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  • Poire, Xavier; Labopin, Myriam; Polge, Emmanuelle; Forcade, Edouard; Ganser, Arnold; Volin, Liisa; Michallet, Mauricette; Blaise, Didier; Yakoub-Agha, Ibrahim; Maertens, Johan; Richard Espiga, Carlos; Cornelissen, Jan; Finke, Jurgen; Mohty, Mohamad; Esteve, Jordi; Nagler, Arnon (2020)
    Deletion 5q or monosomy 5 (-5/5q-) in acute myeloid leukemia (AML) is a common high-risk feature that is referred to allogeneic stem cell transplantation. However, -5/5q- is frequently associated with other high-risk cytogenetic aberrations such as complex karyotype, monosomal karyotype, monosomy 7 (-7), or 17p abnormalities (abn (17p)), the significance of which is unknown. In order to address this question, we studied adult patients with AML harboring -5/5q- having their first allogeneic transplantation between 2000 and 2015. Five hundred and one patients with -5/5q- have been analyzed. Three hundred and thirty-eight patients (67%) were in first remission and 142 (28%) had an active disease at time of allogeneic transplantation. The 2-year probabilities of overall survival and leukemia-free survival were 27% and 20%, respectively. The 2-year probability of treatment-related mortality was 20%. We identified four different cytogenetic groups according to additional abnormalities with prognostic impact: -5/5q- without complex karyotype, monosomal karyotype or abn(17p), -5/5q- within a complex karyotype, -5/5q- within a monosomal karyotype and the combination of -5/5q- with abn(17p). In multivariate analysis, factors associated with worse overall survival and leukemia-free survival across the four groups were active disease, age, monosomal karyotype, and abn(17p). The presence of -5/5q- without monosomal karyotype or abn(17p) was associated with a significantly better survival rate while -5/5q- in conjunction with monosomal karyotype or abn(17p) translated into a worse outcome. The patients harboring the combination of -5/5q- with abn(17p) showed very limited benefit from allogeneic transplantation.
  • Vesterinen, Tiina; Mononen, Sanna; Salmenkivi, Kaisa; Mustonen, Harri; Ilonen, Ilkka; Knuuttila, Aija; Haglund, Caj; Arola, Johanna (2018)
    Background: Pulmonary carcinoids (PC) are rare malignant neoplasms that cover approximately 1% of all lung cancers. PCs are classified by histological criteria as either typical (TC) or atypical (AC). Histological subtype is the most studied prognostic factor. The aim of this study was to evaluate if other tissue or clinical features are associated with patient outcomes.Material and methods: We retrospectively reviewed clinical records of 133PC patients who underwent operation in the Helsinki University Hospital between 1990 and 2013. Tissue specimens were re-evaluated, processed into tissue microarray format and stained immunohistochemically with serotonin, calcitonin, adrenocorticotropic hormone (ACTH), thyroid transcription factor-1 (TTF-1) and Ki-67. Survival and risk analyses were performed.Results: Based on histology, 75% (n=100) of the tumors were TCs and 25% (n=33) ACs. TCs had higher 10-year disease-specific survival (DSS) rate than ACs (99% (95% CI, 93-100%) for TCs vs. 82% (95% CI, 61-92%) for ACs). Hormonally active tumors expressing serotonin, calcitonin or ACTH were noted in 53% of the specimens but hormonal expression was not associated with DSS. TTF-1 was positive in 78% of the specimens but was not associated with DSS. Ki-67 index varied between
  • Mohamed, Hesham; Haglund, Caj; Jouhi, Lauri; Atula, Timo; Hagström, Jaana; Mäkitie, Antti (2020)
    Oropharyngeal squamous cell carcinoma (OPSCC) is subclassified by the World Health Organization into two different entities: human papillomavirus (HPV)-positive and HPV-negative tumors. HPV infection promotes the epithelial-to-mesenchymal transition (EMT) and transformation of keratinocyte stem cells into cancer stem cells. EMT is a crucial process in the carcinogenesis of epithelial-derived malignancies, and we aimed to study the role of its markers in OPSCC. This study consists of 202 consecutive OPSCC patients diagnosed and treated with curative intent. We examined E-cadherin, beta-catenin, and vimentin expression using immunohistochemistry and compared these with tumor and patient characteristics and treatment outcome. We found that the cell-membranous expression of beta-catenin was stronger in HPV-positive than in HPV-negative tumors, and it was stronger in the presence of regional metastasis. The stromal vimentin expression was stronger among HPV-positive tumors. A high E-cadherin expression was associated with tumor grade. No relationship between these markers and survival emerged. In conclusion, beta-catenin and vimentin seem to play different roles in OPSCC: the former in the tumor tissue itself, and the latter in the tumor stroma. HPV infection may exploit the beta-catenin and vimentin pathways in carcinogenic process. More, beta-catenin may serve as a marker for the occurrence of regional metastasis:
  • Ihle, Michaela Angelika; Huss, Sebastian; Jeske, Wiebke; Hartmann, Wolfgang; Merkelbach-Bruse, Sabine; Schildhaus, Hans-Ulrich; Büttner, Reinhard; Sihto, Harri; Hall, Kirsten Sundby; Eriksson, Mikael; Reichardt, Peter; Joensuu, Heikki; Wardelmann, Eva (2018)
    Despite of multitude investigations no reliable prognostic immunohistochemical biomarkers in GIST have been established so far with added value to predict the recurrence risk of high risk GIST besides mitotic count, primary location and size. In this study, we analyzed the prognostic relevance of eight cell cycle and apoptosis modulators and of TP53 mutations for prognosis in GIST with high risk of recurrence prior to adjuvant treatment with imatinib. In total, 400 patients with high risk for GIST recurrence were randomly assigned for adjuvant imatinib either for one or for three years following laparotomy. 320 primary tumor samples with available tumor tissue were immunohistochemically analyzed prior to treatment for the expression of cell cycle regulators and apoptosis modulators cyclin D1, p21, p16, CDK4, E2F1, MDM2, p53 and p-RB1. TP53 mutational analysis was possible in 245 cases. A high expression of CDK4 was observed in 32.8% of all cases and was associated with a favorable recurrence free survival (RFS), whereas high expression of MDM2 (12.2%) or p53 (35.3%) was associated with a shorter RFS. These results were independent from the primary KIT or PDGFRA mutation. In GISTs with higher mitotic counts was a significantly increased expression of cyclin D1, p53 and E2F1. The expression of p16 and E2F1 significantly correlated to a non-gastric localization. Furthermore, we observed a significant higher expression of p21 and E2F1 in KIT mutant GISTs compared to PDGFRA mutant and wt GISTs. The overall frequency of TP53 mutations was low (n = 8; 3.5%) and could not be predicted by the immunohistochemical expression of p53. In summary, mutation analysis in TP53 plays a minor role in the subgroup of high-risk GIST before adjuvant treatment with imatinib. Strong expression of MDM2 and p53 correlated with a shorter recurrence free survival, whereas a strong expression of CDK4 correlated to a better recurrence free survival.
  • Toukola, Tomi; Junttila, M. Juhani; Holmström, Lauri T. A.; Haukilahti, M. Anette; Tikkanen, Jani T.; Terho, Henri; Kenttä, Tuomas V.; Aro, Aapo L.; Anttonen, Olli; Kerola, Tuomas; Pakanen, Lasse; Kortelainen, Marja-Leena; Kiviniemi, Antti; Huikuri, Heikki V. (2018)
    Introduction: Little is known about the association between electrocardiographic abnormalities and exercise-related sudden cardiac death.Therefore, our aim was to identify possible electrocardiographic findings related to exercise-induced sudden cardiac death. Methods and results: The FinGesture study includes 3,989 consecutive sudden cardiac deaths in northern Finland between 1998 and 2012, out of whom a total of 647 subjects had a previously recorded electrocardiography acquired from the archives of Oulu University Hospital. In 276 of these cases the death was witnessed, and the activity at the time of death was either rest or physical exercise (PEj; in 40 {14%} cases sudden cardiac death was exercise-related and in 236 (86%) cases death took place at rest. Fragmented QRS complex in at least two consecutive leads within anterior leads (V1-V3) was more common in the exercise-group compared to rest-group (17 of 40, 43% vs. 51 of 236,22%, P = 0.005). Pathologic Q wave in anterior leads was more common in the PE group (9 of 40,23% vs. 26 of 236,11%; P = 0.044). Median QRS duration was prolonged in the exercise-group compared to the rest-group (100 milliseconds vs. 94 milliseconds, P = 0.047), QTc interval, the prevalence of inverted T-waves, or other electrocardiographic abnormalities did not differ significantly between the two groups. Conclusions: As a conclusion, fragmented QRS complex in the anterior leads is associated with an increased risk of sudden cardiac death during PE.
