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ORIGINAL ARTICLE
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Rubidium uptake in chest tumors on positron emission tomography/computed tomography


 Department of Radiology, University of North Carolina, Chapel Hill, NC, USA

Date of Submission05-Feb-2021
Date of Decision06-Mar-2021
Date of Acceptance17-Mar-2021
Date of Web Publication12-Jan-2022

Correspondence Address:
Jorge D Oldan,
Department of Radiology, University of North Carolina, Chapel Hill, NC
USA
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/wjnm.wjnm_15_21

   Abstract 

Chest tumors are often found incidentally on cardiac scans; we aimed to describe the findings of rubidium in incidentally discovered extracardiac tumors. We reviewed a database of cardiac rubidium scans performed over a period of 11 years and identified those with a previously unsuspected malignancy seen on the plane of section. We then measured maximum standardized uptake value for each of the tumors, as well as background lung, liver, mediastinum, and body wall. In cases where fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) was available, we compared rubidium results to FDG-PET/CT. We identified 63 patients meeting criteria including full visualization of a tumor of at least 1.0 cm with no prior treatment. Of these patients, 17 had breast, 36 had lung, and 10 had miscellaneous other tumors. We selected patients with either breast or lung tumors for further analysis. Overall uptake was relatively stable between rest and stress but lower than FDG-PET/CT; it was generally low and similar to blood pool. There was a small but statistically significant correlation between estrogen receptor positivity and rubidium uptake in breast tumors. There was a stable pattern of uptake in background tissues, with liver being greater than mediastinal blood pool, which in turn was more avid than lung, which was more avid than subcutaneous body wall tissues. The lung showed a noticeable tendency toward increased uptake in dependent regions, likely reflecting low-level atelectasis. Uptake was stable between rest and stress but low relative to FDG-PET/CT; some correlations with receptors suggest it may be useful in molecular imaging.

Keywords: Chest radiology, oncology, positron emission tomography-computed tomography, rubidium



How to cite this URL:
Oldan JD, Femi-Abodunde AD, Muhleman MA, Khandani AH. Rubidium uptake in chest tumors on positron emission tomography/computed tomography. World J Nucl Med [Epub ahead of print] [cited 2022 Jun 27]. Available from: http://www.wjnm.org/preprintarticle.asp?id=335715


   Introduction Top


Rubidium-82 chloride (82Rb) is a common myocardial perfusion imaging agent moved into myocytes by the sodium-potassium transporter and often used to diagnose ischemia and infarction.[1] Malignancies such as brain tumors,[2],[3] malignant and metastatic pheochromocytoma,[4],[5] and breast metastases and aggressive prostate cancers also take up 82Rb[6],[7] and are incidentally detected in about 2% of cardiac scans.[8] We reported visual comparisons of tumors to background and semiquantitative analysis of uptake and now aim to confirm our previous results in breast and lung tumors (the most common) and assess possible molecular imaging applications.[1]


   Materials and Methods Top


Selection and description of participants

We first obtained Institutional Review Board (ethics committee) approval and ensuring Health Insurance Portability and Accountability Act compatibility for this retrospective study. IRB study number was 18–1137, approved February 5, 2018. Patient consent was waived under exemption for minimal risk in this retrospective study.

