Browsing by Subject "AMERICAN-SOCIETY"

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  • Varga, Zsuzsanna; Lebeau, Annette; Bu, Hong; Hartmann, Arndt; Penault-Llorca, Frederique; Guerini-Rocco, Elena; Schraml, Peter; Symmans, Fraser; Stoehr, Robert; Teng, Xiaodong; Turzynski, Andreas; von Wasielewski, Reinhard; Guertler, Claudia; Laible, Mark; Schlombs, Kornelia; Joensuu, Heikki; Keller, Thomas; Sinn, Peter; Sahin, Ugur; Bartlett, John; Viale, Giuseppe (2017)
    Background: Accurate determination of the predictive markers human epidermal growth factor receptor 2 (HER2/ERBB2), estrogen receptor (ER/ESR1), progesterone receptor (PgR/PGR), and marker of proliferation Ki67 (MKI67) is indispensable for therapeutic decision making in early breast cancer. In this multicenter prospective study, we addressed the issue of inter- and intrasite reproducibility using the recently developed reverse transcription-quantitative real-time polymerase chain reaction-based MammaTyper (R) test. Methods: Ten international pathology institutions participated in this study and determined messenger RNA expression levels of ERBB2, ESR1, PGR, and MKI67 in both centrally and locally extracted RNA from formalin-fixed, paraffin-embedded breast cancer specimens with the MammaTyper (R) test. Samples were measured repeatedly on different days within the local laboratories, and reproducibility was assessed by means of variance component analysis, Fleiss' kappa statistics, and interclass correlation coefficients (ICCs). Results: Total variations in measurements of centrally and locally prepared RNA extracts were comparable; therefore, statistical analyses were performed on the complete dataset. Intersite reproducibility showed total SDs between 0.21 and 0.44 for the quantitative single-marker assessments, resulting in ICC values of 0.980-0.998, demonstrating excellent agreement of quantitative measurements. Also, the reproducibility of binary single-marker results (positive/negative), as well as the molecular subtype agreement, was almost perfect with kappa values ranging from 0.90 to 1.00. Conclusions: On the basis of these data, the MammaTyper (R) has the potential to substantially improve the current standards of breast cancer diagnostics by providing a highly precise and reproducible quantitative assessment of the established breast cancer biomarkers and molecular subtypes in a decentralized workup.
  • 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.
  • Niemelä, Jussi; Ylänen, Kaisa; Suominen, Anu; Pushparajah, Kuberan; Mathur, Sujeev; Sarkola, Taisto; Jahnukainen, Kirsi; Eerola, Anneli; Poutanen, Tuija; Vettenranta, Kim; Ojala, Tiina (2021)
    Background: The majority of childhood cancer survivors (CCSs) have been exposed to cardiotoxic treatments and often present with modifiable cardiovascular risk factors. Our aim was to evaluate the value of left ventricular (LV) longitudinal strain for increasing the sensitivity of cardiac dysfunction detection among CCSs. Methods: We combined two national cohorts: neuroblastoma and other childhood cancer survivors treated with anthracyclines. The final data consisted of 90 long-term CCSs exposed to anthracyclines and/or high-dose chemotherapy with autologous stem cell rescue and followed up for > 5 years and their controls (n = 86). LV longitudinal strain was assessed with speckle tracking (Qlab) and LV ejection fraction (EF) by three-dimensional echocardiography (3DE). Results: Of the CCSs, 11% (10/90) had abnormal LV longitudinal strain (i.e., < -17.5%); of those, 70% (7/10) had normal 3DE LV EF. Multivariable linear model analysis demonstrated that follow-up time (p = 0.027), sex (p = 0.020), and BMI (p = 0.002) were significantly associated with LV longitudinal strain. Conversely, cardiac risk group, hypertension, age, cumulative anthracycline dose or exposure to chest radiation were not. Conclusion: LV longitudinal strain is a more sensitive method than LV EF for the detection of cardiac dysfunction among CCSs. Therefore, LV longitudinal strain should be added to the screening panel, especially for those with modifiable cardiovascular risk factors.