  • Reijonen, P.; Osterlund, P.; Isoniemi, H.; Arola, J.; Nordin, A. (2019)
    Background and Aims: The impact of biliary invasion on recurrence and survival, after resection of colorectal cancer liver metastases, is not well known as publications are limited to small patient series. The aim was to investigate if biliary invasion in liver resected patients associated with liver relapses and recurrence-free survival. Secondary endpoints included association with other prognostic factors, disease-free survival and overall survival. Materials and Methods: All patients with histologically verified biliary invasion (n = 31, 9%) were identified among 344 patients with liver resection between January 2009 and March 2015. Controls (n = 78) were selected from the same time period and matched for, among others, size and number of colorectal cancer liver metastasis. Results: Median liver recurrence-free survival was significantly shorter in patients with biliary invasion than in controls (15.3 months versus not reached; p = 0.031) and more relapses were noted in the liver (61.3% versus 33.3%; p = 0.010), respectively. In univariate analyses for liver recurrence-free survival, biliary invasion was the only significant prognostic factor; p = 0.034. There were no statistical differences in disease-free and overall survival between the groups. Conclusion: Biliary invasion was associated with higher liver recurrence rates and shorter liver recurrence-free survival in patients with resected colorectal cancer liver metastasis.
  • Juurikka, K.; Dufour, A.; Pehkonen, K.; Mainoli, B.; Campioni Rodrigues, P.; Solis, N.; Klein, T.; Nyberg, P.; Overall, C. M.; Salo, T.; Åström, P. (2021)
    Matrix metalloproteinases (MMPs) modify bioactive factors via selective processing or degradation resulting in tumour-promoting or tumour-suppressive effects, such as those by MMP8 in various cancers. We mapped the substrates of MMP8 to elucidate its previously shown tumour-protective role in oral tongue squamous cell carcinoma (OTSCC). MMP8 overexpressing (+) HSC-3 cells, previously demonstrated to have reduced migration and invasion, showed enhanced cell-cell adhesion. By analysing the secretomes of MMP8 + and control cells with terminal amine isotopic labelling of substrates (TAILS) coupled with liquid chromatography and tandem mass spectrometry (LC-MS/MS), we identified 36 potential substrates of MMP8, including FXYD domain-containing ion transport regulator 5 (FXYD5). An anti-adhesive glycoprotein FXYD5 has been previously shown to predict poor survival in OTSCC. Cleavage of FXYD5 by MMP8 was confirmed using recombinant proteins. Furthermore, we detected a loss of FXYD5 levels on cell membrane of MMP8 + cells, which was rescued by inhibition of the proteolytic activity of MMP8. Silencing (si) FXYD5 increased the cell-cell adhesion of control but not that of MMP8 + cells. siFXYD5 diminished the viability and motility of HSC-3 cells independent of MMP8 and similar effects were seen in another tongue cancer cell line, SCC-25. FXYD5 is a novel substrate of MMP8 and reducing FXYD5 levels either with siRNA or cleavage by MMP8 increases cell adhesion leading to reduced motility. FXYD5 being a known prognostic factor in OTSCC, our findings strengthen its potential as a therapeutic target.
