Longer time to testosterone recovery impacts favorably on outcomes for prostate cancer following androgen deprivation and radiotherapy.

PURPOSE: To evaluate the impact of sustained hypogonadism after androgen deprivation therapy (ADT) associated with radiotherapy in prostate cancer (PCa) patients with biochemical relapse-free survival (bRFS). METHODS: A retrospective cohort analysis of 213 consecutive PCa patients referred for radiotherapy plus ADT was carried out. Follow-up times including time to testosterone recovery (TTR) and bRFS were calculated from the end of ADT. Univariate and multivariate Cox regression analyses predicting bRFS were used. The optimal cutoffs for TTR and duration of ADT were determined using the maximally selected rank statistics (MSRS). RESULTS: After a median follow-up of 104 months, 18 patients relapsed among those who had recovered testosterone levels and 9 among those who did not. Median ADT duration was 36 months. The optimal cutoff for TTR was determined using MSRS. TTR >48 months was significantly associated with better bRFS (logrank, p < 0.0027). Five-year bRFS was 100% for >48 months vs. 85% for <48 months. TTR was the only significant variable for bRFS in multivariate Cox analysis. CONCLUSION: Our data show an association between longer TTR and bRFS values among PCa patients treated with ADT.

METhodological RadiomICs Score (METRICS): a quality scoring tool for radiomics research endorsed by EuSoMII.

PURPOSE: To propose a new quality scoring tool, METhodological RadiomICs Score (METRICS), to assess and improve research quality of radiomics studies. METHODS: We conducted an online modified Delphi study with a group of international experts. It was performed in three consecutive stages: Stage#1, item preparation; Stage#2, panel discussion among EuSoMII Auditing Group members to identify the items to be voted; and Stage#3, four rounds of the modified Delphi exercise by panelists to determine the items eligible for the METRICS and their weights. The consensus threshold was 75%. Based on the median ranks derived from expert panel opinion and their rank-sum based conversion to importance scores, the category and item weights were calculated. RESULT: In total, 59 panelists from 19 countries participated in selection and ranking of the items and categories. Final METRICS tool included 30 items within 9 categories. According to their weights, the categories were in descending order of importance: study design, imaging data, image processing and feature extraction, metrics and comparison, testing, feature processing, preparation for modeling, segmentation, and open science. A web application and a repository were developed to streamline the calculation of the METRICS score and to collect feedback from the radiomics community. CONCLUSION: In this work, we developed a scoring tool for assessing the methodological quality of the radiomics research, with a large international panel and a modified Delphi protocol. With its conditional format to cover methodological variations, it provides a well-constructed framework for the key methodological concepts to assess the quality of radiomic research papers. CRITICAL RELEVANCE STATEMENT: A quality assessment tool, METhodological RadiomICs Score (METRICS), is made available by a large group of international domain experts, with transparent methodology, aiming at evaluating and improving research quality in radiomics and machine learning. KEY POINTS: • A methodological scoring tool, METRICS, was developed for assessing the quality of radiomics research, with a large international expert panel and a modified Delphi protocol. • The proposed scoring tool presents expert opinion-based importance weights of categories and items with a transparent methodology for the first time. • METRICS accounts for varying use cases, from handcrafted radiomics to entirely deep learning-based pipelines. • A web application has been developed to help with the calculation of the METRICS score ( https://metricsscore.github.io/metrics/METRICS.html ) and a repository created to collect feedback from the radiomics community ( https://github.com/metricsscore/metrics ).

Self-Renewal Inhibition in Breast Cancer Stem Cells: Moonlight Role of PEDF in Breast Cancer.

Breast cancer is the leading cause of death among females in developed countries. Although the implementation of screening tests and the development of new therapies have increased the probability of remission, relapse rates remain high. Numerous studies have indicated the connection between cancer-initiating cells and slow cellular cycle cells, identified by their capacity to retain long labeling (LT+). In this study, we perform new assays showing how stem cell self-renewal modulating proteins, such as PEDF, can modify the properties, percentage of biomarker-expressing cells, and carcinogenicity of cancer stem cells. The PEDF signaling pathway could be a useful tool for controlling cancer stem cells' self-renewal and therefore control patient relapse, as PEDF enhances resistance in breast cancer patient cells' in vitro culture. We have designed a peptide consisting of the C-terminal part of this protein, which acts by blocking endogenous PEDF in cell culture assays. We demonstrate that it is possible to interfere with the self-renewal capacity of cancer stem cells, induce anoikis in vivo, and reduce resistance against docetaxel treatment in cancer patient cells in in vitro culture. We have also demonstrated that this modified PEDF protein produces a significant decrease in the percentage of expressed cancer stem cell markers.

