Ruxandra Sfeatcu1, Mariana C?r?mid?1, Loredana Dumitra?cu1, Dan Lambescu1, Mihaela Adina Dumitrache1
1 U.M.F. Carol Davila, Faculty of Dentistry, Oral health and Community dentistry Department, Bucharest
Abstract
According to the World Health Organization (WHO), "oral health is a state of complete physical, mental and social well-being, and not merely the absence of disease or infirmity". Oral health, an important component of general health, involves more than the existence of healthy teeth, it refers to the entire oral cavity and has profound implications for the body. Good oral health allows the realization of the person's social (socialization, communication) and economic functions. Although the oral health status of the population around the world has seen a marked improvement, oral diseases continue to be a major public health problem, especially in communities belonging to disadvantaged social groups in developed and developing countries, which still face increased levels of oral health impairment.
Keywords: oral health, gingivitis, periodontal disease, caries, schoolchildren, oral cancerIntroduction
According to the World Health Organization (WHO), "oral health is a state of complete physical, mental and social well-being, and not merely the absence of disease or infirmity". Health is an essential dimension of the population's quality of life, which includes both the general state of health and the quality of the medical assistance services offered, thus allowing the person to fulfill his role in society. Oral health is an integral part of this balance, so it is especially important to approach it in the same way as general health. Currently, it is considered that "oral health means more than healthy teeth, the focus being more and more important on the psycho-social implications and the quality of life".
Oral health, an important component of general health, involves more than the existence of healthy teeth, it refers to the entire oral cavity and has profound implications for the body.
Good oral health allows the realization of the person's social (socialization,communication) and economicfunctions. At the same time, poor oral health plays an important role in triggering other organ or system ailments, with serious consequences for the body in the medium and long term [1].
The promotion of oral health at the individual and community level is a strategy that aims to reduce the incidence and severity of oral diseases and to maintain an optimal quality of life-related to oral health.
Most oral diseases can be prevented and should be important priorities for any society. Oro-dental prevention strategies mainly aim at reducing the level of exposure to major risk factors and promoting a healthy lifestyle, and the promotion and implementation of preventive measures is a wise investment.
Thus, the World Health Organization (WHO) approaches oral health as an integral part of general health, with diseases of the oral cavity having an impact on the state of health as a whole (cardiovascular diseases, diabetes, joint diseases, kidney diseases, sinusitis, etc.), on the well-being and quality of life of individuals, but also on the health systems and on society, through the high associated costs (in the 27 countries in Europe, 79 billion euros are spent annually on dental treatment, which represents 5% of the
total expenses for health). Oral and general health have common risk factors related to diet, incorrect personal hygiene practices, tobacco use, and excessive alcohol consumption. The control of oral cavity diseases through health promotion and preventive actions in primary dental care must focus on addressing common risk factors for oral and general diseases [1-3].
WHO implemented in 2003 a Program for oral health that includes several directions of action, of which we list the relevant ones for primary dental care prevention programs at the national level [2]:
Diseases of the oral cavity, although largely preventable, are still major public health problems in Europe and throughout the world, namely the
following: dental caries, periodontal disease, trauma, and oropharyngeal cancer.
Epidemiology of dental caries
According to the World Health Organization, tooth decay remains an important public health problem in Eastern European countries and disadvantaged groups in all European Union member countries, affecting 60–90% of school children and most adults. In the countries of Western Europe and those on the North American continent, there is a tendency to decrease the prevalence and severity of oral diseases, evident especially in children, due to the improvement of eating habits and oral hygiene behaviors, as a result of educational campaigns, the implementation primary dental care prevention programs in schools. In Central and South-Eastern Europe, as a result of the political and economic changes that have occurred in the last 20 years, the health systems are in transition, and the level of oral health of the population is below that of Western and Northern European countries, especially because of cultural and socio-economic differences [1].
For Romania, in 2003, WHO statistics showed that for 6-year-old children, the percentage of those without caries is very low (33.3%), and the value of caries indices, at the level of temporary teeth, is high (cao-d 4 .5), compared to developed European countries – Norway (1.4), Finland (1.5), Belgium (1.7), France (1.7), Austria (2.1), Spain (2.1 ), Sweden (2.4), Germany (2.6). At the level of temporary teeth, there is a ratio of 5/1 in favor of the number of untreated caries compared to that of coronal fillings, which shows that the treatment needs of temporary teeth are very high. In the same context, for 12-year-old schoolchildren, in 2000, a cao-d index of 2.7 was reported, which increased to 3.3 by 2007 [2].
