Developing a head and neck cancer treatment plan for a candidate of Intensity Modulated Radiation Therapy (IMRT) requires extensive domain knowledge and subjective experience. Therefore, it takes a cancer treatment team at least 2 to 3 days to develop such a plan from scratch. Many times the team may not use a reference plan. Sometimes, to reduce the amount of time taken to generate each treatment plan, these experts recall a patient, whose plan they recently prepared, and who had similar symptoms as the candidate. Using this recalled patient's plan as the starting point, the cancer treatment team modifies it based on the differences in the symptoms of the new candidate and those of the reference patient record. The resultant plan after modification is presented as the new treatment plan for the oncologist to evaluate its suitability for treatment of the candidate. This approach is heavily dependent on the team's choice of the reference patient record. Choosing a starting treatment plan where the patient's symptoms are not the closest to the new candidate implies that more time will be spent modifying the plan than is necessary and the resultant treatment plan may not be the best achievable under the same circumstances given a better starting plan. Therefore, the team's bias in choosing the starting plan may affect the quality of treatment plan that is finally produced for the candidate. This thesis proposes a system that behaves like an un-biased radiotherapy expert - following a similar process and standards as the human experts and which searches the entire IMRT patient database and returns the record (with patient symptoms and treatment plan) for a patient whose symptoms are most similar to the candidate's symptoms. It takes in the new candidate's information (from diagnosis, scans of the tumor and interviews with the candidate), searches the database and prints out a patient record showing another patient's treatment plan as the suggested starting point for generating the new plan. The system uses Case-Based Reasoning (CBR) because it mimics the experts' approach since it makes use of previous successes and shuns reasoning that has failed in the past. This occurs by considering only treatment plans that have been implemented successfully on patients in the hospital archive. For this thesis, CBR is applied using fuzzy IF-THEN rules to search the patient database. Fuzzy logic is used because it can handle imprecise expressions commonly used in natural language to determine the appropriate weight of the patient attributes in the search process. Filtering of patient records based on parameter value ranges is also used to reduce the number of records that have to be compared. The system code developed for this thesis was prepared in Java and C Language Integrated Production System (CLIPS) using the Java Expert System Shell (JESS). This system is part of a bigger expert system that is being prepared by the Intelligent Systems Applications Center (ISAC) for Thomas Jefferson University Hospital, expected to generate a radiotherapy plan for a patient designated for IMRT treatment. Initial results from the developed prototype prove the viability of selecting similar patients using CBR. It is important to note that the overall objective of the project is to build a system that effectively aids decision support by the IMRT team when generating a new treatment plan and not to replace them. The team is expected to use the generated plan as a starting point in determining a new treatment plan. If the generated plan is sufficient, the oncologist and their team will have to check this plan (in their various capacities) against expected standards for quality control before passing it on for implementation. This will save them time in planning and allow them to focus more on the patient's needs hence a higher quality of life for the patient after treatment. / Electrical and Computer Engineering

Yes / The chemokine receptor CCR7 is expressed on lymphocytes and dendritic cells and is responsible for trafficking of these cells in and out of secondary lymphoid organs. It has recently been shown that CCR7 expression is elevated in a number of cancers, including head and neck cancers, and that its expression correlates to lymph node (LN) metastasis. However, little is known about the factors that can induce CCR7 expression in head and neck cancers. We compared the protein expression and functional responses of CCR7 under normoxia and hypoxia in head and neck cancer cell lines OSC-19, FaDu, SCC-4, A-253 and Detroit-562 cultured as monolayers, spheroids, and grown in vivo as xenografts in balb/c mice. In addition, we analysed the correlation between hypoxia marker HIF-1α and CCR7 expression in a tissue microarray comprising 80 clinical samples with various stages and grades of malignant tumour and normal tissue. Under hypoxia, the expression of CCR7 is elevated in both in vitro and in vivo models. Furthermore, in malignant tissue, a correlation is observed between hypoxia marker HIF-1α and CCR7 across all clinical stages. This correlation is also strong in early histological grade of tumours. Hypoxia plays a role in the regulation of the expression of CCR7 and it may contribute to the development of a metastatic phenotype in head and neck cancers through this axis.