Alberto Diaz de Leon

Telomere Lengths, Pulmonary Fibrosis and Telomerase (TERT) Mutations

Background Telomerase 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 Findings We 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. Conclusions A 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.

Subclinical Lung Disease, Macrocytosis, and Premature Graying in Kindreds With Telomerase (TERT) Mutations

BACKGROUND Mutations in the human gene encoding the protein component of telomerase (TERT) are the most common genetic defect in patients with familial idiopathic pulmonary fibrosis (IPF). The subclinical phenotypes of asymptomatic members of these families have not been evaluated with respect to TERT mutation status or telomere length. METHODS We measured a variety of pulmonary, blood, skin, and bone parameters for 20 subjects with heterozygous TERT mutations (carriers) and 20 family members who had not inherited a TERT mutation (noncarriers) to identify the spectrum of phenotypes associated with mutations in this gene. The two groups were matched for sex, age, and cigarette smoking. Three TERT mutation carriers had IPF (IPF carriers). The rest of the carriers were apparently healthy (asymptomatic carriers) and were compared with the noncarriers. RESULTS Asymptomatic carriers exhibited significantly lower diffusing capacity of lung for carbon monoxide (Dlco), impaired recruitment of Dlco with exercise, radiographic signs of lung fibrosis, and increased fractional lung tissue volume quantified by high-resolution chest CT scan than noncarriers. RBC and platelet counts were significantly lower, and the mean corpuscular volume and mean corpuscular hemoglobin concentration were significantly higher in carriers than in noncarriers. Carriers reported significantly earlier graying of hair than noncarriers. TERT mutation status is more accurately predicted by short telomere lengths than any of these measured phenotypes. CONCLUSIONS 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.

Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging to Identify Clear Cell Renal Cell Carcinoma in cT1a Renal Masses

Purpose: The 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. 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. Materials and Methods: We retrospectively reviewed the records of patients with cT1a masses who underwent magnetic resonance imaging and partial or radical nephrectomy from December 2011 to July 2015. Seven radiologists with different levels of experience who were blinded to final pathology findings independently reviewed studies based on a predefined algorithm. They applied a clear cell likelihood score, including 1—definitely not, 2—probably not, 3—equivocal, 4—probably and 5—definitely. Binary classification was used to determine the accuracy of clear cell vs all other histologies. Interobserver agreement was calculated with the weighted &kgr; statistic. Results: A total of 110 patients with 121 masses were identified. Mean tumor size was 2.4 cm and 50% of the lesions were clear cell. Defining clear cell as scores of 4 or greater demonstrated 78% sensitivity and 80% specificity while scores of 3 or greater showed 95% sensitivity and 58% specificity. Interobserver agreement was moderate to good with a mean &kgr; of 0.53. Conclusions: A clear cell likelihood score used with magnetic resonance imaging can reasonably identify clear cell histology in small renal masses and may decrease the number of diagnostic renal mass biopsies. Standardization of imaging protocols and reporting criteria is needed to improve interobserver reliability.

Quantification of Regional Interstitial Lung Disease from CT-derived Fractional Tissue Volume: A Lung Tissue Research Consortium Study

RATIONALE AND OBJECTIVES Evaluation of chest computed tomography (CT) is usually qualitative or semiquantitative, resulting in subjective descriptions often by different observers over time and imprecise determinations of disease severity within distorted lobes. There is a need for standardized imaging biomarkers to quantify regional disease, maximize diagnostic yield, and facilitate multicenter comparisons. We applied lobe-based voxelwise image analysis to derive regional air (Vair) and tissue (Vtissue) volumes and fractional tissue volume (FTV = tissue/[tissue+air] volume) as internally standardized parameter for assessing interstitial lung disease (ILD). MATERIALS AND METHODS High-resolution CT was obtained at supine and prone end-inspiration and supine end-expiration in 29 patients with ILD and 20 normal subjects. Lobar Vair, Vtissue, and FTV were expressed along standard coordinate axes. RESULTS In normal subjects from end-inspiration to end-expiration, total Vair declined ~43%, FTV increased ~80%, but Vtissue remained unchanged. With increasing ILD, Vair declined and Vtissue rose in all lobes; FTV increased with a peripheral-to-central progression inversely correlated to spirometry and lung diffusing capacity (r(2) = 0.57-0.75, prone end-inspiration). Inter- and intralobar coefficients of variation of FTV increased 84-148% in mild-to-moderate ILD, indicating greater spatial heterogeneity, then normalized in severe ILD. Analysis of discontinuous images incurs <3% error compared to consecutive images. CONCLUSIONS These regional attenuation-based biomarkers could quantify heterogeneous parenchymal disease in distorted lobes, detect mild ILD involvement in all lobes and describe the pattern of disease progression. The next step would be to study a larger series, examine reproducibility and follow longitudinal changes in correlation with clinical and functional indices.

