Veränderung von Inzidenz und Mortalität von Kopf-Hals-Malignomen in Rheinland-Pfalz, 2000-2009 [Changes in Incidence and Mortality Trends of Head and Neck Cancer in Rhineland-Palatinate, 2000-2009].

BACKGROUND: Epidemiological data on HNC are often reported aggregated despite their anatomical and histological heterogeneity. In Germany, few studies have analyzed incidence and mortality trends separately for specific anatomic sites. Furthermore, little is known about whether the incidence of HPV-associated tumour entities of the head and neck region has increased. METHODS: Based on cancer registry data from Rhineland-Palatinate from 2000 to 2009, age-standardized incidence and mortality rates were calculated for all HNC sites and localisation groups that might be HPV-associated according to the literature. Trends were analyzed by Joinpoint regression and reported as the annual percentage change (APC). RESULTS: Throughout the study period, 8 055 incident cases and 3 177 deaths were identified. The incidence rates of overall HNC increased among women (APC:+2.2%) and declined slightly among men (- 0.9%). Significantly increasing incidence rates among women were seen for tumours of the oral cavity (+2.7%) and the oropharynx (+3.6%). Among men, a significant decrease in incidence rates for tumours of the hypopharynx (-3.4%) and the larynx (-2.7%) are noteworthy. Cancers at HPV-associated sites showed increased incidence rates in men (+3.3%) and women (+4.3%). A decrease in mortality was found for tumours of the larynx in both sexes (-5.8% men,-9.1% women). CONCLUSIONS: A detailed analysis by localisation of HNC showed significant and often opposing trends for men and women regarding incidence and mortality.

The radiosensitizing activity of the SMAC-mimetic, Debio 1143, is TNFα-mediated in head and neck squamous cell carcinoma.

BACKGROUND AND PURPOSE: Second mitochondria-derived activator of caspase (SMAC)-mimetics are a new class of targeted drugs that specifically induce apoptotic cancer cell death and block pro-survival signaling by antagonizing selected members of the inhibitor of apoptosis protein (IAP) family. MATERIAL AND METHODS: The present study was designed to investigate the radiosensitizing effect and optimal sequence of administration of the novel SMAC-mimetic Debio 1143 in vitro and in vivo. Apoptosis, alteration of DNA damage repair (DDR), and tumor necrosis factor-alpha (TNF-α) signaling were examined. RESULTS: In vitro, Debio 1143 displayed anti-proliferative activity and enhanced intrinsic radiation sensitivity in 5/6 head and neck squamous cell carcinoma (HNSCC) cell lines in a synergistic manner. In vivo, Debio 1143 dose-dependently radio-sensitized FaDu and SQ20B xenografts, resulting in complete tumor regression in 8/10 FaDu-xenografted mice at the high dose level. At the molecular level, Debio 1143 combined with radiotherapy (RT) induced enhancement of caspase-3 activity, increase in Annexin V-positive cells and karyopyknosis, and increase in TNF-α mRNA levels. Finally, in a neutralization experiment using a TNF-α-blocking antibody and a caspase inhibitor, it was shown that the radiosensitizing effect of Debio 1143 is mediated by caspases and TNF-α. CONCLUSIONS: These results demonstrate that the novel SMAC-mimetic Debio 1143 is a radiosensitizing agent that is worthy of further investigation in clinical trials in combination with radiotherapy.

Impaired aldehyde dehydrogenase 1 subfamily member 2A-dependent retinoic acid signaling is related with a mesenchymal-like phenotype and an unfavorable prognosis of head and neck squamous cell carcinoma.

