Quality of Life of Patients with Head and Neck Cancer Receiving Cetuximab, Fluorouracil, Cisplatin Comparing to Cetuximab, Fluorouracil, Cisplatin, and Docetaxel within the CEFCID Trial.

INTRODUCTION: CeFCiD was a multicenter phase II study comparing the efficacy of cetuximab (C), 5-flourouracil, and cisplatin with the same regimen adding docetaxel (D) in recurrent/metastatic head and neck cancer. The primary analysis trial did not demonstrate survival benefit from therapy intensification in first-line recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The current analysis of the trial assessed the impact of treatment on quality of life (QoL). METHODS: The European Organization for Research and Treatment of Cancer Quality of life Questionnaire QLQ-C30 and the tumor-specific module for head and neck cancer (QLQ-H&N35) were used to assess QoL at baseline (visit 1), after 2 (visit 3), 4 (visit 5), and 6 (visit 7) cycles of chemotherapy. RESULTS: Of 180 patients included in this study, 86 patients (47.8%) completed the questionnaires at baseline. Considering selected scores over treatment time, there was no difference in global QoL, dyspnea, swallowing, and speech between the treatment arms in the course. For fatigue, a significant increase from baseline to visit 3 (p = 0.02), visit 5 (p = 0.002), and to visit 7 (p = 0.003) was observed for patients receiving D, cisplatin or carboplatin (P), 5-fluorouracil (F), and C. At the end of chemotherapy, the manifestation of fatigue was similar compared in the 2 treatment arms. DISCUSSION/CONCLUSION: Therapy intensification not adversely affects selected scores of QoL of patients with recurrent and/or metastatic SCCHN. Nevertheless, fatigue seems to be pronounced in patients treated with D.

Partial mandibulectomy without bony reconstruction in patients with oropharyngeal or mouth cancer.

AIM OF THE STUDY: Resection of tumours of the oral cavity has significant consequences relating to function and aesthetic properties. Advancements in surgical techniques and microvascular surgery have enabled reconstructive outcomes to reach those of pre-surgery levels with good functional and aesthetic results. However, reconstructive options are not without complications. MATERIAL AND METHODS: We report the outcome of 23 patients with large tumours of the oral cavity or floor of the mouth, who underwent resection of the tumour and parts of the mandible without bony reconstruction. The patient population consisted of 19 oropharyngeal carcinomas and four floor of the mouth cancers, all of which had stage cT4 (six female and 17 male patients), and with an average patient age of 59.8 years. The pre- and postoperative ability to open the mouth, level of pain while masticating, mastication function pre and post-surgery, and the aesthetic outcome post-surgery were measured. RESULTS: The results obtained were deemed pleasantly acceptable by the patients, from aesthetic, functional, and analgesic points of view. DISCUSSION: A thorough preoperative work up is required and discussion with a multidisciplinary team is a necessity. This treatment option is more acceptable to the patient than would be expected and provides a satisfactory functional and aesthetic outcome. Therefore, we believe that partial mandibulectomy without bony reconstruction is an acceptable management option for a carefully selected group of patients who may not be suitable for the extensive surgery involved with bony reconstruction.

[Retrospective analysis of risk factors for postoperative bleeding undergoing adenotonsillectomy]. / Retrospektive Analyse von Risikofaktoren bei Adeno-Tonsillektomie im Kindesalter.

OBJECTIVE: Adenotonsillectomy is one of the most common surgical procedures in Germany and the most critical postoperative complication is postoperative hemorrhage, particularly for children. The medical history has been considered superior to laboratory tests. MATERIAL AND METHODS: In a retrospective anonymous examination over a 4 - year period the data of children and adolescent patients subject to surgery of the Waldeyer's tonsillar ring were recorded. Based on the preoperative questionnaire of the blood coagulation history and the laboratory chemical screening, risk factors for hemorrhage as well as for von Willebrand Disease (VWD) were identified. RESULTS: Included in the examination were 171 male and 137 female patients. Postoperative hemorrhage occurred in 43 children (14 %) between the 1st and 13th day after surgery. 4.2 % of the hemorrhage occured within 24 hours and 10.4 % after 24 hours. Children with frequent epistaxis had a significant higher risk of postoperative hemorrhage. A preoperatively pathological hemoglobin value was associated with a significantly higher rate of postoperative bleeding In children with VWD, a significantly increased risk of postoperative hemorrhage was observed, particularly in male VWD patients. CONCLUSIONS: In case of a conspicious family history, especially of the mother in the bleeding questionnaire, a significantly increased risk for VWD could be observed. Here it is advisable to determine the PTT as well as PFA-100 and, to continue with a further VWD step-diagnostics. A suspect preoperative laboratory screening, especially hemoglobin value, is associated with higher risk of postoperative hemorrhage.

