Metastatic Breast Cancer : Efficacy of Bevacizumab-based Chemotherapy and Prognostic Factors

Rintasyöpä on naisten yleisin pahanlaatuinen sairaus. Rintasyövän viiden vuoden elossaoloennusteet ovat hyviä (91 %), mutta johtuen rintasyövän yleisyydestä se on silti naisten suurin syöpäkuolemien aiheuttaja. Suomen syöpärekisterin tilastojen mukaan vuonna 2017 rintasyöpä todettiin 4974 potilaalla ja 928 potilasta kuoli rintasyöpään.1 Tällä vuosisadalla levinneen rintasyövän ennuste on parantunut vain vaatimattomasti. Tehokkaat HER2-vasta-ainehoidot ovat nykyään standardikäytössä levinneen HER2-positiivisen rintasyövän hoitona, ja levinneen rintasyövän ennusteen paraneminen johtuu suurimmalta osin ainoastaan HER2-positiivisesta alatyypistä. Edistysaskeleet hormonireseptoripositiivisen ja kolmoisnegatiivisen rintasyövän hoidossa ovat olleet vähäisiä potilaiden elinajan pidentymisen suhteen. Kolmoisnegatiivisessa rintasyövässä kaikki kolme rintasyöpäreseptoria ovat negatiivisia: estrogeeni, progesteroni ja HER2. Kolmoisnegatiivinen tauti on kaikkein aggressiivisin ja sen hoidossa on eniten haasteita. Levinneen rintasyövän hoitovaihtoehtoihin vaikuttavat syövän reseptoristatus, kasvainkuorma, mahdolliset aiemmat liitännäishoidot, potilaan toimintakyky, muut sairaudet ja potilaan oma mielipide annettavista hoidoista. Hormonireseptoripositiivisessa levinneessä taudissa endokriinista hoitoa suositellaan ensilinjan hoidoksi. Kemoterapiaa suositellaan ensilinjan hoidoksi vain tilanteissa, joissa potilaalla on uhkaavia sisäelinmetastaaseja. Muille potilaille kemoterapiaa harkitaan siinä vaiheessa, kun rintasyöpä on edennyt yhden tai useamman endokriinisen hoidon aikana. Kolmoisnegatiivisessa rintasyövässä hormonaaliset hoidot eivät ole tehokkaita ja siksi kemoterapia on ainoa hoitovaihtoehto tätä aggressiivista tautimuotoa sairastavilla potilailla. Taksaani, dosetakseli ja paklitakseli, on tavanomaisin valinta levinneen rintasyövän ensilinjan kemoterapiahoidoksi. Bevasitsumabi on verisuonen endoteelin kasvutekijä-A:ta kohtaan vaikuttava monoklonaalinen vasta-aine. Verisuonten muodostuminen on yksi pahanlaatuiden kudoksen tunnusomaisista piirteistä, jotta tuumorikudos pystyy lisääntymään. Bevasitsumabi pyrkii estämään kasvaimen uudisverisuonimuodostusta. Useat vaiheen III tutkimukset ovat arvioineet bevasitsumabin tehoa kemoterapiaan yhdistettynä levinneen rintasyövän hoitona. Bevasitsumabitutkimuksissa taudin etenemisvapaassa ajassa ollaan saavutettu muutaman kuukauden hyöty ja hoitovasteet ovat olleet yleisempiä. Kuitenkaan hyötyä kokonaiselossa-ajassa ei ole pystytty osoittamaan missään näistä tutkimuksista. Tämän tutkimuksen tarkoituksena oli arvioida bevasitsumabihoidon soveltuvuutta levinneen HER2-negatiivisen rintasyövän ensilinjan kemoterapiahoidoksi yhdistettynä taksaanihoitoon, plasman biomerkkiaineita levinneen rintasyövän ennustetekijöinä sekä parantaa CA15-3 kasvainmerkkiainemenetelmän herkkyyttä ja tarkkuuta rintasyövän hoidon seurannassa. Tutkimuksemme ensisijainen päätetapahtuma, mediaani taudin etenemisvapaa-aika, oli 11,3 kuukautta, mikä on samaa luokkaa kuin muissa ensilinjan bevasitsumabihoitotutkimuksissa. Tutkimuspotilaidemme mediaani kokonaiselossaolo-aika saavutti kuitenkin lähes kolmen vuoden rajapyykin, mitä voidaan pitää hyvänä tuloksena. Bevasitsumabihoitoon liittyvät haittavaikutukset olivat enimmäkseen hallittavissa huolimatta siitä, että yksi potilas menehtyi bevasitsumabihoidon haittavaikutuksiin. Ennustetekijätutkimuksessa plasman matala interleukiini-8-pitoisuus oli yhteydessä erinomaiseen pitkäaikaisselviytymiseen. Lisäksi korkea plasman Tie1-pitoisuus osoittautui levinneen rintasyövän uudeksi huonon ennusteen merkiksi. Tässä tutkimuksessa huonoin ennuste oli niillä potilailla, joilla todettiin sekä korkea Tie1-reseptorin solunulkoisen osan pitoisuus että plasman korkea angiopoietiini-2-pitoisuus. CA15-3 määritysmenetelmän