Browsing by Subject "BREAST"

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  • Kaprio, Tuomas; Hagstrom, Jaana; Fermer, Christian; Mustonen, Harri; Bockelman, Camilla; Nilsson, Olle; Haglund, Caj (2014)
  • Gupta, Abhishekh; Gautam, Prson; Wennerberg, Krister; Aittokallio, Tero (2020)
    Accurate quantification of drug effects is crucial for identifying pharmaceutically actionable cancer vulnerabilities. Current cell viability-based measurements often lead to biased response estimates due to varying growth rates and experimental artifacts that explain part of the inconsistency in high-throughput screening results. We developed an improved drug scoring model, normalized drug response (NDR), which makes use of both positive and negative control conditions to account for differences in cell growth rates, and experimental noise to better characterize drug-induced effects. We demonstrate an improved consistency and accuracy of NDR compared to existing metrics in assessing drug responses of cancer cells in various culture models and experimental setups. Notably, NDR reliably captures both toxicity and viability responses, and differentiates a wider spectrum of drug behavior, including lethal, growth-inhibitory and growth-stimulatory modes, based on a single viability readout. The method will therefore substantially reduce the time and resources required in cell-based drug sensitivity screening. Abhishekh Gupta et al. present a normalized drug response (NDR) metric for accurate quantification of drug sensitivity in cell-based high-throughput assays. They show that NDR captures both toxicity and viability responses to improve drug effect classification over existing methods.
  • Anttinen, Mikael; Ettala, Otto; Malaspina, Simona; Jambor, Ivan; Sandell, Minna; Kajander, Sami; Rinta-Kiikka, Irina; Schildt, Jukka; Saukko, Ekaterina; Rautio, Pentti; Timonen, Kirsi L.; Matikainen, Tuomas; Noponen, Tommi; Saunavaara, Jani; Loyttyniemi, Eliisa; Taimen, Pekka; Kemppainen, Jukka; Dean, Peter B.; Sequeiros, Roberto Blanco; Aronen, Hannu J.; Seppanen, Marko; Boström, Peter J. (2021)
    Background: Computed tomography (CT) and bone scintigraphy (BS) are the imaging modalities currently used for distant metastasis staging of prostate cancer (PCa). Objective: To compare standard staging modalities with newer and potentially more accurate imaging modalities. Design, setting, and participants: This prospective, single-centre trial (NCT03537391) enrolled 80 patients with newly diagnosed high-risk PCa (International Society of Urological Pathology grade group >= 3 and/or prostate-specific antigen [PSA] >= 20 and/or cT >= T3; March 2018-June 2019) to undergo primary metastasis staging with two standard and three advanced imaging modalities. Outcome measurements and statistical analysis: The participants underwent the following five imaging examinations within 2 wk of enrolment and without a prespecified sequence: BS, CT, Tc-99m-hydroxymethylene diphosphonate (Tc-99m-HMDP) single-photon emission computed tomography (SPECT)-CT, 1.5 T whole-body magnetic resonance imaging (WBMRI) using diffusion-weighted imaging, and F-18-prostate-specific membrane antigen-1007 (F-18-PSMA-1007) positron emission tomography(PET)-CT. Each modality was reviewed by two independent experts blinded to the results of the prior studies, who classified lesions as benign, equivocal, or malignant. Pessimistic and optimistic analyses were performed to resolve each equivocal diagnosis. The reference standard diagnosis was defined using all available information accrued during at least 12 mo of clinical follow-up. Patients with equivocal reference standard diagnoses underwent MRI and/or CT to search for the development of anatomical correspondence. PSMA PET-avid lesions without histopathological verification were rated to be malignant only if there was a corresponding anatomical finding suspicious for malignancy at the primary or follow-up imaging. Results and