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BACKGROUND: The search for factors beyond the radiotherapy dose that could identify patients more at risk of developing radio-induced toxicity is essential to establish personalised treatment protocols for improving the quality-of-life of survivors. To investigate the role of the intestinal microbiota in the development of radiotherapy-induced gastrointestinal toxicity, the MicroLearner observational cohort study characterised the intestinal microbiota of 136 (discovery) and 79 (validation) consecutive prostate cancer patients at baseline radiotherapy. METHODS: Gastrointestinal toxicity was assessed weekly during RT using CTCAE. An average grade >1.3 over time points was used to identify patients suffering from persistent acute toxicity (endpoint). The microbiota of patients was quantified from the baseline faecal samples using 16S rRNA gene sequencing technology and the Ion Reporter metagenomic pipeline. Statistical techniques and computational and machine learning tools were used to extract, functionally characterise, and predict core features of the bacterial communities of patients who developed acute gastrointestinal toxicity. FINDINGS: Analysis of the core bacterial composition in the discovery cohort revealed a cluster of patients significantly enriched for toxicity, displaying a toxicity rate of 60%. Based on selected high-risk microbiota compositional features, we developed a clinical decision tree that could effectively predict the risk of toxicity based on the relative abundance of genera Faecalibacterium, Bacteroides, Parabacteroides, Alistipes, Prevotella and Phascolarctobacterium both in internal and external validation cohorts. INTERPRETATION: We provide evidence showing that intestinal bacteria profiling from baseline faecal samples can be effectively used in the clinic to improve the pre-radiotherapy assessment of gastrointestinal toxicity risk in prostate cancer patients. FUNDING: Italian Ministry of Health (Promotion of Institutional Research INT-year 2016, 5 × 1000, Ricerca Corrente funds). Fondazione Regionale per la Ricerca Biomedica (ID 2721017). AIRC (IG 21479).
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Microbioma Gastrointestinal , Neoplasias de la Próstata , Traumatismos por Radiación , Humanos , Masculino , Microbioma Gastrointestinal/efectos de la radiación , Neoplasias de la Próstata/radioterapia , Anciano , Traumatismos por Radiación/etiología , Traumatismos por Radiación/microbiología , Traumatismos por Radiación/diagnóstico , Persona de Mediana Edad , Metagenómica/métodos , Heces/microbiología , ARN Ribosómico 16S/genética , Radioterapia/efectos adversos , Bacterias/clasificación , Bacterias/genética , Bacterias/efectos de la radiación , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/microbiología , MetagenomaAsunto(s)
Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Neoplasias de Cabeza y Cuello/microbiología , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/microbiología , Fusobacterium/aislamiento & purificación , Carcinoma de Células Escamosas , Infecciones por Fusobacterium/complicaciones , Infecciones por Fusobacterium/microbiología , Masculino , FemeninoRESUMEN
The major aim of Pediatric Normal Tissue Effects in the Clinic (PENTEC) was to synthesize quantitative published dose/-volume/toxicity data in pediatric radiation therapy. Such systematic reviews are often challenging because of the lack of standardization and difficulty of reporting outcomes, clinical factors, and treatment details in journal articles. This has clinical consequences: optimization of treatment plans must balance between the risks of toxicity and local failure; counseling patients and their parents requires knowledge of the excess risks encountered after a specific treatment. Studies addressing outcomes after pediatric radiation therapy are particularly challenging because: (a) survivors may live for decades after treatment, and the latency time to toxicity can be very long; (b) children's maturation can be affected by radiation, depending on the developmental status of the organs involved at time of treatment; and (c) treatment regimens frequently involve chemotherapies, possibly modifying and adding to the toxicity of radiation. Here we discuss: basic reporting strategies to account for the actuarial nature of the complications; the reporting of modeling of abnormal development; and the need for standardized, comprehensively reported data sets and multivariate models (ie, accounting for the simultaneous effects of radiation dose, age, developmental status at time of treatment, and chemotherapy dose). We encourage the use of tools that facilitate comprehensive reporting, for example, electronic supplements for journal articles. Finally, we stress the need for clinicians to be able to trust artificial intelligence models of outcome of radiation therapy, which requires transparency, rigor, reproducibility, and comprehensive reporting. Adopting the reporting methods discussed here and in the individual PENTEC articles will increase the clinical and scientific usefulness of individual reports and associated pooled analyses.
