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DOI: 10.1148/radiol.2312021754
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(Radiology 2004;231:359-364.)
© RSNA, 2004

Molecular Imaging

Metastatic Renal Cell Carcinoma: CT-guided Immunotherapy as a Technically Feasible and Safe Approach to Delivery of Gene Therapy for Treatment1

Robert D. Suh, MD, Jonathan G. Goldin, MD, Amanda B. Wallace, BS, Ramon E. Sheehan, MD, Stefan B. Heinze, MD, Barbara J. Gitlitz, MD and Robert A. Figlin, MD

1 From the Department of Radiological Sciences, UCLA Medical Center, 10833 Le Conte Ave, B2–168 CHS, Los Angeles, CA 90095-1721. Received December 18, 2002; revision requested February 2, 2003; final revision received August 26; accepted September 29. Address correspondence to R.D.S. (e-mail: rsuh@mednet.ucla.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To assess the technical feasibility and safety of weekly outpatient percutaneous computed tomographic (CT)-guided intratumoral injections of interleukin-2 (IL-2) plasmid DNA in a wide variety of superficial and deep tumor sites.

MATERIALS AND METHODS: Twenty-nine patients with metastatic renal cell carcinoma and a total of 30 lesions measuring 1.0 cm2 or greater in accessible thoracic (n = 15) or abdominal (n = 15) locations underwent up to three cycles of six weekly intratumoral IL-2 plasmid DNA injections. CT was used to guide needle placement and injection. After injection cycle 1, patients whose tumors demonstrated stable (<=25% increase and <=50% decrease in product of lesion diameters) or decreased size (>50% decrease in product of lesion diameters) advanced to injection cycle 2. Patients whose lesions decreased in size by more than 50% over the course of injection cycle 2 were eligible to begin injection cycle 3. An acceptable safety and technical feasibility profile for this technique was deemed to be (a) a safety and feasibility profile similar to that of single-needle biopsy and (b) an absence of serious adverse events (as defined in Title 21 of the Code of Federal Regulations) and/or unacceptable toxicities (as graded according to the National Cancer Institute Common Toxicity Criteria).

RESULTS: A total of 284 intratumoral injections were performed, with a mean of 9.8 injections (range, 6–18 injections) received by each patient. Technical success (needle placement and injection of gene therapy agent) was achieved in all cases. Complications were experienced after 42 (14.8%) of the 284 injections. The most common complication was pneumothorax (at 32 [28.6%] of 112 intrathoracic injections), for which only one patient required catheter drainage. Complications occurred randomly throughout injection cycles and did not appear to increase as patients received more injections (P = .532). No patient experienced serious adverse events or unacceptable toxicities.

CONCLUSION: Percutaneous CT-guided intratumoral immunotherapy injections are technically feasible and can be safely performed.

© RSNA, 2004

Index terms: Computed tomography (CT), guidance, 60.1266, 761.1266, 81.1266, 86.1266, 993.1266 • Genes and genetics • Interventional procedures, 60.1266, 761.1266, 81.1266, 86.1266, 993.1266 • Kidney neoplasms, metastases, 60.33, 761.33, 81.33, 86.33, 993.33 • Kidney neoplasms, therapy, 60.1266, 761.1266, 81.1266, 86.1266, 993.1266


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
The treatment of metastatic renal cell carcinoma (RCC) is a particularly challenging clinical problem because the disease is largely resistant to conventional cytotoxic chemotherapy (1). Newer treatment options revolve around the use of immunotherapeutic agents, particularly recombinant interleukin-2 (IL-2), which is currently the only Food and Drug Administration–approved immunotherapeutic treatment for metastatic RCC (2). Cumulative experience with high-dose intravenous bolus recombinant IL-2 regimens has demonstrated an approximate response rate of 15% (2). However, the success of this technique has been limited by clinically important and occasionally life-threatening side effects, including pulmonary edema, bone marrow dysfunction, and end-organ failure (3–5).

