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AJR 2001; 176:17-22
© American Roentgen Ray Society

Review

Prostate Cancer

What Is the Future Role for Imaging?

John R. Thornbury1, David K. Ornstein2, Peter L. Choyke3, Curtis P. Langlotz4 and Jeffrey C. Weinreb5

1 185 Morgan Pl., Castle Rock, CO 80104.
2 Division of Urology, Department of Surgery, University of North Carolina at Chapel Hill, 427 Burnett-Womack Bldg., CB 7235, Chapel Hill, NC 27599-7235.
3 Department of Diagnostic Radiology, National Institutes of Health, 9000 Rockville Pike, Bldg. 10, Rm. 1C600, Bethesda, MD 20892-1182.
4 eDict Systems, 5 Biddle Way, Mt. Laurel, NJ 08054.
5 Department of Radiology, New York University Medical Center, 530 First Ave., New York, NY 10016.

Received March 7, 2000; accepted after revision June 5, 2000.

 
Presented at the semiannual meeting of the American College of Radiology Imaging Network, Washington, DC, October 1999.

Supported in part by grant CA 80098 from the Department of Health and Human Services.

Address correspondence to J. R. Thornbury.


Introduction
Top
 Introduction
Clinical Perspective
 Future Imaging Strategies
 Cost-Effectiveness and Outcomes...
 The ACR Imaging Network...
 Summary
 References
 
T the aim of this article is to lay out the skeleton of a research agenda for imaging in prostate cancer in the context of the effort to elicit research protocols by the American College of Radiology (ACR) Imaging Network. Our primary purpose is to present the major research questions and to describe the potential future imaging areas to address these questions. A secondary purpose is to make potential investigators aware of resources available through the ACR Imaging Network for developing and conducting such research.


Clinical Perspective
Top
 Introduction
 Clinical Perspective
Future Imaging Strategies
 Cost-Effectiveness and Outcomes...
 The ACR Imaging Network...
 Summary
 References
 
The use of serum prostate-specific antigen (PSA) testing has improved the early diagnosis of prostate cancer and monitoring of patients for disease recurrence. However, several clinical dilemmas remain. Is an elevation in the serum PSA level the result of prostate cancer or a benign process? Once the diagnosis of cancer has been made, clinicians must determine if a patient will benefit from aggressive local therapy and even if any form of therapy is necessary. Finally, clinicians must decide the most appropriate therapy for patients whose potentially curative therapy fails. In the following sections, opportunities for novel prostate cancer imaging strategies are presented.

Diagnosis
Men with serum PSA levels exceeding 2.5 ng/mL have a greater than 20% chance of having prostate cancer detected by needle biopsy, whereas more than 50% of men with a PSA level higher than 10.0 ng/mL have prostate cancer [1, 2]. Likewise, data from large screening trials show that a man with a PSA level of less than 2.5 ng/mL has a 1.0% chance of being diagnosed with prostate cancer within 4 years of follow-up, compared with 12.7% for men with PSA levels between 2.6 and 4.0 ng/mL and 38.4% for men with PSA levels between 4.1 and 10.0 ng/mL [3].

Although randomized trial data are lacking, inferential evidence suggests that PSA-based screening may reduce morbidity and mortality. Screening has also affected the incidence of stages, resulting a dramatic downward stage migration. Because PSA screening enhanced early detection [4], the prostate cancer incidence rose dramatically. However, since 1992, the incidence has slowly returned to baseline levels [5]. Now, most newly diagnosed patients have moderate grade, organ-confined disease [6]. Importantly, cancer detected through PSA screening is usually clinically significant and has greater tumor volume and a higher Gleason grade than autopsy-detected cancer. In 1996, prostate cancer mortality decreased for the first time, perhaps because of PSA screening and early detection programs.

However, serum PSA measurements have limitations [7]. Seventy to 80% of men with "abnormal" findings on a PSA test (>4.0 ng/mL) do not have prostate cancer. Furthermore, nearly 20% of men with biopsy-proven prostate cancer have PSA values in the normal range (<4.0 ng/mL). Finally, as many as 30% of men with PSA-detected prostate cancer do not have organ-confined disease.