We then acquired the names and medical record numbers of all patients who had a cardiac 82Rb positron emission tomography-computed tomography (PET/CT) at our institution from July 1, 2007 to July 1, 2018 and a new diagnosis of breast or lung cancer within 60 days from each other. There were a total of 509 patients, of whom 120 had a malignant lesion within the 82Rb PET/CT field of view, which extended roughly from the aortic arch to the liver to provide attenuation correction (Note that this is significantly higher than the usual overall rate of incidentally discovered lesions of about 2%,[8] as patients were specifically selected for having a new diagnosis of breast or lung cancer within 60 days of the scan). A total of 63 cases fulfilled the following criteria and were therefore investigated further: (1) the entire lesion was captured on both stress and rest images, (2) the lesion had a size of at least 1.0 cm, the usual lower limit for visibility by PET/CT, in order to minimize partial volume effects, (3) histologic diagnosis was available in the electronic medical record system, and (4) the patient had not been previously treated by chemotherapy, radiation, or surgery. From these 63, the most common tumor types were breast (17 cases) and lung (36 cases). Other tumors found included 4 lymphomas, 2 esophageal tumors, a carcinoid of the lung, a carcinosarcoma of the ovary, and lung metastases from GI adenocarcinoma and clear cell renal carcinoma. Given the small numbers of other tumors, we only selected the 53 breast and lung tumors for further analysis. We describe uptake of the other 10 tumors in the results for reference. Tumor type was determined from histopathology. Given the fact that a diagnosis of cancer was one of the criteria for selection, there were relatively few benign lesions, and these were not selected for further workup. The lung lesions selected for further analysis were primary lung lesions; the two metastatic lung lesions mentioned above were not selected for further workup.

Technical information

Positron emission tomography-computed tomography data acquisition and processing and image review

As previously described,[1] our routine cardiac 82Rb PET/CT protocol includes a rest PET/CT scan followed by a stress PET/CT scan after pharmacologic stress with 0.4 mg of intravenous regadenoson (Lexiscan) (Astellas US LLC, Northbrook, Illinois, USA). The patients were scanned using either a Biograph mCT 128-slice scanner or a Biograph TruePoint 40-slice (Siemens Healthcare, Malvern, Pennsylvania, USA). We acquire for 8 min in list mode, starting at the completion of 82Rb infusion. Because of the presence of 82Rb in the background and its ongoing uptake in the myocardium, the first 90 s were not used for image reconstruction; the remaining 390 s were reconstructed as a static image with vendor-provided software, using ordered subsets (two iterations and 24 subsets) expectation maximization three-dimensional reconstruction with a 6.5-mm Gaussian postprocessing filter. Both portions of the examination used an intravenous dose of 1480MBq of 82Rb, using a Cardiogen Strontium-82 (82Sr)/82Rb generator (Bracco Diagnostics, Monroe Township, New Jersey, USA). Shallow-breathing low-dose (120 kVp; 50 mAs) CT scans were acquired before the rest portion and after the stress portion of the examination for attenuation correction. The radiologist routinely reviewed these scans to assess for coronary calcification and other incidental findings, such as lung nodules.

Where an 18F-Fluorodeoxyglucose (FDG) PET/CT image obtained within a month was available, this was also included. FDG-PET/CT scans were acquired using either a Biograph TruePoint 40-slice or Biograph mCT 128-slice scanner (Siemens Healthcare, Malvern, PA, USA). Examination was done using 259–740 MBq of 18F-FDG using a weight-based formula, and two minutes per bed position for the TruePoint and 1.5 min per bed position for the mCT. CT parameters were 100 mAs and 120 kVp. Reconstruction used an OSEM algorithm (2 iterations, 8 subsets) with 5 mm Gaussian filter and matrix of 168 × 168 (TruePoint) or 200 × 200 (mCT).

Lesion selection

In each of the 53 cases included in this study, we used the most avid malignant lesion captured on 82Rb PET/CT images for visual, semiquantitative, and quantitative analysis. If the same lesion was visible on an FDG-PET/CT as described above, we obtained maximum standardized uptake value (SUVmax) on that scan as well for comparison.

Visual analysis

Two nuclear medicine physicians (reader 1 and reader 2) with extensive PET/CT imaging experience reviewed the 82Rb rest and stress images independently, using MIM (MIM Software Inc, Cleveland, OH) oncology review workflows. The uptake in each lesion was compared with uptake of subcutaneous fat, lung, mediastinal blood pool (MBP), liver, and apparently healthy myocardium and scored as follows, based on our previous publication:[1] 1-equal or greater to subcutaneous fat but less than lung; 2-greater than lung but less than or equal to MBP; 3-greater than MBP but less or equal to than liver; 4-greater than liver but less than heart. The examples of breast and lung lesions are shown in [Figure 1] and [Figure 2].
Figure 1:Leftbreastlesiononstressimage(redarrow)on(a)fusedimages(b)CTimages(c)SPECTimages(d)MIPSPECTimages,similarinaviditytomediastinalbloodpool;noticetherelativelyhighavidityofmediastinalbloodpool