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Neoplasias , Traumatismos por Radiación , Humanos , Niño , Neoplasias/radioterapia , Traumatismos por Radiación/prevención & control , Traumatismos por Radiación/etiología , Órganos en Riesgo/efectos de la radiación , Radioterapia/efectos adversos , Radioterapia/normas , Supervivientes de Cáncer , Dosificación Radioterapéutica , Proyectos de Investigación/normas , PreescolarRESUMEN
BACKGROUND AND PURPOSE: Given the substantial lack of knowledge, we aimed to assess clinical/dosimetry predictors of late hematological toxicity on patients undergoing pelvic-nodes irradiation (PNI) for prostate cancer (PCa) within a prospective multi-institute study. MATERIALS AND METHODS: Clinical/dosimetry/blood test data were prospectively collected including lymphocytes count (ALC) at baseline, mid/end-PNI, 3/6 months and every 6 months up to 5-year after PNI. DVHs of the Body, ileum (BMILEUM), lumbosacral spine (BMLS), lower pelvis (BMPELVIS), and whole pelvis (BMTOT) were extracted. Current analysis focused on 2-year CTCAEv4.03 Grade ≥ 2 (G2+) lymphopenia (ALC < 800/µL). DVH parameters that better discriminate patients with/without toxicity were first identified. After data pre-processing to limit overfitting, a multi-variable logistic regression model combining DVH and clinical information was identified and internally validated by bootstrap. RESULTS: Complete data of 499 patients were available: 46 patients (9.2 %) experienced late G2+ lymphopenia. DVH parameters of BMLS/BMPELVIS/BMTOT and Body were associated to increased G2+ lymphopenia. The variables retained in the resulting model were ALC at baseline [HR = 0.997, 95 %CI 0.996-0.998, p < 0.0001], smoke (yes/no) [HR = 2.9, 95 %CI 1.25-6.76, p = 0.013] and BMLS-V ≥ 24 Gy (cc) [HR = 1.006, 95 %CI 1.002-1.011, p = 0.003]. When acute G3+ lymphopenia (yes/no) was considered, it was retained in the model [HR = 4.517, 95 %CI 1.954-10.441, p = 0.0004]. Performances of the models were relatively high (AUC = 0.87/0.88) and confirmed by validation. CONCLUSIONS: Two-year lymphopenia after PNI for PCa is largely modulated by baseline ALC, with an independent role of acute G3+ lymphopenia. BMLS-V24 was the best dosimetry predictor: constraints for BMTOT (V10Gy < 1520 cc, V20Gy < 1250 cc, V30Gy < 850 cc), and BMLS (V24y < 307 cc) were suggested to potentially reduce the risk.
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Médula Ósea , Linfopenia , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/patología , Linfopenia/etiología , Estudios Prospectivos , Anciano , Médula Ósea/efectos de la radiación , Persona de Mediana Edad , Pelvis/efectos de la radiación , Dosificación Radioterapéutica , Irradiación Linfática/efectos adversos , Irradiación Linfática/métodos , Anciano de 80 o más AñosRESUMEN
Hypoxia contributes significantly to resistance in radiotherapy. Our research rigorously examines the influence of microvascular morphology on radiotherapy outcome, specifically focusing on how microvasculature shapes hypoxia within the microenvironment and affects resistance to a standard treatment regimen (30×2GyRBE). Our computational modeling extends to the effects of different radiation sources. For photons and protons, our analysis establishes a clear correlation between hypoxic volume distribution and treatment effectiveness, with vascular density and regularity playing a crucial role in treatment success. On the contrary, carbon ions exhibit distinct effectiveness, even in areas of intense hypoxia and poor vascularization. This finding points to the potential of carbon-based hadron therapy in overcoming hypoxia-induced resistance to RT. Considering that the spatial scale analyzed in this study is closely aligned with that of imaging data voxels, we also address the implications of these findings in a clinical context envisioning the possibility of detecting subvoxel hypoxia.
