Primary hyperparathyroidism caused by a tiny mediastinal parathyroid adenoma with non-localising imaging studies.

Variations in parathyroid gland positions often cause failure in initial parathyroid adenoma surgery, especially when imaging fails to localise the adenoma. This report describes a female patient with primary hyperparathyroidism for which preoperative localisation studies did not determine the position of the hyperfunctioning gland. The initial approach with bilateral cervical exploration and intraoperative parathyroid hormone monitoring was performed unsuccessfully. A mediastinal adenoma was suspected due to meticulous negative neck exploration and repeated negative images for a neck adenoma. Subsequently, a second approach involving mediastinal exploration was performed. After the removal of remnant thymic tissue in the mediastinal space, a significant drop in intraoperative parathyroid hormone levels was achieved. The pathological result confirmed the presence of a tiny pathological parathyroid adenoma within the thymus. At 6 months follow-up, postoperative biochemical assessment was consistent with normal calcium and parathyroid hormone levels.

4D SPECT/CT: A Hybrid Approach to Primary Hyperparathyroidism.

Our rationale was to review the imaging options for patients with primary hyperparathyroidism and to advocate for judicious use of 4-dimensional (4D) SPECT/CT to visualize diseased parathyroid glands in patients with complex medical profiles or in whom other imaging modalities fail. We review the advantages and disadvantages of traditional imaging modalities used in preoperative assessment of patients with primary hyperparathyroidism: ultrasound, SPECT, and 4D CT. We describe a scheme for optimizing and individualizing preoperative imaging of patients with hyperfunctioning parathyroid glands using traditional modalities in tandem with 4D SPECT/CT. Using the input from radiologists, endocrinologists, and surgeons, we apply patient criteria such as large body habitus, concomitant multiglandular disease, multinodular thyroid disease, confusing previous imaging, and unsuccessful previous surgery to create an imaging paradigm that uses 4D SPECT/CT yet is cost-effective, accurate, and limits extraneous radiation exposure. 4D SPECT/CT capitalizes on the strengths of SPECT and 4D CT and addresses limitations that exist when these modalities are used in isolation. In select patients with complicated clinical parameters, preoperative imaging with 4D SPECT/CT can improve accuracy yet remain cost-effective.

Update in imaging tests used for the localization of parathyroid pathology.

Preoperative localization of parathyroid pathology, generally a parathyroid adenoma, can be difficult in some cases due to the anatomical variants that these glands present. The objective of this review is to analyse the different imaging techniques used for preoperative localization of parathyroid pathology (scintigraphy, ultrasound, CT, MRI and PET). There is great variability between the different tests for the preoperative localization of parathyroid pathology. The importance of knowing the different diagnostic options lies in the need to choose the most suitable test at each moment and for each patient for an adequate management of primary hyperparathyroidism (PHP) with surgical criteria.

Clinical predictors of negative/equivocal SPECT imaging outcomes in primary hyperparathyroidism: Factors calling for 18F-choline-PET.

PURPOSE: For minimally invasive surgery of parathyroid adenomas, exact localization diagnostics are essential. Main imaging modalities used for diagnostics are sonography, SPECT with/without CT (traditional imaging) and 18F-choline-PET. The aim of our study was to identify predictors for inconclusive SPECT imaging and subsequently determine in which cases 18F-choline-PET is needed. METHODS: Retrospective analysis of 138 patients with histologically confirmed primary hyperparathyroidism (pHPT). After sonography, patients underwent SPECT or SPECT/CT imaging, with subsequent 18F-choline-PET in cases of disconcordant results. Logistic regression analysis was used to identify clinical and laboratory factors predictive for negative SPECT results. RESULTS: Sensitivity rates for sonography, SPECT, SPECT/CT, and choline-PET were 47 %, 49 %, 71.7 %, and 97 %, respectively. Logistic regression revealed lower PTH levels (p < 0.001), presence of structural thyroid disease (p = 0.018), and negative sonography (p < 0.001) as predictive of negative/equivocal SPECT outcome. An additional traditional imaging CT scan to a SPECT enhanced detection odds, as did greater adenoma weight. Urolithiasis, osteoporosis, and calcium values as measurement of activity and duration of disease showed no significant association with the detection rate. Furthermore, our study demonstrated that 18F-choline-PET exhibited remarkable sensitivity in detecting adenomas among patients with negative/equivocal SPECT results. CONCLUSION: Our study reveals potential predictive factors for a negative/equivocal SPECT outcome in pHPT. Identifying these factors might allow minimizing futile SPECT examinations and perhaps encourage timely utilization of 18F-choline-PET imaging. Our study reinforces the clinical significance of 18F-choline-PET, especially in complex cases with disconcordant results by conventional parathyroid imaging methods.