Thus, Romania ranks last in the European hierarchy, with higher values reported by Montenegro, Bosnia-Herzegovina, Albania, Croatia, Lithuania, the Republic of Moldova, and Ukraine. The national study conducted in 2013 demonstrated, in children aged 6–11 years, a prevalence of carious lesions on temporary teeth with a rather high value (75.3%), and for permanent teeth – 39%. The same study shows, at the age of 12, a CAO-D index of 1.88, higher than in other European countries (England 0.7 in 2009, Belgium 0.9 in 2010, Switzerland 0.82 in 2009), given that, for 2011, WHO statistics estimate a global value of 1.61 for the 12-year
-old population, and an average value of 1.95 for Europe [2].
Epidemiology of periodontal disease
Regarding gingivitis and periodontal disease, studies show that gum disease begins in early childhood (5–7 years), with incidence and severity increasing towards adolescence. For the adult population, epidemiological studies show that over 50% of the European population suffers from periodontal diseases and 10% of the entire population presents severe forms of it (increased dental mobility, tooth loss), and for the 60-65 year old group, the proportion of affected subjects severe periodontal disease is 70–85% [3]. Periodontal health is declining as a result of increasing life expectancy and the frequency of diabetes. From this perspective, children and parents should be aware of the risk of gingivitis and periodontal disease. In order to prevent periodontal disease, one should visit the dentist periodically, for professional hygiene, for information on the appropriate brushing technique and the use of age-specific hygiene auxiliary products, and also to detect early signs of periodontal disease.
In the context of this pathology, an aspect of major importance is the state of oral hygiene of children in Romania: the national study carried out in 2013 shows that at the age of 12, when the child must have mastered oral hygiene methods, 92% of students present deposits of dental microbial plaque or tartar, and 22.09% of students have signs of periodontal disease (gingival recessions, periodontal pockets, dental mobility, etc.) [4].
Epidemiology of Oral cancer
Oral cancer, one of the few fatal diseases that dentists may encounter, ranks eighth among the most common forms of cancer worldwide (in 2008 there were 132,000 cases of head and neck cancer, resulting in 62,800 deaths, and the number of cases is increasing, especially in women and young adults, especially in Eastern European countries). Risk factors associated with oral cancer are poor oral hygiene, smoking, and alcohol consumption. Statistics show that 64% of teenagers in Romania smoked in the last 12 months (constantly or occasionally) and also 16.2% of students up to the age of 11 lit up a cigarette for the first time, and of these 1 .5% smoke daily.
The World Health Organization (WHO) has constantly monitored the situation of oral diseases, especially in Europe. The results of epidemiological studies show that over the last 20 years, the prevalence of dental caries in
children and adolescents in developed countries has decreased, while in some developing countries it has increased, as is the case in Romania [3].
Oral health promotion strategies addressed to oral diseases
According to the WHO, carious lesions can be controlled through concerted actions by communities, professionals, and individuals, in order to reduce the impact of sugar consumption and by emphasizing the beneficial role of fluorides, and in developing countries, by increasing access to specialist assistance. From these perspectives, knowing and studying the determinants of health, the trends in oral health and the determining risk factors of oral diseases, as well as the methodology necessary to implement oral health programs for groups at risk are of real importance for establishing effective methods of improvement of oral health [3]. The implementation of oral health promotion programs, with primary dental care prevention strategies for oral diseases, adapted to each age group and type of oral diseases are recommended: sealing, scaling, application of antimicrobial gels with chlorhexidine, periodic control for detection in early stages of caries, marginal periodontopathy, denal-maxillary anomalies and, in particular, precancerous lesions, awareness and education of population groups at risk regarding the etiology and methods of prevention, primary dental care for the main oral diseases, training on personal oral hygiene techniques and adopting a diet without cariogenic potential, with optimal nutrient content, which favors maintaining the functionality of the oral structures.
Although the oral health status of the population around the world has seen a marked improvement, oral diseases continue to be a major public health problem, especially in communities belonging to disadvantaged social groups in developed and developing countries, which still face increased levels of oral health impairment.
