RESUMO
Background: Whole-brain radiotherapy is associated with neurocognitive decline and decreased quality-of-life (QOL) among survivors of brain metastasis. Hippocampal-avoidance whole-brain radiotherapy (HA-WBRT) has shown advantage in delaying or preventing the neurocognitive decline while maintaining disease control. This study was done to assess the benefits and feasibility of HA-WBRT in patients with cerebral metastasis in terms of preservation of neurocognitive function and quality of life. Materials and methods: 27 patients with brain metastasis treated by HA-WBRT and having the records of detailed neurocognitive-assessments were analysed from the database of our hospital. The patients were treated with HA-WBRT to a total dose of 30 Gy in 10 fractions with LINAC based IMRT using the VMAT technique. Cognitive function assessment was carried out using "Examination of the Cognitive Functions" scale provided by Bangur-Institute-of-Neurosciences, Kolkata, 2 weeks prior to radiotherapy and post-treatment two-monthly up to 6 months followed by every 3 months till the last follow up. QOL was assessed at the same interval using the Functional Assessment of Cancer Therapy with Brain Subscale (FACT-BR). Follow-up was done till the date of death. Results: Mean relative cognitive decline percentage decreased over subsequent follow-up visits and was 13% (SD ± 6%), 5% (SD ± 5%), 5% (SD ± 9%) and 2% (SD ± 12%) at 2 months, 6 months, 9 months and 12 months, respectively (p ≤ 0.05). Statistically significant improvement was seen in the mean social-wellbeing (SWB) parameter of QOL (8%. ± 13%, 12%. ± 16%, 7%. ± 20%, no change at 2 months, 4 months, 6 months and 9 months, respectively) (p ≤ 0.05). Mean relative decline in the Emotional-Well Being (EWB) parameter was significant only at 12 months and was 20% (SD ± 35%) (p = 0.04). Mean FACT-BR total Score showed a slight decrease till 9 months from baseline, and then showed a slight improvement up to 12 months. Conclusion: HA-WBRT is feasible with LINAC-based IMRT using the VMAT technique and beneficial to the patients in preserving neurocognitive function and quality of life without compromising disease control.
RESUMO
BACKGROUND/AIM: Compromised cell-cycle checkpoint is a major obstacle for rendering radiotherapeutic success of radioresistant cells. Aspirin (ASA), an anti-inflammatory agent was repurposed previously for improving radiotherapy by limiting radiation toxicity. However, the underlying mechanism was unclear. The present study aimed to identify the mechanism of ASA mediated reversal of radioresistance in cervical cancer cells. METHODS: Radioresistant subline SiHa/RR was developed from parental cervical squamous carcinoma cell line SiHa by chronic fractionated irradiation (IR). The radioresistance property of SiHa/RR was confirmed by clonogenic assay. Alteration in cell-cycle by ASA was determined by flow cytometry. ASA induced nuclear damage as consequence of mitotic catastrophe was confirmed by microscopic observation. The interaction between ASA and G2/M regulators was explored through in silico docking analysis and expressional change of them was affirmed by western blotting. Immunofluorescence study to examine Aurora Kinase A localization in presence and absence of ASA treatment was conducted. Finally the radiosensitizing ability of ASA was verified by apoptotic parameters (flow cytometrically and by western blotting). RESULT: Higher colony forming ability of SiHa/RR compared to SiHa became restrained upon ASA (5µM) treatment prior to IR. Flow cytometric analysis of ASA treated cells showed increased G2/M population followed by enlargement of cells displaying giant multinucleated morphology; typical characteristics of mitotic catastrophe. Underlying noteworthy mechanisms involved decreased expressions of G2/M regulatory proteins (Cyclin B1, CDK1, Aurora A Kinase, pAurora A Kinase) in IR/ASA along with inhibiting nuclear localization of Aurora Kinase A in SiHa/RR. Docking results also supported the findings. Prolonged treatment (12 h) with ASA led to apoptosis by altering expressions of Bcl2, Bax and Cytochrome C; which was achieved through the event of mitotic catastrophe. CONCLUSION: This work established that G2/M arrest and mitotic catastrophe can be considered as the principle mechanism of restoration of radiosensitivity in SiHa/RR by ASA pretreatment.