Maternal Iron Deficiency and Environmental Lead (Pb) Exposure Alter the Predictive Value of Blood Pb Levels on Brain Pb Burden in the Offspring in a Dietary Mouse Model: An Important Consideration for Cumulative Risk in Development.

Maternal iron deficiency (ID) and environmental lead (Pb) exposure are co-occurring insults that both affect the neurodevelopment of offspring. Few studies have investigated how ID affects brain-region-specific Pb accumulations using human-relevant Pb concentrations. Furthermore, how these Pb exposures impact blood and brain Fe levels remains unclear. Importantly, we also wanted to determine whether the use of blood Pb levels as a surrogate for the brain Pb burden is affected by underlying iron status. We exposed virgin Swiss Webster female mice to one of six conditions differing by iron diet and Pb water concentration (0 ppm, 19 ppm, or 50 ppm lead acetate) and used Inductively Coupled Plasma Mass Spectrometry to measure the maternal and offspring circulating, stored, and brain Pb levels. We found that maternal ID rendered the offspring iron-deficient anemic and led to a region-specific depletion of brain Fe that was exacerbated by Pb in a dose-specific manner. The postnatal iron deficiency anemia also exacerbated cortical and hippocampal Pb accumulation. Interestingly, BPb levels only correlated with the brain Pb burden in ID pups but not in IN offspring. We conclude that ID significantly increases the brain Pb burden and that BPb levels alone are insufficient as a clinical surrogate to make extrapolations on the brain Pb burden.

Sex hormones and repolarization dynamics during the menstrual cycle in women with congenital long QT syndrome.

BACKGROUND: Women with congenital long QT syndrome (LQTS) experience increased cardiac event risk after the onset of adolescence, perhaps stemming from the known modulating effects of sex hormones on the cardiac potassium channels. OBJECTIVE: We hypothesized that the effect of sex hormones on cardiac ion channel function may modify electrocardiographic (ECG) parameters associated with the propensity for ventricular tachyarrhythmias during the menstrual cycle in women with LQTS. METHODS: We prospectively enrolled 65 women with congenital LQTS (type 1 LQTS [LQT1], n = 24 [36.9%]; type 2 LQTS [LQT2], n = 20 [30.8%]) and unaffected female relatives (n = 21 [32.3%]). Patients underwent three 7-day ECG recordings during their menstrual cycles. Simultaneous saliva testing of sex hormone levels was conducted on the first day of each 7-day ECG recording cycle. RESULTS: The mean age was 35 ± 8 years, without a significant difference among the groups. In women with LQT2, linear mixed effects models showed significant inverse correlations of the corrected QT interval with progesterone levels (P < .001) and with the progesterone to estradiol ratio (P < .001). Inverse relationships of the R-R interval with estradiol levels (P = .003) and of the T-wave duration with testosterone levels (P = .014) were also observed in women with LQT2. In contrast, no significant associations were observed between ECG parameters and sex hormone levels in women with LQT1 or unaffected relatives. CONCLUSION: This is the first study to prospectively assess correlations between repolarization dynamics and sex hormone levels during the menstrual cycle in women with congenital LQTS. Our findings show genotype-specific unique corrected QT dynamics during the menstrual cycle that may affect the propensity for ventricular tachyarrhythmia in women with LQTS, particularly women with LQT2.

Use of angiotensin converting enzyme inhibitors is associated with reduced risk of late bladder toxicity following radiotherapy for prostate cancer.

