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  • Wilkman, Tommy; Apajalahti, Satu; Wilkman, Erika; Törnwall, Jyrki; Lassus, Patrik (2017)
    Purpose: The aim of the present study was to compare the resorption of the bone in the free scapular, free iliac crest, and free fibular microvascular flaps in mandibular reconstruction over time. Patients and Methods: In the present retrospective study, we analyzed 186 consecutive patients with scapular, fibular, or deep circumflex iliac artery (DCIA) osseous free microvascular flaps in mandibular reconstruction. We followed up the patients clinically and using multislice computed tomography (MSCT) with volume analyses of the bone. The volume of the bone was analyzed against time. Results: A total of 38 patients fulfilled the study criteria. Resorption of the osseous flaps was found to continue for several years. At 2 years, the volume loss was 14% for the scapula, 3% for the DCIA, and 1% for the fibula. Three-dimensional (3D) volume analysis of the MSCT scans showed more resorption than 2-dimensional analyses of the radiographs. Postoperative radiation therapy, patient age, and patient gender did not correlate with bone resorption. Conclusions: After microvascular mandibular reconstruction, the volume reduction over time is the least in the fibula and the greatest in scapula, with that of the DCIA in between. The volume reduction continues for several years in all of these. For assessment of the volume reduction of osseal reconstruction, a 3D volume analysis is more reliable than height by width measurements. (C) 2016 American Association of Oral and Maxillofacial Surgeons
  • 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).
  • Comai, Glenda; Heude, Eglantine; Mella, Sebastian; Paisant, Sylvain; Pala, Francesca; Gallardo, Mirialys; Langa, Francina; Kardon, Gabrielle; Gopalakrishnan, Swetha; Tajbakhsh, Shahragim (2019)
    In most vertebrates, the upper digestive tract is composed of muscularized jaws linked to the esophagus that permits food ingestion and swallowing. Masticatory and esophagus striated muscles (ESM) share a common cardiopharyngeal mesoderm (CPM) origin, however ESM are unusual among striated muscles as they are established in the absence of a primary skeletal muscle scaffold. Using mouse chimeras, we show that the transcription factors Tbx1 and Isl1 are required cell-autonomously for myogenic specification of ESM progenitors. Further, genetic loss-of-function and pharmacological studies point to MET/HGF signaling for antero-posterior migration of esophagus muscle progenitors, where Hgf ligand is expressed in adjacent smooth muscle cells. These observations highlight the functional relevance of a smooth and striated muscle progenitor dialogue for ESM patterning. Our findings establish a Tbx1-Isl1-Met genetic hierarchy that uniquely regulates esophagus myogenesis and identify distinct genetic signatures that can be used as framework to interpret pathologies arising within CPM derivatives.
  • 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)
  • Hirvonen, Outi M.; Leskelä, Riikka-Leena; Gronholm, Lotta; Haltia, Olli; Rissanen, Antti; Tyynela-Korhonen, Kristiina; Rahko, Eeva K.; Lehto, Juho T.; Saarto, Tiina (2019)
    Background: To avoid aggressive treatments at the end-of-life and to provide palliative care (PC), physicians need to terminate futile anti-cancer treatments and define the palliative goal of the treatment in time. This single center study assesses the practices used to make the decision that leads to treatment with a palliative goal, i.e., the PC decision and its effect on anti-cancer treatments at the end of life. Material and methods: Patients with a cancer diagnosis treated in tertiary hospital during 1st January 2013 - 31st December 2014 and deceased by the end of 2014 were identified in the hospital database (N = 2737). Of these patients, 992 were randomly selected for this study. The PC decision was screened from patient records, i.e., termination of cancer-specific treatments and a focus on symptom-centered PC. Results: The PC decision was defined in 82% of the patients during the last year of life (49% >30 days and 33%
  • Esmaeilikia, Mahsa; Radun, Igor; Grzebieta, Raphael; Olivier, Jake (2019)
    A long-standing argument against bicycle helmet use is the risk compensation hypothesis, i.e., increased feelings of safety caused by wearing a helmet results in cyclists exhibiting more risky behaviour. However, past studies have found helmet wearing is not associated with risky behaviour, e.g., committing a traffic violation was positively associated with a lower frequency of helmet use. There is a lack of consensus in the research literature regarding bicycle helmet use and the risk compensation hypothesis, although this gap in knowledge was identified in the early 2000s. This is the first study to carry out a systematic review of the literature to assess whether helmet wearing is associated with risky behaviour. Two study authors systematically searched the peer-reviewed literature using five research databases (EMBASE, MEDLINE, COMPENDEX, SCOPUS, and WEB OF SCIENCE) and identified 141 unique articles and four articles from other sources. Twenty-three articles met inclusion criteria and their findings were summarised. Eighteen studies found no supportive evidence helmet use was positively associated with risky behaviour, while three studies provided mixed findings, i.e., results for and against the hypothesis. For many of these studies, bicycle helmet wearing was associated with safer cycling behaviour. Only two studies conducted from the same research lab provided evidence to support the risk compensation hypothesis. In sum, this systematic review found little to no support for the hypothesis bicycle helmet use is associated with engaging in risky behaviour. (C) 2018 The Authors. Published by Elsevier Ltd.