Several "PSA derivatives" have been studied in an attempt to limit the number of benign prostate biopsies without missing a significant number of clinically important cancers. These PSA derivatives (testing items related to, or derived from, the traditional serum PSA test) include velocity, density, age-specific reference ranges, serum-free and complexed PSA measurements, serum human kallikrein II measurement, and neural networks. Currently, the most widely used is the serum percent-free PSA measurement. In general, using this measure for men with indeterminate total PSA levels (4.0-10.0 ng/mL) can save 20-30% of unnecessary biopsies and only miss 5-10% of cancers [8].

Some investigators have advocated simply lowering the total PSA threshold from 4.0 to 2.5 ng/mL to enhance detection of cancers at a curable stage. One study showed that 22% of men with benign-feeling prostates and a serum PSA level of 2.6-4.0 ng/mL had positive results at biopsy, and 81% of those cancers were organ-confined [2]. Others have suggested that initiating screening at a younger age (40 instead of 50 years old) will increase the chance of detecting curable prostate cancer, because for any given PSA strata, younger age is a predictor of favorable disease features [9].

Although an abnormal serum PSA measurement suggests cancer, the diagnosis is always made histologically. Transrectal sonographically guided needle biopsy is a safe and effective method of diagnosing prostate cancer. However, a single set of six systematic biopsies may still miss the cancer [10]. More than 20% of men with cancer require more than two sets of biopsies before the diagnosis is made [11]. Two recent studies suggest that taking more than six biopsies at a time enhances cancer detection by as much as 30% [12, 13]. Another study failed to show an advantage for more biopsies [14]. Clearly, new improvements in imaging that could more accurately direct urologists' biopsies to the areas of malignancy would be of great value.

Is Curative Therapy Possible?
Men with high-grade (Gleason grade = 8-10) or advanced stage prostate cancer are much less likely to be cured by radical prostatectomy or radiation therapy than are men with organ-confined and a low or moderate grade of prostate cancer (Gleason grade <= 7) [15, 16]. Ten-year survival per grade was for cancer-specific: low, 94%; moderate, 80%; high, 77%; for metastasis-free: low, 87%; moderate, 62%; high, 52% [16]. Yet a significant number of men with highgrade or locally invasive cancer can be cured with aggressive local therapy. One study found that 59% of men with non—organ-confined prostate cancer were alive without evidence of metastatic disease 10 years after radical prostatectomy [16]. This suggests that assessing the biologic activity could be more important than the anatomic location of prostate cancer.

Although we do not want to subject men to futile therapy, we also do not want to deny them the opportunity for cure. Currently, tables based on clinical stage, serum PSA level, and the biopsy-determined Gleason grade are used to predict the pathologic extent of a given patient's cancer (Table 1) [17]. However, these facts merely provide statistical information, and uncertainties remain regarding optimal therapy for a particular patient. We must develop better methods (e.g., imaging) to determine with greater certainty those men for whom cure is possible or not possible.


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  		TABLE 1 Percentage of T1c Patients with Organ-Confined Disease Predicted Before Surgery from Serum Prostate-Specific Antigen (PSA) Level and Gleason Grade

 

Is Curative Therapy Necessary?
The most appropriate therapy for men with clinically localized prostate cancer remains hotly debated. Prostate cancer can be an indolent malignancy, but it also results in more cancer-related deaths among American men than any other malignancy except lung cancer [18]. Studies from watchful-waiting series suggest that some men will be unlikely to benefit from aggressive local therapy (Table 2) [19]. For example, a 68-year-old man with clinically organ-confined prostate cancer (Gleason grade = 6) and a PSA of 3.9 ng/mL is more likely to die from a cause other than prostate cancer (48% versus 27%) if the prostate cancer is treated conservatively.


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  		TABLE 2 Risk of Death in Men with Conservatively Treated Prostate Cancer Based on 15-Year Outcome

 

Unfortunately, clinicians have no accurate method to determine whether a given man will be among the unlucky men who will die from their prostate cancer unless they are treated. New techniques based on biologic activity imaging are needed to distinguish between life-threatening and clinically indolent prostate cancer.

Recurrent Prostate Cancer After Radical Prostatectomy
Coincident with the downward stage migration of newly diagnosed prostate cancer, the number of patients undergoing potentially curative local prostate cancer therapy has dramatically increased [20, 21]. Although the success rate of radical prostatectomy has greatly improved, 30-40% of men still develop recurrent disease [22]. Serum PSA is a sensitive test to diagnose recurrence, and, typically, an elevated PSA level is the only evidence of treatment failure.