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Hipoxia , Fotones , Humanos , Fotones/uso terapéutico , CarbonoRESUMEN
PURPOSE: Different ML models were compared to predict toxicity in RT on a large cohort (n = 1314). METHODS: The endpoint was RTOG G2/G3 acute toxicity, resulting in 204/1314 patients with the event. The dataset, including 25 clinical, anatomical, and dosimetric features, was split into 984 for training and 330 for internal tests. The dataset was standardized; features with a high p-value at univariate LR and with Spearman ρ>0.8 were excluded; synthesized data of the minority were generated to compensate for class imbalance. Twelve ML methods were considered. Model optimization and sequential backward selection were run to choose the best models with a parsimonious feature number. Finally, feature importance was derived for every model. RESULTS: The model's performance was compared on a training-test dataset over different metrics: the best performance model was LightGBM. Logistic regression with three variables (LR3) selected via bootstrapping showed performances similar to the best-performing models. The AUC of test data is slightly above 0.65 for the best models (highest value: 0.662 with LightGBM). CONCLUSIONS: No model performed the best for all metrics: more complex ML models had better performances; however, models with just three features showed performances comparable to the best models using many (n = 13-19) features.
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BACKGROUND: Toxicity after whole breast Radiotherapy is a relevant issue, impacting the quality-of-life of a not negligible number of patients. We aimed to develop a Normal Tissue Complication Probability (NTCP) model predicting late toxicities by combining dosimetric parameters of the breast dermis and clinical factors. METHODS: The skin structure was defined as the outer CT body contour's 5â¯mm inner isotropic expansion. It was retrospectively segmented on a large mono-institutional cohort of early-stage breast cancer patients enrolled between 2009 and 2017 (nâ¯=â¯1066). Patients were treated with tangential-field RT, delivering 40â¯Gy in 15 fractions to the whole breast. Toxicity was reported during Follow-Up (FU) using SOMA/LENT scoring. The study endpoint was moderate-severe late side effects consisting of Fibrosis-Atrophy-Telangiectasia-Pain (FATP Gâ¯≥â¯2) developed within 42â¯months after RT completion. A machine learning pipeline was designed with a logistic model combining clinical factors and absolute skin DVH (cc) parameters as output. RESULTS: The FATP G2â¯+â¯rate was 3.8â¯%, with 40/1066 patients experiencing side effects. After the preprocessing of variables, a cross-validation was applied to define the best-performing model. We selected a 4-variable model with Post-Surgery Cosmetic alterations (Odds Ratio, ORâ¯=â¯7.3), Aromatase Inhibitors (as a protective factor with ORâ¯=â¯0.45), V20 Gy (50â¯% of the prescribed dose, ORâ¯=â¯1.02), and V42 Gy (105â¯%, ORâ¯=â¯1.09). Factors were also converted into an adjusted V20Gy. CONCLUSIONS: The association between late reactions and skin DVH when delivering 40â¯Gy/15 fr was quantified, suggesting an independent role of V20 and V42. Few clinical factors heavily modulate the risk.