kehitystä selvittäneessä osatyössä uusi lektiinipohjainen CA15-3WGA menetelmä oli perinteistä CA15-3 määritysmenetelmää tilastollisesti merkitsevästi herkempi.Breast cancer is the most common malignancy in women worldwide. Five-year survival rates of breast cancer are high (91 %), but due to its high incidence, it is still the leading cause of cancer death in females. In 2017, breast cancer was diagnosed in 4974 patients, and 928 patients died of breast cancer, according to Finnish Cancer registry data.1 The prognosis of metastatic breast cancer has only modestly improved during the last few decades. This improved survival is mostly due to the implementation of effective anti-HER2 therapy in standard clinical care of metastatic HER2-positive breast cancer. During this century, the advances in the treatment of the other metastatic breast cancer subtypes, hormone receptor positive and triple-negative, have been minimal in terms of improving patient survival. The most aggressive subtype with the greatest treatment challenges is the triple-negative breast cancer, in which all three clinically significant breast cancer receptors, i.e., estrogen, progesterone and HER2, are not expressed. The oncological treatment options for metastatic breast cancer depend on the receptor status, tumor burden, prior adjuvant therapies, patient performance status, other comorbidities and patient preferences. For hormone receptor-positive disease, endocrine therapy is recommended as a first-line treatment option. Chemotherapy should be considered as the first-line treatment only in cases of visceral crisis. In addition, all patients with advanced breast cancer can be treated with chemotherapy after disease progression on endocrine therapy. For triple-negative patients, endocrine therapy is not effective, so chemotherapy is the only valid option for these patients. The taxanes docetaxel and paclitaxel are the most common choices for the first-line chemotherapy treatment of metastatic breast cancer. Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor A. Angiogenesis is one of the hallmark processes of malignant tissue, needed for its proliferation, and bevacizumab aims to inhibit tumor neovascularization. Several phase III trials have evaluated bevacizumab as a treatment for metastatic breast cancer in combination with several chemotherapy agents. These studies with bevacizumab have resulted in a few months’ benefit in progression-free survival and higher frequency of response rates. However, an overall survival benefit was not established in any of the studies. This study was designed to evaluate the feasibility of bevacizumab in combination with taxane chemotherapy as first-line chemotherapy treatment of metastatic HER2- negative breast cancer, to evaluate biomarkers for their prognostic value in advanced breast cancer and to improve the sensitivity and specificity of the CA15-3 tumor marker in disease monitoring. The median progression-free survival, which was the primary endpoint in our trial, was 11.3 months. This is similar to other results from first-line bevacizumab combinations. The median overall survival of our patients reached almost three years, which can be considered a good outcome. The toxicity related to bevacizumab treatment was mostly manageable, although one patient died of treatment-related side effects. In the biomarker study, low plasma interleukin-8 level was associated with excellent long-term survival. In addition, high plasma Tie1 was found to be a novel factor for poor prognosis in metastatic breast cancer. In this study, patients with high levels of the extracellular fragment of the Tie1 receptor and angiopoietin-2 had the poorest survival. In the substudy aiming to improve CA15-3 as a breast cancer tumor marker, the new nanoparticle-lectin immunoassay CA15-3WGA was significantly more sensitive than the conventional CA15-3 assay

