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  • Mäkitie, Antti; Kamali, Alexander; Mroueh, Rayan; Lindford, Andrew; Koivunen, Petri; Autio, Timo; Lassus, Patrik; Halle, Martin; Bäck, Leif; Palmgren, Björn; Hammarstedt-Nordenvall, Lalle (2020)
    Background and aims: Stage II cancer of the tongue is mostly managed surgically both locally and regionally. However, indications for postoperative radiotherapy and reconstructive options vary between centers. This paper aims to describe differences in treatment in a geographically homogenous cohort. Methods: A retrospective comparison was made between two cohorts of clinical T2N0 tongue cancer from Finland and Sweden. The Finnish cohort included 75 patients and the Swedish 54. All patients had curative intent of treatment and no previous head and neck cancer. Data analyzed consisted of pathological stage, size and thickness of tumor, frequency of reconstruction, radiotherapy delivered, and survival. Results: The Finnish cohort included a higher proportion of patients managed with reconstructive surgery (67%) than the Swedish cohort (0%), p <.00001. More patients were treated with postoperative radiotherapy (84%) in the Swedish cohort than in the Finnish (54%), p <.0002. The Finnish cohort had a higher level of survival and included more frequent downstaging (cTNM to pTNM).
  • Reis, Patricia P.; Waldron, Levi; Perez-Ordonez, Bayardo; Pintilie, Melania; Galloni, Natalie Naranjo; Xuan, Yali; Cervigne, Nilva K.; Warner, Giles C.; Mäkitie, Antti Aarni; Simpson, Colleen; Goldstein, David; Brown, Dale; Gilbert, Ralph; Gullane, Patrick; Irish, Jonathan; Jurisica, Igor; Kamel-Reid, Suzanne (2011)
  • Farnebo, Lovisa; Laurell, Goran; Makitie, Antti (2016)
    Conclusion: The management of Head and Neck Cancer of Unknown Primary (HNCUP) patients varies both between centres within and also between the Nordic countries. This study contributes to a continuing discussion of how to improve the accuracy of diagnosis and quality of treatment of HNCUP patients.Objectives: The initiative for this study was based on the lack of common guidelines for diagnostic procedures and for treatment of HNCUP patients in the Nordic countries constituting a region having a rather homogeneous population.Method: A structured questionnaire was sent to all university hospitals in the five Nordic countries.Results: Four of the five Nordic countries use either national guidelines or specific protocols when handling HNCUP. The main diagnostic tools are PET-CT, fine needle aspiration, endoscopic evaluation with biopsies, and most often bilateral tonsillectomy. At 21 of 22 university hospitals the treatment decision is made at a multidisciplinary conference. Three of seven Swedish centres use only radiotherapy or chemoradiotherapy to treat N+ HNCUP patients. Robotic surgery for biopsy of the tongue base is beginning to become an alternative to targeted biopsies in Sweden and Finland. Narrow Band Imaging is used only in Finland.
  • Nieminen, Mikko Tapani; Novak-Frazer, Lily; Rautemaa, Vilma; Rajendran, Ranjith; Sorsa, Timo; Ramage, Gordon; Bowyer, Paul; Rautemaa-Richardson, Riina (2014)
  • Renkonen, Suvi; Linden, Riikka; Bäck, Leif; Silen, Robert; Mäenpää, Hanna; Tapiovaara, Laura; Aro, Katri (2017)
    Primary treatment of papillary thyroid carcinoma (PTC) with lateral lymph node metastasis is surgery, but the extent of lateral neck dissection remains undefined. Preoperative imaging is used to guide the extent of surgery, although its sensitivity and specificity for defining the number and level of affected lymph nodes on the lateral neck is relatively modest. Our aim was to assess the role of preoperative magnetic resonance imaging (MRI) in predicting the requisite levels of neck dissection in patients with regionally metastatic PTC, with a focus on Levels II and V. All patients with PTC and lateral neck metastasis who had undergone neck dissection at the Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital, Helsinki, Finland from 2013 to 2016 and had a preoperative MRI available were retrospectively reviewed. A head and neck radiologist re-evaluated all MRIs, and the imaging findings were compared with histopathology after neck dissection. In the cohort of 39 patients, preoperative MRI showed concordance with histopathology for Levels II and V as follows: sensitivity of 94 and 67%, specificity of 20 and 91%, positive predictive value of 56 and 75%, and negative predictive value of 75 and 87%, respectively. In PTC, MRI demonstrated fairly high specificity and negative predictive value for Level V metastasis, and future studies are needed to verify our results to omit prophylactic dissection of this level. Routine dissection of Level II in patients with regionally metastatic PTC needs to be considered, as MRI showed low specificity.
