Integrating Clinical and Polygenic Factors to Predict Breast Cancer Risk in Women Undergoing Genetic Testing.

PURPOSE: Screening and prevention decisions for women at increased risk of developing breast cancer depend on genetic and clinical factors to estimate risk and select appropriate interventions. Integration of polygenic risk into clinical breast cancer risk estimators can improve discrimination. However, correlated genetic effects must be incorporated carefully to avoid overestimation of risk. MATERIALS AND METHODS: A novel Fixed-Stratified method was developed that accounts for confounding when adding a new factor to an established risk model. A combined risk score (CRS) of an 86-single-nucleotide polymorphism polygenic risk score and the Tyrer-Cuzick v7.02 clinical risk estimator was generated with attenuation for confounding by family history. Calibration and discriminatory accuracy of the CRS were evaluated in two independent validation cohorts of women of European ancestry (N = 1,615 and N = 518). Discrimination for remaining lifetime risk was examined by age-adjusted logistic regression. Risk stratification with a 20% risk threshold was compared between CRS and Tyrer-Cuzick in an independent clinical cohort (N = 32,576). RESULTS: Simulation studies confirmed that the Fixed-Stratified method produced accurate risk estimation across patients with different family history. In both validation studies, CRS and Tyrer-Cuzick were significantly associated with breast cancer. In an analysis with both CRS and Tyrer-Cuzick as predictors of breast cancer, CRS added significant discrimination independent of that captured by Tyrer-Cuzick (P < 10-11 in validation 1; P < 10-7 in validation 2). In an independent cohort, 18% of women shifted breast cancer risk categories from their Tyrer-Cuzick-based risk compared with risk estimates by CRS. CONCLUSION: Integrating clinical and polygenic factors into a risk model offers more effective risk stratification and supports a personalized genomic approach to breast cancer screening and prevention.

Breast reconstruction with a deep inferior epigastric perforator flap: imaging appearances of the normal flap and common complications.

OBJECTIVE: The purpose of this essay is to illustrate the normal imaging appearance of deep inferior epigastric perforator (DIEP) flap breast reconstruction and common postoperative complications. CONCLUSION: Familiarity with the anatomy and normal imaging appearance of a DIEP flap reconstruction will help the breast imager recognize normal postsurgical findings and common postoperative complications.

Hepatic arterial waveforms on early posttransplant Doppler ultrasound.

OBJECTIVES: To determine the significance of spectral Doppler hepatic artery waveforms obtained in the first 10 days after primary liver transplantation and to determine the best early predictor of hepatic arterial thrombosis (HAT). SUBJECTS AND METHODS: A total of 645 patients were retrospectively followed up to 1 year after liver transplantation. Doppler waveforms of the hepatic arteries were categorized as normal, abnormally elevated, not visualized, or with resistive index (RI) <0.5 on all examinations performed within the first 10 days. Waveforms were then correlated with patient outcomes within 1 year. RESULTS: Of the 645 patients, 83 (12.8%) had nonvisualization of at least one hepatic artery on Doppler evaluation and 56 (8.7%) developed HAT or stenosis within the first year after transplantation. Odds ratios (ORs) demonstrate that a single nonvisualized hepatic artery (OR, 9.66; 95% confidence interval [CI], 4.51-20.70) has a much higher incidence of HAT in the first 10 days after transplantation compared to low RI (OR, 1.93; 95% CI, 0.77-4.79)] or high RI (OR, 1.06; 95% CI, 0.44-2.55]. The loss or reversal of diastolic flow on Doppler ultrasound performed in the first 10 days after transplantation does not seem to correlate with active or impending HAT. CONCLUSION: Absence of hepatic arterial flow Doppler signal in the first 10 days after liver transplantation is associated with higher incidence of thrombosis than previously demonstrated, whereas persistently high diastolic flow early on seems to be more significant and leads to further hepatic arterial complications than decreased diastolic flow.

Management of vascular and nonvascular complications after renal transplantation.

Renal transplantation is the treatment of choice for end-stage renal disease. Despite medical and surgical advances, vascular and nonvascular complications remain common post transplantation, occurring in 12%-20% of patients (Kobayashi K, Censullo ML, Rossman LL, et al: Radiographics 27:1109-1130, 2007; Orons PD, Zajko AB: Radiol Clin North Am 33:461-471, 1995). Complications of renal transplantation can range from minor complications, such as peri-graft fluid collections, to severe complications, such as renal vein thrombosis or transplant renal artery stenosis (TRAS). These complications may compromise graft function and cause significant morbidity. Most postoperative complications can be diagnosed by radiologic evaluation and often times can be treated by minimally-invasive, interventional radiologic procedures. A thorough understanding of how the complications impair allograft function and survival is essential in allowing adequate treatment. Interventional radiology plays an invaluable role in the postoperative management of renal transplantation and related complications. The general indications for renal transplantation related procedures and the most commonly used and latest techniques are described in more detail.

Plasma cathepsin D isoforms and their active metabolites increase after myocardial infarction and contribute to plasma renin activity.

Plasma renin activity (PRA) is often found to increase after myocardial infarction (MI). Elevated PRA may contribute to increased myocardial angiotensin II that is responsible for maladaptive remodeling of the myocardium after MI. We hypothesized that MI would also result in cardiac release of cathepsin D, a ubiquitous lysosomal enzyme with high renin sequence homology. Cathepsin D release from damaged myocardial tissue could contribute to angiotensin formation by acting as an enzymatic alternate to renin. We assessed circulating renin and cathepsin D from both control and MI patient plasma (7-20 hours after MI) using shallow gradient focusing that allowed for independent measurement of both enzymes. Cathepsin D was increased significantly in the plasma after MI (P < 0.001). Furthermore, circulating active cathepsin D metabolites were also significantly elevated after MI (P < 0.04), and contained the majority of cathepsin D activity in plasma. Spiking control plasma with cathepsin D resulted in a variable but significant (P = 0.005) increase in PRA using a clinical assay. We conclude that 7-20 hours after MI, plasma cathepsin D is significantly elevated and most of the active enzymatic activity is circulating as plasma metabolites. Circulating cathepsin D can falsely increase clinical PRA determinations, and may also provide an alternative angiotensin formation pathway after MI.