Rintasyövän ennustetekijät täsmentyvät

Vertaisarvioitu.Rintasyöpä jaetaan biologisten ominaisuuksien mukaan hormonireseptoripositiiviseen, HER2-positiiviseen ja kolmoisnegatiiviseen alaryhmään. Kolmoisnegatiivinen rintasyöpä on alaryhmistä aggressiivisin ja huonoennusteisin. Hormonireseptoripositiivisen taudin luonnollinen kulku on hitaampi, ja se on rintasyövistä hyväennusteisin. HER2-positiivinen tauti on aggressiivinen, mutta täsmälääkkeiden myötä ennuste on parantunut lähes samalle tasolle kuin hormonireseptoripositiivisen HER2-negatiivisen rintasyövän ennuste. Rintasyövän levinneisyys on keskeinen ennustetekijä sekä paikallisessa että levinneessä taudissa. Geeniprofilointitestien avulla voidaan säästää pieni osa kliinisesti suuren uusiutumisriskin potilaista liitännäissolunsalpaajahoidon haitoilta. Neoadjuvanttihoidoilla saavutettu täydellinen histologinen hoitovaste on jäännöstautiin verrattuna pitkäaikaisennusteen osalta suotuisa ennustetekijä. Nestebiopsiat tulevat tulevaisuudessa käyttöön rintasyöpään monessa eri hoidon vaiheessa ennusteen ja hoidon hyödyn mittarina.Peer reviewe

Rintasyövän ennustetekijät täsmentyvät

Rintasyöpä jaetaan biologisten ominaisuuksien mukaan hormonireseptoripositiiviseen, HER2-positiiviseen ja kolmoisnegatiiviseen alaryhmään. Kolmoisnegatiivinen rintasyöpä on alaryhmistä aggressiivisin ja huonoennusteisin. Hormonireseptoripositiivisen taudin luonnollinen kulku on hitaampi, ja se on rintasyövistä hyväennusteisin. HER2-positiivinen tauti on aggressiivinen, mutta täsmälääkkeiden myötä ennuste on parantunut lähes samalle tasolle kuin hormonireseptoripositiivisen HER2-negatiivisen rintasyövän ennuste. Rintasyövän levinneisyys on keskeinen ennustetekijä sekä paikallisessa että levinneessä taudissa. Geeniprofilointitestien avulla voidaan säästää pieni osa kliinisesti suuren uusiutumisriskin potilaista liitännäissolunsalpaajahoidon haitoilta. Neoadjuvanttihoidoilla saavutettu täydellinen histologinen hoitovaste on jäännöstautiin verrattuna pitkäaikaisennusteen osalta suotuisa ennustetekijä. Nestebiopsiat tulevat tulevaisuudessa käyttöön rintasyöpään monessa eri hoidon vaiheessa ennusteen ja hoidon hyödyn mittarina.publishedVersionPeer reviewe

