Browsing by Subject "COLORECTAL-CANCER"

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  • MISiCOL Task Force (2018)
    Aim: To investigate the rate of laparoscopic colectomies for colon cancer using registries and population based studies. To provide a position paper on mini-invasive (MIS) colon cancer surgery based on the opinion of experts leader in this field. Methods: A systematic review of the literature was conducted using PRISMA guidelines for the rate of laparoscopy in colon cancer. Moreover, Delphi methodology was used to reach consensus among 35 international experts in four study rounds. Consensus was defined as an agreement >= 75.0%. Domains of interest included nosology, essential technical/oncological requirements, outcomes and MIS training. Results: Forty-four studies from 42 articles were reviewed. Although it is still sub-optimal, the rate of MIS for colon cancer increased over the years and it is currently >50% in Korea, Netherlands, UK and Australia. The remaining European countries are un-investigated and presented lower rates with highest variations, ranging 7-35%. Using Delphi methodology, a laparoscopic colectomy was defined as a "colon resection performed using key-hole surgery independently from the type of anastomosis". The panel defined also the oncological requirements recognized essential for the procedure and agreed that when performed by experienced surgeons, it should be marked as best practice in guidelines, given the principles of oncologic surgery be respected (RO procedure, vessel ligation and mesocolon integrity). Conclusion: The rate of MIS colectomies for cancer in Europe should be further investigated. A panel of leaders in this field defined laparoscopic colectomy as a best practice procedure when performed by an experienced surgeon respecting the standards of surgical oncology. (C) 2018 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
  • Heervä, Eetu; Väliaho, Vesa; Salminen, Tapio; Nieminen, Lasse; Carpelan, Anu; Kurki, Samu; Sundström, Jari; Huhtinen, Heikki; Rantala, Arto; Carpen, Olli; Minn, Heikki; Österlund, Pia; Ålgars, Annika; Ristamäki, Raija (2020)
  • Siltanen, Sanna; Fischer, Daniel; Rantapero, Tommi; Laitinen, Virpi; Mpindi, John Patrick; Kallioniemi, Olli; Wahlfors, Tiina; Schleutker, Johanna (2013)
  • Sievanen, Tero; Tormakangas, Timo; Laakkonen, Eija K.; Mecklin, Jukka-Pekka; Pylvänäinen, Kirsi; Seppälä, Toni T.; Peltomäki, Paivi; Sipila, Sarianna; Sillanpää, Elina (2021)
    Simple Summary Lifestyle modifies cancer risk in the general public. How lifestyle modifies cancer risk in individuals carrying the inherited pathogenic gene variants in DNA mismatch repair genes (Lynch syndrome) remains understudied. We conducted a retrospective study with cancer register data to investigate associations between body weight, physical activity, and cancer risk among Finnish Lynch syndrome carriers (n = 465, 54% women). The results of our study indicated that longitudinal weight gain increases cancer risk, whereas being highly physically active during adulthood could decrease cancer risk in men. Further, women were observed to be less prone to lifestyle-related risk factors than men. The results emphasize the role of weight maintenance and high-intensity physical activity throughout the lifespan, especially in men with Lynch syndrome. Lynch syndrome (LS) increases cancer risk. There is considerable individual variation in LS cancer occurrence, which may be moderated by lifestyle factors, such as body weight and physical activity (PA). The potential associations of lifestyle and cancer risk in LS are understudied. We conducted a retrospective study with cancer register data to investigate associations between body weight, PA, and cancer risk among Finnish LS carriers. The participants (n = 465, 54% women) self-reported their adulthood body weight and PA at 10-year intervals. Overall cancer risk and colorectal cancer (CRC) risk was analyzed separately for men and women with respect to longitudinal and near-term changes in body weight and PA using extended Cox regression models. The longitudinal weight change was associated with an increased risk of all cancers (HR 1.02, 95% CI 1.00-1.04) and CRC (HR 1.03, 1.01-1.05) in men. The near-term weight change was associated with a lower CRC risk in women (HR 0.96, 0.92-0.99). Furthermore, 77.6% of the participants retained their PA category over time. Men in the high-activity group had a reduced longitudinal cancer risk of 63% (HR 0.37, 0.15-0.98) compared to men in the low-activity group. PA in adulthood was not associated with cancer risk among women. These results emphasize the role of weight maintenance and high-intensity PA throughout the lifespan in cancer prevention, particularly in men with LS.
