Effect of radiotherapy on the expression of cardiovascular disease-related miRNA-146a, -155, -221 and -222 in blood of women with breast cancer.

Breast cancer (BC) is one of the most important neoplasias among women. Many patients receive radiotherapy (RT), which involves radiation exposure of the thoracic zone, including the heart and blood vessels, leading to the development of cardiovascular disease (CVD) as a long-term side effect. The severity of CVD-related pathologies leads research on assessing novel CVD biomarkers as diagnostic, prognostic or therapeutic agents. Currently, the possible candidates include blood microRNAs (miRNAs). Previous studies have supported a role for miRNA-146a, -155, -221, and -222 in the progression of CVD. Our purpose was to evaluate the RT-induced modulation of the expression of these miRNAs in the blood of women with BC. Pre-RT control and post-RT blood samples were collected, and after miRNA isolation and reverse transcription, the levels of the selected miRNAs were measured by real-time PCR. Our results showed that miRNA-155 exhibited the lowest expression, while miRNA-222 exhibited the highest expression, followed by miRNA-221. The expression of each individual miRNA was positively correlated with that of the others both pre-RT control and post-RT and inversely correlated with age before RT. Furthermore, RT promoted the overexpression of the selected miRNAs. Their levels were also affected by CVD-linked clinical parameters, treatment and BC side. Modulation of the expression of the selected miRNAs together with other risk factors might be associated with the development of future cardiovascular pathologies. Further confirmatory studies are needed to assess their potential as possible biomarkers in the progression of or as therapeutic targets for RT-induced CVD in BC patients.

Metabolite normalization with local radiotherapy following breast tumor resection.

The aims of this study were to investigate changes in energy balance-associated metabolites associated with radiotherapy in patients with breast cancer, and to relate these changes to the clinical and pathological response-to-treatment. We studied 151 women with breast cancer who received radiotherapy following surgical excision of the tumor. Blood was obtained before and after the irradiation procedure. The control group was composed of 44 healthy women with a similar age distribution to that of the patients. We analyzed the concentrations of metabolites involved in glycolysis, citric acid cycle and amino acid metabolism using targeted quantitative metabolomics. Post-surgery, pre-radiotherapy, patients had major alterations in the serum concentrations of products of glycolysis, citric acid cycle and amino acid metabolism. The strongest alterations were decreases in serine, leucine and isoleucine concentrations. Alterations in metabolite levels were partially, or totally, reversed after irradiation; the concentrations of serine, leucine and isoleucine approached equivalence to those of the control group. Estrogen receptor-positive patients were those with lower concentrations, while triple negative patients had higher concentrations of these amino acids. The normalization of the amino acids serine, leucine and isoleucine concentrations could be clinically relevant because the normalization of these energy-balance metabolites would suggest that residual micro-metastatic disease had been effectively diminished by the radiotherapy, and may be an indicator of its efficacy.

Influence of body habitus on dose parameters of nodal levels III to IV irradiation for breast cancer: comparison of 3 techniques.

This study aimed to investigate the effect of body habitus on supraclavicular (SC) dose-volume histogram (DVH) parameters among breast cancer patients according to 3 different techniques. Three SC irradiation plans were generated for 24 postoperative breast cancer patients: (1) direct antero-posterior field only (1fieldP), with dose prescribed to a 3-cm depth; (2) 3-cm depth plan (3cmP) using an antero-posterior field plus a posterior boost with the dose prescription defined to 3 cm; and (3) optimized plan (OptP) similar to 3cmP, with dose prescribed depending on the anatomy. The OptP plans had the least variation in DVH parameters with body habitus; 3cmP plans were the most varied. Conformity index among normal weight patients were 0.73, 0.78, and 0.87 (p = 0.02) and 0.61, 0.6, and 0.82 among overweight-obese patients for 1fieldP, 3cmP, and OptP, respectively (p < 0.001). V95% of the planning target volume among normal weight patients were 72.63%, 78.03%, and 87.18% for 1fieldP, 3cmP, and OptP, respectively (p = 0.02). The corresponding values among overweight-obese patients were 60.5%, 59.62%, and 81.62%, respectively (p = 0.001). Fixed depth dose prescriptions caused greater SC under dose than plans optimized according to patient's anatomy.

Effect of radiotherapy on activity and concentration of serum paraoxonase-1 in breast cancer patients.

