Browsing by Subject "PROGNOSIS"

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  • Efraim Investigators Nine; Mokart, Djamel; Darmon, Michael; Schellongowski, Peter; Valkonen, Miia; Azoulay, Elie (2020)
    Background The impact of neutropenia in critically ill immunocompromised patients admitted in a context of acute respiratory failure (ARF) remains uncertain. The primary objective was to assess the prognostic impact of neutropenia on outcomes of these patients. Secondary objective was to assess etiology of ARF according to neutropenia. Methods We performed a post hoc analysis of a prospective multicenter multinational study from 23 ICUs belonging to the Nine-I network. Between November 2015 and July 2016, all adult immunocompromised patients with ARF admitted to the ICU were included in the study. Adjusted analyses included: (1) a hierarchical model with center as random effect; (2) propensity score (PS) matched cohort; and (3) adjusted analysis in the matched cohort. Results Overall, 1481 patients were included in this study of which 165 had neutropenia at ICU admission (11%). ARF etiologies distribution was significantly different between neutropenic and non-neutropenic patients, main etiologies being bacterial pneumonia (48% vs 27% in neutropenic and non-neutropenic patients, respectively). Initial oxygenation strategy was standard supplemental oxygen in 755 patients (51%), high-flow nasal oxygen in 165 (11%), non-invasive ventilation in 202 (14%) and invasive mechanical ventilation in 359 (24%). Before adjustment, hospital mortality was significantly higher in neutropenic patients (54% vs 42%;p = 0.006). After adjustment for confounder and center effect, neutropenia was no longer associated with outcome (OR 1.40, 95% CI 0.93-2.11). Similar results were observed after matching (52% vs 46%, respectively;p = 0.35) and after adjustment in the matched cohort (OR 1.04; 95% CI 0.63-1.72). Conclusion Neutropenia at ICU admission is not associated with hospital mortality in this cohort of critically ill immunocompromised patients admitted for ARF. In neutropenic patients, main ARF etiologies are bacterial and fungal infections.
  • Gunnarsson, Ulf; Strigård, Karin; Edin, Sofia; Gkekas, Ioannis; Mustonen, Harri; Kaprio, Tuomas; Böckelman, Camilla; Hagström, Jaana; Palmqvist, Richard; Haglund, Caj (2020)
    Systemic inflammatory response in colorectal cancer (CRC) has been established as a prognostic factor for impaired cancer-specific survival, predominantly in patients with right-sided tumors. On the other hand, defective mismatch repair (dMMR) tumors, primarily located in the right colon, are known to have favorable survival and dense local immune infiltration. The aim of this study was to see if there is any form of relationship between these seemingly diverse entities.
  • NBCS Collaborators; ABCTB Investigators; kConFab Investigators; Morra, Anna; Escala-Garcia, Maria; Beesley, Jonathan; Muranen, Taru A.; Nevanlinna, Heli (2021)
    Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). Results Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
  • Honkamäki, Jasmin; Piirilä, Päivi; Hisinger-Mölkänen, Hanna; Tuomisto, Leena E.; Andersen, Heidi; Huhtala, Heini; Sovijärvi, Anssi; Lindqvist, Ari; Backman, Helena; Lundbäck, Bo; Rönmark, Eva; Lehtimäki, Lauri; Pallasaho, Paula; Ilmarinen, Pinja; Kankaanranta, Hannu (2021)