limitations: Seventy-nine men underwent all imaging modalities except for one case of interrupted MRI. The median interval per patient between the first and the last imaging study was 8 d (interquartile range [IQR]: 6-9). The mean age was 70 yr (standard deviation: 7) and median PSA 12 ng/mL (IQR:7-23). The median follow-up was 435 d (IQR: 378-557). Metastatic disease was detected in 20 (25%) patients. The imaging modality F-18-PSMA-1007 PET-CT had superior sensitivity and highest inter-reader agreement. The area under the receiver-operating characteristic curve (AUC) values for bone metastasis detection with PSMA PET-CT were 0.90 (95% confidence interval [CI]: 0.85-0.95) and 0.91 (95% CI: 0.87-0.96) for readers 1 and 2, respectively, while the AUC values for BS, CT, SPECT-CT, and WBMRI were 0.71 (95% CI: 0.58-0.84) and 0.8 (95% CI: 0.67-0.92), 0.53 (95% CI: 0.39-0.67) and 0.66 (95% CI: 0.54-0.77), 0.77 (95% CI: 0.65-0.89) and 0.75 (95% CI: 0.62-0.88), and 0.85 (95% CI: 0.74-0.96) and 0.67 (95% CI: 0.54-0.80), respectively, for the other four pairs of readers. The imaging method F-18-PSMA-1007 PET-CT detected metastatic disease in 11/20 patients in whom standard imaging was negative and influenced clinical decision making in 14/79 (18%) patients. In 12/79 cases, false positive bone disease was reported only by PSMA PET-CT. Limitations included a nonrandomised study setting and few histopathologically validated suspicious lesions. Conclusions: Despite the risk of false positive bone lesions, F-18-PSMA-1007 PET-CT outperformed all other imaging methods studied for the detection of primary distant metastasis in high-risk PCa. Patient summary: In this report, we compared the diagnostic performance of conventional and advanced imaging. It was found that F-18-prostate-specific membrane antigen-1007 positron emission tomography/computed tomography (F-18-PSMA-1007 PET-CT) was superior to the other imaging modalities studied for the detection of distant metastasis at the time of initial diagnosis of high-risk prostate cancer. PSMA PET-CT also appears to detect some nonmetastatic bone lesions. (C) 2020 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology.
  • Auvinen, Anssi; Rannikko, Antti; Taari, Kimmo; Kujala, Paula; Mirtti, Tuomas; Kenttämies, Anu; Rinta-Kiikka, Irina; Lehtimäki, Terho; Oksala, Niku; Pettersson, Kim; Tammela, Teuvo L. (2017)
    The current evidence of PSA-based prostate cancer screening shows a reduction in cause-specific mortality, but with substantial overdiagnosis. Recently, new developments in detection of clinically relevant prostate cancer include multiple kallikreins as biomarkers besides PSA, and multiparametric magnetic resonance imaging (mpMRI) for biopsy decision. They offer opportunities for improving the outcomes in screening, particularly reduction in overdiagnosis and higher specificity for potentially lethal cancer. A population-based randomized screening trial will be started, with 67,000 men aged 55-67 years at entry. A quarter of the men will be allocated to the intervention arm, and invited to screening. The control arm will receive no intervention. All men in the screening arm will be offered a serum PSA determination. Those with PSA of 3 ng/ml or higher will have an additional multi-kallikrein panel and those with indications of increased risk of clinically relevant prostate cancer will undergo mpMRI. Men with a malignancy-suspect finding in MRI are referred to targeted biopsies. Screening interval is 6 years for men with baseline PSA <1.5 ng/ml, 4 years with PSA 1.5-3.0 and 2 years if initial PSA > 3. The main outcome of the trial is prostate cancer mortality, with analysis at 10 and 15 years. The statistical power is sufficient for detecting a 28% reduction at 10 years and 22% at 15 years. The proposed study has the potential to provide the evidence to justify screening as a public health policy if mortality benefit can be sustained with substantially reduced overdiagnosis.