  • Matovic, Jelena; Järvinen, Juulia; Bland, Helena C.; Sokka, Iris K.; Imlimthan, Surachet; Ferrando, Ruth Mateu; Huttunen, Kristiina M.; Timonen, Juri; Peräniemi, Sirpa; Aitio, Olli; Airaksinen, Anu J.; Sarparanta, Mirkka; Johansson, Mikael P.; Rautio, Jarkko; Ekholm, Filip S. (2020)
    Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing toward the significant potential embedded in this approach.
  • Autio, Reija; Saarela, Matti; Jarvinen, Anna-Kaarina; Hautaniemi, Sampsa; Astola, Jaakko (2009)
  • Lachenmeier, Dirk W.; Salaspuro, Mikko (2017)
    Humans are cumulatively exposed to acetaldehyde from various sources including alcoholic beverages, tobacco smoke, foods and beverages. The genetic-epidemiologic and biochemical evidence in ALDH2-deficient humans provides strong evidence for the causal relationship between acetaldehyde-exposure due to alcohol consumption and cancer of the upper digestive tract. The risk assessment has so far relied on thresholds based on animal toxicology with lower one-sided confidence limit of the benchmark dose values (BMDL) typically ranging between 11 and 63 mg/kg bodyweight (bw)/day dependent on species and endpoint. The animal data is problematic for regulatory toxicology for various reasons (lack in study quality, problems in animal models and appropriateness of endpoints - especially cancer - for transfer to humans). In this study, data from genetic epidemiologic and biochemical studies are reviewed. The increase in the daily exposure dose to acetaldehyde in alcohol-consuming ALDH2-deficients vs. ALDH2-actives was about twofold. The acetaldehyde increase due to ALDH2 inactivity was calculated to be 6.7 mu g/kg bw/day for heavy drinkers, which is associated with odds ratios of up to 7 for head and neck as well as oesophageal cancer. Previous animal toxicology based risk assessments may have underestimated the risk of acetaldehyde. Risk assessments of acetaldehyde need to be revised using this updated evidence. (C) 2017 The Authors. Published by Elsevier Inc.
  • Heikkinen, Ilkka; Bello, Ibrahim O.; Wahab, Awais; Hagström, Jaana; Haglund, Caj; Coletta, Ricardo D.; Nieminen, Pentti; Makitie, Antti A.; Salo, Tuula; Leivo, Ilmo; Almangush, Alhadi (2019)
    Tumor-infiltrating lymphocytes (TILs) have shown a promising prognostic value in many epithelial cancers. We sought to assess the prognostic value of TILs in a multicenter cohort of early oral tongue squamous cell carcinoma (OTSCC). The percentage of TILs was assessed on the surgical resection slides stained with hematoxylin and eosin. The assessment of TILs was performed in the stromal compartment and in the intraepithelial compartment (at the invasive front and at the center of the tumor). We followed the method that was described recently by the International Immuno-Oncology Biomarker Working Group for the assessment of TILs. A total of 308 cases from the 5 Finnish university hospitals and from A.C. Camargo Cancer Center, Sao Paulo, Brazil, were included. We found a promising prognostic value for stromal TILs at the invasive front in the multivariable analysis with a hazard ratio of 2.61 (95% confidence interval [CI], 1.77-3.83; P
  • Lundberg, Marie; Renkonen, Suvi; Haglund, Caj; Mattila, Petri S.; Leivo, Ilmo; Hagstrom, Jaana; Makitie, Antti A. (2016)
    Conclusions BMI-1 is an upstream repressor of tumor suppressor p16 and their inverse expression patterns have been linked with patient survival in OPSCC. In this material only p16 remained a relevant prognostic marker in OPSCC. Objectives HNSCC tumors carry variable phenotypes and clinical outcomes depending on their anatomical location. In OPSCC, expression of tumor suppressor p16 is used as a surrogate marker of HPV infection and has prognostic value. There are no good prognostic biomarkers for HNSCC tumors of other anatomical locations. Aim To study the expression patterns of p16 and BMI-1 in not only oropharyngeal but also oral, hypopharyngeal, and laryngeal squamous cell carcinomas and to clarify their putative connections with clinical parameters, survival, and each other. Method Hospital records on 130 patients (59 OPSCC, 18 OSCC, 20 HPSCC, and 33 LSCC) diagnosed between 1997-2008 at the Helsinki University Hospital, Finland, were reviewed. BMI-1 and p16 expressions were studied by immunohistochemistry. Results Sixty-eight per cent of OPSCC expressed p16 and expression correlated with lower age, lower T- and higher N-category, and with improved OS and DFS. BMI-1 expression was most prevalent in OPSCC and LSCC, but had no clinical correlations. No correlation between p16 and BMI-1 expression was found.