BACKGROUND: An inverse correlation between expression of the aldehyde dehydrogenase 1 subfamily A2 (ALDH1A2) and gene promoter methylation has been identified as a common feature of oropharyngeal squamous cell carcinoma (OPSCC). Moreover, low ALDH1A2 expression was associated with an unfavorable prognosis of OPSCC patients, however the causal link between reduced ALDH1A2 function and treatment failure has not been addressed so far. METHODS: Serial sections from tissue microarrays of patients with primary OPSCC (n = 101) were stained by immunohistochemistry for key regulators of retinoic acid (RA) signaling, including ALDH1A2. Survival with respect to these regulators was investigated by univariate Kaplan-Meier analysis and multivariate Cox regression proportional hazard models. The impact of ALDH1A2-RAR signaling on tumor-relevant processes was addressed in established tumor cell lines and in an orthotopic mouse xenograft model. RESULTS: Immunohistochemical analysis showed an improved prognosis of ALDH1A2(high) OPSCC only in the presence of CRABP2, an intracellular RA transporter. Moreover, an ALDH1A2(high)CRABP2(high) staining pattern served as an independent predictor for progression-free (HR: 0.395, p = 0.007) and overall survival (HR: 0.303, p = 0.002), suggesting a critical impact of RA metabolism and signaling on clinical outcome. Functionally, ALDH1A2 expression and activity in tumor cell lines were related to RA levels. While administration of retinoids inhibited clonogenic growth and proliferation, the pharmacological inhibition of ALDH1A2-RAR signaling resulted in loss of cell-cell adhesion and a mesenchymal-like phenotype. Xenograft tumors derived from FaDu cells with stable silencing of ALDH1A2 and primary tumors from OPSCC patients with low ALDH1A2 expression exhibited a mesenchymal-like phenotype characterized by vimentin expression. CONCLUSIONS: This study has unraveled a critical role of ALDH1A2-RAR signaling in the pathogenesis of head and neck cancer and our data implicate that patients with ALDH1A2(low) tumors might benefit from adjuvant treatment with retinoids.

Postoperative Adjuvant Lapatinib and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib Monotherapy in High-Risk Patients With Resected Squamous Cell Carcinoma of the Head and Neck: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study.

PURPOSE: This multicenter phase III study evaluated the efficacy and safety of lapatinib, an epidermal growth factor receptor/ErbB2 inhibitor, administered concomitantly with chemoradiotherapy and as maintenance monotherapy in patients with high-risk surgically treated squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with resected stage II to IVA SCCHN, with a surgical margin ≤ 5 mm and/or extracapsular extension, were randomly assigned to chemoradiotherapy (66 Gy total radiation dose and cisplatin 100 mg/m(2) per day administered on days 1, 22, and 43) plus placebo or lapatinib (1,500 mg per day) before and during chemoradiotherapy, followed by 12 months of maintenance monotherapy. RESULTS: Six hundred eighty-eight patients were enrolled (lapatinib, n = 346; placebo, n = 342). With a median follow-up time of 35.3 months, the study ended early because of the apparent plateauing of disease-free survival (DFS) events. Median DFS assessed by an independent review committee was 53.6 months and not reached for lapatinib and placebo, respectively (hazard ratio, 1.10; 95% CI, 0.85 to 1.43). Investigator-assessed results confirmed the independent review committee assessment. No significant differences in DFS by human papillomavirus status or overall survival were observed between treatment arms. Similar numbers of patients in both treatment arms experienced adverse events (AEs), with more patients in the lapatinib arm than the placebo arm experiencing serious AEs (48% v 40%, respectively). The most commonly observed treatment-related AEs were diarrhea and rash, both predominantly in the lapatinib arm. CONCLUSION: Addition of lapatinib to chemoradiotherapy and its use as long-term maintenance therapy does not offer any efficacy benefits and had additional toxicity compared with placebo in patients with surgically treated high-risk SCCHN.

Low-level laser therapy for the prevention of low salivary flow rate after radiotherapy and chemotherapy in patients with head and neck cancer

Abstract Objective: To determine whether low-level laser therapy can prevent salivary hypofunction after radiotherapy and chemotherapy in head and neck cancer patients. Materials and Methods: We evaluated 23 head and neck cancer patients, of whom 13 received laser therapy and 10 received clinical care only. An InGaAlP laser was used intra-orally (at 660 nm and 40 mW) at a mean dose of 10.0 J/cm2 and extra-orally (at 780 nm and 15 mW) at a mean dose of 3.7 J/cm2, three times per week, on alternate days. Stimulated and unstimulated sialometry tests were performed before the first radiotherapy and chemotherapy sessions (N0) and at 30 days after the end of treatment (N30). Results: At N30, the mean salivary flow rates were significantly higher among the laser therapy patients than among the patients who received clinical care only, in the stimulated and unstimulated sialometry tests (p = 0.0131 and p = 0.0143, respectively). Conclusion: Low-level laser therapy, administered concomitantly with radiotherapy and chemotherapy, appears to mitigate treatment-induced salivary hypofunction in patients with head and neck cancer.