  • Muranen, Taru A.; Blomqvist, Carl; Doerk, Thilo; Jakubowska, Anna; Heikkila, Paivi; Fagerholm, Rainer; Greco, Dario; Aittomäki, Kristiina; Bojesen, Stig E.; Shah, Mitul; Dunning, Alison M.; Rhenius, Valerie; Hall, Per; Czene, Kamila; Brand, Judith S.; Darabi, Hatef; Chang-Claude, Jenny; Rudolph, Anja; Nordestgaard, Borge G.; Couch, Fergus J.; Hart, Steven N.; Figueroa, Jonine; Garcia-Closas, Montserrat; Fasching, Peter A.; Beckmann, Matthias W.; Li, Jingmei; Liu, Jianjun; Andrulis, Irene L.; Winqvist, Robert; Pylkas, Katri; Mannermaa, Arto; Kataja, Vesa; Lindblom, Annika; Margolin, Sara; Lubinski, Jan; Dubrowinskaja, Natalia; Bolla, Manjeet K.; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Easton, Douglas F.; Pharoah, Paul D. P.; Schmidt, Marjanka K.; Nevanlinna, Heli (2016)
    Background: P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers. Methods: We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO:GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature. Results: P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors. Conclusions: Our analyses suggest that there are fundamental differences in breast tumors of CHEK2: p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations.
  • Wu, Teddy Y.; Putaala, Jukka; Sharma, Gagan; Strbian, Daniel; Tatlisumak, Turgut; Davis, Stephen M.; Meretoja, Atte (2017)
    Background-Hyperglycemia may be associated with worse outcome after intracerebral hemorrhage (ICH). We assessed the association of early glycemic trajectory on ICH mortality and edema growth. Methods and Results-We included patients from the Helsinki ICH study with glucose measurements at least once between both 0 to 24 and 24 to 72 hours from onset. Hyperglycemia was defined as blood glucose >= 8 mmol/L (144 mg/dL) based on the local threshold for treatment. Glycemic trajectory was defined on maximum values 0 to 24 and 24 to 72 hours after ICH: (1) persistent normoglycemia in both epochs; (2) late hyperglycemia (only between 24 and 72 hours); (3) early hyperglycemia (only before 24 hours); and (4) persistent hyperglycemia in both epochs. Logistic regression with known predictors of outcome estimated the association of glycemic trajectory and 6-month mortality. A generalized linear model assessed the association of glycemic trajectory and interpolated 72-hour edema extension distance. A total of 576 patients met eligibility criteria, of whom 214 (37.2%) had persistent normoglycemia, 44 (7.6%) late hyperglycemia, 151 (26.2%) early hyperglycemia, and 167 (29.0%) persistent hyperglycemia. Six-month mortality was higher in the persistent (51.1%) and early (26.3%) hyperglycemia groups than the normoglycemia (19.0%) and late hyperglycemia (3.6%) groups. Persistent hyperglycemia was associated with 6-month mortality (odds ratio 3.675, 95% CI 1.989-6.792; P <0.001). Both univariate (P=0.426) and multivariable (P=0.493) generalized linear model analyses showed no association between glycemic trajectory and 72-hour edema extension distance. Conclusion-Early hyperglycemia after ICH is harmful if it is persistent. Strategies to achieve glycemic control after ICH may influence patient outcome and need to be assessed in clinical trials.
  • Bono, Petri; Massard, Christophe; Peltola, Katriina J.; Azaro, Analia; Italiano, Antoine; Kristeleit, Rebecca S.; Curigliano, Giuseppe; Lassen, Ulrik; Arkenau, Hendrik-Tobias; Hakulinen, Pasi; Garratt, Chris; Ikonen, Tarja; Mustonen, Mika V. J.; Rodon, Jordi A. (2020)
    Background Genetic alterations in fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) signalling are observed in various tumours. We report a first-in-human phase I/IIa trial evaluating tolerability, pharmacokinetics and preliminary antitumour activity of ODM-203, a novel FGFR and VEGFR inhibitor. Methods Open-label, non-randomised, multicentre, phase I/IIa dose escalation and expansion study in patients with advanced or metastatic solid tumours. Results Overall, 84 patients received treatment; optimal tablet dose was found to be 400 mg/day with food. All patients experienced at least one adverse event; the majority (89.2%) were grade 1 or 2% and 70.4% were considered treatment related. The most commonly reported events were bilirubin increase-related events (75%) and diarrhoea (50%). Overall response rate was 9.2% and median progression-free survival was 16.1 and 12.4 weeks for patients with aberrant or non-aberrant FGFR tumours. Median time on treatment was 10.1 weeks for all patients and 14.5 weeks for patients who received 400 mg tablets. Conclusion This study suggests ODM-203 400 mg/day results in sufficient plasma concentrations and acceptable tolerability in most patients. Preliminary signs of therapeutic activity of ODM-203 in patients with solid tumours was observed.