Several gene therapy agents have been developed in an attempt to improve the efficacy of IL-2 and minimize the associated side effects. One such technique involves the introduction of a recombinant gene encoding the IL-2 protein directly into malignant tumor cells in vivo (6). This material, known as Leuvectin (Vical, San Diego, Calif), is a plasmid DNA and lipid complex composed of a plasmid DNA expression vector encoding human IL-2 complexed with 1,2-dimyristyloxypropyl-3-dimethylhydroxyethyl ammonium bromide/dioleoyl phosphatatidyl ethanolamine (DMRIE/DOPE). DMRIE/DOPE is a cationic lipid that has been shown to facilitate transfection with plasmid DNA. When transfected into target tumor cells, the IL-2 gene product is expressed and secreted, generating a systemic antitumor immune response (7).

Results of phase I trials have confirmed that Leuvectin is safe, does not cause systemic toxicity, is well tolerated, and demonstrates biologic activity (8). In animal models, intratumoral gene therapy with IL-2 plasmid DNA has been shown to increase the efficacy of immunotherapy without increasing toxicity (9). A multicenter phase II trial of Leuvectin is currently being undertaken in patients with metastatic RCC. In the study protocol, each patient receives a series of weekly intratumoral injections with image guidance at the same site for 6 consecutive weeks. If reassessment after the first injection cycle reveals radiographic stability or regression of disease, the patient becomes eligible for a second and possibly a third cycle of injections.

If intratumoral immunotherapy is to become a mainstay of treatment for metastatic RCC, a safe and reliable drug delivery technique will be of the utmost importance. Thus, the purpose of our study, which was conducted independently of the aforementioned phase II trial, was to assess the technical feasibility and safety of weekly outpatient percutaneous computed tomographic (CT)-guided intratumoral injections of IL-2 plasmid DNA in a wide variety of superficial and deep tumor sites.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Patients and Protocol
After institutional review board clearance for this study had been obtained, patients with histologically confirmed metastatic RCC who were not eligible for conventional treatment (ie, surgical resection of the primary tumor, chemotherapy, and radiation) or whose tumors had progressed despite conventional treatment were referred to our program. Entry criteria included target lesions of 1.0 cm2 or larger in accessible thoracic or abdominal locations and prior resection of the primary tumor. We chose 1.0 cm2 (measured as the product of lesion diameters at CT) as the smallest acceptable lesion size because we believed that tumors smaller than 1.0 cm2 would be too small to allow safe injection of the entire 1.0-mL volume of Leuvectin. Criteria for exclusion from the study included prior therapy with Leuvectin or IL-2 protein, active autoimmune disease, concurrent anticancer or immunosuppressant therapy, intrathoracic or intraabdominal surgery within 1 month of the study, inadequate bone marrow reserve (white blood cells, <3,000/µL; platelets, <100,000/µL; or hemoglobin, <9 g/dL), and a life expectancy of less than 24 weeks. Written informed consent was obtained from all patients after the risks and benefits of participation had been fully explained.

Ultimately, 29 patients (19 men and 10 women) enrolled in our study. The mean age of our male subjects was 63.4 years (range, 51–73 years); female subjects had a mean age of 63.9 years (range, 39–77 years). Of note, one patient underwent treatment of two separate lesions (one lymph node lesion and one pulmonary lesion); therefore, although only 29 patients were enrolled in our study, 30 lesions were treated. Target lesions ranged from 1.9–48.0 cm2 (mean, 15.9 cm2) in size and were located in the lung (n = 10), the liver (n = 6), lymph nodes (n = 4), the renal fossa (n = 3), the skin and/or subcutaneous tissue (n = 3), adrenal glands (n = 2), the chest wall (n = 1), or the pleura (n = 1). Of the 10 intrapulmonary lesions, two were in the right upper lobe, one was in the right middle lobe, three were in the right lower lobe, two were in the left upper lobe, and two were in the left lower lobe.

