Göran Laurell

Evaluation of Human Papillomavirus Antibodies and Risk of Subsequent Head and Neck Cancer

PURPOSE Human papillomavirus type 16 (HPV16) infection is causing an increasing number of oropharyngeal cancers in the United States and Europe. The aim of our study was to investigate whether HPV antibodies are associated with head and neck cancer risk when measured in prediagnostic sera. METHODS We identified 638 participants with incident head and neck cancers (patients; 180 oral cancers, 135 oropharynx cancers, and 247 hypopharynx/larynx cancers) and 300 patients with esophageal cancers as well as 1,599 comparable controls from within the European Prospective Investigation Into Cancer and Nutrition cohort. Prediagnostic plasma samples from patients (collected, on average, 6 years before diagnosis) and control participants were analyzed for antibodies against multiple proteins of HPV16 as well as HPV6, HPV11, HPV18, HPV31, HPV33, HPV45, and HPV52. Odds ratios (ORs) of cancer and 95% CIs were calculated, adjusting for potential confounders. All-cause mortality was evaluated among patients using Cox proportional hazards regression. RESULTS HPV16 E6 seropositivity was present in prediagnostic samples for 34.8% of patients with oropharyngeal cancer and 0.6% of controls (OR, 274; 95% CI, 110 to 681) but was not associated with other cancer sites. The increased risk of oropharyngeal cancer among HPV16 E6 seropositive participants was independent of time between blood collection and diagnosis and was observed more than 10 years before diagnosis. The all-cause mortality ratio among patients with oropharyngeal cancer was 0.30 (95% CI, 0.13 to 0.67), for patients who were HPV16 E6 seropositive compared with seronegative. CONCLUSION HPV16 E6 seropositivity was present more than 10 years before diagnosis of oropharyngeal cancers.

High‐Dose cisplatin treatment: Hearing loss and plasma concentrations

Fifty‐four patients with metastatic cancer were followed audiometrically during high‐dose (100‐120 mg/m2) cisplatin chemotherapy. Eighty‐one percent of the patients showed significant changes in air‐conduction hearing thresholds after completion of therapy. Thirteen percent sustained a significant hearing handicap. An interindividual variation was found, ranging from severe hearing loss after the first course to unaffected hearing after three courses. The oto‐toxic effect was not increased by pre‐existing hearing loss, but was slightly increased by age. The risk was determined more by the amount of the single dose than by the cumulative dose. The further ototoxic effect could not be predicted on the basis of the audiogram after the first coursa Peak plasma concentration of platinum was measured in eight patients, and no ototoxic changes were noted below a concentration of 1 μg/L.

Stricture of the proximal esophagus in head and neck carcinoma patients after radiotherapy

It is well recognized that many patients with head and neck carcinoma have problems with food intake and malnutrition. The objective of the current study was to determine the clinical pattern of patients with nonneoplastic stricture of the upper esophagus after radiotherapy for head and neck carcinoma.

Dose and time-dependent protection of the antioxidant N-l-acetylcysteine against impulse noise trauma

Noise-induced hearing loss is one of the most common causes of hearing disability, and at present there is no effective biological protection or cure. Firearms and some industrial equipment can generate very high levels of impulse noise, which is known to cause sensorineural hearing loss. It has been shown that antioxidants such as N-L-acetylcysteine (NAC) can protect the inner ear from oxidative damage. The present study investigates whether NAC (i.p.) can protect the cochlea from impulse noise trauma. Rats were exposed to 50 noise pulses at 160 dB SPL peak value. Electrophysiological hearing thresholds were assessed with auditory brainstem response (ABR) up to 4 weeks after noise exposure. Animals exposed to impulse noise, without treatment of NAC, had larger threshold shifts in the frequency range 4-40 kHz than animals injected with NAC. Hair cell loss was significantly reduced using a schedule of three NAC injections in the rats. These results suggest that NAC can partially protect the cochlea against impulse noise trauma.

The ototoxic effect of cisplatin on guinea pigs in relation to dosage.

The effect on the electrophysiological hearing thresholds and the endocochlear DC potential (EP) was studied in four groups of guinea pigs receiving different doses of cisplatin. By multiple low-dose intraperitoneal injections a permanent hearing loss was produced without a permanent decrease of the EP. On the other hand, when cisplatin was given as a single high-dose intravenous injection, there was an impairment of the electrophysiological hearing thresholds and EP, depending upon the level of cisplatin dose. It is concluded that cisplatin-induced hearing loss is not necessarily a sequela to a loss of EP.