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Neoplasias de la Mama , Dosificación Radioterapéutica , Piel , Humanos , Femenino , Neoplasias de la Mama/radioterapia , Persona de Mediana Edad , Piel/efectos de la radiación , Estudios Retrospectivos , Anciano , Traumatismos por Radiación/etiología , Adulto , Órganos en Riesgo/efectos de la radiación , Anciano de 80 o más AñosRESUMEN
PURPOSE: The purpose of this study is to study the evolution of quality of life (QoL) in the first 5 years following Intensity-modulated radiation therapy (IMRT) for prostate cancer (PCa) and to determine possible associations with clinical/treatment data. MATERIAL AND METHODS: Patients were enrolled in a prospective multicentre observational trial in 2010-2014 and treated with conventional (74-80 Gy, 1.8-2 Gy/fr) or moderately hypofractionated IMRT (65-75.2 Gy, 2.2-2.7 Gy/fr). QoL was evaluated by means of EORTC QLQ-C30 at baseline, at radiation therapy (RT) end, and every 6 months up to 5 years after IMRT end. Fourteen QoL dimensions were investigated separately. The longitudinal evaluation of QoL was analysed by means of Analysis of variances (ANOVA) for multiple measures. RESULTS: A total of 391 patients with complete sets of questionnaires across 5 years were available. The longitudinal analysis showed a trend toward the significant worsening of QoL at RT end for global health, physical and role functioning, fatigue, appetite loss, diarrhoea, and pain. QoL worsening was recovered within 6 months from RT end, with the only exception being physical functioning. Based on ANOVA, the most impaired time point was RT end. QoL dimension analysis at this time indicated that acute Grade ≥ 2 gastrointestinal (GI) toxicity significantly impacted global health, physical and role functioning, fatigue, appetite loss, diarrhoea, and pain. Acute Grade ≥ 2 genitourinary (GU) toxicity resulted in lower role functioning and higher pain. Prophylactic lymph-nodal irradiation (WPRT) resulted in significantly lower QoL for global health, fatigue, appetite loss, and diarrhoea; lower pain with the use of neoadjuvant/concomitant hormonal therapy; and lower fatigue with the use of an anti-androgen. CONCLUSIONS: In this prospective, longitudinal, observational study, high radiation IMRT doses delivered for PCa led to a temporary worsening of QoL, which tended to be completely resolved at six months. Such transient worsening was mostly associated with acute GI/GU toxicity, WPRT, and higher prescription doses.
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Neoplasias de la Próstata , Radioterapia de Intensidad Modulada , Masculino , Humanos , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Calidad de Vida , Estudios Prospectivos , Neoplasias de la Próstata/tratamiento farmacológico , Dolor/etiología , Diarrea , Fatiga/etiologíaRESUMEN
BACKGROUND AND PURPOSE: To quantify patient-reported 2-year intestinal toxicity (IT) from pelvic nodal irradiation (PNI) for prostate cancer. The association between baseline/acute symptoms and 2-year worsening was investigated. MATERIALS AND METHODS: Patient-reported IT was prospectively assessed through the Inflammatory Bowel Disease Questionnaire (IBDQ), filled in at baseline, radiotherapy mid-point and end, at 3 and 6 months and every 6 months until 5 years. Two-year deterioration of IBDQ scores relative to the Bowel Domain was investigated for 400 patients with no severe baseline symptoms and with questionnaires available at baseline, 2 years, RT mid-point and/or end and at least three follow-ups between 3 and 18 months. The significance of the 2-year differences from baseline was tested. The association between baseline values and ΔAcute (the worst decline between baseline and RT mid-point/end) was investigated. RESULTS: In the IBDQ lower scores indicate worse symptoms. A significant (p < 0.0001) 2-year mean worsening, mostly in the range of -0.2/-0.4 points on a 1-7 scale, emerged excepting one question (IBDQ29, "nausea/feeling sick"). This decline was independent of treatment intent while baseline values were associated with 2-year absolute scores. The ΔAcute largely modulated 2-year worsening: patients with ΔAcute greater than the first quartile (Q1) and ΔAcute less or equal than Q1 showed no/minimal and highly significant (p < 0.0001) deterioration, respectively. Rectal incontinence, urgency, frequency and abdominal pain showed the largest mean changes (-0.5/-1): risk of severe worsening (deemed to be of clinical significance if ≤ 2) was 3-5 fold higher in the ΔAcute ≤ Q1 vs ΔAcute > Q1 group (p < 0.0001). CONCLUSION: A modest but significant deterioration of two-year patient-reported intestinal symptoms from PNI compared to baseline was found. Patients experiencing more severe acute symptoms are at higher risk of symptom persistence at 2 years, with a much larger prevalence of clinically significant symptoms.