Determining the site of recurrence is important because men with isolated local recurrences are the only ones likely to benefit from radiation or other treatment. The most helpful clinical factors to predict recurrence are the time of the PSA elevation, PSA doubling time, PSA velocity, and pathologic stage and grade. Although these clinical parameters provide some predictive information, the site of recurrence often remains elusive. Further complicating the management of asymptomatic recurrences is the wide variation in the natural history of prostate cancer at this stage.

After the detection of an elevated PSA level after prostatectomy, men develop clinically apparent metastasis after a median of 8 years and die after a median of another 5 years [23]. In other words, men with recurrence may live for as long as another 13 years. These data suggest that not all men with recurrent prostate cancer after radical prostatectomy need treatment. Thus, new tests (e.g., biologically based imaging) are needed that will help clinicians decide the most appropriate treatment strategy for a given man with recurrent prostate cancer.

Conclusion
Despite the recent advances in the care of patients with cancer prostate, many challenges remain. New methods that individualize patients and provide indexes of biologic activity in specific patients are needed. Three areas in which advances in imaging technology are likely to lead to immediate improvements in prostate cancer care are detecting and especially localizing early-stage prostate cancer, identifying those men for whom treatment is necessary and likely to be curative, and determining the site of recurrent disease and the most appropriate treatment strategy.

Completion of the human genome project and major advances in molecular biology will enable us to understand all molecular changes responsible for cancer development and progression. Current reports describe the evidence for prostate cancer susceptibility loci on multiple chromosomes in the hereditary form of this cancer [24, 25]. These molecular and genetic factors will change the way we diagnose and classify human cancer. It will be important to have future imaging technology capable of detecting molecular changes in a specific patient's cancer.


Future Imaging Strategies
Top
 Introduction
 Clinical Perspective
 Future Imaging Strategies
Cost-Effectiveness and Outcomes...
 The ACR Imaging Network...
 Summary
 References
 
Despite revolutionary advances during the past 25 years that have greatly improved our ability to detect and stage malignancies (e.g., lung, colon, and breast cancer), imaging has had a minor role in the care of prostate cancer. For prostate cancer imaging to advance, we must be prepared to look beyond contemporary strategies.

Imaging techniques may be roughly divided into three categories. For the greater part of its history, imaging has largely been based on anatomic alterations—that is, the detection of disorders caused by macroscopic changes in organ structure. Anatomic imaging has been remarkably successful in many cases, such as mammography, but it is inherently limited by its lack of tissue specificity.

Functional imaging is a refinement of anatomic imaging in which physiologic measurements are obtained and displayed within the mass. For instance, the response of a lesion to IV contrast material is a form of functional imaging. The effect of functional imaging on improving patient care is unclear, but many new parameters of tumor function can now be imaged.

Ultimately, diagnosis will be based on the molecular features of tumors rather than anatomic or even functional features. The first step toward molecular diagnosis is being taken when the prognosis of some tumors is based on the presence or absence of certain genetic alterations. The same ex vivo markers used today may soon be used as targets for in vivo labeling for diagnosis and therapy. Molecular imaging is still in its infancy but is the imaging most likely to offer the needed combination of high sensitivity, tissue specificity, and information on tumor aggressiveness.

Different imaging techniques will be reviewed for their future potential role in prostate cancer. This review is not intended to be comprehensive but rather to stimulate interest in the advancement of imaging techniques.

Sonography
Because sonography can accurately reveal the peripheral zone—the region where most cancers develop—some initially advocated this technology for prostate cancer screening. By the mid 1980s, however, it became clear that sonography lacked both the sensitivity and the specificity to be used for early detection. Currently, sonography is primarily used to help guide needle placement for transrectal systematic prostate biopsies. The advent of three-dimensional sonography has not yet altered this role.

Nevertheless, functional imaging is now being done with sonography. Color Doppler sonography depicts flow within the prostate gland and can locate tumors that are otherwise invisible on gray-scale imaging. However, color Doppler signal alone often lacks sufficient specificity [26]. A host of new IV sonographic contrast agents have been developed during the past 10 years [27]. Typically, these are microbubbles that intensely reflect insonated sound waves. These agents are strictly intravascular and better depict tumor vascularity than do conventional imaging agents that quickly leak into the extravascular space [28]. These agents will not necessarily provide improved tissue specificity but rather may provide prognostic information on the degree of angiogenesis and hence the aggressiveness of tumors.

