Yes / Epidemiological studies have shown that head and neck cancer (HNC) is a complex multistage process that in part involves exposure to a combination of carcinogens and the capacity of certain drug-metabolising enzymes including cytochrome P450 (CYP) to detoxify or activate such carcinogens. In this study, CYP1A1, CYP1B1 and CYP2W1 expression in HNC was correlated with potential as target for duocarmycin prodrug activation and selective therapy. In the HNC cell lines, elevated expression was shown at the gene level for CYP1A1 and CYP1B1 whereas CYP2W1 was hardly detected. However, CYP2W1 was expressed in FaDu and Detroit-562 xenografts and in a cohort of human HNC samples. Functional activity was measured in Fadu and Detroit-562 cells using P450-Glo™ assay. Antiproliferative results of duocarmycin prodrugs ICT2700 and ICT2706 revealed FaDu and Detroit-562 as the most sensitive HNC cell lines. Administration of ICT2700 in vivo using a single dose of ICT2700 (150 mg/kg) showed preferential inhibition of small tumour growth (mean size of 60 mm3) in mice bearing FaDu xenografts. Significantly, our findings suggest a potential targeted therapeutic approach to manage HNCs by exploiting intratumoural CYP expression for metabolic activation of duocarmycin-based prodrugs such as ICT2700. / The authors would like to thank Bradford Institute for Health Research for funding a PhD studentship to DP through a competitive scheme and Yorkshire Cancer Research programme Grant (B381PA) for supporting our cytochrome P450-focused drug discovery research.

Background: Head and neck cancer (HNC)-specific symptoms have a substantial impact on health-related quality of life. The aim of this study was to determine whether self-reported dysphagia, voice problems and pain of HNC patients changed over time and whether specific clinical or sociodemographic variables were associated with these symptoms. Methods: HNC patients (n = 299) in an outpatient setting answered questionnaires (Eating Assessment Tool-10; questions from the EORTC QLQ-C30 and EORTC H&N35) on dysphagia, voice problems and pain, collected with the software “OncoFunction” at three different timepoints (t1–t3) after diagnosis. The mean score changes from t1 to t3 were expressed in terms of effect sizes d. The impact of sociodemographic and clinical factors on the course of the variables was tested with multivariate analyses of variance. Results: Dysphagia, voice impairment and pain in HNC survivors significantly improved over a period of approximately 14 months after diagnosis. Tumor site, stage, treatment modality, occupational state and ECOG state were significantly correlated with self-reported functional outcome. The pain level of the HNC patients was rather low. Conclusions: Patients suffer from functional impairments after HNC treatment, but an improvement in self-reported symptoms could be demonstrated within this time period.

No description available.

Our contact with nature is decreasing in what has been referred to as the “extinction of experience”. Consequences of the loss of nature experiences are far-reaching and involve not only changes in health and wellbeing, but also changes emotions, attitudes, and behaviour towards nature. This research aims to fill a knowledge gap in understanding specific characteristics of nature experiences in relation to both a) generating human wellbeing, and b) improving Human-Nature Connection (HNC), defined as how people relate to nature. The aim is to increase our understanding of the characteristics of nature experiences that can achieve both of these positive outcomes. Furthermore, this research explores an organisational perspective through interviewing organisations that are currently incorporating or thinking to implement practices that include nature experiences. To address the main aim, an integrative literature review was conducted, and the results revealed that intentional contact, active engagement (specifically appreciative outdoor activities, cognitive engagement, cues, and direct earth contact), and biodiversity and wildness to be significant characteristics that positively impact human beings. Moreover, appreciative outdoor activities and cognitive engagement have been shown to be beneficial even when passive. In addition, there is some evidence that there is a link between HNC and wellbeing, which suggests that improving HNC would increase the wellbeing effects experienced by an individual during a nature experience. This knowledge is crucial for designing nature experiences that are able to more efficiently improve wellbeing, as well as improve HNC. Regarding the organisational perspective, a barrier that needs to be overcome is reaching an understanding of the benefits of such experiences, not only for the employees but for the business. One major opportunity identified is the hybrid working model, which allows employees to work remotely, and the possibility for the company to actively encourage its employees to experience nature.