  • Vento, Seija Inkeri; Vähämurto, Pauli; Silventoinen, Kaija; Karjalainen-Lindsberg, Marja-Liisa; Mannisto, Susanna; Leppa, Sirpa; Makitie, Antti Aarni (2017)
    Objectives: Extramedullary plasmacytoma in the sinonasal tract or nasopharynx is rare. The aim of the study was to review data on symptoms, clinical findings, treatment and follow-up of plasmacytomas in the sinonasal and nasopharyngeal regions in order to delineate the main clinical characteristics and the optimal management. Method: Twenty-five patients with sinonasal or nasopharyngeal plasmacytoma, diagnosed and treated at the Helsinki University Hospital during a 39-year period from 1975 to 2013 were retrospectively reviewed. Results: There were 18 males and 7 females with a median age of 66 years (range, 36-80). Sixty-eight percent received only radiotherapy or (chemo)radiotherapy. Forty-seven percent of them had a complete response to primary radiotherapy and one patient had a complete response after receiving additional brachytherapy. Four patients were treated primarily with surgery only. Two of them had a local recurrence, but were then successfully treated with radiotherapy. Altogether, four patients received a combination of surgery and (chemo)radiotherapy. Forty-four percent were alive with no evidence of disease after a median follow-up time of 78 months. Forty percent died of their disease and 16% died of other causes. Conclusions: Our study supports radiotherapy as a treatment of choice, but for small tumours surgery alone or in combination with radiotherapy may also be considered. Chinese abstract
  • Passador-Santos, F.; Gronroos, M.; Irish, J.; Gilbert, R.; Gullane, P.; Perez-Ordonez, B.; Makitie, A.; Leivo, I. (2016)
    Myoepithelial carcinoma (MCA) is a rare malignancy of salivary glands that was included in the WHO Classification of Head and Neck Tumors in 1991. MCA has shown a broad spectrum of clinical outcomes, but attempts to identify prognostic markers for this malignancy have not resulted in significant progress. Conventional histopathological characteristics such as tumour grade, nuclear atypia, mitotic index and cell proliferation have failed to predict the outcome of MCA. In this study, we reviewed the histopathology of 19 cases of MCA focusing on nuclear atypia, mitotic count, tumour necrosis, nerve and vascular invasion and occurrence of a pre-existing pleomorphic adenoma in connection to the MCA. Histopathological characteristics and clinical information were correlated with the immunohistochemical expression of cell cycle proteins including c-Myc, p21, Cdk4 and Cyclin D3. The proportion of tumour cells immunoreactive for these markers and their intensity of staining were correlated with clinical information using logistic regression, Kaplan-Meier and Cox regression. Using logistic regression analysis, cytoplasmic c-Myc expression was associated with the occurrence of metastases (P = 0.019), but limitations of semi-quantitation of immunostaining and the limited number of cases preclude definitive conclusions. Our data show that the occurrence of tumour necrosis predicts poor disease-free survival in MCA (P = 0.035).
