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.

Lidocaine: neurobiological targets and effects on the auditory system.

Lidocaine, a local anesthetic and anti-arrhythmic agent, is also known both as a tinnitus- and as a pain-suppressing drug. The sites of action in tinnitus suppression are in the cochlea as well as in the central auditory nervous system. In the present study, audiological and brain imaging studies in humans were used to identify the anatomical structure where lidocaine has its action on tinnitus. Molecular studies were used to elucidate the action of lidocaine on the cellular level. Various ion channels and receptors (e.g. voltage-gated Na(+), K(+) and Ca(2+) channels, glutamate, GABA, glycine and vanilloid receptors), found in the auditory system and possibly connected to tinnitus, are affected by lidocaine. Identification of molecular structures involved in expression of neuroplasticity in the auditory system in tinnitus and modeling the binding sites of local anesthetics could lead to the design of subtype-specific inhibitors that could provide new pharmacological targets for treatment.

High accumulation of platinum-DNA adducts in strial marginal cells of the cochlea is an early event in cisplatin but not carboplatin ototoxicity.

Ototoxicity is a typical dose-limiting side effect of cancer chemotherapy with cisplatin but much less so with carboplatin. To elucidate the underlying molecular pathological mechanisms, we have measured the formation and persistence of drug-induced DNA adducts in the nuclei of inner ear cells of guinea pigs after short-term exposure to either cisplatin or carboplatin using immunofluorescence staining and quantitative image analysis. After application of carboplatin, all cells of the cochlea exhibited a similar burden of guanine-guanine intrastrand cross-links in DNA. In contrast, we observed a pronounced 3- to 5-fold accumulation of this cytotoxic adduct exclusively in the marginal cells of the stria vascularis between 8 and 48 h after treatment with cisplatin. In the kidney, the other critical target tissue of cisplatin toxicity, a similar high preferential formation of cytotoxic DNA adducts was measured in the tubular epithelial cells but not in other renal cell types. As for the ear, this excessive formation of DNA damage in a particular cell type was seen in animals treated with cisplatin but not those treated with carboplatin. Because cisplatin ototoxicity is often attributed to oxidative stress mediated by the generation of radical oxygen species (ROS), we have measured in parallel the levels of the lead DNA oxidation product 8-oxoguanine (8-oxoG) in cochlear cryosections. Compared with basal levels in untreated control cochleas, no additional formation of 8-oxoG was detectable up to 48 h after cisplatin treatment in the DNA of either inner-ear cell type. This suggests that the generation of ROS may be a secondary event in cisplatin ototoxicity.

Management of an "Ear Camp" for children in Namibia.

OBJECTIVE: In this publication, we present our experiences with managing an "Ear Camp" in northern Namibia, where the population is predominantly black. Medical coverage for ear problems is poor in this part of the country. METHODS: Within 10 days, 38 children (median age 12 years) were operated mainly for (sub) total defects of the tympanic membrane. In two cases, an open cavity had to be created because of a cholesteatoma. We performed a tympanoplasty type I in 18 cases and a tympanoplasty type III in 20 cases. Additionally, in 8 cases an antrotomy and in another 8 cases a mastoidectomy was performed. The ossicular chain was reconstructed with a titanium-PORP (14 cases), a titanium-TORP, interposition of the head of the malleus or a cartilage columella (one case each) or by placing the reconstructed tympanic membrane directly onto the head of the stapes (three cases). The tympanic membrane was reconstructed by the use of tragal cartilage with overlapping perichondrium in underlay-technique. RESULTS: Thirty-one children could be followed up. A defect of the tympanic membrane was found in five cases because of continuous purulent discharge. The average improvement of air conduction thresholds in the frequencies between 250 and 4000 Hz was 15 dB. CONCLUSIONS: Surgical techniques, antibiotic treatment and perioperative management have to be adapted to limited possibilities of pre-treatment and aftercare. As development aid should support people to look after themselves, we started to instruct local doctors with regard to pre- and postoperative care in ear surgery. Training of the local doctors will be continued in our next "Ear Camp" in 2004.