  • Kaapu, Kalle J.; Rantaniemi, Lauri; Talala, Kirsi; Taari, Kimmo; Tammela, Teuvo L. J.; Auvinen, Anssi; Murtola, Teemu J. (2018)
    In-vitro studies have suggested that the antiarrhythmic drug digoxin might restrain the growth of cancer cells by inhibiting Na+/K+-ATPase. We evaluated the association between cancer mortality and digoxin, sotalol and general antiarrhythmic drug use in a retrospective cohort study. The study population consists of 78,615 men originally identified for the Finnish Randomized Study of Screening for Prostate Cancer. Information on antiarrhythmic drug purchases was collected from the national prescription database. We used the Cox regression method to analyze separately overall cancer mortality and mortality from the most common types of cancer. During the median follow-up of 17.0 years after the baseline 28,936 (36.8%) men died, of these 8,889 due to cancer. 9,023 men (11.5%) had used antiarrhythmic drugs. Overall cancer mortality was elevated among antiarrhythmic drug users compared to non-users (HR 1.43, 95% CI 1.34-1.53). Similar results were observed separately for digoxin and for sotalol. However, the risk associations disappeared in long-term use and were modified by background co-morbidities. All in all, cancer mortality was elevated among antiarrhythmic drug users. This association is probably non-causal as it was related to short-term use and disappeared in long-term use. Our results do not support the anticancer effects of digoxin or any other antiarrhythmic drug.
  • But, Anna; De Bruin, Marie L.; Bazelier, Marloes T.; Hjellvik, Vidar; Andersen, Morten; Auvinen, Anssi; Starup-Linde, Jakob; Schmidt, Marjanka K.; Furu, Kari; de Vries, Frank; Karlstad, Oystein; Ekstrom, Nils; Haukka, Jari (2017)
    Aims/hypothesis The aim of this work was to investigate the relationship between use of certain insulins and risk for cancer, when addressing the limitations and biases involved in previous studies. Methods National Health Registries from Denmark (1996-2010), Finland (1996-2011), Norway (2005-2010) and Sweden (2007-2012) and the UK Clinical Practice Research Datalink database (1987-2013) were used to conduct a cohort study on new insulin users (N = 327,112). By using a common data model and semi-aggregate approach, we pooled individual-level records from five cohorts and applied Poisson regression models. For each of ten cancer sites studied, we estimated the rate ratios (RRs) by duration (6 years) of cumulative exposure to insulin glargine or insulin detemir relative to that of human insulin. Results A total of 21,390 cancer cases occurred during a mean follow-up of 4.6 years. No trend with cumulative treatment time for insulin glargine relative to human insulin was observed in risk for any of the ten studied cancer types. Of the 136 associations tested in the main analysis, only a few increased and decreased risks were found: among women, a higher risk was observed for colorectal (RR 1.54, 95% CI 1.06, 2.25) and endometrial cancer (RR 1.78, 95% CI 1.07, 2.94) for 6 years (RR 0.22, 95% CI 0.05, 0.92). Comparisons of insulin detemir with human insulin also showed no consistent differences. Conclusions/interpretation The present multi-country study found no evidence of consistent differences in risk for ten cancers for insulin glargine or insulin detemir use compared with human insulin, at follow-up exceeding 5 years.
