52 research outputs found
Ovarian cancer marker HE4 in hormone-related gynecological conditions and diagnosis of ovarian granulosa cell tumors
Ovarian cancer is commonly diagnosed at an advanced stage as the early stages are symptom-free. Despite the development in the fields of surgery and chemotherapy, the prognosis remains poor. In order to improve the diagnostic methods, research on biomarkers such as HE4 (Human epididymis protein 4) is actively ongoing. According to previous studies, HE4 is sensitive in detecting even early stages of epithelial ovarian cancer, yet its specificity needs further studies.
Altogether 359 women were included in this study. The aims were to evaluate the performance of serum tumor marker HE4 in benign gynecological conditions and to determine confounding factors in the interpretation of the marker analysis. The usability of epithelial ovarian cancer markers HE4 and CA125 in comparison with inhibin B and AMH was evaluated in the diagnosis and follow-up of ovarian granulosa cell tumors.
HE4 serum concentration was not significantly dependent on hormonal factors, which simplifies the interpretation of the serum HE4 assays particularly in women of fertile age. In tubal pregnancies we detected elevated serum HE4 concentrations, and the tubal epithelium showed more intense and continuous immunohistochemical HE4 staining than normal fallopian tubes.
Combining HE4 with CA125 improves accuracy in ovarian cancer diagnostics. However, normal serum levels of these epithelial ovarian cancer markers do not exclude other ovarian cancer subtypes, which must be kept in mind particularly in premenopausal women. The best serum marker for the diagnosis and follow-up of ovarian granulosa cell tumors is inhibin B, yet its accuracy can be further improved by combining AMH to the analysis.MunasarjasyöpÀ on diagnosoitaessa useimmiten laajalle levinnyt, koska alkuvaiheen tauti on oireeton. TÀmÀn vuoksi selviytymisennuste on sekÀ kirurgisten ettÀ lÀÀkkeellisten hoitojen kehityksestÀ huolimatta edelleen huono. Diagnostiikan parantamiseksi tutkimuksissa on kehitetty uusia kasvainmerkkiaineita, kuten HE4 (Human Epididymis Secretory protein 4). HE4 on osoittautunut tehokkaaksi epiteliaalisen munasarjasyövÀn varhaisdiagnostiikassa, mutta sen tarkkuudesta tarvitaan lisÀtutkimuksia.
Tutkimukseen osallistui yhteensÀ 359 naista. Tutkimuksen tarkoituksena oli selvittÀÀ kasvainmerkkiaine HE4:n seerumipitoisuuksien vaihtelua erilaisissa hyvÀnlaatuisissa gynekologisissa tiloissa sekÀ selvittÀÀ mahdollisia virhelÀhteiden vaikutusta merkkiainepitoisuuksien tulkinnassa. LisÀksi arvioitiin epiteliaalisen munasarjasyövÀn merkkiaineiden HE4:n ja CA125:n kÀytettÀvyyttÀ munasarjan granuloosasolukasvainten erotusdiagnostiikassa ja seurannassa verrattuna inhibiini B- ja AMH-merkkiaineisiin.
HE4-merkkiaineen seerumipitoisuuksissa ei todettu hormonivaikutuksesta, kuten yhdistelmÀehkÀisypillereistÀ, kuukautiskierrosta tai koeputkihoitoon liittyvÀstÀ munasarjojen stimulaatiosta, johtuvaa merkittÀvÀÀ vaihtelua. TÀmÀ yksinkertaistaa HE4-mÀÀritysten tulkintaa etenkin fertiili-ikÀisillÀ naisilla. Munanjohdinraskaudessa sen sijaan totesimme kohonneita HE4-seerumipitoisuuksia sekÀ lisÀÀntynyttÀ voimakasta immunohistokemiallista vÀrjÀytymistÀ munanjohtimen epiteelissÀ.
YhdistÀmÀllÀ HE4- ja CA125-mÀÀritykset munasarjasyövÀn diagnostiikassa on pÀÀsty parempaan herkkyyteen ja tarkkuuteen. Etenkin hedelmÀllisessÀ iÀssÀ olevien naisten kohdalla on kuitenkin muistettava, ettÀ nÀiden epiteliaalisen munasarjasyövÀn merkkiaineiden viiterajoissa olevat pitoisuudet eivÀt poissulje harvinaisempia munasarjasyöpÀtyyppejÀ. Munasarjan granuloosasolukasvainten diagnostiikassa ja seurannassa toimivin kasvainmerkkiaine on inhibiini B, jonka diagnostista osuvuutta voidaan parantaa yhdistÀmÀllÀ mÀÀritykseen AMH-pitoisuuden mÀÀritys.Siirretty Doriast
Biomarkers in Ovarian Pathology: From Screening to Diagnosis. Review of the Literature.