BACKGROUND AND PURPOSE: Genome-wide association studies (GWAS) of late hematuria following prostate cancer radiotherapy identified single nucleotide polymorphisms (SNPs) near AGT, encoding angiotensinogen. We tested the hypothesis that patients taking angiotensin converting enzyme inhibitors (ACEi) have a reduced risk of late hematuria. We additionally tested genetically-defined hypertension. MATERIALS AND METHODS: Prostate cancer patients undergoing potentially-curative radiotherapy were enrolled onto two multi-center observational studies, URWCI (N = 256) and REQUITE (N = 1,437). Patients were assessed pre-radiotherapy and followed prospectively for development of toxicity for up to four years. The cumulative probability of hematuria was estimated by the Kaplan-Meier method. Multivariable grouped relative risk models assessed the effect of ACEi on time to hematuria adjusting for clinical factors and stratified by enrollment site. A polygenic risk score (PRS) for blood pressure was tested for association with hematuria in REQUITE and our Radiogenomics Consortium GWAS. RESULTS: Patients taking ACEi during radiotherapy had a reduced risk of hematuria (HR 0.51, 95%CI 0.28 to 0.94, p = 0.030) after adjusting for prior transurethral prostate and/or bladder resection, heart disease, pelvic node radiotherapy, and bladder volume receiving 70 Gy, which are associated with hematuria. A blood pressure PRS was associated with hypertension (odds ratio per standard deviation 1.38, 95%CI 1.31 to 1.46, n = 5,288, p < 0.001) but not hematuria (HR per standard deviation 0.96, 95%CI 0.87 to 1.06, n = 5,126, p = 0.41). CONCLUSIONS: Our study is the first to show a radioprotective effect of ACEi on bladder in an international, multi-site study of patients receiving pelvic radiotherapy. Mechanistic studies are needed to understand how targeting the angiotensin pathway protects the bladder.

Lymphocyte-Specific Biomarkers Associated With Preterm Birth and Bronchopulmonary Dysplasia.

Many premature babies who are born with neonatal respiratory distress syndrome (RDS) go on to develop Bronchopulmonary Dysplasia (BPD) and later Post-Prematurity Respiratory Disease (PRD) at one year corrected age, characterized by persistent or recurrent lower respiratory tract symptoms frequently related to inflammation and viral infection. Transcriptomic profiles were generated from sorted peripheral blood CD8+ T cells of preterm and full-term infants enrolled with consent in the NHLBI Prematurity and Respiratory Outcomes Program (PROP) at the University of Rochester and the University at Buffalo. We identified outcome-related gene expression patterns following standard methods to identify markers for oxygen utilization and BPD as outcomes in extremely premature infants. We further identified predictor gene sets for BPD based on transcriptomic data adjusted for gestational age at birth (GAB). RNA-Seq analysis was completed for CD8+ T cells from 145 subjects. Among the subjects with highest risk for BPD (born at <29 weeks gestational age (GA); n=72), 501 genes were associated with oxygen utilization. In the same set of subjects, 571 genes were differentially expressed in subjects with a diagnosis of BPD and 105 genes were different in BPD subjects as defined by physiologic challenge. A set of 92 genes could predict BPD with a moderately high degree of accuracy. We consistently observed dysregulation of TGFB, NRF2, HIPPO, and CD40-associated pathways in BPD. Using gene expression data from both premature and full-term subjects (n=116), we identified a 28 gene set that predicted the PRD status with a moderately high level of accuracy, which also were involved in TGFB signaling. Transcriptomic data from sort-purified peripheral blood CD8+ T cells from 145 preterm and full-term infants identified sets of molecular markers of inflammation associated with independent development of BPD in extremely premature infants at high risk for the disease and of PRD among the preterm and full-term subjects.

Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy.

BACKGROUND: A total of 10%-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. METHODS: We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided. RESULTS: Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10-10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10-10), and rs11122573 with hematuria (Pmeta = 1.8 × 10-8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. CONCLUSIONS: This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.

Phase 1 trial of carfilzomib (PR-171) in combination with vorinostat (SAHA) in patients with relapsed or refractory B-cell lymphomas.

A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30-min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3 + 3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m2 carfilzomib and 100 mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and two patients had stable disease. Correlative studies showed a decrease in NF-κB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response.

Cardiovascular Disease Mortality After Chemotherapy or Surgery for Testicular Nonseminoma: A Population-Based Study.