  • Sinha, Snehadri; Narjus-Sterba, Matilda; Tuomainen, Katja; Kaur, Sippy; Seppänen-Kaijansinkko, Riitta; Salo, Tuula; Mannerström, Bettina; Al-Samadi, Ahmed (2020)
    Mesenchymal stem cells (MSCs) are commonly isolated from bone marrow and adipose tissue. Depending on the tissue of origin, MSCs have different characteristics and physiological effects. In various cancer studies, MSCs have been found to have either tumor-promoting or tumor-inhibiting action. This study investigated the effect of adipose tissue-MSCs (AT-MSCs) and bone marrow-MSCs (BM-MSCs) on global long interspersed nuclear element-1 (LINE-1) methylation, the expression level of microenvironment remodeling genes and cell proliferation, migration and invasion of oral tongue squamous cell carcinoma (OTSCC). Additionally, we studied the effect of human tongue squamous carcinoma (HSC-3)-conditioned media on LINE-1 methylation and the expression of microenvironment remodeling genes in AT-MSCs and BM-MSCs. Conditioned media from HSC-3 or MSCs did not affect LINE-1 methylation level in either cancer cells or MSCs, respectively. In HSC-3 cells, no effect of MSCs-conditioned media was detected on the expression ofICAM1, ITGA3orMMP1. On the other hand, HSC-3-conditioned media upregulatedICAM1andMMP1expression in both types of MSCs. Co-cultures of AT-MSCs with HSC-3 did not induce proliferation, migration or invasion of the cancer cells. In conclusion, AT-MSCs, unlike BM-MSCs, seem not to participate in oral cancer progression.
  • Kokkonen, Kristiina; Tasmuth, Tiina; Lehto, Juho T.; Kautiainen, Hannu; Elme, Anneli; Jaaskelainen, Anna-Stina; Saarto, Tiina (2019)
    Background/Aim: To observe changes in symptoms and health-related quality of life (HRQoL) over 7 years among cancer patients at different stages of the disease. Patients and Methods: This prospective cross-sectional study at the Helsinki University Hospital Cancer Center, was carried out in 2006 and repeated in 2013. All participants filled in the EORTC-QLQ-C30 questionnaire. Results: Altogether, 581 patients responded (49% in 2006 and 54% in 2013). The disease was local in 51% and advanced in 49% of patients. The HRQoL was significantly lower, except for emotional and cognitive functions, and the symptom burden more severe in advanced cancer. The most prevalent symptoms were fatigue (93% and 85%; moderate/severe 22% and 9%), pain (65% and 47%; moderate/severe 16% and 5%), and insomnia (64% and 60%; moderate/severe 20 and 21%), respectively. No changes in HRQoL or symptoms were found at 7 years. Conclusion: There is a need for early integrated palliative care to improve HRQoL during cancer treatments.
  • Lawrenson, Kate; Li, Qiyan; Kar, Siddhartha; Seo, Ji-Heui; Tyrer, Jonathan; Spindler, Tassja J.; Lee, Janet; Chen, Yibu; Karst, Alison; Drapkin, Ronny; Aben, Katja K. H.; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Anne; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Doerk, Thilo; Du Bois, Andreas; Duerst, Matthias; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.; Australian Ovarian Canc Study Grp (2015)
    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P
  • Siltanen, Sanna; Wahlfors, Tiina; Schindler, Martin; Saramaki, Outi R.; Mpindi, John Patrick; Latonen, Leena; Vessella, Robert L.; Tammela, Teuvo L. J.; Kallioniemi, Olli; Visakorpi, Tapio; Schleutker, Johanna (2011)
  • Idehen, Esther E.; Korhonen, Tellervo; Castaneda, Anu; Juntunen, Teppo; Kangasniemi, Mari; Pietila, Anna-Maija; Koponen, Paivikki (2017)
    Background: Previous studies revealed low participation in cervical cancer screening among immigrants compared with non-immigrants. Only a few studies about factors associated with immigrants' lower participation rates have been conducted in European countries that have universal access for all eligible women. Our study aimed to explore factors associated with cervical screening participation among women of Russian, Somali, and Kurdish origin in Finland. Methods: We used data from the Migrant Health and Well-being Survey, 2010-2012. Structured face-to-face interviews of groups of immigrants aged 25-60 yielded 620 responses