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Figure 2: Leftlunglesionadjacenttomediastinum(redarrow)onstressimageon(a)fusedimages(b)CTimages(c)SPECTimages(d)MIPSPECTimages,significantlymoreavidthanmediastinalbloodpoolandlung

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Quantitative analysis

Reader 1 quantitatively assessed uptake in the malignant lesions on 82Rb PET/CT and FDG PET/CT at a different time point than visual analysis, using SUVmax. This is the most commonly used quantitative method of assessing uptake due to reproducibility, particularly where dynamic data such as arterial input functions are not available. SUVmax of each malignant lesion was calculated by placing a three-dimensional region of interest (ROI) around the most intense area in the lesion on rest and stress 82Rb PET/CT, and FDG images (maximum standardized uptake value for rubidium rest study, maximum standardized uptake value for rubidium stress study and SUVFDG, respectively). SUVmax in subcutaneous fat, (SUVfat), lung (SUVlung), SUVMBP, and liver (SUVliver) on both rest and stress images were calculated to be used as internal references, as previously described.[1] SUVfat was calculated in the right and left upper and lower posterior chest walls, SUVlung in the right and left lower and upper lobes roughly midway between anterior and posterior chest walls, in areas free from abnormal CT findings, and SUVliver in four areas roughly equidistant from left to right within the liver. ROI diameter was 1.5 cm for reference SUVmax calculations, adjusted to smaller sizes for SUVfat if needed. The results for both visual and semiquantitative analysis of individual lesions are in [Table 1] and [Table 2]. Ratios of tumor to various background tissues are in [Table 3] and [Table 4].
Table 1: Visual assessments and maximum standard uptake value of each identified lesion, stress, rest, and fluorodeoxyglucose Breast cancer

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Table 2: Visual assessments and maximum standard uptake value of each identified lesion, stress, rest, and fluorodeoxyglucose: Lung cancer

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Table 3: Maximum standard uptake value (rubidium rest and stress) ratios to fat, lung, mediastinal blood pool, and liver: Breast cancer

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Table 4: Maximum standard uptake value (rubidium rest and stress) ratios to fat, lung, mediastinal blood pool, and liver: Lung cancer

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Uptake in the lungs was noted visually to vary significantly between locations (a top-to-bottom and posterior-to-anterior gradient was noted), and so specific data relating to position was calculated by a third observer. Data were obtained as described before in the apex (as far up as one could go without visible end-of-image noise), in the midlung (roughly at the carina), and in the anterior and posterior base of each lung.

Statistics

We used Cohen's kappa with linear weighting (using MATLAB, The MathWorks, Natick, MA) to compare readers. We compared each reader to the other reader on both rest and stress images and a kappa statistic calculated. We calculated descriptive statistics on SUVmax for both rest and stress images separately and used two-tailed two-sample paired t-tests (using Microsoft Excel 2016, Redmond, WA) to compare rest and stress values of SUVmax, for both breast and lung tumors. Two-tailed two-sample paired t-tests were also used to compare SUVmax of each patient's tumor with the average value of their normal structures, and two-tailed two-sample unpaired tests were used to compare the breast and lung cancer groups, as well as the receptor positive and negative groups for breast cancer patients. Too few lung cancer patients had receptor analysis done to make statistical studies possible.


   Results Top


Visual analysis

In 25/53 patients, visual scores matched for both rest and stress images; in most other patients readers disagreed by 1 category, though in 3 cases (rest) and 5 cases (stress) they disagreed by 2. Reader 2 tended to have higher readings by about 0.4 on average. Cohen's kappa with linear weighting for readers 1 and 2 was 0.57 for rest and 0.50 for stress, indicating moderate agreement between observers.