    BACKGROUND: Child-onset asthma is known to remit with high probability, but remission in adult-onset asthma is seem-ingly less frequent. Reports of the association between remission and asthma age of onset up to late adulthood are scarce. OBJECTIVE: To evaluate the association between asthma remission, age at diagnosis and gender, and assess risk factors of nonremission. METHODS: In 2016, a random sample of 16,000 subjects aged 20 to 69 years from Helsinki and Western Finland were sent a FinEsS questionnaire. Physician-diagnosed asthma was catego-rized by age at diagnosis to early-(0-11 years), intermediate-(12-39 years), and late-diagnosed (40-69 years) asthma. Asthma remission was defined by not having had asthma symptoms and not having used asthma medication in the past 12 months. RESULTS: Totally, 8199 (51.5%) responded, and 879 reported physician-diagnosed asthma. Remission was most common in early-diagnosed (30.2%), followed by intermediate-diagnosed (17.9%), and least common in late-diagnosed asthma (5.0%) (P < .001), and the median times from diagnosis were 27, 18.5, and 10 years, respectively. In males, the corresponding remission rates were 36.7%, 20.0%, and 3.4%, and in females, 20.4%, 16.6%, and 5.9% (gender difference P < .001). In multivariable binary logistic regression analysis, signifi-cant risk factors of asthma nonremission were intermediate (odds ratio [OR] = 2.15, 95% confidence interval: 1.373.36) and late diagnosis (OR = 11.06, 4.82-25.37) compared with early diagnosis, chronic obstructive pulmonary disease (COPD) (OR = 5.56, 1.26-24.49), allergic rhinitis (OR = 2.28, 1.50-3.46), and family history of asthma (OR = 1.86, 1.22-2.85). Results were similar after excluding COPD. CONCLUSION: Remission was rare in adults diagnosed with asthma after age 40 years in both genders. Late-diagnosed asthma was the most significant independent risk factor for nonremission. (C) 2020 American Academy of Allergy, Asthma & Immunology
  • Guo, Qi; Burgess, Stephen; Turman, Constance; Bolla, Manjeet K.; Wang, Qin; Lush, Michael; Abraham, Jean; Aittomäki, Kristiina; Andrulis, Irene L.; Apicella, Carmel; Arndt, Volker; Barrdahl, Myrto; Benitez, Javier; Berg, Christine D.; Blomqvist, Carl; Bojesen, Stig E.; Bonanni, Bernardo; Brand, Judith S.; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Caldas, Carlos; Campa, Daniele; Canzian, Federico; Chang-Claude, Jenny; Chanock, Stephen J.; Chin, Suet-Feung; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Cybulski, Cezary; Czene, Kamila; Darabi, Hatef; Devilee, Peter; Diver, W. Ryan; Dunning, Alison M.; Earl, Helena M.; Eccles, Diana M.; Ekici, Arif B.; Eriksson, Mikael; Evans, D. Gareth; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Flyger, Henrik; Gapstur, Susan M.; Gaudet, Mia M.; Giles, Graham G.; Muranen, Taru A.; Nevanlinna, Heli; kConFab AOCS Investigators (2017)
    There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer. We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis. BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13,P = 0.95). Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.
  • Kanerva, Anna; Koski, Anniina; Liikanen, Ilkka; Oksanen, Minna; Joensuu, Timo; Hemminki, Otto; Palmgren, Juni; Hemminki, Kari; Hemminki, Akseli (2015)
  • Lundin, Catarina; Forestier, Erik; Andersen, Mette Klarskov; Autio, Kirsi; Barbany, Gisela; Cavelier, Lucia; Golovleva, Irina; Heim, Sverre; Heinonen, Kristiina; Hovland, Randi; Johannsson, Johann H.; Kjeldsen, Eigil; Nordgren, Ann; Palmqvist, Lars; Johansson, Bertil; Nordic Soc Pediat Hematology Oncol; Swedish Cytogenetic Leukemia Study; NOPHO Leukemia Cytogenetic Study G (2014)
  • Sveen, Anita; Bruun, Jarle; Eide, Peter W.; Eilertsen, Ina A.; Ramirez, Lorena; Murumägi, Astrid; Arjama, Mariliina; Danielsen, Stine A.; Kryeziu, Kushtrim; Elez, Elena; Tabernero, Josep; Guinney, Justin; Palmer, Hector G.; Nesbakken, Arild; Kallioniemi, Olli; Dienstmann, Rodrigo; Lothe, Ragnhild A. (2018)
