Browsing by Subject "CHEMOTHERAPY"

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  • Kasanen, Henna; Hernberg, Micaela; Mäkelä, Siru; Brück, Oscar; Juteau, Susanna; Kohtamäki, Laura; Ilander, Mette; Mustjoki, Satu; Kreutzman, Anna (2020)
    Anti-PD1 treatment has improved the survival of metastatic melanoma patients, yet it is unknown which patients benefit from the treatment. In this exploratory study, we aimed to understand the effects of anti-PD1 therapy on the patients' immune system and discover the characteristics that would result in successful treatment. We collected peripheral blood (PB) samples from 17 immuno-oncology-naive metastatic melanoma patients before and after 1 and 3 months of anti-PD1 therapy. In addition, matching tumor biopsies at the time of diagnosis were collected for tissue microarray. The complete blood counts, PB immunophenotype, serum cytokine profiles, and tumor-infiltrating lymphocytes were analyzed and correlated with the clinical data. Patients were categorized based on their disease control into responders (complete response, partial response, stable disease > 6 months, N = 11) and non-responders (progressive disease, stable disease
  • Sobral-Leite, Marcelo; Wesseling, Jelle; Smit, Vincent T. H. B. M.; Nevanlinna, Heli; van Miltenburg, Martine H.; Sanders, Joyce; Hofland, Ingrid; Blows, Fiona M.; Coulson, Penny; Patrycja, Gazinska; Schellens, Jan H. M.; Fagerholm, Rainer; Heikkila, Paivi; Aittomaki, Kristiina; Blomqvist, Carl; Provenzano, Elena; Ali, Hamid Raza; Figueroa, Jonine; Sherman, Mark; Lissowska, Jolanta; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Phillips, Kelly-Anne; Couch, Fergus J.; Olson, Janet E.; Vachon, Celine; Visscher, Daniel; Brenner, Hermann; Butterbach, Katja; Arndt, Volker; Holleczek, Bernd; Hooning, Maartje J.; Hollestelle, Antoinette; Martens, John W. M.; van Deurzen, Carolien H. M.; van de Water, Bob; Broeks, Annegien; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Easton, Douglas F.; Pharoah, Paul D. P.; Garcia-Closas, Montserrat; de Graauw, Marjo; Schmidt, Marjanka K.; kConFab AOCS Investigators (2015)
    Background: Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods: Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results: The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05-1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91-1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17-2.45). Conclusions: ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
  • Vahermo, Mikko; Krogerus, Sara; Nasereddin, Abdelmajeed; Kaiser, Marcel; Brun, Reto; Jaffe, Charles L.; Yli-Kauhaluoma, Jari; Moreira, Vânia M. (2016)
    Derivatives of dehydroabietic acid bearing different amino acids scaffolds have potent antiprotozoal activity against Leishmania donovani and Trypanosoma cruzi, with good to high selectivity, and can therefore be regarded as good models for further development into new drugs to fight leishmaniasis and Chagas disease. Several of the tested compounds were able to kill parasites residing inside cells, with IC50 values ranging from 2.3 to 9 mu M (L. donovani) and 1.4 to 5.8 mu M (T. cruzi), reflecting their ability to fight these infections at the relevant stage responsible for disease. One of the compounds, bearing a 3-pyridyl-Dalanine side chain, was 1.5-fold more potent against T. cruzi amastigotes residing in L6 cells than the reference compound benznidazole.