One interesting feature of microbubbles is that they emit harmonic frequencies of the insonating frequency, thus allowing better signal-to-noise ratios because the nonenhancing regions do not produce harmonic frequencies to the same degree [27]. Another interesting feature of microbubbles is that some can be locally destroyed by the application of sound waves. If molecular markers can be inserted into such bubbles, the markers could be selectively delivered to the prostate by destroying the protective bubble only within the prostate. Such work, however, is still at an early stage.

MR Imaging
MR imaging has not been considered a primary screening method for detecting prostate cancer, although its use in men with previously negative findings at biopsy is being studied [29]. To date, the primary goal of MR imaging for prostate cancer has been to detect extracapsular spread of tumor. When good-quality endorectal coil MR imaging is performed with strict adherence to specific feature analysis, it is highly sensitive (80-90%) for the detection of extraprostatic disease [30].

The importance of detecting extracapsular spread is being challenged on the basis of reports of long-term survival (10-year survival, 60-67%) after surgery in men with extracapsular disease [16, 23, 31, 32]. Thus, most urologists are unwilling to deny patients potentially curable resections even if MR imaging suggests extracapsular spread.

However, when used as a functional imaging technique, MR imaging has many desirable features. For instance, MR spectroscopy is considered one of the most promising areas of prostate imaging research. Proton spectra of prostate cancers reveal a depletion of citrate relative to other substrates such as choline and creatine [33]. Voxels, color-encoded to reflect abnormal ratios of metabolites, can be viewed directly as tumor maps [34], especially when MR spectroscopy is combined with MR anatomic imaging. Thus, MR spectroscopy has been shown to improve detection, localization, and staging of prostate cancer as well as to detect recurrent disease after therapy [34]. The magnitude of creatine—citrate ratios is thought to have prognostic value [35].

One limitation of MR spectroscopy is that it has relatively poor spatial resolution ({approx}4 mm). Also, it is technically demanding, requiring specialized software and expertise in obtaining and interpreting spectral peaks. Nonetheless, MR spectroscopy remains a promising functional technique for future study.

Several other MR imaging techniques are also promising. These include dynamic contrast-enhanced MR imaging in which tumor angiogenesis (vascular microdensity) can be assessed [36] and T2*-weighted imaging in which hypoxia may be assessed. Tissue elastography is another potential functional tool provided by MR imaging [37]. These techniques, used together, may provide a more comprehensive evaluation of tumor aggressiveness than anatomic MR imaging now provides. Ultrasmall iron-based particles taken up by the lymphatic system may provide a more sensitive MR method of detecting nodal involvement than other current methods [38].

To date, MR imaging has not entered the realm of molecular imaging, at least not for prostate cancer. However, a number of agents are under development in the laboratory that label a paramagnetic substance, such as gadolinium or iron chelate, to a "universal" ligand, which in turn could be bound to a variety of antibodies, receptors, or intracellular proteins, among other potential targets [39]. This should make it possible to customize contrast agents to individual tumors. A number of potential molecular imaging targets have already been identified, such as the proteins related to the suppressor genes p53 and p27kip1, which are negative prognostic indicators, and p16, which may be involved with tumor neogenesis [40, 41]. To date, no imaging based on these proteins has been performed in vivo.

Nuclear Medicine
Nuclear medicine is considered more a functional than an anatomic technique. Bone scans, for instance, provide poor spatial resolution but are highly sensitive to metabolic activity. The most recent dramatic forays into prostate cancer imaging have been with indium-111 capromab pendetide (Prostascint; Cytogen, Princeton, NJ), a prostate-specific membrane-based antibody labeled to indium [42].

Indium-111 capromab pendetide antibody imaging is used to identify extraprostatic disease in initial stages (i.e., nodal disease) and to detect the site of recurrences after surgery. The antibody is targeted against prostate-specific membrane antigen. It represents a new class of agents that are targeted to specific cellular characteristics. The antibody does not yet play a role in staging; however, it is being used in the treatment decision process [42]. Sensitivity for lymph node involvement is 52-62%, and specificity is 72-96%. Sensitivity for local recurrence in the prostatic bed is 49-77% and specificity 35-71% [43]. These, combined with the steep learning curve associated with its use and the existing usefulness of bone scanning, have limited the use of the indium-111 capromab pendetide antibody in identifying extranodal disease. Although prostate-specific membrane antigen may not be the best target antigen, many other antigens and receptors remain to be studied [44].

