Prostate cancer is the most common cancer in men and diagnosis involves a combination of assessments. Levels of the biomarker prostate-specific antigen (PSA) are commonly measured, but do not always equate to cancer status. Testing of PSA in combination with other biomarkers may help to improve diagnostic and prognostic accuracy, as well as minimizing overdiagnosis as well as unnecessary intervention. This article provides a summary of the information currently known about biomarkers showing promise for use in prostate cancer screening.

by Dr Alexandra Tabakin, Dr Sung Un Bang and Dr Isaac Y. Kim

Introduction
Prostate cancer is the most commonly diagnosed cancer type in the USA and second leading cause of cancer deaths in men. In 2018, there will be an estimated 164 690 new cases with an estimated 29 430 deaths [1]. Although many prostate cancers are indolent in nature and can be safely monitored with active surveillance, a significant proportion of patients will require intervention with surgery, radiation, or other therapies. One of the major challenges in treating prostate cancer is risk stratification and differentiating clinically significant prostate cancers in order to avoid overdiagnosis and overtreatment [2]. To do so, patients undergo risk stratification, which conventionally includes a combination of prostate-specific antigen (PSA) screening, digital rectal exam (DRE), trans-rectal ultrasonography (TRUS)-guided biopsy. Currently clinically insignificant prostate cancer, according to Epstein criteria, is defined as cancer with preoperative PSA <10ng/ml, clinical stage <T1c, Gleason score <6, PSA density <0.15, <2 positive biopsy cores, and <50% cancer involvement in any core [3–5]. However, as we learn more about the heterogeneity of prostate cancer tumours, various serum biomarkers have been investigated to improve diagnostic and prognostic accuracy and minimize treatment. In this review, we discuss various biomarkers and their utilization for the prediction of clinically significant prostate cancer.

Serum biomarkers
PSA
PSA, or prostate-specific antigen, is a serine protease released by the prostate. PSA gained notoriety in the 1980s when it was reported to have various uses including screening, monitoring disease progression, and detecting recurrence of the cancer. As PSA screening for prostate cancer increased, the incidence of prostate cancer also rose in the 1990s. However, PSA only has a 25–40% specificity rate for prostate cancer and can be elevated with infection, trauma, and benign prostatic hyperplasia (BPH) [6]. In fact, about 15% of men with a low level of PSA (<4.0 ng/ml) have prostate cancer [7].

Because the harms of biopsy and prostate cancer treatment may outweigh the benefits in some patients with clinically insignificant prostate cancer, efforts have been made to improve the validity of PSA in differentiating benign conditions and prostate cancer. One such effort is the use of free PSA; those with an elevated PSA and a lower serum percentage of free PSA (%f-PSA) are more likely to have BPH rather than prostate cancer [8]. The Prostate Health Index (PHI) formula incorporates serum total PSA, free PSA, and the [−2]proPSA to discriminate Gleason 3+4 and greater cancers with 90% sensitivity and 17% specificity [9]. 4K score is another novel test which is comprised of total PSA, free PSA, intact PSA, and human kallikrein-related peptidase 2 to detect clinically significant prostate cancer and discern those who would benefit from a prostate biopsy while preventing 30–58% of biopsies [10].

PAP
Prostatic acid phosphatase (PAP) was the first popularized prostate cancer serum biomarker, but was eventually replaced by PSA, as it is less sensitive in diagnosing prostate cancer and detecting recurrence. Elevated PAP level has been associated with a high risk of bone metastases [11], significantly shortened overall survival [12] as well as disease-free survival [13], and increased risk of biochemical recurrence [14]. Interestingly, recent studies have shown that PAP may be useful in detecting high-risk clinically significant prostate cancer patients; it is speculated that PAP may be associated with micro-metastatic disease prior to treatment, and therefore, predict response to treatment [15].