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Enfermedades Inflamatorias del Intestino , Neoplasias de la Próstata , Oncología por Radiación , Masculino , Humanos , Neoplasias de la Próstata/radioterapia , Pelvis/efectos de la radiación , Recto/efectos de la radiación , Medición de Resultados Informados por el Paciente , Calidad de VidaRESUMEN
The development of normal tissue radiation dose-response models for children with cancer has been challenged by many factors, including small sample sizes; the long length of follow-up needed to observe some toxicities; the continuing occurrence of events beyond the time of assessment; the often complex relationship between age at treatment, normal tissue developmental dynamics, and age at assessment; and the need to use retrospective dosimetry. Meta-analyses of published pediatric outcome studies face additional obstacles of incomplete reporting of critical dosimetric, clinical, and statistical information. This report describes general methods used to address some of the pediatric modeling issues. It highlights previous single- and multi-institutional pediatric dose-response studies and summarizes how each PENTEC taskforce addressed the challenges and limitations of the reviewed publications in constructing, when possible, organ-specific dose-effect models.
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Relación Dosis-Respuesta en la Radiación , Neoplasias , Órganos en Riesgo , Humanos , Niño , Neoplasias/radioterapia , Órganos en Riesgo/efectos de la radiación , Preescolar , Dosificación Radioterapéutica , Modelos Biológicos , Factores de Edad , Lactante , Adolescente , Traumatismos por Radiación/prevención & controlRESUMEN
PURPOSE: To evaluate the persistence of symptoms after radiotherapy (RT) for localised prostate cancer (PCa) and the association with quality of life (QOL). MATERIALS AND METHODS: Prospective patient-reported outcome (PRO) from a multi-institutional study on PCa treated with radical RT (2010-2014) was analysed. Data was collected at baseline (BL) and follow-ups (FUPs) up to 5 years. Patients with BL and ≥3 late FUPs (≥6 months) were analysed. PRO was scored by means of the IPSS and ICIQ-SF (urinary), LENT-SOMA (gastrointestinal [GI]), and EORTC-C30 (pain, insomnia, fatigue, and QOL) questionnaires. Symptoms were defined 'persistent' if the median score over FUPs was ≥3 (urinary) or ≥2 (GI, pain, insomnia, and fatigue), and worse than BL. Different thresholds were chosen to have enough events for each symptom. QOL was linearly transformed on a continuous scale (0-100). Linear-mixed models were used to identify significant differences between groups with and without persistent symptoms including age, smoking status, previous abdominal surgery, and diabetes as confounders. Mean QOL differences between groups were evaluated longitudinally over FUPs. RESULTS: The analysis included 293 patients. Persistent urinary symptoms ranged from 2% (straining) to 12% (weak stream, and nocturia). Gastrointestinal symptoms ranged from 7% (rectal pain, and incontinence) to 30% (urgency). Proportions of pain, insomnia, and fatigue were 6, 13, and 18%. Significant QOL differences of small-to-medium clinical relevance were found for urinary incontinence, frequency, urgency, and nocturia. Among GI symptoms, rectal pain and incontinence showed small-to-medium differences. Fatigue was associated with the largest differences. CONCLUSIONS: The analysis showed that symptoms after RT for PCa occur with different persistence and their association with QOL varies in magnitude. A number of persistent urinary and GI symptoms showed differences in a comparable range. Urinary incontinence and frequency, rectal pain, and faecal incontinence more often had significant associations. Fatigue was also prevalent and associated with largely deteriorated QOL.
