Profiling invasiveness in head and neck cancer: recent contributions of genomic and transcriptomic approaches.

High-throughput molecular profiling approaches have emerged as precious research tools in the field of head and neck translational oncology. Such approaches have identified and/or confirmed the role of several genes or pathways in the acquisition/maintenance of an invasive phenotype and the execution of cellular programs related to cell invasion. Recently published new-generation sequencing studies in head and neck squamous cell carcinoma (HNSCC) have unveiled prominent roles in carcinogenesis and cell invasion of mutations involving NOTCH1 and PI3K-patwhay components. Gene-expression profiling studies combined with systems biology approaches have allowed identifying and gaining further mechanistic understanding into pathways commonly enriched in invasive HNSCC. These pathways include antigen-presenting and leucocyte adhesion molecules, as well as genes involved in cell-extracellular matrix interactions. Here we review the major insights into invasiveness in head and neck cancer provided by high-throughput molecular profiling approaches.

Improved VMAT planning for head and neck tumors with an advanced optimization algorithm

OBJECTIVE In this study, the "Progressive Resolution Optimizer PRO3" (Varian Medical Systems) is compared to the previous version "PRO2" with respect to its potential to improve dose sparing to the organs at risk (OAR) and dose coverage of the PTV for head and neck cancer patients. MATERIALS AND METHODS For eight head and neck cancer patients, volumetric modulated arc therapy (VMAT) treatment plans were generated in this study. All cases have 2-3 phases and the total prescribed dose (PD) was 60-72Gy in the PTV. The study is mainly focused on the phase 1 plans, which all have an identical PD of 54Gy, and complex PTV structures with an overlap to the parotids. Optimization was performed based on planning objectives for the PTV according to ICRU83, and with minimal dose to spinal cord, and parotids outside PTV. In order to assess the quality of the optimization algorithms, an identical set of constraints was used for both, PRO2 and PRO3. The resulting treatment plans were investigated with respect to dose distribution based on the analysis of the dose volume histograms. RESULTS For the phase 1 plans (PD=54Gy) the near maximum dose D2% of the spinal cord, could be minimized to 22±5 Gy with PRO3, as compared to 32±12Gy with PRO2, averaged for all patients. The mean dose to the parotids was also lower in PRO3 plans compared to PRO2, but the differences were less pronounced. A PTV coverage of V95%=97±1% could be reached with PRO3, as compared to 86±5% with PRO2. In clinical routine, these PRO2 plans would require modifications to obtain better PTV coverage at the cost of higher OAR doses. CONCLUSION A comparison between PRO3 and PRO2 optimization algorithms was performed for eight head and neck cancer patients. In general, the quality of VMAT plans for head and neck patients are improved with PRO3 as compared to PRO2. The dose to OARs can be reduced significantly, especially for the spinal cord. These reductions are achieved with better PTV coverage as compared to PRO2. The improved spinal cord sparing offers new opportunities for all types of paraspinal tumors and for re-irradiation of recurrent tumors or second malignancies.

Outcomes in Advanced Head and Neck Cancer Treated with Up-front Neck Dissection prior to (Chemo)Radiotherapy.

OBJECTIVE Our aim was to compare outcomes with and without up-front neck dissection prior to (chemo)radiotherapy in head and neck squamous cell carcinoma. STUDY DESIGN Case series with chart review. SETTING Tertiary referral center. SUBJECTS AND METHODS Outcomes of oropharyngeal, laryngeal, and hypopharyngeal squamous cell carcinoma cases with neck lymph node metastases treated from January 2001 to March 2012 were analyzed. Due to imbalances in baseline characteristics between groups treated with (n = 129) and without (n = 95) up-front neck dissection, propensity score matching was performed. RESULTS Median follow-up was 48 months (range, 12-148). With up-front neck dissection, the hazard ratio for the primary end point, disease-free survival, was 0.63 (95% confidence interval: 0.37-1.06, P = .08). Up-front neck dissection reduced acute grade ≥3 toxicity significantly when xerostomia was excluded (odds ratio: 0.40, 95% confidence interval: 0.20-0.82, P = .012). CONCLUSION Our results indicate less acute treatment toxicity without any significant difference in terms of oncologic outcome with up-front neck dissection prior to (chemo)radiotherapy as compared with (chemo)radiotherapy alone. Well-designed randomized trials are required to verify this result and further investigate the impact of this strategy on late toxicity and oncologic outcome.