PURPOSE: Increased risks of incident cardiovascular disease (CVD) in patients with testicular cancer (TC) given chemotherapy in European studies were largely restricted to long-term survivors and included patients from the 1960s. Few population-based investigations have quantified CVD mortality during, shortly after, and for two decades after TC diagnosis in the era of cisplatin-based chemotherapy. PATIENTS AND METHODS: Standardized mortality ratios (SMRs) for CVD and absolute excess risks (AERs; number of excess deaths per 10,000 person-years) were calculated for 15,006 patients with testicular nonseminoma reported to the population-based Surveillance, Epidemiology, and End Results program (1980 to 2010) who initially received chemotherapy (n=6,909) or surgery (n=8,097) without radiotherapy and accrued 60,065 and 81,227 person-years of follow-up, respectively. Multivariable modeling evaluated effects of age, treatment, extent of disease, and other factors on CVD mortality. RESULTS: Significantly increased CVD mortality occurred after chemotherapy (SMR, 1.36; 95% CI, 1.03 to 1.78; n=54) but not surgery (SMR, 0.81; 95% CI, 0.60 to 1.07; n=50). Significant excess deaths after chemotherapy were restricted to the first year after TC diagnosis (SMR, 5.31; AER, 13.90; n=11) and included cerebrovascular disease (SMR, 21.72; AER, 7.43; n=5) and heart disease (SMR, 3.45; AER, 6.64; n=6). In multivariable analyses, increased CVD mortality after chemotherapy was confined to the first year after TC diagnosis (hazard ratio, 4.86; 95% CI, 1.25 to 32.08); distant disease (P<.05) and older age at diagnosis (P<.01) were independent risk factors. CONCLUSION: This is the first population-based study, to our knowledge, to quantify short- and long-term CVD mortality after TC diagnosis. The increased short-term risk of CVD deaths should be further explored in analytic studies that enumerate incident events and can serve to develop comprehensive evidence-based approaches for risk stratification and application of preventive and interventional efforts.

Dual targeting of the thioredoxin and glutathione antioxidant systems in malignant B cells: a novel synergistic therapeutic approach.

B-cell malignancies are a common type of cancer. One approach to cancer therapy is to either increase oxidative stress or inhibit the stress response systems on which cancer cells rely. In this study, we combined nontoxic concentrations of Auranofin (AUR), an inhibitor of the thioredoxin system, with nontoxic concentrations of buthionine-sulfoximine (BSO), a compound that reduces intracellular glutathione levels, and investigated the effect of this drug combination on multiple pathways critical for malignant B-cell survival. Auranofin interacted synergistically with BSO at low concentrations to trigger death in multiple malignant B-cell lines and primary mantle-cell lymphoma cells. Additionally, there was less toxicity toward normal B cells. Low AUR concentrations inhibited thioredoxin reductase (TrxR) activity, an effect significantly increased by BSO cotreatment. Overexpression of TrxR partially reversed AUR+BSO toxicity. Interestingly, the combination of AUR+BSO inhibited nuclear factor κB (NF-κB) signaling. Moreover, synergistic cell death induced by this regimen was attenuated in cells overexpressing NF-κB proteins, arguing for a functional role for NF-κB inhibition in AUR+BSO-mediated cell death. Together, these findings suggest that AUR+BSO synergistically induces malignant B-cell death, a process mediated by dual inhibition of TrxR and NF-κB, and such an approach warrants further investigation in B-cell malignancies.

Phase 2 study of imexon, a prooxidant molecule, in relapsed and refractory B-cell non-Hodgkin lymphoma.

Lymphoma cells are subject to higher levels of oxidative stress compared with their normal counterparts and may be vulnerable to manipulations of the cellular redox balance. We therefore designed a phase 2 study of imexon (Amplimexon/NSC-714597), a prooxidant molecule, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Imexon was administered at 1000 mg/m(2) IV daily for 5 days in 21-day cycles. Gene expression analysis performed on pretreatment tumor specimens included 13 transcripts used to generate a redox signature score, previously demonstrated to correlate with lymphoma prognosis. Twenty-two patients were enrolled having follicular (n = 9), diffuse large B-cell (DLBCL) (n = 5), mantle cell (n = 3), transformed follicular (n = 2), small lymphocytic (n = 2), and Burkitt (n = 1) lymphoma. The most common grade 3/4 adverse events were anemia (14%) and neutropenia (9%). The overall response rate was 30%, including responses in follicular lymphoma (4 of 9) and DLBCL (2 of 5). Gene expression analyses revealed CD68 and the redox-related genes, GPX1 and SOD2, as well as a higher redox score to correlate with clinical responses. Therefore, pretreatment markers of oxidative stress may identify patients likely to respond to this therapeutic approach. This trial was registered at www.clinicaltrials.gov as #NCT01314014.

Copper transporter CTR1 expression and tissue platinum concentration in non-small cell lung cancer.

