN2, THBS2, and TACSTD2 show no correlation with lymph node metastases, OS, or DSS. CONCLUSION: Although SLPI expression correlates with lymph node metastases, it has no additional value in determining lymph node metastases in early oral cancer. However, it is an independent predictor for both OS and DSS and therefore a relevant prognostic biomarker in OSCC.

Cannabinoid receptor-2 immunoreactivity is associated with survival in squamous cell carcinoma of the head and neck.

The prediction of progression of individual tumours, prognosis, and survival in squamous cell carcinoma (SCC) of the head and neck is difficult. Cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptor expression is related to survival in several types of cancer, and the aim of this study was to find out whether the expression of CB1 and CB2 receptors is associated with survival in primary SCC of the head and neck. We made immunohistochemical analyses of the cannabinoid receptors on tissue arrays from 240 patients with the disease. Receptor immunoreactivity was classified as none, weak, moderate, or strong staining. Overall survival and disease-specific survival were plotted using Kaplan-Meier survival curves. A multivariate Cox proportional hazard model was created with all the relevant clinical and pathological features. Strong immunoreactivity of the CB2 receptor was significantly associated with reduced disease-specific survival (p=0.007). Cox-proportional hazard ratio (HR) showed that CB2 receptor immunoreactivity contributed to the prediction of survival (HR 3.6, 95% CI 1.5-8.7, p=0.004). Depth of invasion (HR 2.2, 95% CI 1.2-4.2, p=0.01) and vascular invasion (HR 2.5, 95% CI 1.4-4.5, p=0.001) were also associated with survival.

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.