Types of Evidence Needed to Assess the Clinical Value of Diagnostic Imaging.

AbstractThe evidence underlying the use of advanced diagnostic imaging is based mainly on diagnostic accuracy studies and not on well-designed trials demonstrating improved patient outcomes. This has led to an expansion of low-value and potentially harmful patient care and raises ethical issues around the widespread implementation of tests with incompletely known benefits and harms. Randomized clinical trials are needed to support the safety and effectiveness of imaging tests and should be required for clearance of most new technologies. Large, diverse cohort studies are needed to quantify disease risk associated with many imaging findings, especially incidental findings, to enable evidence-based management. The responsibility to minimize the use of tests with unknown or low value requires engagement of clinicians, medical societies, and the public.

Sestamibi as an alternative to mebrofenin for the diagnosis of acute cholecystitis: An alternative option during supply chain disruption.

Purpose: To determine the accuracy of Tc-99 m sestamibi for the diagnosis of acute cholecystitis during a supply chain disruption of mebrofenin. Material and methods: During a national shortage of Tc-99 m mebrofenin in 2019, our institution initiated sestamibi imaging for suspected cases of acute cholecystitis using a standard hepatobiliary imaging protocol. Forty-one patients underwent hepatobiliary imaging with sestamibi, 39 to assess for acute cholecystitis. The examinations were initially interpreted by one nuclear medicine physician and subsequently overread by 5 blinded nuclear medicine physicians (8-30 years' experience). SPECT/CT was obtained for 8 of these patients at the discretion of the primary interpreter. An additional 23 asymptomatic patients (6 with prior cholecystectomy) underwent abdominal scintigraphy as a negative control to determine the normal time to sestamibi accumulation in the gallbladder. A composite reference standard was used (chart review by 3 physicians). Sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values were calculated with and without SPECT/CT (mean ± 95%CI). Results: Of 39 symptomatic patients, 17/39 had acute cholecystitis and 22 did not. The sensitivity, specificity, PPV and NPV for acute cholecystitis at planar imaging were 97.6 ± 4.6, 62.7 ± 5.2, 67.0 ± 3.6, and 97.3 ± 5.2 % (N = 39). The values changed to 95.7 ± 4.7, 77.9 ± 4.7, 72.1 ± 4.1, and 97.0 ± 3.3 % when control patients were included (N = 62). With SPECT/CT, these mildly improved to 98.8 ± 2.3 %, 69.1 ± 4.4 %, 71.3 ± 3.2 %, and 98.7 ± 2.6 % (N = 39), but not significantly different. On average, sestamibi activity was detected in the gallbladder in negative controls within 1 h. Conclusion: Tc-99 m sestamibi has excellent sensitivity and NPV for diagnosing acute cholecystitis and can serve as an alternative when mebrofenin is unavailable for evaluating cystic duct obstruction during shortages of standard agents.

Extragonadal germ cell tumors: A clinicopathologic study with emphasis on molecular features, clinical outcomes and associated secondary malignancies.

Extragonadal germ cell tumors (EGCTs) are rare, representing <5% of all germ cell tumors (GCTs). Whilst EGCTs share morphological and immunohistochemical features with their gonadal counterparts, they tend to be more aggressive and are frequently associated with secondary somatic malignancies. The aim of our study was to evaluate the clinical, morphological and immunohistochemical features, and to analyze tumors for chromosomal abnormalities of 12p, in addition to any novel genetic alterations, in a series of EGCTs. Seventy-seven EGCTs were included. Anterior mediastinum was the most common anatomic site, followed by central nervous system, retroperitoneum, sacroccygeal area, and neck. Whole genome SNP array identified isochromosome 12p in 26% of tumors. Additional cytogenetic abnormalities included the presence of gain of chr 21 in 37% of tumors. Somatic-type malignancies were identified in 8% of patients. Disease progression (metastasis and/or recurrence) was documented in 8 patients, most of whom died from their relapse. Three patients who died of disease had somatic-type malignancies. Mediastinal seminomas had a significantly better overall survival when compared to mediastinal non-seminomatous GCTs. Our study demonstrates that EGCTs share similar histologic features, but diverse clinical outcomes compared to their gonadal counterparts. Outcomes vary according to anatomic location and histologic subtypes. Our data corroborate that somatic-type malignancies are frequently encountered in mediastinal EGCTs and that their presence portends a poorer prognosis.

Direct Quantification of Gadolinium Retention in Young Patients by ICP-MS Analysis of Extracted Teeth.