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Supervivientes de Cáncer , Enfermedades Gastrointestinales , Nocturia , Neoplasias de la Próstata , Enfermedades del Recto , Trastornos del Inicio y del Mantenimiento del Sueño , Incontinencia Urinaria , Masculino , Humanos , Calidad de Vida , Próstata , Estudios Prospectivos , Nocturia/complicaciones , Neoplasias de la Próstata/radioterapia , Incontinencia Urinaria/complicaciones , Dolor , Fatiga , Encuestas y CuestionariosRESUMEN
Voxel-based analysis (VBA) allows the full, 3-dimensional, dose distribution to be considered in radiotherapy outcome analysis. This provides new insights into anatomical variability of pathophysiology and radiosensitivity by removing the need for a priori definition of organs assumed to drive the dose response associated with patient outcomes. This approach may offer powerful biological insights demonstrating the heterogeneity of the radiobiology across tissues and potential associations of the radiotherapy dose with further factors. As this methodological approach becomes established, consideration needs to be given to translating VBA results to clinical implementation for patient benefit. Here, we present a comprehensive roadmap for VBA clinical translation. Technical validation needs to demonstrate robustness to methodology, where clinical validation must show generalisability to external datasets and link to a plausible pathophysiological hypothesis. Finally, clinical utility requires demonstration of potential benefit for patients in order for successful translation to be feasible. For each step on the roadmap, key considerations are discussed and recommendations provided for best practice.
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Background and Purpose: The association between dose to selected bladder and rectum symptom-related sub-regions (SRS) and late toxicity after prostate cancer radiotherapy has been evidenced by voxel-wise analyses. The aim of the current study was to explore the feasibility of combining knowledge-based (KB) and multi-criteria optimization (MCO) to spare SRSs without compromising planning target volume (PTV) dose delivery, including pelvic-node irradiation. Materials and Methods: Forty-five previously treated patients (74.2 Gy/28fr) were selected and SRSs (in the bladder, associated with late dysuria/hematuria/retention; in the rectum, associated with bleeding) were generated using deformable registration. A KB model was used to obtain clinically suitable plans (KB-plan). KB-plans were further optimized using MCO, aiming to reduce dose to the SRSs while safeguarding target dose coverage, homogeneity and avoiding worsening dose volume histograms of the whole bladder, rectum and other organs at risk. The resulting MCO-generated plans were examined to identify the best-compromise plan (KB + MCO-plan). Results: The mean SRS dose decreased in almost all patients for each SRS. D1% also decreased in the large majority, less frequently for dysuria/bleeding SRS. Mean differences were statistically significant (p < 0.05) and ranged between 1.3 and 2.2 Gy with maximum reduction of mean dose up to 3-5 Gy for the four SRSs. The better sparing of SRSs was obtained without compromising PTVs coverage. Conclusions: Selectively sparing SRSs without compromising PTV coverage is feasible and has the potential to reduce toxicities in prostate cancer radiotherapy. Further investigation to better quantify the expected risk reduction of late toxicities is warranted.
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BACKGROUND: Normal tissue complication probability (NTCP) models can be useful to estimate the risk of fibrosis after breast-conserving surgery (BCS) and radiotherapy (RT) to the breast. However, they are subject to uncertainties. We present the impact of contouring variation on the prediction of fibrosis. MATERIALS AND METHODS: 280 breast cancer patients treated BCS-RT were included. Nine Clinical Target Volume (CTV) contours were created for each patient: i) CTV_crop (reference), cropped 5 mm from the skin and ii) CTV_skin, uncropped and including the skin, iii) segmenting the 95% isodose (Iso95%) and iv) 3 different auto-contouring atlases generating uncropped and cropped contours (Atlas_skin/Atlas_crop). To illustrate the impact of contour variation on NTCP estimates, we applied two equations predicting fibrosis grade ≥ 2 at 5 years, based on Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) models, respectively, to each contour. Differences were evaluated using repeated-measures ANOVA. For completeness, the association between observed fibrosis events and NTCP estimates was also evaluated using logistic regression. RESULTS: There were minimal differences between contours when the same contouring approach was followed (cropped and uncropped). CTV_skin and Atlas_skin contours had lower NTCP estimates (-3.92%, IQR 4.00, p < 0.05) compared to CTV_crop. No significant difference was observed for Atlas_crop and Iso95% contours compared to CTV_crop. For the whole cohort, NTCP estimates varied between 5.3% and 49.5% (LKB) or 2.2% and 49.6% (RS) depending on the choice of contours. NTCP estimates for individual patients varied by up to a factor of 4. Estimates from "skin" contours showed higher agreement with observed events. CONCLUSION: Contour variations can lead to significantly different NTCP estimates for breast fibrosis, highlighting the importance of standardising breast contours before developing and/or applying NTCP models.
