Abstract Purpose: The aim of this work was to determine how the spatial pattern of dose in the ano-rectal wall is related to late gastro-intestinal toxicity for prostate cancer patients treated with mainly IMRT. Patients and methods: Patients from the DUE-01 multicentre study with patient-reported (prospective) follow-up and available dosimetric data were included. Conventionally fractionated patients received 74–80 Gy and hypofractionated patients received 65–75.2 Gy. A large majority of the patients were treated with intensity-modulated radiotherapy (IMRT). Dose-surface maps (DSMs) for the anal canal and rectum as a single structure, and for the anal canal and the rectum separately, were co-registered rigidly in two dimensions and, for the patients with and without toxicity, respectively, the mean value of the dose in each pixel was calculated. A pixel-wise t-test was used to highlight the anatomical areas where there was a significant difference between the ‘mean dose maps’ of each group. Univariate models were also fitted to a range of spatial parameters. The endpoints considered were a mean grade ≥1 late fecal incontinence and a maximum grade ≥2 late rectal bleeding. Results: Twenty-six out of 213 patients had fecal incontinence, while 21/225 patients had rectal bleeding. Incontinence was associated with a higher dose in the caudal region of the anal canal; the most relevant spatial parameter was the lateral extent of the low and medium isodoses (5–49 Gy in EQD2). Bleeding was associated with high isodoses reaching the posterior rectal wall. The spatial dose parameters with the highest AUC value (.69) were the lateral extent of the 60–70 Gy isodoses. Conclusions: To avoid fecal incontinence it is important to limit the portion of the anal canal irradiated. Our analysis confirms that rectal bleeding is a function of similar spatial dose parameters for patients treated with IMRT, compared to previous studies on patients treated with three-dimensional conformal radiotherapy.

Purpose: This study aimed to validate a previously published predictive model for late fecal incontinence (FI) in a contemporary population of prostate cancer patients treated with radical radiation therapy. Methods and Materials: The validation included patients treated with intensity-modulated radiation therapy (IMRT) (2010-2014). Prescribed dose range was 6580 Gy, including conventional and moderate hypo-fractionated treatments. Rectal toxicity was scored using LENT/SOMA, a minimum 2-year follow up was considered. We chose to validate the model published by Rancati et al for predicting chronic FI, developed on a 3-dimensional conformal radiation therapy (3DCRT) population. It considered a longitudinal endpoint defined as the average toxicity grade during the follow up. This continuous endpoint was dichotomized using a cut-off value of mean FI grade > 1. The model included mean rectal dose (Dmean), previous diseases of the colon (COLO) and previous abdominal surgery (SURG). Doses were corrected to 2 Gy/fraction using the linear-quadratic model and applying alpha/beta ratio = 4.8 Gy. Results: 228 patients constituted the validation population. A mean FI grade > 1 was scored in 25 patients (11%). Logistic regression confirmed risk factors reported in the literature, with similar odds ratios (ORs) for Dmean (1.04 +/- 0.03 vs 1.06 +/- 0.04) and SURG (1.9 +/- 1.7 vs 1.6 +/- 1.45); COLO was not confirmed. Consequently, the predictive models including Dmean/Dmean + SURG were evaluated using calibration plots. Both showed a clear discriminative trend, but the absolute observed toxicity rates were underestimated (ie, absolute predicted rates were always lower than corresponding absolute observed rates). This result was consistent with an unexpected effect of hypofractionation (OR=2.20, conventional=8.1% vs hypofractionated = 17.4%) beyond the standard correction using linear-quadratic model. Nevertheless, the FI rate in the conventionally treated group was almost double the rate observed in the previously studied cohort (4.3% vs 8.1%). Conclusions: The study confirms previously published results indicating that abdominal surgery and rectal mean dose are risk factors for late FI. Calibration plots highlight a possible role of hypofractionation beyond linear-quadratic correction. (C) 2018 Elsevier Inc. All rights reserved.