The definitions of health care and social welfare informatics competencies

Digital transformation is changing the ecosystem and at the same time professionals’ competencies worldwide. Minimising health care and social welfare costs while increasing citizens’ health and well-being is challenging. Technology and digital tools play an important role in reaching this goal. However, there are inequalities concerning technology, and this has many impacts. Digitalisation brings challenges not only to health care and social welfare professionals but to citizens, too. Working with or using services in digital environments demands new skills. This has social and ethical impacts, e.g. how is equal access to services ensured. Health and social care professionals should have different competencies to respond to this, such as societal competencies. The purpose of this article is to describe how the definition of competencies in health care and social welfare version 1.0 (developed in the national SotePeda 24/7 project) was finalised as the final version 2.0 for Finnish healthcare and social welfare education by experts’ evaluation. Data was collected through an electronic questionnaire administered to selected experts (N=140) during January 2020. The number of experts who responded to the study was 52. These experts (social and health, business and IT) work or have worked in tasks related to the digitalisation of social and health care. The questionnaire was based on version 1.0 of the definition of digital competencies of health care and social welfare informatics. The questionnaire was mainly quantitative, but it also included open-ended qualitative questions. The experts agreed to a large extent on the version 1.0 definition, but some adjustments were made to the definition based on our study. The resulting definition is intended for use in the planning, implementation and evaluation of health care and social welfare education, but it can also be used for polytechnic education. The aim is to develop the digital skills of educators, degree students and in-service trainees in a multidisciplinary way (social and health, business and IT) to meet the needs of working life.Digital transformation is changing the ecosystem and at the same time professionals’ competencies worldwide. Minimising health care and social welfare costs while increasing citizens’ health and well-being is challenging. Technology and digital tools play an important role in reaching this goal. However, there are inequalities concerning technology, and this has many impacts. Digitalisation brings challenges not only to health care and social welfare professionals but to citizens, too. Working with or using services in digital environments demands new skills. This has social and ethical impacts, e.g. how is equal access to services ensured. Health and social care professionals should have different competencies to respond to this, such as societal competencies. The purpose of this article is to describe how the definition of competencies in health care and social welfare version 1.0 (developed in the national SotePeda 24/7 project) was finalised as the final version 2.0 for Finnish healthcare and social welfare education by experts’ evaluation. Data was collected through an electronic questionnaire administered to selected experts (N=140) during January 2020. The number of experts who responded to the study was 52. These experts (social and health, business and IT) work or have worked in tasks related to the digitalisation of social and health care. The questionnaire was based on version 1.0 of the definition of digital competencies of health care and social welfare informatics. The questionnaire was mainly quantitative, but it also included open-ended qualitative questions. The experts agreed to a large extent on the version 1.0 definition, but some adjustments were made to the definition based on our study. The resulting definition is intended for use in the planning, implementation and evaluation of health care and social welfare education, but it can also be used for polytechnic education. The aim is to develop the digital skills of educators, degree students and in-service trainees in a multidisciplinary way (social and health, business and IT) to meet the needs of working life

IV Thrombolysis-Bridging and Endovascular Treatment for Occlusive Internal Carotid Artery Dissection with Tandem Occlusion

Compared to other etiologies of ischemic stroke, occlusive internal carotid artery dissection responds worse to intravenous (IV) thrombolysis. Intracranial tandem occlusion is a predictor of poor outcome. A direct endovascular approach has been proposed as a safe and probably superior alternative to IV thrombolysis. However, it may lead to considerable treatment delays. We used rapidly initiated IV thrombolysis-bridging and subsequent endovascular treatment in two patients with severe hemispheric ischemia due to occlusive internal carotid artery dissection with tandem occlusion and achieved good outcomes. Minimizing recanalization times likely improves patient outcome and IV thrombolysis-bridging may be a reasonable strategy to achieve this. The positive initial results obtained with endovascular approaches and IV thrombolysis-bridging in this patient group deserve further scientific exploration

Computational Methods for Estimation of Cell Cycle Phase Distributions of Yeast Cells

Two computational methods for estimating the cell cycle phase distribution of a budding yeast (Saccharomyces cerevisiae) cell population are presented. The first one is a nonparametric method that is based on the analysis of DNA content in the individual cells of the population. The DNA content is measured with a fluorescence-activated cell sorter (FACS). The second method is based on budding index analysis. An automated image analysis method is presented for the task of detecting the cells and buds. The proposed methods can be used to obtain quantitative information on the cell cycle phase distribution of a budding yeast S. cerevisiae population. They therefore provide a solid basis for obtaining the complementary information needed in deconvolution of gene expression data. As a case study, both methods are tested with data that were obtained in a time series experiment with S. cerevisiae. The details of the time series experiment as well as the image and FACS data obtained in the experiment can be found in the online additional material at http://www.cs.tut.fi/sgn/csb/yeastdistrib/