Epidemiological studies in our country draw attention to the low level of oral health in Romanian children. Thus, the PAROGIM study in 2013, conducted on a number of 1595 students, aged between 10-17 years, from public schools in Bucharest, showed that 75% of them were affected by caries in the antecedents, and 64% presented untreated caries at the time of the study. The importance of parents' education level is demonstrated by the fact that 70% of children
whose parents had only finished high school had untreated caries, compared to only 49% of children whose parents were university graduates [4].
Another study carried out by GSK Consumer Healthcare (2013) in schools in 7 cities in the country (Bucharest, Iasi, Constan?a, Timisoara, Cluj, Oradea, Craiova), on a group of 6,786 students between the ages of 5 and 13, found that 40% of children under the age of 13 had caries in permanent teeth, 75% of children had caries in temporary teeth, 75% of their teeth had untreated caries, and 4% were extracted because of caries [5].
Another cross-sectional epidemiological study "Oral health Study in Romania", designed and carried out in 2019–2020, focusing on two age groups (6 and 12 years old), aimed to describe the prevalence of caries and the severity of carious lesions in schoolchildren who live in rural and urban areas in Romania and correlate it with behaviors related to oral health. For the 11-14 age group, the lowest prevalence was in Bucharest (73.76%), followed by Oltenia, Moldova, NW Transylvania, Central Transylvania, Muntenia, and the highest in the west of the country, Banat (92, 5%). The prevalence of caries (dentinal caries index) in Romanian schoolchildren is strongly influenced by their socio-economic environment, as well as by their specific consumption behavior. The level of education of the parents, the cariogenic diet, as well as the residence in the rural-urban environment, influence the prevalence of caries in Romanian schoolchildren [6-8].
References
Screeningul în cancerul de prostat?
Prostate cancer screening
George-Daniel R?d?voi1,2
1Department of Urology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
2Department of Urology, “Prof. Dr. Theodor Burghele” Clinical Hospital, Bucharest, Romania
Abstract
Prostate cancer represents one of the most frequent cancers affecting men worldwide. Screening for prostate cancer remains an essential strategy in reducing mortality and morbidity and also in improving the quality of life of men affected by this pathology. On the other hand, there is a fine line between screening, diagnosis, and treatment of prostate cancer and overdiagnosis with unnecessary biopsies. In this direction, many strategies have been carried out, the first evaluation stratifying men into low-risk and high-risk for prostate cancer. Low-risk male patients should undergo an evaluation every eight years, while high-risk male patients are recommended to be evaluated every two years. The aim of this paper is to describe the target population for prostate cancer screening, as well as different methods of prostate cancer assessment and monitoring, in order to ensure the optimum healthcare for male patients.
Keywords: prostate cancer, screening, PSA, MRI, biomarkers
Introduction
Early detection of prostate cancer (PC) in the general population is defined as the systematic screening of asymptomatic men to identify individuals at risk, with the goals of reducing prostate cancer mortality and improving quality of life (QoL). Prostate cancer mortality has a great variation from country to country in the industrialized world [1]. In Western countries, cancer mortality prostate has decreased significantly, but the results differ between countries. Despite all these results, prostate cancer screening remains one of the most controversial topics in the literature [2]. Initially, an aggressive screening was carried out in the United States, which was associated with a decrease in mortality [3]. In 2012, a recommendation against performing PSA screening alone was initiated in the USA, which was adopted in 2013 in the American Urological Association (AUA) guidelines, which in the following years led to a reduction in the use of prostate-specific antigen (PSA) for the early detection of PC [4,5]. Along with the reduction in the use of PSA as a PC detection method, there has been an increase in cases of advanced neoplastic disease at the time of diagnosis. While PC mortality has decreased over the past 2 decades since the introduction of PSA testing, the incidence of advanced stages has increased slowly and progressively since 2008, with a significant decrease in 2012 [6,7]. Most authors emphasize the need and benefits of using PSA as a population-wide screening tool to reduce PC mortality [8,9]. An updated Cochrane review [10] published in 2013, outlines the principles of screening for PC, respectively screening is associated with an increased rate of PC diagnosis and screening is associated with a more frequent diagnosis of localized disease and less advanced prostate cancer.