Ultrasonographic Detective Flow Imaging for Evaluating Parathyroid Adenoma in Patients with Primary Hyperparathyroidism.

BACKGROUND: Detective flow imaging (DFI) is a new imaging technology that displays low-velocity blood flow, which is difficult to visualize on conventional color Doppler ultrasonography (CDU). In this study, we compared the usefulness of DFI with that of CDU and methoxy-isobutyl-isonitrile (MIBI) scintigraphy for detecting parathyroid adenoma (PA) in patients with primary hyperparathyroidism (PHPT). METHODS: From March 2021 to March 2023, 87 PHPT patients underwent surgery, and 66 had a single PA. We performed preoperative conventional ultrasonography with CDU, MIBI scintigraphy, and DFI for 42 patients (5 males and 37 females; mean age: 61.6 ± 15.4 years). RESULTS: MIBI scintigraphy detected PA in 85.7% (36/42) patients, and both CDU and DFI detected PA in all patients. The rates of vascularity in PA detected by CDU and DFI were 71.4% (30/42) and 85.7% (36/42), respectively. Vascularity was detected by DFI in 6 patients who were negative for vascularity on MIBI scintigraphy. Furthermore, DFI detected blood supply in 6 of the 12 patients with undetectable blood supply on CDU. Fisher's exact test revealed that high or low blood flow, as determined by DFI, was significantly associated with detection of feeding vessels in PA by CDU (P < 0.001). CONCLUSIONS: DFI was useful for preoperative detection of PA blood flow.

Use of [18F]fluorocholine PET/CT in the detection of primary hyperparathyroidism in paediatrics: a case report.

OBJECTIVES: The most common cause of primary hyperparathyroidism (PPH) in children is a parathyroid adenoma. Among this population, PPH exhibits higher levels of morbidity, severity and target organ involvement compared to adults. When there is suspicion of PPH, cervical ultrasound and 99mTc-sestamibi SPECT/CT are the imaging test traditionally indicated. Among adults, the use of [18F]fluorocholine PET/CT has shown a higher sensitivity than ultrasound and [99mTc]sestamibi SPECT/CT, leading to an expanding adoption in recent years. However, its role in paediatrics has not been clearly defined yet. CASE PRESENTATION: The patient is an adolescent female aged 13 years presented with lithiasis. The analytical study revealed elevated PTH, hipovitaminosis D, hypercalcaemia and hypophosphataemia. Due to the suspicion of PPH, cervical ultrasound and 99mTc-sestamibi SPECT/C were performed, failing to identify hyperfunctioning parathyroid glands. We proceeded to carry out a [18F]fluorocholine PET/CT where a hypermetabolic nodular image was identified, compatible with a hyperfunctioning parathyroid adenoma. The patient underwent surgery, resulting in the normalisation of PTH levels. Pathological anatomy confirmed the presence of a parathyroid adenoma. CONCLUSIONS: In cases where conventional imaging tests yield negative results or discrepancies, we suggest the possibility of the use of [18F]fluorocholine PET/CT for the detection of hyperfunctioning parathyroid adenomas.

Don't chase the adenoma: A probabilistic approach to imaging before parathyroidectomy.

