A Randomized, Controlled, Parallel-Group, Trial on the Long-term Effects of Melatonin on Fatigue Associated With Breast Cancer and Its Adjuvant Treatments.

OBJECTIVE: Cancer related fatigue is a distressing condition and correlated with decrease in quality of life of patients with malignant conditions. In continuation of our previous research, we assessed long term anti-fatigue effects of melatonin in patients with the breast cancer. MATERIAL AND METHODS: In this clinical trial, 92 breast cancer patients were randomly assigned to receive either melatonin (18 mg/day) or placebo from 1 week before the adjuvant treatments until 2 years after their completion. The levels of fatigue were assessed before and after intervention using Brief Fatigue Inventory (BFI) and were compared at a significance level of P ≤ .05. RESULTS: The BFI scores were similar between the 2 groups at the baseline (placebo group: 5.56 ± 1.59 and melatonin group: 5.72 ± 1.68, P = .67). After the intervention, not only the mean fatigue score was significantly lower in melatonin group (2.93 ± 1.04 vs 1.99 ± 1.02, P < .001, P ≤ .05), but also a greater reduction in fatigue score in intervention group was evident over time (P ≤ .001). CONCLUSION: Long-term usage of melatonin even after completion of adjuvant therapies in women with breast cancer decreased the levels of fatigue associated with the malignant condition and its treatments. THE TRIAL REGISTRY NAME AND URL, AND REGISTRATION NUMBER: Iranian Registry of Clinical Trials, https://en.irct.ir/trial/62267, IRCT20180426039421N3.

Ewing's Sarcoma of Mandible: Practical Approach to a Challenging Case.

As a rare entity, sarcomas of the head and neck are challenging cases. In this paper, we represent a unique case of Ewing sarcoma of mandible, serving as an example of multidisciplinary team importance in a developing country.

DCLK1 Inhibition Sensitizes Colorectal Cancer Cells to Radiation Treatment.

Colorectal cancer (CRC) is one of the most prevalent diagnosed cancers and a common cause of cancer-related mortality. Despite effective clinical responses, a large proportion of patients undergo resistance to radiation therapy. Therefore, the identification of efficient targeted therapy strategies would be beneficial to overcome cancer radioresistance. Doublecortin-like kinase 1 (DCLK1) is an intestinal and pancreatic stem cell marker that showed overexpression in a variety of cancers. The transfection of DCLK1 siRNA to normal HCT-116 cells was performed, and then cells were irradiated with X-rays. The effects of DCLK1 inhibition on cell survival, apoptosis, cell cycle, DNA damage response (ATM and γH2AX proteins), epithelial-mesenchymal transition (EMT) related genes (vimentin, N-cadherin, and E-cadherin), cancer stem cells markers (CD44, CD133, ALDH1, and BMI1), and ß-catenin signaling pathway (ß-catenin) were evaluated. DCLK1 siRNA downregulated DCLK1 expression in HCT-116 cells at both mRNA and protein levels (P <0.01). Colony formation assay showed a significantly reduced cell survival in the DCLK1 siRNA transfected group in comparison with the control group following exposure to 4 and 6 Gy doses of irradiation (P <0.01). Moreover, the expression of cancer stem cells markers (P <0.01), EMT related genes (P <0.01), and DNA repair proteins including pATM (P <0.01) and γH2AX (P <0.001) were significantly decreased in the transfected cells in comparison with the nontransfected group after radiation. Finally, the cell apoptosis rate (P <0.01) and the number of cells in the G0/G1 phase in the silencing DCLK1 group was increased (P <0.01). These findings suggest that DCLK1 can be considered a promising therapeutic target for the treatment of radioresistant human CRC.

Investigation of Collapsed-cone Algorithm Accuracy in Small Fields and Heterogeneous Environments.

BACKGROUND: The use of small fields has increased by the emergence of advanced radiotherapy. Dose calculations of these fields are complex and challenging for many reasons such as lack of electrical equilibrium even in homogeneous environments, and this complexity will increase in presence of heterogeneity. According to the importance of delivery the accurate prescription dose to the target volume in the patient's body, the dose calculation accuracy of used commercial algorithms in clinical treatment planning systems (TPS) should be evaluated. OBJECTIVE: The present study aims to evaluate the accuracy of Collapsed-cone dose measurement algorithm in Isogray treatment planning system. MATERIAL AND METHODS: In this analytical study, the measurements were made in tissue equivalent solid water phantom with lung and bone heterogeneities by Pinpoint dosimeter (0.015 cm3 sensitive volume) in several radiation fields (1×1 to 5×5 cm2). The phantoms were irradiated with 6, 10 and 18 MV photon beams and finally, the results of experimental calculations were compared with treatment planning outputs. RESULTS: In all setups, the maximum deviation occurred in the field of 1×1 cm2. Then, the maximum deviation was observed for 2×2 cm2 field size; however, it was up to 5% for homogeneous water phantom and lung heterogeneity. In 3×3 cm2 and larger fields, there was a good agreement between the results of the TPS and experimental dosimetry. The maximum deviation was observed in water-bone heterogeneity. CONCLUSION: This algorithm was able to pass the standard audit criteria, but it is better to be used more cautiously in bone heterogeneity, especially in low energies.