Risk factors
An individualized strategy for early detection may still be associated with a substantial risk of overdiagnosis. It is essential to remember that separating the diagnosis and the active treatment is the only way to reduce overtreatment while maintaining the potential benefit of early individual diagnosis for patients [11].
Table 1. Summary of the main characteristics of PC*
|
Evidence summary |
Level of evidence |
|
PC represents a major health issue among men, its incidence depending on age |
3 |
|
Genetic factors are associated with a high risk of PC (aggressive form) |
3 |
|
A great variety of diet/exogenous/environmental factors have been associated with the PC incidence and prognosis |
3 |
|
Selenium and vitamin E supplements do not provide a beneficial effect in preventing PC |
2a |
|
In men with hypogonadism, testosterone supplementation does not increase the risk of PC |
2 |
|
There are no data in the literature supporting specific preventive or dietary measures to reduce the risk of developing PC |
1a |
*Adapted after the European Association of Urology guidelines on PC (2022) [12]
Male patients with the age of over 50 years or over 45 years but with a family history of PC are at increased risk of developing PC [13-14]. Germline BRCA 2 mutations are associated with an increased risk of developing aggressive PC. Prostate-specific antigen screening in male BRCA1 and 2 germline mutation carriers managed to diagnose PC at a younger age compared to those without such germline mutations [15]. Men with an initial PSA < 1 ng/mL at age 40 and < 2 ng/mL at age 60 have a low risk of advanced metastatic disease or death from PC several decades later [16].
Patients consulting for an early diagnosis should have a PSA test and a digital rectal examination. The use of rectal examination as the only tool in the diagnosis of PC had a sensitivity and specificity below 60%, possibly due to the lack of experience of the examiner and for this reason, the exclusion of PC cannot be recommended. However, it should be taken into consideration that in 18% of cases, prostate cancer is detected during a rectal examination, regardless of the serum PSA value [17]. Modifications identified during the rectal examination of the patient, in association with elevated serum PSA levels, double the risk of a positive biopsy [18]. Rectal palpation is of great importance in the screening, diagnosis and treatment of PC: an altered rectal palpation is associated with PC with a higher ISUP (International Society of Urological Pathology) grade, can predict progression to clinically significant PC in patients on active surveillance, and represents an indication for performing an MRI and prostate biopsy [18,19].
PSA and digital rectal examination should be repeated, but the optimal intervals for PSA testing and clinical reassessment are unknown, as different results have been published in several prospective studies. A risk-adjusted strategy could be considered based on baseline PSA level. Thus, we can perform this assessment every 2 years for male patients with an initial increased risk or we can delay up to 8 years for male patients at low risk, respectively for patients with an initial PSA serum value less than 1 ng/mL at the age of 40 and a serum PSA value of less than 2 ng/ mL at the age of 60 and a negative family history for prostate cancer [20].
Data from the literature support the recommendation for performing the clinical and biological evaluation with a frequency of every 8 years in men with a baseline PSA concentration <1 μg/L, less than 1% of men with a baseline PSA concentration <1 ng/mL were found to have a PSA concentration above 3 ng/mL at a 4-year follow-up and the 8-year PC diagnosis rate was close to 1% [21].
Table 2. Current recommendations*
|
Recommendation |
Level of recommendation |
|
Do not test men for PSA without counseling them regarding the risks and benefits of PSA testing |
High |
|
Adopting an adapted strategy to the individual risk for early detection PC in well-informed men with a life expectancy of at least 10-15 years |
Low |
|
PSA dosing should be performed on well-informed men with a high risk of developing PC: • Men over the age of 50 • Men over the age of 45 with a family history of PC • Men with African descent, beginning with the age of 45 • Men carrying BRCA2 gene mutation beginning with the age of 40 |
High |
|
Approaching a risk-based strategy (based on the initial value of PSA dosing), with a 2-year reassessment for those initially at risk: • Men with PSA>1 ng/mL at the age of 40 • Men with PSA> 2ng/mL at the age of 60 An 8-year reassessment for those who are not initially at risk |
Low |
|
It is recommended to stop screening for PC men with a life expectancy less than 15 years or who present a reduced performance status (those will probably not present a benefit) |
High |
*Adapted after the European Association of Urology guidelines on PC (2022) [12]
Imaging
Traditionally, transrectal ultrasound (TRUS) represented a way to identify areas in the prostate suspected of being PC, which appear as hypoechoic areas; recent studies have shown that TRUS is not a reliable method of detecting PC, and biopsy hypoechoic areas do not increase the yield of PC diagnosis [22]. New ultrasonographic evaluation methods have been developed, such as HistoScanningTM, micro-doppler, contrast sonoelastography, high-resolution micro-ultrasonography, but these have limited clinical utility, they have not been standardized or evaluated in large-scale studies [23].
