Toenail selenium status and risk of subtypes of head-neck cancer: The Netherlands Cohort Study.

BACKGROUND: There is limited prospective data on the relationship between selenium status and the risk of head-neck cancer (HNC) and HNC subtypes (i.e., oral cavity cancer [OCC], oro-/hypopharyngeal cancer [OHPC] and laryngeal cancer [LC]). Therefore, we investigated the association between toenail selenium, reflecting long-term selenium exposure, and HNC risk within the Netherlands Cohort Study. METHODS: At baseline, 120,852 participants completed a self-administered questionnaire about diet and other cancer risk factors and were asked to provide toenail clippings. After 20.3 years of follow-up, 294 cases of HNC (95 OCC, 62 OHPC, two oral cavity/pharynx unspecified or overlapping and 135 LC) and 2,164 subcohort members were available for case-cohort analysis using Cox proportional hazards models. RESULTS: Toenail selenium status was statistically significantly associated with a decreased risk of HNC overall (multivariate RR for quartile four versus one: 0.55, 95% confidence interval [CI] 0.37-0.82, P trend = 0.001). The association between toenail selenium and risk of HNC overall was stronger among men than women, but no statistically significant interaction with sex was found. Toenail selenium level was also associated with a decreased risk of all HNC subtypes, with statistically significant associations in OHPC and LC. No statistically significant interaction was found between toenail selenium level and cigarette smoking or alcohol consumption for HNC overall. CONCLUSIONS: In this large cohort study, we found an inverse association between toenail selenium level and HNC risk. Among HNC subtypes, this association was strongest for OHPC and LC. Furthermore, the association of toenail selenium status with HNC risk was stronger among men than women.

Vitamin and carotenoid intake and risk of head-neck cancer subtypes in the Netherlands Cohort Study.

BACKGROUND: Head and neck cancer (HNC) is the seventh most-common type of cancer worldwide. Evidence regarding the potential protective effect of vitamins and carotenoids on HNC is limited and mostly based on case-control studies. OBJECTIVE: We evaluated the association of intake of dietary vitamins C and E (including supplementation) and the most-common carotenoids (α-carotene, ß-carotene, lutein plus zeaxanthin, lycopene, and ß-cryptoxanthin) and risk of HNC and HNC subtypes in a large prospective study. DESIGN: The Netherlands Cohort Study included 120,852 participants. For efficiency reasons, a case-cohort design was used. At baseline in 1986, participants completed a food-frequency questionnaire. A subcohort was randomly selected from the total cohort. After 20.3 y of follow-up, 3898 subcohort members and 415 HNC cases [131 oral cavity cancer (OCCs), 88 oro-/hypopharyngeal cancer (OHPs), and 193 laryngeal cancer cases] were available for analysis. Rate ratios and 95% CIs for highest (quartile 4) compared with lowest (quartile 1) quartiles of vitamin and carotenoid intake were estimated by using the Cox proportional hazards model. RESULTS: A strong inverse association was shown between vitamin C and HNC overall (multivariable-adjusted rate ratio for quartile 4 compared with quartile 1: 0.39; 95% CI: 0.23, 0.66; P-trend < 0.001), OCC (multivariable-adjusted rate ratio for quartile 4 compared with quartile 1: 0.35; 95% CI: 0.16, 0.77; P-trend < 0.05), and OHPC (multivariable-adjusted rate ratio for quartile 4 compared with quartile 1: 0.29; 95% CI: 0.12, 0.67; P-trend < 0.01). No statistically significant results were shown for vitamin E, α-carotene, ß-carotene, lycopene, and lutein plus zeaxanthin. The association of vitamin E and HNC was modified by alcohol status (P-interaction = 0.003) with lower risks in alcohol abstainers. CONCLUSIONS: With this study, we show an inverse association between intake of vitamin C and the incidence of HNC and HNC-subtypes. Future research is recommended to investigate the underlying mechanisms and to confirm our results, which may be promising for the prevention of HNC.

Medically unexplained otorhinolaryngological symptoms: Towards integrated psychiatric care.