  • Halonen, Pia; Jakobsson, Maija; Heikinheimo, Oskari; Riska, Annika; Gissler, Mika; Pukkala, Eero (2018)
    The association between Lichen planus (LP) and cancer has been under debate for decades. We studied the connection via population-based Finnish register data. All women with the diagnosis of LP (n=13,100) were identified from the Finnish Hospital Discharge Registry from 1969-2012. These patients were linked with subsequent cancer diagnoses from the Finnish Cancer Registry until 2014. Standardized incidence ratios (SIRs) were counted for different cancers by dividing the observed numbers of cancers by expected numbers, which were based on national cancer incidence rates. In total, 1,520 women with LP were diagnosed with cancer (SIR 1.15, 95% confidence interval [CI] 1.09-1.20). LP was associated with an increased risk of cancer of lip (SIR 5.17, 95% CI 3.06-8.16), cancer of tongue (SIR 12.4, 95% CI 9.45-16.0), cancer of oral cavity (SIR 7.97, 95% CI 6.79-9.24), cancer of esophagus (SIR 1.95, 95% CI 1.17-3.04), cancer of larynx (SIR of 3.47, 95% CI 1.13-8.10) and cancer of vulva (SIR 1.99, 95% CI 1.18-3.13). The risk of cancer was not increased in other locations where LP manifests (pharynx and skin). Patients with diagnosed LP have an increased risk of developing cancer of lip, tongue, oral cavity, esophagus, larynx and vulva. These data are important when considering treatment and follow-up of patients with LP diagnosis. What's new?Lichen planus (LP) is a chronic disease of the skin and mucous membranes that is likely autoimmune in origin. Owing to its inflammatory nature, it is also suspected of causing certain cancers. Whether LP possesses malignant potential, however, remains uncertain. Here, in a cohort of 13,100 women diagnosed with LP between 1969 and 2012 in Finland, some 1,520 were eventually diagnosed with cancer. Malignancies with significant increases in incidence in LP patients included those of the lip, tongue, oral cavity, esophagus, larynx and vulva. The findings suggest that LP patients could benefit from multidisciplinary approaches to care.
  • Nieminen, M.; Aro, K.; Jouhi, L.; Bäck, L.; Mäkitie, A.; Atula, T. (2018)
    Background: Head and neck cancers are often diagnosed at a late stage, thus resulting in a generally poor prognosis. This is partly attributable to patients' hesitancy in seeking treatment. However, the length and causes of these patient delays remain relatively unknown. Material and methods: We included all new head and neck cancer patients treated at our tertiary care center between 2016 and 2017. Using a patient questionnaire, we collected data on patients' symptoms and other factors related to seeking medical care, and recorded both patient- and primary health care-related delays. We then compared the data collected from these patients to patient and tumor characteristics collected from hospital records, and analyzed various causes for delay before a specialist consultation to the Department of Otorhinolaryngology - Head and Neck Surgery. Results: Among the patients (n = 142) in our study, the median patient delay was 35 d with 73% of patients seeking medical care within 3 months. In comparison, the median primary health-care delay was 20 d. Certain symptoms influenced patient delay. Hoarseness and breathing difficulties correlated with longer patient delay while patients with a lump on the neck had a shorter delay. Patient delay was associated with certain tumor-related factors such as the tumor site and the presence of regional metastases, which resulted in shorter patient delay. None of the patient-related factors appeared to impact delay. Important factors influencing primary health-care delay included the initial location visited and whether any follow-up visit was scheduled or not. Conclusions: Although most patients sought medical advice without a major delay and were adequately referred, we found that long delays existed. Raising awareness of the symptoms of head and neck cancer among general population and health-care providers is probably the best way to get patients to curative treatment without delay.