Treatment of Carcinoma of the Cervical Stump

At the ellis fischel State Cancer Hospital 163 carcinomas of the cervical stump were treated between 1940 and 1960. Eighty-one of these cases were classified as carcinomas of the true cervical stump, because the first symptom leading to the diagnosis of carcinoma was noticed three or more years after subtotal hysterectomy done for a benign condition. The remaining 82 are classed as coincidental, because symptoms were noticed before the third postoperative year. In no instance was the primary operation performed at our hospital. The importance of distinguishing between true and coincidental carcinoma of the cervical stump is borne out in the literature. All authors but one, Holmes in England, agree that the prognosis for carcinoma of the true stump is two to three times more favorable than for coincidental cases. The distinction has generally been made in terms of the time of occurrence of the cancer symptoms after surgery. Among the 46 authors listed in Table I, there is a wide range of opinion as to the ...

Role of Multiparametric MR Imaging in Malignancies of the Urogenital Tract

Multiparametric MR imaging (mpMRI) combine different sequences that, properly tailored, can provide qualitative and quantitative information about the tumor microenvironment beyond traditional tumor size measures and/or morphologic assessments. This article focuses on mpMRI in the evaluation of urogenital tract malignancies by first reviewing technical aspects and then discussing its potential clinical role. This includes insight into histologic subtyping and grading of renal cell carcinoma and assessment of tumor response to targeted therapies. The clinical utility of mpMRI in the staging and grading of ureteral and bladder tumors is presented. Finally, the evolving role of mpMRI in prostate cancer is discussed.

Diagnostic performance and interreader agreement of a standardized MR imaging approach in the prediction of small renal mass histology

Purpose To assess the diagnostic performance and interreader agreement of a standardized diagnostic algorithm in determining the histologic type of small (≤4 cm) renal masses (SRMs) with multiparametric magnetic resonance (MR) imaging. Materials and Methods This single-center retrospective HIPAA-compliant institutional review board-approved study included 103 patients with 109 SRMs resected between December 2011 and July 2015. The requirement for informed consent was waived. Presurgical renal MR images were reviewed by seven radiologists with diverse experience. Eleven MR imaging features were assessed, and a standardized diagnostic algorithm was used to determine the most likely histologic diagnosis, which was compared with histopathology results after surgery. Interreader variability was tested with the Cohen κ statistic. Regression models using MR imaging features were used to predict the histopathologic diagnosis with 5% significance level. Results Clear cell renal cell carcinoma (RCC) and papillary RCC were diagnosed, with sensitivities of 85% (47 of 55) and 80% (20 of 25), respectively, and specificities of 76% (41 of 54) and 94% (79 of 84), respectively. Interreader agreement was moderate to substantial (clear cell RCC, κ = 0.58; papillary RCC, κ = 0.73). Signal intensity (SI) of the lesion on T2-weighted MR images and degree of contrast enhancement (CE) during the corticomedullary phase were independent predictors of clear cell RCC (SI odds ratio [OR]: 3.19; 95% confidence interval [CI]: 1.4, 7.1; P = .003; CE OR, 4.45; 95% CI: 1.8, 10.8; P < .001) and papillary RCC (CE OR, 0.053; 95% CI: 0.02, 0.2; P < .001), and both had substantial interreader agreement (SI, κ = 0.69; CE, κ = 0.71). Poorer performance was observed for chromophobe histology, oncocytomas, and minimal fat angiomyolipomas, (sensitivity range, 14%-67%; specificity range, 97%-99%), with fair to moderate interreader agreement (κ range = 0.23-0.43). Segmental enhancement inversion was an independent predictor of oncocytomas (OR, 16.21; 95% CI: 1.0, 275.4; P = .049), with moderate interreader agreement (κ = 0.49). Conclusion The proposed standardized MR imaging-based diagnostic algorithm had diagnostic accuracy of 81% (88 of 109) and 91% (99 of 109) in the diagnosis of clear cell RCC and papillary RCC, respectively, while achieving moderate to substantial interreader agreement among seven radiologists.