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. It has commonly been associated with exposure to tobacco-derived carcinogens and alcohol consumption. Pembrolizumab has shown to be effective in the treatment of many types of cancers such as melanoma, non-small cell lung cancer, due to its antiproliferative, immunoregulatory properties. The aim of this study was to investigate the effects of naked Pembrolizumab and Pembrolizumab liposome on the level of DNA damage, gene, and protein expressions in peripheral lymphocytes from HNC patients and compared to the healthy individuals by using the Comet and micronucleus assays. Western blotting and real-time polymerase chain reaction were performed to assess the potential of improving the repair mechanisms after treatment with naked Pembrolizumab and Pembrolizumab liposome. According to the results, Comet assay and micronucleus assay showed a significantly decreased DNA damage in the lymphocytes from HNC patients after being treated with naked Pembrolizumab and pembrolizumab liposome. Furthermore, the results have shown that naked Pembrolizumab and pembrolizumab liposomes (10 μg/ml) greatly decreased the oxidative stress produced by H2O2. Both forms of pembrolizumab have also demonstrated improving the repair mechanisms in lymphocytes from HNC patients by modulating the expression of P53, P21, and Bcl-2 at mRNA and protein levels. This study suggested that Pembrolizumab naked and liposome could have an antioxidant role alongside other actions in the treatment of HNSCC. However, further studies on Cancer cell lines and in vivo observation are required to validate the anticancer potential of pembrolizumab naked with liposome in HNC. / Ministry of Higher Education and Scientific Research, Libya

We aimed to evaluate possible factors influencing the long-term survival of teeth after tumor therapy to the head and neck region with and without radiation. Between January 2019 and January 2020, patients who underwent for head and neck cancer and received dental treatment before and after at the Department of Prosthetic Dentistry of the Martin Luther University Halle- Wittenberg were enrolled in the study. Clinical examination with assessment of dental status and stimulated salivary flow rate (SFR) was performed and information about disease progression and therapy was retrieved from medical records. Of 118 patients (male: 70.3%; mean age: 63.2 12.4 years), 95 received radiotherapy (RT), and 47 were administered radio-chemotherapy (RCT). The teeth of irradiated patients exhibited a lower 5-year survival probability (74.2%) than those of nonirradiated patients (89.4%). The risk of loss (RL) after RT increased with nicotine use, presence of intraoral defects, reduced SFR, RCT and regarding mandibular teeth, and decreased with crowning following. Lower SFR increased the RL even without RT. Consideration of patient’s treatment history, individual risk profile, and clinical findings during the prosthetic planning phase could enable earlier, more targeted dental treatment after (e.g., timely crowning).

This thesis investigates the feasibility of utilizing biodegradable polymeric microspheres loaded with the anticancer drug 5-fluorouracil (5FU) and superparamagnetic iron oxide nanoparticles (SPIONs) to magnetically deliver the cancer therapeutic 5FU to a target tumor in the human body. The primary method of material loading consisted of a w/o/w double emulsion mechanism which 1) loads and protects 5FU in the inner water phase consisting of distilled water and polyvinyl alcohol (PVA), 2) dispersed SPIONs in the biodegradable polymeric organic phase consisting of methylene chloride (MeCl2) for eventual magnetic transport, and 3) suspended these w/o emulsion droplets in an outer aqueous phase comprised of water and PVA and then evaporating the solvent by convection. This procedure produced dried double emulsion microspheres below 2 µm in diameter. They were characterized using scanning electron microscopy (SEM), and magnetometry, which demonstrated their size and superparamagnetic properties. The encapsulation efficiency of 5FU into these polymeric microspheres was above 95%. Drug release of 5FU from dried double emulsion microspheres was significant over 63 days in water and phosphate buffered saline (PBS). Drug release was faster at 37 °C compared to room temperature (21 °C). The medium of PBS at pH 7.4 and 5.4 promoted faster release than distilled water at pH 7.0. Release was faster from PLGA than from PLA. Antibiotic potency of 5FU remained effective after drug release and degradation of carrier. Application of these microspheres in future clinical trials may present a noninvasive, low-risk method to treating malign tumors in nonresectable regions while demonstrating more effective results than systemic administration of chemotherapy. This research presents a significant innovation in therapeutic drug delivery technology for nonresectable cancerous tumors, particularly in the head and neck regions.