BACKGROUND: Platinum resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue platinum concentration in NSCLC specimens was significantly associated with reduced tumor response. Furthermore, low expression of the copper transporter CTR1, a transporter of platinum uptake was associated with poor clinical outcome following platinum-based therapy in NSCLC patients. We investigated the relationship between tissue platinum concentrations and CTR1 expression in NSCLC specimens. METHODS: We identified paraffin-embedded NSCLC tissue blocks of known tissue platinum concentrations from 30 patients who underwent neoadjuvant platinum-based chemotherapy at MD Anderson Cancer Center. Expression of CTR1 in tumors and normal adjacent lung specimens was determined by immunohistochemistry with adequate controls. RESULTS: Tissue platinum concentration significantly correlated with tumor response in 30 patients who received neoadjuvant platinum-based chemotherapy (P<0.001). CTR1 was differentially expressed in NSCLC tumors. A subset of patients with undetectable CTR1 expression in their tumors had reduced platinum concentrations (P=0.058) and tumor response (P=0.016) compared to those with any level of CTR1 expression. We also observed that African Americans had significantly reduced CTR1 expression scores (P=0.001), tissue platinum concentrations (P=0.009) and tumor shrinkage (P=0.016) compared to Caucasians. CONCLUSIONS: To our best knowledge this is the first study investigating the function of CTR1 in clinical specimens. CTR1 expression may be necessary for therapeutic efficacy of platinum drugs, consistent with previous preclinical studies. A prospective clinical trial is necessary to develop CTR1 into a potential biomarker for platinum drugs.

Constructing multivariate prognostic gene signatures with censored survival data.

Modern high-throughput technologies allow us to simultaneously measure the expressions of a huge number of candidate predictors, some of which are likely to be associated with survival. One difficult task is to search among an enormous number of potential predictors and to correctly identify most of the important ones, without mistakenly identifying too many spurious associations. Mere variable selection is insufficient, however, for the information from the multiple predictors must be intelligently combined and calibrated to form the final composite predictor. Many commonly used procedures overfit the training data, miss many important predictors, or both. Although it is impossible to simultaneously adjust for a huge number of predictors in an unconstrained way, we propose a method that offers a middle ground where some partial multivariate adjustments can be made in an adaptive fashion, regardless of the number of candidate predictors. We demonstrate the performance of our proposed procedure in a simulation study within the Cox proportional hazards regression framework, and we apply our new method to a publicly available data set to construct a novel prognostic gene signature for breast cancer survival.

Neoadjuvant gemcitabine and cisplatin chemotherapy for locally advanced urothelial cancer of the bladder.

BACKGROUND: The purpose of this study was to investigate the effect of neoadjuvant chemotherapy with gemcitabine and cisplatin (GC) on pathologic down-staging of patients with locally advanced urothelial cancer (UC) of the bladder. METHODS: This was a retrospective cohort study of patients treated with radical cystectomy (RC) for clinical stage cT2-T4, N any, M0 bladder UC at Strong Memorial Hospital from 1999 to 2009. The primary exposure variable was use of neoadjuvant chemotherapy (GC vs none). The primary outcome was stage pT0 at RC. Secondary outcomes included other down-staging end points in the bladder (

Impact of long-term serum platinum concentrations on neuro- and ototoxicity in Cisplatin-treated survivors of testicular cancer.

PURPOSE: Cisplatin-induced neurotoxicity and ototoxicity (NTX) are important adverse effects after chemotherapy for testicular cancer (TC). Although serum platinum is measurable years after therapy, its impact on NTX has not been evaluated. PATIENTS AND METHODS: In all, 169 cisplatin-treated survivors of TC provided blood samples at Survey I and reported NTX during Survey I (1998-2002) and Survey II (2007-2008). Serum platinum was quantified by inductively coupled plasma mass spectrometry. Patient-reported outcomes were evaluated with the Scale for Chemotherapy-Induced Neurotoxicity (SCIN), regarding the extent of symptom bother as 0, "not at all"; 1, "a little"; 2, "quite a bit"; or 3, "very much." Summing the six symptom scores yielded a total SCIN score of 0 to 18. Categorizing total SCIN scores into quartiles yielded similar-sized groups with increasing symptoms. Multivariate ordinal logistic regression analyses evaluated associations between NTX and long-term serum platinum levels, adjusting for cisplatin dose, dosing schedule, and age. RESULTS: At Survey I, a significant four- to five-fold association with total SCIN score emerged for the highest serum platinum quartile (odds ratio [OR], 4.69; 95% CI, 1.82 to 12.08). Paresthesias and Raynaud's syndrome (hands and feet) showed significant two- to four-fold increased risks with the highest platinum quartile. At Survey II, total SCIN score remained significantly associated with the highest platinum quartile (OR, 4.28; 95% CI, 1.36 to 13.48). Paresthesias (hands and feet) and tinnitus showed significant three- to four-fold increased risks for the highest platinum quartile. Cumulative cisplatin dose was not associated with total SCIN score or individual SCIN symptoms in multivariate analyses. CONCLUSION: Here we document a significant relationship between increasing levels of residual serum platinum and NTX severity after adjusting for initial cisplatin dose.