concerning screening participation in the previous five years. Statistical analysis employed logistic regression. Results: The age-adjusted participation rates were as follows: among women of Russian origin 73.9% (95% CI 68.1-79.7), for Somalis 34.7% (95% CI 26.4-43.0), and for Kurds 61.3% (95% CI 55.0-67.7). Multiple logistic regressions showed that the most significant factor increasing the likelihood of screening participation among all groups was having had at least one gynecological check-up in the previous five years (Odds ratio [OR] = 6.54-26.2; p <0.001). Other factors were higher education (OR = 2.63; p = 0.014), being employed (OR = 4.31; p = 0.007), and having given birth (OR = 9.34; p= 0.014), among Kurds; and literacy in Finnish/Swedish (OR = 3.63; p = 0.003) among Russians. Conclusions: Our results demonstrate that women who refrain from using reproductive health services, those who are unemployed and less educated, as well as those with poor language proficiency, might need more information on the importance of screening participation. Primary and occupational healthcare services may have a significant role in informing immigrant women about this importance.
  • Karvonen, Hanna; Arjama, Mariliina; Kaleva, Laura; Niininen, Wilhelmiina; Barker, Harlan; Koivisto-Korander, Riitta; Tapper, Johanna; Pakarinen, Päivi; Lassus, Heini; Loukovaara, Mikko; Bützow, Ralf; Kallioniemi, Olli; Murumägi, Astrid; Ungureanu, Daniela (2020)
    Glucocorticoids are routinely used in the clinic as anti-inflammatory and immunosuppressive agents as well as adjuvants during cancer treatment to mitigate the undesirable side effects of chemotherapy. However, recent studies have indicated that glucocorticoids may negatively impact the efficacy of chemotherapy by promoting tumor cell survival, heterogeneity, and metastasis. Here, we show that dexamethasone induces upregulation of ROR1 expression in ovarian cancer (OC), including platinum-resistant OC. Increased ROR1 expression resulted in elevated RhoA, YAP/TAZ, and BMI-1 levels in a panel of OC cell lines as well as primary ovarian cancer patient-derived cells, underlining the translational relevance of our studies. Importantly, dexamethasone induced differentiation of OC patient-derived cells ex vivo according to their molecular subtype and the phenotypic expression of cell differentiation markers. High-throughput drug testing with 528 emerging and clinical oncology compounds of OC cell lines and patient-derived cells revealed that dexamethasone treatment increased the sensitivity to several AKT/PI3K targeted kinase inhibitors, while significantly decreasing the efficacy of chemotherapeutics such as taxanes, as well as anti-apoptotic compounds such as SMAC mimetics. On the other hand, targeting ROR1 expression increased the efficacy of taxane drugs and SMAC mimetics, suggesting new combinatorial targeted treatments for patients with OC.
  • Färkkilä, Anniina; Gulhan, Doga C.; Casado, Julia; Jacobson, Connor A.; Nguyen, Huy; Kochupurakkal, Bose; Maliga, Zoltan; Yapp, Clarence; Chen, Yu-An; Schapiro, Denis; Zhou, Yinghui; Graham, Julie R.; Dezube, Bruce J.; Munster, Pamela; Santagata, Sandro; Garcia, Elizabeth; Rodig, Scott; Lako, Ana; Chowdhury, Dipanjan; Shapiro, Geoffrey; Matulonis, Ursula A.; Park, Peter J.; Hautaniemi, Sampsa; Sorger, Peter K.; Swisher, Elizabeth M.; D'Andrea, Alan D.; Konstantinopoulos, Panagiotis A. (2020)
    Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8+T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8+T-cells and PD-L1+macrophages and PD-L1+tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8+T-cells with PD-L1+macrophages in the first, and exhausted CD8+T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second. A Phase I/II trial previously revealed variable anti-tumor efficacy of the PARP inhibitor niraparib in combination with the PD-1 inhibitor pembrolizumab in platinum-resistant ovarian cancer patients. Here, the authors perform an integrated genomic and immunomics analysis of tumor samples from the same patients and find potential predictive biomarkers of response to such combination therapy.