CONTEXT:C-cyanomethanimine (HNCHCN), existing in the two Z and E isomeric forms, is a key prebiotic molecule, but, so far, only the E isomer has been detected toward the massive star-forming region. Sagittarius B2(N) using transitions in the radio wavelength domain. AIMS:With the aim of detecting HNCHCN in Sun-like-star forming regions, the laboratory investigation of its rotational spectrum has been extended to the millimeter-/submillimeter-wave (mm-/submm-) spectral window in which several unbiased spectral surveys have been already carried out. METHODS:High-resolution laboratory measurements of the rotational spectrum of C-cyanomethanimine were carried out in the 100-420 GHz range using a frequency-modulation absorption spectrometer. We then searched for the C-cyanomethanimine spectral features in the mm-wave range using the high-sensitivity and unbiased spectral surveys obtained with the IRAM 30-m antenna in the ASAI context, the earliest stages of star formation from starless to evolved Class I objects being sampled. RESULTS:For both the Z and E isomers, the spectroscopic work has led to an improved and extended knowledge of the spectroscopic parameters, thus providing accurate predictions of the rotational signatures up to ~700 GHz. So far, no C-cyanomethanimine emission has been detected toward the ASAI targets, and upper limits of the column density of ~ 1011-1012 cm-2 could only be derived. Consequently, the C-cyanomethanimine abundances have to be less than a few 10-10 for starless and hot-corinos. A less stringent constraint, ≤ 10-9, is obtained for shocks sites. CONCLUSIONS:The combination of the upper limits of the abundances of C-cyanomethanimine together with accurate laboratory frequencies up to ~ 700 GHz poses the basis for future higher sensitivity searches around Sun-like-star forming regions. For compact (typically less than 1″) and chemically enriched sources such as hot-corinos, the use of interferometers as NOEMA and ALMA in their extended configurations are clearly needed.

Purpose To develop a modelling procedure for late rectal bleeding (LRB) that goes beyond maximum likelihood model fitting of data. Thus, to create a metamodel for grade 2–3 (G23) and grade 3 (G3) LRB starting from literature evidence and validate it on a large population. Methods Metamodelling allows to highlight specific features of the model itself. Characteristics that predictive models for LRB have in common are: the global harmony of radiobiological parameters (volume effect parameter, n, steepness of the curve, k, and dose parameter associated to 50% of complication probability, D50) and specific clinical factors that frequently occur. Models including rectal Equivalent Uniform Dose (EUD) with/without patient-related dose-modifying factors (DMF) were retrieved by literature search. Dosimetric coefficients were resolved by weighted mean of published values, using their standard deviation as weight. Identified clinical features, expressed by DMF, were differently weighted taking into account the prevalence of the features and the size of the study. Finally, both factors were inserted in a modified logit-EUD model. Metamodel was validated on a pooled population (3DCRT/IMRT) of three international cohorts. Performance was assessed through calibration. Results Literature search identified rectal EUD, previous abdominal surgery, hormone therapy and use of cardiovascular drugs as relevant features: associated coefficients are presented in Table 1. Validation cohort included 1591 pts with 240 (15%) LRBG23 and 98 (6.2%) LRBG3 pts. The calibration (Fig. 1) showed the following results: concerning LRBG23 the slope was equal to 0.22 (R2 = 0.38); the corresponding values for LRBG3 were 1.12 and 0.97. Conclusions A metamodel for prediction of LRB was derived from literature. LRBG3 model was successfully validated on a large population proving to be a valuable tool for predicting toxicity before RT. The model for LRBG23 predicted very well toxicity rate below 25% (which involved 87% of the population) while partially failing at higher probabilities. To develop a modelling procedure for late rectal bleeding (LRB) that goes beyond maximum likelihood model fitting of data. Thus, to create a metamodel for grade 2–3 (G23) and grade 3 (G3) LRB starting from literature evidence and validate it on a large population. Metamodelling allows to highlight specific features of the model itself. Characteristics that predictive models for LRB have in common are: the global harmony of radiobiological parameters (volume effect parameter, n, steepness of the curve, k, and dose parameter associated to 50% of complication probability, D50) and specific clinical factors that frequently occur. Models including rectal Equivalent Uniform Dose (EUD) with/without patient-related dose-modifying factors (DMF) were retrieved by literature search. Dosimetric coefficients were resolved by weighted mean of published values, using their standard deviation as weight. Identified clinical features, expressed by DMF, were differently weighted taking into account the prevalence of the features and the size of the study. Finally, both factors were inserted in a modified logit-EUD model. Metamodel was validated on a pooled population (3DCRT/IMRT) of three international cohorts. Performance was assessed through calibration. Literature search identified rectal EUD, previous abdominal surgery, hormone therapy and use of cardiovascular drugs as relevant features: associated coefficients are presented in Table 1. Validation cohort included 1591 pts with 240 (15%) LRBG23 and 98 (6.2%) LRBG3 pts. The calibration (Fig. 1) showed the following results: concerning LRBG23 the slope was equal to 0.22 (R2 = 0.38); the corresponding values for LRBG3 were 1.12 and 0.97. A metamodel for prediction of LRB was derived from literature. LRBG3 model was successfully validated on a large population proving to be a valuable tool for predicting toxicity before RT. The model for LRBG23 predicted very well toxicity rate below 25% (which involved 87% of the population) while partially failing at higher probabilities.