  • Ollila, Aino; Virolainen, Juha; Vanhatalo, Joonas; Vikatmaa, Pirkka; Tikkanen, Ilkka; Venermo, Maarit; Salmenpera, Markku; Pettila, Ville; Vikatmaa, Leena (2017)
    Objectives: Elderly patients undergoing vascular surgery are at major risk for perioperative cardiac complications. The authors investigated continuous electrocardiographic Holter monitoring in a postoperative setting to determine the degree of postoperative ischemic load and its possible associations with perioperative myocardial infarction. Design: A prospective, observational study. Setting: One university hospital. Participants: The study comprised 51 patients aged 65 years or older undergoing peripheral arterial surgery. Interventions: Continuous electrocardiographic monitoring with a Holier device was started postoperatively and continued for 72 hours or until discharge. Postural changes were recorded using a 3-axis accelerometer. Standard 12-lead electrocardiography, high-sensitive troponin T measurements, and an inquiry of ischemic symptoms were performed 4 times perioperatively. Measurements and Main Results: The primary outcomes were ischemic load (area under the function of ischemic ST-segment deviation and ischemic time) and perioperative myocardial infarction. During 3,262.7 patient-hours of monitoring, 17 patients (33.3%) experienced 608 transient ischemic events, all denoted by ST-segment depression. Of these 17 patients, 5 experienced perioperative myocardial infarction. The mean ischemic load in all patients was 913.2 +/- 2,797.3 mu V x minute. Ischemic load predicted perioperative myocardial infarction, with an area under receiver operating characteristics curve (95% confidence interval) of 0.87 (0.75-0.99). Ischemic changes occurred most frequently during hours 24 to 60 of monitoring. Ischemia was asymptomatic in 14 of 17 patients (82.4%). Conclusion: Postoperative myocardial ischemia was common in peripheral vascular surgery patients and may progress to perioperative myocardial infarction. Ischemic load was a good predictor of perioperative myocardial infarction. Ambulatory electrocardiographic monitoring solutions for continuous postoperative ischemia detection are warranted in the surgical ward. (C) 2017 Elsevier Inc. All rights reserved.
  • CardShock Study Investigators; Great Network; Tolppanen, Heli; Javanainen, Tuija; Nieminen, Tuomo; Harjola, Veli-Pekka; Jurkko, Raija; Lassus, Johan (2018)
    Changes in QRS duration and pattern are regarded to reflect severe ischemia in acute coronary syndromes (ACS), and ventricular conduction blocks (VCBs) are recognized high-risk markers in both ACS and acute heart failure. Our aim was to evaluate the prevalence, temporal evolution, association with clinical and angiographic parameters, and impact on mortality of VCBs in ACS-related cardiogenic shock (CS). Data of 199 patients with ACS-related CS from a prospective multinational cohort were evaluated with electrocardiogram data from baseline and day 3. VCBs including left or right bundle branch block, right bundle branch block and hemiblock, isolated hemiblocks, and unspecified intraventricular conduction delay were assessed. Fifty percent of patients had a VCB at baseline; these patients were older, had poorer left ventricular function and had more often left main disease compared with those without VCB. One-year mortality was over 2-fold in patients with VCB compared with those without VCB (68% vs 32%, p
  • Skrifvars, Markus B.; Hästbacka, Johanna (2018)
  • Andersson, Saana; Ilonen, Ilkka; Järvinen, Tommi; Rauma, Ville; Räsänen, Jari; Salo, Jarmo (2018)
    The role of positive lymph node location in non-small-cell lung cancer (NSCLC) patients and effects on survival was assessed. A total of 88 operated patients with unsuspected N2 disease or station 10 lymph nodes were included. No difference was found in survival between inferior positive mediastinal N2 node patients compared to multilevel N2 disease patients. The survival of patients with positive hilar disease was similar to the inferior mediastinal positive N2 group. Background: The role of surgery in the treatment of non-small-cell lung cancer that has spread to ipsilateral mediastinal or hilar lymph nodes (LNs) is controversial. We examined whether the location of LNs positive for non-small-cell lung cancer in mediastinum or hilum influences the survival of these patients. Patients and Methods: We reviewed data from 881 patients and