Are 7.5 Gy×2 fractions more efficient than 6 Gy×3 in exclusive postoperative endometrial cancer brachytherapy? A clinical and dosimetrical analysis.

PURPOSE: To compare two vaginal brachytherapy (VBT) schedules in postoperative endometrial carcinoma (PEC) patients considering vaginal-cuff relapses (VCR), late toxicities, dosimetry analysis and vaginal dilator use. MATERIAL AND METHODS: 110 PEC patients were treated with exclusive high-dose-rate VBT using two schedules. Group-1:44-patients received 6 Gy×3fractions (September-2011-April-2014); Group-2:66-patients were treated with 7.5 Gy×2fractions with a dose limit of equivalent total doses in 2-Gy fr (EQD2(α/ß=3)) of 68 Gy in the most exposed 2 cm3 of clinical target volume (CTV) (July-2015-November-2021). The dose was prescribed at 5 mm from the applicator surface. Were evaluated the overall radiation dose delivered to 90% of the CTV (D90), the CTV receiving 100% of the prescription dose (V100) and the EQD2(α/ß=3) received in the most exposed 2 cm3 to dose in CTV. Late toxicity was prospectively assessed using RTOG scores for bladder and rectum and objective LENT-SOMA criteria for late vaginal toxicity (LVT). STATISTICS: Descriptive analysis, Chi-square, Student's t-tests and Kaplan and Meier method. RESULTS: The median follow-up was 60 months (15.9-60). There were no VCR or late toxicities in bladder or rectum. LVT ≥ G1 appeared in 26/44 (59.1%) in Group-1 and 25/66 (37.9%) in Group-2. The mean EQD2(α/ß=3) received by the most exposed 2 cm3 of CTV was 63.7 Gy ± 10.0 in Group-1 and 60.5 Gy ± 3.8 in Group-2 (p = 0.063). There were no differences in adherence to vaginal dilator use ≥9 months, overall D90 and V100. CONCLUSION: Considering the lack of vaginal relapses and similar LVT over time, 7.5 Gy×2fractions seem more efficient in terms of patient comfort, workload, and cost. This is the first study using dosimetry parameters to compare effectivity of schedules. Larger series are needed to confirm the present results.

Pilot Study for the Assessment of the Best Radiomic Features for Bosniak Cyst Classification Using Phantom and Radiologist Inter-Observer Selection.

Since the Bosniak cysts classification is highly reader-dependent, automated tools based on radiomics could help in the diagnosis of the lesion. This study is an initial step in the search for radiomic features that may be good classifiers of benign-malignant Bosniak cysts in machine learning models. A CCR phantom was used through five CT scanners. Registration was performed with ARIA software, while Quibim Precision was used for feature extraction. R software was used for the statistical analysis. Robust radiomic features based on repeatability and reproducibility criteria were chosen. Excellent correlation criteria between different radiologists during lesion segmentation were imposed. With the selected features, their classification ability in benignity-malignity terms was assessed. From the phantom study, 25.3% of the features were robust. For the study of inter-observer correlation (ICC) in the segmentation of cystic masses, 82 subjects were prospectively selected, finding 48.4% of the features as excellent regarding concordance. Comparing both datasets, 12 features were established as repeatable, reproducible, and useful for the classification of Bosniak cysts and could serve as initial candidates for the elaboration of a classification model. With those features, the Linear Discriminant Analysis model classified the Bosniak cysts in terms of benignity or malignancy with 88.2% accuracy.

LDR brachytherapy offers superior tumor control to single-fraction HDR prostate brachytherapy: A prospective study.

PURPOSE: To compare the clinical outcomes of single-fraction high-dose-rate (HDR) brachytherapy and single-fraction low-dose-rate (LDR) brachytherapy as the sole treatment for primary prostate cancer. MATERIAL AND METHODS: A quasi-randomized study that allocated, from March 2008 to February 2012, 129 low and intermediate risk prostate cancer patients to one single-fraction HDR of 19 Gy (61 patients) or to a 145 Gy 125 I LDR permanent implant (68 patients. Biochemical relapse-free survival (bRFS) and overall survival (OS) were compared using the Kaplan-Meier method and Cox regression analysis. RESULTS: After a median follow-up of 72 months in the HDR group, 26 patients relapsed, and after a median follow-up of 84 months in the LDR group, 7 patients relapsed (p < 0.0001). The 5-year bRFS was significantly better for the LDR group than for the HDR group (93.7% and 61.1%, respectively) (p < 0.0001). The 5-year OS also was significantly better in the LDR group (95.5% vs. 89.9%) (p = 0.0436). CONCLUSIONS: Permanent LDR prostate implant brachytherapy offers better clinical outcomes than single-fraction HDR for prostate cancer.