The full text will be available at the end of the embargo: 17th July 2024

科学研究費補助金 研究種目:一般研究(B)(2) 課題番号:07457240 研究代表者:宮田 敏男 研究期間:1995-1996年度

Purpose: The Hedgehog-signalling pathway (Hh) is frequently active in head and neck squamous cell carcinoma (HNSCC). Overexpressed Hh associates with poor prognosis. The Hh inhibitor vismodegib targets smoothened (SMO) and, based on molecular data, may prevent resistance to EGFR targeting. Methods: To elucidate potential roles of vismodegib in HNSCC therapy, its sole effects and those combined with cisplatin, docetaxel, and cetuximab on HNSCC cell lines were assessed by MTT metabolisation and BrdU incorporation. Colony formation (CF) of primary HNSCC cells was studied utilizing the FLAVINO-protocol. Combinatory effects were analysed regarding antagonism, additivity or synergism. Associations between the ex vivo detected mode of action of vismodegib with other treatments related to patient characteristics were assessed and progression-free survival (PFS) in patient groups compared using Kaplan-Meier curves. Results: Vismodegib suppressed BrdU incorporation significantly stronger than MTT turnover; CF was significantly inhibited at ≥20 µM vismodegib while concentrations <20 µM acted hormetic. Combining 20 µM vismodegib plus docetaxel (T), cisplatin (P), and cetuximab (E), additively enhanced antitumoral activity in HNSCC samples from patients with superior PFS highlighting a potential role for ex-vivo testing of this combination for use as a prognostic classifier. Conclusion: We provide ex-vivo evidence for vismodegib’s potential in HNSCC therapies especially if combined with cetuximab, cisplatin and docetaxel.:Abkürzungsverzeichnis 1 Einleitung 1.1 Kopf-Hals-Tumore 1.1.1 Therapie von Kopf-Hals-TumoreN 1.1.2 Limitationen der etablierten Therapien 1.2 Eingesetzte Chemotherapeutika 1.2.1 Cisplatin 1.2.2 Docetaxel 1.2.3 Cetuximab 1.3 Hedgehog-Signaltransduktionsweg 1.3.1 Hedgehog-Signalweg und Karzinogenese 1.3.2 Vermittlung von Tumortherapieresistenz durch den Hedgehog-Signalweg 1.3.3 Zielgerichtete Tumortherapie durch Blockade des Hedgehog-Signalweges 1.4 Vismodegib 1.5 Ex-Vivo-Chemoresponse-Testung mittels FLAVINO-Assay 1.6 Zusammenfassung der Rationale der Untersuchung 1.7 Aufgabenstellung der Promotionsarbeit 2 Publikation 2.1 Reduzierte Proliferation und Koloniebildung von Plattenepithelkarzinomen der Kopf Hals Region unter dualer Inhibition des EGFR- und Hedgehog-Signalweges 3 Zusammenfassung der Arbeit 4 Literaturverzeichnis 5 Anlagen 5.1 Darstellung des Eigenanteils 5.2 Erklärung über die eigenständige Abfassung der Arbeit 5.3 Lebenslauf 5.4 Publikationen 5.5 Danksagung