NLR, ANC, ALC
Inflammation and tissue microenvironment are important factors in cancer development. Although the temporal relationship is not well established, a lymphocyte-mediated immune response is thought to occur early in the development of prostate cancer. Neutrophil-to-lymphocyte ratio (NLR) compares the activity of both neutrophils and lymphocytes in the inflammatory response. NLR is a useful prognostic biomarker in mCRPC, where a higher score correlates less relative lymphocyte activity and a worse prognosis. When looking at localized low-risk prostate cancer, studies have shown that NLR is not associated with upstaging, upgrading, or biochemical recurrence. However, increased absolute lymphocyte count (ALC) and absolute neutrophil count (ANC) were associated with upstaging and lower 5-year biochemical recurrence-free survival. More development on these markers may guide clinicians in re-stratifying patients who meet conventional criteria for low-risk prostate cancer [16].

Urine biomarkers
PCA3
Urinary prostate cancer antigen 3 (PCA3) is among the most promising non-invasive biomarker among non-PSA based tests, as it is overexpressed in over 95% of prostate cancers [6]. PCA3 is a long noncoding RNA collected from shed prostate cells during urination. PCA3 is a more specific biomarker for prostate cancer because, unlike PSA, PCA3 levels are not influenced by prostate size, BPH, prostatitis, or the use of 5α-reductase inhibitors [17]. At the genetic level, PCA3 may help distinguish between prostate cancer and high-grade prostatic intraepithelial neoplasia (HG-PIN), as PCA3 is seldom expressed in HG-PIN [18]. Several studies have demonstrated that a higher PCA3 score correlates with clinically significant prostate cancer and larger tumour volume, therefore potentially aiding in selecting patients for active surveillance [19]. In 2012, the FDA approved the PROGENSA PCA3 assay predict men who would benefit from a repeat biopsy in those with a previous negative prostate biopsy [6]. In a recent meta-analysis of 46 clinical trials, the sensitivity and specificity of PROGENSA PCA3 was 65% and 73%, respectively [20].

Genetic mutations
TMPRSS2::ERG
TMPRSS2::ERG, or T2:ERG, gene fusions constitute 90% of gene fusions implicated in prostate cancer, as well as half of all prostate cancers [21, 22]. When the androgen responsive regulatory element TMPRSS2 and the gene for the transcription factor ERG are fused together, androgen-driven genes are overexpressed and tumorigenesis occurs [21]. When used alone, urinary T2:ERG RNA has a reported 86% specificity and 45% sensitivity in prostate cancer detection. However, when used in conjunction with PCA3, specificity and sensitivity improve to 90% and 80%, respectively [6, 23]. Moreover, this test may prevent up to 42% of unnecessary biopsies, limiting healthcare costs [24].

PTEN
Loss of the tumour-suppressor gene, PTEN, or phosphatase and tensin homologue, leading to activation of the PI3K/AKT/mTOR signalling has been found in both early stage and castrate-resistant prostate cancers. Preclinical data show that PI3K pathway activation is related to resistance to androgen deprivation, leading to disease progression and poor response to treatment. In mouse models, conditional deletion of PTEN initially led to the development of prostate hyperplasia and later on invasive and metastatic prostate cancers likely by modulating the p110β catalytic subunit of PI3K. In addition, ablation of p110β hindered AKT signalling and reduced tumorigenesis [25]. In a cohort of 77 men, loss of PTEN at initial prostate biopsy was predictive of the development of castrate-resistant prostate cancer, response to androgen deprivation therapy, and prostate-cancer-specific mortality [26]. Additionally, decreased PTEN expression has been associated with increased risk of biochemical and clinical recurrence after prostatectomy [27]. Therefore, the association between castrate-resistant prostate cancer and PTEN loss as well as PI3K/AKT/mTOR pathway activation suggests that PTEN may have prognostic value in prostate cancer risk stratification.

CHD1
The CHD1 gene, encoding chromodomain helicase DNA-binding protein 1, is commonly deleted in 10–26% of all prostate cancers. The loss of CHD1 affects the ability to repair DNA double-strand breaks via homologous recombination. CHD1 deletion has generally been associated with a poor prognosis. However, studies have demonstrated tumours with CHD1 deletions to be sensitive to both PARP inhibitors and carboplatin, both in vitro and in vivo, suggesting that future research may be able to identify to response to treatment based off of tumour genotypes [28].

