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Purpose To analyze the risk of postoperative hemorrhage in tonsil surgery with different surgical methods, instruments, indications, and age groups. Monopolar diathermy compared to bipolar diathermy was of particular interest. Methods The data from tonsil surgery patients were retrospectively collected between 2012 and 2018 in the Hospital District of Southwest Finland. The surgical method, instruments, indication, sex and age and their association with a postoperative hemorrhage were analyzed. Results A total of 4434 patients were included. The postoperative hemorrhage rate for tonsillectomy was 6.3% and for tonsillotomy 2.2%. The most frequently used surgical instruments were monopolar diathermy (58.4%) cold steel with hot hemostasis (25.1%) and bipolar diathermy (6.4%) with the overall postoperative hemorrhage rates 6.1%, 5.9% and 8.1%, respectively. In tonsillectomy patients, the risk for a secondary hemorrhage was higher with bipolar diathermy compared to both monopolar diathermy (p = 0.039) and the cold steel with hot hemostasis technique (p = 0.029). However, between the monopolar and the cold steel with hot hemostasis groups, the difference was statistically non-significant (p = 0.646). Patients aged > 15 years had 2.6 times higher risk for postoperative hemorrhage. The risk of a secondary hemorrhage increased with tonsillitis as the indication, primary hemorrhage, tonsillectomy or tonsillotomy without adenoidectomy, and male sex in patients aged ≤ 15 years. Conclusion Bipolar diathermy increased the risk for secondary bleedings compared to both monopolar diathermy and the cold steel with hot hemostasis technique in tonsillectomy patients. Monopolar diathermy did not significantly differ from the cold steel with hot hemostasis group regarding the bleeding rates.

The incidence of human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCC) has increased globally. Our research goal was to study HNSCC incidence in a representative Northern European population and evaluate the utility of the HPV surrogate marker p16 in clinical decision-making. All new HNSCC patients diagnosed and treated in Southwest Finland from 2005–2015 (n = 1033) were identified and analyzed. During the follow-up period, the incidence of oropharyngeal (OPSCC) and oral cavity squamous cell carcinoma (OSCC) increased, while the incidence of laryngeal squamous cell carcinoma (LSCC) decreased. This clinical cohort was used to generate a population-validated tissue microarray (PV-TMA) archive for p16 analyses. The incidence of p16 positivity in HNSCC and OPSCC increased in southwest Finland between 2005 and 2015. p16 positivity was mainly found in the oropharynx and was a significant factor for improved survival. p16-positive OPSCC patients had a better prognosis, regardless of treatment modality. All HNSCC patients benefited from a combination of chemotherapy and radiotherapy, regardless of p16 expression. Our study reaffirms that p16 expression offers a prognostic biomarker in OPSCC and could potentially be used in cancer treatment stratification. Focusing on p16 testing for only OPSCC might be the most cost-effective approach in clinical practice.

Mutations in hundreds of genes have been associated with formation of human cancer, with different oncogenic lesions prevalent in different cancer types. Yet, the malignant phenotype is simple, characterized by unrestricted growth of cells that invade neighboring healthy tissue and in many cases metastasize to distant organs. One possible hypothesis explaining this dichotomy is that the cancer genes regulate a common set of target genes, which then function as master regulators of essential cancer phenotypes, such as growth, invasion and metastasis. To identify mechanisms that drive the most fundamental feature shared by all tumors – unrestricted cell proliferation – we used a multiomic approach to identify common transcriptional and posttranslational targets of major oncogenic pathways active in different cancer types, and combined this analysis with known regulators of the cell cycle. We identified translation and ribosome biogenesis as common targets of both transcriptional and posttranslational oncogenic pathways. By combining proteomic analysis of clinical samples with functional studies of cell cultures, we also establish NOLC1 as a key node whose convergent regulation both at transcriptional and posttranslational level is critical for tumor cell proliferation. Our results indicate that lineage-specific oncogenic pathways commonly regulate the same set of targets important for growth control, revealing novel key downstream nodes that could be targeted for cancer therapy or chemoprevention.

Introduction Prognostic biomarkers and novel therapeutic approaches have been slow to emerge in the treatment of head and neck squamous cell carcinoma (HNSCC). In this study, an HNSCC patient cohort is created and performance of putative prognostic biomarkers investigated in a population-validated setting. The overall goal is to develop a novel way to combine biomarker analyses with population-level clinical data on HNSCC patients and thus to improve the carryover of biomarkers into clinical practice. Materials and methods To avoid selection biases in retrospective study design, all HNSCC patients were identified and corresponding clinical data were collected from the Southwest Finland geographical area. A particular emphasis was laid on avoiding potential biases in sample selection for immunohistochemical staining analyses. Staining results were evaluated for potential prognostic resolution. Results After comprehensive evaluation, the patient cohort was found to be representative of the background population in terms of clinical characteristics such as patient age and TNM stage distribution. A negligible drop-out of 1.3% (6/476) was observed during the first follow-up year. By immunohistochemical analysis, the role of previously implicated HNSCC biomarkers (p53, EGFR, p16, CIP2A, Oct4, MET, and NDFIP1) was investigated. Discussion Our exceptionally representative patient material supports the use of population validation to improve the applicability of results to real-life situations. The failure of the putative prognostic biomarkers emphasizes the need for controlling bias in retrospective studies, especially in the heterogenous tumor environment of HNSCC. The resolution of simple prognostic examination is unlikely to be sufficient to identify biomarkers for clinical practice of HNSCC.