Quantitative analysis

SUVmax for breast cancer lesions ranged from 0.3 to 4.6, with an average of 1.6 (median 1.2, standard deviation [SD] 1.1); only 3 of these had FDG PET/CT, but SUVmax was 5.9, 19.0, and 21.0, showing the greater avidity of FDG PET/CT for breast cancer lesions. SUVmax for lung cancer lesions ranged from 0.8 to 6.3, with an average of 3.1 (median 3.0, SD 1.6); 21 of these had FDG PET/CT, and again lung cancers showed more avidity for FDG PET/CT with a range from 0.8 to 20.0, with average 9.4. In nearly all cases, SUVmax was higher for FDG PET/CT. Correlation coefficient between SUVmax for FDG and for Rb was 0.16, showing essentially no significant correlation. As a result, the possibility that Rb essentially “tracks with” FDG is excluded. Specificity is difficult to assess as no equivalent database of benign tumors exists (patients would be unlikely to be admitted for a known benign tumor). As in our prior study, SUVmax was slightly higher at rest than at stress for both types of cancers (1.7 vs. 1.5 for breast, 3.2 vs. 3.0 for lung); the effect was not significant in either case (P = 0.57 breast, P = 0.61 lung). Lung values were significantly higher than breast values (P < 0.0001). Tumor values were significantly different from lung, fat, and liver (P < 0.0001), but interestingly not significantly different from blood pool (P = 0.16). However, subdividing this into comparing breast groups (P = 0.005) and lung groups (P = 0.0002) shows both groups have uptake in tumors significantly different from blood pool.

Average uptake was 2.4 for MBP (2.5 rest, 2.3 stress), 1.2 for lung (1.2 rest, 1.1 stress), 0.3 for chest wall (this did not vary), and 3.6 for liver (3.5 rest, 3.7 stress). (Note the distinction from FDG: Most cancers were less avid than liver, used as a benchmark for low-grade uptake in cancers such as lymphoma). There is thus a very slight movement from blood pool and lung (and tumors) into liver with stress imaging.

Location-indexed SUVs for background lung gave similar overall values (1.2 rest, 1.1 stress), with the left lung marginally more avid than the right (1.3 left, 1.2 right). Average uptake was 1.1 at the apex, 1.2 at the midlung, 1.1 at the anterior base, and 1.5 at the posterior base, confirming the general tendency of the lungs to accumulate tracer in dependent regions [Figure 3]. As can be seen, lesions may be less avid than blood pool and similar to surrounding lung [Figure 4].
Figure 3: Dependentaccumulationoftracerinthelung(restimage).Thechangesof3stepsintherainbow-colormap(a)image(eachrepresenting0.25)indicatesadifferenceofatleast0.75betweenpartsofthelung.Animageusingthesamecolormapastheremainingversions(b)isprovided

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Figure 4: Lessavidlunglesion(redarrow)onrestimageon(a)fusedimages(b)CTimages(c)SPECTimages(d)MIPSPECTimages,lessavidthanmediastinalbloodpoolandsimilartosurroundinglung

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All breast cancer lesions had estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) receptor data available. Receptor data for lung cancer lesions was inconsistent as lesions were variably assessed over a period of 10 years which included considerable evolution in tests available and their use in oncologic practice, but histopathology was available in all cases. SUVmax averaged 0.8 for ER-and 1.8 for ER + tumors (significant, P = 0.0004), 1.3 for PR + and 1.8 for PR-tumors (not significant, P =0.15), and 1.6 for HER2-and 1.4 for HER2+ tumors (not significant, P =0.54). The ER receptor result fits the thallium pattern of being higher in better-differentiated tumors (in this case breast cancer rather than lymphomas), though with such a small sample size it is difficult to be definitive; still, the finding bears further study. For lung cancer, SUVmax averaged 3.3 for adenocarcinoma, 3.1 for squamous cell, and 3.1 for small cell, not significantly different. The six tumors with PD-L1 mutations had SUVmax of 4.1 at rest and 4.0 at stress, but the others were not tested for this mutation.