    Purpose: Response to standard oncologic treatment is limited in colorectal cancer. The gene expression-based consensus molecular subtypes (CMS) provide a new paradigm for stratified treatment and drug repurposing; however, drug discovery is currently limited by the lack of translation of CMS to preclinical models. Experimental Design: We analyzed CMS in primary colorectal cancers, cell lines, and patient-derived xenografts (PDX). For classification of preclinical models, we developed an optimized classifier enriched for cancer cell-intrinsic gene expression signals, and performed high-throughput in vitro drug screening (n = 459 drugs) to analyze subtype-specific drug sensitivities. Results: The distinct molecular and clinicopathologic characteristics of each CMS group were validated in a single-hospital series of 409 primary colorectal cancers. The new, cancer cell-adapted classifier was found to perform well in primary tumors, and applied to a panel of 148 cell lines and 32 PDXs, these colorectal cancer models were shown to recapitulate the biology of the CMS groups. Drug screening of 33 cell lines demonstrated subtype-dependent response profiles, confirming strong response to EGFR and HER2 inhibitors in the CMS2 epithelial/canonical group, and revealing strong sensitivity to HSP90 inhibitors in cells with the CMS1 microsatellite instability/immune and CMS4 mesenchymal phenotypes. This association was validated in vitro in additional CMS-predicted cell lines. Combination treatment with 5-fluorouracil and luminespib showed potential to alleviate chemoresistance in a CMS4 PDX model, an effect not seen in a chemosensitive CMS2 PDX model. Conclusions: We provide translation of CMS classification to preclinical models and uncover a potential for targeted treatment repurposing in the chemoresistant CMS4 group. (C) 2017 AACR.
  • Matz, Karl; Tuomilehto, Jaakko; Teuschl, Yvonne; Dachenhausen, Alexandra; Brainin, Michael (2020)
    Background Diabetes is an increasingly important risk factor for ischemic stroke and worsens stroke prognosis. Yet a large proportion of stroke patients who are eventually diabetic are undiagnosed. Therefore, it is important to have sensitive assessment of unrecognized hyperglycaemia in stroke patients. Design Secondary outcome analysis of a randomized controlled trial focussing on parameters of glucose metabolism and detection of diabetes and prediabetes in patients with acute ischemic stroke (AIS). Methods A total of 130 consecutively admitted patients with AIS without previously known type 2 diabetes mellitus (T2DM) were screened for diabetes or prediabetes as part of secondary outcome analysis of a randomized controlled trial that tested lifestyle intervention to prevent post-stroke cognitive decline. Patients had the oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) measurements in the second week after stroke onset and after 1 year. The detection rates of diabetes and prediabetes based on the OGTT or HbA1c values were compared. Results By any of the applied tests at the second week after stroke onset 62 of 130 patients (48%) had prediabetes or T2DM. Seventy-five patients had results from both tests available, the OGTT and HbA1c; according to the OGTT 40 (53.3%) patients had normal glucose metabolism, 33 (44%) had prediabetes, two (2.7%) T2DM. In 50 (66.7%) patients the HbA1c results were normal, 24 (32%) in the prediabetic and one (1.3%) in the diabetic range. The detection rate for disorders of glucose metabolism was 10% higher (absolute difference; relative difference 29%) with the OGTT compared with HbA1c. After 1 year the detection rate for prediabetes or T2DM was 7% higher with the OGTT (26% relative difference). The study intervention led to a more favourable evolution of glycemic status after 1 year. Conclusion The OGTT is a more sensitive screening tool than HbA1c for the detection of previously unrecognized glycemic disorders in patients with acute stroke with an at least a 25% relative difference in detection rate. Therefore, an OGTT should be performed in all patients with stroke with no history of diabetes. Trial registration. Unique identifier: NCT01109836.