In this 10-patient prospective pilot study, we show the feasibility of pragmatic direct ex vivo measurement of gadolinium retention from group II gadolinium-based contrasts agents (GBCAs) in young patients after routine tooth extraction. This noninvasive method may support future research attempting to understand the link between GBCA exposure and clinical outcomes.

Gold nanoshells for prostate cancer treatment: evidence for deposition in abdominal organs.

PURPOSE: Gold-silica nanoshell therapy [AuroShells with subsequent focal laser therapy (AuroLase)] is an emerging targeted treatment modality for prostate cancer. We reviewed pre- and post-treatment unenhanced CT imaging to assess for retained gold-silica nanoshells in the abdomen and pelvis. METHODS: This single-institution retrospective study identified patients in the AuroLase pilot who underwent pre- and post-treatment unenhanced abdominopelvic CT. The attenuation, before and after gold-silica nanoshell administration, of the liver, spleen, pancreas, kidneys, prostate, blood pool, paraspinal musculature, and abnormal lymph nodes were manually measured by two readers. After inter-reader agreement was calculated using intraclass correlation (ICC), a permutation test was used to assess pre- and post-therapy attenuation differences. RESULTS: Four patients met the inclusion criteria. Mean age was 72.3 ± 5.9 years. Median time interval between pre-treatment CT and treatment, and between treatment and post-treatment CT, was 232 days and 236.5 days, respectively. The two readers' attenuation measurements had very high agreement (ICC = 0.99, p < 0.001). The highest differences in organ attenuation between pre- and post-therapy scans were seen in all four patients in the liver and spleen (liver increased by an average of 28.9 HU, p = 0.010; spleen increased by an average of 63.7 HU, p = 0.012). A single measured lymph node increased by an average of 58.9 HU. In the remainder of the measured sites, the change in attenuation from pre- to post-therapy scans ranged from -0.1 to 3.8 HU (p > 0.05). CONCLUSION: Increased attenuation of liver and spleen at CT can be an expected finding in patients who have received gold-silica nanoshell therapy.

Radiologists predict differential resource utilization but not clinical outcome in emergency department patients imaged with ultrasound for right upper quadrant pain.

PURPOSE: Radiologists with diverse training, specialization, and habits interpret imaging in the Emergency Department. It is necessary to understand if their variation predicts differential value. The purpose of this study was to determine whether attending radiologist variation predicts major clinical outcomes in adult Emergency Department patients imaged with ultrasound for right upper quadrant pain. METHODS: Consecutive ED patients imaged with ultrasound for RUQ pain from 10/8/2016 to 8/10/2022 were included (N = 7097). The primary outcome was prediction of hospital admission by signing attending radiologist. Secondary outcomes included: ED and hospital length of stay (LOS), 30-day mortality, 30-day re-presentation rate, subspecialty consultation, advanced imaging follow up (HIDA, MRI, CT), and intervention (ERCP, drainage or surgery). Sample size was determined a priori (detectable effect size: w = 0.06). Data were adjusted for demographic data, Elixhauser comorbidities, number of ED visits in prior year, clinical data, and system factors (38 covariates). P-values were corrected for multiple comparisons (false discovery rate-adjusted p-values). RESULTS: The included ultrasounds were read by 35 radiologists (median exams/radiologist: 145 [74.5-241.5]). Signing radiologist did not predict hospitalization (p = 0.85), abdominopelvic surgery or intervention within 30 days, re-presentation to the Emergency Department within 30 days, or subspecialty consultation. Radiologist did predict difference in Emergency Department length of stay (p < 0.001) although this difference was small and imprecise. HIDA was mentioned variably by radiologists (range 0-19%, p < 0.001), and mention of HIDA in the ultrasound report increased 10-fold the odds of HIDA being performed in the next 72 h (odds ratio 10.4 [8.0-13.4], p < 0.001). CONCLUSION: Radiologist variability did not predict meaningful outcome differences for patients with right upper quadrant pain undergoing ultrasound in the Emergency Department, but when radiologists mention HIDA in their reports, it predicts a 10-fold increase in the odds a HIDA is performed. Radiologists are relied on for interpretation that shapes subsequent patient care, and it is important to consider how radiologist variability can influence both outcome and resource utilization.

Continuity of Radiologists Between Diagnostic Breast Imaging and Image-Guided Breast Biopsy: Impact on Patient-Reported Biopsy Morbidity Experiences.