Fast Prediction of Femoral Biomechanics Using Supervised Machine Learning and Statistical Shape Modeling

Finite element (FE) analysis is an important computational tool in biomechanics. However, its adoption into clinical practice has been hampered by its computational complexity and required high technical competences for clinicians. In this paper we propose a supervised learning approach to predict the outcome of the FE analysis. We demonstrate our approach on clinical CT and X-ray femur images for FE predictions ( FEP), with features extracted, respectively, from a statistical shape model and from 2D-based morphometric and density information. Using leave-one-out experiments and sensitivity analysis, comprising a database of 89 clinical cases, our method is capable of predicting the distribution of stress values for a walking loading condition with an average correlation coefficient of 0.984 and 0.976, for CT and X-ray images, respectively. These findings suggest that supervised learning approaches have the potential to leverage the clinical integration of mechanical simulations for the treatment of musculoskeletal conditions.

Periacetabular osteotomy restores the typically excessive range of motion in dysplastic hips with a spherical head

BACKGROUND Residual acetabular dysplasia is seen in combination with femoral pathomorphologies including an aspherical femoral head and valgus neck-shaft angle with high antetorsion. It is unclear how these femoral pathomorphologies affect range of motion (ROM) and impingement zones after periacetabular osteotomy. QUESTIONS/PURPOSES (1) Does periacetabular osteotomy (PAO) restore the typically excessive ROM in dysplastic hips compared with normal hips; (2) how do impingement locations differ in dysplastic hips before and after PAO compared with normal hips; (3) does a concomitant cam-type morphology adversely affect internal rotation; and (4) does a concomitant varus-derotation intertrochanteric osteotomy (IO) affect external rotation? METHODS Between January 1999 and March 2002, we performed 200 PAOs for dysplasia; of those, 27 hips (14%) met prespecified study inclusion criteria, including availability of a pre- and postoperative CT scan that included the hip and the distal femur. In general, we obtained those scans to evaluate the pre- and postoperative acetabular and femoral morphology, the degree of acetabular reorientation, and healing of the osteotomies. Three-dimensional surface models based on CT scans of 27 hips before and after PAO and 19 normal hips were created. Normal hips were obtained from a population of CT-based computer-assisted THAs using the contralateral hip after exclusion of symptomatic hips or hips with abnormal radiographic anatomy. Using validated and computerized methods, we then determined ROM (flexion/extension, internal- [IR]/external rotation [ER], adduction/abduction) and two motion patterns including the anterior (IR in flexion) and posterior (ER in extension) impingement tests. The computed impingement locations were assigned to anatomical locations of the pelvis and the femur. ROM was calculated separately for hips with (n = 13) and without (n = 14) a cam-type morphology and PAOs with (n = 9) and without (n = 18) a concomitant IO. A post hoc power analysis based on the primary research question with an alpha of 0.05 and a beta error of 0.20 revealed a minimal detectable difference of 4.6° of flexion. RESULTS After PAO, flexion, IR, and adduction/abduction did not differ from the nondysplastic control hips with the numbers available (p ranging from 0.061 to 0.867). Extension was decreased (19° ± 15°; range, -18° to 30° versus 28° ± 3°; range, 19°-30°; p = 0.017) and ER in 0° flexion was increased (25° ± 18°; range, -10° to 41° versus 38° ± 7°; range, 17°-41°; p = 0.002). Dysplastic hips had a higher prevalence of extraarticular impingement at the anteroinferior iliac spine compared with normal hips (48% [13 of 27 hips] versus 5% [one of 19 hips], p = 0.002). A PAO increased the prevalence of impingement for the femoral head from 30% (eight of 27 hips) preoperatively to 59% (16 of 27 hips) postoperatively (p = 0.027). IR in flexion was decreased in hips with a cam-type deformity compared with those with a spherical femoral head (p values from 0.002 to 0.047 for 95°-120° of flexion). A concomitant IO led to a normalization of ER in extension (eg, 37° ± 7° [range, 21°-41°] of ER in 0° of flexion in hips with concomitant IO compared with 38° ± 7° [range, 17°-41°] in nondysplastic control hips; p = 0.777). CONCLUSIONS Using computer simulation of hip ROM, we could show that the PAO has the potential to restore the typically excessive ROM in dysplastic hips. However, a PAO can increase the prevalence of secondary intraarticular impingement of the aspherical femoral head and extraarticular impingement of the anteroinferior iliac spines in flexion and internal rotation. A cam-type morphology can result in anterior impingement with restriction of IR. Additionally, a valgus hip with high antetorsion can result in posterior impingement with decreased ER in extension, which can be normalized with a varus derotation IO of the femur. However, indication of an additional IO needs to be weighed against its inherent morbidity and possible complications. The results are based on a limited number of hips with a pre- and postoperative CT scan after PAO. Future prospective studies are needed to verify the current results based on computer simulation and to test their clinical importance.

