Browsing by Subject "pancreatic cancer"

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  • Mahlamaki, E H; Kauraniemi, P; Monni, O; Wolf, Maija; Hautaniemi, S; Kallioniemi, Anne (2004)
  • Xia, Guanggai; Zhang, Hongbo; Cheng, Ruoyu; Wang, Hongcheng; Song, Ziliang; Deng, Lianfu; Huang, Xinyu; Santos, Helder A.; Cui, Wenguo (2018)
    The low radical surgery rate of pancreatic cancer leads to increased local recurrence and poor prognosis. Gemcitabine (GEM) is the preferred chemotherapeutic for pancreatic cancer. However, systemic chemotherapy with GEM has reached a bottleneck due to its serious side effects after frequent injections. In this study, GEM is successfully enwrapped into electrospun fibers via microsol electrospinning technology to form a stable core-shell fibrous structure. The GEM release rate can be adjusted by altering the thickness of the hyaluronan-sol inner fiber and the quantity of loaded GEM, and the release can be sustained for as long as three weeks. In vitro assays show that these electrospun fibers effectively inhibit pancreatic cancer cells and promote apoptosis. In vivo studies show that the fibrous membranes are better for inhibiting the growth of residual tumors than that of integrated tumors. Furthermore, immunohistochemistry results show that GEM-loaded fibers promote a higher cell apoptosis rate than does systemically injected GEM in residual tumors. In addition, the local delivery of GEM with fibers significantly reduces liver toxicity. In summary, a core-shell electrospun fiber for the controlled and localized delivery of GEM, which greatly improves the treatment of residual tumors and prevents pancreatic tumor recurrence, is developed.
  • Kaasinen, Mirjami; Hagström, Jaana; Mustonen, Harri; Sorsa, Timo; Sund, Malin; Haglund, Caj; Seppänen, Hanna (2022)
    Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-related death globally, and, despite improvements in diagnostics and treatment, survival remains poor. Matrix metalloproteinases (MMPs) are enzymes involved in stroma remodelling in inflammation and cancer. MMP-8 plays a varied prognostic role in cancers of the gastrointestinal tract. We examined the prognostic value of MMP-8 immunoexpression in tumour tissue and the amount of MMP-8-positive polymorphonuclear cells (PMNs) in PDAC and their association with immune responses using C-reactive protein (CRP) as a marker of systemic inflammation. Tumour samples from 141 PDAC patients undergoing surgery in 2002-2011 at the Department of Surgery, Helsinki University Hospital were stained immunohistochemically, for which we evaluated MMP-8 expression in cancer cells and the amount of MMP-8-positive PMNs. We assessed survival using the Kaplan-Meier analysis while uni- and multivariable analyses relied on the Cox proportional hazards model. A negative MMP-8 stain and elevated CRP level predicted a poor prognosis (hazard ratio [HR] = 6.95; 95% confidence interval (CI) 2.69-17.93; p < 0.001) compared to a positive stain and low CRP level (
  • Sammallahti, Heidelinde; Kokkola, Arto; Rezasoltani, Sama; Ghanbari, Reza; Asadzadeh Aghdaei, Hamid; Knuutila, Sakari; Puolakkainen, Pauli; Sarhadi, Virinder Kaur (2021)
    Pancreatic cancer (PC) is an aggressive disease with a high mortality and poor prognosis. The human microbiome is a key factor in many malignancies, having the ability to alter host metabolism and immune responses and participate in tumorigenesis. Gut microbes have an influence on physiological functions of the healthy pancreas and are themselves controlled by pancreatic secretions. An altered oral microbiota may colonize the pancreas and cause local inflammation by the action of its metabolites, which may lead to carcinogenesis. The mechanisms behind dysbiosis and PC development are not completely clear. Herein, we review the complex interactions between PC tumorigenesis and the microbiota, and especially the question, whether and how an altered microbiota induces oncogenomic changes, or vice versa, whether cancer mutations have an impact on microbiota composition. In addition, the role of the microbiota in drug efficacy in PC chemo- and immunotherapies is discussed. Possible future scenarios are the intentional manipulation of the gut microbiota in combination with therapy or the utilization of microbial profiles for the noninvasive screening and monitoring of PC.