BACKGROUND: Preoperative imaging before parathyroidectomy can localize adenomas and reduce unnecessary bilateral neck explorations. We hypothesized that (1) the utility of preoperative imaging varies substantially depending on the preoperative probability of having adenoma(s) and (2) that a selective imaging approach based on this probability could avoid unnecessary patient costs and radiation. METHODS: We analyzed 3,577 patients who underwent parathyroidectomy for primary hyperparathyroidism from 2001 to 2022. The predicted probability of patients having single or double adenoma versus hyperplasia was estimated using logistic regression. We then estimated the relationship between the predicted probability of single/double adenoma and the likelihood that sestamibi or 4-dimensional computed tomography was helpful for operative planning. Current Medicare costs and published data on radiation dosing were used to calculate costs and radiation exposure from non-helpful imaging. RESULTS: The mean age was 62 ± 13 years; 78% were women. Adenomas were associated with higher mean calcium (11.2 ± 0.74 mg/dL) and parathyroid hormone levels (140.6 ± 94 pg/mL) than hyperplasia (9.8 ± 0.52 mg/dL and 81.4 ± 66 pg/mL). The probability that imaging helped with operative planning increased from 12% to 65%, as the predicted probability of adenoma increased from 30% to 90%. For every 10,000 patients, a selective approach to imaging that considered the preoperative probability of having adenomas could save patients up to $3.4 million and >239,000 millisieverts of radiation. CONCLUSION: Rather than imaging all patients with primary hyperparathyroidism, a selective strategy that considers the probability of having adenomas could reduce costs and avoid excess radiation exposure.

Four-Dimensional Computed Tomography for Parathyroid Adenoma Localization: A Pre-Operative Imaging Protocol.

OBJECTIVE: Primary hyperparathyroidism (PHPT) affects approximately 0.86% of the population, with surgical resection as the treatment of choice. A 4D computed tomography (CT) is a highly effective tool in localizing parathyroid adenomas; however, there is currently no defined role for 4D CT when stratified against ultrasonography (USG) and nuclear medicine Technetium Sestamibi SPECT/CT (SES) imaging. STUDY DESIGN: Retrospective Study. SETTING: University Hospital. METHODS: All patients who underwent parathyroidectomy for PHPT between 2014 and 2019 at a single institution were reviewed. Patients who had a 4D CT were included. We compared outcomes of 4D CT as a second line imaging modality to those of USG and SES as first line modalities. An imaging algorithm was proposed based on these findings. RESULTS: There were 84 patients identified who had a 4D CT after unsuccessful first line imaging. A 4D CT localized parathyroid adenoma to the correct quadrant in 64% of cases, and to the correct laterality in 75% of cases. Obese patients had significantly lower rates of adenoma localization with USG (33.4%), compared to non-obese patients (67.5%; P = .006). In determining multigland disease the sensitivity of 4D CT was 86%, while the specificity was 87%. CONCLUSIONS: A 4D CT has impressive rates of accurate localization of parathyroid adenomas; however due to the radiation exposure involved, it should remain a second line imaging modality. PHPT patients should first be evaluated with USG, with 4D CT used if this is unsuccessful and patients are greater than 40 years old, have a high BMI, or are having revision surgery.

Microwave ablation for recurrent primary hyperparathyroidism in four patients with multiple endocrine neoplasia type 1: a case series report.

Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome, is inherited in an autosomal dominant pattern, mainly manifested as primary hyperparathyroidism (PHPT). Surgery is preferred for patients with MEN1 and PHPT. Thermal ablation has been widely applied for PHPT but rarely for postoperative recurrent PHPT in MEN1 patients. Based on a series of cases, we aimed to investigate the clinical efficacy and safety of ultrasound-guided percutaneous microwave ablation in the treatment of MEN1 patients with postoperative recurrence of PHPT.

Diagnostic Performance of 99mTc-Sestamibi SPECT/CT and 18F-Choline PET/CT in Locating Hyperfunctioning Parathyroid Glands in Patients with Primary Hyperparathyroidism.

OBJECTIVE: This study aimed to assess the diagnostic performance of 99mTc-sestamibi SPECT/CT and 18F-choline PET/CT in detecting hyperfunctioning parathyroid glands in patients undergoing surgery for primary hyperparathyroidism (PHPT). METHODS: A retrospective analysis was conducted on patients who underwent PHPT-related surgery between April 2019 and May 2022. The study focused on patients undergoing either 99mTc-sestamibi SPECT/CT (81 patients) or 18F-choline PET/CT (33 patients) scans before surgery to pinpoint hyperfunctioning parathyroid gland(s). In the majority of patients, 18F-choline PET/CT was performed after negative or inconclusive findings on 99mTc-sestamibi SPECT/CT. Pathohistological reports were utilized as the reference standard for evaluating the accuracy of the imaging findings. RESULTS: The study encompassed 83 patients (70 females, 84.3%) with an average age of 57.2 years (24-80 years). The pathohistological analysis identified a total of 98 glands. In a per-lesion analysis, the detection rate of 99mTc-sestamibi SPECT/CT was 57% (95% CI 45.3-68.1), while the detection rate of 18F-choline PET/CT was 90.3% (95% CI 74.3-98.0). CONCLUSION: The results of our study showed the significant usefulness of 18F-choline PET/CT in patients with negative or inconclusive results of 99mTc-sestamibi SPECT/CT in accurately locating hyperfunctioning parathyroid glands in PHPT patients.

