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- Schindele, Alexandra, 1967-
(author)
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Mapping viruses in non-malignant tonsils, nasal polyps, sinonasal inverted papilloma and laryngeal cancer
- 2022
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Doctoral thesis (other academic/artistic)abstract
- Background: The upper respiratory tract is exposed to viruses, which can lead to infection and cancer development. We chose to study common and/or chronic diseases along with common and cancer related viruses in the upper airway. High-risk human papillomavirus (HPV) causes cancer in tonsils and base of tongue, and Epstein-Barr virus (EBV) in the nasopharynx. p16 is used as a site-specific tumor marker for HPV. Human cytomegalovirus (HCMV) and human adenovirus (HAdV) are proposed to be oncomodulatory. It is unclear what significance these viruses have in benign tonsillar disease, chronic rhinosinusitis with nasal polyps (CRSwNP), sinonasal inverted papillomas (SIP) and laryngeal squamous cell carcinoma (LSCC). If virus is identified, it could make possible the use of current vaccines in prevention and treatment, as well as protection of healthcare providers.Material and Methods: We analyzed 40 benign tonsils, 45 paired nasal polyp and healthy nasal mucosa samples, 53 SIP and 78 LSCC samples. We used PCR/microarrays (PapilloCheck®) for HPV detection and genotyping, immunohistochemistry (IHC) for p16 expression and real-time PCR for EBV, HCMV and HAdV detection. Additionally, Epstein-Barr encoding region (EBER) in situ hybridization (ISH) was used for EBV localization and count.Results: HPV and p16 were not co-expressed, and p16 levels were low in benign tonsils, nasal polyps, and paired controls. Also, 9% of LSCC samples were high-risk HPV 16 positive and over-expressed p16.EBV-positive cells were detected in 65% of the tonsils, nasal polyps (36%) versus controls (12%), 30% of SIP cases and 33% of LSCC samples.Conclusions: EBV is commonly identified in benign tonsils, nasal polyps, SIP and LSCC, when using sensitive and robust detection methods. At the same time, viral infection with HPV, HCMV or HAdV appears to be uncommon in these conditions. p16 does not emerge as a reliable marker for HPV infection in LSCC.
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| 2. |
- Wilms, Torben, 1973-
(author)
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Squamous cell carcinoma of the head and neck, focusing on Epstein-Barr-virus, programmed cell death ligand 1 and serum lipoproteins
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Background: Squamous cell carcinoma of the head and neck (SCCHN)comprises a large group of tumours including the oral cavity and nasopharyngealarea, and typically affects older males in association with alcohol/tobacco usage.Within the oral cavity, the mobile tongue is the most common site for tumourdevelopment. The incidence of squamous cell carcinoma of the oral tongue(SCCOT) is increasing in younger people, which has been suggested to associatewith other than the traditional risk factors for this disease. Two common humanoncogenic viruses, human papillomavirus (HPV) and Epstein-Barr virus (EBV)are connected to certain types of SCCHN, in oropharynx and nasopharynxrespectively. The receptor programmed cell death 1 (PD)-1 and its ligandprogrammed cell death ligand 1 (PD-L1) are particularly relevant in immunecheckpoint control, and elevated levels have been seen in various cancer types. Alink between hyperlipidemia and cancer risk has previously been suggested. Theaim of this thesis was to investigate risk factors and prognostic features forSCCHN, by focusing on EBV, PD-L1 and serum lipoproteins.Materials and methods: Ninety-eight cases of SCCOT and 15 cases of tonsillarsquamous cell carcinoma were examined for the presence of EBV-encodedribonucleic acids (EBERs), EBV deoxyribonucleic acid (DNA) and the proteinEBV-encoded nuclear antigen-1 (EBNA-1), using in situ hybridisation,polymerase chain reaction (PCR) and immunohistochemistry respectively. Onehundred and one cases of SCCOT were examined for expression of PD-L1 intumour and surrounding immune cells using Ventana SP263immunohistochemistry assay and a QuickScore (QS) method. An estimation oftumour-infiltrating immune cells was also performed in 25 of the patients.Circulating levels of PD-L1 were measured using an electrochemiluminescenceassay platform in serum from 30 patients. Finally, serum samples from 106patients and 28 healthy controls were investigated for levels of total cholesterol,low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides andlipoprotein(a).Results: In the first study, using an in situ hybridisation kit no EBER transcriptswere detected. No EBV DNA was identified with PCR analysis, andimmunohistochemistry for EBNA-1 was also negative. In the second study, highertumour cell PD-L1 levels were found in females than males (p = 0.019). Forpatients with low PD-L1 in tumour cells, better survival was shown in males thanfemales (overall survival p = 0.021, disease-free survival p = 0.020). Tumourinfiltrating natural killer (NK) T cells, immature dendritic cells (DCs) and M1macrophages correlated positively with tumour cell PD-L1 (p < 0.05). In the laststudy, the only lipoprotein showing significant difference in concentration iiibetween healthy controls and patients was HDL (p = 0.012). Kaplan-Meiersurvival curves showed that patients with high levels of total cholesterol or LDLhad better survival than patients with normal levels (p = 0.028 and p = 0.007respectively). Adjusting for the effects of age at diagnosis, TNM stage and weightchange, multivariate Cox regression models showed LDL to be an independentprognostic factor for both overall (p = 0.010) and disease-free survival (p =0.018).Conclusion: We excluded EBV as a potential player in SCCOT in both old andyoung patients and highlight the importance of appropriate controls for EBVencoded RNA in-situ hybridization (EBER-ISH) when investigating EBV inhuman diseases. Regarding PD-L1, our data supported the significance of genderon tumour cell PD-L1 expression and demonstrated combined effects of genderand PD-L1 levels on clinical outcome in patients with SCCOT. Data also indicatedthe involvement of specific immune cell types in PD-L1-regulated immuneevasion. Looking at serum lipoproteins, we found high LDL levels to be beneficialfor survival outcome in patients with SCCHN. Furthermore, the use of cholesterollowering medicine for prevention or management of SCCHN needs to be carefullyevaluated.