MRI (magnetic resonance imaging) is an imaging evaluation method that shows increased sensitivity for the detection and localization of PC lesions with ISUP grade ≥2, especially if the diameter of the lesion is over 10 mm [24]. In a Cochrane meta-analysis, MRI had a sensitivity of 0.91 (95% CI: 0.83–0.95) and a specificity of 0.37 (95% CI: 0.29–0.46) for ISUP≥2 cancers [25]. For ISUP 1 lesions, MRI shows lower sensitivity, identifying less than 30% of cysts with a volume of less than 0.5 cc [24]. MRI evaluation of the prostate was standardized by creating the PI-RADS (Prostate Imaging Reporting and Data System) score, reaching the PI-RADS v2.1 version. A PI-RADS score ≥ 3 shows an increased suspicion of the lesion being malignant and is an indication to perform a prostate biopsy [26].
Despite its usefulness, MRI is not recommended by the European Urological Association Guidelines as a screening method for prostate cancer [12].
Other tools useful in the diagnosis of PC are now available to determine the need for a prostate biopsy to establish the diagnosis of PC.
Biomarkers
Prostate cancer can produce elevated PSA levels per tissue volume compared to benign prostatic hyperplasia. To account for prostate volume, Benson et al. introduced PSA density (PSAD) in the early 1990s [27]. This was done to improve the accuracy of serum PSA testing to differentiate localized PC from benign prostatic hypertrophy. PSAD was calculated by dividing serum PSA by prostate volume, which was measured by transrectal ultrasonography or MRI. Several studies have demonstrated that PSAD has the potential to influence the decision to perform a prostate biopsy by helping to identify men with clinically significant PC. Thus, the PSAD represents a simple-to-use and an inexpensive diagnostic tool allowing a better orientation towards patients who need a prostate biopsy and those who do not [27,28].
The alteration of certain PSA parameters, such as the doubling time (PSADT- the time interval in which the PSA doubles its value) and the PSA velocity (PSAV- the rate of change of PSA/year), provide additional information. Evidence indicates that PSAV has better value in post-treatment monitoring rather than in the pre-treatment setting. PSADT has been a promising element used as a predictive biomarker for the detection of PC in a repeated biopsy, thus demonstrating its potential in avoiding unnecessary prostate biopsies [29]. In the monitoring process of the recurrence or progression of PC after undergoing curative therapy, PSADT can be useful, for example, the presence of a doubling time <3 months revealing a reduced survival. PSADT can also predict the occurrence of metastases [30,31]. The formula used to calculate PSADT is [log(2)*T2-T1(time difference)]/[log PSA2/logPSA1]. PSADT is considered to be more useful when regarding the treatment phases of PC and also in monitoring the recurrence of prostate cancer, rather than in the diagnosis process [32]. PSAV is defined by the absolute annual increase, measured in ng/mL/year. At a cut-off point of 0.3–0.5 ng/mL/year, the specificity of PSAV was 90% in monitoring patients with prostate cancer, compared with 60% if total PSA was used [33].
Prostate-specific antigen is found in the blood in several forms and is classified as free PSA (fPSA) or complexed PSA (cPSA). fPSA does not bind to proteins or carrier molecules, cPSA binds to protease inhibitors (α1-antichymotrypsin, α2 macroglobulin or α1-antitrypsin). fPSA levels are generally expressed as a percentage of total PSA (%fPSA). In general, men with PC have low %fPSA levels compared to men without PC, the fPSA level tends to decrease in association with PC, and clinicians can distinguish PC from benign prostatic hyperplasia [34]. In addition, maneuvers that stimulate the prostate, such as digital rectal examination and prostatic puncture, lead to an increase in the amount of fPSA; also, the increase in prostate volume influences %fPSA, thus %fPSA provides meaningful data only in patients with prostate volume <40 cm3 [35].