There is a paucity of knowledge regarding the association of alcohol use with overall survival (OS) of patients with head and neck squamous cell carcinoma (HNSCC).All 1033 patients treated for new HNSCC in Southwest Finland regional referral center of Turku University Hospital in 2005-2015. Cox regression analysis was used. Tumor TNM classification, age at baseline and tobacco smoking status were assessed as potential confounders.A history of severe harmful alcohol use with major somatic complications (HR: 1.41; 95%CI: 1.06-1.87; p = 0.017) as well as current use of at least 10 units per week (HR: 1.44, 95%CI: 1.16-1.78; p = 0.001) were associated with OS.Alcohol consumption of 10-20 units/week, often regarded as moderate use, was found to increase risk of mortality independent of other prognostic variables. Systematic screening of risk level alcohol use and prognostic evaluation of alcohol brief intervention strategies is highly recommended.

Background MET has emerged as target in head and neck squamous cell carcinoma (HNSCC). However, clinical data on MET inhibition in HNSCC are limited. Methods HNSCC biopsies and cell lines were tested for MET activity. The response of cell lines to BAY-853474 was tested in proliferation assays. The prognostic value of MET expression was also analyzed. Results HNSCC cell lines do not respond to MET inhibition. MET-dependent gastric cancer cell lines have much higher levels of MET expression and phosphorylation than HNSCC cell lines. Clinical samples of HNSCC contain much less MET than responsive models. Conclusions No clinical response to MET inhibitors in monotherapy may be expected in unselected cases of HNSCC. Only selected patients with MET amplifications should be treated with MET inhibitors. Patients with increased MET immunoreactivity have shorter overall survival. MET might be useful as marker for the detection of patients with more aggressive types of HNSCC.

BackgroundCochlear implantation can be used when a patient's hearing cannot satisfactorily be improved after optimised hearing aid fitting. However, in patients with a cochlear nerve or brain disorder affecting hearing, the benefits of cochlear implants are not so straightforward.MethodsThis paper describes a 58-year-old patient suffering from multiple sclerosis and profound sensorineural hearing loss, rehabilitated with a cochlear implant. Literature concerning cochlear implantation in demyelinating conditions was systematically reviewed using PubMed/Medline and Web of Science databases.ResultsThe patient's cochlear implantation was successful, with speech discrimination scores remaining above 90 per cent for eight years post-operatively. No previous cases of cochlear implantation with multiple sclerosis related hearing loss have been reported, despite the high incidence of hearing loss in multiple sclerosis patients.ConclusionThis paper demonstrates that multiple sclerosis lesions should not be an exclusion criterion in an otherwise suitable candidate for cochlear implantation.

Background Currently, no clinically useful biomarkers for radioresistance are available in head and neck squamous cell carcinoma (HNSCC). This study assesses the usefulness of Cell Line Microarray (CMA) method to enhance immunohistochemical screening of potential immunohistochemical biomarkers for radioresistance in HNSCC cell lines. Methods Twenty-nine HNSCC cell lines were cultured, cell pellets formalin-fixed, paraffin-embedded, and arrayed. Radioresistance features of the cell lines were combined to immunohistochemical stains for p53, NDFIP1, EGFR, stem cell marker Oct4, and PP2A inhibitor CIP2A. Results Expression of p53, EGFR or CIP2A did not indicate intrinsic radioresistance in vitro. Stem cell marker Oct4 nuclear positivity and NDFIP1 nuclear positivity was correlated with increased intrinsic radioresistance. Conclusion The usefulness of CMA in analysis of HNSCC cell lines and discovery of biomarkers is demonstrated. CMA is very well adapted to both testing of antibodies in a large panel of cell lines as well as correlating staining results with other cell line characteristics. In addition, CMA-based antibody screening proved an efficient and relatively simple method to identify potential radioresistance biomarkers in HNSCC.