Among the rarer tumors, the well-differentiated carcinoid had SUVmax 4.8 on average, the esophageal tumors 3.2 and 4.1, the ovarian carcinosarcoma 1.7, the lymphomas ranged from 1.2 to 2.8 (1.2 mantle cell, 2.5 follicular, 2.8 SLL and PTLD), the renal cell metastasis 0.92, and the GI metastasis 1.4.


   Discussion Top


There was only moderate agreement between observers, from. 50 to. 56 Cohen's kappa with linear weighting. This is somewhat lower than agreement in the prior study, where recalculating Cohen's kappa with linear weighting gave agreements of. 808 and. 869. Collapsing categories 1 and 2 has only minimal effect (it rises to 0.61 to 0.64). The largest number of discrepancies at both rest and stress was between categories 2 and 3 (between fat and lung and between fat and mediastinum) and may reflect the considerable variability of uptake within the lung. This suggests that future benchmarks might include fat, MBP, and liver only if this form of grading is to be useful in the future. It is worth noting that the Deauville scale comfortably uses MBP and liver alone. Given the interobserver variability, however, it may not be useful as a primary imaging study in the oncologic setting. Instead, close attention should be paid to reviewing rubidium cardiac scans for the presence of incidental tumors. While our study was “enriched” in incidental tumors as a result of the patients being specifically selected for having had a tumor found, the usual previously described 2% incidental cancer discovery rate[8] still suggests this is an important incidental finding to beware of.

Values are relatively similar at rest and stress. This is compatible with a prior case report of two patients with metastases detected on a rubidium scan which showed little response to adenosine.[9] Of course, this case report uses a different agent and a very small sample size. Nonetheless, it does confirm that vasodilation does not significantly affect tumor perfusion (all stress tests in this study used regadenoson).

There is a substantial amount of variability in tumor-to-background ratios, whether lung, fat, MBP, or liver is used. Descriptive statistics in [Table 3] and [Table 4] suggest a high degree of variation relative to the mean for most ratios. Again, breast tumors are less avid than many background lesions, whereas lung tumors are more avid than fat, blood pool, and lung, but still less avid than normal liver.

There is little correlation between intensity and histology or receptor status, with the interesting exception of ER + tumors being more Rb-avid. While this is an intriguing result, raising the possibility of being able to assess tumors for ER status using existing tracers (rather than tracers like FES which are difficult to manufacture), it is based on a small sample size and would require confirmation in a larger data set. Since almost all ER + tumors had an expression level of 91%–100%, any sort of quantitative dose-response relationship is difficult to ascertain.

The role of perfusion is another open question. Rubidium's primary purpose in nuclear imaging is to be used in the heart as a perfusion tracer, after all. Common intravenous contrast does assess perfusion, but additional contrast-enhanced CT images were not available pretreatment or even post-treatment on most of these patients, as our institution usually performs dedicated CTs of the chest without contrast. Only about 15 had such scans, and the protocol of the CT varied between venous-phase cancer staging CTs and pulmonary-arterial-phase CTs for pulmonary embolus detection.

Rubidium is most similar pharmacologically to thallium, which the cell also transports inside via the sodium-potassium exchange transporter, and which was investigated as a tumor agent in the late 1980s and early 1990s. Histopathologic data on Na+/K + ATPase are not available, as this is a retrospective study and this is not commonly assessed in clinical practice. Correlation of thallium uptake with grade is inconsistent. While a higher uptake correlates with a worse prognosis in lung cancer and sensitivity better for poorly differentiated lung cancers.[10],[11] thallium is more sensitive in low-grade lymphomas,[12],[13] though it may be even more so in intermediate-grade lymphomas.[14] As thallium tumor studies were usually minutes to hours after injection rather than immediately after injection for 82Rb,[10],[11],[12],[13],[14] the physiology may be very different in any case. Nonetheless, despite the inconsistent correlation of thallium with tumor differentiation, the possibility of a correlation of rubidium with ER activity bears further study.


