Development and evaluating multimarker models for guiding treatment decisions

Financial support for ProTWIN trial was provided by The Netherlands Organisation for Health Research and Development (ZonMw), the Hague, the Netherlands (grant number 200310004). Parvin Tajik is supported by an AXA Research Fund.Peer reviewedPublisher PD

Future medical applications of single-cell sequencing in cancer

Advances in whole genome amplification and next-generation sequencing methods have enabled genomic analyses of single cells, and these techniques are now beginning to be used to detect genomic lesions in individual cancer cells. Previous approaches have been unable to resolve genomic differences in complex mixtures of cells, such as heterogeneous tumors, despite the importance of characterizing such tumors for cancer treatment. Sequencing of single cells is likely to improve several aspects of medicine, including the early detection of rare tumor cells, monitoring of circulating tumor cells (CTCs), measuring intratumor heterogeneity, and guiding chemotherapy. In this review we discuss the challenges and technical aspects of single-cell sequencing, with a strong focus on genomic copy number, and discuss how this information can be used to diagnose and treat cancer patients

The Potential for Circulating Tumor Cells in Pancreatic Cancer Management.

Pancreatic cancer is one the most lethal malignancies. Only a small proportion of patients with this disease benefit from surgery. Chemotherapy provides only a transient benefit. Though much effort has gone into finding new ways for early diagnosis and treatment, average patient survival has only been improved in the order of months. Circulating tumor cells (CTCs) are shed from primary tumors, including pre-malignant phases. These cells possess information about the genomic characteristics of their tumor source in situ, and their detection and characterization holds potential in early cancer diagnosis, prognosis, and treatment. Liquid Biopsies present an alternative to tumor biopsy that are hard to sample. Below we summarize current methods of CTC detection, the current literature on CTCs in pancreatic cancer, and future perspectives

Prognostication in acute heart failure and cardiogenic shock : focus on electrocardiography and biomarkers