  • Vered, Marilena; Lehtonen, Meri; Hotakainen, Lari; Pirila, Emma; Teppo, Susanna; Nyberg, Pia; Sormunen, Raija; Zlotogorski-Hurvitz, Ayelet; Salo, Tuula; Dayan, Dan (2015)
  • Almangush, Alhadi; Alabi, Rasheed Omobolaji; Troiano, Giuseppe; Coletta, Ricardo D.; Salo, Tuula; Pirinen, Matti; Mäkitie, Antti A.; Leivo, Ilmo (2021)
    Background The clinical significance of tumor-stroma ratio (TSR) has been examined in many tumors. Here we systematically reviewed all studies that evaluated TSR in head and neck cancer. Methods Four databases (Scopus, Medline, PubMed and Web of Science) were searched using the term tumo(u)r-stroma ratio. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) were followed. Results TSR was studied in nine studies of different subsites (including cohorts of nasopharyngeal, oral, laryngeal and pharyngeal carcinomas). In all studies, TSR was evaluated using hematoxylin and eosin staining. Classifying tumors based on TSR seems to allow for identification of high-risk cases. In oral cancer, specifically, our meta-analysis showed that TSR is significantly associated with both cancer-related mortality (HR 2.10, 95%CI 1.56-2.84) and disease-free survival (HR 1.84, 95%CI 1.38-2.46). Conclusions The assessment of TSR has a promising prognostic value and can be implemented with minimum efforts in routine head and neck pathology.
  • Carnielli, Carolina Moretto; Soares Macedo, Carolina Carneiro; De Rossi, Tatiane; Granato, Daniela Campos; Rivera, Cesar; Domingues, Romenia Ramos; Pauletti, Bianca Alves; Yokoo, Sami; Heberle, Henry; Busso-Lopes, Ariane Fidelis; Cervigne, Nilva Karla; Sawazaki-Calone, Iris; Meirelles, Gabriela Vaz; Marchi, Fabio Albuquerque; Telles, Guilherme Pimentel; Minghim, Rosane; Prado Ribeiro, Ana Carolina; Brandao, Thais Bianca; Castro, Gilberto de; Alejandro Gonzalez-Arriagada, Wilfredo; Gomes, Alexandre; Penteado, Fabio; Santos-Silva, Alan Roger; Lopes, Marcio Ajudarte; Rodrigues, Priscila Campioni; Sundquist, Elias; Salo, Tuula; da Silva, Sabrina Daniela; Alaoui-Jamali, Moulay A.; Graner, Edgard; Fox, Jay W.; Della Coletta, Ricardo; Paes Leme, Adriana Franco (2018)
    Different regions of oral squamous cell carcinoma (OSCC) have particular histopathological and molecular characteristics limiting the standard tumor-node-metastasis prognosis classification. Therefore, defining biological signatures that allow assessing the prognostic outcomes for OSCC patients would be of great clinical significance. Using histopathology-guided discovery proteomics, we analyze neoplastic islands and stroma from the invasive tumor front (ITF) and inner tumor to identify differentially expressed proteins. Potential signature proteins are prioritized and further investigated by immunohistochemistry (IHC) and targeted proteomics. IHC indicates low expression of cystatin-B in neoplastic islands from the ITF as an independent marker for local recurrence. Targeted proteomics analysis of the prioritized proteins in saliva, combined with machine-learning methods, highlights a peptide-based signature as the most powerful predictor to distinguish patients with and without lymph node metastasis. In summary, we identify a robust signature, which may enhance prognostic decisions in OSCC and better guide treatment to reduce tumor recurrence or lymph node metastasis.