Circulating matrix metalloproteinase 9 levels in relation to sampling methods, femoral and carotid atherosclerosis.

OBJECTIVES To examine whether circulating levels of matrix metalloproteinase 9 (MMP-9) were associated with ultrasound-assessed intima-media thickness (IMT) and echolucent plaques in the carotid and femoral arteries. To examine preanalytical sources of variability in MMP-9 concentrations related to sampling procedures. SUBJECTS AND DESIGN Plasma and serum MMP-9 levels were compared with ultrasound assessed measures of femoral and carotid atherosclerosis, in a cross-sectional study of 61-year-old men (n = 473). Preanalytical sources of variability in MMP-9 levels were examined in 10 healthy subjects. Main outcome measures were circulating levels of MMP-9 in serum and plasma, IMT of the carotid and femoral arteries, and plaque status based on size and echolucency. SETTING Research unit at university hospital. RESULTS Plasma concentrations of total and active MMP-9 were associated with femoral artery IMT independently of traditional cardiovascular risk factors, and were higher in subjects with moderate to large femoral plaques. Plasma MMP-9 concentration was higher in men with echolucent femoral plaques (P = 0.006) compared with subjects without femoral plaques. No similar associations were found for carotid plaques. MMP-9 concentrations were higher in serum than in plasma, and higher when sampling was performed with Vacutainer than with syringe. MMP-9 levels in serum were more strongly associated with peripheral neutrophil count compared with MMP-9 levels in plasma. CONCLUSIONS Plasma MMP-9 levels were associated with atherosclerosis in the femoral artery, and total MMP-9 concentration was higher in men with echolucent femoral plaques. The choice of sample material and sampling method affect the measurements of circulating MMP-9 levels.

Circulating oxidized low-density lipoprotein is associated with echolucent plaques in the femoral artery independently of hsCRP in 61-year-old men.

OBJECTIVES The aim of the study was to test the hypothesis that circulating markers of inflammation (high-sensitive C-reactive protein, hsCRP) and oxidative modification of lipids (oxidized low-density lipoprotein, oxLDL) were associated with the occurrence of echolucent rather than echogenic femoral artery plaques in a cross-sectional population based cohort of 513, 61-year-old men. BACKGROUND The relationships between circulating oxLDL, hsCRP and the occurrence of echolucent plaques in the femoral artery have not previously been investigated. METHODS The levels of circulating oxLDL and hsCRP were determined in plasma by ELISA. Plaque occurrence, size and echogenicity were measured by B-mode ultrasound in the right femoral artery. Assessment of plaque echogenicity was based on the classification (grades 1-4) proposed by Gray-Weale et al. RESULTS A higher frequency of echolucent femoral plaques was observed in subjects with the metabolic syndrome and current smokers (p=0.01 and p<0.001, respectively) as well as with increasing levels of oxLDL and hsCRP (p=0.002 and p=0.005, respectively). In a multiple logistic regression analysis oxLDL and current smokers turned out to be independent associated with the presence of echolucent femoral artery plaques. CONCLUSIONS The results of the present study support our hypothesis that circulating oxLDL is a marker of an unstable echolucent plaque phenotype in the femoral artery in man.

Serial [18F]-fluoromisonidazole PET during radiochemotherapy for locally advanced head and neck cancer and its correlation with outcome.