Acute heart failure (AHF) is a leading cause of hospitalizations in patients over the age of 65 worldwide, and is associated with high mortality. Cardiogenic shock (CS), the most severe form of AHF, is characterized by hypotension and end-organ hypoperfusion. Acute coronary syndrome (ACS) precipitates a third of all cases of AHF, and up to 80% of CS. Objective and timely risk assessment in AHF is challenging due to the heterogeneity in its pathophysiology and clinical picture. Risk assessment has traditionally relied on clinical parameters, which may remain subjective or become evident too late, after end-organ dysfunction has become irreversible. Considering the costs and possible adverse effects, application of the most aggressive therapies should be limited to those that most likely procure benefit. The aim of this thesis is to evaluate the prognostic value of electrocardiographic changes and biomarkers in AHF and CS. The patient data come from three cohorts of AHF and two cohorts of CS. All cohorts are independent, prospective, observational, investigator-initiated European cohorts. Study I compared the prognostic value of ventricular conduction blocks (VCB) in patients with new-onset (de novo) AHF and in patients with acutely decompensated chronic heart failure (ADCHF). Study II investigated the role of VCBs in ACS-related CS. Half the patients had a VCB in their baseline ECG, and the presence of any VCB predicted mortality independently of baseline clinical variables or angiographic findings. Studies III-IV investigated the role of two novel biomarkers, sST2 and bio-ADM, in cariogenic shock. Study III showed that sST2 provide strong and complementary prognostic value to NT-proBNP in ACS-related CS, and can help in stratification of patients into low, intermediate and high-risk groups as early as 12 hours after detection of shock. Study IV evaluated in CS patients the prognostic value and association with haemodynamic parameters of bio-ADM compared to lactate. Whereas lactate had good prognostic value in the early phase, its levels normalized during the first 24 hours in the majority of patients, with a decreasing prognostic value thereafter. In contrast, levels of bio-ADM stayed elevated in non-survivors during the first 4 days of intensive care, and bio-ADM had good prognostic value when measured on days 2 to 4. In conclusion, in patients with AHF or CS, electrocardiographic alterations may prove useful in early risk assessment on top of clinical parameters. In addition, biomarkers provide a novel approach in CS risk assessment.Akuutti sydämen vajaatoiminta on yksi yleisimmistä sairaalahoitoon johtavista sairauksista, ja siihen liittyy merkittävä kuolleisuus. Sydänperäinen sokki on akuutin vajaatoiminnan vaikein muoto; sille on tunnusomaista matala verenpaine ja yleinen elimistön verenkierron vajaus. Sepelvaltimotautikohtaus on akuutin vajaatoiminnan taustalla noin kolmasosassa tapauksista, mutta jopa 80 %:ssa tapauksista sydänperäisessä sokissa. Johtuen akuutin vajaatoiminnan kliinisen kuvan ja taustalla vaikuttavien patofysiologisten mekanismien moninaisuudesta objektiivinen ja oikea-aikainen riskinarvio on haastavaa. Varhainen riskinarvio on kuitenkin tärkeää hoitomuotojen valintaa ja ajoitusta ajatellen erityisesti sokkipotilailla. Perinteisesti riskinarvio on perustunut kliinisiin löydöksiin, joiden tulkinnassa voi kuitenkin olla subjektiivisuutta ja ne voivat ilmetä sairauden liian myöhäisessä vaiheessa, kun peruuttamattomia elinvaurioita on jo ehtinyt kehittyä. Huomioiden raskaimpien hoitomuotojen, kuten sydämen apupumppujen, korkea komplikaatioriski ja hinta, niiden käyttö tulisi rajata potilaille jotka todennäköisimmin niistä hyötyvät. Tämän väitöskirjatyön tavoitteena on määrittää sydänsähkökäyrä (EKG) –muutosten sekä uusien biomerkkiaineiden ennustearvo akuutissa sydämen vajaatoiminnassa ja sydänperäisessä sokissa. Väitöskirjatyön potilasmateriaali on peräisin kolmesta akuutin sydämen vajaatoiminnan sekä kahdesta sydänperäisen sokin potilaskohortista. Kaikki aineistot ovat eteneviä, havainnoivia, tutkijalähtöisiä eurooppalaisia potilasaineistoja. Osatyössä I tutkittiin EKG:ssa nähtävien kammiojohtumishäiriöiden yhteyttä kuolleisuuteen potilailla joilla akuutti vajaatoiminta ilmeni ensimmäistä kertaa (de novo) verrattuna potilaisiin joilla oli kroonisen sydämen vajaatoiminnan pahenemisvaihe. Osatyössä II tutkittiin kammiojohtumishäiriöitä äkillisestä sepelvaltimokohtauksesta johtuvassa sydänperäisessä sokissa. Puolella potilaista alkuvaiheen EKG:ssa oli jokin kammiojohtumishäiriö, ja kammiojohtumishäiriöt ennustivat suurempaa kuolleisuutta kliinisistä piirteistä ja sepelvaltimotaudin vaikeusasteesta riippumatta. Osatöissä III ja IV tutkittiin kahden uuden biomerkkiaineen, sST2:n ja bio-ADM:n, ennustearvoa kardiogeenisessä sokissa. Osatyö III osoitti, että sST2:lla ja NT-proBNP:llä on vahva itsenäinen ja toisiaan tukeva ennustearvo sydänperäisessä sokissa, ja niiden yhteismäärityksellä potilaat voidaan jakaa matalan, keskisuuren ja suuren riskin ryhmiin jo 12 tuntia sokin toteamisesta. Osatyö IV määritti bio-ADM:n ennustearvoa sekä yhteyttä hemodynaamisiin muuttujiin verrattuna laktaattiin sydänperäisessä sokissa. Laktaatilla oli hyvä ennustearvo ensimmäisten 24 tunnin aikana sokin toteamisesta, mutta sen pitoisuus normaalistui valtaosalla potilaista 24 tunnissa ja sen ennustearvo väheni sen jälkeen. Korkea bio-ADM pitoisuus heijasti matalaa verenpainetta ja sydämen minuuttivoluumia sekä korkeaa keskuslaskimo- ja keuhkovaltimopainetta, ja bio-ADM:n ennustearvo oli parhaimmillaan kun se mitattiin 2.-4. päivänä sokin toteamisesta. Yhteenvetona voidaan todeta, että EKG-muutoksia voidaan hyödyntää kliinisten muutosten rinnalla varhaisessa riskinarviossa akuuttia sydämen vajaatoimintaa tai sydänperäistä sokkia sairastavilla potilailla. Lisäksi uudet biomerkkiaineet mahdollistavat täysin uuden lähestymistavan sydänperäisen sokin riskinarviossa