  • Garofalo, M.; Saari, H.; Somersalo, P.; Crescenti, D.; Kuryk, L.; Aksela, L.; Capasso, C.; Madetoja, M.; Koskinen, K.; Oksanen, T.; Mäkitie, A.; Jalasvuori, M.; Cerullo, V.; Ciana, P.; Yliperttula, M. (2018)
    Standard of care for cancer is commonly a combination of surgery with radiotherapy or chemoradiotherapy. However, in some advanced cancer patients this approach might still remaininefficient and may cause many side effects, including severe complications and even death. Oncolytic viruses exhibit different anti-cancer mechanisms compared with conventional therapies, allowing the possibility for improved effect in cancer therapy. Chemotherapeutics combined with oncolytic viruses exhibit stronger cytotoxic responses and oncolysis. Here, we have investigated the systemic delivery of the oncolytic adenovirus and paclitaxel encapsulated in extracellular vesicles (EV) formulation that, in vitro, significantly increased the transduction ratio and the infectious titer when compared with the virus and paclitaxel alone. We demonstrated that the obtained EV formulation reduced the in vivo tumor growth in animal xenograft model of human lung cancer. Indeed, we found that combined treatment of oncolytic adenovirus and paclitaxel encapsulated in EV has enhanced anticancer effects both in vitro and in vivo in lung cancer models. Transcriptomic comparison carried out on the explanted xenografts from the different treatment groups revealed that only 5.3% of the differentially expressed genes were overlapping indicating that a de novo genetic program is triggered by the presence of the encapsulated paclitaxel: this novel genetic program might be responsible of the observed enhanced antitumor effect. Our work provides a promising approach combining anticancer drugs and viral therapies by intravenous EV delivery as a strategy for the lung cancer treatment.
  • Kuryk, Lukasz; Moller, Anne-Sophie W.; Garofalo, Mariangela; Cerullo, Vincenzo; Pesonen, Sari; Alemany, Ramon; Jaderberg, Magnus (2018)
    Oncolytic adenoviral immunotherapy activates the innate immune system with subsequent induction of adaptive tumor-specific immune responses to fight cancer. Hence, oncolytic viruses do not only eradicate cancer cells by direct lysis, but also generate antitumor immune response, allowing for long-lasting cancer control and tumor reduction. Their therapeutic effect can be further enhanced by arming the oncolytic adenovirus with costimulatory transgenes and/or coadministration with other antitumor therapies. ONCOS-102 has already been found to be well tolerated and efficacious against some types of treatment-refractory tumors, including mesothelin-positive ovarian cancer (NCT01598129). It induced local and systemic CD8+ T-cell immunity and upregulated programmed death ligand 1. These results strongly advocate the use of ONCOS-102 in combination with other therapeutic strategies in advanced and refractory tumors, especially those expressing the mesothelin antigen. The in vivo work presented herein describes the ability of the oncolytic adenovirus ONCOS-102 to induce mesothelin-specific T-cells after the administration of the virus in bagg albino (BALB/c) mice with mesothelin-positive tumors. We also demonstrate the effectiveness of the interferon-gamma the enzyme-linked immunospot (ELISPOT) assay to detect the induction of T-cells recognizing mesothelin, hexon, and E1A antigens in ONCOS-102treated mesothelioma-bearing BALB/c mice. Thus, the ELISPOT assay could be useful to monitor the progress of therapy with ONCOS-102.