P38 MAPK and Radiotherapy: Foes or Friends?

Over the last 30 years, the study of the cellular response to ionizing radiation (IR) has increased exponentially. Among the various signaling pathways affected by IR, p38 MAPK has been shown to be activated both in vitro and in vivo, with involvement in key processes triggered by IR-mediated genotoxic insult, such as the cell cycle, apoptosis or senescence. However, we do not yet have a definitive clue about the role of p38 MAPK in terms of radioresistance/sensitivity and its potential use to improve current radiotherapy. In this review, we summarize the current knowledge on this family of MAPKs in response to IR as well as in different aspects related to radiotherapy, such as their role in the control of REDOX, fibrosis, and in the radiosensitizing effect of several compounds.

Gradient Boosting Machine Identified Predictive Variables for Breast Cancer Patients Pre- and Post-Radiotherapy: Preliminary Results of an 8-Year Follow-Up Study.

Radiotherapy (RT) is part of the standard treatment of breast cancer (BC) because of its effects on relapse reduction and survival. However, response to treatment is highly variable, and some patients may develop disease progression (DP), a second primary cancer, or may succumb to the disease. Antioxidant systems and inflammatory processes are associated with the onset and development of BC and play a role in resistance to treatment. Here, we report our investigation into the clinical evolution of BC patients, and the impact of RT on the circulating levels of the antioxidant enzyme paraoxonase-1 (PON1), cytokines, and other standard biochemical and hematological variables. Gradient Boosting Machine (GBM) algorithm was used to identify predictive variables. This was a retrospective study in 237 patients with BC. Blood samples were obtained pre- and post-RT, with samples of healthy women used as control subjects. Results showed that 24 patients had DP eight years post-RT, and eight patients developed a second primary tumor. The algorithm identified interleukin-4 and total lymphocyte counts as the most relevant indices discriminating between BC patients and control subjects, while neutrophils, total leukocytes, eosinophils, very low-density lipoprotein cholesterol, and PON1 activity were potential predictors of fatal outcome.

Effect of Low-Dose Radiotherapy on the Circulating Levels of Paraoxonase-1-Related Variables and Markers of Inflammation in Patients with COVID-19 Pneumonia.

The aim of our study was to investigate the changes produced by low-dose radiotherapy (LDRT) in the circulating levels of the antioxidant enzyme paraoxonase-1 (PON1) and inflammatory markers in patients with COVID-19 pneumonia treated with LDRT and their interactions with clinical and radiological changes. Data were collected from the IPACOVID prospective clinical trial (NCT04380818). The study included 30 patients treated with a whole-lung dose of 0.5 Gy. Clinical follow-up, as well as PON1-related variables, cytokines, and radiological parameters were analyzed before LDRT, at 24 h, and 1 week after treatment. Twenty-five patients (83.3%) survived 1 week after LDRT. Respiratory function and radiological images improved in survivors. Twenty-four hours after LDRT, PON1 concentration significantly decreased, while transforming growth factor beta 1 (TGF-ß1) increased with respect to baseline. One week after LDRT, patients had increased PON1 activities and lower PON1 and TGF-ß1 concentrations compared with 24 h after LDRT, PON1 specific activity increased, lactate dehydrogenase (LDH), and C-reactive protein (CRP) decreased, and CD4+ and CD8+ cells increased after one week. Our results highlight the benefit of LDRT in patients with COVID-19 pneumonia and it might be mediated, at least in part, by an increase in serum PON1 activity at one week and an increase in TGF-ß1 concentrations at 24 h.

Alterations in femoral neck strength following pelvic irradiation. A finite element analysis of simulated eccentric forces using bone density data derived from CT.

BACKGROUND AND PURPOSE: Radiotherapy is known to produce long-term skeletal complications. We aim to evaluate the biomechanical effect on femoral neck bone from hypothetical eccentric loads on pre- and post-radiotherapy CT-images for patients treated for rectal cancer. MATERIAL AND METHODS: Pre- and post-radiotherapy CT-images of rectal cancer from 10 patients were selected randomly. The cortical and trabecular bone was segmented by hand. The biomechanical simulations of 4 eccentric loads and one load aligned with the femoral neck axis were completed using finite element analysis (FEA) in both pre- and post-patient models. RESULTS: A comparative statistical study was completed of pre- and post-radiotherapy patient models of stress and displacement factors. Significant differences were found in eccentric loads in both factors. Natural load has a significant difference in stress, but no differences were found for displacements. The absolute difference in eccentric load applied to the anterior area location on the same patient implies from 5.3% to 40.5% of the stress yield values reported in previous studies. CONCLUSIONS: Loads applied to the anterior area of the femoral head must be considered in fracture simulations because the percentage of yield stress of pre- and post-irradiated bones shows a significant biomechanical change.