  • Karihtala, Peeter; Porvari, Katja; Kilpivaara, Outi (2022)
    Background/Aim: Mutational signatures reflect common patterns based on the counts of mutations and their sequence context. The prognostic value of these signatures, mirroring various carcinogenetic processes of cancers, are unexplored in gastrointestinal cancers. Our aim was to evaluate possible prognostic relevance of mutational signatures in gastrointestinal carcinomas after adjusting with the traditional prognostic factors. Materials and Methods: We used publicly available data from The Cancer Genome Atlas and Pan-Cancer Analysis of Whole Genomes to evaluate the associations between survival endpoints and activity of mutational signatures in seven types of gastrointestinal cancers. Results: Most strikingly, the high activity of age -related single-base substitution 5 (SBS5) and SBS40 signatures were in rectal adenocarcinomas associated with both improved overall survival (OS) [for SBS5 hazard ratio (HR) 0.130; 95% CI=0.03-0.56, for SBS40 HR=0.072; 95% CI=0.012-0.44, respectively] and similarly also to rectal cancer-specific survival. In patients with left-sided (but not right-sided) colon adenocarcinoma, the high activity of SBS2 signatures, formed due to APOBEC activity, predicted shortened OS. In pancreatic cancer, the high activity of SBS10b, caused by polymerase epsilon exonuclease proofreading defects, was associated both with longer OS (HR=0.44; 95% CI=0.205-0.96) and pancreatic cancer-specific survival (HR=0.32; 95% CI=0.112-0.91). Conclusion: Several mutational signatures seem to have clinically meaningful, cancer-specific associations with prognosis among gastrointestinal cancers.
  • Sammallahti, Heidelinde; Sarhadi, Virinder Kaur; Kokkola, Arto; Ghanbari, Reza; Rezasoltani, Sama; Asadzadeh Aghdaei, Hamid; Puolakkainen, Pauli; Knuutila, Sakari (2022)
    Pancreatic cancer (PC) is an aggressive malignancy with a dismal prognosis. To improve patient survival, the development of screening methods for early diagnosis is pivotal. Oncogenomic alterations present in tumor tissue are a suitable target for non-invasive screening efforts, as they can be detected in tumor-derived cells, cell-free nucleic acids, and extracellular vesicles, which are present in several body fluids. Since stool is an easily accessible source, which enables convenient and cost-effective sampling, it could be utilized for the screening of these traces. Herein, we explore the various oncogenomic changes that have been detected in PC tissue, such as chromosomal aberrations, mutations in driver genes, epigenetic alterations, and differentially expressed non-coding RNA. In addition, we briefly look into the role of altered gut microbiota in PC and their possible associations with oncogenomic changes. We also review the findings of genomic alterations in stool of PC patients, and the potentials and challenges of their future use for the development of stool screening tools, including the possible combination of genomic and microbiota markers.
  • Varkila, Nora (Helsingfors universitet, 2016)
    Syövän ja veren hyytymisen välillä on useita yhteyksiä. Erityisesti haimasyöpä, kuten duktaalinen adenokarsinooma (PDAC), lisää merkittävästi hyytymisaktiviteettia. Tutkimuksemme tavoitteena oli selvittää syövän levinneisyyden, hoitojen ja preoperatiivisten biomarkkereiden yhteyttä haimasyövässä, verraten sitä hyvänlaatuiseen intraduktaaliseen papillaariseen musinoottiseen neoplasiaan (IPMN). Tutkimukseen otettiin 158 haimatuumorin vuoksi leikattua potilasta, joiden kasvain diagnosoitiin joko PDAC:ksi tai IPMN:ksi. Verenkuvaa, hyytymis- ja tuumorimarkkereita analysoitiin preoperatiivisesti. Potilaat jaettiin ryhmiin riippuen syövän levinneisyydestä ja neoadjuvanttihoidoista (NT). Hyytymistekijä VIII (FVIII:C) oli aktiivisempi PDAC potilailla kuin IPMN potilailla (p<0.05), paitsi paikallisilla NT-hoidetuilla PDAC potilailla. D-dimeeripitoisuus oli suurempi paikallista hoitamatonta PDAC:ta ja metastasoinutta NT-hoidettua PDAC:ta sairastavilla kuin IPMN potilailla (p<0.02). Tuumorimarkkeri CA 19-9 oli koholla PDAC potilailla, lukuun ottamatta paikallista NT-hoidettua PDAC:ta. Yhdistämällä FVIII:C, D-dimeeri ja CA 19-9-tulokset aikaansaimme paneelipisteytyksen, joka erotti kaikki PDAC ryhmät IPMN potilaista (p<0.05). Tutkimuksessamme CA 19-9 ei yksinään erottanut kaikkia PDAC ryhmiä IPMN:stä. Yhdistämällä CA 19-9:ään hyytymistä kuvaavat FVIII:C:n ja D-dimeerin syntyy paneelipisteytys, joka preoperatiivisesti ennustaa PDAC:a.