Yes / Introduction: Evolution of a patient-reported symptom-based risk stratification system to redesign the suspected head and neck cancer (HNC) referral pathway (EVEREST-HN) will use a broad and open approach to the nomenclature and symptomatology. It aims to capture and utilise the patient reported symptoms in a modern way to identify patients’ clinical problems more effectively and risk stratify the patient. Method: The review followed the PRISMA checklist for scoping reviews. A search strategy was carried out using Medline, Embase and Web of Science between January 1st 2012 and October 31st 2023. All titles, abstracts and full paper were screened for eligibility, papers were assessed for inclusion using predetermined criteria. Data was extracted pertaining to the aims, type of study, cancer type, numbers of patients included and symptoms, presenting complaints or signs and symptoms. Results: There were 9,331 publications identified in the searches, following title screening 350 abstracts were reviewed for inclusion and 120 were considered for eligibility for the review. 48 publications met the eligibility criteria and were included in the final review. Data from almost 11,000 HNC patients was included. Twenty-one of the publications were from the UK, most were retrospective examination of patient records. Data was extracted and charted according to the anatomical area of the head and neck where the symptoms are subjectively and objectively found, and presented according to lay terms for symptoms, clinical terms for symptoms and the language of objective clinical findings. Discussion: Symptoms of HNC are common presenting complaints, interpreting these along with clinical history, examination and risk factors will inform a clinician’s decision to refer as suspected cancer. UK Head and Neck specialists believe a different way of triaging the referrals is needed to assess the clinical risk of an undiagnosed HNC. EVEREST-HN aims to achieve this using the patient history of their symptoms. This review has highlighted issues in terms of what is considered a symptom, a presenting complaint and a clinical finding or sign. / National Institute for Health and Care Research Programme Grant for Applied Research NIHR 202862.

Yes / Introduction: Between 2009/2010 and 2019/2020, England witnessed an increase in suspected head and neck cancer (sHNC) referrals from 140 to 404 patients per 100 000 population. 1 in 10 patients are not seen within the 2-week target, contributing to patient anxiety. We will develop a pathway for sHNC referrals, based on the Head and Neck Cancer Risk Calculator. The evolution of a patient-reported symptom-based risk stratification system to redesign the sHNC referral pathway (EVEREST-HN) Programme comprises six work packages (WPs). This protocol describes WP1 and WP2. WP1 will obtain an understanding of language to optimise the SYmptom iNput Clinical (SYNC) system patient-reported symptom questionnaire for sHNC referrals and outline requirements for the SYNC system. WP2 will codesign key elements of the SYNC system, including the SYNC Questionnaire, and accompanying behaviour change materials. Methods and analysis: WP1 will be conducted at three acute National Health Service (NHS) trusts with variation in service delivery models and ensuring a broad mixture of social, economic and cultural backgrounds of participants. Up to 150 patients with sHNC (n=50 per site) and 15 clinicians (n=5 per site) will be recruited. WP1 will use qualitative methods including interviews, observation and recordings of consultations. Rapid qualitative analysis and inductive thematic analysis will be used to analyse the data. WP2 will recruit lay patient representatives to participate in online focus groups (n=8 per focus group), think-aloud technique and experience-based codesign and will be analysed using qualitative and quantitative approaches. Ethics and dissemination: The committee for clinical research at The Royal Marsden, a research ethics committee and the Health Research Authority approved this protocol. All participants will give informed consent. Ethical issues of working with patients on an urgent cancer diagnostic pathway have been considered. Findings will be disseminated via journal publications, conference presentations and public engagement activities. / This work was supported by NIHR Programme Grants for Applied Research (grant number: NIHR202862).