Background: Ovarian cancer has a low incidence, but high mortality due to a habitual diagnosis in advanced cancer stages. Currently, used biomarkers have good sensitivity, but low specificity. Aim: To determine the usefulness of the biomarkers and algorithms used up to now in the screening, diagnosis, response to treatments and identification of recurrence in patients with ovarian masses. Methodology: Systematic search of publications in English in the Medline-PubMed database with the terms: âbiomarkersâ, âtumourâ, âtumour biomarkersâ, âmarkerâ, âtumour markerâ, âovarian cancerâ, âovarianâ, âNeoplasmsâ, âcancerâ, CA-125 Antigen; Human Epididymis-specific Protein E4; Risk of Malignancy Index (RMI); Risk of Ovarian Malignancy Algorithm (ROMA); Ovarian Neoplasms. Original articles, clinical trials, reviews, systematic reviews and meta-analyses, published between January 2000 and November 2020, were selected to determine the usefulness (among others) of CA 125 and HE4 antigen in ovarian cancer. Results: Finally, 39 transcendental publications were selected to write this article to determine the usefulness of tumour markers and algorithms in ovarian cancer. Conclusions: The usefulness of the tumour markers antigen CA125 and antigen HE4 individually or as a basis for decision-making algorithms has low specificity; however, there is little evidence that confirms their usefulness as markers in ovarian cancer screening.post-print723 K
Biochemical markers and combination testing for the diagnosis of ovarian cancer in women with symptoms or signs suspicious of ovarian cancer
Ovarian cancer (OC) has the highest mortality of all gynaecological cancers. A significant contributing factor to the high mortality in OC is delayed diagnosis. Currently, there is no consensus regarding the best test for early diagnosis.
A review of existing systematic reviews about symptoms, biochemical markers and US test used alone or in combination for the diagnosis of OC in symptomatic women demonstrated that existing reviews were variable in quality, applicability and limited by poor reporting. I attempted to address these deficiencies in two reviews on the accuracy of biomarkers alone and symptoms, biomarkers or US in combination for the diagnosis of OC in symptomatic women in generalist settings in pre and postmenopausal women separately.
My thesis finds key methodological issues, e.g., literature is not applicable to generalist settings as studies included women typical of tertiary healthcare settings, some studies excluded borderline tumours which inflates estimates of sensitivity, important differences exist in test performance between pre and postmenopausal women. Main results are 1) reviews not applicable to primary care settings â more research is needed. 2) for biomarkers i) HE4 at the threshold of 60-80pMol/L and 130-150pMol/L is recommended in pre and postmenopausal women for low prevalence settings ii) ROMA or LR2 in premenopausal women to replace RMI in secondary/tertiary setting; continue with RMI for postmenopausal women as it shows comparable accuracy to ROMA and LR2
A self-calibrating IoT portable electrochemical immunosensor for serum human epididymis protein 4 as a tumor biomarker for ovarian cancer
Nowadays analytical techniques are moving towards the development of smart biosensing strategies for point-of-care accurate screening of disease biomarkers, such as human epididymis protein 4 (HE4), a recently discovered serum markers for early ovarian cancer diagnosis. In this context, the present work represents the first implementation of a competitive enzyme-labelled magneto-immunoassay exploiting a homemade IoT Wi-Fi cloud-based portable potentiostat for differential pulse voltammetry readout. The electrochemical device was specifically designed capable of autonomous calibration and data processing, switching between calibration and measurement modes: in particular, firstly a baseline estimation algorithm is applied for correct peak computation, then calibration function is built by interpolating data with a four-parameter logistic function. The calibration function parameters are stored on the cloud for inverse prediction to determine the concentration of unknown samples. Interpolation function calibration and concentration evaluation are performed directly on-board, reducing the power consumption. The analytical device was validated in human serum, demonstrating good sensing performance for analysis of HE4 with detection and quantitation limits in human serum of 3.5 and 29.2 pM, respectively, reaching the sensitivity required for diagnostic purposes, with high potential for applications as portable and smart diagnostic tool for point-of-care testing
Preoperative Evaluation of Ovarian Tumors
Munasarjakasvaimet ovat ryhmÀ hyvin erilaisia kasvaimia viattomasta
hyvÀnlaatuisesta kasvaimesta aggressiiviseen syöpÀÀn. Ne ovat usein
sattumalöydöksiÀ oireettomilla naisilla, jopa levinneessÀ syövÀssÀ. Diagnostiikan
kulmakivi on emÀttimen kautta tehtÀvÀ ultraÀÀnitutkimus yhdistettynÀ verestÀ
mitattaviin merkkiaineisiin, joista perinteisesti kÀytetyin on CA125-merkkiaine.