OBJECTIVE: To determine whether continuity of care between diagnostic breast imaging and subsequent image-guided breast biopsy could reduce patient-reported biopsy-related morbidity. METHODS: This was a prospective, pragmatically randomized, 2-arm health utilities analysis of 200 women undergoing diagnostic breast imaging followed by US- or stereotactic-guided breast biopsy at a single quaternary care center from September 3, 2019, to April 10, 2023. Breast biopsy-naive women with a BI-RADS 4 or 5 finding at diagnostic imaging were randomly scheduled for the typically first available biopsy appointment. One day after biopsy, enrolled patients were administered the Testing Morbidities Index (TMI). The primary outcome was the difference in TMI summary utility scores in patients who did vs did not have the same radiologist perform diagnostic imaging and biopsy. RESULTS: Response rates were 63% (100/159) for the different radiologist cohort and 71% (100/140) for the same radiologist cohort; all respondents answered all questions in both arms. Mean time to biopsy was 7 ± 6 days and 10 ± 9 days, and the number of participating radiologists was 11 and 18, respectively. There was no difference in individual measured domains (pain, fear, or anxiety before procedure; pain, embarrassment, fear, or anxiety during procedure; mental or physical impact after procedure; all P >.00625) or in overall patient morbidity (0.83 [95% CI, 0.81-0.85] vs 0.82 [95% CI: 0.80-0.84], P = .66). CONCLUSION: Continuity of care between diagnostic breast imaging and image-guided breast biopsy did not affect morbidity associated with breast biopsy, suggesting that patients should be scheduled for the soonest available biopsy appointment rather than waiting for the same radiologist.

Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency.

Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin. In obese leptin knockout mice, REGN4461 normalized body weight, food intake, blood glucose, and insulin sensitivity. In a mouse model of generalized lipodystrophy, REGN4461 alleviated hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, and hepatic steatosis. In a phase 1, randomized, double-blind, placebo-controlled two-part study, REGN4461 was well tolerated with an acceptable safety profile. Treatment of individuals with overweight or obesity with REGN4461 decreased body weight over 12 weeks in those with low circulating leptin concentrations (<8 ng/ml) but had no effect on body weight in individuals with higher baseline leptin. Furthermore, compassionate-use treatment of a single patient with atypical partial lipodystrophy and a history of undetectable leptin concentrations associated with neutralizing antibodies to metreleptin was associated with noteable improvements in circulating triglycerides and hepatic steatosis. Collectively, these translational data unveil an agonist LEPR mAb that may provide clinical benefit in disorders associated with relatively low leptin concentrations.

A Multicenter Assessment of Interreader Reliability of LI-RADS Version 2018 for MRI and CT.

Background Various limitations have impacted research evaluating reader agreement for Liver Imaging Reporting and Data System (LI-RADS). Purpose To assess reader agreement of LI-RADS in an international multicenter multireader setting using scrollable images. Materials and Methods This retrospective study used deidentified clinical multiphase CT and MRI and reports with at least one untreated observation from six institutions and three countries; only qualifying examinations were submitted. Examination dates were October 2017 to August 2018 at the coordinating center. One untreated observation per examination was randomly selected using observation identifiers, and its clinically assigned features were extracted from the report. The corresponding LI-RADS version 2018 category was computed as a rescored clinical read. Each examination was randomly assigned to two of 43 research readers who independently scored the observation. Agreement for an ordinal modified four-category LI-RADS scale (LR-1, definitely benign; LR-2, probably benign; LR-3, intermediate probability of malignancy; LR-4, probably hepatocellular carcinoma [HCC]; LR-5, definitely HCC; LR-M, probably malignant but not HCC specific; and LR-TIV, tumor in vein) was computed using intraclass correlation coefficients (ICCs). Agreement was also computed for dichotomized malignancy (LR-4, LR-5, LR-M, and LR-TIV), LR-5, and LR-M. Agreement was compared between research-versus-research reads and research-versus-clinical reads. Results The study population consisted of 484 patients (mean age, 62 years ± 10 [SD]; 156 women; 93 CT examinations, 391 MRI examinations). ICCs for ordinal LI-RADS, dichotomized malignancy, LR-5, and LR-M were 0.68 (95% CI: 0.61, 0.73), 0.63 (95% CI: 0.55, 0.70), 0.58 (95% CI: 0.50, 0.66), and 0.46 (95% CI: 0.31, 0.61) respectively. Research-versus-research reader agreement was higher than research-versus-clinical agreement for modified four-category LI-RADS (ICC, 0.68 vs 0.62, respectively; P = .03) and for dichotomized malignancy (ICC, 0.63 vs 0.53, respectively; P = .005), but not for LR-5 (P = .14) or LR-M (P = .94). Conclusion There was moderate agreement for LI-RADS version 2018 overall. For some comparisons, research-versus-research reader agreement was higher than research-versus-clinical reader agreement, indicating differences between the clinical and research environments that warrant further study. © RSNA, 2023 Supplemental material is available for this article. See also the editorials by Johnson and Galgano and Smith in this issue.