Lectin nanoparticle assays for detecting breast cancer-associated glycovariants of cancer antigen 15-3 (CA15-3) in human plasma

Cancer antigen 15–3 (CA15-3) is widely utilized for monitoring metastatic breast cancer (BC). However, its utility for early detection of breast cancer is severely limited due to poor clinical sensitivity and specificity. The glycosylation of CA15-3 is known to be affected by BC, and therefore it might offer a way to construct CA15-3 glycovariant assays with improved cancer specificity. To this end, we performed lectin-based glycoprofiling of BC-associated CA15-3. CA15-3 expressed by a BC cell line was immobilized on microtitration wells using an anti-CA15-3 antibody. The glycosylation of the immobilized CA15-3 was then detected by using lectins coated onto europium (III)-doped nanoparticles (Eu+3-NPs) and measuring the time-resolved fluorescence of Eu. Out of multiple lectin-Eu+3-NP preparations, wheat germ agglutinin (WGA) and macrophage galactose-type lectin (MGL) -Eu3+-NPs bound to the BC cell line-dericed CA15-3 glycovariants (CA15-3Lectin). To evaluate the clinical performance of these two lectin-based assays, plasma samples from metastatic BC patients (n = 53) and healthy age-matched women (n = 20).Plasma CA15-3Lectin measurements better distinguished metastatic BC patients from healthy controls than the conventional CA15-3 immunoassay. At 90% specificity, the clinical sensitivity of the assays was 66.0, 67.9 and 81.1% for the conventional CA15-3, CA15-3MGL and CA15-3WGA assays, respectively. Baseline CA15-3MGL and CA15-3WGA were correlated to conventional baseline CA15-3 levels (r = 0.68, p0.001, respectively). However, very low baseline CA15-3MGL levels ≤ 5 U/mL were common in this metastatic breast cancer patient population.In conclusion, the new CA15-3Lectin concept could considerably improve the clinical sensitivity of BC detection compared to the conventional CA15-3 immunoassays and should be validated further on a larger series of subjects with different cancer subtypes and stages.</p

Lectin nanoparticle assays for detecting breast cancer-associated glycovariants of cancer antigen 15-3 (CA15-3) in human plasma

Cancer antigen 15-3 (CA15-3) is widely utilized for monitoring metastatic breast cancer (BC). However, its utility for early detection of breast cancer is severely limited due to poor clinical sensitivity and specificity. The glycosylation of CA15-3 is known to be affected by BC, and therefore it might offer a way to construct CA15-3 glycovariant assays with improved cancer specificity. To this end, we performed lectin-based glycoprofiling of BC-associated CA15-3. CA15-3 expressed by a BC cell line was immobilized on microtitration wells using an anti-CA15-3 antibody. The glycosylation of the immobilized CA15-3 was then detected by using lectins coated onto europium (III)-doped nanoparticles (Eu+3-NPs) and measuring the time-resolved fluorescence of Eu. Out of multiple lectin-Eu+3-NP preparations, wheat germ agglutinin (WGA) and macrophage galactose-type lectin (MGL) -Eu3+-NPs bound to the BC cell line-dericed CA15-3 glycovariants (CA15-3Lectin). To evaluate the clinical performance of these two lectin-based assays, plasma samples from metastatic BC patients (n = 53) and healthy age-matched women (n = 20).Plasma CA15-3Lectin measurements better distinguished metastatic BC patients from healthy controls than the conventional CA15-3 immunoassay. At 90% specificity, the clinical sensitivity of the assays was 66.0, 67.9 and 81.1% for the conventional CA15-3, CA15-3MGL and CA15-3WGA assays, respectively. Baseline CA15-3MGL and CA15-3WGA were correlated to conventional baseline CA15-3 levels (r = 0.68, p0.001, respectively). However, very low baseline CA15-3MGL levels ≤ 5 U/mL were common in this metastatic breast cancer patient population.In conclusion, the new CA15-3Lectin concept could considerably improve the clinical sensitivity of BC detection compared to the conventional CA15-3 immunoassays and should be validated further on a larger series of subjects with different cancer subtypes and stages