  • Sonnenblick, Amir; Brohee, Sylvain; Fumagalli, Debora; Vincent, Delphine; Venet, David; Ignatiadis, Michail; Salgado, Roberto; Van den Eynden, Gert; Rothe, Francoise; Desmedt, Christine; Neven, Patrick; Loibl, Sibylle; Denkert, Carsten; Joensuu, Heikki; Loi, Sherene; Sirtaine, Nicolas; Kellokumpu-Lehtinen, Pirkko-Liisa; Piccart, Martine; Sotiriou, Christos (2015)
    Background: The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance. Methods: We integrated reverse phase protein array (RPPA) and gene expression data from patients with HER2-positive breast cancer treated with trastuzumab in the adjuvant setting. Results: We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02). This suggests that STAT3 induces a characteristic set of gene expression changes in HER2-positive cancers. Tumors characterized as high pSTAT3-GS were associated with trastuzumab resistance (log rank P = 0.049). These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02). Of interest, constitutively activated pSTAT3 tumors were associated with loss of PTEN, elevated IL6, and stromal reactivation. Conclusions: This study provides compelling evidence for a link between pSTAT3 and trastuzumab resistance in HER2-positive primary breast cancers. Our results suggest that it may be valuable to add agents targeting the STAT3 pathway to trastuzumab for treatment of HER2-positive breast cancer.
  • Fleischer, Thomas; Klajic, Jovana; Aure, Miriam Ragle; Louhimo, Riku; Pladsen, Arne V.; Ottestad, Lars; Touleimat, Nizar; Laakso, Marko; Halvorsen, Ann Rita; Alnaes, Grethe I. Grenaker; Riis, Margit L. H.; Helland, Aslaug; Hautaniemi, Sampsa; Lonning, Per Eystein; Naume, Bjorn; Borresen-Dale, Anne-Lise; Tost, Joerg; Kristensen, Vessela N. (2017)
    Breast cancer patients with Luminal A disease generally have a good prognosis, but among this patient group are patients with good prognosis that are currently overtreated with adjuvant chemotherapy, and also patients that have a bad prognosis and should be given more aggressive treatment. There is no available method for subclassification of this patient group. Here we present a DNA methylation signature (SAM40) that segregates Luminal A patients based on prognosis, and identify one good prognosis group and one bad prognosis group. The prognostic impact of SAM40 was validated in four independent patient cohorts. Being able to subdivide the Luminal A patients may give the two-sided benefit of identifying one subgroup that may benefit from a more aggressive treatment than what is given today, and importantly, identifying a subgroup that may benefit from less treatment.
  • Almangush, Alhadi; Youssef, Omar; Pirinen, Matti; Sundström, Jari; Leivo, Ilmo; Mäkitie, Antti A. (2019)
    Tumour budding has emerged as a promising prognostic marker in many cancers. We systematically reviewed all studies that evaluated tumour budding in diagnostic biopsies. We conducted a systematic review of PubMed, MEDLINE, Scopus, Web of Science and Cochrane library for all articles that have assessed tumour budding in diagnostic (i.e. pretreatment or pre-operative) biopsies of any tumour type. Two independent researchers screened the retrieved studies, removed duplicates, excluded irrelevant studies and extracted data from the eligible studies. A total of 13 reports comprising 11 cohorts were found to have studied tumour budding in diagnostic biopsies. All these reports showed that evaluation of tumour budding in diagnostic biopsies was easily applicable. A strong association was observed between tumour budding score in diagnostic biopsies and corresponding surgical samples. Evaluation of tumour budding in diagnostic biopsies had a significant prognostic value for lymph node metastasis and patient survival. In all studies, tumour budding was a valuable marker of tumour aggressiveness and can be evaluated in technically satisfactory diagnostic biopsies. Thus, the assessment of tumour budding seems to identify the behaviour of cancer, and therefore to facilitate treatment planning.