OBJECTIVE: To evaluate the presence of medically unexplained otorhinolaryngological symptoms in a patient cohort and propose an interdisciplinary approach for their care. STUDY DESIGN: Prospective cohort study. METHODS: The study describes the population of patients presenting consecutively at the Department of Otorhinolaryngology at the Maastricht University Medical Center. Patients with symptoms who did not meet clear "medical" criteria and were associated with psychological distress and high health care utilization were enrolled in the study by two experienced otorhinolaryngologists following informed consent. The aim of the study is 1) to specify the presence of medically unexplained otorhinolaryngological symptoms and 2) to evaluate the integration of otorhinolaryngological and psychiatric treatment in an interdisciplinary approach in order to help otorhinolaryngologists improve patient care. RESULTS: Of the 102 patients included, 41% (N = 42) did not have a proven somatic otorhinolaryngological diagnosis. For only 10.8% (N = 4) of the latter, no psychiatric diagnosis had been established. Overall, 78% of the study population (N = 80) was diagnosed with psychiatric morbidity/comorbidity, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. CONCLUSION: The preliminary data suggest that the majority of patients with these unexplained complaints may suffer from under- or undiagnosed psychiatric morbidity. Therefore, easy access to integrated interdisciplinary care (otorhinolaryngology and psychiatry) should be offered to patients with medically unexplained otorhinolaryngological symptoms after detailed information is made available to them about the pathogenesis of the complaints and the foreseen psychosomatic approach.

A modified random oligonucleotide-based combination therapy for adjuvant treatment of pancreatic ductal adenocarcinoma.

Anti-cancer therapy in pancreatic ductal adenocarcinoma (PDAC) is mostly based on surgical removal or palliative therapy using antimetabolites, like 5'-fluorouracil or gemcitabine. Adjuvant treatment using these chemotherapeutics has recently proven a beneficial concept, though general survival rates are still poor. Most recently, combination therapy of gemcitabine with other targeted drugs was evaluated in clinical trials. We present here a study performed in a mouse orthotopic xenotransplant model of PDAC, using an oligo-nucleotide-based approach. We have shown previously that antisense oligonucleotides against p53 reduce the weight of orthotopic pancreatic tumours in immune-deficient mice. We further characterised terminal modifications of phosphorothioate oligonucleotides in vitro and found a random, unrelated control sequence carrying a D,L-alpha-tocopherol modification at the 5' and 3' ends to be most efficient in induction of cell death in PancTu-1 cells. Modified random oligonucleotide (MRON) were thus further tested in vivo. MRON showed a reduction of tumour weight in established primary orthotopic tumours in SCID/bg mice. In a surgically adapted pre-clinical model, where primary tumours were resected and animals received adjuvant treatment, MRON was very efficient in suppression of relapse and metastasis, when combined with gemcitabine. While the exact molecular mechanism of MRON activity still needs to be elucidated, the compound showed a remarkable preference for uptake into tumour cells in vivo.

Terminally modified oligodeoxynucleotides directed against p53 in an orthotopic xenograft model: a novel adjuvant treatment strategy for pancreatic ductal carcinoma.

OBJECTIVES: Investigation of a terminally modified oligodeoxynucleotide (ODN) directed against p53 mRNA (p53-3' polyethylene glycol-5' tocopherol ODN as a novel drug for pancreatic ductal carcinoma therapy in vitro and in vivo. METHODS: The impact of lipophilic modifications at the 5' end of p53-directed ODNs on cellular uptake was analyzed in vitro using proliferation assays, fluorescence-activated cell sorting analysis, and confocal laser scanning microscopy. The in vivo effects of p53-PT-ODN on the growth of orthotopically xenografted human pancreatic ductal carcinoma cells (PancTuI) were studied in SCID beige mice. Distribution was examined in vitro and in vivo using Cy3-labeled ODNs. RESULTS: Terminally modified p53-PT-ODN showed excellent cellular uptake without using transfection reagents. Microscopically detectable levels of p53-PT-ODN were reached in vivo within 3 hours after intraperitoneal injection, even in extraperitoneal organs. At this time, Cy3-labeled p53-PT-ODN was found in solid tumor formations. We observed a significant inhibition of tumor growth (50%) in vivo at low doses of p53-PT-ODN, whereas at high doses, 2 of 9 animals had no detectable tumors at necropsy. When p53-PT-ODN was injected on the day of tumor cell inoculation, the growth inhibition of solid tumors was significantly stronger compared with that with delayed treatment. CONCLUSIONS: p53-Directed modified ODNs might be of therapeutic value in pancreatic ductal carcinoma, particularly as adjuvant therapy after pancreatic tumor resection.