The PHI (prostatic health index) test was initially established to aid in the clinically significant detection of PC. The PHI test represents a score calculated from the total PSA, fPSA and proPSA values with the help of the formula (proPSA/fPSA) × √PSA total. ProPSA is a preferentially produced in cancerous cells peptide precursor of mature PSA. Its main advantage is the fact that it permits clinicians to assess individual PSA parameters in association with the overall score. The leading utility of PHI is to diminish the number of unnecessary biopsies performed on patients with borderline PSA serum levels, keeping the detection capacity of aggressive prostatic tumors, thus avoiding unnecessary prostate biopsies performed in male patients with PSA serum levels in the "gray zone", respectively 4-10 nl/mL [36].
There are also other biomarkers that are involved in the pre-diagnosis setting. An optimal biomarker should have the capacity to increment the probability of distinguishing clinically significant PC on biopsied tissues. These biomarkers can be classified into those used to whether the patients present an indication for prostate biopsy (TMPRSS2-ERG score, SelectMDX) and those used to assess the necessity of a re-biopsy (prostate cancer antigen 3 [PCA3]).
SelectMDx represents a urine test designed to identify PC after performing a biopsy. SelectMDx is performed after the prostate massage, measuring mRNA levels of the DLX1 respectively HOXC6 genes (genes that have gained their reputation for being accurate predictors for the identification of high-grade prostate cancer, quantified in urine using qRT-PCR. Further, DLX1 and HOXC6 gene expression levels are assessed alongside clinical parameters (PSA density, rectal palpation, age, and family history information). SelectMDx presents a 98% negative predictive value for a patient with a Gleason score disease ≥ 7 while it presents a 99% negative predictive value for a male patient with a Gleason score disease of 8, while diminishing the number of unnecessary biopsies with up to 53% [37].
Another biomarker involved in determining the necessity for a prostate biopsy is represented by the TMPRSS2-ERG score, which implies chromosomal translocations directing to the fusion of the TMPRSS2 (androgen-regulated transmembrane protease serine 2 gene) and ETS transcription factors (predominantly the ETS-regulated gene - ERG), also known as TMPRSS2-ERG [38]. In order to measure TMPRSS2-ERG mRNA a real-time quantitative polymerase chain reaction (qRT-PCR) is the method used to evaluate urine samples after prostate massage. Concurrently, the PSA mRNA assessment provides the TMPRSS2-ERG score generation as a result of the TMPRSS2-ERG mRNA/PSA mRNA ratio. In the literature, there has been demonstrated the fact that the assessment of the TMPRSS2-ERG gene fusions evaluated in the urine, can predict the PC diagnosis from urine samples performed immediately after prostate biopsy [39].
Prostate cancer antigen 3 (PCA3) also known as DD3 (Differential Display Code 3) represents a non-coding RNA produced almost exclusively in prostate tissue [40]. Bussemakers et al., the pioneers who first identified and described it in 1999, have also shown that the PCA3 gene is significantly overexpressed in cancerous prostatic tissue compared to the normal prostate [41]. Similar to another genetic testing, PCA3 is realized from the urine after prostate massage and with the aim to analyze a qRT-PCR. This method is used because digital rectal examination induces pressure inside the prostate, causing the release of prostate cells through the prostate ducts and into the urethra. The most appropriate cut-off for the FDA-recommended PCA3 score is less than 25, being associated with a low probability of a positive biopsy [41].
|
Table 3. Screening for prostate cancer recommendation*Recommendation |
Level of recommendation |
|
For asymptomatic men with a low PSA serum value between 3-10ng/mL and a normal digital rectal examination, it is necessary to repeat PSA before any other investigation |
Low |
|
For asymptomatic men with a low PSA serum value between 2-10 ng/mL and a normal digital rectal examination, we can use the following tools in order to evaluate the necessity of a prostate biopsy - risk calculators - prostate MRI |
High |
|
- a serum, urine or tissue biomarker test |
Low |
In conclusion, screening for PC should be performed in patients at risk, because screening tests can help detect prostate cancer in early stages, before the appearance of any symptoms. In addition, discovered early, the disease can be successfully treated.
References
41. Bussemakers MJ, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HF, Schalken JA, Debruyne FM, Ru N, Isaacs WB. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 1999 Dec 1;59(23):597