  • Ilmarinen, Pinja; Juboori, Hind; Tuomisto, Leena E.; Niemelä, Onni; Sintonen, Harri; Kankaanranta, Hannu (2019)
    Health-related quality of life (HRQoL) is a well-established aspect of health that can be measured by both disease-specific and general instruments. The effect of uncontrolled asthma on generic HRQoL has not been shown in patients with clinically confirmed adult-onset asthma and with asthma control defined according to the Global Initiative for Asthma, so the aim of this study was to determine this. In the 12-year follow-up cohort of the Seinajoki Adult Asthma Study (n = 203), patients with uncontrolled and partially controlled asthma had lower generic HRQoL as determined by 15D compared to the controlled group. On 10 out of 15 dimensions of 15D, the mean scores were significantly lower in patients with uncontrolled asthma compared with those with controlled asthma. The affected dimensions were mobility, breathing, sleeping, usual activities, mental function, discomfort and symptoms, depression, distress, vitality and sexual activity. In the Tobit regression analysis, a poorer 15D score was associated with uncontrolled asthma, lower postbronchodilator FEV1, female sex, depression, treated dyspepsia and poorer 15D score at diagnosis. Our results show that uncontrolled asthma affects everyday life in several aspects, including previously unknown components such as sexual activity and vitality.
  • Hanninen, Ulrika A.; Wirta, Erkki-Ville; Katainen, Riku; Tanskanen, Tomas; Hamberg, Jiri; Taipale, Minna; Böhm, Jan; Renkonen-Sinisalo, Laura; Lepistö, Anna; Forsström, Linda M.; Pitkänen, Esa; Palin, Kimmo; Seppälä, Toni T.; Mäkinen, Netta; Mecklin, Jukka-Pekka; Aaltonen, Lauri A. (2019)
    BACKGROUND: Approximately 4% of colorectal cancer (CRC) patients have at least two simultaneous cancers in the colon. Due to the shared environment, these synchronous CRCs (SCRCs) provide a unique setting to study colorectal carcinogenesis. Understanding whether these tumours are genetically similar or distinct is essential when designing therapeutic approaches. METHODS: We performed exome sequencing of 47 primary cancers and corresponding normal samples from 23 patients. Additionally, we carried out a comprehensive mutational signature analysis to assess whether tumours had undergone similar mutational processes and the first immune cell score analysis (IS) of SCRC to analyse the interplay between immune cell invasion and mutation profile in both lesions of an individual. RESULTS: The tumour pairs shared only few mutations, favouring different mutations in known CRC genes and signalling pathways and displayed variation in their signature content. Two tumour pairs had discordant mismatch repair statuses. In majority of the pairs, IS varied between primaries. Differences were not explained by any clinicopathological variable or mutation burden. CONCLUSIONS: The study shows major diversity within SCRCs. Rather than rely on data from one tumour, our study highlights the need to evaluate both tumours of a synchronous pair for optimised targeted therapy.
  • Dourado, Mauricio Rocha; Korvala, Johanna; Åström, Pirjo; De Oliveira, Carine Ervolino; Cervigne, Nilva K.; Mofatto, Luciana Souto; Bastos, Debora Campanella; Pereira Messetti, Ana Camila; Graner, Edgard; Paes Leme, Adriana Franco; Coletta, Ricardo D.; Salo, Tuula (2019)
    As one of the most abundant constituents of the tumour microenvironment (TME), cancer-associated fibroblasts (CAF) display critical roles during tumour progression and metastasis. Multiple classes of molecules including growth factors, cytokines, proteases and extracellular matrix proteins, are produced by CAF to act as mediators of the stroma-tumour interactions. One of the main channels for this communication is associated with extracellular vesicles (EV), which are secreted particles loaded with protein and genetic information. In this study, we evaluated the effects of EV derived from CAF primary human cell lines (n = 5) on proliferation, survival, migration, and invasion of oral squamous cell carcinoma (OSCC) cells. As controls, EV from human primary-established normal oral fibroblasts (NOF, n = 5) were used. Our in vitro assays showed that CAF-EV significantly induces migration and invasion of OSCC cells and promote a disseminated pattern of HSC-3 cell invasion in the 3D organotypic assay. Furthermore, gene expression analysis of EV-treated cancer cells revealed changes in the pathways associated with tumour metabolism and up-regulation of tumour invasion genes. Our findings suggest a significant role of CAF-EV in promoting the migration and invasion of OSCC cells, which are related to the activation of cancer-related pathways.
