Publications

PURPOSE

We sought to show the relevance of a lymphoblastoid cell line (LCL) model in the discovery of clinically relevant genetic variants affecting chemotherapeutic response by comparing LCL genome-wide association study (GWAS) results to clinical GWAS results.

EXPERIMENTAL DESIGN

A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMap Project and compared with a GWAS of sensory peripheral neuropathy in patients with breast cancer (n = 855) treated with paclitaxel in the Cancer and Leukemia Group B (CALGB) 40101 trial. Significant enrichment was assessed by permutation resampling analysis.

RESULTS

We observed an enrichment of LCL cytotoxicity-associated single-nucleotide polymorphisms (SNP) in the sensory peripheral neuropathy-associated SNPs from the clinical trial with concordant allelic directions of effect (empirical P = 0.007). Of the 24 SNPs that overlap between the clinical trial (P < 0.05) and the preclinical cytotoxicity study (P < 0.001), 19 of them are expression quantitative trait loci (eQTL), which is a significant enrichment of this functional class (empirical P = 0.0447). One of these eQTLs is located in RFX2, which encodes a member of the DNA-binding regulatory factor X family. Decreased expression of this gene by siRNA resulted in increased sensitivity of Neuroscreen-1(NS-1; rat pheochromocytoma) cells to paclitaxel as measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of RFX2 in nerve cell response to paclitaxel.

CONCLUSIONS

The enrichment results and functional example imply that cellular models of chemotherapeutic toxicity may capture components of the underlying polygenic architecture of related traits in patients.

PURPOSE

To develop and validate modified Look-Locker (MOLLI) protocols to generate myocardial T1 maps within clinically acceptable breath-hold durations and to compare partition coefficients (λ) of gadolinium (Gd)-DTPA determined from either bolus injection (BI) or continuous infusion (CI) techniques.

MATERIALS AND METHODS

T1 mapping was performed in phantoms and in 10 volunteers on a 1.5T scanner using the standard (3-3-5) MOLLI technique and two MOLLI schemes with shorter breath-hold durations. Imaging was performed precontrast and every 5 minutes following a bolus of 0.1 mmol/kg Gd-DTPA and a 15-minute delayed continuous infusion of 0.001 mmol/kg Gd-DTPA until equilibrium T1 in the myocardium was achieved to enable direct comparison of T1 relaxation times between techniques and λ's between the BI and CI methods.

RESULTS

There was good agreement of T1 values between the 3-3-5 standard MOLLI protocol and the modified 3-5 MOLLI protocol in both phantom studies over a range of heart rates and in human subjects. Both MOLLI protocols produced similar measurements of λ using both the BI and CI methods.

CONCLUSION

A reduced breath-hold MOLLI T1 mapping protocol combined with the BI method can accurately characterize T1 and λ in clinically applicable breath-hold durations without requiring a long equilibrium phase infusion.

Many human immunodeficiency virus (HIV) infected individuals suffer from persistent immune activation. Chronic inflammation and immune dysregulation have been associated with an increased risk of age-related diseases even among patients on highly active antiretroviral therapy. The factors leading to immune activation are complex, but have been hypothesized to include persistent viral replication with cellular death as well as microbial translocation across the gastrointestinal tract. Both processes may trigger innate immune responses since many native molecules released from dying cells are similar in structure to pathogen associated molecular patterns. These damage associated molecular patterns include mitochondrial DNA and formylated peptides. We hypothesized that circulating mitochondrial nucleic acid could serve as a biomarker for HIV-associated cell death and drive innate immune activation in infected individuals. We developed a quantitative polymerase chain reaction assay for plasma mitochondrial DNA and validated it on normal blood donors. We then measured mitochondrial DNA levels in acute and chronic HIV infection. While the assay proved to be accurate with a robust dynamic range, we did not find a significant association between HIV disease status and circulating mitochondrial DNA. We did, however, observe a negative correlation between age and plasma mitochondrial DNA levels in individuals with well-controlled HIV.

UNLABELLED

Recurrent CNS lymphoma continues to be associated with poor outcomes in the rituximab era. Although IV rituximab mediates superior disease control of systemic non-Hodgkin lymphoma (NHL), it fails to completely eliminate the risk of meningeal recurrence, likely due to minimal CNS penetration. Given that rituximab acts synergistically with chemotherapy, we conducted the first phase 1 study of intraventricular immunochemotherapy in patients with recurrent CNS NHL. Fourteen patients received 10 mg or 25 mg intraventricular rituximab twice weekly for 4 weeks, with rituximab administered as monotherapy during the first treatment each week and rituximab administered in combination with methotrexate (MTX) during the second treatment each week. More than 150 doses were administered without serious toxicity. In a population with high-refractory CNS NHL, 75% of patients achieved complete cytologic responses and 43% achieved an overall complete response in CSF and/or brain parenchyma. Two patients achieved a first complete response of CNS NHL with intraventricular rituximab/MTX, including 1 with CNS lymphoma refractory to high-dose systemic and intrathecal MTX plus IV rituximab. We conclude that intraventricular rituximab in combination with MTX is feasible and highly active in the treatment of drug-resistant CNS NHL that is refractory or unresponsive to IV rituximab.

KEY POINTS

Phase I study showed that intraventricular rituximab plus methotrexate is feasible and active in the treatment of refractory CNS lymphoma.

The current standard treatment of chronic heart failure (HF) is based on clinical judgment, with the goal of achieving the maximally tolerated therapeutic program. The complexity of this approach may contribute to the well-established treatment gaps that exist in HF management; consequently, the risks for morbidity and mortality in this population remain extremely high. Alternative means are needed to improve the outcomes of patients with HF. Natriuretic peptides are biological markers for HF disease--its presence, severity, and prognosis--and show unique interactions with therapeutics known to have benefit in HF. Accordingly, interest has recently developed in "biomarker-guided" care for HF. This approach involves applying these assays to identify patients in need of therapy intensification and to provide an objective "monitor" of disease status. This review examines the biology of natriuretic peptides, discusses the rationale for their use in HF, and details the aggregate experience gained thus far in biomarker-guided care.