Ammattikorkeakouluopettajien monialainen sosiaali- ja terveydenhuollon tiedonhallinnan osaaminen

The quick digital transformation (DT) in society has affected the development of service in health and social services strongly during the last five years. The digitalization has resulted in a change in the paradigm, which has required a strong reaction from education to respond to the needs of competence in working life. The students who graduate from a university of applied sciences must be provided with sufficient readiness to operate in working life and to cope with change. The precondition is that the educators of health and social care, business, service design and IT keep up with the development of digitalization. The purpose of this study was to evaluate the informatics competences of the educators at the universities of applied sciences with an emphasis on the operational environments of health and social services. The survey is a part of the SotePeda 24/7 project. The survey was sent to Finnish universities of applied sciences (22) participating in the project in April- May 2019. The survey form was based on national and international evidence-based information. The form included 12 fields of competence and their contents. 172 answers were obtained after three reminders. A factor analysis was conducted utilizing the maximum likelihood method and the result was 18 factors. The largest load factor was named as the information management and digitalization competence factor. This article discusses the informatics variables loaded for this factor in the survey. The correspondence and discriminant analyses conducted in the study showed the competences vary in different education fields. The biggest differences in informatics competence were found in the social services education field, whereas the competences of the educators of the health care education were good and extremely good more evenly. In other fields participating in the study there were big differences inside single education fields regarding the informatics competences of health and social services.Nopea yhteiskunnan digitaalinen muutos (Digital Transformation, DT) on vaikuttanut viimeisten viiden vuoden aikana vahvasti sosiaali- ja terveydenhuollon palvelukehitykseen. Digitalisaatio on synnyttänyt paradigman muutoksen, mihin koulutuksen on pitänyt vahvasti reagoida vastatakseen vaadittaviin työelämän osaamistarpeisiin. Ammattikorkeakoulusta valmistuvalle ammattilaiselle on koulutuksessa taattava riittävät valmiudet toimia työelämässä ja selviytyä muutoksesta. Edellytyksenä on, että sosiaali- ja terveysalan, liiketalouden, palvelumuotoilualan ja IT-alan opettajat hallitsevat digitalisaation kehityksen. Tutkimuksen tarkoituksena oli arvioida ammattikorkeakouluopettajien sosiaali- ja terveydenhuollon digitaalisessa toimintaympäristössä tarvittavaa tiedonhallinnan osaamista. Tutkimus on osa SotePeda 24/7 -hanketta. Hankkeessa mukana oleville Suomen ammattikorkeakouluille (22) lähetettiin huhti-toukokuussa 2019 kyselylomake, joka pohjautui kansalliseen ja kansainväliseen näyttöön perustuvaan tietoon. Lomakkeessa oli 12 osaamisaluetta sisältöineen. Vastauksia saatiin kolmen muistutuksen jälkeen 172. Aineisto analysoitiin faktorianalyysillä hyödyntäen maximum likelihood menetelmää, ja tuloksena saatiin 18 faktoria. Suurimman latauksen saanut faktori nimettiin tiedonhallinnan ja digitaalisuuden osaamisen faktoriksi. Tässä artikkelissa tarkastellaan kyselyssä tälle faktorille latautuneita tiedonhallinnan muuttujia. Korrespondenssianalyysit ja tarkentavat erotteluanalyysit osoittivat osaamisen eroavan eri koulutusaloilla. Sosiaalialalla tiedonhallinnan osaamisessa oli koulutusaloista isommat erot kuin terveysalan opettajilla, joiden osaaminen oli tasaisemmin hyvää ja erittäin hyvää. Sosiaali- ja terveydenhuollon tiedonhallinnan osaamisessa oli muilla tutkimukseen osallistuvilla aloilla isoja eroja oman koulutusalan sisällä

Radiological and pathological assessment of response to neoadjuvant CDK4/6 inhibitor and endocrine treatments in a real-life setting : initial results

publishedVersionPeer reviewe