Circulating biologics
Circulating tumour cells
Circulating tumour cells (CTCs) are defined as cells that leave the site of a primary cancer, travel through the bloodstream, and settle at other sites in the body where they grow into new tumours, or metastases [29]. In 2004, CellSearch Circulating Tumor Cell System was approved by the FDA as an assay for enumerating CTCs. In recent studies, CTC count, deemed the ‘liquid biopsy’, has been shown to have a role in predicting overall survival and response to treatment, risk stratification, and detecting metastases. In addition, using CTCs to detect biomarkers, such as ERG, PTEN, and AR may allow for personalized treatments based on tumour genomes [9, 30].

Circulating exosomes
Circulating prostate cancer-related exosomes are double-membrane vesicles carrying RNA and pro-oncogenic molecules, which induce malignant transformation in normal cells. ExoDx prostate Intelliscore urine exosome assay (developed by Exosome Diagnostics Inc.) detects exosomal RNA expression of ERG, PCA3 and SPDEF (SAM pointed domain containing ETS transcription factor) in voided urine samples. A score is generated that is able to predict high-grade prostate cancer (Gleason >7) with a negative predictive value of 91%. This assay may be useful in discriminating clinically significant prostate cancer and reducing the number of unnecessary biopsies [31].

Conclusion
The emergence and widespread usage of PSA as a routine screening test for prostate cancer allows for early detection and risk stratification. Testing for PSA in combination with novel biomarkers such as PCA3, TMPRSS2::ERG, PTEN, and others may improve our diagnostic abilities, given the heterogeneity of prostate cancers and their treatments. There are many challenges in establishing useful biomarkers including creating affordable and accessible testing, determining cut-offs, and determining accuracy. As the clinical utility of these biomarkers is further defined, we hope to better risk stratify patients and select appropriate treatments early on in diagnosis. Further research efforts should focus on the synergism between the Epstein criteria, biomarker utility, and how to best bring these tools from bench to bedside.

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The authors
Alexandra Tabakin MD,
Sung Un Bang MD, Isaac Yi Kim MD PhD
Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Division of Urology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA

*Corresponding author
E-mail: kimiy@cinj.rutgers.edu

Lyme disease is caused by Borrelia spirochaetes: predominantly Borrelia burgdorferi in North America (but also present in Europe), and predominantly B. afzelii and B. garinii in Europe and Asia and is spread to people via infected deer ticks. Infection occurs after only a minority of tick bites, but is typified by three stages. Stage 1, early localized lyme disease is characterized by the bull’s eye rash (erythema migrans (EM)). Stage 2, early disseminated infection occurs within days to weeks after the local infection as the bacteria begin to spread through the bloodstream. Stage 3, late disseminated infection, where the infection has spread throughout the body, can occur several months later in untreated or inadequately treated patients involving chronic symptoms that can be severe and disabling. Treatment by antibiotics is effective in the early localized stage of the disease but this is often hampered by late diagnosis. Diagnosis can be delayed for a number of reasons: there is a lack of awareness in the general public (as well as GPs outside of what are thought to be the high-risk areas); approximately 25% of people do not get the typical bull’s eye rash; and symptoms can be so varied and vague that, when occurring weeks or months later, are difficult to relate back to the time of the tick bite. Knowledge of a tick bite and an associated EM rash is sufficient for diagnosis. However, in cases where there is a clinical suspicion of Lyme disease but no EM rash, laboratory testing is advised. Testing for antibodies is done via a two-tiered approach, starting with a sensitive ELISA, which, if positive or equivocal, is followed by a more specific immunoblot. However, the overall sensitivity of the two-tiered tests is only 64% when done in the early stages of infection, which is when accurate diagnosis is most needed. Because of these diagnostic limitations, the prevalence of Lyme disease is likely to be far higher than is currently thought. With increasing incidence and geographic spread of the disease, better testing for diagnosis, particularly in the early stages of infection, is perhaps required. Research is ongoing into PCR methods as well as and for the detection of OspA antigens that are shed into urine. An LLT-MELISA (lymphocyte transformation test-memory lymphocyte immunostimulation assay) has been developed and is suggested to be a useful supportive diagnostic tool, particularly in infections acquired in Europe. In the USA, next-generation sequencing (NGS) has been used for specific pathogen identification and to guide treatment decisions. With technological advances making NGS quicker and cheaper, could this eventually become the next gold standard test for Lyme disease?