HNSCC accounts for 7 percent of all new cancer occurrences. Despite currently available treatments, there continues to be a high mortality and recurrence rate in HNSCC. Well over 50 percent of all cancer patients receive chemotherapy as a standard treatment. However, only 5 percent of these cases have been shown to help with treatment of the disease. Formerly, two options were available for drug testing: in vivo animal models, and in vitro two-dimensional models. While in vivo models remain the most representative, their use is burdened by high costs, time constraints, and ethical concerns. 2D models are simple to use and cost effective, although they have been shown to produce inaccurate data regarding chemotherapeutic drug resistance due to their 2D arrangement and altered gene expression. Researchers for the past decade have been working to create 3D models that more accurately represent in vivo systems in order to evaluate chemotherapeutic efficacy and improve clinical outcomes. In line with this agenda, novel 3D head and neck cancer models were created out of electrospun synthetic polymers seeded with either HN6 or HN12 cancer cells. The models were then treated with chemotherapeutic drugs (either paclitaxel or cisplatin), and, after 72 hours, subjected to a live-dead assay in order to determine the cytotoxic effects of the drugs. 2D cultures of HN6 and HN12 were also and subject to a WST-1 assay after 72 hours. The results of the treated-scaffold assays were then compared to the results of the 2D culture assays, and, as predicted, the cancer cells in a 3D culture system proved to be more resistant to chemotherapeutic drugs. The underlying assumption for this study being that a 3D culture system based on precisely defined structural parameters would provide a practical environment to screen therapeutics for anti-cancer efficacy. To prove this, 3D scaffolds of three different fiber sizes were developed by electrospinning different concentrations of Poly(L-lactic acid) (“PLLA”) (55mg/ml, 115mg/ml, and 180mg/ml) onto a mandrel that was perforated to allow for increased porosity. The resultant small, medium, and large scaffolds were then subjected to concentrated hydrochloric acid (HCl) pretreatment in order to make them less hydrophobic. Different fiber diameters represented different ECM environments for both HN6 and HN12. It was proven that both cell types thrived best in small fibers (55mg/ml-115mg/ml) than in large fibers. It was also reaffirmed through live-dead anlaysis of cells seeded on 3D scaffolds and treated with IC90 values of cisplatin that the head and neck cancer cells were more resistant which is more representative to the 3D environment of cancer cells in vivo.

O câncer de cabeça e pescoço (CCP) apresentam incidência mundial sendo considerado um problema de saúde pública. O diagnóstico tardio dos carcinomas ainda é uma realidade presente, implicando em terapias como a radioterapia (RT). Esta terapia antineoplásica pode causar diversos efeitos colaterais tais como: mucosite, dificuldade de deglutição, alteração ou perda do paladar, xerostomia, trismo, cárie de radiação, osteorradionecrose, alterações do ligamento periodontal e infecções oportunistas. Os efeitos adversos da RT instituída para tratamento de pacientes com CCP, podem interferir significativamente na qualidade de vida desses indivíduos, causando possíveis alterações ósseas e dentais, daqueles que acometem as partes moles. Dentre elas podemos citar as mucosites, hipossialia, agenesia, cáries por radiação, trismo e osteorradionecrose (ORN). Esta última constitui uma complicação grave e de difícil tratamento. O presente estudo objetivou ponderar a relação dose-efeito da radioterapia de cabeça e pescoço, em consideração aos dentes e estruturas ósseas do complexo maxilo - mandibular, avaliando e explorando o impacto do tamanho do tumor ,sua distribuição e dosimetria no complexo maxilo mandibular de pacientes submetidos a radioterapia de CCP. A IMRT se mostrou a melhor indicação de tratamento quando comparada a RT, pois reduziu muito os efeitos encontrados nas radiografias, o que mostrou sua baixa toxicidade nos tecidos adjacentes saudáveis. A partir dos resultados obtidos observou se que a radioterapia pode provocar alterações significativas na estrutura do CMM, ademais da região própria ao tumor, e os médicos oncologistas juntamente com dentistas devem se apoiar na detecção e abordagem dessas sequelas e acompanhamento dos seus tratamentos e prevenções, sendo necessário que os profissionais de odontologia orientem e façam as devidas intervenções para proporcionar melhores condições aos pacientes em tratamento de radioterapia de cabeça e pescoço. / Head and neck neoplasms present a worldwide incidence and are considered a public health problem. The late diagnosis of carcinomas is still a reality, implicating in thera-pies such as radiotherapy. This antineoplastic therapy can cause several side effects such as: mucositis, difficulty in swallowing, alteration or loss of taste, xerostomia, tris-mus, radiation caries, osteoradionecrosis, alterations of the periodontal ligament and opportunistic infections. The adverse effects of radiotherapy instituted for the treatment of patients with cancer of the head and neck region can significantly interfere in the quality of life of these individuals, causing possible bone and dental changes in those that affect the soft parts. Among them we can mention mucositis, hyposialia, agenesis, radiation caries, trismus and osteoradionecrosis (ORN). The latter constitutes a seri-ous complication and is difficult to treat. The present study aims to evaluate the dose-effect relationship of head and neck radiotherapy, considering the teeth and bone structures of the maxillo-mandibular complex, evaluating and exploring the impact of tumor size, its distribution and dosimetry in the mandibular nipple complex of patients submitted to CCP radiotherapy. The IMRT performed a better comparison procedure when compared to what is more difficult to see on radiographs when compared to toxicity in adjacent healthy systems. From the results obtained, the effects of radio-therapy can cause changes in the structure of the CMM, besides being responsible for the tumor, and the oncologists. It is necessary that dental professionals guide and withdraw care for the treatment of head and neck radiotherapy.