  • Andre, T.; Vernerey, D.; Im, S. A.; Bodoky, G.; Buzzoni, R.; Reingold, S.; Rivera, F.; McKendrick, J.; Scheithauer, W.; Ravit, G.; Fountzilas, G.; Yong, W. P.; Isaacs, R.; Österlund, P.; Liang, J. T.; Creemers, G. J.; Rakez, M.; Van Cutsem, E.; Cunningham, D.; Tabernero, J.; de Gramont, A. (2020)
    Background: The bevacizumab-Avastin (R) adjuVANT (AVANT) study did not meet its primary end point of improving disease-free survival (DFS) with the addition of bevacizumab to oxaliplatin-based chemotherapy in stage III colon cancer (CC). We report here the long-term survival results (S-AVANT). Patients and methods: Patients with curatively resected stage III CC were randomly assigned to FOLFOX4, FOLFOX4-bevacizumab, or XELOX-bevacizumab. Results: A total of 2867 patients were randomized: FOLFOX4: n = 955, FOLFOX4-bevacizumab: n = 960, XELOX-bevacizumab: n = 952. With a median of 6.73 years follow-up (interquartile range 5.51-10.54), 672 patients died, of whom 198 (20.7%), 250 (26.0%), and 224 (23.5%) were in the FOLFOX4, FOLFOX4-bevacizumab, and XELOX-bevacizumab arms, respectively. The 10-year overall survival (OS) rates were 74.6%, 67.2%, and 69.9%, (P = 0.003) and 5-year disease-free survival (DFS) rates were 73.2%, 68.5%, and 71.0% (P = 0.174), respectively. OS and DFS hazard ratios were 1.29 [95% confidence interval (CI) 1.07-1.55; P = 0.008] and 1.16 (95% CI 0.99-1.37; P = 0.063) for FOLFOX4-bevacizumab versus FOLFOX4 and 1.15 (95% CI 0.95-1.39; P = 0.147) and 1.1 (95% CI 0.93 -1.29; P = 0.269) for XELOX-bevacizumab versus FOLFOX4, respectively. CC-related deaths (n = 542) occurred in 157 (79.3%) patients receiving FOLFOX4, 205 (82.0%) receiving FOLFOX4-bevacizumab, and 180 (80.4%) receiving XELOX-bevacizumab (P = 0.764), while non-CC-related deaths occurred in 41 (20.7%), 45 (18.0%), and 44 (19.6%) patients, respectively. Cardiovascular-related and sudden deaths during treatment or follow-up were reported in 13 (6.6%), 17 (6.8%), and 14 (6.3%) patients, in the FOLFOX4, FOLFOX4-bevacizuamb, and XELOX-bevacizumab arms, respectively (P = 0.789). Treatment arm, sex, age, histological differentiation, performance status, T/N stages, and localization of primary tumor were independent prognostic factors of OS in stage III. Conclusions: S-AVANT confirms the initial AVANT report. No benefit of the bevacizumab addition to FOLFOX4 adjuvant therapy in patients with stage III CC was observed in terms of DFS with a negative effect in OS, without increase in non-CC related deaths.
  • Koski, Anniina; Bramante, Simona; Kipar, Anja; Oksanen, Minna; Juhila, Juuso; Vassilev, Lotta; Joensuu, Timo; Kanerva, Anna; Hemminki, Akseli (2015)
    In clinical trials with oncolytic adenoviruses, there has been no mortality associated with treatment vectors. Likewise, in the Advanced Therapy Access Program (ATAP), where 290 patients were treated with 10 different viruses, no vector-related mortality was observed. However, as the patient population who received adenovirus treatments in ATAP represented heavily pretreated patients, often with very advanced disease, some patients died relatively soon after receiving their virus treatment mandating autopsy to investigate cause of death. Eleven such autopsies were performed and confirmed disease progression as the cause of death in each case. The regulatory requirement for investigating the safety of advanced therapy medical products presented a unique opportunity to study tissue samples collected as a routine part of the autopsies. Oncolytic adenoviral DNA was recovered in a wide range of tissues, including injected and noninjected tumors and various normal tissues, demonstrating the ability of the vector to disseminate through the vascular route. Furthermore, we recovered and cultured viable virus from samples of noninjected brain metastases of an intravenously treated patient, confirming that oncolytic adenovirus can reach tumors through the intravascular route. Data presented here give mechanistic insight into mode of action and biodistribution of oncolytic adenoviruses in cancer patients.
