Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer.

Head and neck cancer constitutes the 6th most common malignancy worldwide and affects the crucial anatomical structures and physiological functions of the upper aerodigestive tract. Classical therapeutic strategies such as surgery and radiotherapy carry substantial toxicity and functional impairment. Moreover, the loco-regional control rates as well as overall survival still need to be improved in subgroups of patients. The scatter-factor/hepatocyte growth factor receptor tyrosine kinase MET is an established effector in the promotion, maintenance and progression of malignant transformation in a wide range of human malignancies, and has been gaining considerable interest in head and neck cancer over the last 15 years. Aberrant MET activation due to overexpression, mutations, tumor-stroma paracrine loops, and cooperative/redundant signaling has been shown to play prominent roles in epithelial-to-mesenchymal transition, angiogenesis, and responses to anti-cancer therapeutic modalities. Accumulating preclinical and translational evidence highly supports the increasing interest of MET as a biomarker for lymph node and distant metastases, as well as a potential marker of stratification for responses to ionizing radiation. The relevance of MET as a therapeutic molecular target in head and neck cancer described in preclinical studies remains largely under-evaluated in clinical trials, and therefore inconclusive. Also in the context of anti-cancer targeted therapy, a large body of preclinical data suggests a central role for MET in treatment resistance towards multiple therapeutic modalities in malignancies of the head and neck region. These findings, as well as the potential use of combination therapies including MET inhibitors in these tumors, need to be further explored.

Metformin and the risk of head and neck cancer: a case-control analysis

AIMS Metformin use has been associated with a decreased risk of some cancers, although data on head and neck cancer (HNC) are scarce. We explored the relation between the use of antidiabetic drugs and the risk of HNC. METHODS We conducted a case-control analysis in the UK-based Clinical Practice Research Datalink (CPRD) of people with incident HNC between 1995 and 2013 below the age of 90 years. Six controls per case were matched on age, sex, calendar time, general practice and number of years of active history in the CPRD prior to the index date. Other potential confounders including body mass index (BMI), smoking, alcohol consumption and comorbidities were also evaluated. The final analyses were adjusted for BMI, smoking and diabetes mellitus (or diabetes duration in a sensitivity analysis). Results are presented as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS Use of metformin was neither associated with a statistically significant altered risk of HNC overall (1-29 prescriptions: adjusted OR 0.87, 95% CI 0.61-1.24 and ≥ 30 prescriptions adjusted OR 0.80, 95% CI 0.53-1.22), nor was long-term use of sulphonylureas (adjusted OR 0.87, 95% CI 0.59-1.30), or any insulin use (adjusted OR 0.92, 95% CI 0.63-1.35). However, we found a (statistically non-significant) decreased risk of laryngeal cancer associated with long-term metformin use (adjusted OR 0.41, 95% CI 0.17-1.03). CONCLUSIONS In this population-based study, the use of antidiabetic drugs was not associated with a materially altered risk of HNC. Our data suggest a protective effect of long-term metformin use for laryngeal cancer.

Sharp neck injuries in suicidal intention

Sharp neck injuries in suicidal intention often present as serious emergency situations with the need for an immediate diagnosis and treatment. We report our study of the clinical evolution of this emergency condition. This study investigates the cases of sharp neck injuries in suicidal intention treated at our institution between 2000 and 2010. Patient records were collected in a retrospectively reviewed and analyzed database. The current literature was compared to our findings. We found 36 cases (10 female and 26 male). The neck injuries were superficial and profound in 16 and 20 patients, respectively. Twenty-two patients were seen by the Head and Neck surgeon. A surgical neck exploration was necessary in 19 cases. Tracheal, laryngeal, pharyngeal and vascular injuries were found in one, five, three and three cases, respectively. The hospital stay ranged from 1 to 47 days. All the patients underwent emergency psychiatric assessment and were subsequently referred for psychiatric treatment. One patient died in the emergency room from an additional arterial injury to the wrist. Sharp neck injuries in suicidal intention treated with an interdisciplinary medical, surgical and psychiatric emergency assessment and treatment have low mortality and morbidity.

Bilateral chylothorax following neck dissection: a case report.

BACKGROUND Chylothorax is an extremely rare but potentially life-threatening complication after radical neck dissection. We report the case of a bilateral chylothorax after total thyroidectomy and cervico-central and cervico-lateral lymphadenectomy for thyroid carcinoma. CASE PRESENTATION A 40-year-old European woman underwent total thyroidectomy and neck dissection for papillary thyroid carcinoma. Postoperatively she developed dyspnoea and pleural effusion. A chylothorax was found and the initial conservative therapy was not successful. She had to be operated on again and the thoracic duct was legated. CONCLUSION The case presentation reports a very rare complication after total thyroidectomy and neck dissection, but it has to be kept in mind to prevent dangerous complications.

Pneumomediastinum and soft tissue emphysema of the neck in postmortem CT and MRI; a new vital sign in hanging?