  • Pussila, Marjaana; Sarantaus, Laura; Dermadi Bebek, Denis; Valo, Satu; Reyhani, Nima; Ollila, Saara; Päivärinta, Essi Mari-Anna; Peltomäki, Päivi T; Mutanen, Marja; Nyström, Minna (2013)
  • Scheinin, Ilari; Ferreira, Jose A.; Knuutila, Sakari; Meijer, Gerrit A.; van de Wiel, Mark A.; Ylstra, Bauke (2010)
  • Forsgard, Richard A.; Marrachelli, Vannina G.; Korpela, Katri; Frias, Rafael; Carmen Collado, Maria; Korpela, Riitta; Monleon, Daniel; Spillmann, Thomas; Osterlund, Pia (2017)
    Purpose Chemotherapy-induced gastrointestinal toxicity (CIGT) is a complex process that involves multiple pathophysiological mechanisms. We have previously shown that commonly used chemotherapeutics 5-fluorouracil, oxaliplatin, and irinotecan damage the intestinal mucosa and increase intestinal permeability to iohexol. We hypothesized that CIGT is associated with alterations in fecal microbiota and metabolome. Our aim was to characterize these changes and examine how they relate to the severity of CIGT. Methods A total of 48 male Sprague-Dawley rats were injected intraperitoneally either with 5-fluorouracil (150 mg/kg), oxaliplatin (15 mg/kg), or irinotecan (200 mg/kg). Body weight change was measured daily after drug administration and the animals were euthanized after 72 h. Blood, urine, and fecal samples were collected at baseline and at the end of the experiment. The changes in the composition of fecal microbiota were analyzed with 16S rRNA gene sequencing. Metabolic changes in serum and urine metabolome were measured with 1 mm proton nuclear magnetic resonance (1H-NMR). Results Irinotecan increased the relative abundance of Fusobacteria and Proteobacteria, while 5-FU and oxaliplatin caused only minor changes in the composition of fecal microbiota. All chemotherapeutics increased the levels of serum fatty acids and N(CH3)(3) moieties and decreased the levels of Krebs cycle metabolites and free amino acids. Conclusions Chemotherapeutic drugs, 5-fluorouracil, oxaliplatin, and irinotecan, induce several microbial and metabolic changes which may play a role in the pathophysiology of CIGT. The observed changes in intestinal permeability, fecal microbiota, and metabolome suggest the activation of inflammatory processes.
  • Landais, Edwige; Moskal, Aurelie; Mullee, Amy; Nicolas, Genevieve; Gunter, Marc J.; Huybrechts, Inge; Overvad, Kim; Roswall, Nina; Affret, Aurelie; Fagherazzi, Guy; Mahamat-Saleh, Yahya; Katzke, Verena; Kuehn, Tilman; La Vecchia, Carlo; Trichopoulou, Antonia; Valanou, Elissavet; Saieva, Calogero; de Magistris, Maria Santucci; Sieri, Sabina; Braaten, Tonje; Skeie, Guri; Weiderpass, Elisabete; Ardanaz, Eva; Chirlaque, Maria-Dolores; Garcia, Jose Ramon; Jakszyn, Paula; Rodriguez-Barranco, Miguel; Brunkwall, Louise; Huseinovic, Ena; Nilsson, Lena; Wallstroem, Peter; Bueno-de-Mesquita, Bas; Peeters, Petra H.; Aune, Dagfinn; Key, Tim; Lentjes, Marleen; Riboli, Elio; Slimani, Nadia; Freisling, Heinz (2018)
    Background: Coffee and tea are among the most commonly consumed nonalcoholic beverages worldwide, but methodological differences in assessing intake often hamper comparisons across populations. We aimed to (i) describe coffee and tea intakes and (ii) assess their contribution to intakes of selected nutrients in adults across 10 European countries. Method: Between 1995 and 2000, a standardized 24-h dietary recall was conducted among 36,018 men and women from 27 European Prospective Investigation into Cancer and Nutrition (EPIC) study centres. Adjusted arithmetic means of intakes were estimated in grams (=volume) per day by sex and centre. Means of intake across centres were compared by sociodemographic characteristics and lifestyle factors. Results: In women, the mean daily intake of coffee ranged from 94 g/day (similar to 0.6 cups) in Greece to 781 g/day (similar to 4.4 cups) in Aarhus (Denmark), and tea from 14 g/day (similar to 0.1 cups) in Navarra (Spain) to 788 g/day (similar to 4.3 cups) in the UK general population. Similar geographical patterns for mean daily intakes of both coffee and tea were observed in men. Current smokers as compared with those who reported never smoking tended to drink on average up to 500 g/day more coffee and tea combined, but with substantial variation across centres. Other individuals' characteristics such as educational attainment or age were less predictive. In all centres, coffee and tea contributed to less than 10% of the energy intake. The greatest contribution to total sugar intakes was observed in Southern European centres (up to similar to 20%). Conclusion: Coffee and tea intake and their contribution to energy and sugar intake differed greatly among European adults. Variation in consumption was mostly driven by geographical region.
