BackgroundTelomerase is an enzyme that catalyzes the addition of nucleotides on the ends of chromosomes. Rare loss of function mutations in the gene that encodes the protein component of telomerase (TERT) have been described in patients with idiopathic pulmonary fibrosis (IPF). Here we examine the telomere lengths and pulmonary fibrosis phenotype seen in multiple kindreds with heterozygous TERT mutations.Methods and FindingsWe have identified 134 individuals with heterozygous TERT mutations from 21 unrelated families. Available medical records, surgical lung biopsies and radiographs were evaluated retrospectively. Genomic DNA isolated from circulating leukocytes has been used to measure telomere lengths with a quantitative PCR assay. We find that telomere lengths of TERT mutation carriers decrease in an age-dependent manner and show progressive shortening with successive generations of mutation inheritance. Family members without TERT mutations have a shorter mean telomere length than normal, demonstrating epigenetic inheritance of shortened telomere lengths in the absence of an inherited TERT mutation. Pulmonary fibrosis is an age-dependent phenotype not seen in mutation carriers less than 40 years of age but found in 60% of men 60 years or older; its development is associated with environmental exposures including cigarette smoking. A radiographic CT pattern of usual interstitial pneumonia (UIP), which is consistent with a diagnosis of IPF, is seen in 74% of cases and a pathologic pattern of UIP is seen in 86% of surgical lung biopsies. Pulmonary fibrosis associated with TERT mutations is progressive and lethal with a mean survival of 3 years after diagnosis. Overall, TERT mutation carriers demonstrate reduced life expectancy, with a mean age of death of 58 and 67 years for males and females, respectively.ConclusionsA subset of pulmonary fibrosis, like dyskeratosis congenita, bone marrow failure, and liver disease, represents a “telomeropathy” caused by germline mutations in telomerase and characterized by short telomere lengths. Family members within kindreds who do not inherit the TERT mutation have shorter telomere lengths than controls, demonstrating epigenetic inheritance of a shortened parental telomere length set-point.

Purpose: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the a subunit, which heterodimerizes with HIF1b, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control !4 months was achieved in 42% of patients.Patients and Methods: We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW (n ¼ 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNAsequencing studies.Results: PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2a, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired TP53 mutation elsewhere, suggesting a possible alternate mechanism of resistance.Conclusions: These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).

Purpose Detection of small renal masses is increasing with the use of cross-sectional imaging, although many incidental lesions have negligible metastatic potential. Among malignant masses, clear cell renal cell carcinoma is the most prevalent and aggressive subtype, and a method to identify such histology would aid in risk stratification. Our goal was to evaluate a likelihood scale for multiparametric magnetic resonance imaging in the diagnosis of clear cell histology. Methods Patients with cT1a masses who underwent MRI and partial or radical nephrectomy from December 2011 to July 2015 were retrospectively reviewed. Seven radiologists with different levels of experience and blinded to final pathology independently reviewed studies based on a predefined algorithm, and applied a clear cell likelihood score: 1) definitely not, 2) probably not, 3) equivocal, 4) probably, and 5) definitely. Binary classification determined the accuracy of clear cell versus ‘all other’ histologies, and inter-observer agreement was calculated with a weighted κ statistic. Results In total, 110 patients with 121 masses were identified. Mean tumor size was 2.4 cm and 50% were clear cell. Defining clear cell as scores ≥4 demonstrated sensitivity and specificity of 78% and 80%, respectively, while scores ≥3 were 95% and 58%, respectively. Inter-observer agreement was moderate to good, with a mean κ of 0.53. Conclusions A clear cell likelihood score with MRI can reasonably identify clear cell histology in small renal masses, and may reduce the number of diagnostic renal mass biopsies. Standardization of imaging protocols and reporting criteria are needed to improve inter-observer reliability.

TERT mutation carriers exhibit early preclinical signs of lung fibrosis, bone marrow dysfunction, and premature graying. These clinical features and short telomere lengths characterize patients with germline TERT mutations.

BACKGROUND AND PURPOSE:Differentiating between tumors and pseudotumoral lesions by conventional MR imaging may be a challenging question. This study aims to evaluate the potential usefulness and the added value that single-voxel proton MR spectroscopy could provide on this discrimination.