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Neoplasias de la Mama , Enfermedad Fibroquística de la Mama , Femenino , Humanos , Dosificación Radioterapéutica , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Mama/diagnóstico por imagen , Planificación de la Radioterapia Asistida por Computador , Probabilidad , FibrosisRESUMEN
Three-dimensional (3D) imaging techniques (e.g., confocal microscopy) are commonly used to visualize in vitro models, especially microvasculature on-a-chip. Conversely, 3D analysis is not the standard method to extract quantitative information from those models. We developed the µVES algorithm to analyze vascularized in vitro models leveraging 3D data. It computes morphological parameters (geometry, diameter, length, tortuosity, eccentricity) and intravascular flow velocity. µVES application to microfluidic vascularized in vitro models shows that they successfully replicate functional features of the microvasculature in vivo in terms of intravascular fluid flow velocity. However, wall shear stress is lower compared to in vivo references. The morphological analysis also highlights the model's physiological similarities (vessel length and tortuosity) and shortcomings (vessel radius and surface-over-volume ratio). The addition of the third dimension in our analysis produced significant differences in the metrics assessed compared to 2D estimations. It enabled the computation of new indices, such as vessel eccentricity. These µVES capabilities can find application in analyses of different in vitro vascular models, as well as in vivo and ex vivo microvasculature.
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OBJECTIVE: Most patients receive whole breast radiotherapy in a supine position. However, two randomised trials showed lower acute toxicity in prone position. Furthermore, in most patients, prone positioning reduced doses to the organs at risk. To confirm these findings, we compared toxicity outcomes, photographic assessment, and dosimetry between both positions using REQUITE data. METHODS: REQUITE is an international multi-centre prospective observational study that recruited 2069 breast cancer patients receiving radiotherapy. Data on toxicity, health-related quality of life (HRQoL), and dosimetry were collected, as well as a photographic assessment. A matched case control analysis compared patients treated prone (n = 268) versus supine (n = 493). Exact matching was performed for the use of intensity-modulated radiotherapy, boost, lymph node irradiation, chemotherapy and fractionation, and the nearest neighbour for breast volume. Primary endpoints were dermatitis at the end of radiotherapy, and atrophy and cosmetic outcome by photographic assessment at two years. RESULTS: At the last treatment fraction, there was no significant difference in dermatitis (p = .28) or any HRQoL domain, but prone positioning increased the risk of breast oedema (p < .001). At 2 years, patients treated in prone position had less atrophy (p = .01), and higher body image (p < .001), and social functioning (p < .001) scores. The photographic assessment showed no difference in cosmesis at 2 years (p = .22). In prone position, mean heart dose (MHD) was significantly lower for left-sided patients (1.29 Gy vs 2.10 Gy, p < .001) and ipsilateral mean lung dose (MLD) was significantly lower for all patients (2.77 Gy vs 5.89 Gy, p < .001). CONCLUSIONS: Prone radiotherapy showed lower MLD and MHD compared to supine position, although the risk of developing breast oedema during radiotherapy was higher. At 2 years the photographic assessment showed no difference in the cosmetic outcome, but less atrophy was seen in prone-treated patients and this seems to have a positive influence on the HRQoL domain of body image.
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Stability analysis remains a fundamental step in developing a successful imaging biomarker to personalize oncological strategies. This study proposes an in silico contour generation method for simulating segmentation variations to identify stable radiomic features. Ground-truth annotation provided for the whole prostate gland on the multi-parametric MRI sequences (T2w, ADC, and SUB-DCE) were perturbed to mimic segmentation differences observed among human annotators. In total, we generated 15 synthetic contours for a given image-segmentation pair. One thousand two hundred twenty-four unfiltered/filtered radiomic features were extracted applying Pyradiomics, followed by stability assessment using ICC(1,1). Stable features identified in the internal population were then compared with an external population to discover and report robust features. Finally, we also investigated the impact of a wide range of filtering strategies on the stability of features. The percentage of unfiltered (filtered) features that remained robust subjected to segmentation variations were T2w-36% (81%), ADC-36% (94%), and SUB-43% (93%). Our findings suggest that segmentation variations can significantly impact radiomic feature stability but can be mitigated by including pre-filtering strategies as part of the feature extraction pipeline.