  • Wirtz, Ralph M.; Sihto, Harri; Isola, Jorma; Heikkila, Paivi; Kellokumpu-Lehtinen, Pirkko-Liisa; Auvinen, Paivi; Turpeenniemi-Hujanen, Taina; Jyrkkio, Sirkku; Lakis, Sotiris; Schlombs, Kornelia; Laible, Mark; Weber, Stefan; Eidt, Sebastian; Sahin, Ugur; Joensuu, Heikki (2016)
    The biological subtype of breast cancer influences the selection of systemic therapy. Distinction between luminal A and B cancers depends on consistent assessment of Ki-67, but substantial intra-observer and inter-observer variability exists when immunohistochemistry (IHC) is used. We compared RT-qPCR with IHC in the assessment of Ki-67 and other standard factors used in breast cancer subtyping. RNA was extracted from archival breast tumour tissue of 769 women randomly assigned to the FinHer trial. Cancer ESR1, PGR, ERBB2 and MKI67 mRNA content was quantitated with an RT-qPCR assay. Local pathologists assessed ER, PgR and Ki-67 expression using IHC. HER2 amplification was identified with chromogenic in situ hybridization (CISH) centrally. The results were correlated with distant disease-free survival (DDFS) and overall survival (OS). qPCR-based and IHC-based assessments of ER and PgR showed good concordance. Both low tumour MKI67 mRNA (RT-qPCR) and Ki-67 protein (IHC) levels were prognostic for favourable DDFS [hazard ratio (HR) 0.42, 95 % CI 0.25-0.71, P = 0.001; and HR 0.56, 0.37-0.84, P = 0.005, respectively] and OS. In multivariable analyses, cancer MKI67 mRNA content had independent influence on DDFS (adjusted HR 0.51, 95 % CI 0.29-0.89, P = 0.019) while Ki-67 protein expression had not any influence (P = 0.266) whereas both assessments influenced independently OS. Luminal B patients treated with docetaxel-FEC had more favourable DDFS and OS than those treated with vinorelbine-FEC when the subtype was defined by RT-qPCR (for DDFS, HR 0.52, 95 % CI 0.29-0.94, P = 0.031), but not when defined using IHC. Breast cancer subtypes approximated with RT-qPCR and IHC show good concordance, but cancer MKI67 mRNA content correlated slightly better with DDFS than Ki-67 expression. The findings based on MKI67 mRNA content suggest that patients with luminal B cancer benefit more from docetaxel-FEC than from vinorelbine-FEC.
  • Tharmalingam, Melissa D.; Matilionyte, Gabriele; Wallace, William H. B.; Stukenborg, Jan-Bernd; Jahnukainen, Kirsi; Oliver, Elizabeth; Goriely, Anne; Lane, Sheila; Guo, Jingtao; Cairns, Bradley; Jorgensen, Anne; Allen, Caroline M.; Lopes, Federica; Anderson, Richard A.; Spears, Norah; Mitchell, Rod T. (2020)
    Background Clinical studies indicate chemotherapy agents used in childhood cancer treatment regimens may impact future fertility. However, effects of individual agents on prepubertal human testis, necessary to identify later risk, have not been determined. The study aimed to investigate the impact of cisplatin, commonly used in childhood cancer, on immature (foetal and prepubertal) human testicular tissues. Comparison was made with carboplatin, which is used as an alternative to cisplatin in order to reduce toxicity in healthy tissues. Methods We developed an organotypic culture system combined with xenografting to determine the effect of clinically-relevant exposure to platinum-based chemotherapeutics on human testis. Human foetal and prepubertal testicular tissues were cultured and exposed to cisplatin, carboplatin or vehicle for 24 h, followed by 24-240 h in culture or long-term xenografting. Survival, proliferation and apoptosis of prepubertal germ stem cell populations (gonocytes and spermatogonia), critical for sperm production in adulthood, were quantified. Results Cisplatin exposure resulted in a significant reduction in the total number of germ cells (- 44%, p <0.0001) in human foetal testis, which involved an initial loss of gonocytes followed by a significant reduction in spermatogonia. This coincided with a reduction (- 70%, p <0.05) in germ cell proliferation. Cisplatin exposure resulted in similar effects on total germ cell number (including spermatogonial stem cells) in prepubertal human testicular tissues, demonstrating direct relevance to childhood cancer patients. Xenografting of cisplatin-exposed human foetal testicular tissue demonstrated that germ cell loss (- 42%, p <0.01) persisted at 12 weeks. Comparison between exposures to human-relevant concentrations of cisplatin and carboplatin revealed a very similar degree of germ cell loss at 240 h post-exposure. Conclusions This is the first demonstration of direct effects of chemotherapy exposure on germ cell populations in human foetal and prepubertal testis, demonstrating platinum-induced loss of all germ cell populations, and similar effects of cisplatin or carboplatin. Furthermore, these experimental approaches can be used to determine the effects of established and novel cancer therapies on the developing testis that will inform fertility counselling and development of strategies to preserve fertility in children with cancer.