After undergoing a baseline CT examination, patients were scheduled for two cycles of image-guided immunotherapy. Each cycle involved weekly intratumoral injections of Leuvectin for a total of 6 weeks. Of note, injection frequency, dose, and technique were predetermined by the manufacturer (Vical) on the basis of results of animal studies and phase I trials (8). Four weeks after the completion of injection cycle 1, patients underwent repeat CT examinations. Those patients whose tumors had remained radiographically stable (defined by the World Health Organization [10] as <=25% increase and <=50% decrease in the product of lesion diameters) or diminished in size (>50% decrease in the product of lesion diameters) were eligible to advance to injection cycle 2; patients whose tumors had substantially increased in size (>25% increase in the product of lesion diameters) were not eligible to advance. All lesion measurements were made by using CT, and all CT scans were read by the same radiologist (R.D.S.). The final decision as to whether a patient would begin a second injection cycle was made after consulting with the referring oncologists (B.J.G., R.A.F.), who evaluated patients for adverse effects of treatment and overall performance status. Four weeks after completion of injection cycle 2, patients underwent repeat CT. Any patients whose tumors had substantially decreased in size (>50% decrease in the product of lesion diameters compared with the same measurements obtained 4 weeks after injection cycle 1) were given the opportunity to complete a third cycle of treatment.

Procedure
CT was the primary imaging modality used to guide procedures. All CT imaging was performed with a HighSpeed Advantage scanner (GE Medical Systems, Milwaukee, Wis). Fluoroscopic imaging was not used in any case. Limited transverse scanning was performed with contiguous image sections and 3-, 5-, or 10-mm collimation (depending on lesion size) through the target lesion before, during, and after needle placement to plan the needle placement approach and to confirm successful and uncomplicated injection. In one patient only, injections were performed with ultrasonographic (US) guidance because his lesion was difficult to visualize at CT performed without contrast material. An ATL HDI 3000 US unit (ATL, Bothell, Wash) was used in this case.

All procedures were performed by the same radiologist (R.D.S.). Patients were prepared and draped in the usual sterile fashion. Local anesthesia was achieved with 1% lidocaine (Xylocaine; AstraZeneca International, Wilmington, Del). No sedative agents were used. Vital signs (temperature, blood pressure, pulse, and oxygen saturation) were measured before injection in all patients. In patients undergoing treatment for pulmonary lesions, blood pressure and oxygen saturation were monitored throughout the procedure.

A 22- or 23-gauge Chiba aspiration needle (Cook, Bloomington, Ind) was used to deliver the gene therapy agent (the smaller-gauge needle was used for all pulmonary lesions). In large heterogeneous tumors, care was taken to place the needle in the most solid portion of the tumor (as determined at baseline CT imaging). After the needle tip was confirmed to be within the selected target lesion, aspiration was applied to the syringe to prevent inadvertent intravenous injection. A total of 1.0 mL of Leuvectin was then slowly injected (over 10–30 seconds) at four separate points within the lesion (ie, 250 µL was injected at each point), followed by a single 1.0-mL injection of normal saline at the fourth injection site to flush the needle. With all transpleural and intrapulmonary injections, the distance from the lesion to the visceral pleural surface was measured and patched with 2–5 mL of autologous blood. When feasible, all pneumothoraces were aspirated through the Chiba needle as it was being withdrawn.

Feasibility and Safety
Before we began this study, it was decided that an acceptable safety and technical feasibility profile for this technique would be (a) a safety and feasibility profile similar to that of single-needle biopsy and (b) an absence of serious adverse events and/or unacceptable toxicities. A serious adverse event, as defined in Title 21 of the Code of Federal Regulations (11), includes any adverse drug experience occurring at any dose that results in death, a life-threatening experience, or persistent disability. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (12); unacceptable toxicity was defined as grade 3 or 4 toxicities or grade 4 vomiting.

Patients who received intrathoracic injections were observed for 4 hours in our posttreatment recovery unit. Chest radiographs were obtained at 2 and 4 hours to evaluate for pneumothorax in these patients. All other patients were observed for at least 1 and up to 4 hours after injection. Vital signs were measured approximately every 15 minutes in all patients during postprocedure observation. All patients completed identical questionnaires regarding the severity of pain they experienced during and after the procedure by using a scale from 1–5, where 1 meant no pain; 3, moderate pain; 4, moderate to severe pain; and 5, severe pain. Before each subsequent injection, patients were evaluated for toxicities from the previous injection and were given the next dose only if no grade 3 or 4 toxicities (12) had occurred. Procedure safety was evaluated by both the radiologist who performed the injections (R.D.S.) and the referring oncologists (B.J.G., R.A.F.). Technical feasibility was evaluated by the primary radiologist (R.D.S.).