Fluorine-18-fluorodeoxyglucose positron emission tomography is enjoying a renaissance in assessing metabolism to detect cancer. The specific uptake value is a reproducible index of metabolic activity and reliably predicts the presence of cancer, at least in cancer of the lung and colon. However, fluorodeoxyglucose positron emission tomography has proven to be disappointing in prostate cancer [45]. Nonetheless, many other positron-emitting radiopharmaceuticals, such as labeled choline, could be targeted specifically to prostate cancer [46].

Other Techniques
Other imaging techniques not yet in the clinical realm hold promise. Electron paramagnetic resonance depends on the resonance of electrons, rather than protons, to produce a signal. The signal is of a much higher frequency but a much lower intensity than proton MR imaging. A number of potential applications exist for electron paramagnetic resonance, especially in mapping tissue hypoxia [47]. Unfortunately, this technique is limited to structures located 1-2 cm from the receiver. An endorectal coil would be required for prostate imaging.

Optical imaging methods are potentially useful in the study of disease. Although they offer superb resolution, few, if any, optical imaging techniques are capable of scanning the prostate externally. However, internal catheter-based optical probes have been developed that offer realtime high-resolution imaging of the prostate [48].

Conclusion
Although prior attempts to impact treatment of prostate cancer have been limited, advances in technology now offer more robust and potentially cost-effective methods. The future of imaging in prostate cancer will depend on the ability to detect prostate cancer, especially in the setting of negative biopsy findings; the ability to determine biologic aggressiveness and predict nodal extension; and the ability to distinguish local and distant recurrences after treatment. Strictly anatomic imaging is unlikely to yield much better results in the future. Functional imaging represents our most immediate hope. The next major frontier will be in the development of molecular imaging and will require the combined skills of molecular biologists, pharmaceutical chemists, imaging specialists, pathologists, and urologists.


Cost-Effectiveness and Outcomes Research
Top
 Introduction
 Clinical Perspective
 Future Imaging Strategies
 Cost-Effectiveness and Outcomes...
The ACR Imaging Network...
 Summary
 References
 
Forty to 60% of men who undergo surgical resection are found to have clinically occult advanced disease after careful pathologic analysis of the excised gland [49,50,51]. Details of extraglandular spread are described by Stamey et al. [49]. This large reservoir of clinically occult advanced disease has generated much interest in new techniques designed to detect preoperatively the spread of disease from the gland. If these understaged men could be identified before surgery using imaging, some of them could be spared the unnecessary risks and costs of prostatectomy and in the future could be treated with other methods more suited to the advanced stage of their disease.

Whether MR imaging of the prosate is an efficacious and cost-effective addition to the conventional staging regimen, and for which groups of men, remain subjects of some controversy and debate. Most of this debate stems from uncertainty about the accuracy of various forms of prostate MR imaging for cancer staging. A large multiinstitutional study [52] suggested that endorectal imaging has lower sensitivity and specificity than body-coil imaging. These results were strikingly different from most previously published data on endorectal prostate MR imaging. A subsequent exchange of views between the study's authors and a group of prostate MR investigators offered explanations for the paradoxic results [53, 54].

Additional studies provide more direct evidence for the efficacy of prostate MR imaging. A study examining the relationship between prostate MR imaging results and biochemical recurrence, as measured by PSA level, suggests that MR imaging findings of definite extracapsular disease predict tumor recurrence with high specificity. Furthermore, the study suggests that subtle features of possible capsular penetration may not be relevant to patient outcome [55].

Since the publication of the Radiology Diagnostic Oncology Group study in 1994 that compared three MR imaging techniques [52], new methods of performing MR imaging of the prostate gland [56] have shown significant potential to improve its clinical usefulness for staging. Decision models, which are essentially mathematic simulations of randomized trials using data from the published literature, have indicated which groups of men may benefit most from MR imaging. Prostate MR imaging may be the most beneficial (and cost saving) for younger men with a high likelihood of clinically occult advanced disease, such as those with high preoperative PSA values or advanced T stage on digital rectal examination (Langlotz CP, unpublished data). Like the many other decisions related to prostate cancer, the results were highly sensitive to patient preferences [57].