Point-of-care testing (POCT) is becoming an important part of laboratory medicine although instruments are not operated by laboratory personnel. In this study, we describe the planning and insertion of regulated policies for POCT and quality management, outside of the clinical laboratory. Our results emphasize the importance of the clinical laboratory department involvement to ensure accountable and accurate results in POCT testing.

by Dr Judith Attias, Svetlana Timoshchuk and Dr Marielle Kaplan

Introduction
Point-of-care testing (POCT) refers to tests conducted outside of the central clinical laboratory division. Point-of-care (POC) tests are performed mainly by clinical staff (nurses, physicians, respiratory therapists, etc) and not by clinical lab medicine specialists who understand and work in compliance with quality control (QC) and quality assurance (QA) practices [1]. The major advantage of POCT is the improvement in turnaround time (TAT) of the results by removing transport and clinical lab processing times [2]. As a result, the global POCT market is growing steadily in recent years and it is expected to grow from 23.16 billion USD in 2016 to 36.96 billion USD in 2021 [3]. POCT can be performed in primary, secondary or tertiary healthcare institutions. The list of tests that are permitted to be performed outside the clinical lab differs from one country to another, as do the requirements for quality management, ISO 22870 insertion included [4]. In Europe, current POCT exists for complete blood count including five-part differential, pregnancy testing, blood glucose concentration, cardiac biomarkers, coagulation testing, platelet function, group A streptococcus, HIV testing, malaria screening, etc.

In Israel, a list of the tests allowed to be performed as POC tests (published by the Ministry of Health), as well as the QA requirement exists but, in fact, until recently no policy was applied for POCT insertion and specialist involvement (clinical lab staff and biomedical engineering).

The aim of our work was to list all POCT conducted in a major hospital (1000 beds) located in the north of Israel, to insert a policy for device insertion, to plan and insert a QC and QA programme and to determinate the role of the clinical lab department.

Methods
First a list of all the POCT devices dispersed all over the hospital departments was prepared by the clinical lab department while building up a strong collaboration with the biomedical engineering unit, thus allowing a multidisciplinary approach.

All the blood gas instruments were replaced by GEM family devices to ensure standardization, and connected to the hospital laboratory information system (LIS), as were the glucometers.

Then a policy for POCT insertion was written. A committee composed of representatives of the clinical lab department directors, the biomedical engineering directors and directors from the department where the POCT procedure was to be employed was formed each time. The definition of the committee’s role was to check the relevance of new POCT device insertion from professional and economic aspects.

A policy for QC performance and frequency was adopted. Four quality indices were adopted and reviewed annually:

• Optimization of the use of tests in the cartridge for blood gas.
• Cancellation of test as a result of wrong identification of the patients.
• For glucometers, performance of three QC levels by the department’s staff once a month.
• For blood gas devices, standardization in comparison to the clinical lab was performed by the lab staff monthly. The ratio between the lab results and the POCT device results was calculated. A range for acceptable results was determined (0.9–1.1 for pH, 0.8–1.2 for PCO₂ and PO₂).

Results
We have now 80 similar glucometers all over the hospital, 10 blood gas instruments from the same family, no general urine instrument (only sticks similar to the sticks used in the clinical lab) and 2 thromboelastograms (TEGs). At the start of the process only 27% of the departments performed glucose QC. After training, the percentage of departments performing QC had grown to 76%. At the end of 2017, we decided that glucose tests would not be done without QC or if the QC results did not meet the expected target of 100% QC performance (Fig. 1). In 2015, there were seven blood gas analysers in five different departments; the instruments were from three different companies and were not connected to the LIS. Now, ten blood gas devices similar to those used in the clinical lab (GEM family instrument which performed QC after every test) are connected to the LIS and dispersed in eight departments. The clinical lab staff audits the use of reagents annually and performs standardization in comparison to the clinical lab once a month. The results show that not all the reagents are used optimally in all departments. The Ambulatory Operating Theatre (Ambulatory OP, which includes outpatient surgery as well as elective caesarean sections) and Intensive Cardiac Care Unit (ICCU) used only 14% and 56% of the reagents, respectively, in 2017 (Fig. 2). The performance level of the instruments is good for the all instruments. Figure three show the standardization results of the Children’s Intensive Care Unit comparatively to the clinical lab results (Fig. 3). No irregularity was obtained. POCT result cancellation is performed only after a clinician’s request to the clinical lab division by mail to the clinical lab staff.