  • Helanterä, I.; Janes, R.; Anttila, V-J (2018)
    Background: Influenza A(H1N1) causes serious complications in immunocompromised patients. The efficacy of seasonal vaccination in these patients has been questioned. Aim: To describe two outbreaks of influenza A(H1N1) in immunocompromised patients. Methods: Two outbreaks of influenza A(H1N1) occurred in our institution: on the kidney transplant ward in 2014 including patients early after kidney or simultaneous pancreas-kidney transplantation, and on the oncology ward in 2016 including patients receiving chemotherapy for malignant tumours. Factors leading to these outbreaks and the clinical efficacy of seasonal influenza vaccination were analysed. Findings: Altogether 86 patients were exposed to influenza A(H1N1) during the outbreaks, among whom the seasonal influenza vaccination status was unknown in 10. Only three out of 38 vaccinated patients were infected with influenza A(H1N1), compared with 20 out of 38 unvaccinated patients (P = 0.02). The death of one out of 38 vaccinated patients was associated with influenza, compared with seven out of 38 unvaccinated patients (P = 0.06). Shared factors behind the two outbreaks included outdated facilities not designed for the treatment of immunosuppressed patients. Vaccination coverage among patients was low, between 40% and 70% despite vaccination being offered to all patients free of charge. Vaccination coverage of healthcare workers on the transplant ward was low (46%), but, despite high coverage on the oncology ward (92%), the outbreak occurred. Conclusion: Seasonal influenza vaccination was clinically effective with both a reduced risk of influenza infection and a trend towards reduced mortality in these immunocompromised patients. Several possible causes were identified behind these two outbreaks, requiring continuous awareness in healthcare professionals to prevent further outbreaks. (C) 2017 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
  • Varmavuo, Ville; Silvennoinen, Raija; Anttila, Pekka; Saily, Marjaana; Sankelo, Marja; Putkonen, Mervi; Ahonen, Jouni; Mahlamaki, Eija; Mantymaa, Pentti; Savolainen, Eeva-Riitta; Remes, Kari; Jantunen, Esa (2016)
    Upfront autologous stem cell transplantation (ASCT) is the standard therapy for younger multiple myeloma (MM) patients. MM patients usually undergo stem cell mobilization with cyclophosphamide (CY) followed by granulocyte colony-stimulating factor (G-CSF), or with G-CSF alone. A limited number of randomized studies are available comparing costs of different mobilization strategies. Eighty transplant-eligible patients aged up to 70 years with untreated MM were included in this prospective study. The patients were treated with RVD induction for three 21-day cycles and randomized 1: 1 at inclusion into one of the two mobilization arms CY 2 g/m(2) + G-CSF [arm A] vs. G-CSF alone [arm B]. Plerixafor was given according to a specific algorithm if needed. Sixty-nine patients who received mobilization followed by blood graft collection were included in the cost analysis. The median total costs of the mobilization phase were significantly higher in arm A than in arm B (3855 (sic) vs. 772 (sic), p
  • Murtojärvi, Mika; Halkola, Anni S.; Airola, Antti; Laajala, Teemu D.; Mirtti, Tuomas; Aittokallio, Tero; Pahikkala, Tapio (2020)