Statistical Analysis
We wanted to determine whether patients experienced complications more frequently as they advanced through the injection cycles. To test whether or not complications were related to the number of injections received and/or the injection cycle, a Cochran-Mantel-Haenszel test involving modified Ridit scores was used (13). It was decided that P > .05 would indicate randomness of complications.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Injection Cycle Completion
All 29 patients completed injection cycle 1 (six injections). A total of 17 patients advanced to injection cycle 2; 12 patients had interval tumor progression (a >25% increase in the product of lesion diameters) and, for this reason, did not advance. Of the 17 patients who advanced to injection cycle 2, 15 completed the cycle. Two patients did not receive their last cycle 2 injection owing to respiratory infection in one and pancreatitis in the other. Of note, the case of pancreatitis was believed to be a complication of our injection protocol, while the respiratory infection was considered to be unrelated. Two patients advanced to a third cycle of treatment (the remaining 15 patients who received cycle 2 injections were found to have stable or progressive disease and therefore did not advance). One patient finished injection cycle 3, and the other did not receive her last two injections owing to respiratory infection (her illness was felt to be unrelated to participation in our study). At no point during the study did patients decline further treatment because of the protocol of repeated injections.

Feasibility
A total of 284 injections were performed within the patient group: 174 in injection cycle 1, 100 in injection cycle 2, and 10 in injection cycle 3. The mean number of injections received per patient was 9.8 (range, 6–18); one patient received 18 injections, one patient received 16 injections, 13 patients received 12 injections, two patients received 11 injections, and 12 patients received six injections. There were no cases in which technical placement of the needle and injection of the gene therapy agent could not be achieved. Total procedure duration was approximately 1 hour (not including postprocedure observation), with each injection lasting 10–30 seconds. Figure 1 shows examples of image-guided injection at various target sites. The locations and sizes of the target lesions are listed in Table 1. Figure 2 shows examples of intrapulmonary injections received over two treatment cycles.



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  		Figure 1a. Transverse thin-section CT scans used to guide intratumoral injection of IL-2 plasmid DNA show injection at various target sites, including (a) the lung, (b) the liver, (c) a lymph node, and (d) an adrenal gland. Injections were performed with patients in the prone position.

 


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  		Figure 1b. Transverse thin-section CT scans used to guide intratumoral injection of IL-2 plasmid DNA show injection at various target sites, including (a) the lung, (b) the liver, (c) a lymph node, and (d) an adrenal gland. Injections were performed with patients in the prone position.

 


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  		Figure 1c. Transverse thin-section CT scans used to guide intratumoral injection of IL-2 plasmid DNA show injection at various target sites, including (a) the lung, (b) the liver, (c) a lymph node, and (d) an adrenal gland. Injections were performed with patients in the prone position.

 


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  		Figure 1d. Transverse thin-section CT scans used to guide intratumoral injection of IL-2 plasmid DNA show injection at various target sites, including (a) the lung, (b) the liver, (c) a lymph node, and (d) an adrenal gland. Injections were performed with patients in the prone position.

 

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  		TABLE 1. Location and Size of Target Lesions

 


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  		Figure 2a. Intratumoral immunotherapeutic injection into a pulmonary nodule performed with transverse thin-section CT guidance and the patient, a 79-year-old woman, in the prone position. (a) CT scan obtained during first injection cycle shows successful needle placement in a nodule in the left lower lobe. (b) CT scan obtained during second injection cycle demonstrates interval regression of the nodule.

 


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  		Figure 2b. Intratumoral immunotherapeutic injection into a pulmonary nodule performed with transverse thin-section CT guidance and the patient, a 79-year-old woman, in the prone position. (a) CT scan obtained during first injection cycle shows successful needle placement in a nodule in the left lower lobe. (b) CT scan obtained during second injection cycle demonstrates interval regression of the nodule.

