Genome-wide methylation profiling in decitabine-treated patients with acute myeloid leukemia

The outcome of older (≥ 60 years) acute myeloid leukemia (AML) patients is poor, and novel treatments are needed. In a phase 2 trial for older AML patients, low-dose (20 mg/m(2) per day for 10 days) decitabine, a DNA hypomethylating azanucleoside, produced 47% complete response rate with an excellent toxicity profile. To assess the genome-wide activity of decitabine, we profiled pretreatment and post treatment (day 25/course 1) methylomes of marrow samples from patients (n = 16) participating in the trial using deep-sequencing analysis of methylated DNA captured by methyl-binding protein (MBD2). Decitabine significantly reduced global methylation compared with pretreatment baseline (P = .001). Percent marrow blasts did not correlate with global methylation levels, suggesting that hypomethylation was related to the activity of decitabine rather than to a mere decrease in leukemia burden. Hypomethylation occurred predominantly in CpG islands and CpG island-associated regions (P ranged from .03 to .04) A significant concentration (P < .001) of the hypomehtylated CpG islands was found in chromosome subtelomeric regions, suggesting a differential activity of decitabine in distinct chromosome regions. Hypermethylation occurred much less frequently than hypomethylation and was associated with low CpG content regions. Decitabine-related methylation changes were concordant with those previously reported in distinct genes. In summary, our study supports the feasibility of methylome analyses as a pharmacodynamic endpoint for hypomethylating therapies.     

Preliminary results of biodistribution and dosimetric analysis of [68Ga]Ga-DOTAZOL: a new zoledronate-based bisphosphonate for PET/CT diagnosis of bone diseases

Annals of Nuclear Medicine - Pre-clinical studies with gallium-68 zoledronate ([68Ga]Ga-DOTAZOL) have proposed it to be a potent bisphosphonate for PET/CT diagnosis of bone diseases and diagnostic...     

Semiquantitative Parameters in PSMA-Targeted PET Imaging with [18F]DCFPyL: Impact of Tumor Burden on Normal Organ Uptake

Purpose

In this study, we aimed to quantitatively investigate the biodistribution of [¹⁸F]DCFPyL in patients with prostate cancer (PCa) and to determine whether uptake in normal organs correlates with an increase in tumor burden.

Procedures

Fifty patients who had been imaged with [¹⁸F]DCFPyL positron emission tomography/computed tomography (PET/CT) were retrospectively included in this study. Forty of 50 (80 %) demonstrated radiotracer uptake on [¹⁸F]DCFPyL PET/CT compatible with sites of PCa. Volumes of interests (VOIs) were set on normal organs (lacrimal glands, parotid glands, submandibular glands, liver, spleen, and kidneys) and on tumor lesions. Mean standardized uptake values corrected to lean body mass (SUL_mean) and mean standardized uptake values corrected to body weight (SUV_mean) for normal organs were assessed. For the entire tumor burden, SUL_mean/max, SUV_mean, tumor volume (TV), and the total activity in the VOI were obtained using tumor segmentation. A Spearman’s rank correlation coefficient was used to investigate correlations between normal organ uptake and tumor burden.

Results

There was no significant correlation between TV with the vast majority of the investigated organs (lacrimal glands, parotid glands, submandibular glands, spleen, and liver). Only the kidney showed significant correlation: With an isocontour threshold at 50 %, left kidney uptake parameters correlated significantly with TV (SUV_mean, ρ?=???0.214 and SUL_mean, ρ?=???0.176, p?<?0.05, respectively).

Conclusions

Only a minimal sink effect with high tumor burden in patients imaged with [¹⁸F]DCFPyL was observed. Other factors, such as a high intra-patient variability of normal organ uptake, may be a much more important consideration for personalized dosimetry with PSMA-targeted therapeutic agents structurally related to [¹⁸F]DCFPyL than the tumor burden.

     

Letter to the Editor re: “Semiquantitative Parameters in PSMA-Targeted PET Imaging with [18F]DCFPyL: Impact of Tumor Burden on Normal Organ Uptake”

Molecular Imaging and Biology -