Expression of COX-1, COX-2, 5-LOX and CysLT 2 in nasal polyps and bronchial tissue of patients with aspirin exacerbated airway disease.

BACKGROUND: Aspirin exacerbated respiratory disease (AERD) is a disease of the upper and lower airways. It is characterized by severe asthma, chronic sinusitis with nasal polyps (CRSwNP) and intolerance towards nonsteroidal analgesics (NSAR). Arachidonic acid (AA) metabolites play an important role in the pathogenesis of AERD. It is still unknown, whether metabolism of AA is comparable between the upper and lower airways as well as between patients with and without NSAR intolerance. OBJECTIVE: We sought to analyze differences in the expression of cyclooxygenases type 1 and 2 (COX-1, COX-2), arachidonate 5-lipoxygenase (5-LOX) and cysteinyl leukotriene receptor type 2 ( CysLT 2 ) in nasal polyps and the bronchial mucosa of patients with aspirin intolerant asthma (AIA, n = 23 ) as compared to patients with aspirin tolerant asthma (ATA, n = 17 ) and a control group with nasal polyps, but without asthma (NPwA, n = 15 ). METHODS: Tissue biopsies from nasal polyps and bronchial mucosa were obtained during surgical treatment of nasal polyps by endonasal functional endoscopic sinus surgery (FESS) under general anesthesia from intubated patients. Immunohistochemistry was used to analyze the expression of COX-1, COX-2, 5-LOX and CysLT 2 in nasal and bronchial mucosa. Categorization into the different patient groups was performed according to the patient history, clinical and laboratory data, pulmonary function and provocation tests, as well as allergy testing. RESULTS: We observed a stronger expression of 5-LOX and CysLT 2 in submucosal glands of nasal and bronchial tissue compared to epithelial expression. The expression of COX-1 and COX-2 was stronger in epithelia compared to submucosal glands. There was a similar expression of the enzymes and CysLT 2 between upper and lower airways in all patient groups. We did not detect any significant differences between the patient groups. CONCLUSIONS: The AA-metabolizing enzymes and the CysLT 2 were expressed in a very similar way in different microscopic structures in samples of the upper and lower airways of individual patients. We did not detect differences between the patient groups indicating the pathogenetic role of AA metabolism in these disorders is independent of the presence of NSAR-intolerance.

[Comparision of Clinical Versus Histopathological Staging in Patients with Oropharyngeal Carcinoma]. / Vergleich von klinischem und histopathologischem Staging bei Patienten mit Oropharynxkarzinom.

Despite all the progress in clinical diagnostics and multimodal therapy, the prediction of oropharyngeal carcinoma remains to be limited. Therefore, it is important to further improve clinical staging to set therapy modalities based on that.In a retrospective pseudonymized study over a 13 years period of time the clinical classification (cTNM) was compared with the histopathologic classification (pTNM) of 84 patients with oropharyngeal squamous cell carcinoma and who were treated primarily with surgery. Furthermore, the existence of occult metastases as well as overall survival as a function of histopathologic extent of the tumor and regional infestation of lymph nodes were considered.The highest agreement between cTNM and pTNM was observed with computer tomography. A definite evaluation with histopathological reliability is not possible with cTNM. MRT examinations showed the tendency to estimate T -, N- and UICC-stage compared with the histopathologic findings. In the context of the examinations of survival probabilities, separated by sex and histopathologic T- and N-categories, a lower overall survival probability was seen for the higher T- and N-category.Despite all the progress in imaging diagnostics for patients with oropharyngeal carcinoma the cTNM, compared with pTNM, is only partially able to determine the TNM classification of the cancer with requested clinical accuracy. With the trend of decreasing predictions and in spite of present-day multimodal therapy it is essential to improve and optimize the pre-therapeutic clinical staging.

Detection of surfactant proteins A, B, C, and D in human nasal mucosa and their regulation in chronic rhinosinusitis with polyps.