    Introduction Predictive survival modeling offers systematic tools for clinical decision-making and individualized tailoring of treatment strategies to improve patient outcomes while reducing overall healthcare costs. In 2015, a number of machine learning and statistical models were benchmarked in the DREAM 9.5 Prostate Cancer Challenge, based on open clinical trial data for metastatic castration resistant prostate cancer (mCRPC). However, applying these models into clinical practice poses a practical challenge due to the inclusion of a large number of model variables, some of which are not routinely monitored or are expensive to measure. Objectives To develop cost-specified variable selection algorithms for constructing cost-effective prognostic models of overall survival that still preserve sufficient model performance for clinical decision making. Methods Penalized Cox regression models were used for the survival prediction. For the variable selection, we implemented two algorithms: (i) LASSO regularization approach; and (ii) a greedy cost-specified variable selection algorithm. The models were compared in three cohorts of mCRPC patients from randomized clinical trials (RCT), as well as in a real-world cohort (RWC) of advanced prostate cancer patients treated at the Turku University Hospital. Hospital laboratory expenses were utilized as a reference for computing the costs of introducing new variables into the models. Results Compared to measuring the full set of clinical variables, economic costs could be reduced by half without a significant loss of model performance. The greedy algorithm outperformed the LASSO-based variable selection with the lowest tested budgets. The overall top performance was higher with the LASSO algorithm. Conclusion The cost-specified variable selection offers significant budget optimization capability for the real-world survival prediction without compromising the predictive power of the model.
  • Poganitsch-Korhonen, M.; Masliukaite, I.; Nurmio, M.; Lahteenmaki, P.; van Wely, M.; van Pelt, A. M. M.; Jahnukainen, K.; Stukenborg, J-B (2017)
  • Narvi, Elli; Vaparanta, Katri; Karrila, Anna; Chakroborty, Deepankar; Knuutila, Sakari; Pulliainen, Arto; Sundvall, Maria; Elenius, Klaus (2018)
    Therapeutic protocols including EGFR antibodies in the context of oxaliplatin-based regimens have variable clinical effect in colorectal cancer. Here, we tested the effect of the EGFR antibody cetuximab in different sequential combinations with oxaliplatin on the growth of colorectal cancer cells in vitro and in vivo. Cetuximab reduced the efficacy of oxaliplatin when administered before oxaliplatin but provided additive effect when administered after oxaliplatin regardless of the KRAS or BRAF mutation status of the cells. Systemic gene expression and protein phosphorylation screens revealed alternatively activated pathways regulating apoptosis, cell cycle and DNA damage response. Functional assays indicated that cetuximab-induced arrest of the cells into the G1 phase of the cell cycle was associated with reduced responsiveness of the cells to subsequent treatment with oxaliplatin. In contrast, oxaliplatin-enhanced responsiveness to subsequent treatment with cetuximab was associated with increased apoptosis, inhibition of STAT3 activity and increased EGFR down-regulation. This preclinical study indicates that optimizing the sequence of administration may enhance the antitumor effect of combination therapy with EGFR antibodies and oxaliplatin.
