Brain-derived neurotrophic factor genetic polymorphism (rs6265) is protective against chemotherapy-associated cognitive impairment in patients with early-stage breast cancer

Background

Brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal function and development, is implicated in several neurodegenerative conditions. Preliminary data suggest that a reduction of BDNF concentrations may lead to postchemotherapy cognitive impairment. We hypothesized that a single nucleotide polymorphism (rs6265) of the BDNF gene may predispose patients to cognitive impairment. This study aimed to evaluate the effect of BDNF gene polymorphism on chemotherapy-associated cognitive impairment.

Methods

Overall, 145 patients receiving chemotherapy for early-stage breast cancer (mean age: 50.8 ± 8.8 y; 82.1% Chinese) were recruited. Patients'' cognitive functions were assessed longitudinally using the validated Functional Assessment of Cancer Therapy–Cognitive Function (v.3) and an objective computerized tool, Headminder. Genotyping was performed using Sanger sequencing. Logistic regression was used to evaluate the association between BDNF Val66Met polymorphism and cognition after adjusting for ethnicity and clinically important covariates.

Results

Of the 145 patients, 54 (37%) reported cognitive impairment postchemotherapy. The Met/Met genotype was associated with statistically significant lower odds of developing cognitive impairment (odds ratio [OR] = 0.26; 95% CI: 0.08–0.92; P = .036). The Met carriers were less likely to experience impairment in the domains of verbal fluency (OR = 0.34; 95% CI: 0.12–0.90; P = .031) and multitasking ability (OR = 0.37; 95% CI: 0.15–0.91; P = .030) compared with the Val/Val homozygote. No associations were observed between Headminder and the BDNF Val66Met polymorphism.

Conclusions

This is the first study to provide evidence that carriers of the BDNF Met allele are protected against chemotherapy-associated cognitive impairment. Further studies are required to validate the findings.     

Anti‐DFS70 antibodies in 597 healthy hospital workers

Objective

Autoantibodies against DFS70 (dense fine speckles 70) antigen (also known as lens epithelium–derived growth factor) have been recently identified among the antinuclear antibodies (ANAs) in patients with atopic disorders. We undertook this study to examine the frequency of anti‐DFS70 antibodies in a large number of healthy people.

Methods

Sera of 597 healthy individuals working in a hospital (142 men, 455 women) were analyzed for ANAs and for anti‐DFS70 antibodies by indirect immunofluorescence (IIF) with HEp‐2 cells as a substrate and by immunoblotting using DFS70 recombinant protein and whole HeLa cell extract.

Results

ANAs were present in 20% of all individuals by IIF. Nine percent of subjects were ANA positive at a serum dilution of 1:40, 4.0% at 1:80, 5.5% at 1:160, 1.0% at 1:320, and 0.3% at 1:640. There were 64 anti‐DFS70 antibody–positive individuals. Surprisingly, this was 11% of the whole population and 54% of the ANA‐positive population. The percentage of female anti‐DFS70 antibody–positive subjects (86%; 55 of 64 subjects) was higher than the percentage of female anti‐DFS70 antibody–negative subjects (75%; 398 of 533 subjects) (P < 0.05). The prevalence of anti‐DFS70 antibody–positive sera decreased with increasing age (P = 0.0017).

Conclusion

Considering that anti‐DFS70 antibody positivity is rare in patients with systemic autoimmune diseases, introducing the anti‐DFS70 antibody examination as a screening test for ANA‐positive persons could be used to rule out systemic autoimmune diseases, resulting in considerable cost‐saving potential. In addition, this test defines a subpopulation of healthy people in whom long‐term followup might reveal health‐related implications of this finding, since anti‐DFS70 antibodies have been shown to be associated with some illnesses.

     

Drug Clearance and Arterial Uptake After Local Perivascular Delivery to the Rat Carotid Artery

Objectives. We attempted to characterize how drug released into the perivascular space enters the arterial wall and how it is cleared from the local environment.

Background. Drug released into the perivascular space can enter the artery either from the adventitial aspect or from the lumen after absorption by the extraarterial capillaries and mixing within the systemic circulation. Some investigators suggest that this latter mechanism dominates, and they question whether local drug release is synonymous with local deposition.

Methods. We investigated both the pathways by which adventitially released drug is cleared from the perivascular space and those by which drug enters the blood vessel wall. Inulin was used to follow drug release from implanted devices and subsequent entry to the circulation, because of its first-pass urinary excretion. Heparin was used to follow arterial deposition because of its vasoactivity and tissue-binding properties. The different potential pathways of drug entry and egress were systematically removed and the effects on metabolism and deposition determined.

Results. Ligature occlusion of the artery did not decrease inulin excretion or heparin deposition. Extravascular wraps designed to shield the device from extramural capillaries reduced inulin excretion rates 10-fold but did not alter heparin deposition into the vessel wall. The deposition of drug after perivascular delivery was 500 times higher than after intraperitoneal administration.

Conclusions. Although almost all the drug released into the perivascular space is cleared through the extravascular capillaries, virtually all the deposited drug diffuses directly from the perivascular space, and little arrives from the endovascular aspect. These data support the view that local drug release leads directly to increased local drug concentration.

(J Am Coll Cardiol 1997;29:1645–50)