Assessment of left ventricular dysfunction by strain echo in primary hyperparathyroidism and its reversal after parathyroidectomy.

BACKGROUND: Strain echocardiography is a highly sensitive modality for detecting myocardial disease at an early stage. Therefore, we aim to evaluate subclinical left ventricular dysfunction in primary hyperparathyroidism (PHPT) patients with myocardial strain imaging in addition to conventional echocardiography and to look for its reversal after parathyroidectomy (PTx). METHODS: Thirty patients who underwent curative parathyroidectomy for PHPT were included. All patients were evaluated with M mode echo, 2D echo and strain imaging before and 6 months after PTx. Left ventricular ejection fraction, left ventricular diastolic dysfunction, left ventricular hypertrophy (LVH), Global Longitudinal Strain (GLS) and global circumferential strain (GCS) were recorded. RESULTS: On M mode echo, LVH was present in 15 patients and 8 of them improved completely after PTx (p < 0.038). Incidence of systolic and diastolic dysfunction on 2D echo was 10% and 13.3% respectively; while myocardial strain imaging showed impaired systolic function in 46.7% patients. Hence, compared to conventional 2D echo, strain imaging showed 36.7% high detection rate of subnormal cardiac function. There was improvement in left ventricle dysfunction (p = 0.083), GLS and GCS (p = 0.034) after PTx. Serum parathormone demonstrated a strong positive correlation with change in GLS and GCS (p = 0.013, p = 0.126) while serum calcium showed a weak correlation with change in GLS and GCS following surgery. CONCLUSION: Myocardial strain imaging should be considered for all PHPT patients as early identification of subclinical ventricle dysfunction provides an opportunity for an early intervention and thereby preventing development of irreversible LV dysfunction.

Surgery for nonlocalizing hyperparathyroidism in high volume center.

BACKGROUND: Patients with nonlocalizing hyperparathyroidism pose a significant challenge to surgeons when undergoing neck exploration for parathyroidectomy. METHODS: We evaluated 536 patients that had parathyroidectomy for primary hyperparathyroidism (PHPT) from 2005 to 2018 at a single tertiary academic center, and 155 (29%) had standard nonlocalizing preoperative imaging (negative ultrasound and sestamibi scans). RESULTS: There were a total of 102 (66%) non-ectopic single adenomas in the nonlocalizing group and 325 (85%) single adenomas in the localizing group. There was no significant difference (p = 0.09) in adenoma quadrant between localizing and nonlocalizing single adenomas, but the most common location in both groups was right inferior. Patients with nonlocalizing scans were more likely to have double adenomas (21% vs. 9%, p < 0.001), ectopic glands (10% vs. 5%, p = 0.052), and multi-gland disease (13% vs. 8%, p = 0.002). CONCLUSION: Nonlocalizing PHPT patients experienced similar cure and complication rates as localizing PHPT, but required more bilateral explorations and increased operative time.

Ultrasound-based quantitative tools in predicting renal involvement in asymptomatic primary hyperparathyroidism.

PURPOSE: Asymptomatic primary hyperparathyroidism (aPHPT) has been recognized as a condition that can lead to renal complications. Timely identification of prognostic indicators for renal impairment holds the potential to facilitate proactive monitoring and treatment strategies in these patients. This study aims to investigate the utility of acoustic radiation force impulse (ARFI) imaging and renal resistive index (RRI), in identifying renal parenchymal and vascular changes in patients with aPHPT. METHODS: Forty-two patients with aPHPT and 42 controls matched for age, sex, and body mass index were included in the study. The presence of renovascular changes was evaluated by RRI measurement with Doppler ultrasonography, and the presence of renal parenchymal involvement was evaluated by ARFI quantification, given as shear wave velocity (SWV). RESULTS: In aPHPT patients, both the mean RRI and mean SWV values exhibited substantial elevation compared to the control group (P < 0.001 for both). Significant associations were observed between SWV values and serum calcium, parathyroid hormone (PTH), and adenoma size within the patient group (P < 0.001, P < 0.001, P = 0.016, respectively). Similarly, the mean RRI demonstrated positive correlations with serum calcium and PTH levels in the patient group (P< 0.001, P = 0.011, respectively). Multivariate linear regression analysis underscored the connection between mean RRI and mean SWV values with serum calcium levels within the patient group. In addition, serum PTH levels affected mean SWV positively and significantly. CONCLUSION: The use of ARFI imaging and RRI measurements appears to hold potential in identifying renal involvement in patients with aPHPT.

