Impact of chronic blood viral infection on lymphocyte telomere length in Chornobyl clean-up workers in a remote period after radiation exposure. / VPLYV KhRONIChNOÏ VIRUSNOÏ INFEKTsIÏ NA DOVZhYNU TELOMER LIMFOTsYTIV PERYFERYChNOÏ KROVI UChASNYKIV LIKVIDATsIÏ AVARIÏ NA ChAES U VIDDALENOMU PERIODI PISLIa OPROMINENNIa.

OBJECTIVE: To assess whether telomere length in lymphocytes of Chornobyl clean up workers at a late period 30 years after the exposure to ionizing radiation is influenced by a chronic blood viral infection and to determine role of viral carriage in cellular senescence. PATIENTS AND METHODS: Study group included 70 Chornobyl cleanup male workers 30 years after exposure {doses of external exposure (602.67 ± 114.19) mSv (M ± m); age (59.75 ± 0.82) yrs}. Relative telomere length (RTL) was analysed by fluorescence in situ hybridization and flow cytometry, immune cell subsets by standard combinations of monoclonal antibodies (CD45/14, CD3/19, CD4/8, CD3/HLADR, CD3/16/56, TCRγδ) and flow cytometry; antiviral immunity was performed determining the chronic phase antibodies to viruses: Hepatitis C (HCV), Cytomegalovirus (CMV), Toxoplasma gondii (TOX), Herpes simplex (HSV) and Epstein Barr virus (EBV VCA IgG and EBV NA IgG). The object of the study was peripheral blood (PB) of clean up workers. RESULTS: RTL changes were associated at the group level with the carrier state of the viral infection. RTL shortening was demonstrated as a significant difference between the groups (M ± SD) (HCV negative 15.27 ± 3.35, HCV posi tive 13.09 ± 3.05, p < 0.08, n = 12/52) or as a tendency (CMV negative 15.99 ± 5.41, CMV positive 14.86 ± 3.46 (M ± SD), p < 0.57, n = 11/53; HSV negative 17.01 ± 1.35, HSV positive 14.79 ± 3.80, p < 0.33, n = 13/51; TOX neg ative 15.94 ± 3.41, TOX positive 14.30 ± 3.81(M ± SD), p < 0.23, n = 27/37). These unidirectional changes can be associated with premature early cell aging of immune cells. To the contrary the significant RTL elongation was demonstrated in the group of EBV NA chronic carriers (EBV NA negative 11.25 ± 3.02 (M ± SD), EBV NA positive 16.15 ± 3.08 (M ± SD), p < 0.001, n = 15/49). CONCLUSION: The study confirmed the assumption on a relationship existing between the telomere length, chronic viral infection and late effects in immune cells. The changes of telomeres length on the background of immune dys function may be a sign of cellular aging, and concomitant chronic blood viral infection such as Hepatitis C, Epstein Barr viruses carriage could form a background for an error prone DNA reparation system as a factor of accumulation of pathological conditions, including malignant transformation.

Dose-volume toxicity modeling for de-intensified chemo-radiation therapy for HPV-positive oropharynx cancer.

BACKGROUND AND PURPOSE: The aim is to determine the radiobiological parameters of four popular normal tissue complication probability (NTCP) models that describe the dose-response relations of salivary glands and pharyngeal constrictors to the severity of patient reported xerostomia and dysphagia, respectively 6 and 12months post chemo-radiotherapy, furthermore, to evaluate the goodness-of-fit of the NTCP models for different combinations of glands and constrictors. MATERIAL AND METHODS: Forty-three patients were treated on a prospective multi-institutional phase II study (ClinicalTrials.gov, NCT01530997) assessing the efficacy of de-intensified chemoradiotherapy in patients with favorable risk, HPV-associated oropharyngeal squamous cell carcinoma. All patients received 60Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatinum. All patients reported severity of their xerostomia and dysphagia (pre- and post-treatment) using the patient reported outcome version of the CTCAE (PRO-CTCAE). A change in severity (from baseline) of ≥2 was considered clinically meaningful. The Lyman-Kutcher-Burman (LKB), Relative Seriality (RS), Logit, and Relative Seriality Logit (RSL) NTCP models were used to fit the patients' dose/volume data to changes in PRO-CTCAE severity of xerostomia and dysphagia (from baseline to 6 and 12months post-treatment). The correlation of the models with the patient outcomes was performed for different combinations of salivary glands and different sections of pharyngeal constrictors. The goodness-of-fit of the different models was assessed through the area under the receiver operating characteristic curve (AUC), maximum of the log-likelihood function, normal error distribution and Akaike information criterion (AIC). RESULTS: The dose/volume metrics of the combined contralateral (parotid+submandibular) glands appear to correlate best with xerostomia, at both 6- and 12-months. Among the different sections of pharyngeal constrictors, the dose/volume metrics of the superior pharyngeal constrictors appear to correlate best with dysphagia at 6months. The AUC values ranged from 0.72 to 0.85 in the case of xerostomia and 0.73 to 0.74 in the case of dysphagia over the different models. The four NTCP models showed similar goodness-of-fit. The differences in AIC between the different models were less than 2 and ranged within 0.7 and 0.8 in the cases of xerostomia and dysphagia, respectively. The calculated parameters of the LKB model were D50=26.9Gy, m=0.63, n=1.0 for the combined contralateral glands at 12months and D50=62.0Gy, m=0.10, n=0.49 for the superior pharyngeal constrictors at 6months. CONCLUSIONS: The values of the parameters of four NTCP models were determined for salivary glands and pharyngeal constrictors. All four models could fit the clinical data equally well. The NTCP predictions of the combined contralateral glands and superior pharyngeal constrictors showed the best correlation with the patient reported outcomes of xerostomia and dysphagia, respectively.

HIV impact on acute morbidity and pelvic tumor control following radiotherapy for cervical cancer.

OBJECTIVE: To determine the impact of HIV infection on acute morbidity and pelvic tumor control following external beam radiotherapy (EBRT) for cervical cancer. METHOD: 218 patients receiving EBRT who also had HIV testing after informed consent was obtained were evaluated. Acute treatment toxicity was documented weekly during treatment and 1 month post-EBRT. Pelvic tumor control was documented at 4 and 7 months post-EBRT. Clinicians were blinded for HIV results. RESULTS: About 20% of the patients were HIV-positive. Overall, 53.4% of the patients had radiation-related acute toxicity (grade 3-4). HIV infection was associated with a 7-fold higher risk of multisystem toxicity: skin, gastrointestinal tract (GIT) and genitourinary tract (GUT) systems. It was also an independent risk factor for treatment interruptions (adjusted relative risk 2.2). About 19% of the patients had residual tumor at 4 and 7 months post-EBRT. HIV infection was independently and significantly associated with 6-fold higher risk of residual tumor post-EBRT. The hazard ratio of having residual tumor after initial EBRT was 3.1-times larger for HIV-positive than for HIV-negative patients (P = 0.014). CONCLUSION: HIV is associated with increased risk of multisystem radiation-related toxicity; treatment interruptions and pelvic failure (residual tumor) following EBRT. HIV infection is an adverse prognostic factor for outcome of cervical cancer treatment.