  • Dickinson, Amy; Saraswat, Mayank; Syrjänen, Stina; Tohmola, Tiialotta; Silén, Robert; Randén-Brady, Reija; Carpén, Timo; Hagström, Jaana; Haglund, Caj; Mattila, Petri; Mäkitie, Antti; Joenväärä, Sakari; Silén, Suvi (2020)
    Background The surrogate immunohistochemical marker, p16INK4a, is used in clinical practice to determine the high-risk human papillomavirus (HPV) status of oropharyngeal squamous cell carcinomas (OPSCC). With a specificity of 83%, this will misclassify some patients compared with direct HPV testing. Patients who are p16INK4a-positive but HPV DNA-negative, or RNA-negative, may be unsuitable for treatment de-escalation aimed at reducing treatment-related side effects. We aimed to identify cost-effective serum markers to improve decision making for patients at risk of misclassification by p16INK4a alone. Methods Serum proteins from pre-treatment samples of 36 patients with OPSCC were identified and quantified using label-free mass spectrometry-based proteomics. HPV-status was determined using p16INK4a/HPV DNA and E6/E7 mRNA. Serum protein expressions were compared between groups of patients according to HPV status, using the unpaired t-test with a Benjamini-Hochberg correction. ROC curves (AUC) were calculated with SPSS (v25). Results Of 174 serum proteins identified, complement component C7 (C7), apolipoprotein F (ApoF) and galectin-3-Binding Protein (LGALS3BP) significantly differed between HPV-positive and -negative tumors (AUC ranging from 0.84–0.87). ApoF levels were more than twice as high in the E6/E7 mRNA HPV-positive group than HPV-negative. Conclusions Serum C7, ApoF and LGALS3BP levels discriminate between HPV-positive and HPV-negative OPSCC. Further studies are needed to validate these host immunity-related proteins as markers for HPV-associated OPSCC.
  • Jaiswal, Amit; Nenonen, Jukka; Stenroos, Matti; Gramfort, Alexandre; Dalal, Sarang S.; Westner, Britta U.; Litvak, Vladimir; Mosher, John C.; Schoffelen, Jan-Mathijs; Witton, Caroline; Oostenveld, Robert; Parkkonen, Lauri (2020)
    Beamformers are applied for estimating spatiotemporal characteristics of neuronal sources underlying measured MEG/EEG signals. Several MEG analysis toolboxes include an implementation of a linearly constrained minimum-variance (LCMV) beamformer. However, differences in implementations and in their results complicate the selection and application of beamformers and may hinder their wider adoption in research and clinical use. Additionally, combinations of different MEG sensor types (such as magnetometers and planar gradiometers) and application of preprocessing methods for interference suppression, such as signal space separation (SSS), can affect the results in different ways for different implementations. So far, a systematic evaluation of the different implementations has not been performed. Here, we compared the localization performance of the LCMV beamformer pipelines in four widely used open-source toolboxes (MNE-Python, FieldTrip, DAiSS (SPM12), and Brainstorm) using datasets both with and without SSS interference suppression. We analyzed MEG data that were i) simulated, ii) recorded from a static and moving phantom, and iii) recorded from a healthy volunteer receiving auditory, visual, and somatosensory stimulation. We also investigated the effects of SSS and the combination of the magnetometer and gradiometer signals. We quantified how localization error and point-spread volume vary with the signal-to-noise ratio (SNR) in all four toolboxes. When applied carefully to MEG data with a typical SNR (3-15 dB), all four toolboxes localized the sources reliably; however, they differed in their sensitivity to preprocessing parameters. As expected, localizations were highly unreliable at very low SNR, but we found high localization error also at very high SNRs for the first three toolboxes while Brainstorm showed greater robustness but with lower spatial resolution. We also found that the SNR improvement offered by SSS led to more accurate localization.