BACKGROUND: The nasal mucosa is characterized by a multirow high prismatic ciliated epithelium representing the first barrier of the immune defense system against microbial and other environmental pathogenic influences. A number of nonspecific defense mechanisms, including the presence of lactoferrin, peroxidases, proteases, interferons, and lysozymes in nasal secretions, act to counter inflammatory processes. The surfactant proteins (SPs) known from the lungs are important components of the innate immune system. They also influence the rheology of fluids and reduce the surface tension of gas-fluid interphases. The objective of this study was to investigate the protein expression of all four SPs. A specific aim was detection and characterization of SP-C, which had previously not been confirmed in human nasal mucosa. METHODS: The expression of mRNA for SP-A, -B, -C and -D was investigated using reverse transcriptase polymerase chain reaction on samples of both healthy nasal mucosa and nasal mucosa altered by inflammatory processes (allergic rhinitis and chronic rhinosinusitis). The distribution of all four proteins was determined with monoclonal antibodies using Western blot analysis as well as immunohistochemical methods. RESULTS: The results show that all four SPs, including SP-C not detected before this, are nasal mucosa components. A shift was also observed in the expression behavior of the SP-A, -B, and -D in nasal mucosa with inflammatory changes. CONCLUSION: Based on these results, SPs appear to have an important function in immunologic and rheological process of the nasal mucosa and support the prospective therapeutic use of liposomal nasal sprays.

Comparative anatomy of the human and canine efferent tear duct system--impact of mucin MUC5AC on lacrimal drainage.

PURPOSE: To investigate the histomorphology of the canine tear drainage system and to show the distribution of mucin MUC5AC within the tissue. METHODS: Conjunctiva and tear drainage systems of 19 long-nosed dogs were investigated histologically and ultrastructurally. The tissues were stained with eight different antibodies reactive against less glycosylated and highly-glycosylated MUC5AC. Results were compared with findings in human tissue received from 12 body donors. RESULTS: Except for a distinctly longer nasolacrimal duct and several accessory openings of the duct into the nasal cavity, the morphology of the canine tear drainage system is very similar to that of humans. MUC5AC in less- and highly-glycosylated forms was present in the conjunctival tissue of dogs as well of humans. Within the tear sac and the nasolacrimal duct only less-glycosylated MUC5AC could be found in dogs and in human. CONCLUSIONS: These findings demonstrate that the canine tear drainage system is very similar to its human equivalent. In particular the distribution of MUC5AC, supposed to play an important role within the pathogenesis of dry eye syndrome (DES), is the same as in humans. Therefore the canine model seems to be an appropriate model for further DES research.

Adjuvant low single dose cisplatin-based concurrent radiochemotherapy of oral cavity and oropharynx carcinoma: impact of extracapsular nodal spread on distant metastases.

BACKGROUND: The aim of this study was to analyze the prognostic importance of extracapsular nodal spread (ECS) in patients with locally advanced squamous cell carcinoma (SCC) of the oral cavity or oropharynx, and the impact of adjuvant low single dose cisplatin-based radiochemotherapy on distant metastases-free survival (DMFS). PATIENTS AND METHODS: The study population was selected from 195 patients with high-risk oral cavity or oropharyngeal cancer, who had either adjuvant radiotherapy (RT) or radiochemotherapy (RCT) between January 1, 1997 and December 31, 2006, at the University Clinic of Radiation Oncology of the Martin-Luther-University Halle-Wittenberg. A total of 42 matched pairs of patients with UICC stage III-IVa,b disease were analyzed. The patients were matched (one to one) according to tumor site, sex, T stage, N stage, ECS, resection margin status, and Karnofsky performance status. To analyze the correlation between the treatment modality (RT vs. RCT) and the impact of ECS on DMFS, the Cox proportional hazard model was used. Survival rates were calculated using the Kaplan-Meier method. RESULTS: There was a strong correlation between the degree of nodal involvement and ECS (pN1: 33%; pN2b: 45%; pN2c: 71%). Moreover, the 5-year locoregional control rates (LC) in patients with ECS were 76% vs. 63% (n.s.) for RT and RCT, respectively. However, for patients without ECS, the LC was more favorable after RCT (RT vs. RCT: 62% vs. 88%, p < 0.05). DMFS again was better after RT, and this observation was independent of the presence or absence of ECS. Finally, in multivariate analyses, the presence of ECS significantly decreased the DMFS (p = 0.04, hazard ratio (HR) 2.64). CONCLUSIONS: Patients with ECS have an increased risk of distant metastases. Adjuvant low single dose cisplatin-based concurrent chemotherapy seems to have no influence on occult microscopic systemic disease.

Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out.

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs approximately US$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age

Allergic and idiopathic rhinitis: an ultrastructural study.

Nasal hyperreactivity is one of the most important underlying mechanisms in both allergic (AR) and idiopathic rhinitis (IR). In order to study the pathomorphological changes in this entity, tissue samples from patients with AR, IR, and from patients without chronic inflammation were taken during nasal surgery. Primary antibodies against Substance P (SP), calcitonin gene-related peptide (CGRP), and endothelial nitric oxide synthases (NOS III) were applied and the immunocomplexes were visualized by immunocytochemistry. The nasal mucosa of patients with AR and IR showed similarities on the ultrastructural level. Neurogenic inflammation was indicated by a strong innervation pattern with sensory nerve fibers containing SP and CGRP. We could show that extensive edema and cellular infiltration might be characteristic for AR. On other hand there was no evidence of eosinophilic or NO involvement in IR. Finally, on the ultrastructural level, AR and IR showed many similarities. Based on these findings anti-inflammatory therapy modalities could be recommended for both types of rhinitis.