Lääketieteellisen diagnoosin tarkoitusta ja tehtävää tarkastellaan useimmiten sen moninaisten esiintymismuotojen kautta. Taudinmääritystä koskevissa tarkasteluissa on kyetty epätyydyttävästi esittämään diagnoosin saavuttamisen merkitys ja tehtävä lääketieteen kannalta. Diagnoosin merkitys havaintoja jäsentävänä totuuskäsitteenä, joka muodostaa lähtöpisteen hoitovalinnoille ja joka syntyy abduktiivisen hypoteesinmuodostuksen kautta, tarjoaa näkökulman, jossa diagnoosin muodostumista tarkastellaan mahdollisuuskäsitteen kautta. Tämä fenomenologinen tutkimus pyrkii kuvaamaan diagnostisen mahdollisuuden ilmiötä hyödyntäen Martin Heideggerin työkalun ja Lauri Routilan mahdollisuuksien pelitilan käsitteistöä. Mahdollisuutta tarkastellaan sekä loogisena että ontologisena käsitteenä pitäen se erillään todennäköisyyden käsitteestä. Tutkimuksen tuloksia havainnollistetaan virheellistä diagnostista päättelyketjua edustavien tapausesimerkkien valossa. Lääketieteellisen diagnoosin todetaan muodostuvan mahdollisuuksista rajautuvasta välttämättömyydestä, joka määrittelee hoidonvalinnan toimintaympäristön. Mahdollisuuksien pelitila todetaan käyttökelpoiseksi välineeksi diagnoosinmäärittämisen jälkikäteisessä arvioinnissa. Toisaalta sillä nähdään paikkansa tapahtumanaikaisessa diagnoosimahdollisuuksien ja diagnoosin ilmiön jäsennyksessä.

OBJECTIVES Tracheobronchial stenting has an established role in the palliation of malignant central airway obstruction (CAO). The purpose of this study is to describe the experience with self-expanding metal airway stents in 2 tertiary referral centres, covering a third of the population of Finland. METHODS Patients referred to and treated with airway stenting for malignant CAO using self-expanding metal-stents were identified from electronic patient records, and data were collected using a structured Endoscopic Lower Airway Management instrument. Statistical analysis to reveal factors affecting patient benefit and survival was carried out. RESULTS A total of 101 patients (mean age 65.8) and 116 procedures were identified. Procedure-related mortality was rare (3/101 patients) and complications infrequent. The median survival was 2.3 months [95% confidence interval (CI): 1.4–3.1). Stent benefit was not significantly affected by clinical characteristics. Survival was impacted by the use of adjunct procedures [hazard ratio (HR) 0.36, 95% CI: 0.23–0.58, P CONCLUSIONS The beneficial impact observed supports the further use of tracheobronchial stenting in malignant CAO. The use of self-expanding metal stents is encouraged.

Objectives: Cisplatin is combined with radiotherapy for advanced head and neck squamous cell carcinoma (HNSCC). While providing a beneficial effect on survival, it also causes side effects and thus is an important target when considering treatment de-escalation. Currently, there are no biomarkers to predict its patientselective therapeutic utility. In this study, we examined the role of the stem cell factor OCT4 as a potential biomarker to help clinicians stratify HNSCC patients between radiotherapy and chemoradiotherapy. Materials and methods: OCT4 immunohistochemical staining of a population-validated tissue microarray (PV-TMA) (n = 166) representative of a standard HNSCC patients was carried out, and 5-year survival was analyzed. The results were validated using ex vivo drug sensitivity analysis of HNSCC tumor samples, and further crossvalidated in independent oropharyngeal (n = 118), nasopharyngeal (n = 170), and vulvar carcinoma (n = 95) clinical datasets. In vitro, genetically modified, patient-derived HNSCC cells were used. Results: OCT4 expression in HNSCC tumors was associated with radioresistance. However, combination therapy with cisplatin was found to overcome this radioresistance in OCT4-expressing HNSCC tumors. The results were validated by using several independent patient cohorts. Furthermore, CRISPRa-based OCT4 overexpression in the HNSCC cell line resulted in apoptosis resistance, and cisplatin was found to downregulate OCT4 protein expression in vitro. Ex vivo drug sensitivity analysis of HNSCC tumors confirmed the association between OCT4 expression and cisplatin sensitivity. Conclusion: This study introduces OCT4 immunohistochemistry as a simple and cost-effective diagnostic approach for clinical practice to identify HNSCC patients benefitting from radiosensitization by cisplatin using either full or reduced dosing.

Background CIP2A, an inhibitor of PP2A tumour suppressor function, is a widely overexpressed biomarker of aggressive disease and poor therapy response in multiple human cancer types. Methods CIP2A and DPPA4 copy number alterations and expression were analysed by fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in different cell lines and a tissue microarray of 52 HNSCC patients. Results were correlated with patient survival and other clinicopathological data. Results CIP2A and DPPA4 copy number increase occurred at a relatively high frequency in human HNSCC patient samples. CIP2A but not DPPA4 FISH status was significantly associated with patient survival. CIP2A detection by combining IHC with FISH yielded superior resolution in the prognostication of HNSCC. Conclusions CIP2A copy number increase is associated with poor patient survival in human HNSCC. We suggest that the reliability and prognostic value of CIP2A detection can be improved by performing FISH analysis to CIP2A IHC positive tumours.

