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Background: Epithelial tumors of lacrimal glands are rare and primary ductal adenocarcinoma of the lacrimal gland accounts for only 2% of all epithelial lacrimal gland tumors. Considering its rarity and lack of uniform diagnostic criteria, treatment protocols are not well defined. In this study, we describe a Her-2 positive case and review previously reported cases. Methods: In 2012, a 42-year-old woman affected by primary ductal adenocarcinoma of the lacrimal gland was treated with transpalpebral anterior orbitotomy and adjuvant radiotherapy. In July 2013, she presented local relapse and she underwent orbital exenteration. In November 2013, for neck nodal progression, seven cycles of chemotherapy (cisplatin and epirubicin) associated with a humanized monoclonal antibody-targeting HER 2 therapy (trastuzumab and pertuzumab) were performed, with a marked response rate. Then, she underwent total parotidectomy with right neck lymphadenectomy and adjuvant hadrontherapy. Results: Nine years later (113 months) after treatment completion, the patient was alive without disease and with acceptable toxicity. Conclusions: In primary ductal adenocarcinoma of the lacrimal gland, early diagnosis and multimodal treatments could be crucial, considering its often aggressive tendency. Considering the lack of treatment guidelines, case report recording can be useful in patient management., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 C. L. Deantoni et al.)

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 5 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 (n = 1066). Patients were treated with tangential-field RT, delivering 40 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 G ≥ 2) developed within 42 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 G2 + rate was 3.8 %, 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, OR = 7.3), Aromatase Inhibitors (as a protective factor with OR = 0.45), V20 Gy (50 % of the prescribed dose, OR = 1.02), and V42 Gy (105 %, OR = 1.09). Factors were also converted into an adjusted V20Gy., Conclusions: The association between late reactions and skin DVH when delivering 40 Gy/15 fr was quantified, suggesting an independent role of V20 and V42. Few clinical factors heavily modulate the risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To report long-term outcomes of relapsed prostate cancer (PC) patients treated in a prospective single-arm study with extended-nodal radiotherapy (ENRT) and [11C]-choline positron emission tomography (PET)/computed tomography (CT)-guided simultaneous integrated boost (SIB) to positive lymph nodes (LNs)., Methods: From 12/2009 to 04/2015, 60 PC patients with biochemical relapse and positive LNs only were treated in this study. ENRT at a median total dose (TD) = 51.8 Gy/28 fr and PET/CT-guided SIB to positive LNs at a median TD = 65.5 Gy was prescribed. Median PSA at relapse was 2.3 (interquartile range, IQR:1.3-4.0) ng/ml. Median number of positive LNs: 2 (range: 1-18). Androgen deprivation therapy (ADT) was prescribed for 48 patients for a median of 30.7 (IQR: 18.5-43.1) months., Results: Median follow-up from the end of salvage treatment was 121.8 (IQR: 116.1, 130.9) months; 3-, 5-, and 10-year BRFS were 45.0%, 36.0%, and 24.0%, respectively; DMFS: 67.9%, 57.2%, and 45.2%; CRFS: 62.9%, 53.9%, and 42.0%; and OS: 88.2%, 76.3%, and 47.9%, respectively. Castration resistance (p < 0.0001) and ≥ 6 positive LN (p = 0.0024) significantly influenced OS at multivariate analysis. Castration resistance (p < 0.0001 for both) influenced DMFS and CRFS in multivariate analysis., Conclusions: In PC relapsed patients treated with ENRT and [11C]-choline-PET/CT-guided SIB for positive LNs, with 10-year follow-up, a median Kaplan-Meier estimate CRFS of 67 months and OS of 110 months were obtained. These highly favorable results should be confirmed in a prospective, randomized trial., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: Radiation-induced oral mucositis (RIOM) is the most frequent side effect in head and neck cancer (HNC) patients treated with curative radiotherapy (RT). A standardized strategy for preventing and treating RIOM has not been defined. Aim of this study was to perform a real-life survey on RIOM management among Italian RT centers., Methods: A 40-question survey was administered to 25 radiation oncologists working in 25 different RT centers across Italy., Results: A total of 1554 HNC patients have been treated in the participating centers in 2021, the majority (median across the centers 91%) with curative intent. Median treatment time was 41 days, with a mean percentage of interruption due to toxicity of 14.5%. Eighty percent of responders provide written oral cavity hygiene recommendations. Regarding RIOM prevention, sodium bicarbonate mouthwashes, oral mucosa barrier agents, and hyaluronic acid-based mouthwashes were the most frequent topic agents used. Regarding RIOM treatment, 14 (56%) centers relied on literature evidence, while internal guidelines were available in 13 centers (44%). Grade (G)1 mucositis is mostly treated with sodium bicarbonate mouthwashes, oral mucosa barrier agents, and steroids, while hyaluronic acid-based agents, local anesthetics, and benzydamine were the most used in mucositis G2/G3. Steroids, painkillers, and anti-inflammatory drugs were the most frequent systemic agents used independently from the RIOM severity., Conclusion: Great variety of strategies exist among Italian centers in RIOM management for HNC patients. Whether different strategies could impact patients' compliance and overall treatment time of the radiation course is still unclear and needs further investigation., (© 2023. The Author(s).)