   Conclusions Top


Malignant tumors can be depicted and quantified on 82Rb PET/CT; while uptake is low relative to FDG PET/CT, and interobserver variability suggests it is not useful as a primary oncologic imaging modality, early findings involving receptors suggest further investigation is needed to see if it can be useful as a form of molecular imaging.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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Khandani AH, Commander CW, Desai H, Oldan JD, Wong TZ, Benefield T, et al. Visual and semiquantitative analysis of 82Rb uptake in malignant tumors on PET/CT: First systematic analysis. Nucl Med Commun 2019;40:532-8.  Back to cited text no. 1
    
2.
Roelcke U, Radü E, Ametamey S, Pellikka R, Steinbrich W, Leenders KL. Association of rubidium and C-methionine uptake in brain tumors measured by positron emission tomography. J Neurooncol 1996;27:163-71.  Back to cited text no. 2
    
3.
Roelcke U, Radü EW, Hausmann O, Vontobel P, Maguire RP, Leenders KL. Tracer transport and metabolism in a patient with juvenile pilocytic astrocytoma. A PET study. J Neurooncol 1998;36:279-83.  Back to cited text no. 3
    
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Neumann DR, Basile KE, Bravo EL, Chen EQ, Go RT. Malignant pheochromocytoma of the anterior mediastinum: PET findings with [18F] FDG and 82Rb. J Comput Assist Tomogr 1996;20:312-6.  Back to cited text no. 4
    
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Gupta A, DiFilippo FP, Brunken RC. Rubidium-82 uptake in metastases from pheochromocytoma on PET myocardial perfusion images. Clin Nucl Med 2011;36:930-1.  Back to cited text no. 5
    
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Lu Y. FDG and (82) Rb PET/MRI features of brain metastasis of breast cancer. Clin Nucl Med 2015;40:494-5.  Back to cited text no. 6
    
7.
Jochumsen MR, Tolbod LP, Pedersen BG, Nielsen MM, Hoyer S, Frokiaer J, et al. Quantitative tumor perfusion imaging with (82) Rubidium-PET/CT in prostate cancer – Analytical and clinical validation. J Nucl Med 2019;60:1059-65.  Back to cited text no. 7
    
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Mirpour S, Khandani AH. Extracardiac abnormalities on rubidium-82 cardiac positron emission tomography/computed tomography. Nucl Med Commun 2011;32:260-4.  Back to cited text no. 8
    
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Hasbak P, Enevoldsen LH, Fosbøl MØ, Skovgaard D, Knigge UP, Kjær A. Rubidium-82 uptake in metastases from neuroendocrine tumors: No flow response to adenosine. J Nucl Cardiol 2016;23:840-2.  Back to cited text no. 9
    
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Takekawa H, Takaoka K, Tsukamoto E, Kanegae K, Miller F, Kawakami Y. Thallium-201 single photon emission computed tomography as an indicator of prognosis for patients with lung carcinoma. Cancer 1997;80:198-203.  Back to cited text no. 10
    
11.
Takekawa H, Itoh K, Abe S, Ogura S, Isobe H, Furudate M, et al. Thallium-201 uptake, histopathological differentiation and Na-K ATPase in lung adenocarcinoma. J Nucl Med 1996;37:955-8.  Back to cited text no. 11
    
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Roach PJ, Cooper RA, Arthur CK, Ravich RB. Comparison of thallium-201 and gallium-67 scintigraphy in the evaluation of non-Hodgkin's lymphoma. Aust N Z J Med 1998;28:33-8.  Back to cited text no. 12
    
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Waxman AD, Eller D, Ashook G, Ramanna L, Brachman M, Heifetz L, et al. Comparison of gallium-67-citrate and thallium-201 scintigraphy in peripheral and intrathoracic lymphoma. J Nucl Med 1996;37:46-50.  Back to cited text no. 13
    
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Mansberg R, Wadhwa SS, Mansberg V. Tl-201 and Ga-67 scintigraphy in non-Hodgkin's lymphoma. Clin Nucl Med 1999;24:239-42.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

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