The cancellation percentage as a result of wrong identification in the different departments is low, less than 1% of the totals tests performed (data not shown). The two thromboelastograms are in the open heart surgery theatre and are mainly used by one specific anesthetist. The anesthetist performs internal QC once a week and also participates in an external QC programme. The clinical lab prepares the specimen to be analysed and the anesthetist perform the tests. The clinical lab staff then receive and review the results. The results demonstrate that the results are acceptable but not always performed in the time limit required.

From 2015 to 2017, three new blood gas devices were inserted in the Intensive Care Unit (ICU), ICCU and ambulatory surgery theatre via the POCT device committee. In 2017 the delivery room requested a blood gas device. The number of blood gas tests ordered monthly by this department was reviewed and found to be low. As the clinical lab agreed to give priority to this department for very quick results, the request for a POC blood gas device in the delivery room was rejected by the POCT committee. At the beginning of 2018, a POCT coagulation device was inserted in one department without any consultation with the POCT committee. As in Israel partial thromboplastin time is not a part of the POC allowed tests, the instrument was removed immediately as a result of the committee’s intervention.

Discussion and Conclusion
Our results demonstrate that clinical lab involvement in POCT management led to QC performance and increase QA and insertion procedure supervision. Our results demonstrate that POCT device insertion may be considerate even when it means no optimum reagent use (depending on the need of immediate results). Laboratories all over the world work according to strict QA standard and improve continually QC performance and QC review to ensure results quality. In clinical lab testing, the majority of quality errors occur in the preanalytical phase, which is performed outside the laboratory [5]. In contrast, for POCT the majority of quality errors occurred in the analytic phase [6]. There is no doubt that POCT reduces TAT but we must consider if there is a price to pay and ensure that we do not significantly lower quality. Catherine Zimmerman proposes in her review to improve clinical lab TAT by reducing the transport time of the tubes to the clinical lab and the analytic processes inside the lab, as well as at the post-analytic phase [7]. Another aspect of this issue is whether POCT improves clinical parameters significantly; for example, the length of patient stay in the Emergency Department or mortality. Some results show that rapid results with POCT did not necessarily lead to shorter stays in the Emergency Department [8]. Larsson et al. show that when properly used, POCT improves patient care, workflow and even provides significant financial benefits [9]. They also agree with Pecoraro et al. who demonstrate that further studies may be required for defining the real utility of POCT on clinical decision making [10].
Our results show only a few cancellations owing to wrong patient identification. It is important to take into consideration the possibility of underestimation because of underreporting and unknown errors. In the clinical lab, results are reviewed before release to the clinicians. If an error of any kind is suspected (for example, identification error), the clinical lab staff call the physician, inquire about the quality of the sample and ask for a new sample if there is any doubt. The source of POCT errors are usually operator incompetence, not adhering to test procedures, and use of uncontrolled reagents and devices. Consequences of POCT error may affect patient management decisions and treatment [11]. In the literature, we cannot find data about the percentage of POCT error, especially when the clinical lab is not involved in the processes.
In conclusion, in a world where everything is happening so fast and any data can be obtained so quickly, the real challenge for the clinical lab profession is to overcome POCT antagonism and, on the contrary, to be involved with and supervise all POCT processes.

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The authors
Judith Attias* PhD, Svetlana Timoshchuk and Marielle Kaplan PhD
Rambam Health Care Campus,
POB9602, Haifa 3109601, Israel

*Corresponding author
E-mail: J_attias@rmc.gov.il