Background and Purpose: Artificial Intelligence (AI)-based auto-contouring for treatment planning in radiotherapy needs extensive clinical validation, including the impact of editing after automatic segmentation. The aims of this study were to assess the performance of a commercial system for Clinical Target Volumes (CTVs) (prostate/seminal vesicles) and selected Organs at Risk (OARs) (rectum/bladder/femoral heads + femurs), evaluating also inter-observer variability (manual vs automatic + editing) and the reduction of contouring time., Materials and Methods: Two expert observers contoured CTVs/OARs of 20 patients in our Treatment Planning System (TPS). Computed Tomography (CT) images were sent to the automatic contouring workstation: automatic contours were generated and sent back to TPS, where observers could edit them if necessary. Inter- and intra-observer consistency was estimated using Dice Similarity Coefficients (DSC). Radiation oncologists were also asked to score the quality of automatic contours, ranging from 1 (complete re-contouring) to 5 (no editing). Contouring times (manual vs automatic + edit) were compared., Results: DSCs (manual vs automatic only) were consistent with inter-observer variability (between 0.65 for seminal vesicles and 0.94 for bladder); editing further improved performances (range: 0.76-0.94). The median clinical score was 4 (little editing) and it was <4 in 3/2 patients for the two observers respectively. Inter-observer variability of automatic + editing contours improved significantly, being lower than manual contouring (e.g.: seminal vesicles: 0.83vs0.73; prostate: 0.86vs0.83; rectum: 0.96vs0.81). Oncologist contouring time reduced from 17 to 24 min of manual contouring time to 3-7 min of editing time for the two observers (p < 0.01)., Conclusion: Automatic contouring with a commercial AI-based system followed by editing can replace manual contouring, resulting in significantly reduced time for segmentation and better consistency between operators., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Purpose: To extend the knowledge-based (KB) automatic planning approach to CyberKnife in the case of Stereotactic Body Radiation Therapy (SBRT) for prostate cancer., Methods: Seventy-two clinical plans of patients treated according to the RTOG0938 protocol (36.25 Gy/5fr) with CyberKnife were exported from the CyberKnife system to Eclipse to train a KB-model using the Rapid Plan tool. The KB approach provided dose-volume objectives for specific OARs only and not PTV. Bladder, rectum and femoral heads were considered in the model. The KB-model was successfully trained on 51 plans and then validated on 20 new patients. A KB-based template was tuned in the Precision system for both sequential optimization (SO) and VOLO optimization algorithms. Plans of the validation group were re-optimized (KB-TP) using both algorithms without any operator intervention and compared against the original plans (TP) in terms of OARs/PTV dose-volume parameters. Paired Wilcoxon signed-rank tests were performed to assess statistically significant differences (p < 0.05)., Results: Regarding SO, automatic KB-TP plans were generally better than or equivalent to TP plans. PTVs V95% was slightly worse while OARs sparing for KB-TP was significantly improved. Regarding VOLO optimization, the PTVs coverage was significantly better for KB-TP while there was a limited worsening in the rectum. A significant improvement was observed in the bladder in the range of low-intermediate doses., Conclusions: An extension of the KB optimization approach to the CyberKnife system has been successfully developed and validated in the case of SBRT prostate cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Purpose/objective: The purpose of the study is to externally validate published 18 F-FDG-PET radiomic models for outcome prediction in patients with oropharyngeal cancer treated with chemoradiotherapy., Material/methods: Outcome data and pre-radiotherapy PET images of 100 oropharyngeal cancer patients (stage IV:78) treated with concomitant chemotherapy to 66-69 Gy/30 fr were available. Tumors were segmented using a previously validated semi-automatic method; 450 radiomic features (RF) were extracted according to IBSI (Image Biomarker Standardization Initiative) guidelines. Only one model for cancer-specific survival (CSS) prediction was suitable to be independently tested, according