The uncertainty about the diagnostic accuracy of imaging of prostate cancer, the dependence of modeling results on patient preferences, and the availability of novel imaging techniques make future outcomes research essential, but also complex. One of the most fruitful avenues for future research would be a definitive randomized trial comparing various forms of imaging-based staging with conventional staging alone. Because prostate cancer mortality is a distant end point, the assessment of near-term end points, such as patient preferences and quality-adjusted life years, is particularly important. Modeling may be helpful in planning such a trial and in quantifying the clinical impact of the trial results, because modeling can identify particular groups of men who may benefit most from diagnostic imaging.


The ACR Imaging Network Research Process and MR Spectroscopy
Top
 Introduction
 Clinical Perspective
 Future Imaging Strategies
 Cost-Effectiveness and Outcomes...
 The ACR Imaging Network...
Summary
 References
 
A promising method for improving the diagnosis of prostate cancer is in vivo proton MR spectroscopy [58, 59]. Preliminary studies suggest that this technique could be valuable for assessing the presence, location, and grade of prostate cancer before and after therapy [34, 60], and it could provide guidance for biopsies and direct cancer therapies [61]. As promising as this may seem, to our knowledge, in the United States, only the group working at the University of California, San Francisco, who developed combined MR imaging and three-dimensional proton spectroscopy for the prostate, has performed diagnostic accuracy studies and preliminary treatment impact type studies that characterize the discovery and early diffusion stages in the emergence of an imaging method [34, 62]. Now the technique must be validated at many institutions, an undertaking that requires an interdisciplinary approach, a well-organized infrastructure, cooperation of multiple vendors, and substantial financial resources.

The ACR Imaging Network was created to facilitate such a study [63]. It is a national cooperative group funded by the Department of Health and Human Services. It is dedicated to improving the health and longevity of patients with cancer through the performance of rigorous, multiinstitutional, interdisciplinary clinical trials (including outcomes and cost-effectiveness [62, 64]) for diagnostic imaging and imaging-guided therapy. The ACR Imaging Network provides an infrastructure for conducting trials and includes among its functions protocol design; biostatistical services; data and image transmission, storage, and management; development and maintenance of standards; quality assurance; and data analysis.

Recently, the Urinary Committee of the ACR Imaging Network has been fostering the development of a preliminary protocol for MR imaging and spectroscopy in prostate cancer. The protocol will be interdisciplinary (MR imaging and spectroscopic experts and clinical specialists) and multiinstitutional. Initial response of the Research Strategy Committee of the Imaging Network was favorable, and this protocol is progressing in the ACR Imaging Network process [63].


Summary
Top
 Introduction
 Clinical Perspective
 Future Imaging Strategies
 Cost-Effectiveness and Outcomes...
 The ACR Imaging Network...
 Summary
References
 
A potential research agenda for the future role of imaging in prostate cancer has been presented. From the clinical perspective, future use of imaging will depend on its potential to more accurately detect and stage prostate cancer; more accurately direct needle biopsies to the actual areas of malignant involvement; aid in the determination of whether a cancer is more likely to be aggressive or indolent; and determine the sites and extent of recurrent disease to aid in treatment decisions.

From an imaging perspective, new methods need to be biologically based in the realm of functional and molecular imaging. Ultimately, new methods will need to reflect genetic aspects of prostate cancer. Investigators should consider the resources potentially available to them from the ACR Imaging Network to enhance their future interdisciplinary, multiinstitutional imaging research.


Acknowledgments
 
The section on Clinical Perspective was written by D. K. Ornstein, the section on Future Imaging Strategies by P. L. Choyke, the section on Cost-Effectiveness and Outcomes Research by C. P. Langlotz, and the section on the ACR Imaging Network Research Process and MR Spectroscopy by J. C. Weinreb and J. R. Thornbury.

Gail P. Jarvik, associate professor of medicine, Division of Medical Genetics, Department of Medicine, University of Washington, generously provided state-of-the-art genetic information and current references about prostate cancer.


References
Top
 Introduction
 Clinical Perspective
 Future Imaging Strategies
 Cost-Effectiveness and Outcomes...
 The ACR Imaging Network...
 Summary
 References
 

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