HPV & head and neck cancer: a descriptive update

The incidence of head and neck squamous cell carcinoma (HNSCC) has been gradually increasing over the last three decades. Recent data have now attributed a viral aetiology to a subset of head and neck cancers. Several studies indicate that oral human papillomavirus (HPV) infection is likely to be sexually acquired. The dominance of HPV 16 in HPV+ HNSCC is even greater than that seen in cervical carcinoma of total worldwide cases. Strong evidence suggests that HPV+ status is an important prognostic factor associated with a favourable outcome in head and neck cancers. Approximately 30 to 40% of HNSCC patients with present with early stage I/II disease. These patients are treated with curative intent using single modality treatments either radiation or surgery alone. A non-operative approach is favored for patients in which surgery followed by either radiation alone or radiochemotherapy may lead to severe functional impairment. Cetuximab, a humanized mouse anti-EGFR IgG1 monoclonal antibody, improved locoregional control and overall survival in combination with radiotherapy in locally advanced tumours but at the cost of some increased cardiac morbidity and mortality. Finally, the improved prognosis and treatment responses to chemotherapy and radiotherapy by HPV+ tumours may suggest that HPV status detection is required to better plan and individualize patient treatment regimes.

Targeting Adenoviral Gene Therapy Vectors to Head and Neck Squamous Cell Carcinoma and Heart

Gene therapy aims to treat diseases by introducing genetic material to the diseased tissue. For cancer treatment it is important to destroy cancerous cells; this can be achieved by introducing a gene, which induces cell death or by allowing viral vectors to replicate, which also results in destruction of cancerous cells. For cardiac diseases the approach is more like the former, except the gene produces beneficial effects, like angiogenesis. Adenoviruses have many beneficial qualities, which make the virus an interesting gene therapy vector; it can be produced relatively easily, its manipulation is quite easy and it has naturally broad tropism. By removing or replacing certain genes in the adenoviral genome, it can be made non-replicative. In this study, adenoviral receptor expression patterns were characterized in both head and neck squamous cell carcinoma and the human heart. Adenovirus serotype 5 receptor expression in head and neck cancer cell lines was found to be highly variable between cell lines and overall at lower levels, while Ad35 receptor expression was more uniform and at higher levels in all analyzed cell lines. It was also shown that a hybrid virus Ad5/35 is able to infect cells refractory to Ad5, which correlates with receptor expression in these cells. Furthermore, this difference in infection properties extends to cell killing efficiency in case of conditionally replicative viruses. Expression levels of adenoviral receptors CAR, CD46, CD86 and αv-integrins were found to be high both in normal and dilated cardiomyopathy heart tissue. The receptor levels also correlate with transduction efficiency after intracardiac injection. Ad5 showed superior transduction ability compared with Ad5/35, but evoked also a more profound immune reaction when administered this way. Adenoviral gene therapy vectors are the most used delivery vehicles in clinical trials to date. These vectors have proven to be well tolerated and positive results have been obtained when combined with traditional treatments, although poor transduction efficiency has often been reported due to low-level expression of viral receptors on target cells. In spite of this, the results are encouraging and merit for further research.

Safety and tolerability of controlled-release oxycodone on postoperative pain in patients submitted to the oncologic head and neck surgery

Objective: To evaluate the safety and tolerability of controlled-release oxycodone in the treatment of postoperative pain of head and neck oncologic resections.Methods: We conducted a prospective, observational and open study, with 83 patients with moderate to severe pain after head and neck oncological operations. All patients received general anesthesia with propofol, fentanyl and sevoflurane. Postoperatively, should they have moderate or severe pain, we began controlled-release oxycodone 20 mg 12/12 b.i.d on the first day and 10 mg b.i.d. on the second. We assessed the frequency and intensity of adverse effects, the intensity of postoperative pain by a verbal numeric scale and the use of rescue analgesia from 12 hours after administration of the drug and between 7 and 13 days after the last oxycodone dose.Results: The most common adverse events were nausea, vomiting, dizziness, pruritus, insomnia, constipation and urinary retention, most mild. No serious adverse events occurred. In less than 12 hours after the use of oxycodone, there was a significant decrease in the intensity of postoperative pain, which remained until the end of the study. The rescue medication was requested at a higher frequency when the opioid dose was reduced, or after its suspension.Conclusion: Controlled release oxycodone showed to be safe and well tolerated and caused a significant decrease in post-operative pain.

Differentiation of Metabolically Distinct Areas within Head and Neck Region using Dynamic 18F-FDG Positron Emission Tomography Imaging