  • Alabi, Rasheed Omobolaji; Elmusrati, Mohammed; Sawazaki-Calone, Iris; Kowalski, Luiz Paulo; Haglund, Caj; Coletta, Ricardo D.; Mäkitie, Antti A.; Salo, Tuula; Almangush, Alhadi; Leivo, Ilmo (2020)
    Background: The proper estimate of the risk of recurrences in early-stage oral tongue squamous cell carcinoma (OTSCC) is mandatory for individual treatment-decision making. However, this remains a challenge even for experienced multidisciplinary centers. Objectives: We compared the performance of four machine learning (ML) algorithms for predicting the risk of locoregional recurrences in patients with OTSCC. These algorithms were Support Vector Machine (SVM), Naive Bayes (NB), Boosted Decision Tree (BDT), and Decision Forest (DF). Materials and methods: The study cohort comprised 311 cases from the five University Hospitals in Finland and A.C. Camargo Cancer Center, Sao Paulo, Brazil. For comparison of the algorithms, we used the harmonic mean of precision and recall called F1 score, specificity, and accuracy values. These algorithms and their corresponding permutation feature importance (PFI) with the input parameters were externally tested on 59 new cases. Furthermore, we compared the performance of the algorithm that showed the highest prediction accuracy with the prognostic significance of depth of invasion (DOI). Results: The results showed that the average specificity of all the algorithms was 71% The SVM showed an accuracy of 68% and F1 score of 0.63, NB an accuracy of 70% and F1 score of 0.64, BDT an accuracy of 81% and F1 score of 0.78, and DF an accuracy of 78% and F1 score of 0.70. Additionally, these algorithms outperformed the DOI-based approach, which gave an accuracy of 63%. With PFI-analysis, there was no significant difference in the overall accuracies of three of the algorithms; PFI-BDT accuracy increased to 83.1%, PFI-DF increased to 80%, PFI-SVM decreased to 64.4%, while PFI-NB accuracy increased significantly to 81.4%. Conclusions: Our findings show that the best classification accuracy was achieved with the boosted decision tree algorithm. Additionally, these algorithms outperformed the DOI-based approach. Furthermore, with few parameters identified in the PFI analysis, ML technique still showed the ability to predict locoregional recurrence. The application of boosted decision tree machine learning algorithm can stratify OTSCC patients and thus aid in their individual treatment planning.
  • Chen, Ping; Lepikhova, Tatiana; Hu, Yizhou; Monni, Outi; Hautaniemi, Sampsa (2011)
  • Almangush, Alhadi; Bello, Ibrahim O.; Keski-Santti, Harri; Mäkinen, Laura; Kauppila, Joonas H.; Pukkila, Matti; Hagstrom, Jaana; Laranne, Jussi; Tommola, Satu; Nieminen, Outi; Soini, Ylermi; Kosma, Veli-Matti; Koivunen, Petri; Grenman, Reidar; Leivo, Ilmo; Salo, Tuula (2014)
  • Hellquist, Henrik; Ferlito, Alfio; Mäkitie, Antti A.; Thompson, Lester D. R.; Bishop, Justin A.; Agaimy, Abbas; Hernandez-Prera, Juan C.; Gnepp, Douglas R.; Willems, Stefan M.; Slootweg, Pieter J.; Rinaldo, Alessandra (2020)
    During the last 60 years numerous significant attempts have been made to achieve a widely acceptable terminology and histological grading for laryngeal squamous intraepithelial lesions. While dysplasia was included in the pathology of the uterine cervix already in 1953, the term dysplasia was accepted in laryngeal pathology first after the Toronto Centennial Conference on Laryngeal Cancer in 1974. In 1963 Kleinsasser proposed a three-tier classification, and in 1971 Kambic and Lenart proposed a four-tier classification. Since then, four editions of the World Health Organisation (WHO) classification have been proposed (1978, 1991, 2005 and 2017). Several terms such as squamous intraepithelial neoplasia (SIN) and laryngeal intraepithelial neoplasia (LIN) are now being abandoned and replaced by squamous intraepithelial lesions (SIL). The essential change between the 2005 and 2017 WHO classifications is the attempt to induce a simplification from a four- to a two-tier system. The current WHO classification (2017) thus recommends the use of a two-tier system with reasonably clear histopathological criteria for the two groups: low-grade and high-grade dysplasia. Problems with interobserver variability apart, subjectivities and uncertainties remain, but to a lesser degree. Ongoing and additional molecular studies may help to clarify underlying events that will increase our understanding and possibly can facilitate our attempts to obtain an even better classification. The classification needs to be easier for the general pathologist to perform and easier for the clinician to interpret. These two objectives are equally important to provide each patient the best personalised treatment available for squamous intraepithelial lesions.