  • Olander, R. F. W.; Sundholm, J. K. M.; Ojala, T. H.; Andersson, S.; Sarkola, T. (2020)
    Objectives Both excessive and restricted fetal growth are associated with changes in cardiac geometry and function at birth. There are significant issues when indexing cardiac parameters for body size in the neonatal period. The aims of this study were to determine to what extent cardiac geometry is dependent on body size in term and preterm neonates with restricted or excessive fetal growth and how this is affected by adiposity. Methods This was a cross-sectional study of neonates born between 31 and 42 weeks of gestation, divided into three groups: (1) small-for-gestational age (SGA, birth weight > 2 SD below the mean); (2) large-for-gestational age (LGA, birth weight > 2 SD above the mean); and (3) appropriate-for-gestational-age controls (AGA, birth weight Results In total, 174 neonates were included, of which 39 were SGA, 45 were LGA and 90 were AGA. Body size was reflected in cardiac dimensions, with differences in cardiac dimensions disappearing between the SGA and AGA groups when indexed for body surface area (BSA) or thoracic circumference. The same was true for the differences in atrial and ventricular areas between the LGA and AGA groups. However, left ventricular inflow and outflow tract dimensions did not follow this trend as, when indexed for BSA, they were associated negatively with adiposity, resulting in diminished dimensions in LGA compared with AGA and SGA neonates. Adiposity was associated positively with left ventricular mass, right ventricular length and area and right atrial area. The SGA group showed increased right ventricular fractional area change, possibly reflecting differences in the systolic function of the right ventricle. We found evidence of altered diastolic function between the groups, with the mitral valve inflow E-to lateral E'-wave peak velocity ratio being increased in the LGA group and decreased in the SGA group. Conclusions Cardiac geometry is explained by body size in both term and preterm AGA and SGA infants. However, the nature of the relationship between body size and cardiac dimensions may be influenced by adiposity in LGA infants, leading to underestimation of left ventricular inflow and outflow tract dimensions when adjusted for BSA. Adjustments for thoracic circumference provide similar results to those for BSA. Copyright (C) 2020 ISUOG. Published by John Wiley & Sons Ltd.
  • Helin, Henrik O.; Tuominen, Vilppu J.; Ylinen, Onni; Helin, Heikki; Isola, Jorma (2016)
    Evaluation of human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) is subject to interobserver variation and lack of reproducibility. Digital image analysis (DIA) has been shown to improve the consistency and accuracy of the evaluation and its use is encouraged in current testing guidelines. We studied whether digital image analysis using a free software application (ImmunoMembrane) can assist in interpreting HER2 IHC in equivocal 2+ cases. We also compared digital photomicrographs with whole-slide images (WSI) as material for ImmunoMembrane DIA. We stained 750 surgical resection specimens of invasive breast cancers immunohistochemically for HER2 and analysed staining with ImmunoMembrane. The ImmunoMembrane DIA scores were compared with the originally responsible pathologists' visual scores, a researcher's visual scores and in situ hybridisation (ISH) results. The originally responsible pathologists reported 9.1 % positive 3+ IHC scores, for the researcher this was 8.4 % and for ImmunoMembrane 9.5 %. Equivocal 2+ scores were 34 % for the pathologists, 43.7 % for the researcher and 10.1 % for ImmunoMembrane. Negative 0/1+ scores were 57.6 % for the pathologists, 46.8 % for the researcher and 80.8 % for ImmunoMembrane. There were six false positive cases, which were classified as 3+ by ImmunoMembrane and negative by ISH. Six cases were false negative defined as 0/1+ by IHC and positive by ISH. ImmunoMembrane DIA using digital photomicrographs and WSI showed almost perfect agreement. In conclusion, digital image analysis by ImmunoMembrane can help to resolve a majority of equivocal 2+ cases in HER2 IHC, which reduces the need for ISH testing.
  • Talwelkar, Sarang S.; Mäyränpää, Mikko; Soraas, Lars; Potdar, Swapnil; Bao, Jie; Hemmes, Annabrita; Linnavirta, Nora; Lomo, Jon; Räsänen, Jari; Knuuttila, Aija; Wennerberg, Krister; Verschuren, Emmy W. (2021)
    Functional profiling of a cancer patient's tumor cells holds potential to tailor personalized cancer treatment. Here, we report the utility of fresh uncultured tumor-derived EpCAM(+) epithelial cells (FUTCs) for ex vivo drug response interrogation. Analysis of murine Kras mutant FUTCs demonstrates pharmacological and adaptive signaling profiles comparable to subtype-matched cultured cells. By applying FUTC profiling on non-small cell lung cancer patient samples, we report robust drug-response data in 19 of 20 cases, with cells exhibiting targeted drug sensitivities corresponding to their oncogenic drivers. In one of these cases, an EGFR mutant lung adenocarcinoma patient refractory to osimertinib, FUTC profiling is used to guide compassionate treatment. FUTC profiling identifies selective sensitivity to disulfiram and the combination of carboplatin plus etoposide, and the patient receives substantial clinical benefit from treatment with these agents. We conclude that FUTC profiling provides a robust, rapid, and actionable assessment of personalized cancer treatment options.