  • Frank, Christoph; Sundquist, Jan; Yu, Hongyao; Hemminki, Akseli; Hemminki, Kari (2017)
    Relatives of cancer patients are at an increased risk of the same (concordant) cancer but whether they are at a risk for different (discordant) cancers is largely unknown - beyond well characterized hereditary cancer syndromes - but would be of major scientific and clinical interest. We therefore decided to resolve the issue by analyzing familial risks when family members were diagnosed with any discordant cancers. We compared the population impact of concordant to discordant familial cancer. The Swedish Family-Cancer Database (FCD) was used to calculate familial relative risks (RRs) for family members of cancer patients, for the 27 most common cancers. Population attributable fractions (PAFs) were estimated for concordant and discordant family histories. Discordant cancers in the family were detected as significant risk factors for the majority of cancers, although the corresponding RRs were modest compared to RRs for concordant cancers. Risks increased with the number of affected family members with the highest RRs for pancreatic (2.31), lung (1.69), kidney (1.98), nervous system (1.79) and thyroid cancers (3.28), when 5 or more family members were diagnosed with discordant cancers. For most cancers, the PAF for discordant family history exceeded that for concordant family history. Our findings suggest that there is an unspecific genetic predisposition to cancer with clinical consequences. We consider it unlikely that shared environmental risk factors could essentially contribute to the risks for diverse discordant cancers, which are likely driven by genetic predisposition. The identification of genes that moderately increase the risk for many cancers will be a challenge.
  • 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)
  • Roine, Eija; Farkkila, Niilo; Sintonen, Harri; Taari, Kimmo; Roine, Risto P.; Saarto, Tiina (2019)
    Background/Aim: This cross-sectional study estimated direct cancer-related health care, productivity and informal care costs for a six-month period for different states of breast cancer (BC). Patients and Methods: A total of 827 BC patients answered a questionnaire enquiring about informal care, work capacity, and demographic factors. Direct health care resource use and productivity costs were obtained from registries. Mutually exclusive groups were formed based on disease state and time from diagnosis: primary treatment (first six months after diagnosis), rehabilitation (>six months after diagnosis), remission (>1.5 years after diagnosis), and metastatic. Results: Mean total costs were: primary treatment (sic)22,876, rehabilitation (sic)3,456, remission (sic)1,728, and metastatic (sic)24,320. Mean direct health care costs were: primary treatment (sic)11,798, rehabilitation (sic)2,398, remission (sic)1,147, and metastatic (sic)13,923. Mean productivity costs varied between 18-39% and indirect costs (productivity and informal care costs) between 31-48% of the total costs. Conclusion: Direct medical costs were highest, but indirect costs constituted up to half of the total costs and are essential when estimating the total cost burden, as many patients are of working age.