A Randomized, Controlled, Parallel-Group, Trial on the Effects of Melatonin on Fatigue Associated with Breast Cancer and Its Adjuvant Treatments.

OBJECTIVE: Fatigue associated with malignant conditions and their treatments is a disabling condition. This trial assessed the anti-fatigue effects of melatonin coadministration during adjuvant treatment of patients with the breast cancer. MATERIAL AND METHODS: Patients with breast cancer were randomly assigned to receive melatonin or placebo during adjuvant chemotherapy and radiotherapy. Thirty-seven patients were randomly enrolled in each group. The mean ages of patients in the intervention and control groups were 50.47 ± 10.79 and 46.05 ± 10.55 years, respectively (P = .223). The intervention group received oral melatonin (18 mg/day) from 1 week before until 1 month after the adjuvant radiotherapy. The level of fatigue was assessed before and after intervention using Brief Fatigue Inventory (BFI) in both groups. To analyze data, the Student's t-test and the Chi-square test were used at a significance level of P ≤ .05. RESULTS: The BFI score was similar before the intervention in both groups, however, after the intervention, it was significantly lower in the melatonin group (P < .001). Moreover, the frequency of severe fatigue in the melatonin group was significantly lower than in the placebo group after intervention (42.1% vs 83.3%, P < .001). CONCLUSION: Coadministration of melatonin during adjuvant chemotherapy and radiotherapy of women with breast cancer decreased the levels of fatigue associated with the malignant condition and its treatments.

Cross-Resistance of Acquired Radioresistant Colorectal Cancer Cell Line to gefitinib and regorafenib.

BACKGROUND: Usually, chemoradiotherapy can be used for the treatment of locally advanced colorectal cancer (CRC) before surgery. On the other hand, some studies have shown that fractional radiation of tumor cells leads to chemoresistance. The aim of this study was to evaluate the chemoresistance of radioresistant sub-line (RR sub-line). METHODS: This study was done in Hamadan University of Medical Sciences in 2017-2018. MTT assay and sub-G1 fraction analysis by flow cytometry were used to evaluate cross-resistance of RR sub-line to gefitinib and regorafenib. Real-time PCR was used to investigate the role of four miRNAs and their target genes in the cross-resistance of RR sub-line. The t test and repeated measures test were used for the assessment of statistical significance between groups. RESULTS: The IC50 of gefitinib and regorafenib for RR sub-line were significantly higher than those of the parental cell line. On the other hand, the resistance index of RR sub-line for gefitinib and regorafenib were 1.92 and 1.44, respectively. The sub-G1 fraction of RR sub-line following treatment with gefitinib and regorafenib was significantly lower than that of the parental cell line (P=0.012 and P=0.038, respectively). The expression of miR-9, Let-7e, and Let-7b in RRsub-line was significantly lower than that of the parental cell line. However, NRAS, IGF1R, NFKB1, and CCND1 found to be upregulated in RR sub-line in comparison with the parental cell line. CONCLUSION: We can conclude that the acquired RR sub-line was cross-resistance to gefitinib and regorafenib. Furthermore, miR-9/NFKB1, let-7b/CCND1, let-7e/NRAS, and IGF1R played essential roles in the chemoradioresistance of CRC.

Investigating the effect of radiosensitizer for Ursolic Acid and Kamolonol Acetate | on HCT-116 cell line.

PURPOSE: The aim of this study was evaluating the cytotoxic and radiosensitizing effects of Ursolic Acid (UA) and Kamolonol Acetate (KA) on HCT116 cell line and finally investigating the functional role of NF-κB and CCND1 genes in the radiosensitizing activity of UA and KA. MATERIALS AND METHOD: The cytotoxic effects of UA and KA by MTT assay was evaluated on HCT-116. Clonogenic assay was performed to investigate of radiosensitizing effects of UA and KA on HCT116. To assessment the expression levels of NF-κB and CCND1 genes, real-time PCR method was used. RESULTS: The results of MTT assay revealed that UA and KA have cytotoxic effects on HCT116 cell line. According to clonogenic assay, survival fraction of treated cells with UA and KA has been decreased compared to the survival fraction of untreated cells. UA and KA lead to the decrease in the expression level of NF-κB. Synergistic effect of radiosensitizing agents with radiation was only approved for UA and 2 Gy of radiation. CONCLUSION: Based on our study, UA and KA have cytotoxic effects on HCT116 cell line. Furthermore, UA may lead to radiosensitization of human colorectal tumor cells by NF-κB1 and CCND1signaling pathways.