Oikea ja mahdollisimman varhainen diagnoosi vaikuttaa kasvaimen hoitolinjoihin ja
ennusteeseen, joka heikkenee merkittÀvÀsti levinneessÀ syövÀssÀ verrattuna
alkuvaiheen munasarjasyöpÀÀn. RiittÀvÀn laaja leikkaushoito on merkittÀvin
munasarjasyövÀn ennusteeseen vaikuttava tekijÀ. Toisaalta hyvÀnlaatuisten
kasvaimien kohdalla konservatiivinen seurantalinja voi olla riittÀvÀ hoito, jolloin
voidaan vÀlttÀÀ turhia leikkausriskejÀ.
VÀitöskirjan tavoitteena oli tutkia kehittyneempiÀ ultraÀÀnitutkimusmenetelmiÀ ja
-luokitteluja verrattuna perinteiseen kaksiulotteiseen ultraÀÀnitutkimukseen, sekÀ
etsiÀ uusia menetelmiÀ ja mahdollisia merkkiaineita munasarjakasvaimien
erotusdiagnostiikkaan. EnsimmÀisessÀ osatyössÀ tutkittiin 100 vÀhintÀÀn 50-
vuotiasta naista, jotka odottivat munasarjakasvaimen vuoksi tehtÀvÀÀ leikkausta.
Naiset tutkittiin ennen leikkausta kolmiulotteisella ultraÀÀnitutkimuksella sekÀ
moderneilla kaksiulotteiseen ultraÀÀnitutkimukseen perustuvilla luokitteluilla, ja
löydöksiÀ verrattiin keskenÀÀn. MikÀÀn menetelmÀ ei ollut parempi kuin kokeneen
ultraÀÀnitutkijan oma arvio (ns. expert opinion) kaksiulotteisesta
ultraÀÀnitutkimuksesta. Kolmiulotteinen ultraÀÀnitutkimus ei tuonut merkittÀvÀÀ
lisÀarvoa perinteisiin menetelmiin verrattuna. JÀlkikÀteen toinen kokenut
ultraÀÀnitutkija arvioi samat potilaat tallennettujen ultraÀÀnikuvien perusteella, ja
löydösten arviointi oli hyvin yhtenevÀistÀ tutkijoiden kesken.
Tutkimuksia laajennettiin kerÀÀmÀllÀ ennen leikkausta 71 munasarjakasvain- ja 22
kontrollipotilailta virtsanÀytteitÀ, joista analysoitiin ja mitattiin nestekromatografiamassaspektrometrialla polyamiineja. Polyamiinit ovat nisÀkÀssoluissa esiintyviÀ mm. solujen kasvulle vÀlttÀmÀttömiÀ molekyylejÀ, joiden on todettu liittyvÀn myös karsinogeneesiin. Erityisesti asetyloituneiden polyamiinien kohonneita pitoisuuksia elimistön nesteissÀ on todettu useissa syövissÀ. Toisessa osatyössÀ osoitettiin ensimmÀistÀ kertaa diasetyloituneen spermiinin (DiAcSpm) pitoisuuden olevan kohonneen myös munasarjasyöpÀpotilaiden virtsassa verrattuna kontrolleihin ja naisiin, joilla on hyvÀnlaatuinen munasarjakasvain. Korkeimmat virtsan DiAcSpmpitoisuudet mitattiin potilailla, joilla oli huonosti erilaistunut ja levinnyt munasarjasyöpÀ (high-grade syöpÀ). Virtsan DiAcSpm oli tutkimuksessa jopa herkempi merkkiaine kuin yleisesti kÀytetty seerumin CA125 raja-arvolla 35 U/ml
(86.5% vs. 75.7%).
