Citations

Abstract Background: Both shorter and longer telomeres in peripheral blood leukocyte (PBL) DNA have been associated with cancer risk. However, associations remain inconsistent across studies of the same cancer type. This study compares DNA preparation methods to determine telomere length from patients with colorectal cancer. Methods: We examined PBL relative telomere length (RTL) measured by quantitative PCR (qPCR) in 1,033 patients with colorectal cancer and 2,952 healthy controls. DNA was extracted with phenol/chloroform, PureGene, or QIAamp. Results: We observed differences in RTL depending on DNA extraction method (P < 0.001). Phenol/chloroform-extracted DNA had a mean RTL (T/S ratio) of 0.78 (range 0.01–6.54) compared with PureGene-extracted DNA (mean RTL of 0.75; range 0.00–12.33). DNA extracted by QIAamp yielded a mean RTL of 0.38 (range 0.02–3.69). We subsequently compared RTL measured by qPCR from an independent set of 20 colorectal cancer cases and 24 normal controls in PBL DNA extracted by each of the three extraction methods. The range of RTL measured by qPCR from QIAamp-extracted DNA (0.17–0.58) was less than from either PureGene or phenol/chloroform (ranges, 0.04–2.67 and 0.32–2.81, respectively). Conclusions: RTL measured by qPCR from QIAamp-extracted DNA was less than from either PureGene or phenol/chloroform (P < 0.001). Impact: Differences in DNA extraction method may contribute to the discrepancies between studies seeking to find an association between the risk of cancer or other diseases and RTL. Cancer Epidemiol Biomarkers Prev; 22(11); 2047–54. ©2013 AACR.

We report the case of a 19-year-old woman with progressive proliferative lupus nephritis (LN) class III after induction and maintenance therapy with mycophenolate mofetil (MMF). Despite a satisfying clinical improvement proteinuria progressed under this medication. We treated the patient with additional belimumab after discussing other options. Following treatment with belimumab, proteinuria rapidly improved to almost normal levels and clinical remission lasted. Belimumab might hold promise for this indication.

Background Biomarkers have many distinct purposes, and depending on their intended use, the validation process varies substantially. Purpose The goal of this article is to provide an introduction to the topic of biomarkers, and then to discuss three specific types of biomarkers, namely, prognostic, predictive, and surrogate. Results A principle challenge for biomarker validation from a statistical perspective is the issue of multiplicity. In general, the solution to this multiplicity challenge is well known to statisticians: pre-specification and replication. Critical requirements for prognostic marker validation include uniform treatment, complete follow-up, unbiased case selection, and complete ascertainment of the many possible confounders that exist in the context of an observational sample. In the case of predictive biomarker validation, observational data are clearly inadequate and randomized controlled trials are mandatory. Within the context of randomization, strategies for predictive marker validation can be grouped into two categories: retrospective versus prospective validation. The critical validation criteria for a surrogate endpoint is to ensure that if a trial uses a surrogate endpoint, the trial will result in the same inferences as if the trial had observed the true endpoint. The field of surrogate endpoint validation has now moved to the multi-trial or meta-analytic setting as the preferred method. Conclusions Biomarkers are a highly active research area. For all biomarker developmental and validation studies, the importance of fundamental statistical concepts remains the following: pre-specification of hypotheses, randomization, and replication. Further statistical methodology research in this area is clearly needed as we move forward.

SummaryDetection of a 17p13.1 deletion (loss of TP53) or 11q22.3 deletion (loss of ATM), by fluorescence in situ hybridization (FISH), in chronic lymphocytic leukaemia (CLL) patients is associated with a poorer prognosis. Because TP53 and ATM are integral to the TP53 pathway, we hypothesized that 17p13.1‐ (17p‐) and 11q22.3‐ (11q‐) occurring in the same cell (clonal 17p‐/11q‐) would confer a worse prognosis than either 17p‐ or 11q‐. We studied 2184 CLL patients with FISH (1995–2012) for the first occurrence of 17p‐, 11q‐, or clonal 17p‐/11q‐. Twenty (1%) patients had clonal 17p–/11q‐, 158 (7%) had 17p‐ (including 4 with 17p‐ and 11q‐ in separate clones), 247 (11%) had 11q‐, and 1759 (81%) had neither 17p‐ nor 11q‐. Eleven of 15 (73%) tested patients with clonal 17p‐/11q‐ had dysfunctional TP53 mutations. Overall survival for clonal 17p‐/11q‐ was significantly shorter (1·9 years) than 17p‐ (3·1 years, P = 0·04), 11q‐ (4·8 years, P ≤ 0·0001), or neither 17p‐ nor 11q‐ (9·3 years, P ≤ 0·0001). Clonal 17p‐/11q‐ thus conferred significantly worse prognosis, suggesting that loss of at least one copy of both TP53 and ATM causes more aggressive disease. Use of an ATM/TP53 combination FISH probe set could identify these very‐high risk patients.