Paraoxonase-1 (PON1) is an intra-cellular antioxidant enzyme found also in the circulation associated with high-density lipoproteins. The activity of this enzyme has been shown to be decreased in breast cancer (BC) patients. The aims of our study were to investigate the changes produced by radiotherapy (RT) on activity and concentration of serum PON1 in BC patients, and to evaluate the observed variations in relation to clinical and pathological characteristics of patients and tumors, and the response to treatment. We studied 200 women with BC who were scheduled to receive RT following excision of the tumor. Blood for analyses was obtained before and after the irradiation procedure. The control group was composed of 200 healthy women. Relative to control, BC patients had significantly lower serum PON1 activities pre-RT, while PON1 concentrations were at similar levels. RT was associated with a significant increase in serum PON1 activities and concentrations. We observed significant differences in serum PON1 concentrations post-RT between patients with luminal A or luminal B tumors. Serum PON1 concentration post-RT was markedly lower in BC patients with metastases. We conclude that benefit from RT accrues to the BC patients not only through its direct effect on cancer cells but also indirectly by improving the organism's anti-oxidant defense mechanisms. In addition, our preliminary evidence suggests that the measurement of serum PON1 concentration post-RT could be an efficient prognostic biomarker, and may be used as an index of the efficacy of the RT.

Prognostic correlation of cell cycle progression score and Ki-67 as a predictor of aggressiveness, biochemical failure, and mortality in men with high-risk prostate cancer treated with external beam radiation therapy.

OBJECTIVES: Ki-67 is a proliferation marker in prostate cancer. A prognostic RNA signature was developed to characterize prostate cancer aggressiveness. The aim was to evaluate prognostic correlation of CCP and Ki-67 with biochemical failure (BF), and survival in high-risk prostate cancer patients (pts) treated with radiation therapy (RT). METHODS: CCP score and Ki-67 were derived retrospectively from pre-treatment paraffin-embedded prostate cancer tissue of 33 men diagnosed from 2002 to 2006. CCP score was calculated as an average expression of 31 CCP genes. Ki-67 was determined by IHC. Single pathologist evaluated all tissues. Factors associated to failure and survival were analyzed. RESULTS: Median CCP score was 0.9 (-0-1 - 2.6). CCP 0: 1 pt; CCP 1: 19 pts; CCP 2: 13 pts. Median Ki-67 was 8.9. Ki-67 cutpoint was 15.08%. BF and DSM were observed in 21% and 9%. Ki-67 ≥ 15% predicted BF (p = 0.043). With a median follow-up of 8.4 years, 10-year BF, OS, DM and DSM for CCP 1 vs. CCP 2 was 76-71% (p = 0.83), 83-73% (p = 0.86), 89-85% (p = 0.84), and 94-78% (p = 0.66). On univariate, high Ki-67 was correlated with BF (p = 0.013), OS (p = 0.023), DM (p = 0.007), and DSM (p = 0.01). On Cox MVA, high Ki-67 had a BF trend (p = 0.063). High CCP score was not correlated with DSM. CONCLUSIONS: High Ki-67 significantly predicted outcome and provided prognostic information. CCP score may improve accuracy stratification. We did not provide prognostic correlation of CCP and DSM. It should be validated in a larger cohort of pts.

Effect of rectal enemas on rectal dosimetric parameters during high-dose-rate vaginal cuff brachytherapy: A prospective trial.

PURPOSE: To evaluate the effects of rectal enemas on rectal doses during postoperative high-dose-rate (HDR) vaginal cuff brachytherapy (VCB). PATIENTS AND METHODS: This prospective trial included 59 patients. Two rectal cleansing enemas were self-administered before the second fraction, and fraction 1 was considered the basal status. Dose-volume histogram (DVH) values were generated for the rectum and correlated with rectal volume variation. Statistical analyses used paired and unpaired t-tests. RESULTS: Despite a significant 15 % reduction in mean rectal volume (44.07 vs. 52.15 cc, p = 0.0018), 35.6 % of patients had larger rectums after rectal enemas. No significant rectal enema-related DVH differences were observed compared to the basal data. Although not statistically significant, rectal cleansing-associated increases in mean rectal DVH values were observed: D0.1 cc: 6.6 vs. 7.21 Gy; D1 cc: 5.35 vs. 5.52 Gy; D2 cc: 4.67 vs. 4.72 Gy, before and after rectal cleaning, respectively (where Dx cc is the dose to the most exposed x cm(3)). No differences were observed in DVH parameters according to rectal volume increase or decrease after the enema. Patients whose rectal volume increased also had significantly larger DVH parameters, except for D5 %, D25 %, and D50 %. In contrast, in patients whose rectal volume decreased, significance was only seen for D25 % and D50 % (Dx % dose covering x % of the volume). In the latter patients, nonsignificant reductions in D2 cc, D5 cc and V5 Gy (volume receiving at least 5 Gy) were observed. CONCLUSION: The current rectal enemas protocol was ineffective in significantly modifying rectal DVH parameters for HDR-VCB.