Koirakokeissa on todettu, ettÀ koulutettu koira tunnistaa hajuaistin avulla
syöpÀkudoksen ja syöpÀpotilaan eritteet. Nykyteknologia mahdollistaa analytiikan,
jolla nÀytteen sisÀltÀmien orgaanisten yhdisteiden muodostama hajuspektri
analysoidaan mm. koneellisen nenÀn (elektroninen nenÀ, eNose) avulla.
Kolmannessa osatyössÀ virtsanÀytteet (51 munasarjakasvain- ja 18 kontrollipotilailta)
tutkittiin FAIMS (field asymmetric waveform ion mobility spectrometry)-
teknologialla, joka on ionimobiliteettispektrometrian muunnelma sijoittuen
massaspektrometrian ja elektronisen nenÀn vÀlimaastoon. FAIMS-teknologian avulla
munasarjasyöpÀpotilaiden virtsa erotettiin kontrollien sekÀ hyvÀnlaatuisten
kasvainpotilaiden virtsasta 81.3%:n ja 77.3%:n tarkkuuksilla. High-grade
munasarjasyöpÀÀ sairastavien potilaiden virtsa oli erotettavissa varhaisvaiheen (lowgrade) munasarjasyöpÀÀ sairastavien naisten virtsasta, joka puolestaan erosi
hyvÀnlaatuisten kasvainpotilaiden virtsasta.
MunasarjasyövÀn metaboliatutkimuksissa on todettu muutoksia myös rasvaaineiden
(lipidi) aineenvaihdunnassa syöpÀpotilailla. On kuitenkin ollut epÀselvÀÀ,
mitkÀ lipidiryhmÀt muuttuvat erityisesti. Aiemmassa suomalais-saksalaisessa
tutkimuksessa todettiin lÀhes kaikkien lipidien pitoisuuden laskevan high-grade
seröösiÀ munasarjasyöpÀÀ sairastavien potilaiden veressÀ verrattuna naisiin, joilla oli
hyvÀnlaatuinen gynekologinen sairaus. NeljÀnnessÀ osatyössÀ
lipidiaineenvaihdunnan muutoksia tutkittiin 354 verinÀytteestÀ, jotka oli otettu
varhais- ja levinneen vaiheen sekÀ erilaisia syöpÀkasvaintyyppejÀ (muitakin kuin
seröösi) sairastavilta munasarjasyöpÀpotilailta ja hyvÀnlaatuista gynekologista
sairautta sairastavilta naisilta. YhteensÀ 39 lipidiÀ oli samansuuntaisesti ja pÀÀosin
tilastollisesti merkitsevÀsti muuttunut sekÀ varhais- ettÀ myöhÀisasteen syövissÀ, ja 23 nÀistÀ lipideistÀ oli muuttunut myös kaikissa kasvaintyypeissÀ. PÀÀosin
lipidipitoisuudet olivat vÀhentyneet syöpÀpotilaiden veressÀ verrattuna eisyöpÀpotilaiden verinÀytteisiin. Vain yksi keramidi (Cer[d18:1/18:0]) ja
triasyyliglyseroli (TAG[18:1/18:1/20:4]) olivat kohonneet kaikissa
levinneisyysasteissa ja kudostyypeissÀ. LipidiyhdistelmÀt yhdessÀ seerumin CA125-
pitoisuuden kanssa paransivat diagnostista osuvuutta yksittÀiseen CA125-arvoon
verrattuna.
Kokeneen tutkijan oma arvio kasvaimen laadusta perinteisessÀ kaksiulotteisessa
ultraÀÀnitutkimuksessa on edelleen luotettavin ultraÀÀnitutkimusmenetelmÀ
munasarjakasvaimien laatua arvioitaessa. Virtsan polyamiinien mittaaminen, FAIMSteknologia ja seerumin lipidiprofiilin tutkiminen ovat lupaavia uusia objektiivisia
tutkimusmenetelmiÀ munasarjakasvainten arvioinnissa.Ovarian tumors involve a wide range of neoplasms, from innocuous benign tumors
to aggressive cancers. Not seldom are they found by chance, without any notable
symptoms, and, as cancers, they may already have metastasized at that point. The
diagnostic golden standard includes vaginal ultrasound (US) along with serum
biomarkers, traditionally CA125, to assess tumor characteristics. The correct
preoperative diagnosis of cancer is essential, as it allows a prompt referral to a center,
where the operations are performed by gynecologic oncologists. In ovarian cancer
(OC), effective and correct primary surgery is the most important prognostic factor.