Symptomatic and incidental thromboembolism are both associated with mortality in pancreatic cancer.

Pancreatic cancer is known to be associated with VTE, but contemporary rates of incidental and symptomatic VTE events and their association with mortality are incompletely understood. We conducted a retrospective cohort study of consecutive pancreatic adenocarcinoma patients at the University of Rochester from 2006-2009. Data were analysed using a Cox model with time-dependent covariates. A total of 1,151 radiologic exams of 135 patients were included. Forty-seven patients (34.8%) experienced VTE including 12 pulmonary emboli (PE), 28 deep-vein thromboses (DVTs) and 47 visceral vein events. Incidental events comprised 33.3% of PEs, 21.4% of DVTs and 100% of visceral VTE. Median (95% CI) conditional survival beyond three months was 233 (162-322) more days for those without VTE, which was significantly greater than 12 (3-60) days for those with DVT as first event (p<0.0001) and 87 (14-322) days with visceral first events (p=0.022). In multivariate analysis, DVT (HR 25, 95% CI 10-63, p <0.0001), PE (HR 8.9, 95% CI 2.5-31.7, p = 0.007) and incidental visceral events (HR 2.6, 95% CI 1.6-4.2, p =0.0001) were all associated with mortality, though anticoagulants reduced these risks by 70% (26-88%, p = 0.009). In conclusion, VTE occurs in over one-third of contemporary pancreatic cancer patients and, whether symptomatic or incidental, is strongly associated with worsened mortality. The role of anticoagulation in treating incidental or visceral VTE warrants further study.

Adverse prognostic factors for testicular cancer-specific survival: a population-based study of 27,948 patients.

PURPOSE: The prognostic significance of age at testicular cancer (TC) diagnosis, socioeconomic status (SES), race, and marital status on TC-specific mortality is not well-characterized. In a cancer that is so curable, it is important to identify any influence that confers an increased risk of TC-specific mortality. PATIENTS AND METHODS: Using multivariate cause-specific Cox regression models that accounted for competing risks, hazard ratios (HRs) were calculated for 10-year TC-specific mortality among 27,948 patients with TC reported to the Surveillance, Epidemiology and End Results program (1978 to 2006). Independent predictors were age at diagnosis, SES, race, marital status, extent of disease (EOD), calendar year of diagnosis, radiotherapy, and retroperitoneal lymph node dissection (RPLND). RESULTS: Compared with younger patients, diagnostic age 40+ was associated with increased mortality (seminoma, HR, 2.00, P < .001; nonseminoma, HR, 2.09; P < .001; most evident in metastatic disease, HR, 8.62; P < .001; HR, 6.35; P < .001, respectively). Unmarried men had two-to three-fold excess mortality compared to married men (HR, 2.97; P < .001; HR, 1.54; P < .001, respectively). Among nonseminoma patients, decreasing SES (P trend < .001) and nonwhite race (HR, 2.11; P < .001) increased mortality. Diagnosis after 1987 resulted in reduced mortality compared to earlier calendar years (HR, 0.58; P = .001; HR, 0.74; P = .001, respectively). Lack of RPLND was associated with seven-fold increase in death (P < .001). CONCLUSION: TC-specific mortality is doubled among US patients diagnosed with seminoma or nonseminoma after age 40, even when initial treatment and EOD are taken into account. Among men with nonseminoma, nonwhite race and lower SES also significantly increase TC-specific mortality. Additional research is needed, enabling the development of interventional strategies and preventive approaches, as applicable.