  • Laitinen, Tomi T.; Ruohonen, Saku; Juonala, Markus; Magnussen, Costan G.; Mikkila, Vera; Mikola, Hanna; Hutri-Kahonen, Nina; Laitinen, Tomi; Tossavainen, Paivi; Jokinen, Eero; Niinikoski, Harri; Jula, Antti; Viikari, Jorma S. A.; Ronnemaa, Tapani; Raitakari, Olli T.; Pahkala, Katja (2017)
    Background: Ideal cardiovascular health (CVH), defined by the American Heart Association, is associated with incident cardiovascular disease in adults. However, association of the ideal CVH in childhood with current and future cardiac structure and function has not been studied. Methods and results: The sample comprised 827 children participating in the longitudinal Special Turku Coronary Risk Factor Intervention Project (STRIP) and The Cardiovascular Risk in Young Finns Study (YFS). In STRIP, complete data on the seven ideal CVH metrics and left ventricular (LV) mass measured with echocardiography were available at the age of 15 (n= 321), 17 (n= 309) and 19 (n= 283) years. In YFS, the cohort comprised children aged 12-18 years (n = 506) with complete ideal CVH metrics data from childhood and 25 years later in adulthood, and echocardiography performed in adulthood. In STRIP, ideal CVH score was inversely associated with LV mass during childhood (P = 0.036). In YFS, childhood ideal CVH score was inversely associated with LV mass, LV end-diastolic volume, E/e' ratio, and left atrium end-systolic volume in adulthood (all P <0.01). In addition, improvement of the ideal CVH score between childhood and adulthood was inversely associated with LV mass, LV end-diastolic volume, E/e' ratio, and left atrium end-systolic volume (all P Conclusions: Childhood ideal CVH score has a long-lasting effect on cardiac structure and function, and the association is evident already in childhood. Our findings support targeting the ideal CVHmetrics as part of primordial prevention of cardiovascular diseases. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Loetsch, Joern; Sipilä, Reetta; Tasmuth, Tiina; Kringel, Dario; Estlander, Ann-Mari; Meretoja, Tuomo; Kalso, Eija; Ultsch, Alfred (2018)
    Background Prevention of persistent pain following breast cancer surgery, via early identification of patients at high risk, is a clinical need. Supervised machine-learning was used to identify parameters that predict persistence of significant pain. Methods Over 500 demographic, clinical and psychological parameters were acquired up to 6 months after surgery from 1,000 women (aged 28-75 years) who were treated for breast cancer. Pain was assessed using an 11-point numerical rating scale before surgery and at months 1, 6, 12, 24, and 36. The ratings at months 12, 24, and 36 were used to allocate patents to either "persisting pain" or "non-persisting pain" groups. Unsupervised machine learning was applied to map the parameters to these diagnoses. Results A symbolic rule-based classifier tool was created that comprised 21 single or aggregated parameters, including demographic features, psychological and pain-related parameters, forming a questionnaire with "yes/no" items (decision rules). If at least 10 of the 21 rules applied, persisting pain was predicted at a cross-validated accuracy of 86% and a negative predictive value of approximately 95%. Conclusions The present machine-learned analysis showed that, even with a large set of parameters acquired from a large cohort, early identification of these patients is only partly successful. This indicates that more parameters are needed for accurate prediction of persisting pain. However, with the current parameters it is possible, with a certainty of almost 95%, to exclude the possibility of persistent pain developing in a woman being treated for breast cancer.
  • Litwin, Linda; Sundholm, Johnny K. M.; Rönö, Kristiina; Koivusalo, Saila B.; Eriksson, Johan G.; Sarkola, Taisto (2020)
    Aims We aimed to investigate associations between pre-pregnancy obesity, gestational diabetes (GDM), offspring body composition, and left ventricular diastolic and systolic function in early childhood. Methods This is an observational study, including 201 mother-child pairs originating from the Finnish Gestational Diabetes Prevention Study (RADIEL; 96 with GDM, 128 with pre-pregnancy obesity) with follow-up from gestation to 6-year postpartum. Follow-up included dyads anthropometrics, body composition, blood pressure, and child left ventricular function with comprehensive echocardiography (conventional and strain imaging). Results Offspring left ventricular diastolic and systolic function was not associated with gestational glucose concentrations, GDM, or pregravida obesity. Child body fat percentage correlated with maternal pre-pregnancy BMI in the setting of maternal obesity (r = 0.23,P = 0.009). After adjusting for child lean body mass, age, sex, systolic BP, resting HR, maternal lean body mass, pre-gestational BMI, and GDM status, child left atrial volume increased by 0.3 ml (95% CI 0.1, 0.5) for each 1% increase in child body fat percentage. Conclusions No evidence of foetal cardiac programming related to GDM or maternal pre-pregnancy obesity was observed in early childhood. Maternal pre-pregnancy obesity is associated with early weight gain. Child adiposity in early childhood is independently associated with increased left atrial volume, but its implications for long-term left ventricle diastolic function and cardiovascular health remain unknown.