Let-7e enhances the radiosensitivity of colorectal cancer cells by directly targeting insulin-like growth factor 1 receptor.

Abnormal expression of various microRNAs (miRNAs), as regulators of biological signaling pathways, has a strong association with cancer resistance to chemotherapy and radiotherapy. The let-7 family of miRNAs as tumor suppressors have shown to be downregulated in different types of human malignancies including colorectal cancer (CRC). However, the biological function of let-7 members in the processes of resistance to radiation in CRC has not yet been completely elucidated. Insulin-like growth factor 1 receptor (IGF-1R) signaling pathway is amplified in CRC and leads to its progression, development, and also radiation resistance. So, it seems like an attractive target for anticancer therapy. In this study, by using bioinformatics analysis, it has been revealed that IGF-1R is a direct target of the let-7e member. Consistent with this, we identified that increased levels of let-7e in CRC cells reduced IGF-1R protein level and subsequently its downstream signaling pathways, which resulted in the G1 cell cycle arrest and a significant reduction in the proliferation, survival and also resistance to radiation of CRC cells. Altogether, these results suggested that let-7e by targeting the IGF-1R signaling pathway might serve as therapeutics in anticancer therapy.

MiR-185 enhances radiosensitivity of colorectal cancer cells by targeting IGF1R and IGF2.

OBJECTIVE: Radioresistance is a significant obstacle for effective treatment of colorectal cancer (CRC). Recent studies have indicated that miR-185 inhibits proliferation, survival, and invasion of CRC; however, the role of this miRNA in radioresistance of CRC has not been identified yet. The aim of this study is to investigate the role of miR-185 in radiosensitivity of CRC. METHODS: After transfecting the cells with mimic miR-185, expressions of IGF1R and IGF2 were evaluated by real-time PCR and western blot. The radiation response of transfected cells was also examined by colony forming assay. Sub-G1 fraction analysis through flow cytometry and caspase 3 activity was used to evaluate apoptosis. RESULTS: The results of real-time PCR and western blot indicated that IGF1R and IGF2 are downregulated in the transfected cells. Colony forming assay revealed that transfected cells were more radiosensitive than other cells. On the other hand,following irradiation the rate of apoptosis was significantly higher in the transfected cells than in the other cells. CONCLUSION: In summary, our study is the first to show that upregulation of miR-185 enhances the sensitivity of CRC cells to ionizing radiation. miR-185 may act as a novel biomarker of radioresistance and may clinically enhance the radiation response of CRC.

Expression of Bcl-2 and Bax in advanced or metastatic prostate carcinoma.

PURPOSE: To evaluate the correlation of Bcl-2 and Bax protein expressions with biochemical failure-free survival in patients with advanced or metastatic prostate carcinoma (PCa) undergoing androgen deprivation therapy. MATERIALS AND METHODS: This retrospective study was performed on patients with locally advanced (≥ T3) or metastatic PCa, who were referred to Omid Hospital between years 2003 and 2007. All subjects had undergone androgen deprivation therapy. Samples were analyzed immunohistochemically for Bax and Bcl-2 expression. The H-score was calculated for each sample based on intensity and percentage of stained cells. H-score > 50 was considered positive. RESULTS: Thirty-seven patients (13 metastatic and 24 locally advanced) were eligible for analysis. Thirty-six (97.3%) samples were positive for Bax and 26 (70.3%) for Bcl-2 expression. The median H-score for Bax and Bcl-2 was 200 (range, 40 to 300) and 85 (range, 0 to 220), respectively. While there was no correlation between Bax expression and Gleason score, high Bcl-2 expression (H-score > 85) was significantly associated with Gleason score > 7 (P = .004). The median time to progression in the advanced and metastatic groups was 22 (range, 10 to 37) months and 16 (range, 9 to 26) months, respectively. High Bcl-2 expression (P = .01) and prostate-specific antigen > 20 ng/mL (P = .01) were significant predictors of lower biochemical progression-free survival. CONCLUSION: High Bcl-2 expression was associated with higher Gleason scores and lower biochemical-free survival in patients with advanced PCa undergoing androgen deprivation therapy.