Positron Emission Tomography (PET) using ¹⁸F-FDG is playing a vital role in the diagnosis and treatment planning of cancer. However, the most widely used radiotracer, ¹⁸F-FDG, is not specific for tumours and can also accumulate in inflammatory lesions as well as normal physiologically active tissues making diagnosis and treatment planning complicated for the physicians. Malignant, inflammatory and normal tissues are known to have different pathways for glucose metabolism which could possibly be evident from different characteristics of the time activity curves from a dynamic PET acquisition protocol. Therefore, we aimed to develop new image analysis methods, for PET scans of the head and neck region, which could differentiate between inflammation, tumour and normal tissues using this functional information within these radiotracer uptake areas. We developed different dynamic features from the time activity curves of voxels in these areas and compared them with the widely used static parameter, SUV, using Gaussian Mixture Model algorithm as well as K-means algorithm in order to assess their effectiveness in discriminating metabolically different areas. Moreover, we also correlated dynamic features with other clinical metrics obtained independently of PET imaging. The results show that some of the developed features can prove to be useful in differentiating tumour tissues from inflammatory regions and some dynamic features also provide positive correlations with clinical metrics. If these proposed methods are further explored then they can prove to be useful in reducing false positive tumour detections and developing real world applications for tumour diagnosis and contouring.

Genetic alterations in head and neck squamous cell carcinomas

The genetic alterations observed in head and neck cancer are mainly due to oncogene activation (gain of function mutations) and tumor suppressor gene inactivation (loss of function mutations), leading to deregulation of cell proliferation and death. These genetic alterations include gene amplification and overexpression of oncogenes such as myc, erbB-2, EGFR and cyclinD1 and mutations, deletions and hypermethylation leading to p16 and TP53 tumor suppressor gene inactivation. In addition, loss of heterozygosity in several chromosomal regions is frequently observed, suggesting that other tumor suppressor genes not yet identified could be involved in the tumorigenic process of head and neck cancers. The exact temporal sequence of the genetic alterations during head and neck squamous cell carcinoma (HNSCC) development and progression has not yet been defined and their diagnostic or prognostic significance is controversial. Advances in the understanding of the molecular basis of head and neck cancer should help in the identification of new markers that could be used for the diagnosis, prognosis and treatment of the disease.

Systematic head and neck physical examination as a predictor of obstructive sleep apnea in class III obese patients

Our aim was to determine if anatomical abnormalities of the upper airway (UA) and facial skeleton of class III severely obese patients are related to the presence and severity of obstructive sleep apnea syndrome (OSAS). Forty-five patients (69% females, mean age 46.5 ± 10.8 years) with a body mass index (BMI) over 40 kg/m² underwent UA and facial skeletal examinations as well as polysomnography. Mean BMI was 49 ± 7 kg/m² and mean neck circumference was 43.4 ± 5.1 cm. Polysomnographic findings showed that 22% had a normal apnea-hypopnea index (AHI) and 78% had an AHI over 5. The presence of OSAS was associated with younger age (P = 0.02), larger neck circumference (P = 0.004), presence of a voluminous lateral wall (P = 0.0002), posteriorized soft palate (P = 0.0053), thick soft palate (P = 0.0014), long uvula (P = 0.04), thick uvula (P = 0.0052), and inferior turbinate hypertrophy (P = 0.04). A larger neck circumference (P = 0.02), presence of a voluminous lateral wall (P = 0.04), posteriorized soft palate (P = 0.03), and thick soft palate (P = 0.04) were all associated with OSAS severity. The prevalence of OSAS in this group was high. A larger neck circumference and soft tissue abnormalities of the UA were markers for both the presence and severity of OSAS. Conversely, no abnormalities in the facial skeleton were associated with OSAS in patients with morbid obesity.

Genetic variability of vascular endothelial growth factor and prognosis of head and neck cancer in a Brazilian population

Vascular endothelial growth factor (VEGF) is one of the most potent endothelial cell mitogens and plays a critical role in angiogenesis. Polymorphisms in this gene have been evaluated in patients with several types of cancer. The objectives of this study were to determine if there was an association of the -1154G/A polymorphism of the VEGF gene with head and neck cancer and the interaction of this polymorphism with lifestyle and demographic factors. Additionally, the distribution of the VEGF genotype was investigated with respect to the clinicopathological features of head and neck cancer patients. The study included 100 patients with histopathological diagnosis of head and neck squamous cell carcinoma. Patients with treated tumors were excluded. A total of 176 individuals 40 years or older were included in the control group and individuals with a family history of neoplasias were excluded. Analysis was performed after extraction of genomic DNA using the real-time PCR technique. No statistically significant differences between allelic and genotype frequencies of -1154G/A VEGF polymorphism were identified between healthy individuals and patients. The real-time PCR analyses showed a G allele frequency of 0.72 and 0.74 for patients and the control group, respectively. The A allele showed a frequency of 0.28 for head and neck cancer patients and 0.26 for the control group. However, analysis of the clinicopathological features showed a decreased frequency of the A allele polymorphism in patients with advanced (T3 and T4) tumors (OR = 0.36; 95%CI = 0.14-0.93; P = 0.0345). The -1154A allele of the VEGF gene may decrease the risk of tumor growth and be a possible biomarker for head and neck cancer. This polymorphism is associated with increased VEGF production and may have a prognostic importance.