  • Deng, Shan; Yang, Xiaojun; Lassus, Heini; Liang, Shun; Kaur, Sippy; Ye, Qunrui; Li, Chunsheng; Wang, Li-Ping; Roby, Katherine F.; Orsulic, Sandra; Connolly, Denise C.; Zhang, Youcheng; Montone, Kathleen; Butzow, Ralf; Coukos, George; Zhang, Lin (2010)
  • Soini, Tea; Pihlajoki, Marjut; Kyronlahti, Antti; Andersson, Leif C.; Wilson, David B.; Heikinheimo, Markku (2017)
    Hepatoblastoma, the most common type of pediatric liver cancer, is treated with a combination of surgery and chemotherapy. An essential drug in the treatment of hepatoblastoma is doxorubicin, which in high doses is cardiotoxic. This adverse effect is due to downregulation of cardiac expression of transcription factor GATA4, leading in turn to diminished levels of anti-apoptotic BCL2 (B-cell lymphoma 2) protein family members. GATA4 is also expressed in early fetal liver, but absent from normal postnatal hepatocytes. However, GATA4 is highly expressed in hepatoblastoma tissue. In this study, we assessed the role of GATA4 in doxorubicin-induced apoptosis of hepatoblastoma cells. Herein, we demonstrate that doxorubicin decreases GATA4 expression and alters the expression pattern of BCL2 family members, most profoundly that of BCL2 and BAK, in the HUH6 hepatoblastoma cell line. Silencing of GATA4 by siRNA prior to doxorubicin treatment sensitizes HUH6 cells to the apoptotic effect of this drug by further shifting the balance of BCL2 family members to the pro-apoptotic direction. Specifically, expression levels of anti-apoptotic BCL2 were decreased and pro-apoptotic BID were increased after GATA4 silencing. On the whole, our results indicate that since high endogenous levels of transcription factor GATA4 likely protect hepatoblastoma cells from doxorubicin-induced apoptosis, these cells can be rendered more sensitive to the drug by downregulation of GATA4.
  • Kuosmanen, Teemu; Cairns, Johannes; Noble, Robert; Beerenwinkel, Niko; Mononen, Tommi; Mustonen, Ville (2021)
    Increasing body of experimental evidence suggests that anticancer and antimicrobial therapies may themselves promote the acquisition of drug resistance by increasing mutability. The successful control of evolving populations requires that such biological costs of control are identified, quantified and included to the evolutionarily informed treatment protocol. Here we identify, characterise and exploit a trade-off between decreasing the target population size and generating a surplus of treatment-induced rescue mutations. We show that the probability of cure is maximized at an intermediate dosage, below the drug concentration yielding maximal population decay, suggesting that treatment outcomes may in some cases be substantially improved by less aggressive treatment strategies. We also provide a general analytical relationship that implicitly links growth rate, pharmacodynamics and dose-dependent mutation rate to an optimal control law. Our results highlight the important, but often neglected, role of fundamental eco-evolutionary costs of control. These costs can often lead to situations, where decreasing the cumulative drug dosage may be preferable even when the objective of the treatment is elimination, and not containment. Taken together, our results thus add to the ongoing criticism of the standard practice of administering aggressive, high-dose therapies and motivate further experimental and clinical investigation of the mutagenicity and other hidden collateral costs of therapies. Author summary Evolution of drug resistance to anticancer and antimicrobial therapies is widespread among cancer and pathogen cell populations. Classical theory posits strictly that genetic and phenotypic variation is generated in evolving populations independently of the selection pressure. However, recent experimental findings among antimicrobial agents, traditional cytotoxic chemotherapies and targeted cancer therapies suggest that treatment not only imposes selection but can also affect the rate of adaptation by increasing mutability. Here we analyse a model with drug-induced increase in mutation rate and explore its consequences for treatment optimisation. We argue that the true biological cost of treatment is not limited to the harmful side-effects, but instead realises even more profoundly by fundamentally changing the underlying eco-evolutionary dynamics within the microenvironment. Using the concept of evolutionary rescue, we formulate the treatment as an optimal control problem and solve the optimal elimination strategy, which minimises the probability of evolutionary rescue. We show that aggressive elimination strategies, which aim at eradication as fast as possible and which represent the current standard of care, can be detrimental even with modest drug-induced increases (fold change
  • Pietila, Sari; Lenko, Hanna L.; Oja, Sakari; Koivisto, Anna-Maija; Pietila, Timo; Mäkipernaa, Anne Marja-Terttu (2016)
    This population-based cross-sectional study evaluates the clinical value of electroretinography and visual evoked potentials in childhood brain tumor survivors. A flash electroretinography and a checkerboard reversal pattern visual evoked potential (or alternatively a flash visual evoked potential) were done for 51 survivors (age 3.8-28.7 years) after a mean follow-up time of 7.6 (1.5-15.1) years. Abnormal electroretinography was obtained in 1 case, bilaterally delayed abnormal visual evoked potentials in 22/51 (43%) cases. Nine of 25 patients with infratentorial tumor location, and altogether 12 out of 31 (39%) patients who did not have tumors involving the visual pathways, had abnormal visual evoked potentials. Abnormal electroretinographies are rarely observed, but abnormal visual evoked potentials are common even without evident anatomic lesions in the visual pathway. Bilateral changes suggest a general and possibly multifactorial toxic/adverse effect on the visual pathway. Electroretinography and visual evoked potential may have clinical and scientific value while evaluating long-term effects of childhood brain tumors and tumor treatment.
