Citations

BACKGROUNDPatients diagnosed with primary sclerosing cholangitis (PSC) and dominant strictures often undergo endoscopic retrograde cholangiopancreatography with brush cytology to exclude or confirm the development of malignancy. Equivocal (atypical or suspicious) routine cytologic results may confound patient management decisions, especially in the absence of a mass on imaging. The objective of the current study was to identify independent predictors of malignancy in patients with PSC with an equivocal cytology diagnosis.METHODSPatients with PSC underwent brush cytology for routine cytology and fluorescence in situ hybridization (FISH) during endoscopy as per standard care. FISH slides were classified as polysomy if at least 5 cells displayed a gain of ≥ 2 probes. A retrospective search identified 102 patients without a mass lesion noted on initial imaging studies, an equivocal routine cytology, and ≥ 2 years of follow‐up.RESULTSOf 102 patients, 30 (29%) with an equivocal cytology result developed cancer within 2 years. Serum carbohydrate antigen 19‐9 (CA 19‐9) levels ≥ 129 U/mL (hazard ratio [HR] 3.19; P = .001) and polysomy (HR 8.70; P < .001) were each found to be predictive of cancer. Of 10 patients who had elevated CA 19‐9 levels and polysomy, all went on to develop cancer (9 within 2 years). Although only 10 patients were included in this subset, the combination of elevated CA 19‐9 and polysomy was found to be predictive of cancer (HR 10.92; P < .001).CONCLUSIONSPolysomy by FISH identified those patients most likely to have or develop malignancy in the challenging clinical scenario of PSC with no mass at baseline and equivocal cytology. The combination of an elevated serum CA 19‐9 level with polysomy is highly suspicious for the presence of malignancy. Cancer (Cancer Cytopathol) 2013;121:708–717. © 2013 American Cancer Society.

Cancers are rarely caused by single mutations, but often develop as a result of the combined effects of multiple mutations. For most cells, the number of possible cell divisions is limited because of various biological constraints, such as progressive telomere shortening, cell senescence cascades or a hierarchically organized tissue structure. Thus, the risk of accumulating cells carrying multiple mutations is low. Nonetheless, many diseases are based on the accumulation of such multiple mutations. We model a general, hierarchically organized tissue by a multi-compartment approach, allowing any number of mutations within a cell. We derive closed solutions for the deterministic clonal dynamics and the reproductive capacity of single clones. Our results hold for the average dynamics in a hierarchical tissue characterized by an arbitrary combination of proliferation parameters. We show that hierarchically organized tissues strongly suppress cells carrying multiple mutations and derive closed solutions for the expected size and diversity of clonal populations founded by a single mutant within the hierarchy. We discuss the example of childhood acute lymphoblastic leukaemia in detail and find good agreement between our predicted results and recently observed clonal diversities in patients. This result can contribute to the explanation of very diverse mutation profiles observed by whole genome sequencing of many different cancers.

Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.

Background— Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling and right heart failure. The right (RV) and left ventricles (LV) do not function in isolation, sharing a common pericardial sac and interventricular septum. We sought to define the clinical and prognostic significance of ventricular interdependence in PAH and its association with LV filling patterns through speckle-tracking strain echocardiography. Methods and Results— Echocardiography was performed in 71 adults with a new diagnosis of PAH. To analyze LV and RV function separately, we measured peak systolic longitudinal and circumferential strain of the LV and RV. Survival was assessed >2 years. Patients had dilated right-sided chambers (right atrial volume index, 44±19 mL/m 2 ; RV end-diastolic area, 34±9 cm 2 ), and reduced RV function (RV fractional area change, 28±12%). Speckle-tracking echocardiography revealed significant reductions in RV free wall peak systolic strain (−15±3%). Despite normal LV size and normal conventional measures of LV systolic function (end-diastolic dimension, 42±6 mm; ejection fraction, 65±8%; cardiac index, 2.6±0.8 L/min per m 2 ), patients had reduced LV free wall systolic strain (−15±3%). Decreased LV free wall systolic strain was associated with a delayed relaxation mitral inflow Doppler pattern, P =0.0002. During 2-year follow-up, 19 patients (27%) died. LV strain was associated with increased mortality (unadjusted hazard ratio, 2.40 per 5% decrease in LV free wall strain, 1.22–4.68), which remained significant when adjusted for age, sex, World Health Organization functional class, and PAH pathogenesis (hazard ratio, 3.11, 1.38–7.20). Conclusions— The pressure loading in PAH results in geometric alterations and functional decline of the RV, with marked reduction in RV systolic strain. Despite preservation of LV ejection fraction, LV systolic strain was also reduced and associated with early mortality, highlighting the significance of ventricular interdependence in PAH.

Background Tools for the prediction of atrial fibrillation ( AF ) may identify high‐risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors. Methods and Results Individual‐level data from 3 large cohorts in the U nited S tates (Atherosclerosis Risk in Communities [ ARIC ] study, the Cardiovascular Health Study [ CHS ], and the Framingham Heart Study [ FHS ]), including 18 556 men and women aged 46 to 94 years (19% A frican A mericans, 81% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment—Reykjavik study ( AGES ) and the Rotterdam Study ( RS ). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5‐year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C‐statistic, 0.765; 95% CI , 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C‐statistic, 0.767; 95% CI , 0.750 to 0.783; categorical net reclassification improvement, −0.0032; 95% CI , −0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable ( AGES C‐statistic, 0.664; 95% CI , 0.632 to 0.697 and RS C‐statistic, 0.705; 95% CI , 0.664 to 0.747) and calibration was adequate. Conclusion A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the U nited S tates and E urope.

The detection of aneuploidy by fluorescence in situ hybridization (FISH) has revolutionized how laboratories diagnose cholangiocarcinoma and pancreatic adenocarcinoma using cytology specimens. Numerous clinical studies have demonstrated that FISH increases the diagnostic sensitivity of routine cytology for detecting pancreatobiliary tract malignancy with minimal decreases in clinical specificity. FISH also provides useful information in difficult clinical scenarios, including the assessment of patients with biliary strictures who have equivocal cytology results and the assessment of patients with primary sclerosing cholangitis who have clinical features suggestive of malignancy. The improved ability to detect pancreatobiliary tract cancers offers the possibility of earlier detection when patients are amenable to surgical intervention and can decrease health care costs by reducing the amount of clinical evaluation required to arrive at a cancer diagnosis. Cytopathology personnel should maintain familiarity with molecular cytology testing methodologies, because morphologic and aneuploidy assessment of tumors will continue to be an integral part of large‐scale genome analyses of individual tumors. Cancer (Cancer Cytopathol) 2013;121:610‐9. © 2013 American Cancer Society.