Site specific differences in vBMD and geometry in postmenopausal women with primary hyperparathyroidism.

PURPOSE: Primary Hyperparathyroidism (PHPT) is associated with catabolic effects at both trabecular and cortical bone. Mechanical loading is one of the most important natural anabolic stimuli for bone at all ages. The present study was designed to assess the impact of PHPT on vBMD and bone geometry using peripheral quantitative computed tomography (pQCT) at the radius and tibia, sites with similar structural characteristics, but subject to different loading conditions. METHODS: We evaluated the impact of PHPT on bone, by comparing the z-scores of volumetric Bone Mineral Density (vBMD) and indices of bone geometry simultaneously at the tibia and the radius by pQCT, skeletal sites with similar structure, but subject to different loading conditions. Forty-one postmenopausal women with PHPT and 79 controls, comprised the study group. RESULTS: At both trabecular and cortical sites, vBMD and bone geometry indices were significantly lower in patients compared with controls. In patients with PHPT, apart from a lower z-score for total vBMD (p = 0.01) at the radius, there was no other difference between the radius and the tibia at the trabecular sites. On the contrary, at cortical sites, the z-scores of cortical bone mineral content (p = 0.02), cortical vBMD (p = 0.01) and cortical cross-sectional area (p = 0.05) were significantly lower at the radius compared with the tibia, indicating that cortical bone at the weight bearing tibia might be less affected by the catabolic actions of continuous parathyroid hormone (PTH) exposure. PTH levels were positively associated with the difference in z-scores of cort BMD (r = 0.439, p < 0.01) indicating that in more severe cases, as expressed by higher PTH levels, the deleterious effects at the non-weight bearing radius might be accentuated. CONCLUSION: We found that in postmenopausal women with PHPT, both trabecular and cortical bone are adversely affected. However, at the weight bearing tibia as compared with the radius, the deleterious effects, especially on cortical bone, seem to be attenuated. TRIAL REGISTRATION NUMBER: NCT05426512, 21/06/2022, "retrospectively registered".

Performance of [18F]fluorocholine PET/CT in MEN1-related primary hyperparathyroidism before initial surgery or for persistent/recurrent disease.

PURPOSE: The aims of the study were to evaluate the performance and robustness of [18F]fluorocholine PET/CT in detecting hyperfunctioning parathyroid glands in MEN1-related primary hyperparathyroidism (pHPT) at different stages of their disease. METHODS: Retrospective French multicenter study including patients with MEN1 pHPT who underwent [18F]fluorocholine PET/CT at initial diagnosis or for evaluation of persistent/recurrent disease. PET/CT were independently reviewed by two readers in a blinded manner. The assessment of PET/CT on a per-patient basis was assessed using a comprehensive set of criteria that considered pathological findings or agreement with alternative diagnostic methods in non-operated patients. The secondary objectives included the analysis of the performance of PET/CT at a per-lesion level, with reference to a pathological Gold Standard, and examining its interobserver reproducibility. RESULTS: A total of 71 MEN1 patients were included (73 PET/CT) in the study. At the per-patient level (entire cohort), [18F]fluorocholine PET/CT sensitivity ranged from 98.5 to 100% among the different readers. An average of 1.77 glands per PET was described, with 2.35 glands at the initial diagnosis (n = 23) and 1.5 in previously operated cases (n = 50). PET/CT detected more lesions than conventional imaging work-up (neck ultrasound and/or scintigraphy). At the per-lesion level (41 operated patients), sensitivity ranged across different readers from 84.4 to 87%, and specificity ranged from 94.7 to 98.8%. At initial diagnosis, all patients that exhibited 3 or more abnormal glands on PET underwent subtotal parathyroidectomy while 7 out of 13 patients with 1 or 2 gland abnormalities on PET underwent less than subtotal parathyroidectomy. Finally, the degree of inter-observer agreement was high. CONCLUSION: [18F]fluorocholine PET/CT is a reliable and robust imaging modality for the evaluation of MEN1-related pHPT and could guide surgeons in achieving the optimal benefit-risk ratio. This study gives a great impetus for its adoption as a primary diagnostic tool in this context.