  • Rodriguez-Wallberg, Kenny A.; Tanbo, Tom; Tinkanen, Helena; Thurin-Kjellberg, Ann; Nedstrand, Elizabeth; Kitlinski, Margareta Laczna; Macklon, Kirsten T.; Ernst, Erik; Fedder, Jens; Tiitinen, Aila; Morin-Papunen, Laure; Einarsson, Snorri; Jokimaa, Varpu; Hippelainen, Maritta; Lood, Mikael; Gudmundsson, Johannes; Olofsson, Jan I.; Andersen, Claus Yding (2016)
    Introduction. The aim of this study is to report the current status of ovarian tissue cryopreservation among alternatives for fertility preservation in the Nordic countries. Material and methods. A questionnaire was sent to 14 Nordic academic reproductive centers with established fertility preservation programs. It covered fertility preservation cases performed up to December 2014, standard procedures for ovarian tissue cryopreservation and oocyte cryopreservation and reproductive outcomes following ovarian tissue transplantation. Results. Among the Nordic countries, Denmark and Norway practice ovarian tissue cryopreservation as a clinical treatment (822 and 164 cases, respectively) and their programs are centralized. In Sweden (457 cases), ovarian tissue cryopreservation is practiced at five of six centers and in Finland at all five centers (145 cases). Nearly all considered ovarian tissue cryopreservation to be experimental. In Iceland, embryo cryopreservation is the only option for fertility preservation. Most centers use slow-freezing methods for ovarian tissue cryopreservation. Most patients selected for ovarian tissue cryopreservation were newly diagnosed with cancer and the tissue was predominantly retrieved laparoscopically by unilateral oophorectomy. Only minor complications were reported. In total, 46 women have undergone ovarian tissue transplantation aiming at recovering fertility, 17 healthy children have been born and several additional pregnancies are currently ongoing. Whenever patients' clinical condition is permissive, oocyte cryopreservation after hormonal stimulation is preferred for fertility preservation. Between 2012 and 2014, a smaller proportion of females have undergone fertility preservation in the Nordic centers, in comparison to males (1: 3). Conclusions. Overall, ovarian tissue cryopreservation was reported to be safe. Slow freezing methods are still preferred. Promising results of recovery of fertility have been reported in Nordic countries that have initiated ovarian tissue transplantation procedures.
  • Mohlkert, Lilly-Ann; Hallberg, Jenny; Broberg, Olof; Rydberg, Annika; Halvorsen, Cecilia Pegelow; Liuba, Petru; Fellman, Vineta; Domellof, Magnus; Sjoberg, Gunnar; Norman, Mikael (2018)
    Background-Preterm birth has been associated with increased risk of cardiovascular morbidity in adult life. We evaluated whether preterm birth is associated with deviating cardiac structure and function before school start. Methods and Results-In total, 176 children aged 6 years and born extremely preterm (EXPT; gestational age of 22-26weeks) and 134 children born at term (control [CTRL]) were studied. We used echocardiography to assess left heart dimensions, geometry, and functions. Recording and off-line analyses of echocardiographic images were performed by operators blinded to group belonging. Body size, blood pressure, and heart rate were also measured. Rates of family history of cardiovascular disease and sex distribution were similar in the EXPT and CTRL groups. Heart rate and systolic blood pressure did not differ, whereas diastolic blood pressure was slightly higher in EXPT than CTRL participants. After adjusting for body surface area, left ventricular length, width, and aortic valve annulus diameter were 3% to 5% smaller in EXPT than CTRL participants. Left ventricular longitudinal shortening and systolic tissue velocity were 7% to 11% lower, and transversal shortening fraction was 6% higher in EXPT than CTRL participants. The EXPT group also exhibited lower atrial emptying velocities than the CTRL group. Sex, fetal growth restriction, or a patent ductus arteriosus in the neonatal period did not contribute to cardiac dimensions or performance. Conclusions-Six-year-old children born extremely preterm exhibit a unique cardiac phenotype characterized by smaller left ventricles with altered systolic and diastolic functions than same-aged children born at term.