Addressing metabolic heterogeneity in clear cell renal cell carcinoma with quantitative Dixon MRI

BACKGROUND Dysregulated lipid and glucose metabolism in clear cell renal cell carcinoma (ccRCC) has been implicated in disease progression, and whole tumor tissue-based assessment of these changes is challenged by the tumor heterogeneity. We studied a noninvasive quantitative MRI method that predicts metabolic alterations in the whole tumor. METHODS We applied Dixon-based MRI for in vivo quantification of lipid accumulation (fat fraction [FF]) in targeted regions of interest of 45 primary ccRCCs and correlated these MRI measures to mass spectrometry-based lipidomics and metabolomics of anatomically colocalized tissue samples isolated from the same tumor after surgery. RESULTS In vivo tumor FF showed statistically significant (P < 0.0001) positive correlation with histologic fat content (Spearman correlation coefficient, ρ = 0.79), spectrometric triglycerides (ρ = 0.56) and cholesterol (ρ = 0.47); it showed negative correlation with free fatty acids (ρ = -0.44) and phospholipids (ρ = -0.65). We observed both inter- and intratumoral heterogeneity in lipid accumulation within the same tumor grade, whereas most aggressive tumors (International Society of Urological Pathology [ISUP] grade 4) exhibited reduced lipid accumulation. Cellular metabolites in tumors were altered compared with adjacent renal parenchyma. CONCLUSION Our results support the use of noninvasive quantitative Dixon-based MRI as a biomarker of reprogrammed lipid metabolism in ccRCC, which may serve as a predictor of tumor aggressiveness before surgical intervention. FUNDING NIH R01CA154475 (YZ, MF, PK, IP), NIH P50CA196516 (IP, JB, RJD, JAC, PK), Welch Foundation I-1832 (JY), and NIH P01HL020948 (JGM).

Imaging and Screening of Kidney Cancer

Renal cell carcinoma (RCC) exhibits a diverse and heterogeneous disease spectrum, but insight into its molecular biology has provided an improved understanding of potential risk factors, oncologic behavior, and imaging features. Computed tomography (CT) and MR imaging may allow the identification and preoperative subtyping of RCC and assessment of a response to various therapies. Active surveillance is a viable management option in some patients and has provided further insight into the natural history of RCC, including the favorable prognosis of cystic neoplasms. This article reviews CT and MR imaging in RCC and the role of screening in selected high-risk populations.

Achieving ideal computed tomographic scan length in patient with suspected urolithiasis.

Purpose The purposes of the study were to determine the frequency and magnitude of extension of computed tomographic (CT) scans performed for the evaluation of urolithiasis, to investigate the potential contributing factors for overscanning, and to establish potential landmarks to assist in estimating the location of the superior margin of the kidneys. Materials and Methods This is a retrospective review of 300 CT studies performed for evaluation of urolithiasis. The total length of the scanned area, performing technologist, and the patient demographics were collected. Results We found that scanning beyond the defined z-axis boundaries is a common phenomenon in CT examinations in patients with suspected urolithiasis with a magnitude that correlates (P < 0.0001) with patient time and setting: greater in the emergent (78.3 mm) and inpatient (79.8 mm) settings as well as on-call hours (80.4 mm). Our study also shows the superior margin of T11 to be consistently within 3 mm of the superior margin of the kidney but not below it. Conclusions Overextension along the z axis is a ubiquitous phenomenon. The appropriate prescription of scan length, however, is an easy, efficient, costless, and universally applicable strategy. In patients with suspected urolithiasis, the superior margin of T11 represents a potential landmark to assist in estimating the upper margin of the kidneys.