The aetiology and pathogenesis of salivary gland malignancies remain unknown. To reveal novel molecular factors behind the development of salivary gland cancer, we performed gene expression analyses from Smgb-Tag mouse salivary gland samples. The overall purpose was to apply these results for clinical use to find new approaches for both possible therapeutic targets and more accurate diagnostic tools. Smgb-Tag mouse strain, in which salivary neoplasms arise through a dysplastic phase in submandibular glands, was investigated using genome-wide microarray expression analysis, ingenuity pathway analysis, RT-PCR, and immunohistochemistry. Thirty-eight human salivary gland adenoid cystic carcinoma samples were investigated using immunohistochemistry for validation purposes. Our genome-wide study showed that Ppp2r1b, a PP2A subunit encoding tumor suppressor gene, is underexpressed in submandibular gland tumors of Smgb-Tag mice. mTOR signaling pathway was significantly enriched and mTOR linked PP2A subunit gene B55 gamma was significantly underexpressed in the analyses. Furthermore, parallel immunohistochemical analysis of three PP2A inhibitors demonstrated that two PP2A inhibitors, CIP2A and SET, are highly expressed in both dysplastic and adenocarcinomatous tumors of the Smgb-Tag mice. In addition, all 38 investigated human salivary adenoid cystic carcinoma samples stained positively for CIP2A and most for SET. Finally, p-S6 staining showed activation of mTOR pathway in human adenoid cystic carcinoma samples. Our results suggest that PP2A inhibition either via PP2A subunit underexpression or PP2A inhibitor overexpression play an important role in the formation of salivary gland malignancy, potentially due to mTOR signaling activation.

DNA damaging therapies such as irradiation therapy and chemotherapy are used in the treatment of numerous cancer types both definitively and in combination with surgery. However, many cancer types show intrinsic resistance to DNA damaging therapies resulting in failure in tumor eradication and relapse after therapy. Thus it would be very useful to identify novel diagnostic strategies to predict for tumor radio tolerance. Head and neck squamous cell carcinoma (HNSCC) is a common cancer type characterized with great heterogeneity and lack of predictive markers for tumor radio resistance. Recent literature has revealed Cancerous inhibitor of PP2A, CIP2A, as a novel potential diagnostic marker for HNSCC, and other tumors, that show high radio resistance. In particular, we recently identified a functional link between stem cell factor Oct4 and CIP2A in HNSCC cells and demonstrated their potential role in predicting for HNSCC tumor response to radiotherapy. CIP2A´s role in mediating radio resistance in vivo has also been recently confirmed by using genetic mouse model. This raises an interesting possibility that diagnostic evaluation of CIP2A in combination with other factors indicative for cancer cell stemness, could be a novel useful diagnostic approach for stratification of HNSCC patients based on their tumor radio resistance. CIP2A could also serve as a target protein for therapeutic radiosensitation.

The aetiology and pathogenesis of salivary gland malignancies remain unknown. To reveal novel molecular factors behind the development of salivary gland cancer, we performed gene expression analyses from Smgb-Tag mouse salivary gland samples. The overall purpose was to apply these results for clinical use to find new approaches for both possible therapeutic targets and more accurate diagnostic tools. Smgb-Tag mouse strain, in which salivary neoplasms arise through a dysplastic phase in submandibular glands, was investigated using genome-wide microarray expression analysis, ingenuity pathway analysis, RT-PCR, and immunohistochemistry. Thirty-eight human salivary gland adenoid cystic carcinoma samples were investigated using immunohistochemistry for validation purposes. Our genome-wide study showed that Ppp2r1b, a PP2A subunit encoding tumor suppressor gene, is underexpressed in submandibular gland tumors of Smgb-Tag mice. mTOR signaling pathway was significantly enriched and mTOR linked PP2A subunit gene B55 gamma was significantly underexpressed in the analyses. Furthermore, parallel immunohistochemical analysis of three PP2A inhibitors demonstrated that two PP2A inhibitors, CIP2A and SET, are highly expressed in both dysplastic and adenocarcinomatous tumors of the Smgb-Tag mice. In addition, all 38 investigated human salivary adenoid cystic carcinoma samples stained positively for CIP2A and most for SET. Finally, p-S6 staining showed activation of mTOR pathway in human adenoid cystic carcinoma samples. Our results suggest that PP2A inhibition either via PP2A subunit underexpression or PP2A inhibitor overexpression play an important role in the formation of salivary gland malignancy, potentially due to mTOR signaling activation.