Saliva as a biomarker for head and neck squamous cell carcinoma: in vitro detection of cytotoxic effects by using the plating efficiency index.

Worldwide, the incidence of head and neck squamous cell carcinoma (HNSCC) is increasing. The development of an effective prevention program would provide a promising opportunity to control this disease. We applied the 'plating efficiency index' of Chinese hamster lung fibroblasts to demonstrate the presence of cytotoxic effects in saliva samples from cancer patients as well as from healthy probands. Correlations between individual risk factors and the cytotoxic effects of saliva specimens were analysed and evaluated. Saliva samples were obtained from male patients (n=43) with carcinomas of the upper aerodigestive tract, and from a healthy age-matched male control group (n=131) with different tobacco and alcohol consumption habits. The extraction of non-stimulated sober saliva was chosen for this investigation. In vitro cytotoxicity of the saliva was detected using the permanent mammalian cell line V79 (lung fibroblasts) of Chinese hamsters. The determination of the plating efficiency index was made in the logarithmic growth phase of the initial cell culture. A reduction in cell colonies (plating efficiency) of at least 50% was defined as strongly cytotoxic. A significant direct correlation was found between daily tobacco consumption and the reduction of plating efficiency (p<0.0001). We found only a moderate increase in the cytotoxicity of tested saliva samples in correlation with daily alcohol uptake. The difference between tumor patients and healthy probands was highly significant (chi(2) test; p=0.001). Using the method of logistic regression analysis, we found a 3.6-fold increased cancer risk in probands with cytotoxic saliva (p<0.001). According to our results, the plating efficiency index seems to be a suitable method for the detection of increased cancer risk. In combination with several effective biomarkers on cytogenetic end-points, it may help to establish biomonitoring programs for secondary cancer prevention.

Cystic fibrosis: ultrastructural changes of nasal mucosa.

Cystic fibrosis (CF) is an inherited multisystemic disorder that results in a generalized dysfunction of exocrine glands. Besides chronic obstructive pulmonary diseases, chronic sinusitis, nasal polyposis and hypertrophy of the inferior turbinates with nasal airway obstruction are typical signs. Tissue samples of the inferior turbinates and nasal polyps were taken during nasal surgery from 21 children, ranging from 3 to 16 years of age. Light- and electron microscopical examination were carried out. Furthermore, specimens of nasal mucosa of patients without chronic inflammation as controls and specimens of duodenal mucosa of patients with CF were investigated. Under a thick layer of respiratory epithelium with a high proportion of goblet cells, the seromucous glands display abnormal morphological structures with wide mucous cells and cystic dilatation. The glandular cells show inhomogeneous glandular droplets in the supranuclear cell portion. The nucleus contains dispersed chromatin as a sign of increased activity and the structures of the Golgi apparatus are clearly detectable. Apart from investigations concerning nasal polyps in CF, studies on the different morphological changes of nasal mucosa at the electron microscopic level are rare. This histological study focuses on various morphological changes of nasal glands at the ultrastructural level in correlation with typical symptoms in CF. In addition, a comparison with electron microscopic findings of CF-enteropathies is proposed. These findings could help to bring information concerning new morphological aspects in the pathophysiology of patients with CF.

Invasive aspergillosis of the paranasal sinuses and the skull base.

Invasive aspergillosis (IA) originating from the paranasal sinuses can cause an intracranial growth mainly along the skull base and larger vessels. This study reports our experience in the diagnosis and treatment of a series of patients with IA. A retrospective chart review of four patients with chronic invasive intracranial aspergillosis was performed. Clinical signs, physical examinations, radiographs, histological samples, and outcome were demonstrated. The patients demonstrated different symptoms like exophthalmus, ophthalmoplegia, loss of vision, and hypaesthesia of the ophthalmic and maxillary nerve. Computed tomography and MRI revealed extensive sino-orbital and skull base lesions. The patients were treated with aggressive endonasal debridement, intravenous antifungal agents and daily irrigations with antimycotic suspensions. Furthermore, we applied hyperbaric oxygenation. Two patients died from complications due to subarachnoidal hemorrhage and accompanied complications respectively. Despite the high mortality rate patients with an invasive aspergillosis can be effectively treated in some cases by an early and rigorous treatment schedule using all surgical and conservative therapeutic options.