EQD2 Analyses of Vaginal Complications in Exclusive Brachytherapy for Postoperative Endometrial Carcinoma.

Background: To evaluate whether EQD2(α/ß = 3Gy) at 2 cm3 of the most exposed area of the vagina is related to late vaginal toxicity in postoperative endometrial cancer (PEC) patients (p) treated with exclusive brachytherapy (BT). Methods: From 2014 to 2017, 43p were included in this study. BT was administered: 3-fractions of 6Gy in 37p and 2-fractions of 7.5Gy in 6p. The dose was prescribed at a depth of 5 mm from the applicator surface with dose-point optimization based on distance. The active treatment length was 2.5 cm. CTV-D90 and the dose to the most exposed 2 cm3 of the vagina was calculated for each patient. Late toxicity of the bladder and rectum was assessed using Radiation Therapy Oncology Group (RTOG) criteria, and vaginal toxicity by objective Late Effects Normal Tissue Task Force (LENT)-Subjective, Objective, Management, Analytic (SOMA) (LENT-SOMA) criteria. Statistics: frequency tables, mean, median, range, standard deviation, and box plot. Results: The median follow-up was 51 months (12-68). 20 p (46.5%) and 2 p (4.7%) developed G1 and G2 vaginal complications, respectively. Only 1/2 p-G2 receiving EQD2(α/ß = 3Gy) at 2 cm3 >68Gy presented vaginal shortening and 18/20 p-G1 received doses < 68Gy. Conclusions: PECp receiving exclusive brachytherapy with doses < 68Gy EQD2(α/ß = 3Gy) at 2 cm2 of the vagina presented only G0-G1 vaginal toxicity, except for one with bleeding telangiectasias. Larger prospective studies are necessary to confirm the present results.

Postoperative endometrial carcinoma treated with external beam irradiation plus vaginal-cuff brachytherapy. Is there a dose relationship with G2 vaginal complications?

AIM: To analyse the possible relationship between the EQD2(α/ß=3Gy) at 2 cm3 of the vagina and late toxicity in vaginal-cuff-brachytherapy (VBT) after external-beam-irradiation (EBRT) for postoperative endometrial carcinoma (EC). MATERIALS AND METHODS: From 2014 to 2016, 62 postoperative EC patients were treated with EBRT + VBT. The median EBRT dose was 45 Gy (44 Gy-50.4 Gy). VBT involved a single 7 Gy dose. Toxicity was prospectively evaluated using the RTOG score for the rectum and bladder and the objective LENT-SOMA criteria for the vagina. EQD2(α/ß = 3Gy) at 2 cm3 of the most exposed part of the vagina was calculated by the sum of the EBRT + VBT dose. Statistics: Boxplot, Student's t and Chi-square tests and ROC curves. RESULTS: Mean follow-up: 39.2 months (15-68). Late toxicity: bladder:0 patient; rectum:2 patients-G1; Vagina: 26 patients-17G1, 9G2; median EQD2(α/ß=3Gy) at 2 cm3 in G0-G1 patients was 70.4 Gy(SD2.36), being 72.5 Gy(SD2.94) for G2p. The boxplot suggested a cut-point identifying the absence of G2: 100 % of G2p received >68 Gy, ROC curves showed an area under the curve of 0.72 (sensitivity of 1 and specificity of 0.15). CONCLUSIONS: Doses >68 Gy EQD2(α/ß=3Gy) at 2 cm3 to the most exposed area of the vagina were associated with late G2 vaginal toxicity in postoperative EC patients treated with EBRT + VBT suggesting a very good dose limit to eliminate the risk of G2 late toxicity. The specificity obtained indicates the need for prospective analyses.

Alterations in plasma concentrations of energy-balance-related metabolites in patients with lung, or head & neck, cancers: Effects of radiotherapy.