analyzed those with unsuspected N2 disease or hilar (station 10) LNs. The patients were stratified into the following groups: group A, positive hilar Naruke 10; group B, superior mediastinal and aortic nodes (Naruke 1, 2, 3, 4, 5, and 6); group C, inferior mediastinal nodes (Naruke 7, 8, and 9), and multilevel group D (2 or more positive N2 levels). Results: A total of 69 pN2 and 19 pN1 patients were included. Progression-free survival (PFS) was statistically significant better in group B versus group C (P = .044) and group B versus group D (P = .0086). The overall survival (OS) of group A did not differ from that of group C. A statistically significant better OS was found between groups B and D (P= .051). Conclusion: Inferior positive mediastinal N2 node patients seem to have an OS and PFS as poor as multilevel N2 disease patients. The OS and PFS of patients with positive hilar disease are similar to those in the inferior mediastinal positive N2 group. Superior positive mediastinal N2 node patients have better OS and PFS than the inferior mediastinal positive N2 group. (C) 2018 Elsevier Inc. All rights reserved.
  • Sundquist, Elias; Kauppila, Joonas H.; Veijola, Johanna; Mroueh, Rayan; Lehenkari, Petri; Laitinen, Saara; Risteli, Juha; Soini, Ylermi; Kosma, Veli-Matti; Sawazaki-Calone, Iris; Soares Macedo, Carolina Carneiro; Bloigu, Risto; Coletta, Ricardo D.; Salo, Tuula (2017)
    Background:Oral tongue squamous cell carcinoma (OTSCC) metastasises early, especially to regional lymph nodes. There is an ongoing debate on which early stage (T1-T2N0) patients should be treated with elective neck dissection. We need prognosticators for early stage tongue cancer. Methods: Mice immunisation with human mesenchymal stromal cells resulted in production of antibodies against tenascin-C (TNC) and fibronectin (FN), which were used to stain 178 (98 early stage), oral tongue squamous cell carcinoma samples. TenascinC and FN expression in the stroma (negative, moderate or abundant) and tumour cells (negative or positive) were assessed. Similar staining was obtained using corresponding commercial antibodies. Results: Expression of TNC and FN in the stroma, but not in the tumour cells, proved to be excellent prognosticators both in all stages and in early stage cases. Among early stages, when stromal TNC was negative, the 5-year survival rate was 88%. Correspondingly, when FN was negative, no cancer deaths were observed. Five-year survival rates for abundant expression of TNC and FN were 43% and 25%, respectively. Conclusions: Stromal TNC and, especially, FN expressions differentiate patients into low-and high-risk groups. Surgery alone of early stage primary tumours might be adequate when stromal FN is negative. Aggressive treatments should be considered when both TNC and FN are abundant.
  • Astrom, Pirjo; Juurikka, Krista; Hadler-Olsen, Elin S.; Svineng, Gunbjorg; Cervigne, Nilva K.; Coletta, Ricardo D.; Risteli, Juha; Kauppila, Joonas H.; Skarp, Sini; Kuttner, Samuel; Oteiza, Ana; Sutinen, Meeri; Salo, Tuula (2017)
    Background: Matrix metalloproteinase-8 (MMP-8) has oncosuppressive properties in various cancers. We attempted to assess MMP-8 function in oral tongue squamous cell carcinoma (OTSCC). Methods: MMP-8 overexpressing OTSCC cells were used to study the effect of MMP-8 on proliferation, apoptosis, migration, invasion and gene and protein expression. Moreover, MMP-8 functions were assessed in the orthotopic mouse tongue cancer model and by immunohistochemistry in patient samples. Results: MMP-8 reduced the invasion and migration of OTSCC cells and decreased the expression of MMP-1, cathepsin-K and vascular endothelial growth factor-C (VEGF-C). VEGF-C was induced by transforming growth factor-beta 1 (TGF-beta 1) in control cells, but not in MMP-8 overexpressing cells. In human OTSCC samples, low MMP-8 in combination with high VEGF-C was an independent predictor of poor cancer-specific survival. TGF-beta 1 treatment also restored the migration of MMP-8 overexpressing cells to the level of control cells. In mouse tongue cancer, MMP-8 did not inhibit metastasis, possibly because it was eliminated in the peripheral carcinoma cells. Conclusions: The suppressive effects of MMP-8 in OTSCC may be mediated through interference of TGF-beta 1 and VEGF-C function and altered proteinase expression. Together, low MMP-8 and high VEGF-C expression have strong independent prognostic value in OTSCC.