  • Tuominen, L; Ritmala-Castren, M; Nikander, P; Makela, S; Vahlberg, T; Leino-Kilpi, H (2021)
    Background: Chemotherapy-induced side effects may have a negative effect on nutrition intake, thus increasing the risk of malnutrition and consequently, other serious complications for patients with cancer. The prevalence of malnutrition is common among patients with colorectal cancer. Nurse-led empowering education may have a positive effect on self-care activity in this patient group. Therefore, our purpose is to develop an empowering educational nursing intervention and test its effect on self-care activation and knowledge level among patients with colorectal cancer during chemotherapy. Secondary outcomes are quality of life and risk of malnutrition. Methods: An interdisciplinary expert group developed a face-to-face empowering educational intervention using teach-back method. A two-arm, single-centre, superiority trial with stratified randomisation (1:1) and pre-post measures will be used to assess the effect of the intervention compared to standard care. Patients (N = 40 + 40) will be recruited in one university hospital outpatient clinic in Finland. Eligibility criteria are adult patients diagnosed with colorectal cancer starting oral fluoropyrimidine or combination chemotherapy treatment. A registered nurse experienced in oncology will deliver the intervention 2 weeks after the first chemotherapy. Outcomes are measured before intervention (M0) and after a two-month follow-up period (M1). Discussion: This study will assess whether nurse-led empowering education using teach-back method is effective on self-care activity among patients with colorectal cancer. If the intervention has a positive effect, it may be implemented into patient education in a corresponding context.
  • Kauppila, Joonas H.; Ohtonen, Pasi; Karttunen, Tuomo J.; Kokkola, Arto; Laine, Simo; Rantanen, Tuomo; Ristimäki, Ari; Räsänen, Jari V.; Saarnio, Juha; Sihvo, Eero; Toikkanen, Vesa; Tyrvänen, Tuula (2019)
    Introduction Surgery for oesophageal and gastric cancers is associated with high morbidity, mortality and poor quality of life postoperatively. The Finnish National Esophago-Gastric Cancer Cohort has been established with the aim of identifying factors that could contribute to improved outcomes in oesophago-gastric cancer. Methods and analysis All patients with oesophageal and gastric cancer diagnosed in Finland between 1987 and 2015 will be identified from the Finnish national registries. The Finnish Cancer Registry and Finnish Patient Registry will be used to identify patients that fulfil the inclusion criteria for the study: (1) diagnosis of oesophageal, gastro-oesophageal junction, or gastric cancer, (2) any surgical treatment for the diagnosed cancer and (3) age of 18 or over at the time of diagnosis. Clinical variables and complication information will be retrieved in extensive data collection from the medical records of the relevant Finnish hospitals and complete follow-up for vital status from Statistics Finland. Primary end point is overall all-cause mortality and secondary endpoints include complications, reoperations, medication use and sick leaves. Sub-studies will be implemented within the cohort to investigate specific populations undergoing oesophageal and gastric cancer surgery. The initial estimated sample size is 1800 patients with surgically treated oesophageal cancer and 7500 patients with surgically treated gastric cancer. Ethics and dissemination The study has been approved by the Ethical Committee in Northern Ostrobothnia, Finland and The National Institute for Health and Welfare, Finland. Study findings will be disseminated via presentations at conferences and publications in peer-reviewed journals.