On the other hand, conservative follow-up may be sufficient for benign tumors.
Against this background, the aim of this thesis was to study advanced US
modalities and to discover new possible biomarkers or methods to distinguish
ovarian pathology preoperatively. First, we examined 100 at least 50-year-old women
scheduled for surgery with an unclear ovarian tumor using traditional US and
comparing it to various US scoring methods and three-dimensional ultrasound (3D
US) with power Doppler (PD). The findings were compared with the results of
examinations made by another experienced US examiner and also with
histopathological diagnoses. None of the advanced US methods exceeded the
accuracy of the subjective opinion of an expert. In addition, the 3D US with PD
added no significant value to traditional methods. However, the results produced by
two examiners were in good agreement.
To extend our investigation, we collected urine samples from 71 women with
indefinite adnexal masses and from 22 controls, and analyzed urinary polyamines
using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Polyamines
are naturally occurring components of all mammalian cells and have many functions,
including cell growth. They are linked to carcinogenesis, and especially their
diacetylated forms are found to be elevated in many cancers, although not previously
in OC. In Study II, we showed that diacetylated spermine (DiAcSpm) was
significantly elevated in urine from OC patients. While the levels of DiAcSpm
differed even between low-stage OCs and benign ovarian tumors, the highest levels
were found in high-grade OCs. Urinary DiAcSpm was even more sensitive than
serum CA125 with its commonly used cutoff value (35 U/mL): their respective
sensitivities were 86.5% and 75.7%.
Based on previous experiments on the ability of dogs to detect the odor of cancer,
urine samples (60 from women with adnexal tumors and 18 from controls) were also
examined using field asymmetric waveform ion mobility spectrometry (FAIMS), a
novel artificial olfactory technology. In our proof-of-concept Study III, we used
FAIMS to differentiate between ovarian malignancy and benign tumors or controls
with respective accuracies of 77.3% and 81.3%. When only high-grade cancers were
taken into account, the accuracy in distinguishing them from low-grade cancers was
88.7%. Even low-grade cancers were differentiated from benign tumors with an
accuracy of 83.9%.
Metabolic alterations, including lipid changes, in blood and tissues are associated
with OC. However, it is unclear which specific lipids or lipid species are altered. A
previous study showed decreases in levels of nearly all lipid species in blood samples
from high-grade serous ovarian carcinoma patients, compared with women with
benign gynecological disorders. In Study IV, our aim was to validate those previous
results in a larger population, including also low-grade and early-stage cancers and
histological pathology other than only serous. Lipidomic analysis was performed on
354 blood samples from women with OCs or benign gynecological pathologies; the
women were from Finland or Germany. The results were compared with the
previous results from 250 women. A total of 39 lipids were altered consistently and
significantly in both early and late stages in all three cohorts (Finnish, German and
previous study), 23 of them in all histological subtypes. Results showed lower levels
of most of the lipids; there were higher levels of only one ceramide (Cer[d18:1/18:0])
and triacylglycerol (TAG[18:1/18:1/20:4]) in all stages and histologies.
Combinations of some lipids and lipid ratios with CA125 improved the diagnostic
value of serum CA125.
In conclusion, the subjective evaluation of two-dimensional US by an expert
remains the most reliable preoperative diagnostic tool of adnexal masses. Emerging
objective biochemical and biophysical methods include urinary polyamine analysis,
FAIMS technology, and serum lipidomic profile
Molecular profiling of human endometrium and endometriosis
Endometriosis is a common hormone-dependent gynecological disease leading to severe menstrual and/or chronic pelvic pain with or without subfertility. The disease is defined by the presence of endometrium-like tissue outside the uterine cavity, primarily on the pelvic peritoneum, ovaries and infiltrating organs of the peritoneal cavity. The current tools for diagnosis and treatment of endometriosis need to be improved to ensure reliable diagnosis and effective treatment. In addition, endometriosis is associated with increased risk of ovarian cancer and, therefore, the differential diagnosis between the benign and malignant ovarian cysts is of importance.