Hypofractionated high-dose-rate plesiotherapy in nonmelanoma skin cancer treatment.

PURPOSE: Nonmelanoma skin cancer (NMSC) is the commonest cancer in humans. NMSC treatment currently includes surgery, radiation therapy, and topical approaches. The objective was to analyze and compare the outcomes, toxicity, and cosmesis of NMSC treated by two hypofractionated high-dose-rate (HDR) plesiotherapy techniques. METHODS AND MATERIALS: A retrospective institutional clinical study of 134 basal cell or squamous cell skin carcinomas treated at Radiation Oncology Department. Lesions were treated from November 2006 to December 2011 with a moderate hypofractionated HDR plesiotherapy using a fixed applicator or a customized mold. RESULTS: After a median follow-up of 33 months, overall disease-free survival at 3 and 5 years was 95.12% and 93.36%, respectively. For Leipzig applicator, disease-free survival at 3 years was 94.9% and 94.9% at 5 years, for customized mold was 93.1% at 3 years and 88% at 5 years. Complete regression was achieved in 98% of lesions. Two lesions persisted after treatment; both had been treated by a Leipzig applicator. Six lesions suffered local recurrence (five Leipzig applicators and three molds, p = 0.404). Grade <2 acute toxicity noted in 57.3% of patients. Only 2.2% of lesions had Grade 4 acute toxicity. Borderline significant increase of toxicity was associated with customized molds (p = 0.067). Larger tumors were associated with higher acute skin toxicity. The cosmesis outcomes were excellent or good in 82% of patients, fair in 13%, and not available in 5%. CONCLUSIONS: Hypofractionated HDR plesiotherapy is an effective and well-tolerated treatment for NMSC with different toxicity levels depending on the plesiotherapy technique used.

The effect of lymphadenectomy and radiotherapy on recurrence and survival in endometrial carcinoma. Experience in a population reference centre.

AIM: To evaluate the effect of lymphadenectomy and/or radiotherapy on recurrence and survival patterns in endometrial carcinoma (EC) in a radiotherapy reference centre population. MATERIAL AND METHODS: A retrospective population-based review was conducted on 261 patients with stages I-III EC. Univariate and multivariate analyses were carried out. Both recurrence and survival were analysed according to patient age, FIGO stage, tumour size, myometrial invasion, tumour grade, lymphadenectomy, external beam irradiation (EBI), and brachytherapy (BT). RESULTS: Median age: 64.8 years. Median follow-up: 151 months. The following treatments were administered: surgery, 97.32%; lymph-node dissection, 54.4%; radiotherapy, 162 patients (62%) (EBI and BT: 64.1%, BT alone: 30.2%, EBI alone: 5.6%). Twenty-six patients (9.96%) suffered loco-regional recurrence, whilst 27 (10.34%) suffered distant failure. The 5-year overall survival (OS) for all stages was 80.1%. The 5-year disease free survival (DFS) was 92.1% for all patients. The 10-year DFS was 89.9%. The independent significant prognostic factors for a good outcome identified through the multivariate analysis were: age <75 years (p = 0.001); tumour size ≤2 cm (p = 0.003); myometrial invasion ≤50% (p = 0.011); lymphadenectomy (p = 0.02); EBI (p = 0.001); and BT (p = 0.031). Toxicity occurred in 114 of the 162 patients who received radiotherapy (70.5%). The toxicity was mainly acute, and late in only 28.3% (n = 45) of cases. The majority experienced G1-2 toxicity, and only 3% of patients experienced G3 late toxicity (5/162). CONCLUSIONS: Our results suggest that age <75 years, tumour size ≤2 cm, myometrial invasion ≤50%, lymphadenectomy, EBI, and BT, are predictors of a good outcome in EC.

Quality assurance in radiotherapy: analysis of the causes of not starting or early radiotherapy withdrawal.