  • Aakko, Sofia; Straume, Anne Hege; Birkeland, Einar Elvbakken; Chen, Ping; Qiao, Xi; Lonning, Per Eystein; Kallio, Marko J. (2019)
    Taxanes are chemotherapeutic agents used in the treatment of solid tumors, particularly of breast, ovarian, and lung origin. However, patients show divergent therapy responses, and the molecular determinants of taxane sensitivity have remained elusive. Especially the signaling pathways that promote death of the taxane-treated cells are poorly characterized. Here we describe a novel part of a signaling route in which c-Myc enhances paclitaxel sensitivity through upregulation of miR-203b-3p and miR-203a-3p; two clustered antiapoptosis protein BcI-xL controlling microRNAs. In vitro, the miR-203b-3p decreases the expression of BcI-xL by direct targeting of the gene's mRNA 3'UTR. Notably, overexpression of the miR-203b-3p changed the fate of paclitaxel-treated breast and ovarian cancer cells from mitotic slippage to cell death. In breast tumors, high expression of the miR-203b-3p and MYC was associated with better therapy response and patient survival. Interestingly, in the breast tumors, MYC expression correlated negatively with BCL2L1 expression but positively with miR-203b-3p and miR-203a-3p. Finally, silencing of MYC suppressed the transcription of both miRNAs in breast tumor cells. Pending further validation, these results may assist in patient stratification for taxane therapy.
  • Nair, Vidhya A.; Valo, Satu; Peltomäki, Päivi; Bajbouj, Khuloud; Abdel-Rahman, Wael M. (2020)
    There is an ample epidemiological evidence to support the role of environmental contaminants such as bisphenol A (BPA) in breast cancer development but the molecular mechanisms of their action are still not fully understood. Therefore, we sought to analyze the effects of three common contaminants (BPA; 4-tert-octylphenol, OP; hexabromocyclododecane, HBCD) on mammary epithelial cell (HME1) and MCF7 breast cancer cell line. We also supplied some data on methoxychlor, MXC; 4-nonylphenol, NP; and 2-amino-1-methyl-6-phenylimidazo [4-b] pyridine, PhIP. We focused on testing the prolonged (two months) exposure to low nano-molar concentrations (0.0015-0.0048 nM) presumed to be oncogenic and found that they induced DNA damage (evidenced by upregulation of pH2A.X, pCHK1, pCHK2, p-P53) and disrupted the cell cycle. Some agents induced epigenetic (methylation) changes of tumor suppressor genes TIMP3, CHFR, ESR1, IGSF4, CDH13, and GSTP1. Obviously, the accumulation of these molecular alterations is an essential base for cancer development. Consistent with this, we observed that these agents increased cellular invasiveness through collagen. Cellular abilities to form colonies in soft agar were increased for MCF7. Toxic agents induced phosphorylation of protein kinase such as EGFR, CREB, STAT6, c-Jun, STAT3, HSP6, HSP27, AMPK alpha 1, FAK, p53, GSK-3 alpha/beta, and P70S6 in HME1. Most of these proteins are involved in potential oncogenic pathways. Overall, these data clarify the molecular alterations that can be induced by some common environmental contaminants in mammary epithelial cells which could be a foundation to understand environmental carcinogenesis.