PURPOSE The aim was to assess changes of tumour hypoxia during primary radiochemotherapy (RCT) for head and neck cancer (HNC) and to evaluate their relationship with treatment outcome. MATERIAL AND METHODS Hypoxia was assessed by FMISO-PET in weeks 0, 2 and 5 of RCT. The tumour volume (TV) was determined using FDG-PET/MRI/CT co-registered images. The level of hypoxia was quantified on FMISO-PET as TBRmax (SUVmaxTV/SUVmean background). The hypoxic subvolume (HSV) was defined as TV that showed FMISO uptake ⩾1.4 times blood pool activity. RESULTS Sixteen consecutive patients (T3-4, N+, M0) were included (mean follow-up 31, median 44months). Mean TBRmax decreased significantly (p<0.05) from 1.94 to 1.57 (week 2) and 1.27 (week 5). Mean HSV in week 2 and week 5 (HSV2=5.8ml, HSV3=0.3ml) were significantly (p<0.05) smaller than at baseline (HSV1=15.8ml). Kaplan-Meier plots of local recurrence free survival stratified at the median TBRmax showed superior local control for less hypoxic tumours, the difference being significant at baseline and after 2weeks (p=0.031, p=0.016). CONCLUSIONS FMISO-PET documented that in most HNC reoxygenation starts early during RCT and is correlated with better outcome.

Comparison of 2.5D and 3D Quantification of Femoral Head Coverage in Normal Control Subjects and Patients with Hip Dysplasia.

Hip dysplasia is characterized by insufficient femoral head coverage (FHC). Quantification of FHC is of importance as the underlying goal of the surgery to treat hip dysplasia is to restore a normal acetabular morphology and thereby to improve FHC. Unlike a pure 2D X-ray radiograph-based measurement method or a pure 3D CT-based measurement method, previously we presented a 2.5D method to quantify FHC from a single anteriorposterior (AP) pelvic radiograph. In this study, we first quantified and compared 3D FHC between a normal control group and a patient group using a CT-based measurement method. Taking the CT-based 3D measurements of FHC as the gold standard, we further quantified the bias, precision and correlation between the 2.5D measurements and the 3D measurements on both the control group and the patient group. Based on digitally reconstructed radiographs (DRRs), we investigated the influence of the pelvic tilt on the 2.5D measurements of FHC. The intraclass correlation coefficients (ICCs) for absolute agreement was used to quantify interobserver reliability and intraobserver reproducibility of the 2.5D measurement technique. The Pearson correlation coefficient, r, was used to determine the strength of the linear association between the 2.5D and the 3D measurements. Student's t-test was used to determine whether the differences between different measurements were statistically significant. Our experimental results demonstrated that both the interobserver reliability and the intraobserver reproducibility of the 2.5D measurement technique were very good (ICCs > 0.8). Regression analysis indicated that the correlation was very strong between the 2.5D and the 3D measurements (r = 0.89, p < 0.001). Student's t-test showed that there were no statistically significant differences between the 2.5D and the 3D measurements of FHC on the patient group (p > 0.05). The results of this study provided convincing evidence demonstrating the validity of the 2.5D measurements of FHC from a single AP pelvic radiograph and proved that it could serve as a surrogate for 3D CT-based measurements. Thus it may be possible to use this method to avoid a CT scan for the purpose of estimating 3D FHC in diagnosis and post-operative treatment evaluation of patients with hip dysplasia.

Protrusio acetabuli: joint loading with severe pincer impingement and its theoretical implications for surgical therapy

Severe pincer impingement (acetabular protrusio) is an established cause of hip pain and osteoarthritis. The proposed underlying pathomechanism is a dynamic pathological contact of the prominent acetabular rim with the femoral head-neck junction. However, this cannot explain the classically described medial osteoarthritis in these hips. We therefore asked: (1) Does an overload exist in the medial aspect of the protrusio joint? and (2) What is the influence of three contemporary joint-preserving procedures on load distribution in protrusio hips? In vivo force and motion data for walking and standing to sitting were applied to six 3D finite element models (normal, dysplasia, protrusio, acetabular rim trimming, acetabular reorientation, and combined reorientation/rim trimming). Compared with dysplasia, the protrusio joint resulted in opposite patterns of von Mises stress and contact pressure during walking. In protrusio hips, we found an overload at the medial margin of the lunate surface (54% higher than normal). Isolated rim trimming further increased the medial overload (up to 28% higher than protrusio), whereas acetabular reorientation with/without rim trimming reduced stresses by up to 25%. Our results can be used as an adjunct for surgical decision making in the treatment of acetabular protrusio.

