Insights on the radiation-induced adaptive response at the cellular level and its implications in cancer therapy.

BACKGROUND: Development of resistance upon exposure to small doses of ionizing radiation followed by higher doses is known as radiation-induced adaptive response (RIAR). Traditionally, the induction of the RIAR phenomenon at the cellular level has been examined in cell lines, animal models, and epidemiological studies where people live in high natural background radiation. SUMMARY: The primary intention of the earlier studies was to corroborate the existence of RIAR and the mechanism involved in mediating the response surveyed by exposure to a low dose of radiation (<500 mGy) as priming dose towards the radiation protection point of view. However, the investigation has shifted the focus to understand the relevance of this phenomenon at clinically relevant set-ups (high doses in the order of Gy) and can be exploited during radiotherapy as RIAR is considered a mechanism for the development of radioresistance. Although the knowledge of molecular mechanisms at the cellular level has evolved significantly in multi-fractionated radiotherapy regimes, its relevance in developing radioresistance at low doses remains elusive. The authors recapitulate the existing knowledge on RIAR at cellular levels, specifically after low-dose exposure as an adaptive dose, and discussed its potential implications in clinical radiotherapy outcomes. KEY MESSAGES: Recent studies contributed to understand the signaling molecules, pathways, and inhibitors to mitigate RIAR-mediated radiation resistance and persistent radio-tolerance at the cellular level. Monitoring the disease progression in tumor samples or liquid biopsies before, during, and after therapy with suitable biomarkers has been proposed as a strategy to translate the phenomena into clinical scenario.

Candidate Gene Expression in Regional Population and Its Relevance for Radiation Triage.

Quantification of gene expression signatures has been substantiated as a potential and rapid marker for radiation triage and biodosimetry during nuclear emergencies. Similar to the established biodosimetry assays, the gene expression assay has drawbacks such as being highly dynamic and transient, not specific to ionizing radiation, and also influenced by confounding factors such as gender, health status, lifestyle, and inflammation. In view of that, prior knowledge of baseline expression of certain candidate genes in a population could complement the discrimination of the unexposed from the exposed individuals without the need for individual pre-exposure controls. We intended to establish a baseline expression of reported radiation-responsive genes such as CDKN1A, DDB2, FDXR, and PCNA in the blood samples of healthy human participants and then compare it with diabetic/hypertension participants (as a chronic inflammatory condition) drawn from south Indian population. Further, we have examined the appropriateness of the assay for radiation triage-like situations; i.e., the expression profiles of those genes were examined in the participants who underwent X-ray-based medical imaging. Acute inflammation induced by lipopolysaccharide exposure in the blood significantly increased the fold expression of those genes (p < 0.0001) compared to the control. Whereas the basal expression level of those genes among the participants with the inflammatory condition is marginally higher than those observed in the healthy participants; despite the excess, the fold increase in those genes between the groups did not differ significantly. Consistent with the inflammatory participants, the basal expression level of those genes in the blood sample of participants who received X-radiation during neuro-interventional and computed tomography imaging is marginally higher than those observed in the pre-exposure of respective groups. Nevertheless, the fold increase in those genes did not differ significantly as the fold change fell within the two folds. Thus, overall results suggest that the utility of CDKN1A, DDB2, FDXR, and PCNA gene expression for radiation triage specific after very low-dose radiation exposure needs to be interpreted with caution for a much more reliable triage.

The Prognostic Role of Maximum Standardized Uptake Value of 18 F-FlouroDeoxy Glucose Positron Emission Tomography-Computed Tomography in Head and Neck Cancer Patients Undergoing Chemoradiotherapy.

AIMS AND OBJECTIVES: This retrospective study aims at correlating the pre- and post-therapy maximal standardized uptake values (SUVmax) of the whole-body 18-flourodeoxy glucose positron emission tomography (FDG-PET) scan with tumor response in patients with head and neck squamous cell cancer undergoing chemoradiotherapy. MATERIALS AND METHODS: Data for this retrospective study were taken from the clinical records of 20 evaluable head and neck cancer patients who had availed treatment and evaluation at our institute during the previous year (March 2017-April 2018). All these above-mentioned patients had undergone chemoradiation at our center for locally advanced squamous cell carcinoma of the head and neck and had undergone pre- and post-therapy whole-body FDG PET scan. The posttherapy PET-computed tomography (CT) was advised after 8 weeks' postcompletion of therapy. During the PET CT scan, images were acquired 1 h after injection of FDG. Pre- and post-therapy SUVmax were recorded and correlated with immediate treatment response. RESULTS: The mean pretherapy SUVMax of the primary tumor was 10.27 ranging from 4.5 to 26.17. The mean pretherapy SUVMax of the node was 5.34 ranging from 0 to 17.9. The mean time of recording the posttherapy SUVMax was 3 months (range 2-5 months). The mean posttherapy SUVMax of the primary tumor was 1.05 ranging from complete metabolic response to 6.4. The mean posttherapy SUVMax of the node was 0.7 ranging from complete metabolic response to 5.43. The statistical analysis based on Wilcoxon-Signed Rank test revealed a statistically significant difference in the pre- and post-therapy SUVmax values for both primary tumor (P < 0.001) and regional node (P = 0.001). Majority of patients (n = 15) showed clinical remission; however, five patients had progressive disease at the time of evaluation. CONCLUSION: Although the retrospective study revealed that complete responders had a statistically significant reduction in the posttherapy SUVmax in comparison to the pretherapy SUVmax it failed to identify a cutoff value for pretherapy SUVmax which could predict the probable outcome of therapy. In view of the same further prospective studies need to be conducted with larger patient numbers including various other tumor metabolic markers for greater clarity.