  • Seppälä, Toni T.; Zimmerman, Jacquelyn W.; Sereni, Elisabetta; Plenker, Dennis; Suri, Reecha; Rozich, Noah; Blair, Alex; Thomas, Dwayne L.; Teinor, Jonathan; Javed, Ammar; Patel, Hardik M; Cameron, John L.; Burns, William R.; He, Jin; Tuveson, David A.; Jaffee, Elizabeth M.; Eshleman, James R; Szabolcs, Annamaria; Ryan, David P.; Ting, David T.; Wolfgang, Christopher L.; Burkhart, Richard A. (2020)
    Objective: PDAC patients who undergo surgical resection and receive effective chemotherapy have the best chance of long-term survival. Unfortunately, we lack predictive biomarkers to guide optimal systemic treatment. Ex-vivo generation of PDO for pharmacotyping may serve as predictive biomarkers in PDAC. The goal of the current study was to demonstrate the clinical feasibility of a PDO-guided precision medicine framework of care. Methods: PDO cultures were established from surgical specimens and endoscopic biopsies, expanded in Matrigel, and used for high-throughput drug testing (pharmacotyping). Efficacy of standard-of-care chemotherapeutics was assessed by measuring cell viability after drug exposure. Results: A framework for rapid pharmacotyping of PDOs was established across a multi-institutional consortium of academic medical centers. Specimens obtained remotely and shipped to a central biorepository maintain viability and allowed generation of PDOs with 77% success. Early cultures maintain the clonal heterogeneity seen in PDAC with similar phenotypes (cystic-solid). Late cultures exhibit a dominant clone with a pharmacotyping profile similar to early passages. The biomass required for accurate pharmacotyping can be minimized by leveraging a high-throughput technology. Twenty-nine cultures were pharmacotyped to derive a population distribution of chemotherapeutic sensitivity at our center. Pharmacotyping rapidly-expanded PDOs was completed in a median of 48 (range 18-102) days. Conclusions: Rapid development of PDOs from patients undergoing surgery for PDAC is eminently feasible within the perioperative recovery period, enabling the potential for pharmacotyping to guide postoperative adjuvant chemotherapeutic selection. Studies validating PDOs as a promising predictive biomarker are ongoing.
  • Heikkila, Pia; But, Anna; Sorsa, Timo; Haukka, Jari (2018)
    Periodontitis, a multifactorial infection-induced low-grade chronic inflammation, can influence the process of carcinogenesis. We studied with 10 years follow-up of 68,273 adults-based cohort the involvement of periodontitis as a risk factor for cancer mortality. Periodontal status was defined based on procedure codes of periodontal treatment. Rate ratios and absolute differences of overall and cancer mortality rates were assessed with respect to periodontal status using multiplicative and additive Poisson regression models, respectively. We adjusted for effect of age, sex, calendar time, socio-economic status, oral health, dental treatments and diabetes. Data about smoking or alcohol consumption were not available. Altogether 797 cancer deaths occurred during 664,020 person-years accumulated over a mean 10.1-year follow-up. Crude cancer mortality rate per 10,000 person-years for participants without and with periodontitis was 11.36 (95% CI 10.47-12.31) and 14.45 (95% CI 12.51-16.61), respectively. Crude rate ratios for periodontitis indicated an increased risk of overall (RR 1.27, 95% CI 1.08-1.39) and pancreatic cancer (RR 1.69, 95% CI 1.04-2.76) mortality. After adjustment, the results showed even stronger associations of periodontitis with increased overall (RR 1.33, 95% CI 1.10-1.58) and pancreatic cancer (RR 2.32, 95% CI 1.31-3.98) mortality. A higher pancreatic cancer mortality among individuals with periodontitis contributed considerably to the difference in overall cancer mortality, but this difference was not due to pancreatic cancer deaths alone. What's new? Periodontitis is characterized by infection-driven inflammation, a type of inflammation that is a factor in about 15% of human tumors. It remains unclear, however, whether periodontitis increases cancer risk or influences cancer mortality. In this study, long-term follow-up on a large cohort of dental patients in Finland suggests that periodontitis is associated with increased overall cancer mortality, especially increased mortality from pancreatic cancer. The findings suggest that the prevention and treatment of periodontitis can help reduce the risk of systemic adverse events, such as death, from cancer.
