Safety and efficacy of p62 DNA vaccine ELENAGEN in a first-in-human trial in patients with advanced solid tumors.

Elenagen is a plasmid encoding p62/SQSTM1, the first DNA vaccine possessing two mutually complementing mechanisms of action: it elicits immune response against p62 and mitigates systemic chronic inflammation. Previously, Elenagen demonstrated anti-tumor efficacy and safety in rodent tumor models and spontaneous tumors in dogs. This multicenter I/IIa trial evaluated safety and clinical activity of Elenagen in patients with advanced solid tumors. Fifteen patients were treated with escalating doses of Elenagen (1- 5 mg per doses, 5 times weekly) and additional 12 patients received 1 mg dose. Ten patients with breast and ovary cancers that progressed after Elenagen were then treated with conventional chemotherapy. Adverse events (AE) were of Grade 1; no severe AE were observed. Cumulatively twelve patients (44%) with breast, ovary, lung, renal cancer and melanoma achieved stable disease for at least 8 wks, with 4 of them (15%) had tumor control for more than 24 wks, with a maximum of 32 wks. The patients with breast and ovary cancers achieved additional tumor stabilization for 12-28 wks when treated with chemotherapy following Elenagen treatment. Therefore, Elenagen demonstrated good safety profile and antitumor activity in advanced solid tumors. Especially encouraging is its ability to restore tumor sensitivity to chemotherapy.

Methodology for estimating cancer risks of diagnostic medical exposure: with an example of the risks associated with computed tomography.

Because of fast growing medical radiation use, estimating possible late health effects of radiation, including potential cancer risk, is an issue of substantial interest. Since physicians make the decision to order or perform a radiological procedure, it is very important to provide them with objective information about possible radiation-associated risks. Methodology for estimating cancer risks based on recommendations of ICRP Publication 103 is presented in the paper. Organ doses, age, and gender are used as basic parameters. An example of the evaluation of radiation-associated risks from computed tomography examination is presented.

Radiation exposure does not significantly contribute to the risk of recurrence of Chernobyl thyroid cancer.

CONTEXT: Papillary thyroid carcinoma (PTC) in patients exposed to environmental radioiodine after the Chernobyl accident is thought to have a relatively aggressive clinical course. Long-term results of treatment are not well known, especially in comparison with sporadic PTC. OBJECTIVE: The determination of risk factors for PTC recurrence in a controlled for baseline factors group of patients with radiation-related and sporadic PTC. DESIGN: Retrospective cohort study involving patients treated for PTC and followed-up in 1991-2008. Risk factors were assessed by stratified analysis using the proportional hazard model. SETTING: Referral center-based. PATIENTS: A total of 497 patients were enrolled. Patients exposed to radioiodine were 172 individuals with reconstructed individual radiation thyroid doses ranging 51-3170 mGy. Patients with sporadic PTC included 325 individuals matched to exposed patients for sex, age ± 5 yr and time to treatment ± 2 yr. MAIN OUTCOME MEASURE: Cancer recurrence. RESULTS: Nodal disease increased the recurrence rate (HR = 5.21; 95% CI = 1.63-16.7) while the presence of tumor capsule (HR = 0.17; 95% CI = 0.06-0.45) and, particularly, treatment according to the Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer significantly reduced it (HR = 0.16; 95% CI = 0.06-0.42). None of the tested variables interacted with radiation factor. CONCLUSIONS: PTC developing after internal exposure to radioiodine does not display specific risk factors for recurrence different from those in sporadic PTC. Common treatment approaches for patients with PTC should be recommended regardless of a history of radiation exposure.

Estimation of individualized radiation risk from chronic occupational exposure in Russia.

Internationally, the upper limit of acceptable individualized risk from occupational exposure for nuclear industry workers is determined by the death probability 10(-3) y(-1). The same risk value of 10(-3) y(-1) is established by the radiation safety standards currently in force in Russia. The United Nations Scientific Committee on the Effects of Atomic Radiation has proposed the formulas for estimating individualized risk of developing cancer with allowance for radiation dose, age at exposure, attained age, and sex. This methodology is first applied to estimate individualized radiation risk for Russian nuclear industry workers (49,900 persons) who were monitored for radiation exposure through the use of personal dosimeters. The estimates show that in 2006 the threshold of 10(-3) y(-1) for individualized risk is exceeded for 755 persons, which is 1.6% of all workers covered by personal dose monitoring. The excess absolute risk (EAR) and attributable risk (AR) were estimated for all cancers, solid cancers, and leukemias.

Morphologic characteristics of Chernobyl-related childhood papillary thyroid carcinomas are independent of radiation exposure but vary with iodine intake.