BACKGROUND: The aim of this study was to analyse the reasons for not starting or for early of radiotherapy at the Radiation Oncology Department. METHODS: All radiotherapy treatments from March 2010 to February 2012 were included. Early withdrawals from treatment those that never started recorded. Clinical, demographic and dosimetric variables were also noted. RESULTS: From a total of 3250 patients treated and reviewed, 121 (4%) did not start or complete the planned treatment. Of those, 63 (52%) did not receive any radiotherapy fraction and 58 (48%) did not complete the course, 74% were male and 26% were female. The mean age was 67 ± 13 years. The most common primary tumour was lung (28%), followed by rectum (16%). The aim of treatment was 62% radical and 38% palliative, 44% of patients had metastases; the most common metastatic site was bone, followed by brain. In 38% of cases (46 patients) radiotherapy was administered concomitantly with chemotherapy (10 cases (22%) were rectal cancers). The most common reason for not beginning or for early withdrawal of treatment was clinical progression (58/121, 48%). Of those, 43% died (52/121), 35 of them because of the progression of the disease and 17 from other causes. Incomplete treatment regimens were due to toxicity (12/121 (10%), of which 10 patients underwent concomitant chemotherapy for rectal cancer). CONCLUSIONS: The number of patients who did not complete their course of treatment is low, which shows good judgement in indications and patient selection. The most common reason for incomplete treatments was clinical progression. Rectal cancer treated with concomitant chemotherapy was the most frequent reason of the interruption of radiotherapy for toxicity.

Do breast cups improve breast cancer dosimetry? A comparative study for patients with large or pendulous breasts.

PURPOSE: Treating patients with large or pendulous breasts is challenging. Although brassiere cups are currently in use, no study has yet been carried out to assess their dosimetric impact. The aim of the present study was to evaluate the possible dosimetric advantages of the use of breast cups on patients with large or pendulous breasts. MATERIALS AND METHODS: Two CT studies were carried out on 12 breast cancer patients with large or pendulous breasts, with one study involving the use of breast cups. Radiation plans were developed in accordance with each of the CT studies. The following were compared: planning target volume (PTV), volume irradiated by the 95% isodose, conformity index, homogeneity index, mean lung dose, and mean heart dose was also compared for left breast treatment. The plan involving the use of cups was found to be the best option, leading to all patients being treated with cups. The resulting acute toxicity and cosmesis were also recorded. Both scenarios involved the use of film dosimetry to evaluate the skin doses. RESULTS: The use of breast cups resulted in a significant reduction of the PTV volume (from 1640 cm3 to 1283 cm3), of the irradiated volume (from 2154 cm3 to 1477 cm3) and of the conformity index (from 1383 to 1213). Despite slight improvements in the homogeneity index (from 0.12 to 0.10), statistical significance was not attained. The use of breast cups also led to significant dose reductions in V20 for lung (from 13.7% to 1.7%) and V5 for heart (from 9.8% to 2.7%). No differences in acute toxicity or cosmesis were observed compared to patients treated without cups. CONCLUSIONS: Our results show that the use of brassiere cups during breast radiation therapy leads to improvements in the main dosimetric factors analyzed. Furthermore, modifications to standard irradiation protocols are not required. In summary, we consider the technique of using breast cups with radiation therapy highly appropriate when treating breast cancer patients with large or pendulous breasts.

Pathologic prognostic factors in stage I-III uterine carcinosarcoma treated with postoperative radiotherapy.

PURPOSE: To analyse the impact of prognostic factors on specific overall survival (SOS) after postoperative radiotherapy (P-RT) in carcinosarcomas. METHODS: We retrospectively analysed 81 patients who received P-RT from 1977 to 2010 after the diagnosis of carcinosarcomas. 2009 FIGO stage: 25-IA, 20-IB, 6-II, 9-IIIA, 11-IIIC. Age, stage, vascular and lymphatic space invasion (VLSI), myometrial invasion, grade, mitotic index, sarcomatous/epithelial components, tumour size and necrosis were considered for the analysis. STATISTICS: we used the Kaplan-Meier method for survival analysis and the Cox model for risk factor evaluation. RESULTS: The mean follow-up of the series was 78.86 months (range 7-381). The median age was 72 years (range 51-89). 30 out 81 (37 %) patients relapsed and died (22.2 % pelvic and abdominal, 13.5 % exclusive distant metastasis). On univariate and multivariate analysis only stage had a significant impact on SOS. At 5 years, stage I-II had a SOS of 66 % in comparison with stage III with 30 %. CONCLUSIONS: Two groups of patients showing different outcome were found after P-RT in uterine carcinosarcomas: stage I-II patients had a life expectancy 2.5-fold longer compared to stage III patients. New therapeutic strategies are warranted in carcinosarcomas considering the high incidence of distant metastasis.