 
Safety
Complications were encountered after 42 (14.8%) of 284 injections (Table 2). The most frequent complication was pneumothorax (with 32 [28.6%] of 112 intrathoracic injections), for which only one patient required placement of a 6-F Turner pneumothorax evacuation catheter (Cook). The catheter was removed after 4 hours of observation, with no recurrence of the pneumothorax. All pneumothoraces occurred during needle placement and were apparent on the limited CT scans used for guidance. With the use of an autologous blood patch as well as manual aspiration of air during needle withdrawal, most patients were observed to have minimal (<=5%), if any, residual pneumothorax on postprocedure CT scans.


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  		TABLE 2. Complications Encountered during Treatment

 
One patient was found to be mildly hypotensive (blood pressure, 96/46 mm Hg; pulse, 80 beats per minute) 15 minutes after injection into a hepatic lesion. A limited CT scan obtained through the lung bases showed no evidence of pneumothorax, hemorrhage, or hematoma. The patient was given a 100-mL bolus of normal saline, after which his blood pressure stabilized at 100–110/50–60 mm Hg. No further fluid resuscitation was required. No patient developed bleeding that resulted in alteration of vital signs or that necessitated fluid resuscitation and/or transfusion.

Although most patients experienced mild discomfort during the injection of local anesthetic, sustained pain either during or after the procedure was reported by only three patients. All other complications, including hemoptysis (after two of 112 intrathoracic injections), hemothorax (after one of 112 intrathoracic injections), pancreatitis (after one of 284 total injections), retroperitoneal hematoma (after one of 284 total injections), and lower extremity dysesthesia (after one of 284 total injections), were self limited and did not require treatment. Of note, the proportion of patients with complications and adverse events did not correlate with the number of injections or the injection cycle (P = .532). Table 3 summarizes the complications encountered with each injection. No patients experienced serious adverse events or unacceptable toxicities.


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  		TABLE 3. Complications Encountered with Each Injection

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Recent advances in the development of gene therapy agents offer new hope in the treatment of metastatic RCC (6–8). Localized intratumoral injection of IL-2 plasmid DNA has been shown to generate a systemic antitumor immune response (7); therefore, immunotherapy injections may ultimately become an effective treatment option even in the setting of widespread metastatic disease. Ideally, these agents will be delivered directly into the same metastatic lesion on a weekly basis for an extended period of time. This requires a safe, reliable, and reproducible method of delivery. The use of cross-sectional imaging to assist in the safe and accurate placement of needles in various sites within the body is a well-established and widely practiced technique (14–18). However, whether regular weekly injections into the same lesion can be performed safely and accurately without increasing the risk of complications is less clearly documented, with studies in the literature limited to only a few cases (19). This is of particular concern in the lung, where potentially substantial morbidity is associated with the development of pneumothorax, hemothorax, and parenchymal hemorrhage.

As previously mentioned, it was decided before commencement of this study that an acceptable safety and technical feasibility profile for this technique would be (a) a safety and feasibility profile similar to that of single-needle biopsy and (b) an absence of serious adverse events (as defined in Title 21 of the Code of Federal Regulations [11]) and/or unacceptable toxicities (as graded according to the National Cancer Institute Common Toxicity Criteria [12]). No patients experienced serious adverse events or unacceptable toxicities, and the complications encountered were similar in both nature and frequency to those reported during single-needle biopsy of the respective thoracic and abdominal organs (20–22).

Our results indicate a pneumothorax rate of 28.6%, which is in keeping with rates quoted in the literature for single-needle biopsy procedures (23,24). On only one occasion was placement of a drainage catheter required to treat an enlarging pneumothorax, resulting in a rate of clinically important complications of less than 1%. Perhaps more important, this treated pneumothorax did not prevent the patient from continuing with and subsequently completing the full course of gene therapy injections. Indeed, one patient developed small pneumothoraces at 11 of 12 lung injections, but none of these pneumothoraces interfered with subsequent routine weekly injections.

One reason for such a low rate of clinically important pneumothorax may have been the techniques used for prevention and early management. All cases of pneumothorax occurred during needle placement and were apparent on the limited CT scans used for guidance. In an attempt to minimize the risk of pneumothorax, the distance from each lesion to the visceral pleural surface was measured and subjected to blood patching after injection. When the Chiba aspirating needle was retracted into the pleural space, all pneumothoraces but one evacuated. With this technique, most patients were observed to have minimal (<=5%), if any, residual pneumothorax on CT scans obtained after removal of the needle.