The long-term objective of the present study was to support the discovery of novel tools for diagnosis and treatment of endometriosis. This was approached by exploiting genome-wide expression analysis of endometriosis specimens. A novel expression profiling -based classification of endometriosis indicated specific subgroups of lesions partially consistent with the clinical appearance, but partially according to unknown factors. The peritoneum of women with endometriosis appeared to be altered in comparison to that of healthy control subjects, suggesting a novel aspect on the pathogenesis of the disease. The evaluation of action and metabolism of sex hormones in endometrium and endometriosis tissue indicated a novel role of androgens in regulation of the tissues. In addition, an enzyme involved in androgen and neurosteroid metabolism, hydroxysteroid (17beta) dehydrogenase 6, was found to be highly up-regulated in endometriosis tissue as compared to healthy endometrium. The enzyme may have a role in the pathogenesis of endometriosis or in the endometriosis associated pain generation. Finally, a new diagnostic biomarker, HE4, was discovered distinguishing patients with ovarian endometriotic cysts from those with malignant ovarian cancer.
The information acquired in this study enables deeper understanding of endometriosis and facilitates the development of improved diagnostic tools and more specific treatments of the diseaseSiirretty Doriast
Ovarian cancer screening in the general population.
Despite significant improvements in therapy, ovarian cancer continues to be a leading cause of death amongst women with gynaecological malignancies. Advanced stage at diagnosis is thought to be a major contributor to mortality. Hence, there is considerable interest in early detection through screening. In the 1990s, Professor Jacobs pioneered the development of a multimodal ovarian cancer screening (OCS) strategy using serum CA125 as the first line screen and pelvic ultrasound as the second line test. This thesis summarises the next steps in the journey with refining of the screening algorithm, feasibility testing in a pilot randomised control trial (RCT) and finally setting up and recruiting 200,000 women into the largest ever RCT . The risk of ovarian cancer in postmenopausal women with elevated CA125 levels was established through a detailed analysis of 1219 pelvic scans from 741 women with raised CA125 levels in the completed trial of 22,000 women. Based on this, the multimodal 'Risk of Ovarian Cancer' (ROC) algorithm was refined and morphology instead of volume was used to interpret the ovarian scans. The refined ROC algorithm was then prospectively evaluated in a pilot RCT of 13,582 postmenopausal women. The trial established that screening using the ROC algorithm was feasible and could achieve high specificity and positive predictive value. The improved performance characteristics of the screening strategy and the experience accumulated in running and organising the pilot trial led to the design and successful implementation of a RCT - the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) - to assess the impact of early detection on disease mortality. The trial commenced in 2001 with recruitment of 202,638 postmenopausal women by September 2005. The issues involved in setting up the trial, recruitment of 202,000 women and the baseline characteristics of this population are described
Screening for gynecological cancers
An estimated 17% of all new cancers in women worldwide are due to cancers of the cervix, the ovary and the uterus. Together, these cancers account for 14.6% of all female cancer deaths. This is a significant societal and economic burden, which can be limited through cancer screening. In the developed world, marked reductions of 50-90% in disease rates have been observed as a result of cervical cancer screening. By contrast, in developing countries, where more than 85% of all new cases and deaths from this cancer are reported, significant challenges need to be overcome. Although cytology remains a key component of cervical screening, the newer molecular tests offer a more targeted, risk-attuned approach. The situation for the other two gynecological cancers is different. The case for ovarian cancer screening has yet to be made with the results of key screening trials in high-and low-risk populations still pending. Screening for endometrial cancer is traditionally not advocated as women become symptomatic during the earlier, treatable stages of disease. However, consideration of screening options for these two cancers is warranted since endometrial cancer rates are on the increase and in ovarian cancer, the high case:fatality ratio remains unchanged. © 2013 Expert Reviews Ltd
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The Utility of CA125 for the Detection of Ovarian Cancer in Primary Care
Background
Ovarian cancer is the 6th most common cancer to affect UK women and has the worst prognosis of any gynaecological cancer. Most women are not diagnosed until the disease is advanced, which leads to poor outcomes. Earlier ovarian cancer diagnosis has the potential to improve these outcomes. Cancer antigen 125 (CA125) is recommended by the National Institute for Health and Care Excellence (NICE) as the first line test for ovarian cancer in symptomatic women presenting to primary care in England. However, the performance of CA125 in this setting is unknown. The overarching aim of this thesis was to determine the diagnostic performance of CA125 for the detection of ovarian cancer when used in primary care, and to develop and evaluate novel approaches to improve its performance and clinical utility.