Rhinitis medicamentosa: electron microscopic changes of human nasal mucosa.

OBJECTIVE: Prolonged application of nasal vasoconstrictors causes rhinitis medicamentosa (RM). Nasal obstruction is induced by rebound swelling when the decongestive effect has disappeared. The aim of this study was to demonstrate ultrastructural changes in RM. STUDY DESIGN AND SETTING: Tissue samples of inferior turbinates from 22 patients with RM and 10 patients without rhinitis were taken during nasal surgery. Ultrathin sections were investigated by using a transmission electron microscope (TEM). RESULTS: The TEM findings revealed severe epithelial damages such as loss of ciliated cells. In the subepithelial region, the vascular endothelium showed gaps and ruptures of basal lamina. CONCLUSION: RM is a drug-induced damage of human nasal mucosa. Loss and destruction of ciliated epithelial cells are the morphologic correlation of the disturbed mucociliary clearance. In addition, vascular endothelium revealed ultrastructural changes. This could be caused by an increased vascular permeability with consecutive interstitial edema. SIGNIFICANCE: This study demonstrated new morphological aspects of rhinitis medicamentosa.

Sclerotherapy of cervical cysts with Picibanil (OK-432).

The effectiveness of intralesional sclerotherapy of lymphangiomas and ranulas with OK-432 (Picibanil) has been proved in several clinical studies. The aim of our study was to review the effectiveness of sclerotherapy of benign cervical cysts with Picibanil as an alternative method to surgical excision. Between March 2002 and March 2006, a prospective observational study was carried out to assess the effects of Picibanil on cervical cysts. Between 2002 and 2006 we treated 14 patients having cervical cysts through intralesional application of Picibanil with a dose of 0.01 mg/ml. So far we used Picibanil with 13 patients achieving a high success rate. In eight cases we observed, both clinically and ultrasonographically, a nearly complete regression, and a complete regression of the cysts in three cases. In two cases the cysts atrophied. In these cases only residual findings could be observed. In one case we extirpated the remaining cyst. If there is no clear reaction of the cyst to the treatment, an excision is indicated 6 weeks after the injections to gain meaningful histological examination. No significant complication after sclerotherapy with Picibanil was observed. According to our results the application of OK-432 (Picibanil) is a safe and effective primary method for sclerotherapy of benign cervical cysts which can replace surgical extirpation in special cases. However, the risk of malign diseases has to be excluded before the commencement of the Picibanil treatment.

Ultrastructural detection of nitric oxide in human nasal mucosa.

OBJECTIVE: Nasal vasculature and seromucous glands are exposed to complex mechanisms influenced by external as well as internal stimuli. In addition to classic and peptidergic neurotransmitters, nitric oxide (NO) was increasingly found to be important in the control of various physiologic functions. NO modulates nasal immunology, influences macrophage activity, and has antiviral and bacteriostatic properties. The aim of this study was to show the localization of nitric oxide synthases (NOS) I and III in the normal human nasal mucosa by using immunoelectron microscopical techniques. STUDY DESIGN: Specimens of noninflammed inferior turbinates from 35 patients who underwent nasal surgery were fixed in phosphate-buffered glutaraldehyde. After dehydration, incubation in unicryl and polymerization, ultrathin sections were cut. Primary antibodies against NOS I and III were applied and the immunocomplexes were visualized by an immunocytochemical staining-technique using gold-labeled antibodies. Immunostained structures were photodocumented using a transmission electron microscope. RESULTS: NOS-immunoreactive nerve fibers were mainly co-located in parasympathetic nerves in the adventitia of arterial vessels and in periglandular axons. Electron microscopy showed that NOS-positive axons were in close contact with acinus cells. A strong NOS III-immunoreactivity was found in endothelial cells of capillaries near the glands as well as in arterial vessels. Furthermore, immunoreaction products were deposited throughout the cytoplasm of fibroblasts. CONCLUSION: Nitric oxide in nerve fibers, seromucous glands, and endothelial cells of capillaries and arterial vessels suggest that NO takes part in the regulation of physiologic processes of the human nasal mucosa. NOS was co-localized in parasympathetic nerves and plays a role in the neurotransmission and neuromodulation of the vascular tone and glandular secretion. Arteries showed a distinctly developed nitrergic innervation and endothelial accumulation. The NO production in axons of the adventitia and in the endothelium of arteries demonstrated that these vessels are influenced by a dual NO system. NO could mainly act on these structures with vasodilatatory effects. Finally, NO would be able to influence the functions of perivascular fibroblasts.