Cisplatin and Oxaliplatin Toxicity: Importance of Cochlear Kinetics as a Determinant for Ototoxicity

Background Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained. Methods In HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration–time curve (AUC). Statistical tests were two-sided. Results In HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 μM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 μg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 μM × minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics. Conclusion Cisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.

D-Methionine and cisplatin ototoxicity in the guinea pig: D-methionine influences cisplatin pharmacokinetics

D-Methionine has recently been advocated as a protectant against cisplatin toxicity. The use of systemic D-methionine as a protector was studied in 58 guinea pigs. Kinetics and distribution of [11CH(3)]D-methionine was analysed by positron emission tomography. Cisplatin and the monohydrated complex of cisplatin was quantified in blood ultrafiltrate using reversed-phase liquid chromatography with post-column derivatisation. Administration of 300 mg/kg of D-methionine caused a 30% decrease in the area under the concentration-time curve (AUC) of cisplatin. The toxic effect of cisplatin was studied after dose adjustment of cisplatin, i.e. with similar cisplatin AUC in the group receiving D-methionine and the saline control group. A significant ototoxic effect, measured as difference in pre- and 96 h post-treatment electrophysiological hearing threshold (auditory brainstem response), was observed at stimulus frequencies of 30 and 20 kHz. There was no difference between the groups in the extent of threshold shift. Quantitative outer hair cell counts showed a similar loss of cells in the two groups. All animals had a significant increase in plasma-creatinine but there was no difference between the groups. The results indicate that protection from cisplatin ototoxicity by systemic D-methionine can be explained by a lowered systemic exposure to the drug.

Cisplatin-induced hearing loss: influence of the mode of drug administration in the guinea pig.

Cisplatin (8 mg/kg) was given intravenously to guinea pigs either as a 15 s bolus injection (25 animals) or as a 1 h infusion (28 animals). To determine the influence of the mode of cisplatin administration and pharmacokinetics on the ototoxic side-effect, the concentrations of cisplatin and the biotransformation product monoaquated cisplatin were determined in blood ultrafiltrate using liquid chromatography with post-column derivatization. Ototoxic effect was evaluated as difference in pre- and 96 h post-exposure auditory brainstem response (ABR) threshold. The cisplatin peak concentration was considerably higher, 19.2+/-2.4 microg/ml, in the bolus injection group than in the infusion group, 6.7+/-0.5 microg/ml (mean+/-S.E.M.). The area under the blood ultrafiltrate concentration time curve (AUC) for cisplatin was slightly greater in the infusion group, 442+/-26 microg/ml/min, than in the bolus injection group, 340+/-5 microg/ml/min. For monoaqua cisplatin, the AUC was not different between the groups (bolus injection: 30.8+/-1. 5 microg/ml/min, infusion: 34.1+/-3.3 microg/ml/min). A significant ototoxic effect was observed in both groups at 20 and 12.5 kHz, but there was no difference between the groups in the extent of threshold shift. The interindividual variability in susceptibility to ABR threshold shift was far greater than the variability in pharmacokinetics, suggesting that other factors are more important in determining the degree of hearing loss.

Early self-care rehabilitation of head and neck cancer patients

Abstract Conclusions: No positive effects of early preventive rehabilitation could be identified. The results do not contradict the proposition that rehabilitation based on self-care can be effective but it is important to establish evidence-based training programs and identify proper instruments for selection of patients and evaluation of intervention. Objectives: Patients with head and neck cancer suffer from functional impairments due to intense treatment. In this study, we investigated the effectiveness of an experimental early preventive rehabilitation using hard, objective end points in a nonselective, longitudinal, prospective cohort study. Methods: In all, 190 patients were included in the program and received instructions for training before the start of treatment with the aim of reducing swallowing problems and reducing mouth opening and stiffness in the neck. A control group of 184 patients was recruited. Results: There was no difference in weight loss and 2-year survival between the two groups. No positive effects concerning functional impairments were found in patient-reported outcome measures.

Protection and treatment of sensorineural hearing disorders caused by exogenous factors: experimental findings and potential clinical application

During the last decade, there have been numerous interesting findings regarding the roles of neurotrophins, nitric oxide, reactive oxygen species, glutamate receptors, and shock protein in the auditory system. These findings have provided a scientific basis for the development of techniques to protect the auditory system against trauma as well as for the treatment of peripheral hearing disorders. This review focuses on recent advances in experimental prevention and treatment of hearing impairment which are expected to be of clinical value in the near future. Viral vector and non-viral vector gene therapy and transplantation of stem cells are discussed as potential treatments of irreversible sensorineural inner ear damage.