  • Sipeky, Csilla; Talala, Kirsi M.; Tammela, Teuvo L. J.; Taari, Kimmo; Auvinen, Anssi; Schleutker, Johanna (2020)
    Hereditary factors have a strong influence on prostate cancer (PC) risk and poorer outcomes, thus stratification by genetic factors addresses a critical need for targeted PC screening and risk-adapted follow-up. In this Finnish population-based retrospective study 2283 clinically diagnosed and 455 screen-detected patients from the Finnish Randomised Study of Screening for Prostate Cancer (FinRSPC), 2400 healthy individuals have been involved. Individual genetic risk through establishment of a polygenic risk score based on 55 PC risk SNPs identified through the Finnish subset of the Collaborative Oncological Gene-Environment Study was assessed. Men with PC had significantly higher median polygenic risk score compared to the controls (6.59 vs. 3.83, P4 ng/mL in polygenic risk score quartile four compared to quartile one (18.7% vs 8.3%, P
  • Kinnunen, Pete T. T.; Murtola, Teemu J.; Talala, Kirsi; Taari, Kimmo; Tammela, Teuvo L. J.; Auvinen, Anssi (2017)
    Background: Venous thromboembolic events (VTE) are common in cancer patients and associated with higher mortality. In vivo thrombosis and anticoagulation might be involved in tumor growth and progression. We studied the association of warfarin and other anticoagulant use as antithrombotic medication and prostate cancer (PCa) death in men with the disease. Methods: The study included 6,537 men diagnosed with PCa during 1995-2009. Information on anticoagulant use was obtained from a national reimbursement registry. Cox regression with adjustment for age, PCa risk group, primary therapy and use of other medication was performed to compare risk of PCa death between warfarin users with 1) men using other types of anticoagulants and 2) non-users of anticoagulants. Medication use was analyzed as a time-dependent variable to minimize immortal time bias. Results: In total, 728 men died from PCa during a median follow-up of 9 years. Compared to anticoagulant nonusers, post-diagnostic use of warfarin was associated with an increased risk of PCa death (overall HR 1.47, 95% CI 1. 13-1.93). However, this was limited to low-dose, low-intensity use. Otherwise, the risk was similar to anticoagulant non-users. Additionally, we found no risk difference between warfarin and other types of anticoagulants. Pre-diagnostic use of warfarin was not associated with the risk of PCa death. Conclusions: We found no reduction in risk of PCa death associated with warfarin use. Conversely, the risk was increased in short-term use, which is probably explained by a higher risk of thrombotic events prompting warfarin use in patients with terminal PCa.
  • Kask, Gilber; Nieminen, Jyrki; Parry, Michael C; van Iterson, Vincent; Pakarinen, Toni-Karri; Ratasvuori, Maire; Laitinen, MK (2019)
    Introduction: Skeletal metastases can weaken the bone, necessitating surgery, and surgical treatment options vary. The aim of this study was to investigate the revision rate of reconstructions in surgically treated diaphyseal skeletal metastases. Materials and methods: Between 2000 and 2018 at Helsinki and Tampere university hospitals in Finland, a total of 164 cases with diaphyseal skeletal metastases were identified from a prospectively maintained database. Tumor location was humerus, femur, and tibia in 106 (65%), 53 (32%), and 5 (3.0%) cases, respectively. A total of 82 (50%) cases were treated with intramedullary nailing (IMN), 73 (45%) with IMN and cementation, and 9 (5%) with another technique. Results: In the upper extremity, implant survival (IS) was 96.4% at 1, 2, and 5 years; in the lower extremity, it was 83.8%, 69.1%, and 57.6% at 1, 2, and 5 years, respectively. Lower extremity IS for impending lesions was 100% at 1, 2, and 5 years, and in cases operated for true pathologic fracture, it was 71.6%, 42.9%, and 21.5% at 1, 2, and 5 years, respectively. In IMN cases without cement, the complication rate was 16% (13/82) when compared to 6% (4/73) in IMN cases with cementation. Discussion: We would advocate for early intervention in patients with metastatic bone disease affecting the femur rather that watchful waiting with the risk for fracture and the need for urgent intervention. However, this choice must be balanced against the underlying risk of surgical intervention in a potentially fragile population with often limited prognoses.