  • Silk, Khadija; Kurki, Samu; Korpela, Taina; Carpen, Olli; Korkeila, Eija; Sundstrom, Jari (2017)
    Currently used factors predicting disease recurrence in stage II colorectal cancer patients are not optimal for risk stratification. Thus, new biomarkers are needed. In this study the applicability of ezrin protein expression together with MSI status and BRAF mutation status were tested in predicting disease outcome in stage II colorectal cancer. The study population consisted of 173 stage II colorectal cancer patients. Paraffin-embedded cancer tissue material from surgical specimens was used to construct tissue microarrays (TMAs) with next-generation technique. The TMA-slides were subjected to following immunohistochemical stainings: MLH1, MSH2, MSH6, PMS2, ezrin and anti-BRAF V600E antibody. The staining results were correlated with clinicopathological variables and survival. In categorical analysis, high ezrin protein expression correlated with poor disease-specific survival (p = 0.038). In univariate analysis patients having microsatellite instabile / low ezrin expression tumors had a significantly longer disease-specific survival than patients having microsatellite stable / high ezrin expression tumors (p = 0.007). In multivariate survival analysis, the presence of BRAF mutation was associated to poor overall survival (p = 0.028, HR 3.29, 95% CI1.14-9.54). High ezrin protein expression in patients with microsatellite stable tumors was linked to poor disease-specific survival (p = 0.01, HR 5.68, 95% CI 1.53-21.12). Ezrin protein expression is a promising biomarker in estimating the outcome of stage II colorectal cancer patients. When combined with microsatellite status its ability in predicting disease outcome is further improved.
  • NBCS Collaborators; Escala-Garcia, Maria; Guo, Qi; Doerk, Thilo; Blomqvist, Carl; Khan, Sofia; Kiiski, Johanna I.; Nevanlinna, Heli (2019)
    BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using similar to 10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP
  • Jääskeläinen, Anniina; Roininen, Nelli; Karihtala, Peeter; Jukkola, Arja (2020)
    While breast cancer prognoses are generally good, different molecular subtypes are known to have varying outcomes. Previous studies using breast cancer registries have suggested that high parity may be an adverse prognostic factor in luminal breast cancer, but breast cancer subtype definitions have varied and there have been few prospective studies. We therefore collected prospective data from patients diagnosed with early breast cancer at a single institution and followed them for a median of 8.5 years. All patients (N= 594) were treated according to Finnish national guidelines using modern treatment modalities in a Finnish university hospital. Clinicopathological surrogates of the intrinsic breast cancer subtypes were updated to match European Society for Medical Oncology 2015 Early Breast Cancer Clinical Practice Guidelines. The overall 10-year breast cancer-specific survival (BCSS) was 91.4%, with the longest 10-year BCSS observed in luminal A-like cancers (97.9%) and the worst in luminal B-like (HER2 positive) cancers (80.6%). Parity of >= 5 deliveries was also associated with poor BCSS (univariateP= 0.0020). However, when the subtypes were assessed separately in a multivariate analysis that included tumor size and nodal status, high parity remained significant only in luminal B-like (HER2 negative) cancers (HR = 2.63; 95% confidence interval = 1.04-6.62;P= 0.040). Our results suggest excellent overall 10-year BCSS but indicate that high parity is an adverse prognostic factor in luminal B-like (HER2 negative) breast cancers.