Current Utility and Future Applications of ctDNA in Colorectal Cancer

Circulating tumour DNA (ctDNA) shows promise as a minimally invasive biomarker with a myriad of emerging applications including early detection and diagnosis, monitoring of disease and treatment efficacy, and identification of actionable alterations to guide treatment. The potential utility of ctDNA in colorectal carcinoma (CRC) is of particular interest given the limitations of current radiographic imaging and blood-based tumour markers in detecting disease and evaluating therapeutic benefit. While ctDNA has yet to demonstrate clinical utility in CRC, a growing body of research highlights the potential of these novel biomarkers. This chapter provides an overview of the current evidence for employing ctDNA in CRC as well as previewing the future directions that these exciting technologies may take

Identification of Biomarkers for Prostate Cancer

BACKGROUND: Prostate cancer (PCa) was the second most common type of cancer and the fifth leading cause of cancer-related death in men. The great challenge for physicians is being able to accurately predict PCa prognosis and treatment response in order to reduce PCa-speciic mortality while avoiding overtreatment by identifying of when to intervene, and in which patients.CONTENT: Currently, PCa prognosis and treatment decision of PCa involved digital rectal examination, Prostate-Speciic Antigens (PSA), and subsequent biopsies for histopathological staging, known as Gleason score. However, each procedure has its shortcomings. Efforts to find a better clinically meaningful and non-invasive biomarkers still developed involving proteins, circulating tumor cells, nucleic acids, and the ‘omics\u27 approaches.SUMMARY: Biomarkers for PCa will most likely be an assay employing multiple biomarkers in combination using protein and gene microarrays, containing markers that are differentially expressed in PCa

An individualized decision between physical therapy or surgery for patients with degenerative meniscal tears cannot be based on continuous treatment selection markers: a marker-by-treatment analysis of the ESCAPE study

Purpose Marker-by-treatment analyses are promising new methods in internal medicine, but have not yet been implemented in orthopaedics. With this analysis, specific cut-off points may be obtained, that can potentially identify whether meniscal surgery or physical therapy is the superior intervention for an individual patient. This study aimed to introduce a novel approach in orthopaedic research to identify relevant treatment selection markers that affect treatment outcome following meniscal surgery or physical therapy in patients with degenerative meniscal tears. Methods Data were analysed from the ESCAPE trial, which assessed the treatment of patients over 45 years old with a degenerative meniscal tear. The treatment outcome of interest was a clinically relevant improvement on the International Knee Documentation Committee Subjective Knee Form at 3, 12, and 24 months follow-up. Logistic regression models were developed to predict the outcome using baseline characteristics (markers), the treatment (meniscal surgery or physical therapy), and a marker-by-treatment interaction term. Interactions with p < 0.10 were considered as potential treatment selection markers and used these to develop predictiveness curves which provide thresholds to identify marker-based differences in clinical outcomes between the two treatments. Results Potential treatment selection markers included general physical health, pain during activities, knee function, BMI, and age. While some marker-based thresholds could be identified at 3, 12, and 24 months follow-up, none of the baseline characteristics were consistent markers at all three follow-up times. Conclusion This novel in-depth analysis did not result in clear clinical subgroups of patients who are substantially more likely to benefit from either surgery or physical therapy. However, this study may serve as an exemplar for other orthopaedic trials to investigate the heterogeneity in treatment effect. It will help clinicians to quantify the additional benefit of one treatment over another at an individual level, based on the patient's baseline characteristics.Orthopaedics, Trauma Surgery and Rehabilitatio