Spine radiography in the evaluation of back and neck pain in an orthopaedic emergency clinic

BACKGROUND AND OBJECTIVES Despite the recommendations of national and international societies for the treatment of patients with acute neck and back pain, still too many radiologic examinations were performed. The purpose of this study was to analyze and optimize diagnostics and treatment of patients with acute back pain. METHODS The medical records of 484 patients presented to the emergency clinic with acute neck or back pain were analyzed for clinical history, physical examination, radiographic findings and therapy. RESULTS Radiographs of the lumbar, cervical, or thoracic spine were performed in 338 cases (70%). Radiographs were normal in 142 patients (42%) and degenerative changes were identified in 123 patients (36%). Only 2 patients (0.4%) had radiographic findings that had direct therapeutic relevance: 1 patient with metastatic disease and 1 patient with posttraumatic C1-C2 instability. For most patients without sensorimotor deficits and absent specific indications for radiography (“red flags”), therapy was not affected by the results of radiography. CONCLUSIONS Plain radiography of the spine was unnecessary in most patients initially evaluated with non-specific acute back pain and does not improve the clinical outcome. The implementation of national and international guidelines is a slow process, but helps to reduce costs and to protect patients from unnecessary ionizing radiation exposure.

Computer Assisted Diagnosis and Treatment Planning of Femoroacetabular Impingement (FAI)

Femoroacetabular impingement (FAI) is a dynamic conflict of the hip defined by a pathological, early abutment of the proximal femur onto the acetabulum or pelvis. In the past two decades, FAI has received increasing focus in both research and clinical practice as a cause of hip pain and prearthrotic deformity. Anatomical abnormalities such as an aspherical femoral head (cam-type FAI), a focal or general overgrowth of the acetabulum (pincer-type FAI), a high riding greater or lesser trochanter (extra-articular FAI), or abnormal torsion of the femur have been identified as underlying pathomorphologies. Open and arthroscopic treatment options are available to correct the deformity and to allow impingement-free range of motion. In routine practice, diagnosis and treatment planning of FAI is based on clinical examination and conventional imaging modalities such as standard radiography, magnetic resonance arthrography (MRA), and computed tomography (CT). Modern software tools allow three-dimensional analysis of the hip joint by extracting pelvic landmarks from two-dimensional antero-posterior pelvic radiographs. An object-oriented cross-platform program (Hip2Norm) has been developed and validated to standardize pelvic rotation and tilt on conventional AP pelvis radiographs. It has been shown that Hip2Norm is an accurate, consistent, reliable and reproducible tool for the correction of selected hip parameters on conventional radiographs. In contrast to conventional imaging modalities, which provide only static visualization, novel computer assisted tools have been developed to allow the dynamic analysis of FAI pathomechanics. In this context, a validated, CT-based software package (HipMotion) has been introduced. HipMotion is based on polygonal three-dimensional models of the patient’s pelvis and femur. The software includes simulation methods for range of motion, collision detection and accurate mapping of impingement areas. A preoperative treatment plan can be created by performing a virtual resection of any mapped impingement zones both on the femoral head-neck junction, as well as the acetabular rim using the same three-dimensional models. The following book chapter provides a summarized description of current computer-assisted tools for the diagnosis and treatment planning of FAI highlighting the possibility for both static and dynamic evaluation, reliability and reproducibility, and its applicability to routine clinical use.

Surgical Technique: Reverse Periacetabular Osteotomy

Acetabular retroversion is the result of an externally rotated hemipelvis rather than a focal overgrowth of the anterior wall and/or hypoplasia of the posterior wall. Acetabular retroversion is a cause of pincer impingement which, if left untreated, can lead to hip pain and osteoarthritis. The causal surgical treatment in hips with acetabular retroversion is acetabular reorientation with a reverse periacetabular osteotomy (PAO). Indication is based on a positive correlation among symptoms (typically groin pain), physical findings on examination (positive anterior impingement test and decreased flexion and internal rotation), and radiographic signs for acetabular retroversion. These include a positive crossover, posterior wall, and ischial spine sign. A reverse PAO is performed with four osteotomies and a controlled fracture. Unlike reorientation of the acetabular fragment in dysplastic hips, correction for acetabular retroversion is achieved by a combined extension and internal rotation of the acetabular fragment. Typically, a small supra-acetabular wedge resection is required to allow sufficient extension of the fragment. The quality of acetabular reorientation is evaluated by intraoperative AP pelvic radiographs. In addition, intraoperative testing of range of motion following acetabular reorientation is mandatory. An arthrotomy and offset correction of the femoral head-neck area is indicated in hips with decreased internal rotation following acetabular reorientation. In a 10-year follow-up study of reverse PAO, a favorable outcome with preservation of all native joints was found. Correct acetabular orientation and, if necessary, a concomitant offset correction were the keys of successful outcome.