Purpose With improved patient care, better diagnosis, and more treatment options after tumor recurrence, outcomes after fluorouracil (FU) -based treatment are expected to have improved over time in early-stage colon cancer. Data from 18,449 patients enrolled onto 21 phase III trials conducted from 1978 to 2002 were evaluated for potential differences in time to recurrence (TTR), time from recurrence to death (TRD), and overall survival (OS) with regard to FU-based adjuvant regimens. Methods Trials were predefined as old versus newer era using initial accrual before or after 1995. Outcomes were compared between patients enrolled onto old- or newer-era trials, stratified by stage. Results Within the first 3 years, recurrence rates were lower in newer- versus old-era trials for patients with stage II disease, with no differences among those with stage III disease. Both TRD and OS were significantly longer in newer-era trials overall and within each stage. The lymph node (LN) ratio (ie, number of positive nodes divided by total nodes harvested) in those with stage III disease declined over time. TTR improved slightly, with larger number of LNs examined in both stages. Conclusion Improved TRD in newer trials supports the premise that more aggressive intervention (oxaliplatin- and irinotecan-based chemotherapy and/or surgery for recurrent disease) improves OS for patients previously treated in the adjuvant setting. Lower recurrence rates with identical treatments in those with stage II disease enrolled onto newer-era trials reflect stage migration over time, calling into question historical data related to the benefit of FU-based adjuvant therapy in such patients.

Abstract Context: Most association studies of bone-related biomarkers (BBMs) with bone mineral density (BMD) have been conducted in postmenopausal women. Objective: We tested whether the following BBMs were cross-sectionally associated with BMD among young adults: serum 1,25-dihydroxyvitamin D (1,25(OH)2D), 25-hydroxyvitamin D (25OHD), PTH, osteocalcin, bone-specific alkaline phosphatase (BAP), and urinary pyridinoline/urinary creatinine. Setting and Participants: We studied 319 individuals (134 women, 149 black, 24–36 years) recruited during 1992 through 1993 in Oakland, California. BMD was assessed with dual-energy x-ray absorptiometry. Linear regression models estimated the association between BMD and each BBM. Results: 1,25(OH)2D was inversely associated with all BMDs. 25OHD was positively, and PTH inversely, associated with lumbar spine, total hip, and whole-body BMD. BAP was inversely associated with left arm, right arm, and whole-body BMD but not with spine or hip BMD. Neither osteocalcin nor urinary pyridinoline/urinary creatinine was associated with BMD. When we placed all BBMs (including 1,25(OH)2D) in one model, the pattern and magnitude of association was similar except for PTH, which was attenuated. The association of BMD and BBMs did not differ significantly by race or sex. Conclusions: In this cross-sectional study of healthy young men and women who had PTH levels considered normal in clinical practice, higher PTH was associated with lower BMD, particularly in weight-bearing sites (ie, spine and hip). The inverse association of 1,25(OH)2D, together with the attenuation of PTH, suggests that the observed association of PTH is mediated by 1,25(OH)2D. BAP was inversely associated with arm BMD. BBMs can be important markers of skeletal activity in young adults, but their clinical role on bone health among this population is yet to be fully determined.

Background— A patent foramen ovale (PFO) may permit arterial embolization of thrombi that accumulate on the leads of cardiac implantable electronic devices in the right-sided cardiac chambers. We sought to determine whether a PFO increases the risk of stroke/transient ischemic attack (TIA) in patients with endocardial leads. Methods and Results— We retrospectively evaluated all patients who had endocardial leads implanted between January 1, 2000, and October 25, 2010, at Mayo Clinic Rochester. Echocardiography was used to establish definite PFO and non-PFO cohorts. The primary end point of stroke/TIA consistent with a cardioembolic etiology and the secondary end point of mortality during postimplantation follow-up were compared in PFO versus non-PFO patients with the use of Cox proportional hazards models. We analyzed 6075 patients (364 with PFO) followed for a mean 4.7±3.1 years. The primary end point of stroke/TIA was met in 30/364 (8.2%) PFO versus 117/5711 (2.0%) non-PFO patients (hazard ratio, 3.49; 95% confidence interval, 2.33–5.25; P <0.0001). The association of PFO with stroke/TIA remained significant after multivariable adjustment for age, sex, history of stroke/TIA, atrial fibrillation, and baseline aspirin/warfarin use (hazard ratio, 3.30; 95% confidence interval, 2.19–4.96; P <0.0001). There was no significant difference in all-cause mortality between PFO and non-PFO patients (hazard ratio, 0.91; 95% confidence interval, 0.77–1.07; P =0.25). Conclusions— In patients with endocardial leads, the presence of a PFO on routine echocardiography is associated with a substantially increased risk of embolic stroke/TIA. This finding suggests a role of screening for PFOs in patients who require cardiac implantable electronic devices; if a PFO is detected, PFO closure, anticoagulation, or nonvascular lead placement may be considered.