Diagnostic Accuracy of Unenhanced Computed Tomography for Evaluation of Acute Abdominal Pain in the Emergency Department.

Importance: Intravenous (IV) contrast medium is sometimes withheld due to risk of complication or lack of availability in patients undergoing computed tomography (CT) for abdominal pain. The risk from withholding contrast medium is understudied. Objective: To determine the diagnostic accuracy of unenhanced abdominopelvic CT using contemporaneous contrast-enhanced CT as the reference standard in emergency department (ED) patients with acute abdominal pain. Design, Setting, and Participants: This was an institutional review board-approved, multicenter retrospective diagnostic accuracy study of 201 consecutive adult ED patients who underwent dual-energy contrast-enhanced CT for the evaluation of acute abdominal pain from April 1, 2017, through April 22, 2017. Three blinded radiologists interpreted these scans to establish the reference standard by majority rule. IV and oral contrast media were then digitally subtracted using dual-energy techniques. Six different blinded radiologists from 3 institutions (3 specialist faculty and 3 residents) interpreted the resulting unenhanced CT examinations. Participants included a consecutive sample of ED patients with abdominal pain who underwent dual-energy CT. Exposure: Contrast-enhanced and virtual unenhanced CT derived from dual-energy CT. Main outcome: Diagnostic accuracy of unenhanced CT for primary (ie, principal cause[s] of pain) and actionable secondary (ie, incidental findings requiring management) diagnoses. The Gwet interrater agreement coefficient was calculated. Results: There were 201 included patients (female, 108; male, 93) with a mean age of 50.1 (SD, 20.9) years and mean BMI of 25.5 (SD, 5.4). Overall accuracy of unenhanced CT was 70% (faculty, 68% to 74%; residents, 69% to 70%). Faculty had higher accuracy than residents for primary diagnoses (82% vs 76%; adjusted odds ratio [OR], 1.83; 95% CI, 1.26-2.67; P = .002) but lower accuracy for actionable secondary diagnoses (87% vs 90%; OR, 0.57; 95% CI, 0.35-0.93; P < .001). This was because faculty made fewer false-negative primary diagnoses (38% vs 62%; OR, 0.23; 95% CI, 0.13-0.41; P < .001) but more false-positive actionable secondary diagnoses (63% vs 37%; OR, 2.11, 95% CI, 1.26-3.54; P = .01). False-negative (19%) and false-positive (14%) results were common. Interrater agreement for overall accuracy was moderate (Gwet agreement coefficient, 0.58). Conclusion: Unenhanced CT was approximately 30% less accurate than contrast-enhanced CT for evaluating abdominal pain in the ED. This should be balanced with the risk of administering contrast material to patients with risk factors for kidney injury or hypersensitivity reaction.

Risk of malignancy in T1-hyperintense Bosniak version 2019 class II and IIF cystic renal masses.