  • Kasurinen, Aaro; Gramolelli, Silvia; Hagström, Jaana; Laitinen, Alli; Kokkola, Arto; Miki, Yuichiro; Lehti, Kaisa; Yashiro, Masakazu; Ojala, Päivi M.; Böckelman, Camilla; Haglund, Caj (2019)
    Matrix metalloproteinase 14 (MMP14), a membrane-associated matrix metalloproteinase, has been shown to influence the invasion and metastasis of several solid tumors. Prospero homeobox protein 1 (PROX1), involved in the development and cell fate determination, is also expressed in malignant diseases functioning either as a tumor-suppressing or oncogenic factor. In certain cancers PROX1 appears to transcriptionally suppress MMP14 expression. This study, therefore, aimed to explore the association between MMP14 and PROX1 and understand their potential as prognostic biomarkers in gastric cancer. The cohort consisted of 313 individuals operated for gastric adenocarcinoma between 2000 and 2009 in the Department of Surgery, Helsinki University Hospital. MMP14 and PROX1 expressions were studied using immunohistochemistry in the patient sample and using immunoblotting and immunofluorescence in gastric cancer cell lines. We generated survival curves using the Kaplan-Meier method, determining significance via the log-rank test. A high MMP14 expression associated with being >= 67 years (P = .041), while a positive nuclear PROX1 expression associated with tumors of a diffuse histological type (P = .041) and a high cytoplasmic PROX1 expression (P <.001). Five-year disease-specific survival among patients with a high MMP14 expression was 35.9% (95% confidence interval [CI] 24.9-46.9), compared to 45.3% (95% CI 38.0-52.6) for patients with a low MMP14 (P = .030). Survival was worse specifically among those with a high MMP14 and absent nuclear PROX1 expression (hazard ratio [HR] 1.65; 95% CI 1.09-2.51; P = .019). Thus, this study confirms that a high MMP14 expression predicts a worse survival in gastric cancer, revealing for the first time that survival is particularly worse when PROX1 is low.
  • Tuominen, Heidi; Al-Samadi, Ahmed; Salo, Tuula; Rautava, Jaana (2020)
    Background This study was designed to investigate the invasion of human papillomavirus (HPV) positive human cervical carcinoma cell lines in human leiomyoma-based extracellular matrices in vitro,and to test the suitability of the model for studying the irradiation effects on the cancer cell invasion. Methods HPV positive cervical carcinoma cell lines SiHa and CaSki, and HPV negative squamous cell carcinoma cell line HSC-3 were used. CaSki cells contain around 600 copies of HPV 16 virus in the genome, whereas SiHa have only 1-2 copies per cell. Cells were analyzed using two different human tumor derived extracellular matrix methods (3D myoma disc model, and Myogel Transwell invasion assay). Cultures were irradiated with 4 Gy. Myoma invasion area and the depth of invasion were measured with ImageJ 1.51j8 software. Statistical analyses were performed with SPSS Statistics (IBM SPSS (R) Statistics 25). Results All cells invaded through Myogel coated Transwell membranes and within myoma discs. In myoma discs, a difference in the invasion depth (p = 0.0001) but not in invasion area (p = 0.310) between the HPV positive cell lines was seen, since SiHa (less HPV) invaded slightly better than CaSki (more HPV). HSC-3 cells (HPV negative) invaded deepest (p = 0.048) than either of the HPV positive cell line cells. No difference was detected in the invasion area (p = 0.892) between HPV positive and HPV negative cells. The ionized radiation significantly reduced the invasion depth of HSC-3 (p = 0.008), SiHa (p = 0.0001) and CaSki (p = 0.005). No significant effect on the invasion area was detected in any of the cell lines. However, a significant difference was observed between SiHa and CaSki in the reduction of the invasion depth after radiation (p = 0.013) as the reduction was greater with SiHa than CaSki. Conclusions Both solid and gelatinous human leiomyoma-based extracellular matrix models were suitable platforms to study the invasion of HPV positive cervical carcinoma cells in vitro. SiHa cells with less HPV copy number cells invaded slightly better and were slightly more sensitive to irradiation than CaSki cells with high HPV copy number. However, there was no drastic differences between the invasion properties of these carcinoma cells.