to our criteria. This model, in addition to HPV status, SUVmean and SUVmax, included two independent meta-factors (F i ), resulting from combining selected RF clusters. In a subgroup of 66 patients with complete HPV information, the global risk score R was computed considering the original coefficients and was tested by Cox regression as predictive of CSS. Independently, only the radiomic risk score R F derived from F i was tested on the same subgroup to learn about the radiomics contribution to the model. The metabolic tumor volume (MTV) was also tested as a single predictor and its prediction performances were compared to the global and radiomic models. Finally, the validation of MTV and the radiomic score R F were also tested on the entire dataset., Results: Regarding the analysis of the subgroup with HPV information, with a median follow-up of 41.6 months, seven patients died due to cancer. R was confirmed to be associated to CSS (p value = 0.05) with a C-index equal 0.75 (95% CI=0.62-0.85). The best cut-off value (equal to 0.15) showed high ability in patient stratification (p=0.01, HR=7.4, 95% CI=1.6-11.4). The 5-year CSS for R were 97% (95% CI: 93-100%) vs 74% (56-92%) for low- and high-risk groups, respectively. R F and MTV alone were also significantly associated to CSS for the subgroup with an almost identical C-index. According to best cut-off value (R F >0.12 and MTV>15.5cc), the 5-year CSS were 96% (95% CI: 89-100%) vs 65% (36-94%) and 97% (95% CI: 88-100%) vs 77% (58-93%) for RF and MTV, respectively. Results regarding RF and MTV were confirmed in the overall group., Conclusion: A previously published PET radiomic model for CSS prediction was independently validated. Performances of the model were similar to the ones of using only the MTV, without improvement of prediction accuracy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: Explainable models of long-term risk of biochemical failure (BF) after post-prostatectomy salvage radiotherapy (SRT) are lacking. A previously introduced radiobiology-based formula was adapted to incorporate the impact of pelvic nodes irradiation (PNI)., Materials and Methods: The risk of post-SRT BF may be expressed by a Poisson-based equation including pre-SRT PSA, the radiosensitivity α, the clonogen density C, the prescribed dose (in terms of EQD2, α/β = 1.5 Gy) and a factor (1-BxλxPSA) accounting for clonogens outside the irradiated volume, being λ the recovery due to PNI. Data of 795 pT2-pT3, pN0/pN1/pNx (n = 627/94/74) patients with follow-up ≥ 5 years and pre-RT PSA ≤ 2 ng/mL were randomly split into training (n = 528) and validation (n = 267) cohorts; the training cohort data were fitted by the least square method. Separate fits were performed for different risk groups. Model performances were assessed by calibration plots and tested in the validation group., Results: The median follow-up was 8.5y, median pre-SRT PSA and EQD2 were 0.43 ng/mL and 71.3 Gy respectively; 331/795 pts received PNI. The most clinically significant prognostic grouping was pT3b and/or ISUP4-5 versus pT2/3a and ISUP1-3. Best-fit parameters were α eff  = 0.26/0.23 Gy -1 , C = 10 7 /10 7 , B = 0.40/0.97, λ = 0.87/0.41 for low/high-risk group. Performances were confirmed in the validation group (slope = 0.89,R 2  = 0.85). Results suggested optimal SRT dose at 70-74 Gy. The estimated reduction of post-SRT BF due to PNI at these dose values was > 5 % for PSA > 1/>0.15 ng/mL for low/high-risk patients, being > 10 % for high-risk patients with pre-SRT PSA > 0.25 ng/mL., Conclusion: An explainable one-size-fits-all equation satisfactorily predicts long-term risk of post-SRT BF. The model was independently validated. A calculator tool was made available., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: To implement knowledge-based (KB) automatic planning for helical TomoTherapy (HTT). The focus of the first clinical implementation was the case of high-risk prostate cancer, including pelvic node irradiation., Methods and Materials: One hundred two HTT clinical plans were selected to train a KB model using the RapidPlan tool incorporated in the Eclipse system (v13.6, Varian Inc). The individually optimized KB-based templates were converted into HTT-like templates and sent automatically to the HTT treatment planning system through scripting. The full dose calculation was set after 300 iterations without any additional planner intervention. Internal (20 patients in the training cohort) and external (28 new patients) validation were performed to assess the performance of the model: Automatic HTT plans (KB-TP) were compared against the original plans (TP) in terms of organs at risk and planning target volume (PTV) dose-volume parameters and by blinded clinical evaluation of 3 expert clinicians., Results: KB-TP plans were generally better than or equivalent to TP plans in both validation cohorts. A significant improvement in PTVs and rectum-PTV overlap dosimetry parameters were observed for both sets. Organ-at-risk sparing for KB-TP was slightly improved, which was more evident in the external validation group and for bladder and bowel. Clinical evaluation reported KB-TP to be better in 60% of cases and worse in 10% compared with TP (P < .05)., Conclusions: The fully KB-based automatic planning workflow was successfully implemented for HTT planning optimization in the case of high-risk patients with prostate cancer., (Copyright © 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Spinal stereotactic body radiotherapy (SBRT) involves large dose gradients and high geometrical accuracy is therefore required. The aim of this work was to assess residual intra-fraction error with a tracking robotic system for non-immobilized patients. Shifts from the first alignment (i.e. mimicking the unavailability of tracking) were also quantified., Materials and Methods: Forty-two patients treated for spinal metastasis (128 fractions, 4220 images) were analyzed. Residual error was quantified as the difference between translations/rotations referring to consecutive x-ray images during delivery (tracking) and to the initial set-up (no-tracking). The error distribution for each fraction/patient and the entire population was assessed for each axis/rotation angle. The impact of lesion sites, fractionation and patient's pain (VAS score) were investigated. Finally, the dosimetric impact of residual motion was quantified in the four most affected fractions., Results: Mean overall errors (OE) were near 0 (SD < 0.1 mm). Residual translations/rotations >1 mm/1° were found in less than 1.5%/1% of measurements. Lesion site and fractionation showed no impact. The dosimetric impact in the most affected fractions was negligible. For "no-tracking", mean OE was <1 mm/0.5°; less than 2% of displacements were >2 mm/1° within 10 min from the start of treatment with an increasing probability of shifts >2 mm over time. A significantly higher fraction of OE ≥ 2 mm was found for patients with pain in case of no-tracking., Conclusions: Spine tracking with a latest-generation robotic system is highly efficient for non-immobilized patients: residual error is time independent and close to 0. For delivery times >7-8 min, tracking should be considered as mandatory for non-immobilized patients., Competing Interests: The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper. The research leading to these results has received funding from 10.13039/501100005010AIRC under IG 2019 – ID. 23150 project – P.I. Fiorino Claudio., (© 2020 The Authors.)

Prostate cancer (PC) is one of the most common leading causes of cancer-related death in men. Currently, the main therapeutic approaches available for PC are based on the androgen deprivation and on radiotherapy. However, despite these treatments being initially effective in cancer remission, several patients undergo recurrence, developing a most aggressive and resistant PC.Emerging evidence showed that abiraterone acetate drug will reduce PC recurrence by a mechanism independent of the inhibition of Cytochrome P450 17α-hydroxylase/17,20-lyase. Here we describe the involvement in the abiraterone-mediated PC cell death of a particular class of bioactive lipids called sphingolipids (SL). Sphingolipids are components of plasma membrane (PM) that organize macromolecular complexes involved in the control of several signaling pathways including the tumor cell death induced by radiotherapy. Here, we show for the first time that both in androgen-sensitive and insensitive PC cells abiraterone and ionizing radiation induce a reorganization of the plasma membrane SL composition. This event is triggered by activation of the PM-associated glycohydrolases that induce the production of cytotoxic ceramide by the in situ hydrolyses of glycosphingolipids. Taken together our data open a new scenario on the SL involvement in the therapy of PC.

