Citations

AbstractThe immunoglobulin free light chain (FLC) is the precursor protein of amyloid in primary systemic amyloidosis (AL). Historically, the ability to monitor the amyloid protein precursor protein has been crude. We evaluated the utility of the FLC assay in a retrospective analysis of patients with AL undergoing peripheral blood stem cell transplantation (PBSCT). Ninety-three such patients had serial FLC measurements performed. The prognostic effects of the initial concentration and the extent of reduction of monoclonal FLC on survival were studied. There was a significantly higher risk of death in patients with higher baseline FLC (hazard ratio 2.6, P < .04). Baseline FLC correlated with serum cardiac troponin levels, and higher FLC levels were associated with more organs involved by amyloid, suggesting that high FLC levels may be associated with more advanced disease. The percent FLC reduction did not predict for survival, but the absolute level of FLC achieved after therapy did. Normalization of FLC level after PBSCT predicted for both organ response and complete hematologic response. Achievement of FLC response was a better predictor of survival than achievement of complete hematologic response or normalization of the FLC ratio. FLC measurements both before and after PBSCT are important predictors of patient outcome.

We investigated the relationship of aortic pulse wave velocity (aPWV), a measure of central arterial stiffness, with the presence and quantity of coronary artery calcium (CAC) in a community-based sample of adults without prior history of heart attack or stroke (n=401, mean age 59.8 years, 53% men). ECG-gated waveforms of the right carotid and right femoral artery were obtained by applanation tonometry, and aPWV was calculated using established methods. CAC was measured noninvasively by electron beam computed tomography, and CAC score was calculated. aPWV was significantly correlated with log(CAC +1; r =0.41; P <0.0001) and pulse pressure ( r =0.47; P <0.0001). Multivariable logistic and linear regression models were used to identify independent predictors of the presence and quantity of CAC, respectively. In multivariable logistic regression analyses, aPWV was associated with the presence of CAC ( P =0.011) after adjustment for age, male sex, total cholesterol, high-density lipoprotein cholesterol, diabetes, history of smoking, systolic blood pressure, body mass index, and use of hypertension and statin medications. In multivariable linear regression analyses, aPWV was significantly associated with log(CAC +1) after adjustment for the covariates enumerated above ( P <0.0001). aPWV remained significantly associated with both the presence and quantity of CAC even after the additional adjustment for diastolic blood pressure. We conclude that aPWV is related to subclinical coronary atherosclerosis independent of conventional risk factors (including indices of blood pressure) and may be a biomarker of cardiovascular risk in asymptomatic individuals.

Abstract Purpose: We examined the feasibility of using molecular characterization of circulating tumor cells as a method for early detection of breast cancer. Research Design: Women without a prior history of cancer who had a breast abnormality detected on imaging followed by a breast biopsy were enrolled in this study. Density gradient centrifugation and immunomagnetic capture were used to enrich for epithelial cells from ∼20 mL of blood. Real-time reverse transcription-PCR was used to quantitate the expression levels of the highly breast-specific genes, mammaglobin, γ-aminobutyric acid type A receptor π subunit (GABA Aπ), B305D-C, and B726P in the epithelial cell–enriched samples. Results: The assay was technically feasible in 154 of 199 accrued patients. From their clinical assessment, 100 patients had benign breast disease, 10 patients had ductal carcinoma in situ, and 44 patients had invasive breast cancer. We constructed a diagnostic test that classified patients with mammaglobin levels of at least 32.2 copies/pg β-actin (units) in their circulating epithelial cells as positive for invasive breast cancer. This resulted in a sensitivity and specificity of 63.3% and 75.0%, respectively. A diagnostic test that classified patients as positive for invasive breast cancer when either mammaglobin levels were &gt;46.3 units or B305D-C levels were &gt;11.6 units increased the sensitivity and specificity to 70.5% and 81.0%, respectively. In the latter test, 12 of the 14 node-positive breast cancer patients were correctly identified. Including GABA Aπ and B726P in the test did not increase its diagnostic potential. Conclusions: These results suggest that molecular characterization of circulating epithelial cells using mammaglobin and B305D-C offers potential for early detection of invasive breast cancer.

Abstract Prostate cancer is a leading and increasingly prevalent cause of cancer death in men. Whereas family history of disease is one of the strongest prostate cancer risk factors and suggests a hereditary component, the predisposing genetic factors remain unknown. We first showed that KLF6 is a tumor suppressor somatically inactivated in prostate cancer and since then, its functional loss has been further established in prostate cancer cell lines and other human cancers. Wild-type KLF6, but not patient-derived mutants, suppresses cell growth through p53-independent transactivation of p21. Here we show that a germline KLF6 single nucleotide polymorphism, confirmed in a tri-institutional study of 3,411 men, is significantly associated with an increased relative risk of prostate cancer in men, regardless of family history of disease. This prostate cancer–associated allele generates a novel functional SRp40 DNA binding site and increases transcription of three alternatively spliced KLF6 isoforms. The KLF6 variant proteins KLF6-SV1 and KLF6-SV2 are mislocalized to the cytoplasm, antagonize wtKLF6 function, leading to decreased p21 expression and increased cell growth, and are up-regulated in tumor versus normal prostatic tissue. Thus, these results are the first to identify a novel mechanism of self-encoded tumor suppressor gene inactivation and link a relatively common single nucleotide polymorphism to both regulation of alternative splicing and an increased risk in a major human cancer.