61 Background: Predictive models for late rectal bleeding (LRB) after radiotherapy (RT) for prostate cancer were established by several studies, with good performance on development population (POP). Nonetheless, they were found to be unsatisfactory in their generalization to independent validation cohorts. Aim of the study is to build a metamodel for grade 2-3 (G23) and grade 3 (G3) LRB (LENT/SOMA) starting from literature evidence and to validate it on a new POP. Methods: The metamodel was constituted by clinical/dosimetric features and by their coefficients. Available predictive models for LRB were selected by literature search. Models including rectal Equivalent Uniform Dose (EUD) with/without patient-related dose-modifying factors were retrieved. The process allowed identification of “evidence-based” clinical/dosimetric features associated to LRB. Coeff. for identified features were resolved by weighted mean of published values, using their standard deviation as weight and then inserted in a sigmoid-shaped logit-EUD model. The resulting metamodel was validated on a pooled POP of radically treated pts (3DCRT & IMRT). Performance was assessed through calibration. Results: The search identified rectal EUD, previous abdominal surgery (SURG), hormone therapy (HT) and use of cardiovascular drugs (CARDIO) as relevant features (coeff. presented in table). Validation POP included 1591 pts with 240 (15%) LRBG23 and 98 (6.2%) LRBG3 pts. Calibration was very good: LRBG23 slope = 1.4 with R2 = 0.86; LRBG3 slope = 1.1 with R2 = 0.96. Conclusions: A metamodel for prediction of LRB has been developed from literature, including all currently available information on association between LRB and clinical/dosimetric factors. The model was successfully validated on a large POP, proving to be a valuable tool for predicting LRB before RT. [Table: see text]

Purpose: This study was designed to apply artificial neural network (ANN) classification methods for the prediction of late fecal incontinence (LFI) after high-dose prostate cancer radiation therapy and to develop a ready-to-use graphical tool. Materials and Methods: In this study, 598 men recruited in 2 national multicenter trials were analyzed. Information was recorded on comorbidity, previous abdominal surgery, use of drugs, and dose distribution. Fecal incontinence was prospectively evaluated through self-reported questionnaires. To develop the ANN, the study population was randomly split into training (n = 300), validation (n = 149), and test (n = 149) sets. Mean grade of longitudinal LFI (ie, expressed as the average incontinence grade over the first 3 years after radiation therapy) >= 1 was considered the endpoint. A suitable subset of variables able to better predict LFI was selected by simulating 100,000 ANN configurations. The search for the definitive ANN was then performed by varying the number of inputs and hidden neurons from 4 to 5 and from 1 to 9, respectively. A final classification model was established as the average of the best 5 among 500 ANNs with the same architecture. An ANN-based graphical method to compute LFI prediction was developed to include one continuous and n dichotomous variables. Results: An ANN architecture was selected, with 5 input variables (mean dose, previous abdominal surgery, use of anticoagulants, use of antihypertensive drugs, and use of neoadjuvant and adjuvant hormone therapy) and 4 hidden neurons. The developed classification model correctly identified patients with LFI with 80.8% sensitivity and 63.7% +/- 1.0% specificity and an area under the curve of 0.78. The developed graphical tool may efficiently classify patients in low, intermediate, and high LFI risk classes. Conclusions: An ANN-based model was developed to predict LFI. The model was translated in a ready-to-use graphical tool for LFI risk classification, with direct interpretation of the role of the predictors. (C) 2018 Elsevier Inc. All rights reserved.

Context.To date, several complex organic molecules have been detected in the interstellar medium, and they have been suggested as precursors of biologically important species. Propargylamine (HC ≡C−CH2−NH2) is structurally similar to a number of other organic molecules which have already been identified by radioastronomy, making it a good candidate for astrophysical detection.Aims.This work provides accurate rest frequencies of propargylamine, from the centimeter-wave to the submillimeter-wave region, useful to facilitate the detection of this molecule in the interstellar medium.Methods.An extensive laboratory study of the rotational spectrum of propargylamine has been performed using a pulsed-jet Fourier Transform Microwave (FTMW) spectrometer (7–19 GHz frequency range) and a frequency modulation microwave spectrometer (75–560 GHz). Several hundred rotational transitions of propargylamine were recorded in the ground and three lowest excited vibrational states. The experiments were supported by high-level ab initio computations, mainly employed to characterize the vibrational state structure and to predict spectroscopic parameters unknown prior to this study.Results.The measured transition frequencies yielded accurate rotational constants and the complete sets of quartic and sextic centrifugal distortion constants for propargylamine in its vibrational ground state.14N-nuclear quadrupole coupling constants were also determined. Rotational and quartic centrifugal distortion constants were also obtained for the low-lying excited statesv13= 1 (A′),v20= 1 (A″), andv21= 1 (A″). Thea-type Coriolis resonance which couples thev13= 1 andv21= 1 levels was analyzed.Conclusions.The determined spectroscopic constants allowed for the compilation of a dataset of highly accurate rest frequencies for astrophysical purposes in the millimeter and submillimeter regions with 1σuncertainties that are smaller than 0.050 MHz, corresponding to 0.03 km s−1at 500 GHz in radial equivalent velocity.