  • Christensen, Jon; El-Gebali, Sara; Natoli, Manuela; Sengstag, Thierry; Delorenzi, Mauro; Bentz, Susanne; Bouzourene, Hanifa; Rumbo, Martin; Felsani, Armando; Siissalo, Sanna; Hirvonen, Jouni; Vila, Maya R.; Saletti, Piercarlo; Aguet, Michel; Anderle, Pascale (2012)
  • Kuuluvainen, Emilia; Domenech-Moreno, Eva; Niemela, Elina H.; Makela, Tomi P. (2018)
    In cancer, oncogene activation is partly mediated by acquired superenhancers, which therefore represent potential targets for inhibition. Superenhancers are enriched for BRD4 and Mediator, and both BRD4 and the Mediator MED12 subunit are disproportionally required for expression of superenhancer-associated genes in stem cells. Here we show that depletion of Mediator kinase module subunit MED12 or MED13 together with MED13L can be used to reduce expression of cancer-acquired superenhancer genes, such as the MYC gene, in colon cancer cells, with a concomitant decrease in proliferation. Whereas depletion of MED12 or MED13/MED13L caused a disproportional decrease of superenhancer gene expression, this was not seen with depletion of the kinases cyclin-dependent kinase 9 (CDK8) and CDK19. MED12-MED13/MED13L-dependent superenhancer genes were coregulated by beta-catenin, which has previously been shown to associate with MED12. Importantly, beta-catenin depletion caused reduced binding of MED12 at the MYC superenhancer. The effect of MED12 or MED13/MED13L depletion on cancer-acquired superenhancer gene expression was more specific than and partially distinct from that of BRD4 depletion, with the most efficient inhibition seen with combined targeting. These results identify a requirement of MED12 and MED13/MED13L for expression of acquired superenhancer genes in colon cancer, implicating these Mediator subunits as potential therapeutic targets for colon cancer, alone or together with BRD4.
  • Kalamo, Mari; Mäenpää, Johanna; Seppälä, Toni; Mecklin, Jukka-Pekka; Pylvänäinen, Kirsi; Staff, Synnöve (2021)
    Background Due to increased risk of endometrial and ovarian cancer, women belonging to known Lynch Syndrome (LS) families are recommended to undergo germline testing. Current practice in Finland is to offer counselling to women with pathogenic variant and advocate risk-reducing surgery (RRS) after completion of childbirth. The present study aimed to clarify the impacts of positive germline testing on family planning and reproductive decisions of these women, which are relatively unknown. Methods Seventy-nine carriers of germline MMR gene pathogenic variant (path_MMR) were identified from the Finnish LS Registry as having genetic testing performed before the age of 45 years and not having undergone hysterectomy or oophorectomy. These women were sent a questionnaire concerning family planning, intimate relationships and psychosocial wellbeing. Results Thirty-five women (44.3%) responded. Parity of path_MMR carriers (2.1) was slightly higher than parity among Finnish women in general (1.8). No significant differences were found between parity, number of induced abortions or sterilizations before and after genetic testing. Only minority of subjects reported any influence on family planning (20%) or negative impact on feminine self and body image (14%). Conclusions The positive germline testing does not seem to have a major negative impact on family planning, intimate relationships or feminine self and body image. According to the open comments, counselling, supportive and empathic attitude of the professionals seem to have a significant impact on this. These results are a valuable addition to the counselling of LS women at reproductive age.