Key methods
I used routinely collected primary care and cancer registry data from 50,780 women who underwent CA125 testing in England between 1st May 2011 â 31st December 2014. First, I performed a diagnostic accuracy study, calculating the performance of CA125 within the cohort, at the national cut-off (â„35 U/ml), for the detection of ovarian cancer. Diagnostic accuracy metrics were also calculated for other types of cancer and all cancer types combined (secondary study outcomes). I used logistic regression to estimate the probability of ovarian cancer at specific CA125 levels (1-1000 U/ml) for women of different ages. CA125 levels equating to a 3% ovarian cancer probability (the ârisk thresholdâ at which NICE advocates urgent specialist cancer investigation) were identified. Next, I examined the associations between CA125 test result and time from testing to diagnosis, tumour type and cancer stage, in those women with ovarian cancer. Finally, I developed and internally validated ovarian cancer diagnostic prediction models (of varying complexity) in a sub-group of women with a relevant symptom recorded prior to CA125 testing (n=29,962). To inform the development of these models, I conducted a systematic review of existing ovarian cancer detection tools.
Key results
CA125 had a sensitivity of 77%, a specificity of 94% and a Positive Predictive Value (PPV) of 10% for ovarian cancer at the national cut-off (â„35 U/ml). The PPV for all cancers combined was 21% overall, and 33% in women â„50 years of age. 20% of women â„50 years with a raised CA125 level, but no ovarian cancer, had another type of cancer. A CA125 value of 53 U/ml equated to a 3% probability of ovarian cancer overall, but this varied markedly by age (40- year-old: 104 U/ml, 70-year-old: 32 U/ml). Women with a ânormalâ CA125 (<35 U/ml) prior to ovarian cancer diagnosis took twice as long to be diagnosed as those with an âabnormalâ CA125, but more frequently had indolent tumour types and were more likely to be diagnosed at an early stage. An ovarian cancer prediction model, incorporating patient age and CA125 level, outperformed CA125 alone. This model showed excellent discrimination on internal validation (AUC: 0.94). Including symptoms, baseline risk factors and other routine blood tests did not improve model performance.
Conclusions
My findings demonstrate that CA125 is a useful test for ovarian cancer detection in primary care. They also indicate that clinicians should consider other types of cancer in women with high CA125 levels, especially if ovarian cancer has been excluded, in order to prevent diagnostic delay. The models presented in this thesis will allow patients and clinicians to determine the estimated probability of ovarian cancer at any given CA125 level and age. This information could inform individual patient decisions on the need for further investigation. If incorporated into the diagnostic pathway, the models would enable patients to be referred on the basis of ovarian cancer risk rather than a generic CA125 cut-off
ENDOMET database â A means to identify novel diagnostic and prognostic tools for endometriosis
Endometriosis is a common benign hormone reliant inflammatory gynecological disease that affects fertile aged women and has a considerable economic impact on healthcare systems. Symptoms include intense menstrual pain, persistent pelvic pain, and infertility. It is defined by the existence of endometrium-like tissue developing in ectopic locations outside the uterine cavity and inflammation in the peritoneal cavity. Endometriosis presents with multifactorial etiology, and despite extensive research the etiology is still poorly understood. Diagnostic delay from the onset of the disease to when a conclusive diagnosis is reached is between 7â12 years. There is no known cure, although symptoms can be improved with hormonal medications (which often have multiple side effects and prevent pregnancy), or through surgery which carries its own risk. Current non-invasive tools for diagnosis are not sufficiently dependable, and a definite diagnosis is achieved through laparoscopy or laparotomy.
This study was based on two prospective cohorts: The ENDOMET study, including 137 endometriosis patients scheduled for surgery and 62 healthy women, and PROENDO that included 138 endometriosis patients and 33 healthy women.