  • Mattila, Nora; Seppänen, Hanna; Mustonen, Harri; Przybyla, Beata; Haglund, Caj; Lassila, Riitta (2018)
    Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer often diagnosed late. Earlier detection is urgently needed. Pancreatic ductal adenocarcinoma is known to associate with increased coagulation activity. We studied whether preoperative coagulation biomarkers are useful in distinguishing PDAC from a benign tumor, intraductal papillary mucinous neoplasm (IPMN) in this observational study. We analyzed standard clinical and coagulation variables in patients operated during 2010 and 2015 at Helsinki University Hospital. Pancreatic ductal adenocarcinoma with preoperative coagulation variables available and no neoadjuvant treatment or other active cancer was observed in 80 patients (stage I-III in 67 and IV in 13) and IPMN in 18 patients. Fibrinogen, factor VIII (FVIII), carbohydrate antigen (CA) 19-9, albumin, alkaline phosphatase, and conjugated bilirubin were higher in both stages I to III and IV PDAC compared to IPMN (P <.05). Factor VIII was highest in stage IV (P <.05). Combining these variables in a panel increased sensitivity and specificity for PDAC. In receiver operating characteristic analysis, the area under the curve (95% confidence interval) was 0.95 (0.90-1.00) for the panel, compared to 0.80 (0.71-0.88) for CA 19-9 alone (P <.01). In conclusion, PDAC was associated with increased fibrinogen and FVIII. Combining these coagulation biomarkers with CA 19-9, albumin, and alkaline phosphatase improves diagnostic accuracy.
  • Kouri, Riikka (Helsingfors universitet, 2011)
    The p53-family consists of three transcription factors, p53, p73 and p63. The family members have similar but also individual functions connected to cell cycle regulation, development and tumorigenesis. p53 and p73 act mainly as tumor suppressors. During DNA damage caused by anticancer drugs or irradiation, p53 and p73 levels are upregulated in cancer cells leading to apoptosis and cell cycle arrest. p53 is mutated in almost 50 per cent of the cancers, causing the cancer cells unable to undergo cell death. Instead, p73 is rarely mutated in cancer cells and because of that could be more viable target for anticancer therapy. The network surrounding the regulation of p73 is extensive and has several potential targets for cancer therapy. One of the most studied is Itch ligase, the negative regulator of p73 levels. Gene therapy directed towards knockdown of Itch ligase is a potential approach but in need for more in vivo proof. p73 has two isoforms, transactivating TA-forms and dominant-negative ΔN-forms. The specific regulation of these isoforms could also offer a possible way for more effective cancer treatment. The literature work includes information of structures, isoforms, functions and possible therapeutic targets of p73. Also the main therapeutic approaches to date are introduced. The experimental part is based on transfection and cytotoxicity studies done e.g. in pancreatic cancer cells (Mia PaCa-2, PANC1, BxPc-3 and HPAC). The aim of the experimental work was to optimize the conditions for effective transfection with DAB16 dendrimer nanoparticles and to measure the cytotoxicity of plain dendrimers and DAB16-pDNA complexes. Also the protein levels of p73 and Itch ligase were measured by Western blotting. The work was done as a part of a bigger project, which was aiming to down regulate Itch ligase (negative regulator of p73) by siRNA/shRNA. Tranfection results were promising, showing good transfection efficacy with DAB16 N/P30 in pancreatic cancer cells (except in BxPc-3). Pancreatic cancer cells showed recovery in 3 days after they were exposed to plain dendrimer solution or to DAB16-pDNA. Measurement of protein levels by Western blotting was not optimal and the proposals for the improvement regarding e.g. the gels and the extracted protein amounts have been done.
  • Grbovic-Huezo, Olivera; Pitter, Kenneth; Lecomte, Nicolas; Saglimbeni, Joseph; Askan, Gokce; Holm, Matilda; Melchor, Jerry; Chandwani, Rohit; Joshi, Suhasini; Haglund, Caj; Iacobuzio-Donahue, Christine; Chiosis, Gabriela; Tammela, Tuomas; Leach, Steven (2020)