None of our patients developed clinically important hemorrhage (defined as hemorrhage resulting in alteration of vital signs or requiring fluid resuscitation and/or transfusion). This is probably attributable to the use of a small 23-gauge needle. Clinically important hemoptysis seems to be related to the caliber of the needle and is much more common with needles that are larger than 18 gauge in caliber—particularly the cutting needles used for biopsy (25–27).

A major concern regarding the use of intratumoral immunotherapy as a treatment method for metastatic RCC has been the potential for cumulative damage as a result of frequent injections. Indeed, if immunotherapy were to become an accepted therapy for metastatic disease, weekly injections over an extended period of time might be required. However, our results indicate that complications occur randomly throughout treatment cycles and do not appear to increase in frequency or severity as patients receive more injections. Furthermore, it should be noted that although patients underwent multiple procedures with CT guidance in our study, their cumulative radiation exposure was kept to a minimum. Because all CT scans were limited to the area of interest, the effective dose equivalent received by patients during each treatment session was much less than that received during full diagnostic chest and/or abdominal CT examinations.

Among metastatic tumors, pulmonary parenchymal lesions are particularly challenging to treat owing to a combination of potential difficulties with breath-hold misregistration, limited routes of access, and the use of small-caliber needles, which can be difficult to direct accurately into deep lesions. Despite these problems, we achieved a 100% technical success rate. For patients with multiple metastases, it is clearly important to carefully choose the most appropriate lesion to target for recurrent injections. In patients with metastatic RCC, the target lesion will frequently be within the lung. Although absolute lesion size is an important consideration, ease of access and safety are equally important. For example, a larger lesion that could only be accessed by having the patient in an uncomfortable position, by crossing a fissure, or by placing the needle close to a large blood vessel may be a less sensible choice than a smaller lesion in a potentially more accessible site. In our study, one patient had a deep intrapulmonary lesion which, after initial treatment, became too small (<1 cm in diameter) for us to attempt further treatment. It was therefore decided that a different lesion would be chosen for subsequent injections.

Perhaps the greatest limitation of our study was the lack of available data regarding treatment efficacy. In the larger sense, to truly determine whether CT-guided immunotherapy has an acceptable safety profile, efficacy data are needed because safety can only truly be measured relative to efficacy. For instance, if a therapy is only moderately effective, even mild complications may be unacceptable. On the other hand, if a treatment is very successful (eg, bone marrow transplant for some leukemias), even high-grade toxicities may be tolerable. To this end, multicenter phase II trials are currently in progress to determine the efficacy of this treatment.

In conclusion, we have demonstrated that multiple CT-guided percutaneous intratumoral immunotherapeutic injections can be delivered at a wide variety of tumor sites with excellent technical success and minimal risk of complications. Of particular note, weekly injection of pulmonary lesions is a safe and feasible option. Pneumothorax, the most frequently encountered complication, is rarely clinically important if it is appropriately managed at the time it occurs. Although assessment of treatment efficacy was beyond the scope of this study, phase II trials are currently underway to determine patient response to therapy.


   FOOTNOTES
 
Abbreviations: IL-2 = interleukin-2, RCC = renal cell carcinoma

Author contributions: Guarantors of integrity of entire study, J.G.G., R.D.S.; study concepts, R.D.S., B.J.G., S.B.H., R.A.F.; study design, J.G.G., R.D.S., R.A.F.; literature research, A.B.W., R.E.S.; clinical and experimental studies, B.J.G., R.D.S., R.A.F., S.B.H.; data acquisition and analysis/interpretation, A.B.W., R.E.S.; statistical analysis, A.B.W., R.E.S.; manuscript preparation and definition of intellectual content, A.B.W., R.E.S.; manuscript editing, J.G.G., A.B.W., R.D.S.; manuscript revision/review and final version approval, all authors


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TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

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RADIOLOGY RADIOGRAPHICS RSNA JOURNALS ONLINE