  • Aakula, Anna; Kohonen, Pekka; Leivonen, Suvi-Katri; Makela, Rami; Hintsanen, Petteri; Mpindi, John Patrick; Martens-Uzunova, Elena; Aittokallio, Tero; Jenster, Guido; Perala, Merja; Kallioniemi, Olli; Ostling, Paivi (2016)
    Background: Systematic approaches to functionally identify key players in microRNA (miRNA)-target networks regulating prostate cancer (PCa) proliferation are still missing. Objective: To comprehensively map miRNA regulation of genes relevant for PCa proliferation through phenotypic screening and tumor expression data. Design, setting, and participants: Gain-of-function screening with 1129 miRNA molecules was performed in five PCa cell lines, measuring proliferation, viability, and apoptosis. These results were integrated with changes in miRNA expression from two cohorts of human PCa (188 tumors in total). For resulting miRNAs, the predicted targets were collected and analyzed for patterns with gene set enrichment analysis, and for their association with biochemical recurrence free survival. Outcome measurements and statistical analysis: Rank product statistical analysis was used to evaluate miRNA effects in phenotypic screening and for expression differences in the prostate tumor cohorts. Expression data were analyzed using the significance analysis of microarrays (SAM) method and the patient material was subjected to Kaplan-Meier statistics. Results and limitations: Functional screening identified 25 miRNAs increasing and 48 miRNAs decreasing cell viability. Data integration resulted in 14 miRNAs, with aberrant expression and effect on proliferation. These miRNAs are predicted to regulate >3700 genes, of which 28 were found up-regulated and 127 down-regulated in PCa compared with benign tissue. Seven genes, FLNC, MSRB3, PARVA, PCDH7, PRNP, RAB34, and SORBS1, showed an inverse association to their predicted miRNA, and were identified to significantly correlate with biochemical recurrence free survival in PCa patients. Conclusions: A systematic in vitro screening approach combined with in vivo expression and gene set enrichment analysis provide unbiased means for revealing novel miRNA-target links, possibly driving the oncogenic processes in PCa. Patient summary: This study identified novel regulatory molecules, which impact on PCa proliferation and are aberrantly expressed in clinical tumors. Thus, our study reveals regulatory nodes with potential for therapy. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
  • PCAWG Evolution Heterogeneity Work; PCAWG Consortium; Gerstung, Moritz; Jolly, Clemency; Leshchiner, Ignaty; Mustonen, Ville; Cao, Shaolong (2020)
    Cancer develops through a process of somatic evolution(1,2). Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes(3). Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)(4), we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
  • Haltia, Olli; Färkkilä, Niilo; Roine, Risto Paavo; Sintonen, Harri; Taari, Kimmo; Hänninen, Juha; Lehto, Juho Tuomas; Saarto, Tiina (2018)
    Background: Palliative care needs are increasing as more people are dying from incurable diseases. Healthcare costs have been reported to be highest during the last year of life, but studies on the actual costs of palliative care are scarce. Aim: To explore the resource use and costs of palliative care among end-stage breast, colorectal and prostate cancer patients after termination of life-prolonging oncological treatments, that is, during the palliative care period. Design: A real-life longitudinal register- and questionnaire-based study of cancer patients' resource use and costs. Participants: In total, 70 patients in palliative care with no ongoing oncological treatments were recruited from the Helsinki University Hospital or from the local hospice. Healthcare costs, productivity costs and informal care costs were included. Results: The mean duration of the palliative care period was 179days. The healthcare cost accounted for 55%, informal care for 27% and productivity costs for 18% of the total costs. The last 2weeks of life contributed to 37% of the healthcare cost. The costs of the palliative care period were higher in patients living alone, which was mostly caused by inpatient care (p=0.018). Conclusion: The 45% share of indirect costs is substantial in end-of-life care. The healthcare costs increase towards death, which is especially true of patients living alone. This highlights the significant role of caregivers. More attention should be paid to home care and caregiver support to reduce inpatient care needs and control the costs of end-of-life care.