Our long-term goal with the current study was to support the discovery of innovative new tools for efficient diagnosis of endometriosis as well as tools to further understand the etiology and pathogenesis of the disease. We set about achieving this goal by creating a database, EndometDB, based on a relational data model, implemented with PostgreSQL programming language. The database allows e.g., for the exploration of global genome-wide expression patterns in the peritoneum, endometrium, and in endometriosis lesions of endometriosis patients as well as in the peritoneum and endometrium of healthy control women of reproductive age. The data collected in the EndometDB was also used for the development and validation of a symptom and biomarker-based predictive model designed for risk evaluation and early prediction of endometriosis without invasive diagnostic methods. Using the data in the EndometDB we discovered that compared with the eutopic endometrium, the WNT- signaling pathway is one of the molecular pathways that undergo strong changes in endometriosis. We then evaluated the potential role for secreted frizzled-related protein 2 (SFRP-2, a WNT-signaling pathway modulator), in improving endometriosis lesion border detection. The SFRP-2 expression visualizes the lesion better than previously used markers and can be used to better define lesion size and that the surgical excision of the lesions is complete.ENDOMET tietokanta â Keino tunnistaa uusi diagnostinen ja ennustava työkalu endometrioosille
Endometrioosi on yleinen hyvĂ€nlaatuinen, hormoneista riippuvainen tulehduksellinen lisÀÀntymisikĂ€isten naisten gynekologinen sairaus, joka kuormittaa terveydenhuoltojĂ€rjestelmÀÀ merkittĂ€vĂ€sti. Endometrioositaudin oireita ovat mm. voimakas kuukautiskipu, jatkuva lantion alueen kipu ja hedelmĂ€ttömyys. Sairaus mÀÀritellÀÀn kohdun limakalvon kaltaisen kudoksen esiintymisenĂ€ kohdun ulkopuolella sekĂ€ siihen liittyvĂ€nĂ€ vatsakalvon tulehduksena. Endometrioosin etiologia on monitahoinen, ja laajasta tutkimuksesta huolimatta edelleen huonosti tunnettu. Kesto taudin puhkeamisesta lopullisen diagnoosin saamiseen on usein jopa 7â12 vuotta. Sairauteen ei tunneta parannuskeinoa, mutta oireita voidaan lievittÀÀ esimerkiksi hormonaalisilla lÀÀkkeillĂ€ (joilla on usein monia sivuvaikutuksia ja jotka estĂ€vĂ€t raskauden) tai leikkauksella, johon liittyy omat tunnetut riskit. Nykyiset ei-invasiiviset diagnoosityökalut eivĂ€t ole riittĂ€vĂ€n luotettavia sairauden tunnistamiseen, ja varma endometrioosin diagnoosi saavutetaan laparoskopian tai laparotomian avulla.
TÀmÀ tutkimus perustui kahteen prospektiiviseen kohorttiin: ENDOMET-tutkimuk-seen, johon osallistui 137 endometrioosipotilasta ja 62 terveellistÀ naista, sekÀ PROENDO-tutkimukseen, johon osallistui 138 endometrioosipotilasta ja 33 terveellistÀ naista.
TĂ€ssĂ€ tutkimuksessa pitkĂ€n aikavĂ€lin tavoitteemme oli löytÀÀ uusia työkalujen endometrioosin diagnosointiin, sekĂ€ ymmĂ€rtÀÀ endometrioosin etiologiaa ja patogeneesiĂ€. EnsimmĂ€isessĂ€ vaiheessa loimme EndometDB âtietokannan PostgreSQL-ohjelmointi-kielellĂ€. TĂ€mĂ€n osittain avoimeen kĂ€yttöön vapautetun tietokannan avulla voidaan tutkia genomin, esimerkiksi kaikkien tunnettujen geenien ilmentymistĂ€ peritoneumissa, endo-metriumissa ja endometrioosipotilaiden endometrioosileesioissa EndometDB-tietokantaan kerĂ€ttyjĂ€ tietoja kĂ€ytettiin oireiden ja biomarkkeripohjaisen ennustemallin kehittĂ€miseen ja validointiin. Malli tuottaa riskinarvioinnin endometrioositaudin varhaiseen ennustamiseen ilman laparoskopiaa. KĂ€yttĂ€en EndometDB-tietokannan tietoja havaitsimme, ettĂ€ endo-metrioositautikudoksessa tapahtui voimakkaita geeni-ilmentymisen muutoksia erityisesti geeneissĂ€, jotka liittyvĂ€t WNT-signalointireitin sÀÀtelyyn. Keskeisin löydös oli, ettĂ€ SFRP-2 proteiinin ilmentyminen oli huomattavasti koholla endometrioosikudoksessa ja SFRP-2 proteiinin immunohistokemiallinen vĂ€rjĂ€ys erottaa endometrioosin tautikudoksen terveestĂ€ kudoksesta aiempia merkkiaineita paremmin. LöydetyllĂ€ menetelmĂ€llĂ€ voidaan siten selvittÀÀ tautikudoksen laajuus ja tarvittaessa osoittaa, ettĂ€ leikkauksella on kyetty poistamaan koko sairas kudos
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