  • Marttila, E.; Thoren, H.; Törnwall, J.; Viitikko, A.; Wilkman, T. (2018)
    The aim of this retrospective study was to analyse the incidence of complications and loss of flaps after primary reconstructions for oral cancer in 191 patients at our hospital over the five years 2005-2010. The patients' clinical and personal details, characteristics of the tumours, types of microvascular flap, complications, and outcomes were recorded. The soft tissue flaps used most often were the fasciocutaneous radial forearm free flap (RFFF) (n = 86, 45%) and the anterolateral thigh free flap (ALTFF) (n = 48, 25%) while the most commonly used osseous flap was the deep circumflex iliac artery flap (DCIA) (n = 25, 13%). There were postoperative complications that required intervention in a quarter of the patients, most often in the age group 41-50 years (p = 0.018). Older age was not associated with the development of complications. The overall survival of all free flaps was 181/191 (95%), and the only significant individual predictor of loss of a flap was reconstruction with a DCIA (p = 0.016), five of the 25 of which were lost. We conclude therefore that DCIA free flaps are associated with an increased risk of failure; the method of osseous reconstruction for maxillofacial reconstruction should be selected carefully; and carefully chosen older patients do not seem to be at increased risk of morbidity. (C) 2018 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
  • Chen, Ping; Lepikhova, Tatiana; Hu, Yizhou; Monni, Outi; Hautaniemi, Sampsa (2011)
  • Kontio, R.; Hagström, J.; Lindholm, P.; Böhling, T.; Sampo, M.; Mesimäki, K.; Saarilahti, K.; Koivunen, P.; Mäkitie, A. A. (2019)
    Background: Osteosarcomas (OS) in the craniomaxillofacial (CMF) region are typically diagnosed at later age than long-bone OS, but they are reported to have better 5-year survival. Curative treatment warrants wide surgical resection, which is often not possible in the CMF region. The purpose of this article is to present a nationwide series of CMF in Finland to discuss the role of surgery. Patients and methods: All 21 CMF OS patients managed in Finland from 1992 to 2009 were included. The mean age was 40 years (range 15e72). Data on patient and tumor characteristics, treatment modalities, and survival were recorded. All patients had a minimum follow-up of 5 years or until death. Results: OS was evenly represented in the mandible and maxillary bones, which together constituted 76% of all sites. Surgery with curative intent was carried out in 20 patients. Clear margins were achieved in only five cases. Eight (40%) of these 20 patients died due to OS, and their average survival time was 1.3 years. Seven (35%) out of the 20 patients received radiotherapy due to close/intralesional surgical margins, and four of them did not develop recurrences during the follow-up. Conclusions: The results suggest that postoperative radiotherapy may alter the prognosis in CMF OS, particularly in cases with close or intralesional margins. This may increase the survival rates achieved by prompt action in performing radical surgery. (C) 2019 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
  • Apu, Ehsanul Hoque; Akram, Saad Ullah; Rissanen, Jouni; Wan, Hong; Salo, Tuula (2018)
    Desmoglein 3 (Dsg3) is an adhesion receptor in desmosomes, but its role in carcinoma cell migration and invasion is mostly unknown. Our aim was to quantitatively analyse the motion of Dsg3-modified carcinoma cells in 2D settings and in 3D within tumour microenvironment mimicking (TMEM) matrices. We tested mutant constructs of C-terminally truncated Dsg3 (Delta 238 and Delta 560), overexpressed full-length (FL) Dsg3, and empty vector control (Ct) of buccal mucosa squamous cell carcinoma (SqCC/Y1) cells. We captured live cell images and analysed migration velocities and accumulated and Euclidean distances. We compared rodent collagen and Matrigel. with human Myogel TMEM matrices for these parameters in 3D sandwich, in which we also tested the effects of monoclonal antibody AK23, which targets the EC1 domain of Dsg3. In monolayer culture, FL and both truncated constructs migrated faster and had higher accumulated distances than Ct cells. However, in the 3D assays, only the mutants invaded faster relative to Ct cells. Of the mutants, the shorter form (Delta 238) exhibited faster migration and invasion than Delta 560 cells. In the Transwell, all of the cells invaded faster through Myogel than Matrigel coated wells. In 3D sandwich, AK23 antibody inhibited only the invasion of FL cells. We conclude that different experimental 2D and 3D settings can markedly influence the movement of oral carcinoma cells with various Dsg3 modifications.
  • 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.