BACKGROUND: The Chernobyl accident caused an unprecedented increase in papillary thyroid carcinoma (PTC) incidence with a surprisingly short latency and unusual morphology. We have investigated whether unexpected features of the PTC incidence after Chernobyl were radiation specific or influenced by iodine deficiency. METHODS: PTCs from children from Belarus, Ukraine, and the Russian Federation exposed to fallout from Chernobyl were compared with PTCs from children not exposed to radiation from the same countries, from England and Wales (E&W) and from Japan. The degree and type of differentiation, fibrosis, and invasion were quantified. RESULTS: There were no significant differences between PTCs from radiation-exposed children from Belarus, Ukraine, and the Russian Federation and PTCs from children from the same countries who were not exposed to radiation. Childhood PTCs from Japan were much more highly differentiated (p < 0.001), showed more papillary differentiation (p < 0.001) and were less invasive (p < 0.01) than "Chernobyl" tumors, while tumors from E&W generally showed intermediate levels of degree and type of differentiation and invasion. There was a marked difference between the sex ratios of children with PTCs who were radiation exposed and those who were not exposed (F:M exposed vs. unexposed 1.5:1 vs. 4.2:1; chi(2) = 7.90, p < or = 0.01005). CONCLUSIONS: The aggressiveness and morphological features of Chernobyl childhood PTCs are not associated with radiation exposure. The differences found between tumors from the Chernobyl area, E&W, and Japan could be influenced by many factors. We speculate that dietary iodine levels may have wide implications in radiation-induced thyroid carcinogenesis, and that iodine deficiency could increase incidence, reduce latency, and influence tumor morphology and aggressiveness.

TP53 codon 72 polymorphism in radiation-associated human papillary thyroid cancer.

The study investigated an association between the germline polymorphism at TP53 codon 72 and the development of papillary thyroid cancer (PTC) following exposure to radiation from the Chernobyl accident. TP53 genotype was examined in 48 pediatric/adolescent (age at diagnosis <18 years) and 68 adult post-Chernobyl patient with PTC, 53 adult patients with sporadic PTC and 313 healthy individuals from Russian-Ukrainian population. In addition, we evaluated loss of heterozygosity for TP53 and the allele expression ratio. The genotype of the patients was correlated with clinicopathological data. Arg TP53 homozygotes were found to be significantly underrepresented among adults with post-Chernobyl PTC, but not in children and adolescents when compared with sporadic PTC cases and the general population. In the tumors, cell transformation did not lead to allelic loss or biased TP53 allele expression in heterozygous individuals. None of TP53 genotypes specifically associated with tumor stage and morphology, however there were particular correlations with lymph node status in certain age groups of radiation-associated cases not seen in sporadic PTCs. The findings suggest TP53 allele combinations other than Arg/Arg may contribute to the risk of development of PTC in individuals exposed to radiation during their late childhood, adolescence or in young adulthood.

Frequency of hemochromatosis gene (HFE) mutations in Russian healthy women and patients with estrogen-dependent cancers.

Possible association between the C282Y and H63D mutations in the HFE gene and estrogen-dependent cancer risk was assessed. Genotyping was performed using PCR amplification followed by digestion of products with specific restrictases. In a population of 260 healthy women (permanent residents of the southwest European Russia), mutant allele frequencies at the C282Y and H63D sites were evaluated as 3.3 and 16.3%, respectively. In patients with breast, ovarian, and endometrial cancer, C282Y frequencies were also low (1.0, 1.3, and 3.8%, respectively), and no cancer risk associated with the C282Y mutation was found. Odds ratios for breast cancer risk associated with the H63D mutation increased significantly with age: 0.5 in women below 48 years old, 1.0 in a range of 48-57 years, and 4.4 in older women (P(trend)=0.002). The latter value was statistically significant (95% CI, 1.4-14.1), indicating that women bearing the H63D mutation may be at an increased breast cancer risk at an age above 57 years. Preliminary results obtained in patients with two other estrogen-dependent malignancies revealed the same tendency to OR increase with age in ovarian cancer patients (P(trend)=0.008), but no age-related OR differences in endometrial cancer patients.

Large deletions in mitochondrial DNA in radiation-associated human thyroid tumors.

Paired DNA samples of tumor and normal thyroid tissue from adult patients possibly exposed to radioactive Chernobyl fallout [11 cases of papillary thyroid carcinoma (PTC) and 6 follicular adenomas] and from control samples (9 PTC occurring in Japanese patients) were examined for the relative mitochondrial DNA (mtDNA) content, prevalence and level of common deletion (CD), and large-scale deletions in mtDNA. Elevated relative mtDNA content as estimated by real-time PCR was found in tumor tissue in most cases, but no significant correlation with the level of radioiodine contamination of patients' residency nor with clinicopathological data were found. CD was detected in every DNA specimen from all types of tissue regardless of the presence of oxyphillic cell changes. Elevated level of the CD was predominantly found in tumor tissue of the radiation-associated group but not in sporadic PTC. No correlation was noted with clinicopathological parameters, radioiodine contamination, and relative mtDNA content. The quantity of large-scale deletions in mtDNA was elevated in most tumor tissues, especially in the radiation-associated group and tended to correlate with the level of radiopollutant in PTC. In contrast to sporadic PTC, highly significant-positive correlation between the presence of large scale mtDNA deletions and relative mtDNA content was found in radiation-associated tumors (P = 0.001 and P = 0.019 in PTC and follicular adenoma, respectively). Normal tissue displayed the inverse tendency. No association with level of the CD was found in either group of cases. Concordant increase of both relative mtDNA content and number of mtDNA deletions was detected more often in radiation-associated PTC than in sporadic PTC. Thus, simultaneous determination of the number of large-scale mtDNA deletions and relative mtDNA content may be useful to elucidate molecular distinctive features of radiation-associated thyroid tumors.