Aims: To report 5 year outcome and late toxicity in prostate cancer patients treated with image-guided tomotherapy with a moderate hypofractionated simultaneous integrated boost approach., Materials and Methods: In total, 211 prostate cancer patients, 78 low risk, 53 intermediate risk and 80 high risk were treated between 2005 and 2011. Intermediate- and high-risk patients received 51.8 Gy to pelvic lymph nodes and concomitant simultaneous integrated boost to prostate up to 74.2 Gy/28 fractions, whereas low-risk patients were treated to the prostate only with 71.4 Gy/28 fractions. Daily megavoltage computed tomography (MVCT) image guidance was applied. Androgen deprivation was prescribed for a median duration of 6 months for low-risk patients (for downsizing), 12 months for intermediate-risk and 36 months for high-risk patients. The 5 year biochemical relapse-free survival (bRFS), cancer-specific survival (CSS), overall survival and late gastrointestinal and genitourinary CTCAE.v3 toxicity were assessed. The effect of several clinical variables on both outcome and gastrointestinal/genitourinary toxicity was tested by uni- and multivariate Cox regression analyses., Results: After a median follow-up of 5 years, the late toxicity actuarial incidence was: genitourinary ≥ grade 2: 20.2%; genitourinary ≥ grade 3: 5.9%; gastrointestinal ≥ grade 2: 17%; gastrointestinal ≥ grade 3: 6.3% with lower prevalence at the last follow-up visit (≥ grade 3: genitourinary: 1.9%; gastrointestinal: 1.9%). Major predictors of ≥ grade 3 genitourinary and gastrointestinal late toxicity were genitourinary acute toxicity ≥ grade 2 (hazard ratio: 4.9) and previous surgery (hazard ratio: 3.4). The overall 5 year bRFS was 93.7% (low risk: 94.6%; intermediate risk: 96.2%; high risk: 91.1%), overall survival and CSS were 88.6% (low risk: 90.5%; intermediate risk: 87.4%; high risk: 87%) and 97.5% (low risk: 98.7%; intermediate risk: 95%; high risk: 94.3%), respectively. Risk classes and androgen deprivation were not significantly correlated with either bRFS, overall survival or CSS. Twelve patients experienced a biochemical relapse but none experienced clinically proven local and/or pelvic recurrence., Conclusion: A satisfactory 5 year outcome with an acceptable toxicity profile was observed. The combination of image-guided radiotherapy-intensity-modulated radiotherapy, high equivalent 2 Gy dose (EQD2) with a moderate hypofractionated approach and extensive prophylactic lymph node irradiation also leads to very good outcome in high-risk patients., (Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Dose escalation and hypofractionation may have a role in postprostatectomy radiotherapy (RT), but at the risk of increasing urinary toxicity., Objective: To address predictors of severe (Grade ≥3) late urinary toxicities (LGUTOX3) after postoperative irradiation., Design, Setting, and Participants: A single-institution cohort of 1176 patients treated between 1993 and 2010 with adjuvant or salvage RT was analyzed. A total of 929 patients underwent conventionally fractionated (CF) RT (1.8 Gy per fraction; median dose to the prostatic bed: 70.2 Gy) with nonconformal RT (n=169), three-dimensional conformal RT (n=657), or intensity-modulated RT (n=103) technique, while 247 patients received hypofractionated helical TomoTherapy (median: 2.50 Gy per fraction) at the following doses: 117 patients at 65.8 Gy (2.35 Gy in 28 fractions), 80 patients at a median of 71.4 Gy (2.5-2.6 Gy in 28 fractions), and 50 patients at 58 Gy in 20 fractions. Total doses were converted into 2 Gy-equivalent doses (EQD2) following the linear quadratic model taking α/β=5., Outcome Measurements and Statistical Analysis: Univariable and multivariable Cox regression models tested the relationship between clinicodosimetric variables and the risk of LGUTOX3 retrospectively, graded according to Common Terminology Criteria for Adverse Events v.4.0., Results and Limitations: After a median follow-up of 98 mo, the 5-yr risk of LGUTOX3 was 6.9% and 18.1% in the CF and hypofractionated cohorts, respectively. At univariable analysis, the risk of LGUTOX3 was predicted by dose per fraction (hazard ratio [HR]: 2.96), acute Grade ≥2 toxicity (HR: 2.37), EQD2, pT4, and year of irradiation. At multivariable analyses, acute Grade ≥2 toxicity and dose per fraction independently predicted LGUTOX3 in the population, while an interaction analysis indicated a predictive role of hypertension in the hypofractionated cohort only. These findings are limited by their retrospective nature., Conclusions: In the postprostatectomy setting, the logistic convenience of hypofractionation should be carefully balanced against the risk of severe late urinary sequelae., Patient Summary: This study investigated the causes of urinary adverse effects after postprostatectomy radiotherapy. Hypofractionation resulted in an increased risk of severe urinary toxicities., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)