  • Hämetoja, Hanna; Hirvonen, Karoliina; Hagström, Jaana; Leivo, Ilmo; Saarilahti, Kauko; Apajalahti, Satu; Haglund, Caj; Mäkitie, Antti; Bäck, Leif (2017)
    The purpose of the study was to evaluate the long-term outcome of minor salivary and mucous gland (MiSG) adenoid cystic carcinoma (ACC) of the head and neck and to compare the results with earlier reports including our recently published series on major salivary gland (MaSG) ACC. The study comprised 68 MiSG ACCs operated during 1974-2012 at the Helsinki University Hospital, Helsinki, Finland. Medical records and histological samples were reviewed. Our previously published cohort comprising 54 MaSG ACCs during the years from 1974 to 2009 was used for comparison. The most common locations were the oral cavity and sinonasal cavities. Most patients presented stages IV (33.8%) and I (23.5%) disease. Primary treatment with curative intent, mainly surgery, was offered for 64 patients. Thirty-three (51.6%) of these patients developed a disease recurrence and 22 (66.7%) patients in less than 5 years. The difference in the length of recurrence-free time (<5 vs. > 5 years) had an impact on OS and DSS (p <0.001) showing worse prognosis for the earlier recurring group. T classes 2-4 (p = 0.005, p <0.001, and p = 0.001, respectively) and stages II-IV (p = 0.019, p <0.001, and p = 0.002, respectively) were associated with worse OS, DSS, and DFS. MiSG ACC had a similar long-term survival compared to MaSG ACC. Patients with stage I MiSG ACC seem to carry a favourable prognosis compared with those with stages II, III, and IV tumours. It is thus noteworthy that stage II tumours represent a truly advanced disease entity warranting a more aggressive treatment approach.
  • Väyrynen, Otto; Piippo, Markku; Jämsä, Hannaleena; Väisänen, Tuomas; de Almeida, Carlos E. B.; Salo, Tuula; Missailidis, Sotiris; Risteli, Maija (2018)
    Chemoradiation is an established approach in the treatment of advanced oral tongue squamous cell carcinoma (OTSCC), but therapy may cause severe side-effects due to signal interchanges between carcinoma and the tumour microenvironment (TME). In this study, we examined the potential use of our human 3D myoma disc and Myogel models in in vitro chemoradiation studies by analysing the effects of ionizing radiation (IR) and the combined effect of heparanase 1 (HPSE1) inhibitors and IR on OTSCC cell proliferation, invasion and MMP-2 and - 9 production. Finally, we analysed the long-term effects of IR by studying clones of previously irradiated and invaded HSC-3 cells. We found that in both human uterine leiomyoma-based extracellular matrix models IR inhibited the invasion of HSC-3 cells, but blocking HPSE1 activity combined with IR induced their invasion. Low doses of IR increased MMP expression and initiated epithelial-mesenchymal transition in cells cultured on myoma discs. We conclude that myoma models offer consistent methods for testing human carcinoma cell invasion and phenotypic changes during chemoradiation treatment. In addition, we showed that IR had long-term effects on MMP-2 and - 9, which might elicit different HSC-3 invasion responses when cells were under the challenge of HPSE1 inhibitors and IR.
  • Jouhi, Lauri; Halme, Elina; Irjala, Heikki; Saarilahti, Kauko; Koivunen, Petri; Pukkila, Matti; Hagström, Jaana; Haglund, Caj; Lindholm, Paula; Hirvikoski, Pasi; Vaittinen, Samuli; Ellonen, Anna; Tikanto, Jukka; Blomster, Henry; Laranne, Jussi; Grenman, Reidar; Mäkitie, Antti; Atula, Timo (2018)
    Background: Treatment for oropharyngeal squamous cell carcinoma (OPSCC) has changed, as the proportion of human papilloma virus (HPV)-related disease has increased. We evaluated nationwide information on its management and outcome during the treatment paradigm change period.Methods: We included all patients diagnosed and treated for OPSCC at the five Finnish university hospitals from 2000 to 2009. Patient records and pathology registries provided the clinicopathological data. p16 staining was performed on primary tumor samples of patients who had received treatment with curative intent.Results: A total of 674 patients were diagnosed and treated for OPSCC and the incidence increased along the study period. Of the evaluable tumors 58.5% were p16-positive and the number of p16-positive tumors increased along the years. The treatment was given with curative intent for 600 patients and it was completed in 564. Of them, 47.9% underwent primary surgery and 52.1% received definitive oncological treatment. Also, the treatment protocol changed towards a more oncological approach. Among patients treated with curative intent the five-year overall, disease-specific and disease-free survival rates were 60.1, 71.5 and 57.0%. In multivariate analysis, p16-positivity seemed to relate to reduced disease mortality in lateral and anterior-wall disease. Depending on primary tumor localization, also sex, classes T3-4, presence of regional metastasis and radiotherapy modality had an association with disease mortality.Conclusion: The incidence of p16-positive OPSCC and delivery of definitive oncological treatment increased in Finland during the study period. An improved survival outcome compared with the previous nationwide investigation was observed in this subset of patients.