S169 ESTRO 37(Median R 2 : 0.94 (range: 0.80-1.00); Figure left).The Identified COMTDVHs (EQD2 (%Vol)) for these symptoms emphasized dose-response relationships both within the low-intermediate, and within the high-dose region (DU: 30(55), 62(25); DI: (28(72), 54(42)); FI: 21(76), 56(32), P: 32(67), 63(24); RB 44(46), 62(32), 70(10)).For BT, DVH thresholds were primarily identified for GI toxicity (Nthresholds GI/GU/SD: 14/4/2), but quantitative synthesis was only possible for RB (R 2 : 0.93; COMTDVH: 103(5); Figure right). ConclusionOverall Rectal bleeding remains the most studied symptom after prostate cancer EBRT and BT, but novel tolerance doses since the Emami paper/QUANTEC reports were found for 17 additional distinct GI, GU, and SD symptoms.Quantitative synthesis was possible for Defecation urgency, Diarrhea, Fecal incontinence, Proctitis, and Rectal bleeding, and suggested coherence between identified DVH thresholds in both the lowintermediate (EQD2: ≤41Gy) and the high-dose region (EQD2: ≥54Gy).Continuous collection of dose-response data for all investigated symptoms is still needed to fully acknowledge the causality of both treatment-and patient-related characteristics on a certain symptom.To accelerate this process, researchers are encouraged to harmonize reporting of tolerance doses and to participate in data sharing initiatives.

Purpose Development of NTCP models of late severe urinary symptoms after radical RT for prostate cancer (PCa). Methods Patients were enrolled in a prospective, multicentre, observational trial in 2010–2014 and treated with conventional (74–80 Gy at 1.8–2 Gy/fr) or moderately hypofractionated IMRT (65–75.2 Gy at 2.2–2.7 Gy/fr). Bladder dose-surface histograms were corrected to 2 Gy/fr equivalent doses (EQD2) and reduced to Equivalent Uniform Doses at varying α / β and n. Urethral stricture requiring urethrotomy and bleeding (assessed by the physicians) and late obstructive symptoms and incontinence (through ICIQ and IPSS questionnaires) were evaluated before RT, at its completion and every 6 months until 5 years of follow-up. Incidence of late obstructive symptoms was defined as an increase of ⩾10 points with respect to baseline in the IPSS, at least once between 6–36 months after RT; incidence of incontinence as the sum ICIQ3 + ICIQ4 > 5, with the same timing, in continent patients before RT (ICIQ3 + ICIQ4 = 0). Maximum likelihood estimation (MLE) was employed for calculating the best-fit NTCP parameters (EUD50 and k) of all symptoms. Results 319 patients were followed for ⩾36 months with at least 3 follow-up evaluations. 27/319 (23%) patients exhibited at least one severe late urinary symptom (details in Table). Bleeding, obstructive symptoms and incontinence showed greater incidence for hypofractionation and EQD2 > 78 Gy. The highest likelihood was obtained for very low n in all cases; low α / β was found for all the endpoints except stricture. Figure shows the best-fit NTCP parameters: incontinence and bleeding curves were steeper with rising EUD. Conclusions Incidence of late severe urinary symptoms in patients treated with IMRT for PCa was about 20%. Bladder seems to act as a serial organ and all the symptoms significantly depend on the prescribed dose. In addition, all the symptoms, except for stenosis, show a surprisingly important effect of hypofractionation. Development of NTCP models of late severe urinary symptoms after radical RT for prostate cancer (PCa). Patients were enrolled in a prospective, multicentre, observational trial in 2010–2014 and treated with conventional (74–80 Gy at 1.8–2 Gy/fr) or moderately hypofractionated IMRT (65–75.2 Gy at 2.2–2.7 Gy/fr). Bladder dose-surface histograms were corrected to 2 Gy/fr equivalent doses (EQD2) and reduced to Equivalent Uniform Doses at varying α / β and n. Urethral stricture requiring urethrotomy and bleeding (assessed by the physicians) and late obstructive symptoms and incontinence (through ICIQ and IPSS questionnaires) were evaluated before RT, at its completion and every 6 months until 5 years of follow-up. Incidence of late obstructive symptoms was defined as an increase of ⩾10 points with respect to baseline in the IPSS, at least once between 6–36 months after RT; incidence of incontinence as the sum ICIQ3 + ICIQ4 > 5, with the same timing, in continent patients before RT (ICIQ3 + ICIQ4 = 0). Maximum likelihood estimation (MLE) was employed for calculating the best-fit NTCP parameters (EUD50 and k) of all symptoms. 319 patients were followed for ⩾36 months with at least 3 follow-up evaluations. 27/319 (23%) patients exhibited at least one severe late urinary symptom (details in Table). Bleeding, obstructive symptoms and incontinence showed greater incidence for hypofractionation and EQD2 > 78 Gy. The highest likelihood was obtained for very low n in all cases; low α / β was found for all the endpoints except stricture. Figure shows the best-fit NTCP parameters: incontinence and bleeding curves were steeper with rising EUD. Incidence of late severe urinary symptoms in patients treated with IMRT for PCa was about 20%. Bladder seems to act as a serial organ and all the symptoms significantly depend on the prescribed dose. In addition, all the symptoms, except for stenosis, show a surprisingly important effect of hypofractionation.