  • Omoruyi, Iyekhoetin Matthew; Ahamioje, Derek; Pohjanvirta, Raimo (2014)
  • Kjällquist, Una; Erlandsson, Rikard; Tobin, Nicholas P.; Alkodsi, Amjad; Ullah, Ikram; Stalhammar, Gustav; Karlsson, Eva; Hatschek, Thomas; Hartman, Johan; Linnarsson, Sten; Bergh, Jonas (2018)
    Background: Tumor heterogeneity in breast cancer tumors is today widely recognized. Most of the available knowledge in genetic variation however, relates to the primary tumor while metastatic lesions are much less studied. Many studies have revealed marked alterations of standard prognostic and predictive factors during tumor progression. Characterization of paired primary- and metastatic tissues should therefore be fundamental in order to understand mechanisms of tumor progression, clonal relationship to tumor evolution as well as the therapeutic aspects of systemic disease. Methods: We performed full exome sequencing of primary breast cancers and their metastases in a cohort of ten patients and further confirmed our findings in an additional cohort of 20 patients with paired primary and metastatic tumors. Furthermore, we used gene expression from the metastatic lesions and a primary breast cancer data set to study the gene expression of the AKAP gene family. Results: We report that somatic mutations in A-kinase anchoring proteins are enriched in metastatic lesions. The frequency of mutation in the AKAP gene family was 10% in the primary tumors and 40% in metastatic lesions. Several copy number variations, including deletions in regions containing AKAP genes were detected and showed consistent patterns in both investigated cohorts. In a second cohort containing 20 patients with paired primary and metastatic lesions, AKAP mutations showed an increasing variant allele frequency after multiple relapses. Furthermore, gene expression profiles from the metastatic lesions (n = 120) revealed differential expression patterns of AKAPs relative to the tumor PAM50 intrinsic subtype, which were most apparent in the basal-like subtype. This pattern was confirmed in primary tumors from TCGA (n = 522) and in a third independent cohort (n = 182). Conclusion: Several studies from primary cancers have reported individual AKAP genes to be associated with cancer risk and metastatic relapses as well as direct involvement in cellular invasion and migration processes. Our findings reveal an enrichment of mutations in AKAP genes in metastatic breast cancers and suggest the involvement of AKAPs in the metastatic process. In addition, we report an AKAP gene expression pattern that consistently follows the tumor intrinsic subtype, further suggesting AKAP family members as relevant players in breast cancer biology.
  • Hänninen, Ulrika A.; Katainen, Riku; Tanskanen, Tomas; Plaketti, Roosa-Maria; Laine, Riku; Hamberg, Jiri; Ristimäki, Ari; Pukkala, Eero; Taipale, Minna; Mecklin, Jukka-Pekka; Forsström, Linda M.; Pitkänen, Esa; Palin, Kimmo; Välimäki, Niko; Mäkinen, Netta; Aaltonen, Lauri A. (2018)
    Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (Al) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.
  • Nummela, Pirjo; Leinonen, Hannele; Järvinen, Petrus; Thiel, Alexandra; Järvinen, Heikki; Lepisto, Anna; Ristimaki, Ari (2016)
    Pseudomyxoma peritonei is a fatal clinical syndrome with mucinous tumor cells disseminated into peritoneal cavity and secreting abundant mucinous ascites. The serum tumor markers CEA, CA19-9, and CA125 are used to monitor pseudomyxoma peritonei remission, but their expression at tissue level has not been well characterized. Herein, we analyzed expression of these proteins and the adenocarcinoma marker EpCAM in 92 appendix-derived pseudomyxoma peritonei tumors by immunohistochemistry. All tumors were found to ubiquitously express CEA and EpCAM. In the majority of the tumors (94.6%), CEA showed polarized immunostaining, but in 5 aggressive high-grade tumors containing numerous signet ring cells, a nonpolarized staining was detected. We found preoperative CEA serum values to correlate with peritoneal cancer index. However, the serum values of the advanced cases with nonpolarized staining pattern were normal, and the patients died within 5 years after diagnosis. Thus, serum CEA measurements did not reflect aggressiveness of these tumors. CA19-9 showed strong immunopositivity in most of the tumors (91.3%), and mutated enzyme FUT3 was demonstrated from the cases showing negative or weak staining. CA125 Was infrequently expressed by tumor cells (focal staining in 6.5% of the cases), but in most of the cages (79.3%), adjacent nonneoplastic mesothelial cells showed immunopositivity. As a conclusion, CEA and EpCAM are invariably expressed by pseudomyxoma peritonei tumor cells and could be exploited to targeted therapies against this malignancy. (C) 2016 Elsevier Inc. All rights reserved.