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BACKGROUND AND PURPOSE: Up to a quarter of breast cancer patients treated by surgery and radiotherapy experience clinically significant toxicity. If patients at high risk of adverse effects could be identified at diagnosis, their treatment could be tailored accordingly. This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity two years following whole breast radiotherapy. MATERIALS AND METHODS: A genome-wide association study (GWAS) was performed in 1,640 breast cancer patients with complete SNP, clinical, treatment and toxicity data, recruited across 18 European and US centres into the prospective REQUITE cohort study. Toxicity data (CTCAE v4.0) were collected at baseline, end of radiotherapy, and annual follow-up. A total of 7,097,340 SNPs were tested for association with the residuals of toxicity endpoints, adjusted for clinical, treatment co-variates and population substructure. RESULTS: Quantile-quantile plots showed more associations with toxicity above the p < 5 × 10-5 level than expected by chance. Eight SNPs reached genome-wide significance. Nipple retraction grade ≥ 2 was associated with the rs188287402 variant (p = 2.80 × 10-8), breast oedema grade ≥ 2 with rs12657177 (p = 1.12 × 10-10), rs75912034 (p = 1.12 × 10-10), rs145328458 (p = 1.06 × 10-9) and rs61966612 (p = 1.23 × 10-9), induration grade ≥ 2 with rs77311050 (p = 2.54 × 10-8) and rs34063419 (p = 1.21 × 10-8), and arm lymphoedema grade ≥ 1 with rs643644 (p = 3.54 × 10-8). Heritability estimates across significant endpoints ranged from 25% to 39%. Our study did not replicate previously reported SNPs associated with breast radiation toxicity at the pre-specified significance level. CONCLUSIONS: This GWAS for long-term breast radiation toxicity provides further evidence for significant association of common SNPs with distinct toxicity endpoints.
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Neoplasias de la Mama , Traumatismos por Radiación , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/radioterapia , Estudio de Asociación del Genoma Completo , Estudios de Cohortes , Estudios Prospectivos , Polimorfismo de Nucleótido SimpleRESUMEN
Fatigue is common in breast-cancer survivors. Our study assessed fatigue longitudinally in breast cancer patients receiving adjuvant radiotherapy (RT) and aimed to identify risk factors associated with long-term fatigue and underlying fatigue trajectories. Fatigue was measured in a prospective multicenter cohort (REQUITE) using the Multidimensional Fatigue Inventory (MFI-20) and analyzed using mixed models. Multivariable logistic models identified factors associated with fatigue dimensions at 2 years post-RT and latent class growth analysis identified individual fatigue trajectories. A total of 1443, 1302, 1203 and 1098 patients completed the MFI-20 at baseline, end of RT, after 1 and 2 years. Overall, levels of fatigue significantly increased from baseline to end of RT for all fatigue dimensions (P < .05) and returned to baseline levels after 2 years. A quarter of patients were assigned to latent trajectory high (23.7%) and moderate (24.8%) fatigue classes, while 46.3% and 5.2% to the low and decreasing fatigue classes, respectively. Factors associated with multiple fatigue dimensions at 2 years include age, BMI, global health status, insomnia, pain, dyspnea and depression. Fatigue present at baseline was consistently associated with all five MFI-20 fatigue dimensions (ORGeneralFatigue = 3.81, P < .001). From latent trajectory analysis, patients with a combination of factors such as pain, insomnia, depression, younger age and endocrine therapy had a particularly high risk of developing early and persistent high fatigue years after treatment. Our results confirmed the multidimensional nature of fatigue and will help clinicians identify breast cancer patients at higher risk of having persistent/late fatigue so that tailored interventions can be delivered.