  • Carpen, Timo; Syrjänen, Stina; Jouhi, Lauri; Randen-Brady, Reija; Haglund, Caj; Mäkitie, Antti; Mattila, Petri S.; Hagström, Jaana (2020)
    Background The etiological role of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) is confirmed. However, the role of other oncoviruses in OPSCC is unknown. Materials and methods A total of 158 consecutive OPSCC patients treated with curative intent were included. DNA extracted from tumor sections was used to detect Epstein-Barr virus (EBV), HPV, and the following polyomaviruses: John Cunningham virus (JCV), Simian virus 40 (SV40), and BK virus (BKV) with PCR. In addition, p16 expression was studied by immunohistochemistry, and EBV-encoded small RNA (EBER) transcripts were localized by in situ hybridization. The effect of viral status on overall survival (OS) and disease-free survival (DFS) was analyzed. Results A total of 94/158 samples (59.5%) were HPV-positive, 29.1% contained BKV DNA, 20.3% EBV DNA, 13.9% JCV DNA, and 0.6% SV40 DNA. EBER was expressed only in stromal lymphocytes adjacent to the tumor and correlated with HPV positivity (p = 0.026). p16 expression associated only with HPV. None of the three polyomaviruses had an impact on survival. Patients with EBER-positive but HPV-negative OPSCC had significantly poorer OS and DFS than those with HPV-positive OPSCC and slightly worse prognosis compared with the patients with EBER-negative and HPV-negative OPSCC. Conclusion Polyomaviruses are detectable in OPSCC but seem to have no impact on survival, whereas HPV was the strongest viral prognostic factor. EBER expression, as a sign of latent EBV infection, may have prognostic impact among patients with HPV-negative OPSCC. EBER analysis may identify a new subgroup of OPSCCs unrelated to HPV.
  • Ruuskanen, Miia; Irjala, Heikki; Minn, Heikki; Vahlberg, Tero; Randen-Brady, Reija; Hagström, Jaana; Syrjänen, Stina; Leivo, Ilmo (2019)
    Background Nasopharyngeal carcinoma (NPC) is related to Epstein-Barr virus (EBV) in endemic areas; however, the role of viruses in nonendemic countries is unclear. Our nationwide study investigated the prevalence and prognostic significance of EBV and human papillomaviruses (HPVs) in Finnish NPC tumors. Methods We analyzed samples from 150 patients diagnosed between 1990 and 2009. Viral status was determined using EBV and HPV RNA in situ hybridizations, and p16 immunohistochemistry. Patient and treatment characteristics were obtained from patient records. Results In our white patient cohort, 93 of 150 (62%) patients were EBV-positive and 21/150 (14%) patients were HPV-positive with no coinfections. Thirty-six (24%) tumors were negative for both viruses. The 5-year disease-specific survival for patients with EBV-positive, HPV-positive, and EBV/HPV-negative tumors was 69%, 63%, and 39%, respectively. In multivariable-adjusted analysis, overall survival was better among patients with EBV-positive (P = .005) and HPV-positive (P = .03) tumors compared to patients with EBV/HPV-negative tumors. Conclusions In our low-incidence population, EBV and HPV are important prognostic factors for NPC.