T-wave morphology abnormalities in benign, potent, and arrhythmogenic I(kr) inhibition.

BACKGROUND: There is a consensus on the limited value of the QTc interval prolongation as a surrogate marker of drug cardiotoxicity and as a risk stratifier in inherited long QT syndrome (LQTS) patients. OBJECTIVE: We investigated the interest of repolarization morphology in the acquired and the inherited LQTS. METHODS: We analyzed 2 retrospective electrocardiographic (ECG) datasets from healthy on/off moxifloxacin and from genotyped KCNH2 patients. We measured QT, RR, and T-peak to T-end intervals, early repolarization duration (ERD) and late repolarization duration, T-roundness, T-amplitude, left (αL) and right slopes of T-waves. We designed multivariate logistic models to predict the presence of the KCNH2 mutation or moxifloxacin while adjusting for the level of QTc prolongation and the level of heart rate in LQT2 patients. Independent learning and validation sets were used. A list of 4,874 ECGs from 411 healthy individuals, 293 from 143 LQT2 carriers and 150 noncarrier family members were analyzed. RESULTS: In the moxifloxacin model, ERD was associated with the presence of the drug (odds ratio = 1.15 per ms increase, confidence interval 1.04 to 1.26, P = .0001) after adjustment for QTc. The model for the LQT2 revealed that left slope was associated with the presence of the KCNH2 mutation (odds ratio = 0.38 per 1.5 µV/ms decrease, confidence interval 0.23 to 0.64, P = .0002). Only T-roundness complemented QTc in the model investigating cardiac events in LQT2. CONCLUSIONS: These observations demonstrate that the phenotypic expression of KCNH2 mutations and the effect of IKr-inhibitory drug on the surface electrocardiogram are specific. Future research should investigate whether this phenomenon is linked to different level/form of loss functions of Ikr channels, and whether they could result in different arrhythmogenic mechanisms.

Phase II study of a TLR-9 agonist (1018 ISS) with rituximab in patients with relapsed or refractory follicular lymphoma.

Toll-like receptor-9 (TLR-9) agonists have pleotropic effects on both the innate and adaptive immune systems, including increased antigen expression, enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and T helper cell type 1 shift in the immune response. We combined a TLR-9 agonist (1018 ISS, 0.2 mg/kg sc weekly x 4 beginning day 8) with standard rituximab (375 mg/m(2) weekly x 4) in patients (n = 23) with relapsed/refractory, histologically confirmed follicular lymphoma, and evaluated immunological changes following the combination. Treatment was well-tolerated with no significant adverse events attributable to therapy. Clinical responses were observed in 48% of patients; the overall median progression-free survival was 9 months. Biologically relevant increases in ADCC and circulating CD-3 positive T cells were observed in 35% and 39% of patients, respectively. Forty-five percent of patients had increased T cells and dendritic cells in skin biopsies of 1018 ISS injection sites 24 h post-therapy. Pre- and post-biopsies of tumour tissue demonstrated an infiltration of CD8(+) T cells and macrophages following treatment. This group of patients had favourable clinical outcome despite adverse prognostic factors. This study is the first to histologically confirm perturbation of the local immune microenvironment following systemic biological therapy of follicular lymphoma.

Ethics of sham surgery: perspective of patients.

Sham surgery is used as a control condition in neurosurgical clinical trials in Parkinson's disease (PD) but remains controversial. This study aimed to assess the perspective of patients with PD and the general public on the use of sham surgery controls. We surveyed consecutive patients from a university-based neurology outpatient clinic and a community-based general internal medicine practice. Background information was provided regarding PD and two possible methods of testing the efficacy of a novel gene transfer procedure, followed by questions that addressed participants' opinions related to the willingness to participate and permissibility of blinded and unblinded trial designs. Two hundred eighty-eight (57.6%) patients returned surveys. Patients with PD expressed less willingness to participate in the proposed gene transfer surgery trials. Unblinded studies received greater support, but a majority would still allow the use of sham surgery. Those in favor of sham surgery were more educated and more likely to use societal perspective rationales. Patients with PD are more cautious about surgical research participation than patients with non-PD. Their policy views were similar to others', with a majority supporting the use of sham controls. Future research needs to determine whether eliciting more considered judgments of laypersons would reveal different levels of support for sham surgery.