Radiation and medical drugs are used to fight head and neck cancer, but unfortunately in some cases these treatments cause development of other diseases and injuries. Osteoradionecrosis (ORN) and medical-related osteonecrosis of the jaw (MRONJ) are dreaded late complications in jaws from radiation therapy and medical drugs and cause great suffering to those affected. The full extent of ORN and MRONJ may be difficult to diagnose due to visualizing problems in quantifying boundaries of osteonecrosis and healthy tissues. Maxillofacial surgeons now use radiology and clinical appearance to differ affected bone, which may result in unprecise estimation of the area that is affected. As a possible adjuvant diagnostic procedure, visualizing osteonecrosis by examining neutrophil elastase (NE) activity in jaws was tested in patients. A newly developed positron emission tomography (PET) tracer specific for NE was used for observation and measurement in PET/CT images. An image processing software was used for visualization, segmentation, and analysis. Areas with osteonecrosis were identified in the ORN patients, but not in their entirety and all activity could not be equated with osteonecrosis as undiagnosed areas as well absorbed the tracer. Visualization of MRONJ displayed unexpectedly low activity in the diagnosed area.    The conclusion drawn from the results and the analysis is that NE activity can be found in osteonecrosis patients, but the activity itself does not provide complete information to visualize and quantify the diseased area and it cannot be equated with osteonecrosis. To verify NE activity as osteonecrosis, tissue samples from the affected area need to be collected for histological examination

Background: About five to 10% of cancers in the head and neck region are neck squamous cell carcinoma of unknown primary (NSCCUP). Their diagnosis and treatment are challenging given the risk of missing occult tumors and potential relapse. Recently, we described human papillomavirus (HPV)-related NSCCUP-patients (NSCCUP-P) as a subgroup with superior survival. However, standardized diagnostic workup, novel diagnostic procedures, decision-making in the multidisciplinary tumor board (MDTB) and multimodal therapy including surgery and post-operative radio-chemotherapy (PORCT) may also improve survival. Methods: For assessing the impact of standardized diagnostic processes simultaneously established with the MDTB on outcome, we split our sample of 115 NSCCUP-P into two cohorts treated with curative intent from 1988 to 2006 (cohort 1; n = 53) and 2007 to 2018 (cohort 2; n = 62). We compared diagnostic processes and utilized treatment modalities applying Chi-square tests, and outcome by Kaplan–Meier plots and Cox regression. Results: In cohort 2, the standardized processes (regular use of [18F]-FDG-PET-CT imaging followed by examination under anesthesia, EUA, bilateral tonsillectomy and neck dissection, ND, at least of the affected site) improved detection of primaries (P = 0.026) mostly located in the oropharynx (P = 0.001). From 66.0 to 87.1% increased ND frequency (P = 0.007) increased the detection of extracapsular extension of neck nodes (ECE+) forcing risk factor-adapted treatment by increased utilization of cisplatin-based PORCT that improved 5-years progression-free and overall survival from 60.4 and 45.3 to 67.7% (P = 0.411) and 66.1% (P = 0.025). Conclusions: Standardized diagnostic workup followed by ND and risk-factor adapted therapy improves survival of NSCCUP-P.

In Scotland, further education colleges provide 28% of all higher education; this includes over half of part-time undergraduate higher education. This provision has contributed to wider participation in higher education in Scotland by “non traditional” students and to progress towards a mass system of higher education within a learning society. This thesis is a case study of higher education students in a Scottish further education college. It explores the nature of the students’ experience and its relevance to institutional management and higher education policy. Evidence is drawn from the college’s records, from focus groups and from a questionnaire survey of whole year groups (full-time and part-time students) over three successive years. The theoretical focus is upon a new definition of lifelong learning as learning integrated with life, drawn from literature on motive, motivation, participation and retention. The research explores the students’ experiences of combining study with work and family life. The student experience is found to be heterogeneous, complex and distinct from the stereotype of a young full-time university student. Vocational motives predominate and there is evidence of a significant investment of meaning, expectation and purpose in the experience of higher education. The students’ ability to balance and integrate learning with life is a determining factor in the achievement of sustained participation. The quality of support networks both in college and in the students’ work and family lives are found to be more significant than personal or demographic characteristics. The case study contributes to current thinking about the professional role of college senior managers in creating a student-centred institutional culture that responds to the complexity of the students’ experience. A case is made for a review of the current inequity of financial support for full-time and part-time higher education students and of the marginal status of colleges in the development of higher education policy.