  • Almangush, Alhadi; Ruuskanen, Miia; Hagstrom, Jaana; Hirvikoski, Pasi; Tommola, Satu; Kosma, Veli-Matti; Nieminen, Pentti; Makitie, Antti; Leivo, Limo (2018)
    The prognostic significance of tumor-infiltrating lymphocytes (TILs) has been studied recently in many cancers. For the first time in a nonendemic region, we have evaluated the prognostic value of TILs in a whole population based nationwide cohort of nasopharyngeal carcinoma (NPC) in Finland. A total of 115 cases from Finnish hospitals were included. TILs were analyzed using hematoxylin and eosin stained slides according to the criteria of the International Immuno-Oncology Biomarker Working Group. TILs were evaluated separately in stromal and tumor compartments. The log-rank test and univariable and multivariable analyses were used to compare survival in patients with tumors with low and high TILs. A significant positive correlation was observed between the occurrence of intratumoral and stromal TILs (P <.001). In multivariable analysis, NPC cases with low intratumoral TILs had poor overall survival with a hazard ratio (HR) of 2.55 and 95% confidence interval (95% CI) of 1.60 to 4.05 (P <.001). Cases with low intratumoral TILs also had poor disease-specific survival (HR, 2.02; 95% CI, 1.16-3.52; P = .015). Keratinized tumors with low intratumoral TILs were associated with an even poorer overall survival (HR, 3.94; 95% CI, 2.17-7.15; P <.001) and a poor disease-specific survival (HR, 2.97; 95% CI, 1.46-6.05; P = .009). Our study demonstrates that the evaluation of TILs is simple and can be assessed routinely in NPC. (C) 2018 Elsevier Inc. All rights reserved.
  • Pirinen, Jani; Putaala, Jukka; Aarnio, Karoliina; Aro, Aapo L.; Mustanoja, Satu; Sinisalo, Juha; Kaste, Markku; Haapaniemi, Elena; Tatlisumak, Turgut; Lehto, Mika (2017)
    Introduction: Ischaemic stroke at young age carries an increased risk for mortality in comparison to the general population, but factors associated with mortality have been poorly studied. We studied the role of electrocardiogram in mortality risk stratification in young stroke patients. Patients and methods: The Helsinki Young Stroke Registry encompasses 1008 patients aged <50 years with ischaemic stroke. We included 690 patients for this electrocardiogram substudy. Our endpoints were all-cause and cardiovascular mortality. Cox regression models - adjusted for clinical and demographic characteristics - were used to identify the electrocardiogram parameters associated with these endpoints. Results: At a mean follow-up of 8.8 years, cumulative all-cause and cardiovascular mortality were 16.1 and 9.1%, respectively. Factors associated with both endpoints included diabetes (type 1 for all-cause, type 2 for cardiovascular mortality), heavy drinking, malignancy, as well as stroke severity and aetiology. Of the electrocardiogram parameters, higher heart rate (hazard ratio 1.35 per 10/min, 95% confidence interval 1.21-1.49), a shorter P-wave (hazard ratio 0.78 per 10 ms decrement, 0.64-0.92) and longer QTc interval (1.09 per 10 ms, 1.03-1.16) were associated with increased all-cause mortality. Only a higher heart rate (1.42 per 10/min, 1.24-1.60) was associated with death from cardiovascular causes. Conclusions: A higher heart rate during the subacute phase after stroke is associated with an elevated risk of all-cause and cardiovascular mortality in young adults. A longer QTc interval is associated only with higher all-cause mortality. P-wave characteristics and their possible association with mortality need further studies.