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| 3. |
- Salehi, Amir M., 1971-
(author)
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Clinical investigation and application of Artificial Intelligence in diagnosis and prognosis of squamous cell carcinoma of the head and neck
- 2023
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Doctoral thesis (other academic/artistic)abstract
- Background: In Sweden around 1400 people are affected by head and neck cancer each year, and around 400 of these tumours are located in the mobile tongue (SCCOT). A major problem with these tumours is the high degree of relapse. In order to broaden our understanding of the group of squamous cell carcinoma of the head and neck (SCCHN) tumours we evaluated and compared the outcomes of panendoscopy with biopsy, ultrasonography with fine needle aspiration cytology (US-FNAC), and preoperative positron emission tomography/computed tomography (PET/CT) data from the same patients. As patients with SCCHN frequently have distant metastasis and locoregional recurrences, machine learning (ML) techniques were used to create classification models that accurately predict the likelihood of an early recurrence.Materials and methods: From patients suspected of having head and neck cancer between 2014–2016 results from PET/CT, panendoscopy with biopsy and US-FNAC were compared. Clinical, genomic, transcriptomic, and proteomic markers identifying recurrence risk were investigated. In blood samples taken from healthy individuals, data from proteins relevant to inflammation and/or tumor processes were evaluated. The SHapley Additive Explanations (SHAP) approach was used to determine the best ML algorithm for feature selection. AdaBoost, Artificial neural networks (ANNs), Decision Tree (DT), eXtreme Gradient Boosting (XGBoost), and Support Vector Machine (SVM) were used to create prediction models. Clinical data from patients were analyzed using statistical and ML techniques.Results: The concordance between results from PET/CT and panendoscopy with biopsy was 91.3%, and somewhat lower, 89.1%, for PET/CT and US-FNAC. The top contributors to classification with the ML approach were five mRNAs (PLAUR, DKK1, AXIN2, ANG, VEGFA), and 10 proteins (RAD50, 4E-BP1, MYH11, MAP2K1, BECN1, NF2, RAB25, ERRFI1, KDR, SERPINE1), using the extreme gradient boosting (XGBoost) method. The SHAP approach was used for feature selection. Using data from analysis of proteins in blood and interpretable ML showed that the Support Vector Machine (SVM) had the best performance with a balanced accuracy of 0.863, and a ROC-AUC of 0.924. The top three contributors to the SVM prediction model's performance were IL10, TNF Receptor Associated Factor 2 (TRAF2), and Kallikrein Related Peptidase 12 (KLK12). Recurrence was correlated with diabetes (p = 0.003), radiographic neck metastasis (p = 0.010), and T stage (p = 0.0012). A ML model got an accuracy rate of 71.2%. In the SCCOT group, diabetics predominated over non-diabetics, and also had lower recurrence rates and better survival (p = 0.012).Conclusion: Results show that the combination PET/CT is useful in diagnosis of SCCHN. It further emphasizes the use of ML to identify transcriptomic and proteomic factors that are significant in predicting risk of recurrence in patients with SCCHN. It provides a methodical strategy for early diagnosis of SCCOT before onset of clinical symptoms using multidimensional plasma protein profiling and interpretable ML. A model for predicting recurrence of SCCOT is provided by ML utilizing clinical data. As SCCOT patients with co-existing diabetes showed a better prognosis than non-diabetics, results suggest that individuals with SCCOT, regardless of diabetes status, may benefit from therapeutic management of glucose levels.
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