O carcinoma epidermoide de cabeça e pescoço (HNSCC) é uma das neoplasias mais frequentes e geralmente está associado a inflamação crônica e níveis sistêmicos de citoquinas. Seus principais fatores de risco são a exposição ao tabaco e álcool. Publicações recentes sugerem que a infecção por papiloma vírus HPV está relacionada com a tumorigênese de cabeça e pescoço e pode alterar o perfil e o desfecho deste tumor. A transição epitelial-mesenquimática (EMT) é um processo importante durante a tumorigênese pelo qual células epiteliais obtêm um fenótipo migratório e invasivo. Os efeitos da infecção por HPV e de citocinas inflamatórias neste processo ainda não são bem compreendidos em HNSCC. O presente estudo teve como objetivo transfectar células normais e neoplásicas com os genes E6/E7 de HPV16 e investigar os mecanismos pelos quais a EMT é ativada por citocinas inflamatórias e por infecção por HPV. Taxas de proliferação, viabilidade, migração e invasão celular induzidas por IL-6, TNF-a e TGF-beta foram avaliadas em linhagens celulares derivadas de queratinócitos normais e de carcinoma de língua (HaCat e SCC25, respectivamente) transfectadas com os genes E6/E7 de HPV16 e a expressão dos marcadores relacionados a EMT foram analisados por PCR em tempo real nas linhagens SCC25, HaCat e FaDu (carcinoma de faringe). Os resultados sugerem que o HPV modificou a morfologia das linhagens normal e tumoral. Na linhagem HaCat, o ambiente inflamatório estimulou modificações importantes para o desenvolvimento de condições patológicas. A inserção dos genes E6/E7 de HPV16 diminuiu a proliferação e a viabilidade na linhagem HaCat e o ambiente inflamatório não modificou a resposta iniciada pelo HPV. Na linhagem SCC25 a inserção de HPV em associação com inflamação reduziu a progressão da EMT, ao contrário do que foi observado na linhagem FaDu. A relação de HPV com inflamação levando a progressão de EMT é controversa e dependente do sítio anatômico em tumores de cabeça e pescoço / Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent neoplasias and is often associated with chronic inflammation and systemic cytokine levels. Its main risk factors are tobacco and alcohol exposition. Recent publications suggest that the infection by human papillomavirus (HPV), especially high-risk types, is related to head and neck tumorigenesis and may alter the tumor profile and outcome. Epithelial-mesenchymal transition (EMT) is an important process during tumorigenesis by which epithelial cells gain a migratory and invasive phenotype. The effects of HPV infection and inflammatory cytokines on this process are still not well understood in HNSCC. The present study aimed to transfect normal and neoplastic cells with E6/E7 genes of HPV type 16, and to investigate the mechanisms by which EMT is activated by inflammatory cytokines and by HPV infection. Proliferation, viability, migration and cell invasion rates induced by IL-6, TNF-a and TGF-beta cytokines will be also evaluated in cell lines derived from normal keratinocyte and tongue carcinoma (HaCat and SCC25, respectively) transfected with HPV16 E6/E7 genes and the expression of the EMT-related markers were analyzed by real-time PCR in the SCC25, HaCat and FaDu (pharyngeal carcinoma). The results suggest that HPV modified the morphology of normal and tumor cell lines. In the HaCat cell line, the inflammatory environment stimulated important modifications for the development of pathological conditions. Insertion of HPV16 E6/E7 genes decreased proliferation and viability in the HaCat and the inflammatory environment did not modify the HPV-initiated response. In the SCC25 cell line the insertion of HPV in association with inflammation reduced the progression of EMT, unlike was observed in FaDu. The relationship of HPV with inflammation leading to progression of EMT is controversial and depends on anatomical site in head and neck carcinoma