We investigated the alterations in the plasma concentrations of energy-balance-related metabolites in patients with lung (LC) or head & neck (HNC) cancer and the changes on these parameters induced by radiotherapy. The study was conducted in 33 patients with non-small cell LC and 28 patients with HNC. We analyzed the concentrations of 17 metabolites involved in glycolysis, citric acid cycle and amino acid metabolism using targeted gas chromatography coupled to quadrupole time-of-flight mass spectrometry. For comparison, a control group of 50 healthy individuals was included in the present study. Patients with LC or HNC had significant alterations in the plasma levels of several energy-balance-related metabolites. Radiotherapy partially normalized these alterations in patients with LC, but not in those with HNC. The measurement of plasma glutamate concentration was an excellent predictor of the presence of LC or HNC, with sensitivity >90% and specificity >80%. Also, associations with disease prognosis were observed with plasma glutamate, amino acids and ß-hydroxybutyrate concentrations. SIGNIFICANCE: This study analyzed the changes produced in the plasma concentrations of energy-balance-related metabolites in patients with lung cancer or head and neck cancer. The results obtained identified glutamate as the parameter with the highest discrimination capacity between patients and the control group. The relationships between various metabolites and clinical outcomes were also analyzed. These results extend the knowledge of metabolic alterations in cancer, thus facilitating the search for biomarkers and therapeutic targets.

Serum Paraoxonase-1-Related Variables and Lipoprotein Profile in Patients with Lung or Head and Neck Cancer: Effect of Radiotherapy.

We investigated alterations in the levels of the antioxidant paraoxonase-1 (PON1) and the lipoprotein profile (analyzed by nuclear magnetic resonance) in patients with lung cancer (LC) or head and neck cancer (HNC), and the effects produced thereon by radiotherapy (RT). We included 33 patients with LC and 28 patients with HNC. Before irradiation, and one month after completion of RT, blood samples were obtained. The control group was composed of 50 healthy subjects. Patients had significantly lower serum PON1 activity and concentration before RT than the control group. PON1-related variables were good predictors of the presence of LC or HNC, with analytical sensitivities and specificities greater than 80%. Patients showed a significant increase in the number of particles of all subclasses of very-low-density lipoproteins (large, medium and small). However, these changes were not maintained when adjusted for age, sex, and other clinical and demographic variables. Irradiation was associated with a significant increase in PON1 concentration and, only in patients with HNC, with an increase in high-density lipoprotein-cholesterol concentration. Our results suggest that determinations of the levels of PON1-related variables may constitute good biomarkers for the evaluation of these diseases. Studies with a larger number of patients are needed to fully confirm this hypothesis.

Patients' view of the differences in topical creams for radiation dermatitis prevention. A pilot study of cosmetic properties.

AIM: To investigate the feasibility of including patients' reports on the cosmetic properties of topical formulations for acute radiation dermatitis (ARD). BACKGROUND: No topical agent tested for acute radiation dermatitis (ARD) has proven to be better than any other, all achieving similar objective outcomes. No clear guidelines have therefore been established in clinics. Because the vehicle for such creams has shown to be an important factor in patient adherence to treatments in other dermatological diseases, patients' opinions are evaluated. MATERIAL AND METHODS: Seventy breast cancer patients referred for postoperative radiotherapy after conservative surgery were enrolled. Patients were assigned to use one of the 7 topical agents that are most-commonly used in the prevention of ARD. Patients' reports were assessed using continuous visual analogue scales (VAS), objective signs and symptoms produced by ARD, and were rated using the RTOG and RISRAS scales. RESULTS: The creams tested differed in their cosmetic properties significantly (p = 0.044). The performance of the agent, their absorption and any residue left over were also significantly different (p = 0.022, 0.014 and 0.02, respectively). CONCLUSIONS: Topical agents for preventive ARD are reported by patients to show different cosmetic properties. Cosmetic properties are important when choosing topical agents for ARD prevention. Recommending those with better cosmetic profiles would improve patient adherence to treatments.

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.

Does postoperative irradiation improve survival in early-stage endometrial cancer?

Endometrial cancer is the most common gynecological cancer in developed countries. Postoperative irradiation has been shown to lower locoregional relapses among high-intermediate risk endometrial cancer patients. In addition, vaginal cuff brachytherapy has demonstrated similar control to external beam radiotherapy but with lower toxicity. Although randomized trials have failed to translate that into better overall survival, reports from large databases, such as the National Cancer Database and the Surveillance, Epidemiology, and End Results database, have shown evidence of a statistical relationship between postoperative irradiation and survival in the intermediate- and high-risk groups. This review will address the risk groups that have led the therapeutic decisions and then we will review the clinical results accordingly. Special attention will be paid to the survival results based on the data presented through an analysis of the large databases that suggest a possible survival benefit.