Purpose To determine the diagnostic performance and inter-reader agreement of a standardized diagnostic algorithm for determining the histologic type of small (<=4cm) renal masses (SRM) with multiparametric magnetic resonance imaging (MRI). Materials and Methods This single-center, retrospective, HIPAA-compliant, IRB-approved study included 103 patients with 109 SRM, resected between December 2011 and July 2015. The requirement for informed consent was waived. Pre-surgical renal MRIs were reviewed by 7 radiologists with diverse experience. Eleven MRI features were assessed and a standardized diagnostic algorithm used to determine the most likely histologic diagnosis, which was compared to histopathology after surgery. Inter-reader variability was tested with Cohen’s κ. Regression models using MRI features were used to predict the histopathologic diagnosis with 5% significance level. Results Clear-cell (ccRCC) and papillary type renal cell carcinomas (pRCC) were diagnosed with respective sensitivities of 85% (47/55) and 80% (20/25), and specificities of 76% (41/54) and 94% (79/84). Inter-reader agreement was moderate-to-substantial (ccRCC, κ=0.58; pRCC, κ=0.73). Signal intensity of the lesion on T2-weighted images (T2W) and degree of contrast enhancement during corticomedullary phase (CE) were independent predictors of ccRCC (T2W OR: 3.19 CI95%: [1.4, 7.1], p=0.003; CE OR: 4.45 [1.8, 10.8], p<0.001) and pRCC (CE OR: 0.053 [0.02, 0.2], p<0.001), both with substantial inter-reader agreement (T2W, κ=0.69; CE, κ=0.71). Lower performance was observed for chromophobe histology, oncocytomas, and minimal-fat angiomyolipomas, [ranges, sensitivity=14%(1/7)–67%(4/6), specificity=97%(100/103)–99%(101/102)], with fair-to-moderate inter-reader agreement (κ=0.23–0.43). Segmental enhancement inversion was an independent predictor of oncocytomas (OR: 16.21 [1.0, 275.4], p=0.049), with moderate inter-reader agreement (κ=0.49). Conclusion The proposed standardized MRI-based diagnostic algorithm had a diagnostic accuracy of 81% (88/109) and 91% (99/109) for the diagnosis of ccRCC and pRCC, respectively, while achieving moderate to substantial inter-reader agreement among 7 radiologists.

Background The high operational cost of MRI limits its utility for hepatocellular carcinoma (HCC) screening. Abbreviated‐protocol dynamic contrast‐enhanced MRI (aMRI) may help lower cost while maintaining the high accuracy of complete‐protocol diagnostic MRI (cMRI). Purpose To compare aMRI to cMRI for HCC detection in cirrhosis patients. Study Type Cross‐sectional study. Study Population Cirrhosis patients undergoing MRI for suspected HCC. Field Strength/Sequence 1.5T and 3T; aMRI (coronal T2‐weighted, axial dynamic contrast‐enhanced T1‐weighted fat‐suppressed sequences); cMRI (aMRI sequences and unenhanced axial T2‐, T1‐, and diffusion‐weighted sequences). Assessment From each cMRI, an abbreviated exam was created by extracting only the aMRI sequences. Five radiologists independently reviewed aMRI and cMRI and assigned per‐patient screening results by the presence/absence of any actionable observation per Liver Imaging and Reporting Data System v2018 (LI‐RADS 4, 5, M, or TIV categories). Per‐patient HCC status was determined by the composite reference standard of histopathology, follow‐up imaging, consensus expert panel imaging review, and clinical follow‐up. Statistical Tests Interreader agreement between aMRI and cMRI was compared with that of cMRI and tested for interchangeability against a tolerance margin of 0.05. Per‐patient screening sensitivity, specificity, and accuracy were compared between aMRI and cMRI and tested for equivalence against a tolerance margin of 0.05. Results In 93 cirrhosis patients, five radiologists recorded on average 121 liver observations. Interreader screening agreement probability (and 95% confidence interval confidence interval [CI]) was 0.914 [0.900, 0.926] between aMRI and cMRI, and 0.927 [0.908, 0.942] for cMRI; their difference was within the 0.05 margin for interchangeability. In 86 patients in whom a final HCC status could be determined, the detection sensitivity and specificity of aMRI was 0.921 [0.864, 0.956] and 0.886 [0.844, 0.918], within the 5% equivalence margin to cMRI, 0.936 [0.881, 0.965] and 0.883 [0.840, 0.915], respectively. Data Conclusion Abbreviated‐protocol screening MRI is interchangeable with, and equivalent to, complete‐protocol diagnostic MRI for per‐patient HCC detection in cirrhosis. Level of Evidence: 4 Technical Efficacy: Stage 6 J. Magn. Reson. Imaging 2020;51:415–425.

SYNOPSIS Renal cell carcinoma (RCC) exhibits a diverse and heterogeneous disease spectrum, but insight into its behavior has provided an improved understanding of potential risk factors, natural history of disease, and imaging features. Appropriately performed, CT and MRI may allow for the identification and accurate preoperative subtyping of RCC and for the assessment of a response to various therapies. Active surveillance is receiving increasing attention as a viable management option in select subgroup of patients and has provided further insight into the natural history of RCC, including the favorable prognosis of cystic renal neoplasms. In this article, we provide a brief review of the epidemiologic, clinical, and imaging features of RCC and the potential role of screening in selected high-risk populations.