To evaluate the incidence of late severe urinary symptoms after radical radiation therapy (RRT) for prostate cancer (PCa) and to fit a Normal Tissue Complication Probability (NTCP) model for predicting these symptoms. Patients were enrolled in a prospective, multicenter, observational trial in 2010-2014 and treated with conventional (74-80 Gy at 1.8-2 Gy/fr) or moderately hypofractionated IMRT (65-75.2 Gy at 2.2-2.7 Gy/fr) in 5 fr/week. Bladder dose-volume histograms were corrected to 2 Gy/fr equivalent doses (EQD2) and reduced to Equivalent Uniform Doses (EUD), computed at varying α/β and n (volume parameter summarizing the organ architecture). Four severe radiation-induced toxicities were considered: urethral stricture requiring urethrotomy and bleeding assessed by the physicians, and late obstructive symptoms and incontinence, patient-reported through the ICIQ-SF and IPSS questionnaires. They were evaluated before RRT and at its completion, thereafter every 6 months until 5 years of follow-up. Incidence of late obstructive symptoms was defined as an increase of ≥10 points with respect to baseline in the IPSS score, occurring at least once between 6 and 36 months after RRT. Incidence of incontinence was defined as a sum of the ICIQ3+ICIQ4 scores >5, with the same timing, in patients without symptoms before RRT (ICIQ3+ICIQ4 = 0). Primary endpoint was the incidence of at least one out of the four symptoms above. Maximum likelihood estimation (MLE) was employed for calculating the best-fit NTCP parameters: EUD50 (EUD at 50% of toxicity risk) and k (NTCP steepness). Two hundred fifty-nine patients were followed for ≥36 months and had at least 3 follow-up evaluations. Overall, 51/259 (20%) patients exhibited a severe urinary symptom: 22/138 (16%) in the conventional cohort and 29/118 (25%) in the hypofractionated one. In detail, 17/259 (7%) experienced urinary bleeding, 5/259 (2%) urethral stricture requiring urethrotomy, 29/258 (11%) late obstructive symptoms and 13/212 (6%) late incontinence. The highest likelihoods were obtained for low α/β and n values. For α/β = 1 Gy and n = 0.01 the best-fit NTCP steepness parameter was k = 4.5±2.1, while EUD50 was 108±15 Gy. Thus resulting in ≈5% toxicity increases every 5 Gy in bladder EUD. The model had high calibration: slope = 0.99, R2 = 0.94. The incidence of radio-induced severe urinary symptoms in a population of patients treated with modern RRT for PCa resulted to be ≈20%. According to NTCP modeling, bladder acts as a serial organ, with urinary toxicity risk depending on small bladder volumes receiving high doses. Furthermore, α/β was found very low, highlighting a hypofractionation effect greater than previously believed.Abstract 359; Table 1Equivalent Uniform Dose (α/β = 1 Gy, n = 0.01) [Gy]Predicted toxicity rate (k = 4.5, EUD50 = 108 Gy) [%]Observed toxicity rate [%]7315.012.7 ± 2.47717.519.0 ± 4.98020.720.3 ± 5.08828.228.1 ± 5.6 Open table in a new tab

Pros-IT CNR study provides a real-life report on changes in quality of life 6 mo after the diagnosis of prostate cancer.