Spontaneous pneumomediastinum commonly occurs in healthy young men or parturient women in whom an increased intra-alveolar pressure (Valsalva maneuver, asthma, cough, emesis) leads to the rupture of the marginal pulmonary alveoli. The air ascends along the bronchi to the mediastinum and the subcutaneous space of the neck, causing cervico-fascial subcutaneous emphysema in 70-90% of cases. Ninety-five forensic cases, including five cases of hanging, were examined using postmortem multi-slice computed tomography (MSCT) and magnetic resonance imaging (MRI) prior to autopsy until December 2003. This paper describes the findings of pneumomediastinum and cervical emphysema in three of five cases of hanging. The mechanism of its formation is discussed based on these results and a review of the literature. In conclusion, when putrefaction gas can be excluded the findings of pneumomediastinum and cervical soft tissue emphysema serve as evidence of vitality of a hanged person. Postmortem cross-sectional imaging is considered a useful visualization tool for emphysema, with a great potential for examination and documentation.

Impact of weight loss on survival after chemoradiation for locally advanced head and neck cancer: secondary results of a randomized phase III trial (SAKK 10/94).

BACKGROUND To analyze the impact of weight loss before and during chemoradiation on survival outcomes in patients with locally advanced head and neck cancer. METHODS From 07/1994-07/2000 a total of 224 patients with squamous cell carcinoma of the head and neck were randomized to either hyperfractionated radiation therapy alone or the same radiation therapy combined with two cycles of concomitant cisplatin. The primary endpoint was time to any treatment failure (TTF); secondary endpoints were locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS). Patient weight was measured 6 months before treatment, at treatment start and treatment end. RESULTS The proportion of patients with >5% weight loss was 32% before, and 51% during treatment, and the proportion of patients with >10% weight loss was 12% before, and 17% during treatment. After a median follow-up of 9.5 years (range, 0.1 - 15.4 years) weight loss before treatment was associated with decreased TTF, LRRFS, DMFS, cancer specific survival and OS in a multivariable analysis. However, weight loss during treatment was not associated with survival outcomes. CONCLUSIONS Weight loss before and during chemoradiation was commonly observed. Weight loss before but not during treatment was associated with worse survival.

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.

Relative femoral neck lengthening improves pain and hip function in proximal femoral deformities with a high-riding trochanter

BACKGROUND Complex proximal femoral deformities, including an elevated greater trochanter, short femoral neck, and aspherical head-neck junction, often result in pain and impaired hip function resulting from intra-/extraarticular impingement. Relative femoral neck lengthening may address these deformities, but mid-term results of this approach have not been widely reported. QUESTIONS/PURPOSES Do patients who have undergone relative femoral neck lengthening show (1) less hip pain and greater function; (2) improved radiographic parameters; (3) significant complications requiring subsequent surgery; and (4) progression of osteoarthrosis (OA) or conversion to total hip arthroplasty (THA) at mid-term followup? METHODS We retrospectively reviewed 40 patients (41 hips) with isolated relative femoral neck lengthening between 1998 and 2006 with sequelae of Legg-Calvé-Perthes disease (38 hips [93%]), slipped capital femoral epiphysis (two hips [5%]), and postseptic arthritis (one hip [2%]). During this time, the general indications for this procedure included a high-riding greater trochanter with a short femoral neck with abductor weakness and symptomatic intra-/extraarticular impingement. Mean patient followup was 8 years (range, 5-13 years), and complete followup was available in 38 patients (39 hips [95%]). We evaluated pain and function with the impingement test, limp, abductor force, Merle d'Aubigné-Postel score, and range of motion. Radiographic parameters included trochanteric height, alpha angle, and progression of OA. Subsequent surgeries, complications, and conversion to THA were summarized. RESULTS The proportion of positive anterior impingement tests decreased from 93% (38 of 41 hips) preoperatively to 49% (17 of 35 hips) at latest followup (p = 0.002); the proportion of limp decreased from 76% (31 of 41 hips) to 9% (three of 35 hips; p < 0.001); the proportion of normal abductor strength increased from 17% (seven of 41 hips) to 91% (32 of 35 hips; p < 0.001); mean Merle d'Aubigné-Postel score increased from 14 ± 1.7 (range, 9-17) to 17 ± 1.5 (range, 13-18; p < 0.001); mean internal rotation increased to 25° ± 15° (range, 0°-60°; p = 0.045), external rotation to 32° ± 14° (range, 5°-70°; p = 0.013), and abduction to 37° ± 13° (range, 10°-50°; p = 0.004). Eighty percent of hips (33 of 41 hips) showed normal trochanteric height; alpha angle improved to 42° ± 10° (range, 27°-90°). Two hips (5%) had subsequent surgeries as a result of lack of containment; four of 41 hips (10%) had complications resulting in reoperation. Fourteen of 35 hips (40%) showed progression of OA; four of 40 hips (10%) converted to THA. CONCLUSIONS Relative femoral neck lengthening in hips with combined intra- and extraarticular impingement results in reduced pain, improved function, and improved radiographic parameters of the proximal femur. Although lack of long-term complications is gratifying, progression of OA was not prevented and remains an area for future research.

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.

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.