5-Methyltetrahydrofolate-homocysteine methyltransferase gene polymorphism (MTR) and risk of head and neck cancer

The functional effect of the A>G transition at position 2756 on the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase), involved in folate metabolism, may be a risk factor for head and neck squamous cell carcinoma (HNSCC). The frequency of MTR A2756G (rs1805087) polymorphism was compared between HNSCC patients and individuals without history of neoplasias. The association of this polymorphism with clinical histopathological parameters was evaluated. A total of 705 individuals were included in the study. The polymerase chain reaction-restriction fragment length polymorphism technique was used to genotype the polymorphism. For statistical analysis, the chi-square test (univariate analysis) was used for comparisons between groups and multiple logistic regression (multivariate analysis) was used for interactions between the polymorphism and risk factors and clinical histopathological parameters. Using univariate analysis, the results did not show significant differences in allelic or genotypic distributions. Multivariable analysis showed that tobacco and alcohol consumption (P < 0.05), AG genotype (P = 0.019) and G allele (P = 0.028) may be predictors of the disease and a higher frequency of the G polymorphic allele was detected in men with HNSCC compared to male controls (P = 0.008). The analysis of polymorphism regarding clinical histopathological parameters did not show any association with the primary site, aggressiveness, lymph node involvement or extension of the tumor. In conclusion, our data provide evidence that supports an association between the polymorphism and the risk of HNSCC.

Education, tobacco smoking, alcohol consumption, and IL-2 and IL-6 gene polymorphisms in the survival of head and neck cancer

The association of education, tobacco smoking, alcohol consumption, and interleukin-2 (IL-2 +114 and -384) and -6 (IL-6 -174) DNA polymorphisms with head and neck squamous cell carcinoma (HNSCC) was investigated in a cohort study of 445 subjects. IL-2 and IL-6 genotypes were determined by real-time PCR. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) of disease-specific survival according to anatomical sites of the head and neck. Mean age was 56 years and most patients were males (87.6%). Subjects with 5 or more years of schooling had better survival in larynx cancer. Smoking had no effect on HNSCC survival, but alcohol consumption had a statistically significant effect on larynx cancer. IL-2 gene +114 G/T (HR = 0.52; 95%CI = 0.15-1.81) and T/T (HR = 0.22; 95%CI = 0.02-3.19) genotypes were associated with better survival in hypopharynx cancer. IL-2 +114 G/T was a predictor of poor survival in oral cavity/oropharynx cancer and larynx cancer (HR = 1.32; 95%CI = 0.61-2.85). IL-2 -384 G/T was associated with better survival in oral cavity/oropharynx cancer (HR = 0.80; 95%CI = 0.45-1.42) and hypopharynx cancer (HR = 0.68; 95%CI = 0.21-2.20), but an inverse relationship was observed for larynx cancer. IL-6 -174 G/C was associated with better survival in hypopharynx cancer (HR = 0.68; 95%CI = 0.26-1.78) and larynx cancer (HR = 0.93; 95%CI = 0.42-2.07), and C/C reduced mortality in larynx cancer. In general, our results are similar to previous reports on the value of education, smoking, alcohol consumption, and IL-2 and IL-6 genetic polymorphisms for the prognosis of HNSCC, but the risks due to these variables are small and estimates imprecise.

Loss of Y-chromosome does not correlate with age at onset of head and neck carcinoma: a case-control study

Loss of Y-chromosome has been correlated with older age in males. Furthermore, current evidence indicates that Y-chromosome loss also occurs in several human tumors, including head and neck carcinomas. However, the association between Y nullisomy and the occurrence of neoplasias in elderly men has not been well established. In the present study, the association between Y-chromosome loss and head and neck carcinomas was evaluated by comparison to cells from peripheral blood lymphocytes and normal mucosa of cancer-free individuals matched for age using dual-color fluorescence in situ hybridization. Twenty-one patients ranging in age from 28 to 68 years were divided into five-year groups for comparison with 16 cancer-free individuals matched for age. The medical records of all patients were examined to obtain clinical and histopathological data. None of the patients had undergone radiotherapy or chemotherapy before surgery. In all groups, the frequency of Y-chromosome loss was higher among patients than among normal reference subjects (P < 0.0001) and was not age-dependent. These data suggest that Y-chromosome loss is a tumor-specific alteration not associated with advanced age in head and neck carcinomas.