BACKGROUND: Bosniak classification version 2019 includes cystic masses in class II and IIF based partly on their hyperintense appearance at T1-weighted MRI. The prevalence of malignancy in non-enhancing heterogeneously T1-hyperintense masses is unknown, nor whether the pattern of T1 hyperintensity affects malignancy likelihood. PURPOSE: To determine the malignancy proportion among six patterns of T1 hyperintensity within non-enhancing cystic renal masses. METHODS: This retrospective, single-institution study included 72 Bosniak class II and IIF, non-enhancing, T1-hyperintense cystic renal masses. Diagnosis was confirmed by histopathology or by follow-up imaging demonstrating 5-year size and morphologic stability, decreased in size by ≥ 30%, resolution, or Bosniak down-classification. Six patterns of T1 hyperintensity were pre-defined: homogeneous (pattern A), fluid-fluid level (pattern B), peripherally markedly T1-hyperintense (pattern C), containing a T1-hyperintense non-enhancing nodule (pattern D), peripherally T1-hypointense (pattern E), and heterogeneously T1-hyperintense without a distinct pattern (pattern F). Three readers independently assigned each mass to a pattern. Individual and mean malignancy proportion were determined. Mann-Whitney test and Fischer's exact test compared the likelihood of malignancy between patterns. Inter-reader agreement was analyzed with Gwet's agreement coefficient (AC). RESULTS: Among 72 masses, the mean number of masses assigned was 11 (15%) to pattern A, 21 (29%) to pattern B, 6 (8%) to pattern C, 7 (10%) to pattern D, 5 (7%) to pattern E, and 22 (31%) to pattern F. Five of 72 masses (7%) were malignant; none was assigned pattern A, B, or D. Mean malignancy proportion was 5% (0/9, 1/6, and 0/4) for pattern C, 13% (0/4, 1/3, and 1/7) for pattern E, and 18% (5/20, 3/21, and 4/25) for pattern F. Malignant masses were more likely assigned to pattern E or F (p = 0.003-0.039). Inter-reader agreement was substantial (Gwet's AC: 0.68). CONCLUSION: Bosniak version 2019 class IIF masses that are non-enhancing and heterogeneously T1-hyperintense with a fluid-fluid level are likely benign. Those that are non-enhancing and heterogeneously T1-hyperintense without a distinct pattern have a malignancy proportion up to 25% (5/20).

Intra-practice Urologist-level Variation in Targeted Fusion Biopsy Outcomes.

OBJECTIVE: To examine the extent to which the urologist performing biopsy contributes to variation in prostate cancer detection during fusion-guided prostate biopsy. METHODS: All men in the Michigan Urological Surgery Improvement Collaborative (MUSIC) clinical registry who underwent fusion biopsy at Michigan Medicine from August 2017 to March 2019 were included. The primary outcomes were clinically significant cancer detection rate (defined as Gleason Grade ≥2) in targeted cores and clinically significant cancer detection on targeted cores stratified by PI-RADS score. Bivariate and multivariable logistic regression analyses were performed. RESULTS: A total of 1133 fusion biopsies performed by 5 providers were included. When adjusting for patient age, PSA, race, family history, prostate volume, clinical stage, and PI-RADS score, there was no significant difference in targeted clinically significant cancer detection rates across providers (range = 38.5%-46.9%, adjusted P-value = .575). Clinically significant cancer detection rates ranged from 11.1% to 16.7% in PI-RADS 3 (unadjusted P = .838), from 24.6% to 43.4% in PI-RADS 4 (adjusted P = .003), and from 69.4% to 78.8% in PI-RADS 5 (adjusted P = .766) lesions. CONCLUSION: There was a statistically significant difference in clinically significant prostate cancer detection in PI-RADS 4 lesions across providers. These findings suggest that even among experienced providers, variation at the urologist level may contribute to differences in clinically significant cancer detection rates within PI-RADS 4 lesions. However, the relative impact of biopsy technique, radiologist interpretation, and MR acquisition protocol requires further study.

Diagnostic yield of whole-body 18F-FDG PET/CT in patients with suspected cardiac sarcoidosis.

BACKGROUND: Whole-body F-18 FDG PET has been included in the 2014 Heart Rhythm Society guidelines for cardiac sarcoidosis evaluation to identify alternate sites of biopsy prior to endomyocardial biopsy. The purpose of this study was to evaluate the diagnostic yield of whole-body F-18 FDG PET/CT. METHODS: All adult patients with suspected cardiac sarcoidosis undergoing same-day cardiac F-18 FDG PET/CT and whole-body F-18 FDG PET/CT between 10/1/2016 and 6/14/2021 to assess potential biopsy sites were retrospectively identified. Clinical indications, findings, recommendations, and outcomes were assessed. RESULTS: Eighty-eight patients were included. Extracardiac PET findings suggestive of sarcoidosis were present in 30 patients (34%), 27 of which had thoracic findings (90%). Sarcoidosis was diagnosed in 11% of patients. Only 1% (1/88) was diagnosed by extrathoracic biopsy of a whole-body PET finding. Incidental findings were common (31%), resulting in 11 additional tests or interventions. Recommendations from extrathoracic findings affected treatment in one case: a drainage catheter placement into an unsuspected pelvic abscess. CONCLUSION: Addition of whole-body F-18 FDG PET/CT to cardiac F-18 FDG PET/CT for the identification of extrathoracic sites of biopsy in patients with suspected cardiac sarcoidosis has marginal diagnostic yield but commonly results in incidental findings that rarely affect patient outcome.