Head-to-head comparison of [11C]methionine PET, [11C]choline PET, and 4-dimensional CT as second-line scans for detection of parathyroid adenomas in primary hyperparathyroidism.

PURPOSE: Accurate preoperative localization is imperative to guide surgery in primary hyperparathyroidism (pHPT). It remains unclear which second-line imaging technique is most effective after negative first-line imaging. In this study, we compare the diagnostic effectiveness of [11C]methionine PET/CT, [11C]choline PET/CT, and four dimensional (4D)-CT head-to-head in patients with pHPT, to explore which of these imaging techniques to use as a second-line scan. METHODS: We conducted a powered, prospective, blinded cohort study in patients with biochemically proven pHPT and prior negative or discordant first-line imaging consisting of ultrasonography and 99mTc-sestamibi. All patients underwent [11C]methionine PET/CT, [11C]choline PET/CT, and 4D-CT. At first, all scans were interpreted by a nuclear medicine physician, and a radiologist who were blinded from patient data and all imaging results. Next, a non-blinded scan reading was performed. The scan results were correlated with surgical and histopathological findings. Serum calcium values at least 6 months after surgery were used as gold standard for curation of HPT. RESULTS: A total of 32 patients were included in the study. With blinded evaluation, [11C]choline PET/CT was positive in 28 patients (88%), [11C]methionine PET/CT in 23 (72%), and 4D-CT in 15 patients (47%), respectively. In total, 30 patients have undergone surgery and 32 parathyroid lesions were histologically confirmed as parathyroid adenomas. Based on the blinded evaluation, lesion-based sensitivity of [11C]choline PET/CT, [11C]methionine PET/CT, and 4D-CT was respectively 85%, 67%, and 39%. The sensitivity of [11C]choline PET/CT differed significantly from that of [11C]methionine PET/CT and 4D-CT (p = 0.031 and p < 0.0005, respectively). CONCLUSION: In the setting of pHPT with negative first-line imaging, [11C]choline PET/CT is superior to [11C]methionine PET/CT and 4D-CT in localizing parathyroid adenomas, allowing correct localization in 85% of adenomas. Further studies are needed to determine cost-benefit and efficacy of these scans, including the timing of these scans as first- or second-line imaging techniques.

Sonographic Features of Atypical and Initially Missed Parathyroid Adenomas: Lessons Learned From a Single-Center Cohort.

CONTEXT: Awareness of typical and atypical ultrasonographic (US) features of parathyroid adenomas (PAs) is crucial since US is the most widely used first-line imaging modality. OBJECTIVE: The purpose of this study was to describe the atypical features of PAs on US and other possible factors leading to a false negative examination in a large single-center cohort. MATERIALS AND METHODS: The US records of 457 PAs in 445 patients with biochemically proven primary hyperparathyroidism (PHPT) were evaluated in a prospectively maintained database. Atypical size, composition, shape, echogenicity, location, and vascular pattern on US were noted. For patients who previously had at least one negative US examination in referring centers, the main possible reason was defined accordingly. RESULTS: The study group included 359 female and 86 male patients with PHPT. Typical sonographic features were observed in 231 PAs (51%), whereas 226 (49%) had at least one atypical US feature. The most common atypical features were atypical size (29%), followed by atypical echogenicity (19%), shape (8%), location (7%), and composition (7%), respectively. There were 122 initially missed PAs in all groups. The most frequent main atypical US features leading to false negative examinations were atypical size (22.1%) and atypical location (18.8%). Inexperience was third most common reason (16.3%) for false negative US examinations. CONCLUSIONS: Almost half of PAs have at least one atypical feature on US. Awareness of the high prevalence of atypical US features could increase the accuracy of US examination and potentially decrease demand for more expensive second-line imaging modalities.